Synthetic Chlorins, Possible Surrogates for ... - ACS Publications

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Synthetic Chlorins, Possible Surrogates for Chlorophylls, Prepared by Derivatization of Porphyrins Masahiko Taniguchi* and Jonathan S. Lindsey* Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204, United States ABSTRACT: Chlorophylls make Earth green, are the central constituents in the engine of photosynthesis, and not surprisingly have garnered immense attention. A chlorin, the core chromophore of a chlorophyll, is a dihydroporphyrin macrocycle that contains one pyrroline ring and three pyrrole rings. The dominant method for the synthesis of chlorins has entailed the derivatization of porphyrins. The present review covers the ostensibly simple conversion of porphyrins, regardless of synthetic or biological origin, to chlorins. The period covered encompasses the entire history since the beginnings of chlorin synthetic chemistry in the early 20th century through 2015. Representative transformations include hydrogenation, cycloaddition, annulation, and diverse “breaking and mending” approaches. Altogether, the synthesis of >1000 chlorins or chlorin-like compounds (containing >50 distinct pyrroline motifs) is described. Such diversity animates the question “what structural features are essential for a chlorin to resemble chlorophyll?” To begin to address the structure−spectrum relationship, > 250 absorption spectra are provided for representative structures. The synthesis and spectral properties of the vast collection of compounds described herein are expected to illuminate the scope to which synthetic chlorins can serve as surrogates for chlorophylls and be exploited in diverse ways.

CONTENTS 1. Introduction 2. ABCs of Chlorophylls and Chlorins 2.1. How Many Chlorophylls? 2.2. Chlorophyll Nomenclature 2.3. Nomenclature Anomalies 2.4. Classical Tetrapyrrole Macrocycles 2.5. Chlorin π-System 2.6. Chlorin Absorption Spectra 2.7. Chlorin Stereochemistry 3. Chlorins from One-Flask Porphyrin-Forming Reactions 4. Chlorins by Hydrogenation of Porphyrins 4.1. Classical Methods 4.2. Whitlock Procedure Using Diimide 4.3. Modifications to the Whitlock Diimide Procedure 4.3.1. Diimide Source 4.3.2. Streamlined Separation of Chlorins 4.3.3. Alteration of Reaction Constituents 4.4. Alternative Methods for Hydrogenation 5. OsO4-Mediated Chlorin Formation from Porphyrins 5.1. Reaction Patterns 5.2. Dihydroxychlorins 6. Alkylative Reduction of Porphyrins 6.1. Reactions with Free Base Porphyrins 6.2. Reactions with Metalloporphyrins 6.3. Reactions of N-Substituted Tetrapyrrole Macrocycles © XXXX American Chemical Society

7. Conversion of Heme to Gem-Dialkylchlorins 7.1. Gem-Dialkylchlorins 7.2. Hemin as a Semisynthetic Feedstock to Chlorins 8. Spirochlorins 8.1. Spiroketones 8.2. Spirolactones 8.3. Spirochlorin Dyads 9. Annulation by Side-Chain Cyclization: Purpurins 9.1. Purpurin Intermediate in the Woodward Chlorin Synthesis 9.2. Purpurins More Broadly 9.3. Purpurins from 5,15-Diarylporphyrins 9.4. Purpurins in Diverse Architectures 10. Annulation by Side-Chain Cyclization: Benzochlorins 10.1. Benzochlorins Contrasted with Purpurins 10.2. Rhodins and Verdins 10.3. Benzochlorin Analogues 10.4. Monoaryl Benzochlorins 10.5. Benzochlorins in Diverse Architectures 10.6. Oxazinochlorins 11. Cycloadditions with β-Vinylporphyrins 11.1. Reaction with O2: Photoprotoporphyrin IX 11.1.1. Sulfheme Analogues via Photoprotoporphyrins

B E E E F G G H K K N N P W W W Y Z AD AD AG AI AI AM

AO AO AP AV AV AX AX AY AZ BB BE BF BH BH BL BO BU BW CC CF CF CI

Special Issue: Light Harvesting Received: November 28, 2015

AM A

DOI: 10.1021/acs.chemrev.5b00696 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 11.1.2. Aza Analogues of Photoprotoporphyrins 11.2. Reactions with Carbon Dienophiles 12. (Cyclo)Additions to Porphyrins without Vinyl Groups 12.1. Undirected Installation of β,β′-Dialkyl Substituents 12.2. Directed Installation of β,β′-Dialkyl Substituents 13. Alternative Pyrroline Motifs 13.1. Breaking and Mending Strategies 13.1.1. Synthesis of Chlorins via Oxidation of Porphyrins 13.1.2. Derivatization of cis-17,18-Dihydroxychlorins (type A1) 13.1.3. Derivatization of 17,18-Dioxochlorins (type B1) 13.1.4. Derivatization of 16,19-Diformyl-secochlorins (type G1) 13.1.5. Derivatization of 18-Oxachlorins (type F1) 13.2. Spectral Properties of Chlorins with Diverse “Pyrroline Rings” 13.3. Synthetic Applications of Breaking and Mending 13.3.1. Annulations of Modified Pyrroline Units 13.3.2. Doubly Fused Chlorins 14. Core-Modified Chlorins 14.1. Other Atoms in Place of Nitrogen 14.2. Heteroatoms in the Peripheral Skeleton 14.2.1. seco-Porphyrazines 14.2.2. Diazachlorins 15. Weird Analogues of Chlorins 16. Outlook: Synthetic Chlorins as Surrogates for Chlorophylls Author Information Corresponding Authors Notes Biographies Acknowledgments Abbreviations References

Review

Scheme 1. Preeminent Pigments of Life and Core Chromophores

CJ CL CX CY DP DS DU DU EA ED EL EP EU EV EV FB FF FF FI FI FM FO FS FT FT FT FT FT FT FU

propanoate where the latter is esterified with a phytyl (or similar hydrocarbon) chain. The alkyl ester substituent comprises about one-third of the total molecular mass2 and constitutes the “tail of the tadpole” in the overall chlorophyll shape. 3 Third, chlorophylls contain one or more conjugated substituents at the β-pyrrolic positions that serve as auxochromes in modifying the absorption spectral features.4 Studies of chlorin chemistry constitute a tapestry woven from multiple threads.2 The threads include (1) isolation and structure elucidation of naturally occurring chlorophylls, (2) total synthesis of such chlorophylls and derivatives, (3) semisynthesis of chlorins beginning with naturally occurring tetrapyrrole macrocycleschiefly chlorophylls and heme, (4) conversion of a synthetic porphyrin to a chlorin, and (5) de novo synthesis of gem-dialkylchlorins wherein the reduced ring is built into the acyclic precursors to the chlorin. Threads 2−4 are illustrated in Scheme 2. Thread 5 is illustrated in Scheme 3. The formal total synthesis of chlorophylls, first achieved by Woodward and co-workers, constitutes a crowning accomplishment in organic chemistry.5−10 The Woodward team employed Knorr’s pyrrole for the de novo synthesis of chlorin e6 trimethyl ester (path 2a), and then pointed to “well-trodden paths”5 for the conversion of chlorin e6 trimethyl ester to chlorophyll a. While how trodden such older paths actually were has been a source of discussion,11,12 others have since developed reliable methods for

1. INTRODUCTION The seminal importance of chlorophylls as Nature’s chief light absorbers has elicited vast studies encompassing biology, chemistry, and physics. Chlorophylls along with heme and bacteriochlorophylls are the most abundant members of the socalled “pigments of life”1 (Scheme 1), which constitute a subset of the large class of tetrapyrrole macrocycles. Heme, chlorophylls, and bacteriochlorophylls differ in the degree of saturation of the chromophore. The fully unsaturated macrocycle is a porphyrin; the saturation of one of the β,β′-pyrrolic double bonds gives the chlorin (a dihydroporphyrin); additional saturation of a second β,β′-pyrrolic double bond distal to the first gives the bacteriochlorin (a tetrahydroporphyrin). In addition to the dihydroporphyrin π-system, chlorophylls differ from simple porphyrins in several ways. First, chlorophylls contain a fifth, isocyclic (or exocyclic), ring in which is embedded a keto group that is coplanar with the chlorin π-system. Second, the substituents in the reduced, pyrroline ring are in a trans configuration; the substituents comprise 18-methyl and 17B


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Scheme 2. Distinct Routes to Chlorins

the conversion.12 A dashed arrow for path 2b is employed to indicate that, to our knowledge, no chlorophyll has ever been chemically synthesized in a single laboratory beginning with pyrrole starting materials, although formal total syntheses, where sequences of transformations in various laboratories are conceptually joined, have been established.

Semisynthesis12−21 typically begins with the richly abundant molecules chlorophyll a (paths 3a-c) or heme (shown as hemin, path 3d). Transformations of chlorophyll a have afforded the versatile chlorin e6 trimethyl ester (path 3a);3 a non-natural analogue of the bacteriochlorophyll c-f compounds (path 3b);22 and the naturally occurring bacteriochlorophyll c (path 3c).23 C


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Scheme 3. De Novo Routes to Gem-Dialkylchlorins

The misnamed macrocycles bacteriochlorophylls c-f are actually chlorins, not bacteriochlorins (see sections 2.2 and 2.3). Whereas paths 3a-c convert one chlorin to another chlorin, path 3d transforms the naturally derived porphyrin hemin (also referred to as hemin chloride) to a non-natural chlorin.24 Hemin, the ClFe(III) chelate of protoporphyrin IX, is derived from heme, the Fe(II) chelate thereof. Routes to synthetic chlorins by way of synthetic porphyrins are shown in paths 4 and 5. The formation of a chlorin as a byproduct in a porphyrin synthesis is shown in path 4a or more deliberately from a highly reduced intermediate in a porphyrin synthesis (e.g., a porphyrinogen) by controlled dehydrogenation in path 4b. Transformation of a synthetic porphyrin to give a chlorin can be achieved in a variety of ways, including hydrogenation (path 4c), cycloaddition of diverse entities (path 4d), annulation (4e), and a rich assortment of methods summarized as “breaking and mending” (path 4f). Other routes entail prototropic rearrangements (path 4g) from hydroporphyrins at the same reduction level (i.e., tautomerizations of a porphodimethene or a phlorin), or reduction of porphyrins via photochemistry, radiolysis, or electrochemical procedures (path 4h); the latter can also lead to more highly saturated hydroporphyrins. Routes that entail considerably more synthesis, yet afford far greater structural control, begin with a geminal-dialkyl substituted pyrroline ring and build the chlorin around this pre-established structural unit (path 5, Scheme 3). The chief contributors to the de novo synthetic routes to such gem-dialkylchlorins have been (in chronological order) Battersby, Montforts, Jacobi, and Lindsey.2 The focus of this review concerns paths 3d and 4a-f (shown in red in Scheme 2), namely, the conversion of porphyrins, regardless of their synthetic or natural origin, to chlorins. A panoply of chlorin-like macrocycles has emerged from the

synthesis laboratory, which may have broadened (or complicated) the possible answers to the simple question “what structural features are essential for a chlorin to resemble chlorophyll?” Consideration of this question is of interest across many areas of science ranging from physical chemistry to photosynthesis. The question about how structure affects spectral properties has perhaps animated tetrapyrrole science since its inception. At the turn of the 20th century, the famous chemist Willstätter sent his students to collect samples of chlorophylls from diverse plants, with the aim to understand how many chlorophylls were responsible for the various hues of green.25 In 1973, Treibs26 reported an examination of more than 500 tetrapyrroles of known composition and spectral features in an attempt to deduce rules concerning the relationship between structural features with spectral properties; in so doing he commented on “the enormous number of facts in this field.” Chlorins were central in this effort. The structural variety has expanded immensely in the ensuing 40 years due to the richness of synthetic chemistry. Hence, the question “what constitutes a chlorin” can now be framed much more broadly. The synthesis of chlorins constitutes the lion’s share of the review. Altogether, the synthesis of >1000 chlorins or chlorin-like compounds is described. To provide the foundation for beginning to address the structure−spectrum relationship, > 250 absorption spectra are provided for representative structures. Such absorption spectra have largely been obtained by digitizing published spectra from the literature (given that data and facts cannot be copyrighted27) and are displayed here without evaluation on our part concerning purity or integrity of the corresponding tetrapyrrole sample. Topics specifically omitted include synthesis of metallochlorins, synthesis of isotopically substituted chlorins, and photoreduction as a path to chlorins D


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(which encompasses prototropic rearrangements). Chlorincontaining dyads are included only when the dyad linkage is created as an essential part of the chlorin formation. Reactions of chlorins also are generally outside the scope of the present review, but selected reactions are included where integral to chlorin chemistry. Before embarking on synthetic routes to chlorins by derivatization of porphyrins, we first provide an overview of basic knowledge concerning chlorophylls and chlorins.

Scheme 4. Representative Naturally Occurring Chlorophylls

2. ABCS OF CHLOROPHYLLS AND CHLORINS 2.1. How Many Chlorophylls?

The answer to the important question “how many chlorophylls are there?” depends on how broadly the net is cast. Upon examining diverse plant samples from across Europe,25 Willstätter determined the number to be two: chlorophyll a and chlorophyll b (Scheme 4). That number remains correct if one is referring to the most abundant chlorophylls in land plants; such chlorophylls are located predominantly in the light-harvesting antenna complexes. There is of course free base chlorophyll a, known as pheophytin a, in the photosynthetic reaction centers. Expanding the net to encompass the all-important cyanobacteria, one finds in selected organisms chlorophyll d and chlorophyll f as well as the divinyl species chlorophylls a2 and b2.28−30 Looking at photosynthetic green bacteria, one finds so-called chlorosomal bacteriochlorophylls c-f (Scheme 5).28,31 The bacteriochlorophylls c-f are dihydroporphyrins (i.e., chlorins, like chlorophylls; not true bacteriochlorins) but contain a hydrated 3-vinyl group and lack the 132-carbomethoxy group characteristic of the chlorophylls shown in Scheme 4. Looking even more broadly among photolithotrophic bacteria, one finds 81-hydroxy chlorophyll aF in the reaction center of heliobacteria (Scheme 4).32,33 A word to the nonbiologist: the chlorophylls from organisms other than the stately plants that color Earth’s verdant landscapes should not be given short shrift. An evolutionary biologist’s view of the world is that land plants are better viewed as “drier algae” rather than “higher plants,” and hence should be classified as a subset of the algae rather than algae as a subset of land plants.34 Indeed, due to algae and photosynthetic bacteria, some half of photosynthetic productivity is believed to occur in aqueous environments (ponds, streams, rivers, lakes, and oceans) of watery Earth.35,36 Moreover, each distinct chlorophyll structure provides a window on the scope of photosynthesis.37 The structures shown in Schemes 4 and 5 are the chief chlorophyll molecules; far greater diversity in the natural world is found upon consideration of processes of biosynthesis, diagenesis, epigenesis (e.g., 132-epimerization), 173-transesterification, transmetalation, allomerization, catabolism, metabolism, photodegradation, and combinations thereof.2 A decade ago, Scheer indicated the number of known chlorophylls was nearly 100.31 Given the above possible combinations, the number of chlorophylls in nature may ultimately not be countable with certainty. Here, as in many other arenas, the term chlorophyll refers generically to chlorophyll a, with recognition that there are many other naturally occurring chlorophyll variants, a subset of which is biologically active.

CAS38 and IUPAC39 has significant flaws, which have been aired out in some depth.2 The nomenclature system employed here is consistent with common usage in the chlorophyll field and is shown in Scheme 6. The key features are as follows: (1) The macrocycle rings are labeled A−D in clockwise fashion with the pyrroline ring taking label D; the isocyclic ring is labeled E. (2) The numbering system begins at the α-carbon of ring A (nearest ring D) and proceeds clockwise, giving the four meso-carbons as 5, 10, 15, and 20, and the β-carbons of the pyrroline ring (D) are numbered 17 and 18. (3) This numbering system is adhered to

2.2. Chlorophyll Nomenclature

Nomenclature is a prerequisite to a meaningful discussion of chlorophyll and chlorin chemistry. If chlorophyll a were the only chlorophyll in Nature, the complexity of nomenclature would be substantially diminished. The nomenclature recommended by E


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as shown. (7) In each case, we have drawn the chlorin π-system consistent with the most stable tautomer (although this has not been done uniformly in the literature). The hydrocarbon skeleton of chlorophylls is a phorbine given the presence of the isocyclic ring. The presence of the keto group embedded in the isocyclic ring thus affords a 131-oxophorbine. A phorbine is a member of the chlorin family (i.e., contains the 17,18-dihydroporphyrin chromophore), but any chlorin lacking the isocyclic ring is not a phorbine. Considering the position of the potent auxochromes on the parent phorbine skeleton, chlorophyll a is a 3-vinyl-131-oxophorbine; chlorophyll b is a 7formyl-3-vinyl-131-oxophorbine. Finally, it warrants emphasis that chlorophyll contains six stereocenters as indicated in Scheme 6 and hence is chiral.40,41 A seventh stereochemical feature stems from the diastereotopic nature of the two faces of the macrocycle, which can be differentiated for example upon binding to the apical site on the magnesium or complexation with the π-system.41 The inherent asymmetry of chlorophyll with regards to interactions in biological systems has been treated by Oba and Tamiaki42 and by Senge and co-workers.40

Scheme 5. Misnamed Bacteriochlorophylls that are True Chlorins

2.3. Nomenclature Anomalies

There are several significant nomenclature anomalies concerning chlorophylls that are best dealt with explicitly. Setting aside the universally present isocyclic ring, a chlorophyll is, first and foremost, a 17,18-dihydroporphyrin. One anomaly is that chlorophyll c-type molecules contain the porphyrin, not dihydroporphyrin, chromophore.28,43 The structures of the porphyrins known as chlorophylls c1, c2, and c3 are shown in Scheme 7. A second anomaly concerns chlorophyll e: the label was employed years ago but a definite structure was not

Scheme 6. Chlorophyll and Chlorin Nomenclature

Scheme 7. Nonchlorins with Chlorophyll Names

regardless of other substituents anywhere else in the macrocycle (in this rule in particular, CAS and IUPAC rules are abandoned). (4) Peripheral substituents are numbered as extensions of the skeleton position; thus, the two carbons of the isocyclic ring are 131 and 132, and the carbon of the propionate ester is 173. (5) The inner nitrogens are numbered 21−24 in clockwise fashion beginning with ring A. (6) While not a nomenclature issue, by convention, ring D is typically displayed in the lower left corner F


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forthcoming; hence the label remains unassigned.44 Thus, in the series chlorophyll a-f, chlorophylls c are not true chlorophylls, and chlorophyll e remains indefinite. A third anomaly, already touched on above, is that bacteriochlorophylls c-f bear the name suggestive of a bacteriochlorin yet actually are dihydroporphyrins (i.e., chlorophylls). Bacteriochlorophylls a, b, and g are true bacteriochlorins.31

clarity). In the period since, however, an astonishing variety of chlorin derivatives and analogues has appeared. The synthesis of such chlorins is treated next, along with presentation of spectral properties where available. 2.5. Chlorin π-System

A chlorin differs from a porphyrin by the presence of a saturated β,β′-bond of one pyrrole. The effective hydrogenation of the β,β′-bond of one pyrrole in the π-electron-rich tetrapyrrole macrocycle has informed studies of aromaticity and has prompted appellation with the term “cryptoolefin”.45,46 The term refers to the presence of a rather isolated double bond despite the putative conjugation with an extensive π-system. While perhaps hidden in plain sight, such a double bond is almost nakedly susceptible to reaction. The aromatic path in a tetrapyrrole macrocycle is shown in Scheme 9, where 18 π-

2.4. Classical Tetrapyrrole Macrocycles

A collection of traditional tetrapyrrole macrocycles is shown in Scheme 8. The collection includes the subject of the present Scheme 8. Types of Tetrapyrrole Macrocycles

Scheme 9. Aromatic Path in Porphyrin and Chlorin

electrons are present along this circuit, and the two β,β′-pyrrolic double bonds are effectively apart therefrom. The scheme shows that reduction of one such β,β′-pyrrolic double bond (porphyrin → chlorin) does not alter the 18 π-electron system, and indeed, the second β,β′-pyrrolic double bond also is susceptible to addition processes without altering the aromaticity of the macrocycle. A chlorin is a dihydroporphyrin, and in suitable tetrapyrroles where structural features do not preclude tautomerization, a chlorin can form by prototropic tautomerization. A simple mechanism for formation of a chlorin from a phlorin is illustrated in Scheme 10. In principle, the conversion can begin from any meso-hydrogenated tetrapyrrole; for example, beginning with a porphyrinogen, tautomerization followed by 4e−/4H+ oxidation forms the chlorin. Such tautomerization may be a source of chlorin contamination in one-flask syntheses of porphyrins from an aldehyde and pyrrole.47 An experiment by Dolphin showed Scheme 10. Phlorin−Chlorin Conversion

review, chlorins, but also a number of chlorin (dihydroporphyrin) derivatives. A porphodimethene and a phlorin are nonaromatic isomers of the chlorin. In addition, two tetrahydroporphyrin species are displayed, the bacteriochlorin and isobacteriochlorin. Were a comprehensive review on chlorin synthetic chemistry written 1−2 generations ago (ca. 1975), the members of the collection shown in Scheme 8 would fairly well encompass the known world of chlorin derivatives (substituents omitted for G


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the existence of an alternative pathway for formation of a chlorin in a one-flask porphyrin synthesis: the condensation of pyrrole and benzaldehyde under Adler conditions (refluxing acetic acid exposed to air) in the presence of meso-tetrakis(pmethoxyphenyl)porphyrin gave the expected meso-tetraphenylporphyrin (from benzaldehyde and pyrrole) as well as mesotetrakis(p-methoxyphenyl)chlorin. The latter chlorin can form only by in situ reduction rather than prototropic tautomerization. The reductant could be pyrrole, a pyrromethane, or hydroporphyrins such as a porphyrinogen.48 The topic of rearrangement of porphodimethenes to phlorins and chlorins is quite rich. The chemistry entails complexity owing to molecular structure (e.g., which pyrrole ring becomes a pyrroline), and kinetic versus thermodynamic processes. The studies of Whitlock49 and of Burns50 are illustrative. A more full treatment is beyond the scope of the present review.

Scheme 11. Chlorins for Spectral Comparisons

2.6. Chlorin Absorption Spectra

The characteristic chlorin absorption spectra are provided here for a set of representative chlorins (Scheme 11). The chlorins include three pairs of synthetic chlorins: the fully unsubstituted chlorin (zinc chelate, ZnC, and free base, H2C); transoctaethylchlorin as a racemic mixture (trans-ZnOEC, transH2OEC); and meso-tetraphenylchlorin (ZnTPC, H2TPC). Natural or naturally derived chlorins include chlorophyll a and chlorophyll b; the free base of each, pheophytin a and pheophytin b; and the zinc chelate of each, Zn-pheophytin a and Zn-pheophytin b. Here, the metalation state of the macrocycle is indicated with a prefix: “H2” denotes the free base (i.e., H, H), Zn indicates zinc(II), and other “M” indicates the metal in appropriate metalation state (an apical ligand is also designated for valencies other than the divalent case). The spectra of the chlorophylls and derivatives are shown in Figure 1, where each panel contains the pair of a and b macrocycles (e.g., panel 1 shows spectra for chlorophyll a and chlorophyll b). The spectra of the synthetic chlorins are shown in Figure 2, where each panel contains spectra for a pair of the free base and the zinc chelate of a given macrocycle (e.g., panel 1 shows spectra for H2C and ZnC). As demonstrated in Figures 1 and 2, a chlorin exhibits a strong absorption band in the violetblue region (∼380−450 nm, known as the B band) and a moderately strong band in the red region (∼600−700 nm, known as the Qy band). The absorption in both the blue and red regions results in the typical green color of chlorins observed in solution or thin films (e.g., a leaf) upon white-light illumination. The B band is sometimes referred to as the Soret band in recognition of the report in 1883 by the scientist Soret, who observed the intense blue-region absorption of diluted samples of blood.51 A series of bands, typically weaker than that of the Qy band, is observed in the region bracketed by the B and Qy bands. In Figures 1 and 2, all spectra in the left column are normalized at the B band, whereas all spectra in the right column are displayed on the basis of molar absorption coefficient values. In this review, >250 absorption spectra are provided in 89 figures. In general, we have tried to adhere to the following format in displaying spectra: (1) porphyrin spectra are displayed in dotted black lines, whereas chlorin spectra are displayed in solid red lines; (2) when free base chlorins and metallochlorins are displayed, the free base chlorin is displayed in red, and each metallochlorin is displayed in a chosen cold colorpurple, blue, aqua, lime, and moss green; (3) when several chlorins are displayed together, regardless of metalation state, the chlorins are displayed in a series of warm colorsred, orange, or lavender;

and (4) when comparisons of solvent effects are made, the display typically employs solid, dashed, and/or dotted lines. Exceptions to these general guidelines proved unavoidable in several instances (e.g., Figures 1 and 2). This coding approach should afford legibility to most color-vision impaired individuals.52,53 The characteristic B and Qy band positions and intensities of all 12 chlorins from Scheme 11 are provided in Table 1. A general trend is that the position of the Qy band shifts bathochromically in proceeding along the series of zinc chelate < magnesium chelate < free base macrocycle. In addition, the relative intensities of the B and Qy bands (IB/IQy ratio and vice versa) are also provided. Painting with a broad brush on the basis of the data for this set of chlorins, the B band of a chlorin typically has a molar absorption coefficient (ε) in the range 50 000−400 000 M−1 cm−1, whereas the Qy band typically has ε in the range 30 000− 100 000 M−1 cm−1. The intensity of the chlorin Qy band typically dwarfs that of the corresponding porphyrin in the same spectral H


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Figure 1. Absorption spectra in diethyl ether of (1a,b) chlorophyll a (red line) and chlorophyll b (blue line);54,55 (2a,b) Zn-pheophytin a (orange line) and Zn-pheophytin b (aqua line);56 (3a,b) pheophytin a (lavender line) and pheophytin b (green line);57 and (4a,b) composite spectra of Znpheophytin b (aqua line), chlorophyll b (blue line), Zn-pheophytin a (orange line), pheophytin b (green line), chlorophyll a (red line), and pheophytin a (lavender line). All spectra in the left column are normalized at the B band, versus plotted on the basis of molar absorption coefficients in the right column.

region; as one example, meso-tetraphenylporphyrin (H2TPP)60 has ε647 nm = 3400 M−1 cm−1 whereas meso-tetraphenylchlorin (H2TPC)58,61,62 exhibits ε652 nm = 42 000 M−1 cm−1. Given that the B and Qy bands are typically the most intense in the ultraviolet−visible spectrum, it has been commonplace to use the ratio of the intensities of the B and Qy bands (i.e., IB/IQy) as a means to gauge purity of a sample, where the ratio is known for a pure, authentic compound.63 Over the years, the IB/IQy ratio has sometimes been regarded as an indication of the relative extent of red absorption.30 An equivalent approach has been to display spectra normalized at

the B band and then view directly the extent of red absorption (i.e., the relative amount of Qy absorption). These approaches are attractive in sidestepping use of molar absorption coefficient (ε) data, which frequently are unavailable in the literature, but even if available are often unreliable. Such data are often unreliable given the necessity to weigh out minute quantities of samples as part of the determination of an ε value.65 On the other hand, to assess relative red-region absorption across diverse compounds, there are serious drawbacks with comparisons of the IB/IQy ratios. A frequent pitfall is illustrated by comparison of the spectra for ZnTPC and H2TPC: the normalized spectra (panel 3a, Figure 2) I


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Figure 2. Absorption spectra of (1a,b) ZnC (blue line) and H2C (red line) in benzene;58 (2a,b) trans-ZnOEC (aqua line) and trans-H2OEC (orange line) in benzene;58 (3a,b) ZnTPC (green line) and H2TPC (lavender line) in toluene;58,59 and (4a,b) composite spectra of ZnC (blue line), transZnOEP (aqua line), ZnTPC (green line), H2C (red line), trans-H2OEC (orange line), and H2TPC (lavender line). All spectra in the left column are normalized at the B band, versus plotted on the basis of molar absorption coefficients in the right column.

region absorption for H2TPC, but again, the known molar absorption coefficient values show that ZnTPC > H2TPC in terms of the intensity of the respective Qy bands. This pitfall is hardly restricted to synthetic chlorins ZnTPC and H2TPC; as one example, the same phenomenon occurs with pheophytin a and 3-desvinyl-3-acetyl pheophytin a (not shown).66 A superior approach may be to make comparisons on the basis of integrated spectra. The integration can treat the respective B and Qy band regions whereupon a ratio of the integrated areas (ΣB/ΣQy) is obtained for comparison. A comparison of IB/IQy and ΣB/ΣQy ratios is available for >150 (chiefly gem-dimethyl-

suggest the latter has a stronger Qy band intensity than the former whereas the spectra on the basis of known molar absorption coefficient values (panel 3b) indicate the opposite relationship is true. A more fundamental limitation is that the B band is a composite of Bx and By transitions; if such transitions are largely coincident, the B band is sharp and strong, whereas if the bands appear at distinct wavelengths, the B band is split with a lower molar absorption coefficient value. The B band for ZnTPC is sharp, whereas that for H2TPC is split and broad (panel 3, Figure 2). As with B-band normalization, the IB/IQy ratio for ZnTPC (5.28) versus H2TPC (4.12) implies greater relative redJ


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Table 1. Absorption Spectral Data for the Compounds in Figures 1 and 2 B band

a

Qy band

band ratios

compound

λmax (nm)

ε (M−1 cm−1)

λmax (nm)

ε (M−1 cm−1)

IQy/IB

IB/IQy

refa

chlorophyll a chlorophyll b Zn-pheophytin a Zn-pheophytin b pheophytin a pheophytin b ZnC H2C trans-ZnOEC trans-H2OEC ZnTPC H2TPC

428.5 455 423 446 408.5 432.5 399 389 400 392 420 421

111 700 159 000 124 600 177 000 106 000 184 000 147 300 126 200 113 100 187 400 354 600 172 100

660.5 642 653 634 667.5 656.5 606 638 617 646 622 653

86 300 56 100 90 300 60 200 52 700 39 800 39 500 50 700 49 200 75 200 67 100 41 800

0.773 0.353 0.725 0.340 0.497 0.216 0.268 0.402 0.435 0.401 0.189 0.243

1.29 2.84 1.38 2.94 2.01 4.62 3.73 2.49 2.30 2.49 5.28 4.12

64 64 56 56 57 57 58 58 58 58 58 58

References pertain solely to the molar absorption coefficient (ε) values.

substituted, synthetic) chlorins.4,67−72 Alternatively, integration over the entire ultraviolet, visible, and if needed, near-infrared regions enables ratioing of the B or Qy band versus the entire integrated area, which has recently been employed for bacteriochlorins73 but not yet for chlorins. In this review article, we simply state the reported position of the Qy band and display the spectra where available and meaningful. The position of the Qy band is important, as this sets an upper limit on the energy of the first excited singlet state, the progenitor of many photochemical processes. Where we believe errors in Qy positions or more plausibly, in molar absorption coefficient values (e.g., baseline offset, scaling errors, order of magnitude mistakes in calculations), have been made in the original publications, we have made appropriate corrections and have noted such in each case. The red-region absorption band is a hallmark physical property that distinguishes a chlorin from a porphyrin. It is typical to regard hydroporphyrins from the vantage point of a porphyrin: chlorins and bacteriochlorins thus constitute dihydro and tetrahydro derivatives of the (unsaturated) porphyrin, respectively; increasing long-wavelength (red and near-infrared) absorption accompanies such saturation. Viewed the other way around, from hydroporphyrins to the porphyrin, “low excited states disappear with increasing unsaturation”. A deep understanding of this phenomenon, which was not available when Rabinowitch made this cogent observation,74 is now available from the Gouterman four-orbital model.75 Still, the effect of substituents located at specific sites about the perimeter of the macrocycle remains a subject of investigation.4,30,59,65,67,68,70−72 A chief objective of the present review, which transcends methods of synthesis, is to gather together the absorption spectra for tetrapyrrole macrocycles equipped with diverse pyrroline motifs, whereupon a future effort can begin to develop a fundamental understanding of the structural and electronic requirements that engender the Qy band characteristic of chlorins. In this regard, all of the chlorin spectra reported herein will in due course be made freely available in digital form as part of PhotochemCAD,54,55 a program with accompanying spectral databases for performing photochemical calculations.

ring where reaction occurs, the nature of substituents at other sites about the perimeter of the macrocycle, and the stereochemical course of reaction in converting the pyrrole to the pyrroline ring. Stereochemistry was well developed as a discipline as of 1950.76 Yet, many publications concerning chlorin formation, including quite recently, often are not explicit about stereochemical outcomes. In many studies the stereochemistry of the product(s) was understandably not of central import. Regardless, for the purposes of this review, we have attempted to interpret the stereochemistry of products in the literature cited herein. In particular, we denote all expected racemic mixtures and often display one of the enantiomers in explicit form, as is common, even though the original publication may be silent on the topic. In addition, we denote the expected presence of diastereomers where appropriate. At the risk of overinterpretation of silence, we believe this approach adds to the present understanding. The reader is referred to the original publications for clarification. We now turn to the occurrence of chlorins as byproducts in attempted syntheses of porphyrins.

3. CHLORINS FROM ONE-FLASK PORPHYRIN-FORMING REACTIONS Most of the early syntheses of chlorins stemmed from one-flask reactions aimed at the synthesis of porphyrins.47 In the 1930s, Rothemund77 reported the synthesis of meso-substituted porphyrins by reaction of pyrrole and an aldehyde in a sealed vessel at elevated temperature.78−80 Calvin and co-workers investigated this method81−83 and found that the yield was increased upon inclusion of zinc acetate.83 Upon use of benzaldehyde, Calvin and co-workers isolated meso-tetraphenylchlorin (H2TPC)82 or the zinc chelate thereof (ZnTPC)83 (Scheme 12, panel A). Dorough and co-workers subsequently improved the isolation of H2TPC and prepared several metal chelates.84,85 Indeed, prior to the advent of a process known as the Whitlock procedure (section 4.2), isolation of the chlorin from the porphyrin-forming reaction mixture was often more facile than to resort to existing methods for reduction of the porphyrin.61 Dorough and co-workers also showed that hydrogenation of H2TPC gave the corresponding mesotetraphenylbacteriochlorin (H2TPBC).86 Eisner and Linstead reported a one-flask synthesis of a chlorin by treatment of the Mannich base of pyrrole (2-(N,Ndimethylaminomethyl)pyrrole, 3-1) with ethylmagnesium bromide at relatively high temperature (Scheme 12, panels B−D).87

2.7. Chlorin Stereochemistry

Most of the chemistry described in this review article dates from 1950 onward. The conversion of a porphyrin to a chlorin can create stereoisomers, including enantiomers and/or diastereomers, depending on the nature of the substituents at the pyrrole K


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Scheme 12. One-Flask Syntheses of Chlorins

ylchlorin H2OMC or octaethylchlorin H2OEC, respectively. The yields were substantially greater than that for chlorin H2C, undoubtedly due to the higher solubility of the octaalkylsubstituted macrocycles. Indeed, the yield of H2OMC was 12.5% (estimated spectroscopically in the crude material) and 6.6%

The resulting magnesium chelates of porphyrin and chlorin were demetalated, and free base chlorin (H2C) was separated by chromatography or counter-current distribution. Application of the method to the similarly substituted 3,4-dimethylpyrrole 3-288 or 3,4-diethylpyrrole 3-389 afforded the corresponding octamethL


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isolated (including 36.5% yield of the octamethylporphyrin).88 Use of piperidine rather than dimethylamine to form the Mannich base (3-4 instead of 3-3) gave an increase in yield of H2OEC from 13% to nearly 21%.89 Finally, the α-methylsubstituted pyrrole 3-5 gave the meso-tetramethylchlorin 3-H26, albeit in tiny amount (yield not provided).90 In 1980, Ibers and co-workers reported an extension of the prior approaches from the 1950s to obtain meso-tetraalkylchlorins, where the alkyl group is short (methyl, ethyl, or propyl).91,92 The lack of easy access at that time to the corresponding porphyrins prompted development of a direct synthesis of the chlorins. Thus, a metal-templated synthesis was employed wherein pyrrole and the diethyl acetal of an alkyl aldehyde were condensed in hot glacial acetic acid containing 2−5% acetic anhydride and nickel acetate in the presence of air. The product mixture with acetaldehyde diethyl acetal (R = Me) contained the chlorin and porphyrin in isobacteriochlorin > bacteriochlorin.” In this manner, a crude sample in benzene containing predominantly chlorin with small quantities of P


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Scheme 17. Hydrogenation of meso-Tetraphenylporphyrin

tetraphenylchlorin (H2TPC) in 72% yield (1.45 g) and cisoctaethylchlorin (cis-H2OEC) in 11% yield (56 mg); modification of the acidic conditions was employed in the latter case.62 Hydrogenation with p-TsNHNH2 has been widely used and has broad scope as illustrated by the diverse structures displayed in the next four tables (Table 3−6). Table 3 shows application to porphyrins with four identical meso-substituents, whereupon all four pyrrole rings are identical and hence only one chlorin can be formed. The reaction is compatible with phenols (entries 2−4),

bacteriochlorin and porphyrin is obtained that can be further purified by chromatography and/or crystallization (step 4). The Whitlock procedure, developed for synthesis of mesotetraphenylchlorin, might be expected to require modification of the acidic partitioning conditions for selective removal of porphyrin and bacteriochlorin upon use of other mesosubstituents. On the other hand, the entire mixture can be chromatographed (although this can be quite tedious) thereby sidestepping the organic/aqueous acid partitioning protocol. Implementation of the Whitlock procedure afforded mesoQ


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Table 3. meso-A4-Chlorins Prepared by p-TsNHNH2 Reduction of a Porphyrin

R


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Table 3. continued

a Not reported. bReaction in 4-methylpyridine. c140 °C. dIron chelate. e120 °C. fDABCO/DMF instead of K2CO3/pyridine. gSolvent-free method and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). hSolvent-free method and H2O2/FeCl3. iOxidize in air at 50 °C. jR = Ac in chlorin synthesis but cleaved in situ; overall yield given for product with R = H.

haloaryls (entries 5, 18−23), heterocycles (entries 7 and 11), polar groups (entries 8, 14, 21), reactive functional groups (entries 9 and 10), sterically hindered aryl groups (entries 16− 22), alkyl groups (entries 36−40), and protected sugars (entries 24−27). The O-acetyl groups of the protected sugars in entries 28−35 were cleaved in situ, an outcome apparently at odds with the retention of the O-acetyl groups reported in entries 24−27. The porphyrin-to-chlorin conversions employed the standard Whitlock procedure except for the meso-naphthyl case (entry 16), where the higher boiling 4-methylpyridine was used in lieu of pyridine. Some of the chlorins have common names: the chlorin in entry 1 is of course H2TPC, the first chlorin prepared by Calvin and then Whitlock and co-workers; the chlorin in entry 3 is widely used in photodynamic therapy and is known as mTHPC, which has trade names of FOSCAN or Temoporfin.106,107 The latter chlorin also was prepared by demethylation of the m-methoxyphenyl-substituted chlorin in entry 13.108 An alternate approach to chlorins of the m-THPC type has entailed derivatization of one or more hydroxy groups in m-THPC with an alkylating or acylating agent, as exemplified by the work of Rogers et al.109

The reaction of a porphyrin with nonidentical mesosubstituents presents the possibility of forming chlorin isomers. A simple case is presented by A3B-porphyrins, where diimide reduction can occur at a pyrrole flanked by A and B groups (ABtype) or flanked by two A groups (AA-type). In this case, both isomers are typically formed and may or may not be easily separated. Examples are shown in Table 4. The range of functionality is similar to that observed with A4-porphyrins, encompassing amides (entries 1 and 10), quinone/hydroquinone (entries 2 and 3), peracetylated sugars (entry 4), other diverse phenyl substituents (entries 5−11), and no mesosubstituent (entries 7 and 8). Again, the reaction conditions typically entailed the standard Whitlock procedure. In entries 2 and 3, the initial product was the chlorin−hydroquinone; treatment with excess p-benzoquinone oxidized the hydroquinone to give the chlorin−quinone. In entry 9, p-TsNHNH2 and K2CO3 were replaced with hydrazine and KOH. The resulting chlorin was used to attach, via an aqueous-solubilizing polyethylene glycol moiety, a folate targeting agent.131 The product distribution of entries 7 and 8 (where B = H) is quite interesting. The AB-type chlorin formed faster than that of S


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Table 4. meso-A3B-Chlorins Prepared by p-TsNHNH2 Reduction of a Porphyrin

a The hydroquinone is produced during the reaction process and was oxidized to the quinone by reaction with excess p-benzoquinone. bIsolated as the zinc chelate. cAA and AB type chlorins were not separated. dSynthesized via a microwave modification of the Whitlock procedure (see section 4.3.3). eAA-type isomer reported. fReaction used hydrazine and KOH. gAB-type isomer reported.

p-TsNHNH2, then upon oxidation were able to selectively obtain the AA-type chlorin; the selectivity was >90:10 for entry 7, and 88:12 for entry 8. The HPLC trace provided in the Supporting Information by the authors138 reveals the difficulty of separation

the AA-type, yet the AA-type chlorin was obtained in 60% yield. The key feature is that the AB-type chlorin also was more susceptible to oxidation than that of the AA-type. The authors drove the reaction entirely to the bacteriochlorin by use of excess T


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Table 5. trans-A2B2−Chlorins Prepared by p-TsNHNH2 Reduction of a Porphyrin

a

Yield not reported. bTosylation of the phenols occurred during the diimide reaction (R = Ts); treatment with 2 M HCl caused cleavage (R = H).

porphyrin with regard to the presence of two distinct types of pyrrole rings, and indeed, two chlorins were formed. Entry 5 shows a core-modified A4-porphyrin containing two selenophene rings. The latter are less susceptible to reaction than the pyrrole rings, and one chlorin was formed. The entries in Tables 2−6 illustrate the outcomes associated with the construction of chlorins from porphyrins that bear various substituent patterns. The A4-, trans-A2-, and trans-A2B2porphyrins each afford a single chlorin upon diimide reduction (Tables 2, 3, and 5). On the other hand, an A3B-, cis-A2B2-, or trans-AB-porphyrin each can give rise to two chlorin isomers (see various examples in Tables 4 and 6). While rational routes to porphyrins bearing up to four distinct meso-substituents are available,150−152 an alternative approach to meso-patterned porphyrins entails derivatization of the substituents of an A4porphyrin to access AmBn-porphyrins (m, n = 0−4; m + n = 4). Regardless of method of preparation, the A3B- and cis-A2B2porphyrins, upon hydrogenation, suffer the limitation of formation of multiple chlorin isomers. Two examples of the

of these types of chlorin isomers in the absence of a regioselective synthesis strategy. A trans-A2-porphyrin provides an architecture wherein only one chlorin (rather than multiple isomers) can be formed, as shown in entries 1, 2, and 4−6 of Table 5. The trans-A2B2porphyrin provides a similar architecture (entry 3). Note that atropisomers may be present for the chlorins in entries 5 and 6. The Whitlock diimide procedure also has been applied to structurally more unusual porphyrins, as shown in Table 6. Entries 1−3 explore the selectivity when at least one of the pyrroles bears β-ethyl substituents. Reaction generally proceeded preferentially at the β-unsubstituted sites, although one surprise occurred as shown in entry 3, where the dominant chlorin was formed by reduction at the pyrrole bearing β-ethyl substituents (only one of the two stereoisomers is shown). As the authors pointed out,129 “reduction of unsubstituted pyrrole rings leads to higher conformational distortion while reduction of β-ethyl substituted pyrrole rings leads to slight decrease in conformational distortion compared to the porphyrin”. Entry 4 contains a trans-AB-porphyrin, which has the same features of an A3BU


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Table 6. More Unusual Chlorins Prepared by p-TsNHNH2 Reduction of a Porphyrin

designed for studies in photodynamic therapy where the presence of the appended nonsteroidal anti-inflammatory moiety was considered to possibly ameliorate some of the adverse effects of the therapeutic treatment.109 Some types of substituents pose significant challenges in purification. In one example, meso-tetraphenylporphyrin was subjected to sulfonation at the p-position of the phenyl rings (Scheme 19).154 The disulfonated cis-isomer, 4-H210, was isolated in 30% yield. The latter was treated to the Whitlock diimide procedure albeit with several modifications. The modifications, which stem from accommodating both the polarity of the tetrapyrrole substituents as well as the two chlorin isomers available from the resulting cis-A2B2-architecture, included the following: (1) the solvent entailed 3-methylpyridine instead of pyridine for a higher reaction temperature, and water for solubilization of the porphyrin−disulfonic acid 4-H210; (2) reversed-phase (RP) chromatography was employed prior to the bacteriochlorin oxidation step; (3) the sulfonic acid moieties were neutralized with 2-aminoethanol; and (4) additional RP chromatography was carried out followed by crystallization to

preparation of AmBn-chlorins that illustrate these complexities are described below. In the first example, the A4-chlorin m-THPC was subjected to alkylation with α-bromo-p-toluic acid. The p-toluic acid moiety provided a bioconjugatable tether for attachment to nanoparticles. Mass spectral data were consistent with the presence of unreacted m-THPC as well as chlorins bearing 1−3 tethers; for the chlorin product bearing a single tether, assignment was made to the three isomers 4-H29a−c shown in Scheme 18.153 In the second example, the A4-chlorin m-THPC was subjected to esterification with one of a handful of carboxylic acids using EDC and HOBt (Table 7).109 The reaction was carried out with 2 equiv of the carboxylic acid whereupon the monoesterified chlorin was isolated as a mixture of two positional isomers, or with 12 equiv of the carboxylic acid to obtain the chlorin− tetraester. The carboxylic acids chosen were nonsteroidal antiinflammatory drugs. The two positional isomers of the A3Bchlorins were isolated as a single fraction upon chromatography in yields of 35−45%. The B4-chlorins were obtained in yields of 61−83%. The eight chlorins prepared in this manner were V


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Table 7. Chlorin−Esters Derived from m-THPC

Scheme 18. Alkylation of an A4-chlorin

obtain the chlorin 4-H211. The chlorin, which bears a cis-A2B2 substitution pattern installed at the porphyrin stage, has been used in liposomes for studies of photodynamic therapy.108 More general modifications to the Whitlock procedure are described in the next section. 4.3. Modifications to the Whitlock Diimide Procedure

Only a few general modifications aimed at improving the Whitlock procedure have been reported. The modifications have addressed the following: (1) source of diimide and the accompanying mildness of reaction conditions; (2) streamlined separation of porphyrin and hydroporphyrins; and (3) variation or replacment of the base, solvent, or oxidant. Each of these modifications is described next. 4.3.1. Diimide Source. The ability to employ milder reaction conditions versus those with p-TsNHNH2 in the presence of K2CO3 occurred with the advent of potassium azodicarboxylate (PADA).102 PADA undergoes decarboxylation at room temperature upon acidification, with accompanying release of diimide (Scheme 20). The sterically hindered 2,4,6triisopropylphenylsulfonyl hydrazide (TPSH) liberates diimide under neutral conditions at 35 °C.155 The availability of PADA has enabled the conversion of architecturally elaborate porphyrins to chlorins. One example is shown in Scheme 21, where a cofacial porphyrin−quinone 4-H212 was converted to the corresponding chlorin−quinones 4-H213a,b, albeit in tiny quantities.156 Two isomers were formed given the inequivalence of the four pyrroles with respect to the quinone structure; the axis

that bisects the nitrogen atoms of one pair of pyrroles is aligned coincident with the two carbonyl groups of the quinone, whereas the axis through the other pair of pyrroles is orthogonal to the quinone carbonyl groups. Conversion of one of each type of spatially distinct pyrrole to the corresponding pyrroline unit afforded the resulting pair of chlorin isomers. 4.3.2. Streamlined Separation of Chlorins. The Whitlock diimide reaction has broad scope as demonstrated by the diverse structures displayed in Tables 3−6. In some cases, however, reports of difficulties have surfaced.117 One aspect is that the meso-aryl substituents can alter the rates substantially. As one W


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Scheme 19. cis-Sulfonated A2B2-Chlorin

Scheme 21. Hydrogenation of a Porphyrin−Quinone

releasing groups can result in formation of greater quantities of the bacteriochlorin.117 A more significant and pervasive difficulty resides in the procedures for quinone-mediated oxidation (of bacteriochlorin to chlorin) and partitioning between benzene and aqueous phosphoric acid. The product mixture of three quite similar tetrapyrrole macrocycles (porphyrin, chlorin, and bacteriochlorin), which differ only in the presence or absence of pyrrolic β,β′double bonds, can present separation challenges. In general, the mixture consists predominantly of porphyrin and chlorin, or if driven further, of chlorin and bacteriochlorin. The removal of unwanted bacteriochlorin from the chlorin typically is more facile than removal of unwanted porphyrin. In this regard, treatment of the reaction mixture with o-chloranil gives somewhat selective dehydrogenation of the bacteriochlorin (forming the chlorin) than the chlorin (forming the porphyrin),62 but the selectivity is often incomplete. Regardless of the process by which the chlorin is prepared, be it as a byproduct of a porphyrin-forming reaction, or by hydrogenation with diimide, the separation of porphyrin, chlorin and/or bacteriochlorin can be arduous. The ease of metalation of tetrapyrroles generally decreases along the series porphyrin > chlorin > bacteriochlorin.157 While some metals are difficult to remove regardless of the macrocycle, others can be displaced with dilute acid. An approach developed by Dorough and Huennekens84 is shown in Scheme 22. The products of a Rothemund synthesis include H2TPP and H2TPC in ∼95:5 ratio. Treatment with zinc acetate gives fast metalation of the porphyrin but slow reaction with the chlorin. Subsequent chromatographic separation of the chief products, the zinc porphyrin and the free base chlorin, is substantially easier than that of the free base porphyrin and free base chlorin. The

Scheme 20. Sources of Diimide

example, aryl groups that bear electron-releasing groups (e.g., methyl) slow the reaction rate for hydrogenation, and the conversion of porphyrin to chlorin is more affected than that of chlorin to bacteriochlorin. Hence, the presence of electronX


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Scheme 22. Metalation-Facilitated Chlorin Separation

Scheme 23. Chlorin Separation Protocol

separation is facilitated because of the polarity imparted by the apical site of the centrally chelated zinc ion, which provides a site for interaction with adsorption media (e.g., silica, alumina, or sugar) upon chromatography. The free base chlorin elutes more rapidly than the zinc chlorin. Magnesium lies further than zinc toward the labile end of the tetrapyrrole metal-chelate stability progression.158 Indeed, magnesium tetrapyrroles often can be demetalated with weak acids, such as acetic acid in a polar medium; dilute trifluoroacetic acid in dichloromethane, or even silica gel.159 A strategy for separation of chlorins was developed that relies on the formation, chromatography, and demetalation of magnesium tetrapyrroles.160 The approach is displayed in Scheme 23. The crude reaction mixture following diimide reduction (with TPSH155), composed of porphyrin, chlorin, and bacteriochlorin, is subjected to magnesium insertion. Two methods for room-temperature magnesiation of tetrapyrrole macrocycles have been developed that employ a magnesium halide (MgX2), a noncoordinating base, and a noncoordinating solvent; the methods differ most demonstrably in affording heterogeneous158 or homogeneous160 reaction conditions. The conditions with a heterogeneous reaction mixture typically result in magnesiation of the porphyrin and chlorin, but not the bacteriochlorin. The mixture can then be separated by chromatography, taking advantage of the enhanced polarity of the magnesiated macrocycles. The apical site of the chelated magnesium ion is quite polarsubstantially more so than that of the aforementioned case of zinc tetrapyrrolesand provides a site of affinity for adsorption chromatographic media. In this case, the free base bacteriochlorin readily elutes, followed by the more polar magnesium porphyrin and magnesium chlorin

upon application of a more polar solvent. The magnesium chlorin can be readily demetalated upon treatment with weak acid to give the free base chlorin if desired. Alternatively, the homogeneous method for magnesium insertion can be employed, which typically magnesiates only the porphyrin and not the hydroporphyrins. In this case, the free base hydroporphyrins are easily removed from the magnesium porphyrin by chromatography. 4.3.3. Alteration of Reaction Constituents. Several valuable modifications to the Whitlock procedure have been developed by members of the esteemed Coimbra school. Pereira and co-workers replaced K 2 CO 3 in pyridine with 1,4diazabicyclo[2.2.2]octane (DABCO) in DMF and carried out the reaction with p-TsNHNH2 at 150 °C for 4 h.122,161 The resulting reaction mixture was chromatographed to obtain the chlorin. Application of the method to meso-tetrakis(2-chloro-5sulfophenyl)porphyrin afforded the corresponding chlorin in 75% yield (entry 21, Table 3).122 Pereira and co-workers went further and eliminated K2CO3 in pyridine altogether.124 Thus, a solventless synthesis relied on making an intimate mixture of two solids, p-TsNHNH2 and the porphyrin, which was then heated at 140 °C in an evacuated tube. When the ratio of p-TsNHNH2/porphyrin was 30:1, the bacteriochlorin was obtained cleanly and in good yield.124,162 With 8:1, a mixture of porphyrin, chlorin, and bacteriochlorin resulted.124 With 15:1, the product consisted of chlorin along with 10−20% of bacteriochlorin.124 Given the substrates examined (meso-tetraarylporphyrins bearing halo and sulfo substituents on the aryl moieties), treatment with Fenton’s reagent (H2O2 and FeCl3) gave selective oxidation of the bacteriochlorin. The chlorins obtained in this manner are shown in entries 21−23 (Table 3).123,124,162 Nascimento, Rocha Gonsalves, and Pineiro developed a clever, streamlined modification of the diimide reduction procedure (Table 8).163 The approach entails two microwave reactions. A porphyrin is treated to the standard cocktail for diimide formation to form chiefly the bacteriochlorin containing residual Y


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irradiation affords faster reactions (25 and 3 min for steps 1 and 2) than traditional convection heating. Second, MnO2 is an improvement over o-chloranil for dehydrogenation of the bacteriochlorin. Third, the microwave conditions appear to give more complete conversion of the starting porphyrin. In each case, the recovered mass of crude product was >85% for the two reaction steps. The examples shown in Table 8 all concern A4porphyrins. The A3B-porphyrin 5-(4-carboxyphenyl)-10,15,20triphenylporphyrin was subjected to the procedure to form the corresponding chlorin (entry 6, Table 4).137

Table 8. Streamlined, Microwave Synthesis of mesoTetraarylchlorins

4.4. Alternative Methods for Hydrogenation

Reagents such as sodium/alcohol or diimide have been employed most often for the hydrogenation of porphyrins to form the corresponding chlorin. More recently, however, direct hydrogenation over Pd/C was investigated for reduction of mesotetrakis(pentafluorophenyl)porphyrin, H2F20TPP (Scheme 24). Scheme 24. Pd-Metal Mediated Hydrogenation of a Labile Porphyrin

a

Ratio of bacteriochlorin/chlorin/porphyrin.

chlorin (and rarely the porphyrin). The latter mixture is then treated with MnO2 to form chiefly chlorin and a lesser amount of porphyrin. Thus, the strategy differs in several ways from that of the standard Whitlock procedure. First, the use of microwave Z


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direction was described but not pursued in depth.165 Thus, reaction of the copper chelate 4-Cu16 with NaBD4 gave the sitespecifically monodeuterated chlorin 4-Cu18, which upon denitration with tributyltin hydride gave the monodeutero chlorin 4-Cu19 (Scheme 25, right panel). Again, the advantage of this method is the ability to introduce a single deuteron in the pyrroline motif; on the other hand, the site-specificity is set at the preceding step of nitration. The borohydride reduction and denitrification also have been employed as key steps in the preparation of a vicinal dibromoporphyrin.110 Thus, 17-nitro5,10,15,20-tetraphenyporphyrin was treated with NBS to give the 7,8-dibromo-17-nitro-5,10,15,20-tetraphenylporphyrin. Reduction of the nitroene gave the chlorin, which underwent elimination of nitrous acid upon exposure to silica, thereby forming the 7,8-dibromo-5,10,15,20-tetraphenylporphyrin (not shown). The yields for dibromination (82%), reduction (84%), and denitrification (98%) were quite high, and vicinal βdibromination was incisively achieved without competing formation of the 7,8,17,18-tetrabromoporphyrin, as would be the case upon attempted bromination of the porphyrin H2TPP. A disadvantage of this approach is the necessity to employ the copper porphyrin for nitration and then displace copper following nitration. An alternative is to prepare H2TPC via the Whitlock procedure, carry out the 7,8-dibromination with NBS, and then oxidize the 7,8-dibromochlorin with 2,3-dichloro-5,6dicyano-1,4-benzoquinone (DDQ), thereby forming the 7,8dibromo-5,10,15,20-tetraphenylporphyrin. The yields of this latter approach also were very high [bromination (98%), oxidation (98%)], and the process avoids all of the steps associated with nitration of the porphyrin (not shown).110 On the other hand, the latter approach requires use of the Whitlock procedure and typically tedious separation of the desired chlorin H2TPC. Regardless, a key aspect of both routes is that the preferred sites of electrophilic bromination of a tetra-mesosubstituted chlorin are the β-positions of ring B, namely the 7and 8-positions, which are distal to the pyrroline ring (ring D).2 A potential yet unexplored advantage of both approaches resides in installation of isotopes at the 17,18- or 18-positions through use of isotopically substituted p-TsNHNH2 or NaBH4, respectively. In some instances, chlorin formation can occur adventitiously during the course of other reactions. Two examples are shown in Scheme 26. In the first example, reported by Bied-Charreton and co-workers, the copolymerization of an acrylamide-substituted porphyrin 4-H220 with styrene afforded the corresponding pendant copolymer 4-H221 containing porphyrin as well as chlorin units, with the latter present at the 10−15% level as determined by absorption spectroscopy.166 The polymerization was initiated with azobis(isobutyronitrile) (AIBN). The mechanism of porphyrin reduction was suggested to entail formation of a sterically hindered radical at the porphyrin βposition, followed by hydrogen abstraction from the solvent. The presence of chlorin was confirmed by zincation of the macrocycles, whereupon the overlapping absorption of the free base (porphyrin and chlorin) macrocycles are converted to the spectrally distinct absorption features of the zinc porphyrin and zinc chlorin. Attempts to remove the chlorin by dehydrogenation with chloranil (o- or p- was not specified) were not successful. Bied-Charreton and coauthors pointed out that the “hypothetic presence of chlorin is very often neglected in reports of radical copolymerisation of porphyrins.” Yet from a broader perspective, tetrapyrrole chemistry and polymer chemistry have largely been mutually exclusive fields of endeavor. In the second example, an attempt to prepare a porphyrin dimer entailed treatment of a

The susceptibility of the p-fluoro substituents to nucleophilic displacement with amines (e.g., p-TsNHNH2) may have prompted the study. The reaction in ethanol with H2 and various cosolvents was examined, whereupon inclusion of 2% DMF (16 h, room temperature) was found to give the best results. The reaction mixture consisted of the porphyrin H2F20TPP, chlorin 4-H214, and isobacteriochlorin 4-H215 in 26:58:16 ratio, respectively.164 An alternative method for hydrogenation entails a multistep sequence of reactions, which at first glance might seem unnecessary but on reflection has considerable attractions. Thus, nitration of H2TPP afforded the mononitro derivative 4H216. The presence of the nitro group activates the adjacent carbon toward attack by borohydride, whereupon the βnitrochlorin 4-H217 was formed. Subsequent treatment with tributyltin hydride caused reductive denitration to give the corresponding chlorin H2TPC (Scheme 25, left panel).165 One Scheme 25. Borohydride Route to Chlorins

advantage of the nitroene intermediate (4-H216) is that the process affords the chlorin without contamination by the bacteriochlorin H2TPBC (not shown). The absence of doublereduction to give the bacteriochlorin arises because the introduction of one nitro group deactivates the macrocycle toward the electrophilic substitution required to install the second nitro group. A second advantage of the nitroene intermediate is that each site of attack, by borohydride and by tributyltin hydride, is known with certainty. Thus, the possibility exists for site-specific (but not stereoselective) introduction of 2 H or 3H at the β-pyrroline position. An initial foray in this AA


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Scheme 26. Inadvertent Chlorin Formation During Reactions

Scheme 27. Enzymatic Formation of Deuterochlorins

porphyrin bearing a single benzonitrile group 4-H222 with hydrazine in DMF at 125 °C (Scheme 26). The linker created in this process was a 3,5-diphenyl-4-amino-1,2,4-triazole unit. The conditions of the reaction caused hydrogenation, whereupon the

resulting construct 4-H223 was a dyad composed of one porphyrin and one chlorin, rather than a dimer of porphyrins.167 As part of studies related to possible metabolism of porphyrins in plants, Dayan and co-workers observed that a green pigment AB


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Scheme 28. Vicinal Dihydroxylation of Porphyrins To Form Oxochlorins

with an absorption spectrum characteristic of chlorins could form upon exposure of the naturally derived porphyrin deuteroporphyrin IX to glutathione in the presence of the enzyme horseradish peroxidase (HRP).168 Glutathione is a tripeptide (γ-Glu-Cys-Gly) containing a free thiol. The reaction occurred under aerobic conditions. In deuteroporphyrin IX, two of the pyrrole rings each contain two alkyl groups whereas the other two pyrroles each contain only one methyl group (Scheme 27, top panel). The pyrroline ring formed from the pyrroles that contain the single methyl group, giving rise to two chlorins (4-

H224a,b). In each case, the pyrroline ring contained an oxo group and a hydroxy group on adjacent carbons, in addition to the methyl group.169 Studies to elucidate reaction requirements revealed that (1) added H2O2 was not necessary for reaction; (2) the hydrogenatom donor, ascorbic acid, inhibited the reaction; (3) the hydroxyl radical scavengers, benzoic acid and mannitol, did not inhibit the reaction; (4) the ferric ion chelator, deferoxamine, strongly inhibited the reaction; (5) without glutathione, little chlorin was formed; (6) adding catalase to the reaction reduced AC


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Scheme 29. Synthesis of 2,2,4-Trimethyldeuterochlorin via Vicinal Dihydroxylation

rather underdeveloped as a means of obtaining target tetrapyrrole macrocycles. We now leave hydrogenation of porphyrins, a reductive method for preparing chlorins, and turn to the use of OsO4, an oxidative method for converting porphyrins to chlorins. This statement may seem contradictory; after all, a chlorin is more saturated than a porphyrin. A better view is that OsO4 is a cycloaddition reagent that causes loss, via an oxidative process, of the porphyrinic double bond between carbons 17 and 18; subsequent pinacol−pinacolone-like rearrangement gives the chlorin bearing adjacent gem-dialkyl and oxo units in the newly formed pyrroline ring. As the heft of this review documents, there are many approaches for creating a pyrroline motif that engenders a chlorin or chlorin-like compound.

the rate of chlorin formation by 50%; (7) adding superoxide dismutase had no effect on chlorin formation; (8) adding the oxygen scavenger, sodium hydrosulfite, stopped chlorin formation; (9) low light levels stimulated the reaction whereas high light levels were inhibitory; and (10) HRP was required and could not be replaced with hemin. The data were interpreted to suggest the occurrence at neutral pH of a free radical chain reaction, perhaps initiated by trace amounts of H2O2, that generates glutathiyl radicals; the latter react with the porphyrin to form porphyrin radicals, which in turn react with oxygen radicals to form the chlorin.168 The reaction appears restricted to deuteroporphyrin IX, as a number of other porphyrins (Scheme 27, bottom panel) did not afford chlorin products.169,170 The common porphyrins include uroporphyrin I (derived from linear tetramerization of porphobilinogen followed by cyclization and oxidation), coproporphyrin III (derived from decarboxylation of uroporphyrin III), protoporphyrin IX (derived by demetalation of hemin chloride), hematoporphyrin IX (derived from acid hydrolysis of hemoglobin), and mesoporphyrin IX (derived by reduction of the vinyl groups of protoporphyrin IX).171 Protoporphyrin IX did give reaction, but the products were water-soluble red products rather than the green species characteristic of chlorins.170 While the results shown in Scheme 27 are perhaps not profound, enzymatic synthesis appears to be

5. OSO4-MEDIATED CHLORIN FORMATION FROM PORPHYRINS 5.1. Reaction Patterns

The treatment of a porphyrin with an oxidant that reacts at the βpyrrolic position(s) has a storied history dating to the time of Fischer.172 Fischer first used hydrogen peroxide in sulfuric acid and obtained a tetrapyrrole product that a generation later was shown to be an oxochlorin.173,174 Inhoffen later employed the milder reagent OsO4.175,176 The reaction of OsO4 with a AD


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porphyrin that bears alkyl groups at the β,β′-positions affords a vicinal dihydroxychlorin, which upon treatment with acid undergoes pinacol−pinacolone-like rearrangement to form the gem-dialkyl oxochlorin. The OsO4 addition is stereospecific and gives rise to the vicinal diol in a cis configuration, as exemplified by the reaction of H2OEP to give 5-H21 (Scheme 28, top panel). The chemistry can be more complicated than might appear because continued oxidation often occurs to give dioxobacteriochlorins and dioxoisobacteriochlorins, each as a mixture of isomers (not shown). A number of reports have surveyed this chemistry176−178 although a comprehensive review has not appeared. Here, we only provide a cursory presentation of the OsO4-route to oxochlorins. The reader is referred to the work of Chang, Pandey, Smith, and Sotiriou for leading references.179−183 Chang in particular has further derivatized the octaethyloxochlorin 5-H22, converting the dione to a thione, alkene, and imine (i.e., O to S, CR1R2, and NR), as stated in a patent.184 The reaction of porphyrin 5-H23 with OsO4 afforded four dihydroxychlorins (5-H24a−d, each of which presumably is racemic) in approximately equal yields (Scheme 28, middle panel). Chlorin 5-H24d was isolated as the lactone (not shown).185 The lack of differentiation of the four distinct pyrrole rings points out a fundamental limitation of this approach. Use of a porphyrin that contains a plane of symmetry perpendicular to the molecular plane (5-H25) afforded an apparent simplification, whereupon only two dihydroxychlorins (5-H26a,b) were formed (Scheme 28, bottom panel). Each dihydroxychlorin 5-H26a,b is presumably racemic (not shown).181,182 Treatment of the vicinal dihydroxychlorin results in pinacol− pinacolone-like rearrangement to form the ketone flanked by a gem-dialkyl group. Note that the pyrrolinyl−alcohols in the dihydroxychlorin are benzylic in nature due to the adjoining aromatic chlorin macrocycle. Studies by Chang and others have revealed the migratory aptitudes of various substituents in the rearrangement process:181 “hydrogen, ethyl, alkyl groups including propionate side chains will migrate over methyl group. The only group that has a lower mobility than methyl is acetate··· the electron-withdrawing nature of the acetate seems to play a determinant role”. Thus, upon pinacol−pinacolone-like rearrangement, dihydroxychlorin 5-H26a gave oxochlorin 5H27a in very high yield, whereas dihydroxychlorin 5-H26b gave oxochlorin 5-H27b in modest yield (Scheme 28, bottom panel).181,182 Both 5-H27a and 5-H27b presumably are racemic. While knowledge of the migratory aptitudes of the various β-alkyl groups enables some degree of synthetic planning, each oxochlorin is obtained (presumably) as a pair of enantiomers. Chang and Sotiriou examined 2,4-dimethyldeuteroporphyrin IX dimethyl ester (5-H28) in vicinal dihydroxylation and subsequent reactions (Scheme 29).186 Porphyrin 5-H28 was chosen for these studies given the inherent symmetry, wherein (1) there are two distinct pyrrole rings versus four for protoporphyrin IX and (2) the synthesis was readily accomplished by condensation of two dipyrrin halves,187 each of which has nominal C2v symmetry (with regard to the pyrrolic α and β substituents). Thus, reaction with OsO4 in the standard way afforded only two positional isomers given the porphyrin symmetry (albeit each as a racemic mixture). The vicinal dihydroxylation proceeded more effectively at the less versus more hindered site to give 5-H29b (37%) and 5-H29a (8%), with 30% recovery of unreacted porphyrin; each chlorin was presumably racemic. Pinacol−pinacolone-like rearrangement of 5-H29b gave two oxochlorins (5-H210, 5-H211), which were

separated by preparative TLC, with each isolated in 42% yield. Ester saponification of 5-H210 was carried out prior to Wittig reaction as a means to block the side reaction leading to the βketomethyl phosphonium salt. Thus, methylenation of the ketone of chlorin−dicarboxylate 5-H212 gave 5-H213; esterification of the latter with acidified methanol gave methylidene− chlorin 5-H214 in 71% overall yield from oxochlorin 5-H210. Hydrogenation of the latter gave the 2,2,4-trimethyldeuterochlorin 5-H215 as a racemic mixture. Chlorin 5-H215 has been referred to as “methylchlorin” and used as the iron chelate in apomyoglobin reconstitution experiments.188 The dihydroxychlorin 5-H29b was treated with copper acetate to afford the corresponding Cu(II) dihydroxychlorin 5-Cu9b. The reaction was carried out in the presence of mild base (sodium acetate or collidine) to avoid possible rearrangement of the vicinal diols (Scheme 30).189 Under similar conditions, the Scheme 30. Lactonization During Copper Insertion of Vicinal Dihydroxychlorinsa

a

All chlorins here are presumably racemic.

dihydroxychlorin 5-H29a gave not only copper insertion but also cyclization to form the copper spirolactone−chlorin 5-Cu16. Note that the stereochemistry of the lactone 5-Cu16 (derived from the dihydroxychlorin) shown here differs from that in the literature. The formation of the lactone of the vicinal dihydroxychlorin is inconsequential with regard to the position of the long-wavelength absorption band. The absorption spectra of copper chlorins 5-Cu9b and 5-Cu16 are shown in Figure 3. Tamiaki and co-workers carried out an elegant study of the OsO4-mediated dihydroxylation of the phytoporphyrin analogue 5-H217. Phytoporphyrin (also termed phylloerythrin) is derived from chlorophyll a, contains the isocyclic ring bearing the 131oxo unit, is equipped with the 17-propionic acid moiety, yet is a porphyrin due to the absence of the dihydro, pyrroline motif (Scheme 31). Phytoporphyrin is a 131-oxophorbine whereas the phytoporphyrin analogue 5-H217 is a phorbine given the absence of the keto moiety. Thus, the phytoporphyrin analogue 5-H217 was treated to the standard conditions for vicinal dihydroxylation with OsO4 (Scheme 32).190 Chlorins 5-H218a and 5-H218c were obtained (each as a racemic mixture) in yields of 25% and 31%, respectively, along with recovery of the starting porphyrin AE


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Scheme 32. Regioselective Vicinal Dihydroxylation of a Phytoporphyrin Analogue

Figure 3. Normalized absorption spectra in dichloromethane of copper chlorin−diol 5-Cu9b (orange line) and copper spirolactone−chlorin 5Cu16 (red line).189

Scheme 31. Phytoporphyrin, a Chlorophyll Derivative

in 24% yield. While trace pigments with chlorin absorption features also were noted, none was isolated; hence, at best only trace quantities of 5-H218b and 5-H218d were obtained. The product distribution can be rationalized by consideration of the tautomeric equilibrium for the phytoporphyrin π-system. The tautomers are of course equivalent for the symmetric octaethylporphyrin, but the presence of the phorbine framework (i.e., the isocyclic ring here lacking the 131-oxo group) renders such tautomers inequivalent. Indeed, calculations indicated that tautomer 5-H217 is more stable than 5-H217-taut (Scheme 32); the former contains “cryptoolefins” in rings A and C whereas the latter contains the isolated double bonds in rings B and D. The greater stability of 5-H217 versus tautomer 5-H217-taut thereby accounts for the selective formation of chlorins 5-H218a,c versus 5-H218b,d.190 Two further examples are provocative concerning the use of OsO4. In the first example, the trans-AB-octaalkylporphyrin 5H219 contains one p-substituted aryl group and one bulky, 2,6disubstituted aryl group (Scheme 33).191 The disparity in size of the two aryl substituents resulted in reaction selectively at the pyrrole flanked by the less hindered aryl unit. Still, pinacol− pinacolone-like rearrangement afforded two oxochlorin isomers (5-H220a,b). The second example stems from a proposal made by Chang and Sotiriou, who suggested that given knowledge of OsO4 selectivity and alkyl group migratory aptitudes, an appropriately chosen porphyrin could serve as the basis for a facile synthesis of the gem-dimethylchlorin Bonellin (Scheme 34).181 Bonellin is the green pigment of the sea worm Bonellia viridis.192,193 The reaction of porphyrin 5-H221 with OsO4 resulted in a set of dihydroxychlorins (reaction in rings A and B, 29%; ring C, 4%; ring D, 13%; and recovered porphyrin, 20%). Reaction of the ring-D dihydroxychlorin with perchloric acid afforded in 41% yield each of the two oxochlorin isomers, 5H222a and 5-H222b, which were readily separable.181,182 Each

isomer was obtained in 5.3% yield (41% yield from the chlorin−diol). The proposed conversion to the racemic Bonellin homologue 5-H223 would entail grafting of a propionic acid unit to the 17-position of oxochlorin 5-H222a. To our knowledge, this conversion has not been carried out. The simplicity of this proposal is offset by (1) the need to prepare the porphyrin macrocycle and (2) the low yield in proceeding from porphyrin to oxochlorin: 150 mg of porphyrin gave 8 mg of oxochlorin 5H222a. Total syntheses of racemic Bonellin dimethyl ester have been performed by installation of the gem-dimethyl group in precursors to the chlorin.2 The results displayed in this section would seem to suggest the approach to chlorins by dihydroxylation of a porphyrin followed by pinacol−pinacolone-like rearrangement is rather limited. Subsequent work by Brückner and others, however, found a fascinating twist on this approach that already has proved to be enormously fecund for chlorin chemistry, as described in the next section. AF


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Scheme 33. Regioselective Vicinal Dihydroxylation To Form Oxochlorins

Scheme 34. Regioselective Vicinal Dihydroxylation To Form Oxochlorins

5.2. Dihydroxychlorins

It is not clear at what point chlorin chemists realized that the dihydroxychlorin, i.e., the OsO4-derived diol intermediate prior to acid-mediated rearrangement, was not only stable but could itself serve as a valuable chlorin rather than a way station on the path to an oxochlorin. Chang and Sotiriou noted in 1985 that the vicinal dihydroxychlorins were (1) inert toward quinone oxidation and (2) stable in most acids (including concentrated HCl) at room temperature, only undergoing pinacol− pinacolone-like rearrangement with >60% H2SO4 or HClO4.186 These prescient observations together with a series of papers in the early 1990s concerning applications likely were pivotal. Bonnett and co-workers reported that a dihydroxychlorin was quite effective in studies of photodynamic therapy.111 The groups of Chang and Smith investigated models for heme d, a dihydroxychlorin.181,185,194,195 Each of these examples entailed vicinal-dihydroxylation of an octaalkylporphyrin. A departure from this paradigm, wherein alkyl groups at the β,β′-positions of the pyrrole rings were considered to be essential, occurred with the publication by Brückner and Dolphin, who prepared the dihydroxychlorin from H2TPP or ZnTPP.196 The alkyl groups are essential to form the stable oxochlorin upon pinacol−pinacolone-like rearrangement, but not necessarily for formation of the vicinal-dihydroxychlorin. The reaction was quite slow (up to 1 week, 50% yield of the dihydroxychlorin, 40% recovery of the porphyrin) versus that of the octaethylporphyrin (2 days, 67% yield, 17% recovery).197 They also made the following observations: (1) the reaction was

compatible with diverse solvents and aryl groups; (2) the vicinal diol of the dihydroxychlorin could be converted into the corresponding isopropylidene acetal upon reaction with acetone; and (3) the zinc chelate could be demetalated with dilute acid without altering the vicinal hydroxy groups, thereby pointing up the (unexpected) robustness of the vicinal diol motif of the chlorin. Note that the term acetal is generally used herein regardless of the nature of the carbonyl substituents. Applications of the Brückner-Dolphin method have been numerous. Derivatives of meso-tetraarylporphyrins wherein all meso-substituents are identical (A4-porphyrins) are displayed in (Table 9−Table 13). Table 10 contains applications to mesotetraaryl-21,23-dithiaporphyrins wherein all meso-substituents are identical. A noteworthy feature of all such applications is that only a single dihydroxychlorin can be formed given the inherent symmetry of the substituted porphyrin. Appplications of the method to trans-A2B-porphyrins and trans-A2-porphyrins are shown in Table 11. Here, each chlorin is presumably racemic. Whereas the reaction to convert meso-tetraarylporphyrins to dihydroxychlorins requires up to 1 week, the analogous reaction with 5,15-diarylporphyrins required only a few hours.198 Further examples of dihydroxychlorin formation from a porphyrin are provided in Tables 12 and 13. The entries compiled in Tables 12 and 13 differ from those in Tables 9−10 in the presence of two complications: (1) there are two distinct AG


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Table 9. A4-Dihydroxychlorins via OsO4 Reaction

a

Metal chelate employed.

were observed, and in selected cases (entries 1, 7−9) such isomers were separated and characterized. The porphyrin substitution pattern in Table 13 includes trans-AB-porphyrins (entries 1−7) and A3B-porphyrins (entries 8 and 9). Additional literature exists wherein chlorins have no doubt been formed as evidenced by characteristic absorption spectral changes208 but in the absence of further data are not emphasized here. Setting aside the issue of positional isomers and stereoisomers, a review of Tables 9−13 reveals broad functional group

pyrrole rings for vicinal dihydroxylation and (2) the peripheral substitution pattern engenders facial enantiotopicity (as is the case with trans-A2B2- or trans-A2-porphyrins). Thus, each positional isomer is expected to exist as a pair of enantiomers. The porphyrin substitution pattern in Table 12 includes a monoarylporphyrin bearing various β-substituents (entry 1) as well as A3B-porphyrins (entries 2−5). In Table 12, only one of the two positional isomers for each dihydroxychlorin was reported. In Table 13, major and minor positional isomers AH


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Table 10. Core-Modified A4-Dihydroxychlorins via OsO4 Reaction

Table 11. trans-A2B2-Chlorins via OsO4 Reactiona

subsequent pinacol−pinacolone-like rearrangement. We now turn to treatment of porphyrins with nucleophiles rather than an electrophile as a means to form chlorins.

6. ALKYLATIVE REDUCTION OF PORPHYRINS 6.1. Reactions with Free Base Porphyrins

a

An approach complementary to the use of the oxidative electrophile OsO4 entails the use of a reductive nucleophile. In this regard, Krattinger and Callot reported the treatment of H2TPP with several n-alkyllithium reagents (Scheme 35). Use of n-butyllithium gave the n-butylphlorin 6-H21 and the nbutylchlorin 6-H22.214 Similar reaction with sec-butyllithium gave the mono-sec-butylchlorin 6-H23, unreacted H2TPP, and uncharacterized other products.215 Treatment with tert-butyllithium gave, in very low yields, the di-tert-butylchlorin (6-H24; presumed trans stereochemistry) and the di-tert-butylporphodimethene (6-H25, confirmed by single-crystal X-ray analysis);215 both are presumably racemic. Subsequent work by Senge and coworkers showed that the even bulkier phenyllithium under similar conditions gave only the hexaphenylporphodimethene (6-H26).216 Note that wherein a single alkyl group has added (6H22, 6-H23) to the β-pyrrole position, the product is expected as a racemic mixture. Treatment of meso-tetraarylporphyrins wherein the meso-aryl groups were 3-methoxyphenyl or 3,4dimethoxyphenyl (not shown) with alkyllithium reagents afforded the monoalkyl and dialkylchlorins without the porphodimethenes or phlorins; on the other hand, treatment with phenyllithium again gave the porphodimethene (aryl = 3methoxyphenyl).216 Senge and co-workers also investigated reductive alkylations in the presence of palladium catalysts using several porphyrins that differ in the nature of the meso-substituent. The substituents include phenyl (H2TPP), isobutyl (6-H27), and 1-ethylpropyl (6-H28) as shown in Scheme 36.216,217 Thus, reaction of H2TPP in the presence of tert-butyllithium gave three productsthe porphodimethene (6-H25), mono-β-butylchlorin (6-H29), and β,β′-dibutylchlorin (6-H24(trans))all in greater yield (64% total) than in the absence of palladium catalysis (∼6% total).216 Single-crystal X-ray analysis confirmed the trans configuration of the two tert-butyl groups in the pyrroline ring of 6-H24(trans). For the meso-tetraalkylporphyrins, the tetraisobutylporphyrin 6H27 gave the mono-β-alkylchlorin (6-H210) and porphodimethene (6-H211), whereas the porphyrin with short “swallowtail”

Only one of the enantiomers is shown.

tolerance. The inventory of compatible functional groups encompasses diverse aryl substituents (including phenols), core-modified porphyrins, sugars (with or without O-acetyl protecting groups), and a fluorenylmethyl-protected alkyl ester. The scope illustrated to date augurs well for widespread application. The diverse chlorins together constitute a sizable scientific advance, given that stable chlorins can be produced from porphyrins via OsO4 treatment without resort to AI


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Table 12. Diverse Dihydroxychlorins via OsO4 Reactiona−d

a

Only one of the enantiomers is shown. bEnantiomers. cYield not reported. dEntries 5a−5d show the Ar groups for the structure shown in entry 5. AJ


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Table 13. Dihydroxychlorin Positional Isomers via OsO4 Reactiona

AK


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Table 13. continued

a

Only one of the enantiomers is shown.

Scheme 35. Reductive Alkylation of meso-Tetraphenylporphyrin

substituents (1-ethylpropyl) gave the mono-β-alkylchlorin (6H212) and β,β′-dialkylchlorin (6-H213). A swallowtail groupa symmetrically substituted alkyl grouphas been incorporated previously with a variety of porphyrins218−226 and a few chlorins227 at one or more meso-substituents. Swallowtail groups are attractive for building steric bulk above and below the plane of the tetrapyrrole macrocycle. The stereochemistry generally was not reported for the products of the meso-tetraalkylporphyr-

ins with the exception of 6-H25 and 6-H24; the other products are displayed with presumed stereochemistry. Note that chlorins wherein a single alkyl group has added (6-H29, 6-H210, and 6H212) are expected as racemic mixtures, as are the chlorins wherein two alkyl groups have added in a trans architecture (6H24(trans), 6-H213). AL


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Scheme 36. Pd-Mediated Reductive Alkylation of meso-Tetrasubstituted Porphyrins

6.2. Reactions with Metalloporphyrins

novel and unexpected reactivity. More extensive studies of the reactions of N-substituted tetrapyrrole macrocycles are examined in the next section.

Krattinger and Callot also carried out a series of studies wherein metalloporphyrins were treated with organolithium reagents.228 A first set of reactions employed an arylcobalt derivative of mesotetraphenylporphyrin (6-Co14), which upon exposure to nbutyllithium afforded a blue-green mixture composed of >20 products. Isolation of the least polar fraction followed by demetalation and nickelation gave three characterizable products in quite low yield (Scheme 37). The three products include a monobutylporphyrin (6-Ni15), a dibutylchlorin (6-Ni16), and a tributylchlorin (6-Ni17). The product mixture suggests initial addition to the β,β′-double bond to generate an anion, which can be alkylated with butyl bromide (if present) or undergo oxidation, followed by successive alkylation processes.228 A second set of reactions employed a chlorozinc(II) N-phenyl derivative of meso-tetraphenylporphyrin (6-Zn18).228 Reaction with n-butyllithium or methyllithium was followed by demetalation, remetalation with cobalt acetate, and treatment with borohydride. The latter causes rearrangement of the Nphenylporphyrin to the metal-arylporphyrin (Scheme 38). The products upon use of n-butyllithium included a butylporphyrin (6-Zn19a) and a butylchlorin (6-Zn20a), whereas methyllithium afforded the methylporphyrin (6-Zn19b) and two methylchlorins (6-Zn20b, 6-Zn21b). Two features of the reactions with 6-Zn18 are noteworthy: (1) In all cases, addition of the alkyl group occurred at the pyrrole ring adjacent to the Nphenyl moiety. (2) The yields of chlorin were higher than those with the arylcobalt porphyrin 6-Co14. While the results to date fall short of robust synthetic applicability, the studies point to

6.3. Reactions of N-Substituted Tetrapyrrole Macrocycles

The reaction of trans-octaethylchlorin (trans-H2OEC) with methyl fluorosulfonate afforded the chlorin 6-H222 bearing a single N-methyl group (Scheme 39). A striking finding was that the N-methylation occurred selectively in ring B, opposite the pyrroline ring (ring D), and in high yield (87%).229,230 On the other hand, use of the electrophilic reagent methyl iodide resulted in a mixture of two dimethylchlorins; upon prolonged reaction, the trimethylchlorin was obtained in 91% yield.230 Similar reaction with meso-tetra-p-tolylchlorin (H2TTC) exhibited the same regioselectivity, affording chlorin 6-H223, although the best conditions that were found entailed use of the methylating agent methyldiphenylsulfonium tetrafluoroborate at elevated temperature (Scheme 40).117 On the other hand, methyl iodide, methyl fluorosulfonate, and methyl trifluoromethylsulfonate did not give satisfactory results with mesotetraarylchlorins. Studies with hydroporphyrins (bacteriochlorins and isobacteriochlorins) prompted the authors to conclude that the distal alkylation is due to kinetic rather than thermodynamic causes.117 While reactions of chlorins are generally outside the scope of the present review, the results displayed in Schemes 39 and 40 bear on observations made by Callot concerning the formation of N-substituted chlorins. Thus, reaction of porphyrin H2TPP with O-mesitylsulfonylhydroxylamine (OMSH) gave the N-aminosubstituted chlorin 6-24 (Scheme 41).231 By contrast, H2OEP AM


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Scheme 37. Alkylation of a meso-Tetrasubstituted Metalloporphyrina

Scheme 38. Alkylation of a meso-Tetrasubstituted Metalloporphyrina

a a

The chlorins are assumed to have trans stereochemistry (racemic).

The chlorins are assumed to have trans stereochemistry (racemic).

Scheme 39. Regioselective N-Methylation of a Chlorin gave the corresponding N-amino-substituted porphyrin 6-25 rather than the chlorin. Treatment of N-aminochlorin 6-24 with p-tosyl chloride gave the N-tosylamino-substituted chlorin (not shown). Control experiments verified that 6-24 did not originate from any possible adventitious chlorin H2TPC present in the sample of H2TPP; nonetheless, treatment of chlorin H2TPC with OMSH gave 6-24 with 2−3-fold faster rate of conversion versus that of H2TPP. Chlorins are known to undergo (electrophilic, nucleophilic, electrocyclic) reaction at ring B;2 for example, hydrogenation or cycloaddition at the β,β′-positions of ring B cause formation of the bacteriochlorin. In the bacteriochlorin, the most stable tautomer has the NH−NH units in rings A and C (along the y axis). In N-aminochlorin 6-24 the N-amino group is located in ring B. Such location, while consistent with the observed preference for reaction of chlorins in ring B, has the somewhat perverse consequence of altering the typical tautomeric system. Thus, ring A (or ring C, not shown) is pyrrolenic rather than pyrrolic. Said differently, the presence of the amino group in ring B is tantamount to a cis tautomer of the chlorin. A novel approach to chlorins was investigated wherein an Nalkylporphyrin was caused to rearrange to form a Ni(II) chlorin.232 The N-alkylporphyrin was prepared in one of two ways: by rational synthesis beginning with N-alkylpyrromethanes or by N-alkylation of an intact porphyrin. The N-alkylporphyrins shown in Scheme 42 were prepared by the former method. Treatment of porphyrin 6-26 with nickel acetate caused Ndealkylation to afford the porphyrin 6-Ni27 as well as the mesoalkylated porphyrins 6-Ni28a and 6-Ni28b. Neither is of interest for our purposes here other than as a counterpart to illustrate

scope and limitation. Of more interest is the nickelation-induced N-dealkylation of porphyrin 6-29, which afforded porphyrin 6Ni30 as well as the chlorin 6-Ni31. Porphyrin 6-29 is a homologue of 6-26, which differs by a single methylene group. The chlorin 6-Ni31, obtained in 61% yield, contains a geminal dialkyl group and a carbomethoxy-substituted methylidene unit, and is expected as a racemic mixture. The good yield is juxtaposed against the apparently exquisite sensitivity of the reaction course to the nature of the peripheral substituents, whereby a single β-propionate group (porphyrin 6-26) gives porphyrins whereas a single β-acetate group (porphyrin 6-29) gives chlorins. In this and the preceding sections, the conversion of a porphyrin to a chlorin has entailed treatment with an exogenous reagent, including H2 and other hydrogenation sources (e.g., diimide), OsO4, and diverse nucleophiles. In the following section, we consider the intramolecular rearrangement of a suitably substituted porphyrin to form a chlorin. As such, the transformation relies on an endogenous “reagent” that undergoes reaction with the porphyrin. The key synthetic handle on AN


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Scheme 40. Regioselective N-Methylation of a Chlorin

Scheme 42. Rearrangement of N-Alkyl Porphyrins

Scheme 41. N-Amino Chlorin Derived from H2TPC, not H2OEP

reactions. Because the α-hydroxyalkyl motif is so readily derived from a vinyl group, and heme bears two vinyl groups, it is natural that heme has been exploited as a key building block for exploring such routes to chlorins. We now turn to consider heme as a precursor to chlorins.

7. CONVERSION OF HEME TO GEM-DIALKYLCHLORINS 7.1. Gem-Dialkylchlorins

Chlorophylls contain a trans-dialkyl configured pyrroline ring, yet a number of chlorins found in nature contain other types of pyrroline substituents. Three examples are shown in Scheme 43. The naturally occurring chlorin Bonellin contains a gemdimethyl unit in the pyrroline ring (section 5.1).192,193 The chlorin Faktor I,233,234 derived by aerobic dehydrogenation of precorrin I, an intermediate in the biosynthesis of cobalamin, contains a gem-dialkyl unit in the pyrroline ring. Heme d, while not a gem-dialkylchlorin, contains a spirolactone unit integral to the pyrroline ring.235 The structure determination and synthesis of Bonellin and Faktor I demarcate a clear point of origin for chemistry aimed at the rational synthesis of gem-dialkylchlorins.2 However, the first examples of geminally disubstituted chlorins were synthesized in a non-rational manner years earlier via pinacol−pinacolone-like rearrangement of vicinal-dihydroxychlorins. The presence of two alkyl or other non-hydrogen substituents at one of the β-carbons in the pyrroline ring blocks adventitious dehydrogenation, as can occur with porphyrins formed by hydrogenation. The resistance of chlorophylls to such aerobic dehydrogenation may stem from the steric penalty associated

the porphyrin that has been explored to date is an α-hydroxyalkyl unit, which can be functionalized for intramolecular cyclization AO


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Scheme 43. Naturally Occurring or Naturally Derived GemDialkylchlorins

Scheme 44. Conversion of Hemin to a Deuteroporphyrin

Scheme 45. Acetylation and Retrosynthesis of Deuteroporphyrins

with planarization of the trans disposed alkyl groups on adjacent β-carbons. The resistance of gem-dialkylchlorins to adventitious dehydrogenation has prompted intense effort toward the development of de novo syntheses of such chlorins.2 This section concerns the formation of gem-dialkylchlorins by intramolecular cyclization of a suitably substituted porphyrin. 7.2. Hemin as a Semisynthetic Feedstock to Chlorins

A great deal, perhaps the majority, of semisynthesis of chlorins begins with chlorophylls, thereby retaining the dihydroporphyrin chromophore throughout the synthesis. A complementary approach entails transformation of hemin to a gem-dialkylchlorin, which was pioneered by Montforts.24,236−240 It almost goes without saying that chlorophylls and hemin are vastly abundant compounds. Note that heme is the Fe(II) chelate of protoporphyrin IX whereas hemin is the Cl−Fe(III) chelate thereof. Heme is often conveniently isolated and handled as hemin. Several illustrative routes are shown in the following schemes. Hemin undergoes devinylation in a resorcinol melt at 160 °C.241,242 The corresponding des-vinyl porphyrin (i.e., deuteroporphyrin) can be methylated and converted to the copper chelate to give Cu(II) deuteroporphyrin IX dimethyl ester 7-Cu1 (Scheme 44). Acetylation affords two positional isomers in comparable yield. The isomers are referred to as the “2-isomer” and the “4-isomer”, in keeping with the traditional numbering system of tetrapyrrole macrocycles.39 In this legacy nomenclature, the β-pyrrole positions were numbered 1−8 and the mesopositions were numbered α−δ in proceeding from rings A−D. Demetalation and remethylation followed by chromatography affords the two isomers, 7-H22a and 7-H22b (Scheme 45).242 Hemin, deuteroporphyrin, and the acetyl derivatives of deuteroporphyrin are displayed “upside down” in Schemes 44

and 45 for congruence with the chlorins derived therefrom (vide infra). The acetyl deuteroporphyrin isomers obtained by statistical derivatization were misassigned, as shown by independent, rational synthesis from dipyrromethanes (7-3a− c) by Clezy and co-workers.243 The availability of monoAP


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Scheme 46. Conversion of a Deuteroporphyrin to Gem-Dialkylchlorinsa

a

Each chlorin was obtained as a racemic mixture.

gave the gem-dialkylchlorin 7-H25a(E) where “E” denotes the configuration of the exocyclic double bond (trace amount), the gem-dialkylchlorin 7-H25a(Z) (82% yield), and the vinyl porphyrin 7-H26 (small amount) due to dehydration as a side reaction. Hydrogenation of 7-H25a(E) and 7-H25a(Z) afforded the cis isomer of the gem-dialkylchlorin 7-H27a(cis).244 Subsequent work identified milder, catalytic transfer hydrogenation conditions, which employed Pd(OAc)2 and the hydrogen donor triethoxysilane. Such conditions were applied to the mixture of 7-H25a(E) and 7-H25a(Z), affording the cis/ trans isomers of the gem-dialkylchlorin [7-H27a(cis) and 7-

acetylporphyrins 7-H22a and 7-H22b, derived from the abundant heme compound, has enabled the synthesis of chlorins. In general, the workers who carried out such transformations paid careful attention to the issues of stereochemistry and noted the formation of enantiomers. The monoacetyl deuteroporphyrin 7-H22a was transformed to a gem-dialkylchlorin as shown in Scheme 46.24,244 Thus, reduction of the acetyldeuteroporphyrin isomer 7-H22a with NaBH 4 gave the racemic α-hydroxyethylporphyrin 7H24a.245,246 Treatment of 7-H24a to Eschenmoser-Claisen rearrangement247 with N,N-dimethylacetamide dimethyl acetal AQ


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Scheme 47. Conversion of a Deuteroporphyrin to Gem-Dialkylchlorinsa

a

All species are racemic.

H27a(trans)] in 2.5:1 ratio.239 The E and Z assignments, which are shown in the inset to Scheme 46, generally hold unless a heteroatom is directly attached to the pyrroline 18-position. In summary, the synthetic transformations convert the red blood pigment heme to green chlorophyll-like pigments.

The mechanism for the Eschenmoser−Claisen rearrangement that ensues following treatment with N,N-dimethylacetamide dimethyl acetal (1,1-dimethoxy-N,N-dimethylethan-1-amine) is shown at the bottom of Scheme 46.248 Acetal exchange between alcohols and N,N-dimethylacetamide dimethyl acetal is fast and leads to the enamine intermediate. Rearrangement then AR


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Scheme 48. Acid-Catalyzed Equilibration of cis/trans Chlorin Isomers

Scheme 49. Conversion of Deuteroporphyrins to Gem-Dialkylchlorins

Catalytic transfer hydrogenation applied to the mixture of E/Z isomers 7-H25b(E) and 7-H25b(Z) gave the cis/trans isomers 7H27b(cis) and 7-H27b(trans) of the gem-dialkylchlorin in 5:1 ratio (Scheme 47, top panel).239 By contrast, direct hydrogenation was applied for the chlorins bearing the long alkyl chain in the pyrroline unit, with somewhat different product ratios. Thus, hydrogenation of the chlorin 7-H29b(Z) afforded the cis/ trans mixture 7-H210b(cis) and 7-H210b(trans) in good yield and ∼3:5 ratio (middle panel), whereas the dominant chlorin isomer 7-H29a(Z) afforded the cis/trans mixture 7-H210a(cis) and 7-H210a(trans) in good yield and ∼1:1 ratio (bottom panel).244 Catalytic transfer hydrogenation also was carried out to obtain 7-H210a(cis) and 7-H210a(trans) in 85% yield and 3:2 ratio, respectively (not shown).250 The mixture of cis/transchlorin−dicarboxylic acids derived from the mixture of 7H210b(cis) and 7-H210b(trans) was subjected to amidation conditions with diethyl 3-aminopropylphosphonate (not shown); the resulting chlorin with two phosphonate feet was attached to a metal-oxide surface for solar cell studies.251 A further observation by Montforts and co-workers concerning isomerization centers on cis−trans equilibration enabled by acid. Thus, the chlorin mixtures shown in Schemes 46 and 47 were treated with p-toluenesulfonic acid in methanol at reflux for 72 h. In each case the trans isomer formed predominantly over the cis isomer: the mixture of 7-H27a(cis) and 7-H27a(trans) converted from 2.5:1 to 1:2.5, whereas 7-H27b(cis) and 7H27b(trans) converted from 5:1 to 1:3.239

proceeds via a chairlike transition state (not shown), which typically results in a high degree of chirality transfer to the product. Given the racemic nature of the alcohol in this case, such transfer is not manifested. Regardless, this route has constituted a robust pathway for transformation of members of a family of porphyrins to the corresponding chlorins. Several implementations of the route are shown in Scheme 47.244 The synthesis and product distribution in each resembles that shown in the prior scheme. Porphyrin 7-H24b was derived from acetyl-deuteroporphyrin IX dimethyl ester, whereas porphyrins 7-H28a and 7-H28b were obtained by acylation with heptanoic anhydride of the copper complex of deuteroporphyrin dimethyl ester, in the same manner as the acetyl derivatives were prepared.244 One somewhat surprising observation was that chlorins 7-H25b(Z) and 7-H29b(Z) were particularly prone to photoisomerization of the exocyclic double bond to give the E isomer 7-H25b(E) and 7-H29b(E), respectively; by contrast, 7-H25a(Z) could be converted to the E isomer 7-H25a(E) only upon prolonged illumination (see structures in Scheme 46). Thus, the position of substitution on the chlorin has an effect on the photoisomerization process. Regardless, one consequence of this phenomenon is that the presence of the E isomers cannot necessarily be attributed to the reaction forming the chlorin as opposed to photoisomerization of an exclusive Z isomeric product giving the E isomer, upon ambient workup.244,249 AS


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Scheme 50. Route to Nickel Oxochlorin from Deuteroporphyrina

a

Each chlorin is racemic.

Scheme 51. Route to Free Base Oxochlorin from Deuteroporphyrina

a


of photodynamic therapy.250 The scope of the alkaline-mediated equilibration is not known. A further example, shown in Scheme 49, also began with deuteroporphyrin, but the first step entailed formylation rather than acetylation or alkanoylation.240 Vilsmeier formylation of 7Cu1 afforded a complex mixture of formylporphyrins due to meso-formylation, β-formylation, and polyformylation.242 On the other hand, the use of trimethyl orthoformate in the presence of TFA provided milder reaction, affording the mixture of the two β-formylated deuteroporphyrin isomers 7-Cu11a and 7Cu11b (66% together with recovery of 7-Cu1 in 30% yield).244 The two β-formylated deuteroporphyrin isomers were separable by chromatography. The “4-isomer” 7-Cu11b was elaborated to

A proposed mechanism for equilibration of the cis/trans isomers is shown in Scheme 48.239 Protonation of the pyrroline nitrogen atom renders the β-protons more acidic and thus susceptible to tautomerization. The Montforts group also reported that alkaline hydrolysis (KOH, aqueous THF, 50 °C, 40 h) of the mixture of chlorin−diester isomers 7-H210a(cis) and 7-H210a(trans) afforded the chlorin−dicarboxylic acid in exclusively the trans configuration (83% yield), in which case stereoselective hydrogenation was not necessary to obtain the trans isomer (not shown).249 Saponification also was carried out with the two esters individually.250 The resulting amphiphilic chlorin−dipropionic acid compounds were attractive for studies AT


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Scheme 52. Elaboration of Oxochlorins via Wittig Chemistrya

give porphyrin 7-H212, which contains a 1,4-dihydroxybutyl group, with the terminal alcohol protected as the THP ether. Treatment of 7-H 2 12 to the standard conditions for Eschenmoser-Claisen rearrangement with N,N-dimethylacetamide dimethyl acetal gave chlorins 7-H213(E) and 7-H213(Z). Hydrogenation gave the cis/trans mixture of gem-dialkylchlorins 7-H214(cis) and 7-H214(trans) in 9:1 ratio. The THP ether was readily removed with pyridinium p-toluenesulfonate (PPTS) in hot ethanol, conditions that did not alter the cis/trans ratio (i.e., did not cause equilibration), thereby affording the amphiphilic gem-dialkylchlorins 7-H215(cis) and 7-H215(trans).240 Each chlorin was obtained as a racemic mixture. Similar chemistry was carried out to form oxochlorins, which were then further elaborated for applications in artificial photosynthesis or photomedicine. The syntheses began with the chlorins 7-H25a(E/Z) derived from the “2-isomer” of acetyldeuteroporphyrin IX dimethyl ester (Scheme 50).236,252 The mixture of E/Z isomers, obtained as shown in Scheme 46,244 was metalated with nickel acetylacetonate to give the nickel chelates 7-Ni5a(E/Z). Treatment of the latter to a series of reactions resulted in the oxochlorin 7-Ni16 where also the amide was converted to an ester. The proposed mechanism for the overall transformation is shown. The sequence of reactions entailed iodination of the alkene with accompanying formation of the iminium lactone (step 1), hydrolysis of the imine and hydroxide displacement of the iodide (step 2), hydrolysis of the amide, hydrolysis of the propionate esters (not shown), and elimination of acetone (step 3), oxidation of the β-hydroxypyrrole to form the oxochlorin (step 4), and methylation of the three carboxylates (step 5). The overall yield was a remarkable 55%.252 Removal of nickel from tetrapyrrole macrocycles often is quite challenging. A route was therefore devised that avoided formation of the nickel chelate (Scheme 51).252 Thus, chlorin 7-H25a(E/Z) was metalated with zinc acetylacetonate, which afforded a mixture of the Z/E isomers 7-Zn5a(E) and 7Zn5a(Z). The mixture was treated to conditions to oxidize the exocyclic ethylidene bond and form the zinc oxochlorin, affording 7-Zn17. The zinc was removed with mild acid to form the free base oxochlorin 7-H217. Methanolic KOH caused saponification of the two propionate esters as well as the amide unit, the latter presumably via anchimeric assistance with the adjacent keto functionality. Subsequent esterification afforded the free base oxochlorin−triester 7-H216 in 82% yield. Several approaches were pursued for synthetic elaboration of oxochlorins. While derivatization of chlorin macrocycles lies outside the scope of this review, a fair evaluation of the utility of the routes to chlorins and oxochlorins shown in this section motivates the following brief presentation. The Wittig reaction of nickel oxochlorin 7-Ni16 gave the corresponding olefins 7-Ni18 and 7-Ni19 (Scheme 52).252 On the other hand, the zinc oxochlorin 7-Zn17 or the free base oxochlorin 7-H216 did not give olefination, which prompted development of an alternative pathway to elaborate the chlorins. The racemic oxochlorin 7-H216 was reduced with LiAlH(Otert-Bu)3 in stereoselective fashion to give the hydroxychlorin 7H220 in 81% yield as well as a trace of the diastereomer 7-H221, which exists as the lactone (Scheme 53).252 The hydroxychlorin 7-H220 was subjected to alkylation with an alkyl bromide under phase-transfer catalysis conditions (Scheme 54). The reaction was carried out with 10 equiv of the alkyl bromide. One alkyl bromide that was employed contained an MEM-protected hydroquinone (7-22); a second contained estrogen with MEMprotection of the phenol group (7-23). In the former case, one

a


Scheme 53. Formation of Hydroxychlorinsa

a

See text for discussion of chlorin stereochemistry.

side reaction entailed ester formation between unveiled carboxylates of the chlorin and the hydroquinone bromide. AU


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mixture of cis/trans isomers to hot acid caused equilibration and formation of a cis/trans ratio of 1:2.5. Chromatography afforded the more polar, trans isomer 7-H 27a(trans), with the enantiomeric ratio of 7-H27a(trans) and 7-H27a(trans)-ent of 89:11 established at the outset upon enantioselective reduction of the prochiral ketone. A similar series of transformations began with the “4 isomer” of acetyl-deuteroporphyrin dimethyl ester 7H22b (Scheme 55, right panel). Enantioselective reduction gave the alcohol 7-H24b:7-H24b-ent in 87:13 ratio, which ultimately gave rise to the trans-chlorin 7-H27b(trans) and 7-H27b(trans)ent in the same 87:13 ratio.238 The advantages of the approach shown in Scheme 55 include the availability of very large quantities of hemin, the synthetic transformation to the gem-dialkylchlorin, and the ability to leverage the vast knowledge basis for semisynthetic transformations of protoporphyrin IX.253 Moreover, the synthesis arguably represents the first de novo enantioselective synthesis of a chlorin.237,254 This claim warrants supporting commentary concerning earlier chlorin syntheses. Battersby’s synthesis of Factor I, an early intermediate in the biosynthesis of cobalamin, proceeded via a racemic building block, the optically active form of which could be derived by degradation of vitamin B12.255 Woodward’s synthesis of chlorin e6 trimethyl ester relied on (1) a quinine-mediated resolution of a racemic mixture toward the end of the synthesis (step 42 of 46), and (2) semisynthetic replenishment (from methyl pheophorbide a) of an advanced, chiral intermediate (the purpurin produced in step 43), to complete the synthesis.10 In short, both of these landmark syntheses relied on the availability of synthetic intermediates derived from naturally occurring tetrapyrrole macrocycles. The route pioneered by Montforts in principle is not limited to hemin but can be applied to porphyrins that contain a β-(αhydroxyalkyl) and β′-alkyl group as well as similarly substituted azaporphyrins (derived from bilirubin); the latter afford the azachlorin (see section 11.1.2).256 More general routes to gemdialkylchlorins, which afford greater control over the nature and patterns of substituents about the perimeter of the macrocycle, have also been developed. We now turn to a special class of gemdialkylchlorins, the spirochlorins, wherein the gem-dialkyl group is itself integral to a cyclic structure.

Scheme 54. Elaboration of Hydroxychlorins via Alkylation

Treatment with aqueous KOH saponified all esters. The carboxylates could be converted to the esters with diazomethane, leaving the MEM groups intact (not shown), or re-esterified with methanolic H2SO4, which also conveniently removed the MEM groups. The chlorin−hydroquinone 7-H224 was obtained as a racemic mixture in 42% yield, along with oxochlorin 7-H216 in 20−25% yield. Given the racemic nature of the starting hydroxychlorin 7-H220, and the enantiopurity of estrogen, the chlorin−estrogen 7-H225 was obtained as a pair of diastereomers (1:1 ratio) in overall yield of 48%, along with oxochlorin 7-H216 in 20−25% yield. One such diastereomer (7-H225) is displayed in Scheme 53. In effect, the alkylation with the tethered estrogen provided a resolution of the enantiomers into an enantiomerically pure pair of diastereomers. The chlorin−hydroquinone 7H224 was designed for studies in artificial photosynthesis whereas the chlorin−estrogen (7-H225) was chosen for studies of photodynamic therapy. An advanced, enantioselective synthesis of chlorins is shown in Scheme 55.237,238 Treatment of acetyl-deuteroporphyrin dimethyl ester 7-H22a to enantioselective reduction with 7-26 afforded the alcohol with 89:11 ratio for 7-H24a:7-H24a-ent for the pair of enantiomers (left panel). Eschenmoser−Claisen rearrangement247 of the latter mixture with N,N-dimethylacetamide dimethyl acetal gave the gem-dialkylchlorin 7-H25a(E/Z), which consisted chiefly of the Z isomer along with a trace of the E isomer. Reduction of the exocyclic double bond under mild catalytic transfer hydrogenation conditions gave the isomers 7H27a(cis) and 7-H27a(trans) in 2.5:1 ratio; the cis isomer formed preferentially owing to the diminished steric hindrance on the side opposite the amidomethyl unit. Treatment of the

8. SPIROCHLORINS In this section, a type of gem-dialkylchlorin is described wherein the gem-dialkyl unit is cyclic, thereby affording a spiro motif. An example of a naturally occurring chlorin that contains a spiro motif in the pyrroline unit is provided by heme d, which is displayed in Scheme 43. In heme d, the spiro motif contains a lactone unit and hence is an oxaspiro entity. 8.1. Spiroketones

Kenner and co-workers (aided by an able graduate student, K. M. Smith) found that exposure of a β-acetamidoethyl-substituted porphyrin to POCl3 in pyridine caused spirocyclization to give a chlorin (Scheme 56).257,258 Thus, porphyrin 8-H21 afforded the spirocyclic chlorin 8-H22 bearing an exocyclic methylene group. An unusual feature of this reaction is the formation of the chlorin by electrophilic attack at the β-position, whereas in a bimolecular reaction, electrophilic substitution of porphyrins bearing a full complement of β-substituents typically occurs at an open mesoposition. Hydrogenation transformed the exocyclic methylene into a methyl group to give the chlorin 8-H23, which bears three alkyl substituents in the pyrroline ring. AV


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Scheme 55. Enantioselective Conversion of Deuteroporphyrins to Gem-Dialkylchlorinsa

a

See text for discussion of chlorin stereoisomers.

butyric acid group (8-H26) or the spiroketo−chlorin bearing an exocyclic methylene group (8-H27). The latter was formed in 19% yield, suggesting significant branching to give the porphyrin. While the spiroketo−chlorin 8-H27 also is at the same oxidation state as that of porphyrin 8-H26, nucleophilic attack at the keto group is expected to be less likely than that of the protonated

A more in-depth study of spirocyclization with porphyrin− amides was carried out by Smith and co-workers.259 A porphyrin bearing a butyramide group (8-H24) underwent spirocyclization upon treatment with POCl3 and pyridine (Scheme 57). The resulting imine 8-H25 is at the same oxidation state as that of the porphyrin; hydrolysis could afford the porphyrin bearing a AW


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Scheme 56. Conversion of a Deuteroporphyrin to the Spirolactone−Chlorins

Scheme 57. Conversion of a Porphyrin to the Spiroketo− Chlorinsa

imine. Regardless, the chlorin oxidation state was attained by hydrogenation of the exocyclic methylene unit in 8-H27. Chlorin 8-H27 is expected to be racemic. The reduction was reported to afford the trans configuration (17-methyl with respect to 18keto); hence, the pair of chlorin enantiomers (8-H28) was obtained rather than all four possible stereoisomers. An analogous spiroketo−chlorin was subjected to mild reduction of the exocyclic methylene group using the diimide source PADA.259

a

8.2. Spirolactones

Clezy and co-workers attempted to add HBr to the vinyl group of various porphyrins (e.g., protoporphyrin IX) and in so doing uncovered a novel route to chlorins, wherein the culprit giving rise to this “side reaction” apparently stemmed from the presence of Br2 in HBr/AcOH (Scheme 58).260 The reaction entailed the intramolecular cyclization of a propionate side chain. A study of appropriate porphyrins, bearing at least one propionate side chain, revealed that 3,8-dibromodeuteroporphyrin dimethyl ester (8-H29) gave a more stable product than that of deuteroporphyrin or protoporphyrin IX. The reaction undoubtedly proceeds via an intermediate bromonium ion followed by intramolecular attack of the propionate carboxylate group. The resulting five-step procedure thus entailed initial treatment with HBr/AcOH to hydrolyze the methyl esters, Br2 to effect spirolactone formation, NaOAc for workup, and aqueous HCl. The acid treatment was employed to extract the residual porphyrin into the aqueous phase. Diazomethane was then employed to esterify the remaining propionic acid group. The chlorin product likely consisted of four isomers (8-H210), as shown in Scheme 58, given comparable reactivity of the two rings bearing propionic acid groups as well as the two faces for bromonium ion attack. Attempts to chromatograph the product

See text for discussion of chlorin stereochemistry.

led to hydrolytic replacement of the bromo−pyrroline with a hydroxy−pyrroline substituent. 8.3. Spirochlorin Dyads

Molecular architectures that contain one chlorin and one porphyrin were prepared from β,β′-sulfolenoporphyrins in a dimerization process (Scheme 59). The two examples shown are unique in (1) beginning with a single porphyrin, and (2) affording a spiro linkage in the pyrroline ring of the chlorin. Both entail cycloaddition processes, which are described in detail in sections 9−12); here we focus on the resulting spirochlorins. The synthesis of 8-H211 began with the monosulfolenoporphyrin, which at 80−110 °C in toluene underwent SO2 extrusion and subsequent self-cycloaddition to form the dyad.261 The synthesis of 8-Zn12 began with the tetrakis(sulfoleno)porphyrin, which upon reaction at 140 °C in 1,2-dichlorobenzene (ODCB) extruded one of the four possible molecules of SO2; subsequent self-cycloaddition gave the all-zinc dyad in 17% yield.262 The absorption spectrum of porphyrin−spirochlorin 8-Zn12 is shown in Figure 4. In both architectures, the π-systems of the respective porphyrin and chlorin macrocycles are held in close proximity but in an orientation that, while not rigidly orthogonal, AX


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Scheme 58. Conversion of a Deuteroporphyrin to the Spirolactone−Chlorins

Scheme 59. Dyads Containing One Porphyrin and One Chlorin

is certainly far from coplanar. Fixing both distance and orientation of porphyrin/hydroporphyrin macrocycles in arrays remains a general challenge in the field of artificial photosynthesis.263,264 The fact that each dyad is racemic is inconsequential to the study of the π-interactions of the respective macrocycles. Osuka and co-workers treated a triply fused porphyrin dimer (8-Zn13) with o-xylylene (derived from benzosultine) and obtained two chlorin-containing products corresponding to [4 + 2] and [4 + 4] cycloadditions (Scheme 60).265 Both cycloadditions occurred in the bay region of the triply fused dimer. The [4 + 2] cycloaddition of o-xylylene across the β,β′-bond of one pyrrole ring gave a gem-dialkylchlorin; the other half of the fused architecture was unaffected, hence the product (8-Zn14, racemic) can be regarded as a triply fused porphyrin−chlorin dyad. The [4 + 4] cycloaddition of o-xylylene occurred at βpositions adjacent to a fused linkage to give a triply fused chlorin−chlorin dimer (8-Zn15). The occurrence of both the [4 + 2] and [4 + 4] cycloadditions is surprising given that, from a formal perspective, the former is symmetry-allowed while the latter is symmetry-forbidden; the mechanism remains open to conjecture. Each pyrroline ring of the chlorin dimer contains β,β′-dialkyl substitution rather than a gem-dialkyl unit. Accordingly, chlorin dimer 8-Zn15 underwent dehydrogenation with DDQ to give the corresponding benzo-substituted porphyrin dimer 8-Zn16. The absorption spectra of 8-Zn13, 8-Zn14, 8-Zn15, and 8Zn16 are provided in Figure 5. For each species, the absorption

Figure 4. Absorption spectra of porphyrin−spirochlorin 8-Zn12 in dichloromethane.262

spectrum extends to beyond 1000 nm, whereas for typical monomeric porphyrins and chlorins, the long-wavelength absorption appears at 750 nm, which is rare for a chlorin. Yet additional routes begin with porphyrins that bear mesoamino substituents (Scheme 89). Thus, condensation of mesoamino-octaethylporphyrin 10-H261 with glyoxal afforded the imino-porphyrin 10-H262, which upon overnight reaction in refluxing toluene containing the acidic clay Montmorillonite K10 gave the chlorin as a mixture of stereoisomers (10-H263a, 10H263b).334 Attempts to convert the mixture via a 1,2-alkyl shift

into the desired pyridochlorin 10-H264 were unsuccessful. On the other hand, amino-porphyrin 10-H261 was converted to the zinc chelate 10-Zn61 and then reacted with glyoxal to give 10Zn62, which on prolonged treatment in refluxing solution resulted in formation of the desired hydroxypyridochlorin 10Zn64. Demetalation of the latter gave the free base 10-H264. Comparison of the reaction outcome with the free base 10-H262 versus the zinc chelate 10-Zn62 provides a clear demonstration

Scheme 88. Meso-Elaboration of a Benzochlorin

BT


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paraformaldehydegave the chlorin dimer 10-Ni67.335 It warrants mention that the use of a Lewis acid in an organic solvent often generates a Brønsted acid by coordination with adventitious water, with adventitious protic species, or with the solvent itself if the solvent is protic (e.g., methanol). Formation of the Brønsted acid can give rise to parallel catalysis or, in this case, protonation of the free base porphyrin.337 Such protonation of the inner (pyrrolenine) nitrogens deactivates the free base porphyrin, but the nickel porphyrin cannot undergo protonation. Hence, in both cases shown in Scheme 90, the different outcomes may not stem from structural/electronic effects of metalation but rather from differences in electrophilic reactivity of the deactivated free base porphyrin (due to protonation) and the unaffected nickel porphyrin. The absorption spectrum of dimer 10-Ni67 is shown in Figure 22.

Scheme 89. Distinct Annulations for Metallo versus Free Base Porphyrins

Figure 22. Absorption spectrum of nickel benzochlorin dimer 10-Ni67 in dichloromethane.335

Scheme 90. Reactions of an Isocyanoporphyrin 10.4. Monoaryl Benzochlorins

A key limitation of benzochlorin chemistry as often practiced has entailed the possible formation of isomers, the planned avoidance of which imposes limits on the available pattern of substituents in the parent porphyrin. An example is provided with an octaethylporphyrin that bears a single meso-aryl substituent (Scheme 91).307 Installation of the acrolein group on porphyrin 10-M68 (M = Ni or Cu) can occur at the site adjacent (10-M69a, 10-position) or distal (10-M69b, 15position) to the lone aryl group (5-position); the resulting porphyrin−acroleins typically have been separated. The yields for the 10- versus 15-substituted isomers were 53%:8% (M = Ni) and 60%:6% (M = Cu). Examination of various acid catalysts (TFA, SnCl4, BF3·OEt2) led to the following findings: (1) with neat TFA, Ni(II) chelate 10-Ni69a was converted to benzochlorins 10-Ni70a and 10-Ni70b in >95:5 ratio, respectively, and 66% overall yield; (2) with neat TFA, Cu(II) chelate 10-Cu69a was demetalated and no benzochlorins were obtained; and (3) with BF3·OEt2, Cu(II) chelate 10-Cu69a was converted to benzochlorins 10-Cu70a and 10-Cu70b in 29:71 ratio, respectively, and 61% overall yield. The disparate regioselectivity was attributed to the different electron densities at the adjacent or distal meso-positions of the macrocycle owing to Ni(II) or Cu(II) chelation. By contrast, the cyclization of Ni(II) chelate 10-Ni69b yielded only one product, which in this case was obtained as the free base, 10-H270c. While attractive, the synthesis of the precursor 10-Ni69b suffered from the low yield of acrolein installation. Maillard and co-workers followed similar lines as those in Scheme 91 to prepare a monoaryl

of the subtleties of the cyclization and rearrangement leading to benzochlorin-like architectures. A further example of such subtleties was observed with mesoisocyano-octaethylporphyrin 10-H265 (Scheme 90).335 Condensation of the free base isocyanoporphyrin336 10-H265 with paraformaldehyde in the presence of a Lewis acid afforded the expected α-hydroxyacetamidoporphyrin 10-H266. On the other hand, the Ni(II) chelate 10-Ni65in the presence or absence of BU


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The route to benzochlorins was applied to a porphyrin dimer wherein the porphyrins were joined by a 4,4′-biphenyl linker.307 Installation of the acrolein moiety afforded the mono- or bissubstituted dyad derivative, where the acrolein group in both cases was adjacent to the biphenyl linker. Cyclization of the monoacrolein dyad (neat TFA or BF3·OEt2/dichloromethane) gave the all-nickel or all-copper benzochlorin−porphyrin dyad 10-71a or 10-71b in 58% or 52% yield (cyclization step only), respectively (Scheme 92). Demetalation with H2S/TFA gave the all-free base dyad 10-71c in 41% yield. Cyclization of the bisacrolein dyad in neat TFA gave the all-nickel benzochlorin− benzochlorin dyad 10-71d in 65% yield (cyclization step only). Similar reaction (BF3·OEt2/dichloromethane) of the bis-acrolein dyad followed by demetalation gave a separable mixture of the all-free base benzochlorin−benzochlorin dyads 10-71e and 1071f. The isomeric multiplicity encountered in the route shown in Scheme 91 can in principle be overcome by preinstalling a

Scheme 91. Conversion of a Monoaryl Porphyrin to Several Benzochlorins

Scheme 92. Benzochlorin Dyads

benzochlorin (analogous to 10-M70a).338 The aryl group was derivatized in the para-position with a linker bearing a maltose group for biological targeting studies (not shown). The absorption spectra of benzochlorins 10-H270a and 10-H270b are shown in Figure 23.

leaving group on the ortho-position of an appended aryl substituent. This approach is satisfactory as long as the porphyrin contains a C2 symmetry axis that encompasses the meso-aryl substituent. Examples of this approach are shown in Scheme 93.339 Each monoaryl-octaalkylporphyrin 10-H272a−c was prepared by the condensation of a biladiene and an aryl aldehyde bearing an o-carbomethoxy group followed by reduction with LiAlH4 or DIBAL−H to form the o-hydroxymethyl substituent. In the presence of very strong acid, the o-hydroxymethylsubstituted aryl group underwent cyclization with one of the two flanking β-pyrrole sites. The resulting annulated product was a naphthochlorin 10-H273a−c rather than a benzochlorin. The

Figure 23. Normalized absorption spectra in dichloromethane of free base benzochlorins 10-H270a (red line) and 10-H270b (orange line).307 BV


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Scheme 93. Directed Formation of a Naphthochlorin

Scheme 94. Formation of All-trans Hexatrienyl-Linked Benzochlorin Dimers

naphthochlorins exhibit a characteristic chlorin-like absorption band at 676 nm (10-H273b,c) or 686 nm (10-H273a), to be compared with 658 nm for octaethylbenzochlorin. The absorption spectra of naphthochlorins 10-H273a and 10H273b are shown in Figure 24.340

Scheme 95. Formation of All-trans Hexatrienyl-Linked Benzochlorin Dimers

Figure 24. Absorption spectra in chloroform/isopropanol (1:1) of naphthochlorins 10-H 273a (red line) and 10-H2 73b (orange line).339,340

10.5. Benzochlorins in Diverse Architectures

The reaction of octaethylbenzochlorin (10-Ni7) with acrolein and POCl3 proceeded to give electrophilic substitution at the open meso-position flanking the pyrroline ring (Scheme 94).301,341 The benzochlorin bears a full complement of βpyrrole substituents, and the benzo moiety occupies one of the meso-positions flanking the pyrroline unit (the 15-position). Studies of electrophilic substitution of β-alkylchlorins by Woodward and Skarić 342 showed that the most reactive sites are those that flank the pyrroline ring. Subsequent studies of a variety of substituted chlorins showed that this reaction-site preference prevails even if all β-pyrrole sites are open.2 Hence, electrophilic substitution at the 20-position (rather than 10- or BW


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15-position) of 10-Ni7 is the expected outcome. The resulting benzochlorin−acrolein (10-Ni74) is a chlorin building block. Reductive coupling afforded in a single-flask reaction the corresponding trans,trans,trans-hexatrienyl-linked chlorin dimer (10-Ni75). The same approach also was applied beginning with transNiOEC (Scheme 95).301 Reaction of trans-NiOEC with acrolein and POCl3 gave the acroleinyl derivative 10-Ni76 but also a small amount (10%) of the dehydrogenated product, the porphyrin 10-Ni6. Reductive coupling afforded the corresponding trans,trans,trans-hexatrienyl-linked chlorin dimer 10-Ni77. Given that the chlorin precursor trans-NiOEC is expected to be racemic, dimer 10-Ni77 is expected to exist as a set of four stereoisomers including two pairs of enantiomers. On the other hand, dimer 10Ni75 is achiral. The absorption spectra of chlorin dimer 10-Ni77 and benzochlorin dimer 10-Ni75 are shown in Figure 25.

Scheme 96. Benzochlorin−Barbituric Acid

Scheme 97. Formation of a Pyrido−Oxochlorin via a Dehydropurpurin Intermediate

Figure 25. Absorption spectra in dichloromethane of benzochlorin dimer 10-Ni75 (red line) and chlorin dimer 10-Ni77 (orange line).301

Other routes to dyads containing one or two benzochlorins have entailed (1) preparation of a porphyrin dimer, (2) introduction of one or more meso-acrolein groups, and (3) cyclization to create the benzochlorin motif.307,312 Examples of the dyads derived by this synthetic approach are displayed in Scheme 92. Such strategies often sacrifice regiocontrol for synthetic simplicity. As part of a program to prepare tetrapyrroles with enhanced absorption in the near-infrared region, Morgan and Robinson prepared a number of porphyrin, chlorin, and bacteriochlorin constructs. A capsule summary of their work through 1990 is available.343 One example of a derivative of the benzochlorin− acrolein 10-Ni74 is shown in Scheme 96.344 Reaction of 10-Ni74 with 1,3-dibutyl-2-thiobarbituric acid in pyrrolidine gave the conjugate 10-Ni78. Demetalation of nickel in sulfuric acid gave the free base species 10-H278. While no experimental procedures or characterization data were provided, the authors stated that 10-Ni78 was obtained in good yield, and that the absorption spectrum shows a strong band at 830 nm with correspondingly little Soret character. The free base analogue 10-H278 displayed a large broad absorption centered at 865 nm. A distinctive route to aza-substituted benzochlorins began with a meso-bromo-diarylporphyrin (10-Zn79, readily obtained by bromination of the porphyrin). Pd-mediated annulation with diphenylacetylene afforded the corresponding dehydropurpurin 10-Zn80 in 79% yield (Scheme 97). On standing with illumination, ring oxidation and scission occurred in quantitative yield to give the dibenzoylporphyrin 10-Zn81. The annulation was found to proceed in excellent yield with the nickel or free BX


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base porphyrin and a variety of diaryl or dialkyl acetylenes, whereas the photooxidation was reported only for the zinc dehydropurpurin.345 A triaryldehydropurpurin was prepared in similar fashion and cleaved to give the dibenzoyl derivative 10Zn82.346 Treatment with ammonium acetate under dehydrative conditions gave the pyrido−oxochlorin 10-Zn83. The keto group underwent reduction to the alcohol 10-Zn84, which on standing reverted to the keto species 10-Zn83. Both the zinc (10Zn83) and free base (10-H283, not shown) pyrido−oxochlorins were found to be photochemically active in an assay for generation of singlet oxygen. The absorption spectra of dehydropurpurin 10-Zn80, porphyrins 10-Zn81 and 10-Zn82, pyrido−oxochlorin 10-Zn83, and pyrido−hydroxychlorin 10Zn84 are shown in Figure 26.

Scheme 98. Formation of Naphthyridochlorins with mesoAza Substitution

Figure 26. Absorption spectra of (1) dehydropurpurin 10-Zn80 (black dotted line) formed in situ from porphyrin 10-Zn81 (black solid line) in chloroform, hence at putative equal concentrations;345 and (2) porphyrin 10-Zn82 (black dotted line, ε = 337 000 M−1 cm−1 at 432 nm), pyrido−oxochlorin 10-Zn83 (red line, ε = 78 400 M−1 cm−1 at 403 nm), and pyrido−hydroxychlorin 10-Zn84 (orange line) all in dichloromethane.346

10-Zn85a was isolated in 30% yield. Removal of the trifluoroacetyl unit from 10-Zn85a with methoxide gave the zinc N-phenylporphyrin 10-Zn86a. Demetalation with aqueous acid gave the free base porphyrin 10-H286a. The latter was treated to standard conditions for iron insertion [FeCl2·4H2O in methanolic chloroform], which at room temperature afforded the expected ferric porphyrin 10-Fe86a as well as the free base fused chlorin 10-H287a, both in 25% yield. The fused chlorin 10H287a can be regarded as an aza-substituted naphthochlorin, a benzo-annulated pyridochlorin, or a naphthyridochlorin; regardless of terminology, the aniline moiety of the starting material Ntrifluoroacetamidoaniline constitutes an integral part of the expanded π-system. When the iron insertion reaction was carried out under refluxing conditions, the fused chlorin as the ferric chelate, 10-Fe87a, was isolated in 75% yield (Scheme 98). The change in product outcome due to temperature of metalation

ZnOEP readily undergoes oxidation to give the porphyrin πcation radical, which is susceptible to nucleophilic attack at the meso-positions.347 A typical oxidant is tris(4-bromophenyl)aminium hexachloroantimonate.348 This well-established chemistry has been exploited to introduce an N-(aryl)trifluoroacetamido group at the porphyrin meso-position (Scheme 98−Scheme 100).349 Thus, treatment of the green solution of the porphyrin cation radical ZnOEP+ with the sodium salt of N-trifluoroacetamidoaniline caused immediate discharge of the green solution (characteristic of the oxidized zinc porphyrin) with reversion to the purple solution (characteristic of the neutral porphyrin); after 3 h further, zinc porphyrin BY


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The same route was attempted with use of the Ntrifluoroacetamido derivative of 1-pyrene (not shown). In this case, the meso-amido adduct (counterpart of zinc porphyrins 10Zn85a,b) could not be obtained. Accordingly, 1-(2,4dinitrobenzenesulfonamide)pyrene was used in lieu of the analogous 5-N-(1-pyrenyl)trifluoroacetamide. Thus, reaction of the sodium salt of 1-(2,4-dinitrobenzenesulfonamide)pyrene with the porphyrin cation radical ZnOEP+ upon aqueous acidic workup gave the corresponding pyrene-annulated free base chlorin 10-H287c, albeit in the low yield of 5% (Scheme 100).

was quite remarkable. Note that attempts to carry out the same reaction sequence with the acetamide (rather than trifluoroacetamide) led to the meso-N-phenyl-N-acetamido counterpart of 10-Zn85a, but subsequent cleavage of the acetamido unit proved difficult under a variety of reaction conditions.349 The same route was applied with use of the Ntrifluoroacetamido derivative of fluoranthrene (Scheme 99). Scheme 99. Formation of Fluoroanthreno-Annulated Pyridochlorins

Scheme 100. Formation of Pyreno-Annulated Pyridochlorins

Treatment to iron insertion conditions with ferrous chloride for 6 min at reflux gave the corresponding ferric chelate of the pyrene-annulated chlorin 10-Fe87c.349 The fused chlorins 10H287c and 10-Fe87c can be regarded as pyreno-annulated pyridochlorins. In summary, the present route enables facile preparation of aza-substituted naphthochlorins and analogous aza-substituted arenochlorins, where in each case the nitrogen atom is located at the chlorin meso-position (151-position) flanking the pyrroline ring. The annulated pyridochlorins shown in Schemes 98−100 thus differ from pyridochlorin 10-Zn83 (Scheme 97), where the nitrogen atom is located at the 152position. The absorption spectra of 10-H287a, 10-H287b, and 10-H287c are shown in Figure 27. Strategies for expansion of the tetrapyrrole π-system have been of longstanding interest, as exemplified by the routes to benzochlorins in general and by the annulated chlorins shown in Schemes 93 and 98−100. Yet another approach begins with a β-formylporphyrin (Scheme 101). The β-formylporphyrin can be converted to the corresponding vinylporphyrin via Wittig methenylation (e.g., from 10-Ni22).350 The presence of a β-vinyl group flanking a meso-aryl group enables a ring-closure process. Thus, treatment of the β-vinyl meso-tetraarylporphyrin 10Ni88a,b to dilute sulfuric acid afforded the corresponding naphthochlorin 10-Ni89a,b in good yield (Scheme 101).351 The

Thus, the N-fluoranthrenyl-N-trifluoroacetamido zinc porphyrin 10-Zn85b was isolated in 30% yield and subsequently treated with sodium methoxide to remove the trifluoroacetyl group, affording zinc N-fluoranthrenylporphyrin 10-Zn86b. Demetalation resulted in formation of the corresponding free base porphyrin 10-H286b as well as the free base fused chlorin 10H287b in a 2:1 ratio, respectively. Treatment of free base porphyrin 10-H286b to metalation with ferrous sulfate in refluxing methanolic chloroform afforded the ferric chelate of the fused chlorin 10-Fe87b in 70% yield.349 Here, the fused chlorins 10-H 2 87b and 10-Fe87b can be regarded as pyridochlorins annulated with a fluoroanthreno unit. BZ


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Scheme 102. Oxidative Dimerization of a Naphthochlorin

Figure 27. Absorption spectra in methanol of 10-H287a (orange line), 10-H287b (lavender line), and 10-H287c (red line).349 (The reported molar absorption coefficient value appears to have been in error by a factor of 10; the correct value is employed here.)

Scheme 101. Formation of Naphthochlorins

porphinyl π-systems. Together, the latter are akin to a double allylic or benzylic system at the chlorin 18-position. Callot and co-workers developed a route to gem-dialkylchlorins that bear an expanded π-system.353,354 The route is shown in Scheme 103. Treatment of a meso-tetraarylporphyrin (10-Ni94, 10-Pd94) with benzoic anhydride in the presence of SnCl4 afforded the corresponding β-benzoylporphyrin (10Ni95, 10-Pd95). Subsequent oxidation in the presence of acid led to isomerization of the initial tertiary alcohol to the secondary alcohol (see inset in Scheme 103); the secondary alcohol was then oxidized to give the ketone. In early studies, the reaction produced a variety of annulated species, including a corrole (15%), lactone (7%), and the ketone (23%) (or even a spirolinked porphyrin dimer355);354 the structures are not shown here. The conditions were subsequently refined such that the ketone (10-Ni95, 10-Pd95) could be obtained in 80% yield.353 The availability of the ketone in high yield and one step from simple porphyrins enabled investigation of derivatization reactions. A double-Reformatsky reaction of 10-Ni95 with methyl αbromoacetate or ethyl α-bromoacetate led to the gemdialkylchlorin 10-Ni96a,b in 40 or 48% yield, respectively.353 Similar reaction also was accomplished with the palladium chelate (10-Pd95) or free base (10-H295), albeit in lower yield to give the palladium chelate 10-Pd96a (24%) or zinc chelate (10-Zn96a). When the Reformatsky reaction was carried out at −78 °C, a single addition occurred to form the hydroxy−ester 10-Ni97 in nearly quantitative yield. The long-wavelength absorption band for each gem-dialkylchlorin appears as follows:

naphthochlorin derived from NiTPP (10-Ni89a, R = H) exhibits the long-wavelength absorption band at 670 nm. Smith and co-workers, upon carrying out the reaction of nitrotetraphenylporphyrin 10-Ni90 with tert-butyl isocyanoacetate in a route to β-fused pyrroloporphyrin 10-Ni91, obtained naphthochlorin 10-Ni92 as a byproduct (Scheme 102).352 Upon attempted crystallization of naphthochlorin 10-Ni92 on standing in air, the corresponding dimer 10-Ni93 was isolated instead. Single-crystal X-ray analysis clearly showed the R, S stereochemistry at the β−β′ bond (as well as ruffling of the macrocycles; in the absence of ruffling, the structure is formally a meso compound). The susceptibility of the nonaromatic βcarbon to oxidation is attributed to the stabilization of the resulting methylene radical by the adjacent phenacrylate and CA


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Scheme 103. Formation of Gem-Dialkylchlorins

10-H296a, 686 nm; 10-Zn96a, 670 nm; 10-Ni96a, 668 nm; and 10-Pd96a, 648 nm. The Callot synthesis appears to be a very concise route, comparable to that for the formation of oxochlorins from octaalkylporphyrins, for gaining access to gem-dialkylchlorins from abundant porphyrins. This route complements de novo routes to gem-dialkylchlorins, where the gem-dialkyl unit is installed in acyclic precursors to the chlorin (Scheme 3).2 The absorption spectra of 10-Pd95 and 10-Pd96a are shown in Figure 28. The observation of a corrole during early studies of the reaction processes shown in Scheme 103 suggests a short digression for clarity. A corrole is an aromatic macrocycle containing a 1,19-ring junction (i.e., a direct carbon−carbon bond between the respective α-positions of rings A and D). Corroles were first studied as synthetically accessible analogues of a corrin, which constitutes the core ligand of cobyrinic acid and derivatives (e.g., cobalamin). Corroles have since taken on a life of their own given their utility as a ligand.356,357 The counterpart to a corrole is an A,B,C,D-octadehydrocorrin, which is a fully unsaturated (but not aromatic) analogue of the corrin. The conversion of an A,B,C,D-octadehydrocorrin to a corrin requires an 8e−, 8H+ reduction (Scheme 104).358 Each of the discrete intermediateshexadehydrocorrin, tetradehydrocorrin, and didehydrocorrinhas multiple isomers depending on the position of saturation/unsaturation and nature of the stereochemistry of substituents. The physicochemical properties of

Figure 28. Absorption spectra in benzene of 10-Pd95 (red line) and 10Pd96a (orange line).353

such intermediates along the path of reductive transformation from corroles to corrins have hardly been explored, due chiefly to undeveloped synthetic access. When a mixed condensation of pyrrole, benzaldehyde, and acenaphthenequinone was carried out under conditions resembling those for sterically hindered aldehydes,47,359,360 the resulting porphyrin 10-H298 was obtained (Scheme 105).361 The standard conditions entailed use of BF3·OEt2 in a chlorinated solvent (e.g., CHCl3) containing ethanol. While CB


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Scheme 104. Corrole and Corrin Macrocyclesa

larger quantity of ethanol (7%). The identical condensation in CHCl3 lacking ethanol afforded a much different product distribution composed of the porphyrin−chlorin dyad 10H299a and the porphyrin 10-H2100a.362 Nearly identical results were observed upon replacement of benzaldehyde with ptolualdehyde, affording 10-H299b and 10-H2100b. While the mechanistic origin of the change in reaction course is not known, the products 10-H299 and 10-H2100 are quite intriguing. The ring fusion results in a 7-membered annulated ring for products 10-H299 and 10-H2100. In the dyad, the linker joining the two macrocycles is a carbon−carbon single bond and is attached to βpositions on both the porphyrin and the chlorin; for the chlorin, the linker is attached to the pyrroline ring. The ring fusion in the chlorin constituent of 10-H299a,b results in adjacent sp3-carbons wherein the configuration is transoid; as both carbons are stereocenters, the product consists of a pair of enantiomers. 10.6. Oxazinochlorins

Chlorins with fused exocycles have been prepared by cyclization with a variety of appended groups. Whereas an acrolein group gives a purpurin or benzochlorin, an unusual outcome was observed upon conversion of the porphyrin−acrolein 10-Ni6 to the oxime derivative 10-Ni101. Thus, the oxime 10-Ni101 (syn:anti isomeric mixture 3:2 or 2:3) was subjected to oxidation with Pb(OAc)4 in the presence of triethylamine to give the chlorin 10-Ni102 bearing a 1,2-oxazocine ring and an 18ethylidene group (Scheme 106).363 Four stereoisomers are possible given the stereocenter at position 17 and the adjacent ethylidene group. This unusual chemistry adds to a menagerie of structurally diverse chlorins that are readily accessible from octaethylporphyrin. Related oxazine chemistry is shown in Scheme 107.364 The oxime derived from meso-formyl octaethylporphyrin 10-Zn103 upon treatment to phase-transfer conditions in air followed by acidic workup gave the oxazinochlorin 10-H2104. Treatment of the latter with DBU gave the meso-cyano vicinal-dihydroxyoctaethylchlorin 10-H2105. On the other hand, nickel insertion to 10-H2104 in hot DMF gave the expected nickel chelate 10Ni104 in 71% yeld, accompanied by elimination to give isomers 10-Ni106(Z) and 10-Ni106(E), each with an exocyclic

a

Adapted from ref 358 with permission from the Centre National de la Recherche Scientifique (CNRS) and the Royal Society of Chemistry.

ethanol has traditionally been added to stabilize such solvents, the interaction of BF3·OEt2 and ethanol affords novel catalysis of the reaction. The amount of ethanol present typically is ∼0.75%, which is substantial on consideration of molarity (0.13 M)359 and often far exceeds the concentration of the ostensible added catalyst. The identification of the BF3−ethanol cocatalysis conditions, while serendipitous,47 proved broadly applicable for gaining access to porphyrins bearing diverse 2-substituted and 2,6-disubstituted aryl groups at the meso-positions.359,360 The condensation leading to porphyrin 10-H298 employed a much Scheme 105. Inadvertent Chlorin−Porphyrin Dyad Synthesis

CC


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Scheme 106. Chlorin with a Fused Oxazocine Ring

Scheme 107. Chemistry of Chlorins with Fused Oxazocine Ringsa

a

Stereochemistry assumed (but not proved) to be syn in all cases as shown.

ethylidene group. The reaction of 10-Ni104 with n-Bu4NOH in dichloromethane gave 10-Ni105, the nickel chelate of 10-H2105.

Nickel ethylidene−oxazinochlorin 10-Ni106(Z) under similar conditions gave the corresponding meso-cyano−chlorin 10CD


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Scheme 108. Chemistry of Chlorins with Fused Oxazocine Ringsa

a

Stereochemistry assumed (but not necessarily proved) to be syn in all cases as shown.

5% TFA in dichloromethane gave a putative carbocation intermediate, which was trapped upon addition of a nucleophile. The strong nucleophile methylamine gave the methylaminosubstituted oxazinochlorin 10-Ni109, whereas the weaker nucleophile cyanide gave a small amount of the cyanosubstituted product 10-Ni110 and a large amount of the mesocyano−oxochlorin 10-Ni111 derived from pinacol−pinacolonelike rearrangement. Attempts to trap the putative carbocation intermediate upon addition of methanol gave the oxochlorin 10Ni111 in nearly quantitative yield. Exposure of nickel chlorin 10Ni105 to the same conditions of TFA in dichloromethane gave the exo-ethylidene-substituted chlorin isomers 10-Ni107(E) and Ni107(Z) as well as a small amount of the meso-cyano− oxochlorin 10-Ni111 (Scheme 108, middle panel). In each of these cases, the presence of the oxazine ring or meso-cyano group

Ni107(Z) accompanied by a trace amount of the vinyl− porphyrin 10-Ni108. On the other hand, in the presence of DBU, 10-Ni106(Z) gave the corresponding meso-cyano− chlorin isomers 10-Ni107(Z) and 10-Ni107(E). Finally, a direct path to the exo-ethylidene−oxazinochlorin entailed treatment of the nickel oxime−chlorin 10-Ni103 to lead acetate in the presence of triethylamine. The two exo-ethylidene−oxazinochlorin isomers 10-Ni106(Z) and 10-Ni106(E) were obtained in a total yield of 77% (bottom panel).364 In all cases shown in Scheme 107, the stereochemistry is assumed to be syn, in which case each compound is racemic. The reaction of nickel oxazinochlorin 10-Ni104 with DBU gave the meso-cyano vicinal-dihydroxyoctaethylchlorin 10Ni105, the nickel chelate of 10-H2105, in 91% yield (Scheme 108, top panel).364 On the other hand, treatment of 10-Ni104 to CE


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caused protonation and putative carbocation formation to proceed at the nonadjacent β-pyrroline carbon, in turn controlling (1) the site of nucleophile attack giving 10-Ni109− 111, (2) the migration of the ethyl group in pinacol−pinacolonelike rearrangement giving 10-Ni111, and (3) β-alkyl proton loss giving Ni107(E) and Ni107(Z). NOESY experiments showed 10-Ni109 to exist as a syn isomer, indicating stereoselective formation (and a racemic product). Further insights concerning the site of attack directed by mesosubstituents were obtained with zinc porphyrin 10-Zn112, which contains cyano and oxime groups at flanking meso-positions (Scheme 108, bottom panel).364 Treatment with phase-transfer conditions followed by acidic workup gave the oxazinochlorin 10-H2113 wherein exocyclic ring formation occurred at the pyrrole located away from the meso-cyano group. Exposure of 10-H2113 to DBU gave ring opening to yield the 15,20-dicyano17,18-dihydroxyoctaethylchlorin 10-H2114. This and the prior section have concerned benzochlorins, purpurins, and diverse analogues. In both general classes of benzochlorins and purpurins, an exocyclic ring spans the pyrroline β-position and the flanking meso-position. We now turn to consider a general class of chlorins derived by cycloaddition with a vinyl group attached to a porphyrin. The following section has some parallels with section 7, which concerns conversion of heme to gem-dialkylchlorins, but is far broader and also is a necessary prelude to discussion of diverse cycloadditions with porphyrins to create chlorins.

Scheme 109. Formation of Photoprotoporphyrin IX Isomers

11. CYCLOADDITIONS WITH β-VINYLPORPHYRINS Studies concerning cycloadditions to porphyrins are numerous and bear in part on the topic of tetrapyrrole macrocycles containing fused exocyclic rings. Aspects of these topics have been reviewed previously, and the reader is referred to these more focused reviews.365−369 The following sections provide a broad review of cycloaddition routes that give rise to chlorins.

Scheme 110. Mechanism of Photoprotoporphyrin Formation

11.1. Reaction with O2: Photoprotoporphyrin IX

Inhoffen and co-workers illuminated protoporphyrin IX with white light in the presence of air whereupon the two “photoprotoporphyrin IX” isomers 11-H21a and 11-H21b were formed (Scheme 109, top panel).370 Their work followed a report of Fischer some 30 years earlier concerning the effects of light on porphyrins. The reaction is believed to proceed by [2 + 4] cycloaddition of 1O2 (generated by energy transfer from the porphyrin triplet excited state to 3O2, the ground-state of dioxygen) with the diene comprised of the vinyl group and the adjacent pyrrolic β,β′-double bond to form the dihydro-1,2dioxine intermediate.371 In other words, the reaction does not entail a classical photocycloaddition but rather a photosensitized generation of a reactive intermediate (1O2) that can undergo a [2 + 4] thermal cycloaddition. Subsequent scission of the peroxo bond and rearrangement gives the chlorin product wherein the pyrrolinic ring contains a hydroxy group and a methyl group at one of the β-carbons (shown here at position 18), and an exo formylmethylidene group at the β′ carbon (position 17 here) (Scheme 110). The reaction proceeded cleanly and in yields of ≥70% for the two positional isomers,370−372 which could be separated by chromatography.370 Monoderivatization has been attributed to the electron-withdrawing effect of the formylmethylidene group, which deactivates the macrocycle toward oxidation.373 Kinetic studies of a family of vinyl porphyrins have revealed a slight decrease in rate with increased electron-

withdrawing effect of porphyrin substituents.374 Note that each positional isomer is expected to form as a racemic mixture. The spectral changes upon illumination of protoporphyrin IX in an aerobic medium are shown in Figure 29.375 The reaction was carried out with the porphyrin in N,N-dimethylacetamide that was saturated with oxygen. The clean isosbestic points across the spectrum show the conversion from porphyrin (protoporphyrin IX) to chlorin (i.e., photoprotoporphyrin IX). The source of the longer-wavelength absorption seen growing in at ∼730 nm is not known. The reaction is not restricted to protoporphyrin IX but takes place with a variety of vinyl−porphyrins,371 although porphyrins with electron-withdrawing substituents undergo reaction more slowly.374 Indeed, the formyl-desvinylprotoporphyrin IX reacted CF


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Review

Scheme 111. Transformations of Photoprotoporphyrin IX Isomers

Figure 29. Spectral changes upon illumination of protoporphyrin IX (blue line) in O2-saturated N,N-dimethylacetamide leading to photoprotoporphyrin IX (red line), at arbitrary scale. The red arrows indicate the growing-in of the bands of the chlorin photoprotoporphyrin IX; the blue arrows the disappearance of those of protoporphyrin IX.375 Adapted from ref 375. Copyright 1994, with permission from the Society of Photographic Instrumentation Engineers (SPIE) and coauthor Dr. Christine Vever-Bizet.

with ∼1/10th the efficacy as the parent protoporphyrin IX.372 A cleaner reaction occurs, of course, with a starting macrocycle that contains a single vinyl group. Partial hydrogenation of protoporphyrin IX affords the mixture of monoethyl, monovinyl products, termed ethylvinyl deuteroporphyrin. Thus, ethylvinyl deuteroporphyrin is a mixture of positional isomers wherein each macrocycle contains a single vinyl group. One such member, 11H22, is shown in Scheme 109, bottom panel. Upon photooxygenation, the resulting product 11-H23 (presumed pair of enantiomers for each positional isomer) exhibits a chlorin-like absorption band in the red region of the spectrum.371 The absorption spectrum of 11-H23 is shown in Figure 30.

oxygenation constitutes an intermediate in a net transformation of one of the two vinyl groups of protoporphyrin IX to a formyl group. Nakae and co-workers treated the mixture of photoprotoporphyrin IX isomers 11-H21a,b with hydroxylamine to obtain the corresponding mixture of oximes in quantitative fashion. A similar reaction was carried out with a variety of aminecontaining reactants (e.g., semicarbazide) or active methylene compounds (e.g., nitropropane) to obtain the aldehyde derivatives. The entire collection of such derivatives, 11H26a,b(i-xi), is shown in Scheme 112.378 The propionic acid groups of the photoprotoporphyrin IX oximes also could be amidated with aspartic acid via a carbodiimide-mediated coupling (without transamination at the oxime site) to give the products 11-H27a and 11-H27b (Scheme 113).378 Tai and co-workers significantly extended this derivatization approach, beginning with one of the photoprotoporphyrin IX positional isomers, to create a family of chlorins for use in photomedicine and radiomedicine.379−381 Representative members are shown in Schemes 114 and 115. A distinguishing feature is that the syntheses employed a single positional isomer of photoprotoporphyrin IX (11-H21a). Thus, chlorin 11-H28a was

Figure 30. Absorption spectrum of 11-H23 in N,N-dimethylacetamide.371

Each of the photoprotoporphyrin IX isomers was further elaborated as the dimethyl ester analogue (11-H24a, 11-H24b). Reduction of the aldehyde to the alcohol, rearrangement in aqueous acid, and oxidation with periodate afforded the formyl/ des-vinyl protoporphyrin IX analogues 11-H25a and 11-H25b known as spirographis porphyrin and isospirographis porphyrin, respectively (Scheme 111).370,376 Spirographis porphyrin, also known as chlorocruoroporphyrin, as the iron chelate constitutes the heme employed for oxygen transport in polychaete worms (e.g., Spirographis spallanzanii) indigenous to the Mediterranean.377 In such elaborations, the chlorin derived by photoCG


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Review

Scheme 112. Derivatives of Photoprotoporphyrin IX

Scheme 113. Amidation of Photoprotoporphyrin IX Derivatives

prepared by reaction of 11-H21a with O-ethylhydroxylamine, EDC-mediated amidation with dimethyl iminodiacetate, and saponification of the methyl esters. Chlorin 11-H29a was prepared by conversion of 11-H21a to the bis-iminodiacetate amide bearing the oxime substituent. Elaboration at the Nhydroxy group installed a tether bearing a terminal αbromoacetamide group, to which a mercaptoundecahydrocloso-dodecaborate (BSH) unit was conjugated. Similar chemistry enabled preparation of chlorin 11-H210a (Scheme 114). The routes to chlorins 11-H211a and 11-H212a were also quite similar, here using the boron-neutron capture agent L-4boronophenylalanine containing 10B rather than BSH (Scheme 115). Robinson and Morgan treated the photoprotoporphyrin IX dimethyl ester isomers with 1,3-dibutyl-2-thiobarbituric acid in the presence of pyrrolidine, as is shown for 11-H24a in Scheme 116.344 The resulting chlorin−barbituric acid conjugate 11H213a exhibited an absorption spectrum with a pronounced broad, long-wavelength absorption band. Experimental procedures and characterization data were not provided. The spectrum is shown in Figure 31, along with that of a porphyrin that bears a similar substituent (11-Ni4). While the spectral comparison is not as well-matched as one might like, given that the porphyrin is a nickel chelate and the conjugated barbituric acid is attached at the meso-position (versus free base and β-pyrroline attachment for 11-H213a), the nickel porphyrin also exhibits a strong longwavelength absorption band. Further study would appear to be required to identify the origin of the various spectral features in the two types (porphyrin, chlorin) of tetrapyrrole macrocycles. A further simplification in photoporphyrin formation was realized upon conversion of H2OEP via the intermediacy of the dihydroxychlorin 11-H215 to heptaethylvinylporphyrin 11H216 (Scheme 117, top panel). An early, small-scale method employed benzoyl peroxide at elevated temperature to give the α-benzyloxy derivative of H2OEP (12%) followed by thermolysis

(250−260 °C) to give the β-vinylheptaethylporphyrin 11-H216 (65%; route not shown).382 Alternatively, treatment of the dihydroxychlorin 11-H215 (derived in the standard way from H2OEP and OsO4) in hot acidified benzene gave 11-H216 and octaethyloxochlorin 11-H217 in reasonable yield.383 A serendipitous finding was that merely heating 11-H215 at 140 °C would give 11-H216 in >70% yield.383 A refined method relied on treatment of H2OEP with HBr/ AcOH and NBS to give the α-ethoxyoctaethylporphyrin 11H218, which upon heating in solid form gave 11-H216 in high yield and in nearly 100-mg quantity (Scheme 117, bottom panel).384 Photooxygenation of 11-H216 with 1O2 gave the corresponding chlorin, 11-H219,385 in 57% yield.383 The isomeric purity of 11-H219 (racemic, but no positional isomers as for photoprotoporphyrin IX) is a significant attraction, and 11H219 has been used for conjugation with oligonucleotides to give light-activated nucleases.386,387 The photoporphyrin 11-H219 was reduced to give the chlorin−alcohol 11-H220 (racemic), which upon treatment to Mitsunobu conditions gave oxochlorin 11-H221a (racemic) and chlorin−epoxide 11-H221b (racemic).383 The symmetric divinylporphyrin 11-H222, prepared by selfcondensation of a synthetic dipyrrin, was treated to conditions CH


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Review

Scheme 115. 10B-Containing Derivatives of Photoprotoporphyrin IX

Scheme 114. Derivatives of Photoprotoporphyrin IX

intermediates in the synthesis of analogues of proposed sulfheme compounds. The proposed structures for sulfheme-A, sulfhemeB and sulfheme-C are shown in Scheme 119.383 The structures are clinically relevant:383 “sulfhemoglobin (SHb) and sulfmyoglobin (SMb) are heme proteins in which the heme prosthetic group has been altered by modification of a pyrrole subunit and incorporation of a sulfur atom into the porphyrin macrocycle. SHb is of considerable medical interest because it is formed in vivo under certain pathological conditions, particularly those in which a sulfide source is present or in which there is blood poisoning by certain reducing agents··· The reducing agents serve as catalysts, while the sulfide source is endogenous, probably H2S from intestinal bacteria”. The resulting green pigments were first noted in 1866, and structures proposed to account for the green pigments were put forth over a century later, in 1986.389 The three structures (unknown stereochemistry) are regarded as isoforms with distinct chemical properties including reactivity and stability. Sulfmyoglobin SMbA may be a precursor to SMb-B and SMb-C, but once formed, the latter do not revert to SMb-A.390 Iakovides and Smith embarked on syntheses of oxa analogues of sulfheme-A and sulfheme-C (Scheme 120).383 The photoconversion of pemptoporphyrin dimethyl ester (11-H225), a desvinyl analogue of protoporphyrin IX dimethyl ester, afforded the corresponding photopemptoporphyrin 11-H226. Reduction of the latter gave the alcohol 11-H227, which upon conversion to

for aerobic photooxygenation (Scheme 118).388 The resulting formylmethylidene−chlorin 11-H223 was then metalated to give the copper chelate 11-Cu23. The latter was reacted with an amine (n-butylamine, pyrrolidine) to give the corresponding chlorin−imine (11-Cu24a, 11-Cu24b) or with an active methylene compound (malonitrile, ethyl cyanoacetate) to give the corresponding cyanovinyl-substituted chlorin 11-Cu24c or 11-Cu24d. The imines can undergo protonation, which provides one means for altering the electronic contribution of the conjugated formylmethylidene unit to the chlorin π-system. All chlorins shown in Scheme 118 are expected to be racemic. The absorption spectra of 11-Cu23 and 11-Cu24a as well as those of malononitrile adduct 11-Cu24c and cyanoacetate adduct 11Cu24d are shown in Figure 32. 11.1.1. Sulfheme Analogues via Photoprotoporphyrins. Photoprotoporphyrins also were employed as key CI


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Review

alcohol 11-H230, from which chlorin 11-H231 bearing an annulated dihydrofuran ring was formed albeit in quite low yield (4%) in the final step. In search of milder methods for the overall transformation, the alcohol 11-H230 was dehydrated under Mitsunobu conditions to give the oxochlorin−alcohol 11-H232 and the chlorin−epoxide− alcohol 11-H233 (Scheme 120, bottom panel). The chlorin− epoxide may represent the first compound of its kind. The chlorin 11-H231 bearing an annulated dihydrofuran ring is a homologue of sulfheme-C whereas chlorin−epoxide 11-H233 is a homologue of sulfheme-A, as shown by comparing the structures in Schemes 119 and 120.383 Mechanisms for the formation of the various pyrroline ring structures have been proposed.383,391 The chlorin−epoxide 11-H233 on stirring in the presence of neutral alumina rearranged to chlorin 11-H231 in 40% yield. The absorption spectra of 11-H231 and chlorin− epoxide 11-H233 are shown in Figure 33. The identification of a green, sulfur derivative of myoglobin prompted a number of synthetic investigations in addition to the aforementioned studies with photoprotoporphyrins. One early study to examine possible structures that might account for the green pigment in sulfmyoglobin was carried out by Balch and coworkers, who prepared a thio analogue of an oxochlorin.392 Thus, octaethyloxochlorin 11-H217 was treated with Lawesson’s reagent to afford the bright green thiochlorin 11-H234 in 22% yield following chromatography and crystallization (Scheme 121). The absorption spectra of 11-H217 and 11-H234 are shown in Figure 34. The spectrum of thiochlorin 11-H234 is profoundly different from that of oxochlorin 11-H217, where the bands of 11-H234 are broader and less intense than those of 11H217. 11.1.2. Aza Analogues of Photoprotoporphyrins. Gerlach and Montforts extended their studies of semisynthesis from readily available porphyrins by constructing azachlorins (Scheme 122).256 Heme was converted to bilirubin-IXα, which was oxidized with FeCl3 in hot acid followed by methylation to give biliverdin-IXα dimethyl ester. Zincation of the latter followed by very brief exposure to acetic anhydride gave the zinc oxaporphyrin 11-Zn35.393 The oxaporphyrin 11-Zn35 in the presence of ammonia gave the aminobiliverdin 11-Zn36, which was then cyclized using the condensing agent trimethylsilyl polyphosphate (PPSE) to give the free base azaporphyrin 11-H237.256 Phototransformation of the latter in the presence of air afforded the azachlorins 11-H238 and 11H239 (mixture of E/Z diastereomers) and 11-H240.256 The azachlorins (11-H238−40) are quite sensitive to acid, whereupon rearrangements occur (Scheme 123). Thus, the mixture of 11-H238 and 11-H239 was reduced (converting the aldehyde to the alcohol) to give the corresponding diols, which upon exposure to aqueous acid under allylic rearrangement gave a single porphyrin−glycol (not shown). The latter was cleaved in situ with NaIO4 to give the azaporphyrin−aldehyde 11-H241. Reduction of the aldehyde in 11-H241 to the (allylic) alcohol followed by amide−acetal Claisen rearrangement gave the corresponding azachlorin 11-H242.256 Again, the azachlorins shown here are ultimately derived from the abundant blood pigment, heme. To our knowledge, azachlorins (and other coremodified tetrapyrrole macrocycles) are non-natural entities regardless of the composition and position of the peripheral substituents.

Scheme 116. Barbituric Conjugates of Tetrapyrroles

Figure 31. Absorption spectra in dichloromethane of chlorin−barbituric acid 11-H213a (red line) and octaethylporphyrin−barbituric acid 11Ni14 (black dotted line).344

the p-tosylate 11-H228 resulted in cyclization to form the chlorin 11-H229 bearing an annulated dihydrofuran ring. Photoporphyrin IX dimethyl ester 11-H24b was subjected to the same transformation, including formation of the intermediate CJ


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Scheme 117. Chlorin−Aldehyde Derived from Octaethylporphyrin

Scheme 118. Elaboration of Photoporphyrins

CK


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11.2. Reactions with Carbon Dienophiles

Protoporphyrin IX was further investigated as a diene in cycloaddition reactions with electron-deficient alkenes or alkynes. The diene is comprised of one of the β-vinyl groups and the adjacent β,β′-double bond; saturation of the latter upon cycloaddition affords the chlorin. The first studies were carried out by Johnson and co-workers (including Grigg and Callot)394,395 and were subsequently pursued in-depth by Dolphin and co-workers.396−398 The presence of two distinct vinyl groups led to multiple products even if only a single vinyl group underwent reaction. The products are shown in Scheme 124 (multiple stereoisomers of each are expected to be formed). The key observations are as follows:398 (1) Reaction of porphyrin 11-H243, the di-tert-butyl ester of protoporphyrin IX, with 4 equiv of 1,1,2,2-tetracyanoethylene (TCNE) in chloroform at room temperature for 4 h afforded the bis[2 + 2] adduct 11-H244, a quite insoluble porphyrin, in 45% yield, as a mixture of four stereoisomers. The filtrate contained the mixed [2 + 2]/[4 + 2] adducts 11-H245 and 11-H246, each of which is a chlorin. Chlorins 11-H245 and 11-H246 are positional isomers and each is a presumed mixture of four stereoisomers. (2) Reaction of porphyrin 11-H243 with 6 equiv of TCNE in refluxing chloroform for 4 h afforded the following macrocycles: (i) the bis[2 + 2] porphyrin adduct 11H244; (ii) the mixed [2 + 2]/[4 + 2] chlorin adducts 11H245 and 11-H246 in a total of 55% yield; and (iii) bis[4 + 2] isobacteriochlorin adduct 11-H247 (13% yield). (3) Reaction of porphyrin 11-H243 with 1 equiv of TCNE in refluxing chloroform for 2 h afforded mono[4 + 2] chlorin adducts 11-H248 and 11-H249 in a total of 49% yield. Chlorins 11-H248 and 11-H249 are positional isomers, and each is presumably racemic. (4) When the mono[2 + 2] adducts of porphyrin 11-H243 (not shown) in chloroform at room temperature were allowed to stand overnight, the two corresponding mono[4 + 2] adducts, chlorins 11-H248 and 11-H249, were formed. Together with other data, these results suggest the [2 + 2] cycloaddition is kinetically favored whereas the [4 + 2] cycloaddition is thermodynamically favored. (5) Rearrangement of the mixed [2 + 2]/[4 + 2] chlorin adducts 11-H245 and 11-H246 to give the bis[4 + 2] isobacteriochlorin adduct 11-H247 competed unfavorably with a retro-[2 + 2] process, expelling TCNE to give chlorins 11-H248 and 11-H249. (6) The absorption spectrum of chlorin 11-H248 or 11-H249 is shown in Figure 35, clearly displaying the enhanced long-wavelength absorption band characteristic of a chlorin versus that of a porphyrin. Morgan and Kohli examined the reaction of protoporphyrin IX dimethyl ester 11-H250 with aza dienophiles as shown in Scheme 125.399 Urazines constituted one type of aza dienophile. The urazines were derived by treatment of the corresponding urazoles with tert-butyl hypochlorite and used in situ with the porphyrin at room temperature. Four types of chlorin products (ignoring stereochemistry) were obtained: [4 + 2] cycloaddition at either one of the two distinct vinyl groups accounted for two products (11-H251a, 11-H251b), and further [2 + 2] cycloaddition at the other vinyl group accounted for the remaining two products (11-H252a, 11-H252b). The capital letters A and B

Figure 32. Absorption spectra of (1) 11-Cu23 in THF (red solid line) or dichloromethane (red dotted line) and 11-Cu24a in THF (orange solid line) or dichloromethane (orange dotted line); (2) malononitrile adduct 11-Cu24c (red line) and cyanoacetate adduct 11-Cu24d (orange line) in THF.388

Scheme 119. Proposed Structures for Sulfhemes-A, -B, and -C

CL


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Scheme 120. Oxa Analogues of Green Sulfhemes-A and -C

Uchoa and co-workers recently carried out cycloaddition reactions of N-substituted maleimides with protoporphyrin IX diesters.400,401 The reaction required elevated temperature (120−125 °C) for a prolonged period (12−24 h) despite the use of multiple equivalents of the maleimide. The reaction afforded the cis-endo-adducts 11-H253, which are attractive in preventing the aggregation of the chlorins. The maleimide substituents included aryl and octyl groups (Table 17). In each case, the two positional isomers (due to the distinct vinyl groups)

shown in the scheme refer to the rings where the cycloaddition has occurred. The effects of the R group in the urazine dienophiles are shown in Table 16.399 Issues of stereochemistry were not addressed; regardless, 11-H251a and 11-H251b are each expected to be racemic, whereas 11-H252a and 11-H252b are each expected as a set of four stereoisomers. Two aza dienophiles that did not afford reaction include 3,6-pyridazinedione and di-tert-butyl azodicarboxylate (shown in the inset of Scheme 125). CM


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(not shown). The absorption spectrum of one such adduct is shown in Figure 36. A modification to the maleimide approach was developed that relied on reaction with maleic anhydride followed by reaction of the resulting adduct with a nucleophile.402 The reaction of protoporphyrin IX dimethyl ester 11-H250 with maleic anhydride afforded the two cis-endo adducts, as expected. The mixture containing the two cycloaddition products, each of which contains an anhydride, is shown in brackets in the diagram that accompanies Table 18. The mixture was treated with a nucleophile to open the anhydride ring and create a tethered derivative. The nucleophiles that were employed include methanol (entry 1, Table 18) as well as more elaborate compounds. Thus, the oligoethyleneoxy species (entries 2 and 3) afforded amphiphilic chlorin derivatives wherein the hydrophilic unit was attached via an ester moiety. The reaction with 2aminoethanol afforded the amide linkage (entry 4). Again, each isomer is expected as a mixture of stereoisomers (not shown). The absorption spectra of all the compounds shown in Table 18 were essentially identical, which is not surprising given that the structural differences are far removed from the chlorin π-system. The absorption spectrum of one such adduct is shown in Figure 37. Another dienophile examined was 4-nitro-1-nitrosobenzene. The reaction of 4-nitro-1-nitrosobenzene with protoporphyrin IX dimethyl ester (11-H250) gave mono cycloaddition (Scheme 126).403 The reaction afforded the two expected positional isomers (11-H255a, 11-H255b) due to the two vinyl groups, but no bis cycloaddition (both vinyl groups) was observed. The use of excess 4-nitro-1-nitrosobenzene resulted in oxidation of the remaining vinyl group rather than the second cycloaddition to give the positional isomers of the formyl−chlorins 11-H256a and 11-H256b. The reaction of protoporphyrin IX dimethyl ester (11-H250) with a dialkyl acetylenedicarboxylate is one of the older examples of cycloaddition of the appended vinyl groups with a dienophile. An early report suggested the formation of isobacteriochlorins (owing to cycloaddition at both vinyl groups) upon reaction of dimethyl acetylenedicarboxylate in refluxing chloroform for 2 days.395 A decade later, a study indicated that while TCNE certainly is sufficiently potent to react at both vinyl groups (e.g., Scheme 124), thereby possibly affording isobacteriochlorins, weaker dienophiles such as dimethyl acetylenedicarboxylate generally react at one site to afford chlorins.396,397 The latter result was obtained in refluxing toluene for 6 days; the discrepancy in product outcome in toluene versus chloroform may stem from HCl that arises in chloroform (upon industrial synthesis or adventitiously on standing). The results upon reaction of protoporphyrin IX dimethyl ester with diethyl acetylenedicarboxylate in toluene are shown in Scheme 127.396,397 The cycloaddition with 11-H250 and dimethyl acetylenedicarboxylate in refluxing 1,2-dichloroethane (1,2-DCE) for 3 days proceeded to give the two chlorin positional isomers 11-H257a and 11-H257b (each presumably racemic). Treatment with triethylamine resulted in double bond migration to give the chlorins 11-H258a and 11-H258b, respectively. Treatment of either 11-H257a and 11-H257b, or 11-H258a and 11-H258b, with DBU instantly led to formation of chlorins 11-H259a and 11-H259b with the angular methyl group and the adjacent ester moiety in a trans rather than cis relationship. These results suggest that 11-H258a and 11H258b are kinetic products whereas 11-H259a and 11-H259b are thermodynamic products.397 In this regard, each compound 11-

Figure 33. Absorption spectra in dichloromethane of dihydrofuranannulated chlorin 11-H231 (red line) and chlorin−epoxide 11-H233 (orange line). The absorption spectrum of 11-H233 is displayed on the basis of the data listed in the published experimental section.383

Scheme 121. Thionation of an Oxochlorin

Figure 34. Absorption spectra in dichloromethane of oxochlorin 11H217 (orange line) and thiochlorin 11-H234 (red line).392 The spectrum displayed for 11-H234 employs ε = 83 600 M−1 cm−1, which is 10 times the reported value (which likely is in error).

could be separated by chromatography and were obtained in 1:1 ratio. Each such isomer is expected as a mixture of stereoisomers CN


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Review

Scheme 122. Azachlorin−Aldehyde Derived from Heme

Scheme 123. Azachlorin Derived from Heme

R = Me) were treated with excess diethyl acetylenedicarboxylate: the benzoporphyrins 11-H260a and 11-H260b were formed, which stem from loss of the angular methyl group and accompanying aromatization.396 Note that benzoporphyrins are fundamentally distinct from benzochlorins−benzoporphyrins contain an annulated benzo ring across the β,β′-pyrrole bonds, whereas benzochlorins contain an annulated benzo ring that spans the 15- and 17-positions, which are adjacent meso- and β-pyrroline positions. Moreover, the benzo ring in a benzoporphyrin has four carbons that are exocyclic with regard to the tetrapyrrole (porphyrin) macrocycle whereas the benzo

H257a,b−11-H259a,b as shown represents one member of the pair of enantiomers. Analogous chemistry was carried out with diethyl acetylenedicarboxylate (R = Et in Scheme 127) and 11H250, which in refluxing toluene for six days gave the ethyl ester homologues (R = Et) of 11-H257a and 11-H257b in 19% and 20% yield, respectively. Similar treatment of the [4 + 2] cycloaddition products with triethylamine or DBU also gave rise to the analogous kinetic or thermodynamic tautomerization processes, affording the respective diethyl ester homologues (R = Et) of 11-H258a,b and 11-H259a,b. A further transformation occurred when 11-H258a and 11-H258b (demonstrated only for CO


Chemical Reviews

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Scheme 124. Cycloadditions with a Protoporphyrin IX Diester

sensitivity of the absorption spectral properties to the positional isomers derived by cycloaddition with the distinct vinyl groups. Quite similar cycloaddition chemistry was carried out using the alkyne dienophile β-(phenylsulfonyl)propiolate containing ethyl (11-61) or methyl (11-62) esters (Scheme 128).397 The cycloaddition of protoporphyrin IX dimethyl ester (11-H250) with ethyl β-(phenylsulfonyl)propiolate (11-61) was faster and gave higher yield than that with diethyl acetylenedicarboxylate, affording chlorin positional isomers 11-H263a and 11-H263b. The reaction also was regioselective, with the carboxylate unit located at the carbon adjacent to the β-pyrrole position. The initial product underwent double bond migration upon treatment with triethylamine, affording as kinetic isomers the chlorins 11-H265a and 11-H265b (cis configuration); the latter upon exposure to DBU gave the thermodynamic isomers 11-H267a and 11-H267b (trans configuration). The homologous reactant methyl β-(phenylsulfonyl)propiolate (11-62) gave comparable results although the initial cycloaddition proceeded in slightly lower yield (41% versus 68%), affording chlorins 11-H264a and 11-H264b. The rearrangements proceeded in the same manner as for the ethyl ester, affording the kinetic isomers 11-H266a and 11-H266b (cis configuration) and the thermodynamic isomers 11-H268a and 11-H268b (trans configuration). As such, each represents one member of the pair of enantiomers in the expected racemic mixture.

Figure 35. Absorption spectrum in chloroform of 11-H248 or 11-H249 (uncertain assignment).398

ring in a benzochlorin has only three carbons that are exocyclic with regard to the tetrapyrrole (chlorin) macrocycle. Diethyl acetylenedicarboxylate could be replaced with p-benzoquinone, suggesting the electron-deficient alkyne serves as an oxidant in the aromatization process.396 The absorption spectra of chlorins 11-H257a and 11-H258a are shown in Figure 38. The absorption spectra of 11-H257b and 11-H258b are identical to those of 11H257a and 11-H258a, respectively, indicating the lack of CP


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Scheme 125. Aza Dienophiles with Protoporphyrin IX Dimethyl Ester

Table 17. Maleimides in Cycloadditions with Protoporphyrin IX Diesters

a Of the maleimide reactant. bSealed tube reaction. cThe two isomers were obtained in essentially 1:1 ratio.

Table 16. Urazines in Cycloadditions with Protoporphyrin IX Dimethyl Ester % yield entry

urazine R group

11-H251a + 11-H251b

11-H252a + 11-H252b

1 2 3 4 5 6

phenyl tert-butyl ethyl methyl amino H

10 50 63 48 33 12

3 17 2 8 a a

a

Figure 36. Absorption spectrum of compound 11-H253a (as shown in Table 17, entry 1) in methanol.400

A photosensitizer for photodynamic therapy was derived from protoporphyrin IX dimethyl ester (11-H250) upon cycloaddition with dimethyl acetylenedicarboxylate.404 Subsequent reactions entailed base-mediated rearrangement of the cyclo-

None reported. CQ


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Table 18. Maleic Anhydride with Protoporphyrin IX Dimethyl Ester

Figure 37. Absorption spectrum of 11-H254b (entry 4 in Table 18) in chloroform.402

Scheme 126. Nitrosoarene Cycloaddition with Protoporphyrin IX Dimethyl Esters

a

Of the R-X-H reactant. bTotal yield. cMethanol (neat), reflux, 2 h. Triethylamine, dichloromethane, room temperature, 2 h. eDichloromethane, room temperature, 2 h.

d

adduct and then partial saponification of the propionate substituents. The two esters are not identical given the inherent lack of symmetry of protoporphyrin IX. The resulting sample was composed of a mixture of chlorins, including chlorin isomers (and stereoisomers). Four of the prominent chlorin isomers, 11H269a,b and 11-H270a,b, each representing one member of the expected pair of enantiomers, are shown in Scheme 129. Chlorins 11-H269a and 11-H270a are known as “benzoporphyrin derivative mono-carboxylic acid” (BPD-MA), and were found to be more active in photodynamic therapy studies than the isomeric counterparts 11-H269b and 11-H270b.404

To gain more definitive access to the individual isomers, and prepare derivatives thereof, Smith and co-workers embarked on the comprehensive approach shown in Scheme 130.404 Thus, hematoporphyrin IX dimethyl ester (11-H271, readily derived from protoporphyrin IX by hydration of the vinyl groups and methylation of the carboxylic acids) was partially oxidized to give the monoacetyl/monohydroxyethyl porphyrins. The latter were separated and then individually dehydrated to give the monoacetyl/monovinyl porphyrins 11-H 2 72a and 11CR


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Scheme 127. Acetylenes with Protoporphyrin IX Dimethyl Ester

tively. Chlorins 11-H274a(cis) and 11-H274b(cis) have the cisconfiguration of the angular methyl group and adjacent carbomethoxy group, whereas 11-H274a(trans) and 11-H274b(trans) have the trans-configuration. Note that the cis/trans nomenclature here (referring to the orientation of the angular methyl group and adjacent carbomethoxy group) is reversed from the literature, which described the orientation of the carbomethoxy group with respect to the tetrapyrrole macrocycle.404 The resulting four chlorin isomers were each individually pushed through the sequence of reactions entailing (1) reduction of the ketone forming chlorin−alcohols 11H275a(cis), 11-H275b(cis), 11-H275a(trans), 11-H275b(trans); (2) dehydration forming vinyl−chlorins 11-H276a(cis), 11-H276b(cis), 11-H276a(trans), 11-H276b(trans); and (3) bromination followed by nucleophilic displacement of the bromide with an alcohol. Reduction of the acetyl carbonyl group creates a stereogenic alcohol. Consequently, both the resulting chlorin−alcohol and chlorin−bromide derived therefrom are diastereomeric. Thus, reaction with hexanol gave the hexyloxychlorins 11-H277a(cis), 11-H277b(cis), 11-H277a(trans), and 11-H277b(trans), each as a mixture of diastereomers. Such hexyloxychlorins gave superior activity in photodynamic therapy studies compared with that of chlorins 11-

Figure 38. Absorption spectra of chlorins 11-H257a (orange line) and 11-H258a (red line) in dichloromethane.397

H272b.405 Each such porphyrin was then treated with dimethyl acetylenedicarboxylate to give the cycloaddition products 11H273a and 11-H273b, which upon exposure to triethylamine gave rearrangement and formation of the corresponding chlorins 11-H274a(cis) and 11-H274b(cis), whereas treatment with DBU gave chlorins 11-H274a(trans) and 11-H274b(trans), respecCS


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Scheme 128. Alkynes in Reactions with Protoporphyrin IX Dimethyl Ester

Scheme 129. Selected Constituents of “BPD-MA” and Isomers

acid afforded the chlorin−chlorin dyad 11-H279a as a mixture of stereoisomers (Scheme 131). A new stereocenter originates upon formation of the intervening linker, whereas that of each αhydroxyethyl group is lost. Each dyad thus is composed of up to eight stereoisomers. A likely mechanism entails dehydration of the α-hydroxyethyl group to form the vinyl substituent on the first porphyrin, attack by the vinyl group of the benzylic carbocation (by loss of water) of the second porphyrin, and

H269a and 11-H270a (Scheme 129), which comprise the mixture employed in many such studies. Note that for the structures wherein R3 or R8 contains an achiral substituent (i.e., 11-H274 and 11-H276 series), the diagrams display only one member of the expected enantiomeric pair. An offshoot of the work by Smith and co-workers entailed the preparation of chlorin dyads.404 Treatment of the α-hydroxyethylchlorin 11-H278a (mixture of stereoisomers) with triflic CT


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Scheme 130. More Chlorins Derived from Protoporphyrin IX

Smith and co-workers (including Pandey)406 turned to the use of symmetric divinylporphyrins or monovinylporphyrins to simplify the analysis of the products. The only disadvantage of this approach resided in the necessity to prepare the porphyrins (versus use of readily available but unsymmetric protoporphyrin IX). The results of Smith and co-workers are illustrated in Scheme 133. The prolonged reaction of monovinyl−porphyrin 11-H280 with dimethyl acetylenedicarboxylate in refluxing toluene afforded a cycloadduct, which upon DBU-mediated prototropic tautomerization gave the chlorin 11-H281 (presum-

subsequent loss of a proton to form the ethane linkage. Analogous reaction of (α-hydroxyethyl)chlorin 11-H278b (mixture of diastereomers) afforded the chlorin−chlorin dyad 11-H279b as a mixture of stereoisomers (Scheme 132). Whereas the various monomeric chlorins, including the hexyloxychlorins 11-H277a(cis), 11-H277b(cis), 11-H277a(trans), and 11H277b(trans) shown in Scheme 130, were active in photodynamic therapy studies, the bis-chlorins 11-H279a,b did not show any significant activity. CU


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Scheme 131. Chlorin Dyad Derived from Protoporphyrin IX

Scheme 133. Cycloadditions with a Monovinylporphyrin

Scheme 132. Chlorin Dyad Derived from Protoporphyrin IX

resulted in cycloaddition to only a single vinyl group, affording the chlorin cycloaddition product 11-H284 (presumably as a racemic mixture) (Scheme 134).406 Upon reaction with TCNE (4.5 equiv), reaction occurred at a single vinyl group to give the chlorin cycloaddition product 11-H285. Use of a larger excess of TCNE (9 equiv) and longer reaction time, however, gave cycloaddition at both vinyl groups to yield the isobacteriochlorin 11-H286. The distinctions between the reactivity toward cycloaddition of divinylporphyrins by TCNE (double addition) versus dialkyl acetylenedicarboxylates (single addition) have been seen previously (e.g., Schemes 124 and 127−129). The absorption spectra of chlorin cycloaddition products 11H281 and 11-H284 are shown in Figure 39. The two chlorins differ only in the presence or absence of one vinyl group. Both products exhibit characteristic chlorin-like absorption spectra, albeit with quite broad absorption in the B-band region. The term “benzoporphyrin” has somehow stuck to compounds with general structure 11-H281, yet Smith and co-workers have accurately pointed out that such a structure “is neither a benzo derivative nor a porphyrin”.404 The cycloaddition approach with a vinylporphyrin has many attractions, but has limitations as well. For example, protoporphyrin IX is readily and abundantly available yet results in positional isomers and stereoisomers, whereas analogues such as protoporphyrin III require dedicated synthetic effort to construct the porphyrin with which cycloaddition chemistry can begin. A complementary approach to potentially overcome such limi-

ably as a mixture of stereoisomers). Compound 11-H281 contains two new stereocenters; in similar chemistry, Dolphin and co-workers reported that the cis isomer is a kinetically controlled product whereas the trans isomer is thermodynamically stable.397 By contrast, the more reactive dienophile TCNE under mild conditions (refluxing chloroform for 20 min) gave the chlorin cycloaddition product 11-H282 (presumably as a racemic mixture), which contains a single new stereocenter. Similar reactions were carried out with protoporphyrin III dimethyl ester (11-H283), a symmetric divinylporphyrin (to be compared with protoporphyrin IX dimethyl ester). Thus, reaction of 11-H283 with dimethyl acetylenedicarboxylate CV


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Scheme 135. Cycloadditions with Vinyl mesoTetraphenylporphyrin

Scheme 134. Cycloadditions with a Divinylporphyrin

dimethyl acetylenedicarboxylate also gave the porphyrin 11Ni90 in good yield, here as a stable [4 + 2] adduct.408 Matsumoto and co-workers carried out a series of studies with the same porphyrin but with less electron-deficient dienophiles.408,409 The reaction of 11-Ni87 with a variety of dienophiles again typically resulted in a red rather than green product, namely the porphyrin rather than the chlorin (Table 19). Cycloaddition presumably occurs in standard [4 + 2] fashion to give the chlorin 11-Ni91 followed by prototropic rearrangement to give the annulated porphyrin 11-Ni92. Two exceptions among various dienophiles examined where the chlorin (racemic) was isolated were for N-ethyl maleimide and dimethyl maleate (entries 2 and 3, Table 19).409 The general failure to stabilize at the chlorin stage stems from the absence of an alkyl group adjacent to the vinyl group in the porphyrin. The prepositioned adjacent alkyl group and the alkyl group from the incoming dienophile together constitute a gem-dialkyl unit, whereupon prototropic rearrangement is not a consideration. The β-alkylporphyrins such as protoporphyrin IX and

Figure 39. Absorption spectra in dichloromethane of 11-H281 (orange line) and 11-H284 (red line).406

tations has been explored that makes use of vinyl-containing derivatives of readily available synthetic porphyrins such as H2TPP and H2OEP. An early study by Cavaleiro and co-workers in this regard employed nickel porphyrin 11-Ni87 with the highly electron-deficient dienophile TCNE (Scheme 135).407 The cycloaddition afforded a transient [4 + 2] chlorin intermediate (11-Ni88) that converted to a [2 + 2] porphyrin adduct (11-Ni89).407 Similarly, the reaction of 11-Ni87 with CW


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Table 19. Cycloadditions with Nickel βVinyltetraphenylporphyrin

Vinylporphyrin 11-Ni87 lacks such an adjacent alkyl group and affords a porphyrin upon cycloaddition, not a chlorin. A final example of cycloaddition with readily available vinylporphyrins is shown in Scheme 136.410 BromovinylheptaScheme 136. Cycloaddition with a Vinyl Derivative of H2OEP

ethylporphyrin 11-H293, which contains an ethyl group adjacent to the bromovinyl unit, can be obtained from H2OEP.411 Reaction of 11-H293 with TCNE afforded two products, a spirochlorin bearing an exo-ethylidene group (11-H294) and a gem-dialkylchlorin bearing an exo-ω,ω-dicyanoallylidene group (11-H295) in 22% and 33% yield, respectively. Each product (racemic) exhibited a chlorin-like long-wavelength absorption band with maximum at 672 or 720 nm, respectively, with the bathochromic shift of the latter presumably due to the electronic features of the ω,ω-dicyanoallylidene group. This section has summarized cycloadditions of vinylporphyrins, serving as dienes, with dienophiles as a means to form chlorins. The route has a number of attractions given the natural availability of vinylporphyrins, but can suffer from multiple products and multiple stereoisomers. We now turn to cycloaddition reactions of porphyrins that lack vinyl groups.

a

12. (CYCLO)ADDITIONS TO PORPHYRINS WITHOUT VINYL GROUPS Routes that convert a porphyrin to a chlorin by cycloaddition or addition are potentially quite attractive, achieving the same transformation of the chromophore (porphyrin → chlorin) as in hydrogenation but also enabling the installation of groups that alter polarity or that provide synthetic handles for further elaboration. In the first section, we consider cycloadditions that are undirected by any β-pyrrole substituent on the porphyrin. In

Not observed. bReaction at 600 MPa (toluene, 100 °C, 2 days).

protoporphyrin III have such a key structural feature (i.e., an alkyl group adjacent to the vinyl group) and afford stable chlorins. CX


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the second section, we consider additions and cycloadditions with porphyrins wherein one or more preexisting β-pyrrole substituents may guide the course of the reaction. In all cases, the reactions occur at the β-pyrrole positions of porphyrins devoid of vinyl groups. Whereas in the previous section the vinylporphyrin served as the diene, in this section the porphyrin serves as the dienophile or dipolarophile.

Scheme 138. Cyclopropyl-Annulated meso-Tetraarylchlorins

12.1. Undirected Installation of β,β′-Dialkyl Substituents

Several strategies have been developed wherein a porphyrin undergoes cheletropic reaction of a carbon-containing reactant to form the corresponding bridging methanochlorin. One of the earliest examples was reported by Callot. Thus, ZnTPP underwent addition of a carbene to give the methano-bridged (or cyclopropane-fused) chlorin 12-Zn1−4 (Scheme 137).412,413 The carbenes were derived by nitrogen extrusion Scheme 137. Cyclopropyl-Annulated meso-Tetraarylchlorins

from the diazo precursor, which included diazomethane, methyl diazoacetate, and dimethyl diazomalonate. The reaction with methyl diazoacetate afforded two isomers. The zinc chelate of the porphyrin thwarted any adventitious scavenging of copper by the porphyrin from the CuCl employed for carbene formation. In several cases the reactions also formed bacteriochlorins, which were removed by chromatography. The zinc chelates were demetalated to give the free base chlorins. Subsequent work a generation later employed ZnF20TPP, the zinc chelate of H2F20TPP, in similar chemistry (Scheme 138).414 The products upon carbene insertion encompassed the cyclopropane-fused chlorin isomers (putative 12-Zn5a−d, 12Zn6a−d), the bacteriochlorins, and isobacteriochlorins, although all species were not isolated for each carbene precursor (12-Zn5a−d and 12-Zn6b were isolated). The novelty of the carbene precursors was the ability to install an acetonideprotected glycosyl unit on the cyclopropyl ring that is integral to the pyrroline motif. The absorption spectra of the chlorins 12Zn5b and 12-Zn6b are shown in Figure 40. A penetrating set of advances by Cavaleiro and co-workers has concerned the cycloaddition of a diene or dipolar reactant to a porphyrin, wherein the latter serves as dienophile or dipolarophile.415−419 The reaction supports a wide variety of dienes or dipolar reactants and porphyrin substrates, although the

Figure 40. Normalized absorption spectra in chloroform of chlorins 12Zn5b (orange line, ε = 229 000 M−1 cm−1 at 414.5 nm) and 12-Zn6b (red line, ε = 151 000 M−1 cm−1 at 415 nm).414

electron-deficient free base porphyrin H2F20TPP has been frequently employed. The chlorin derived by cycloaddition with H2F20TPP only undergoes dehydrogenation to give the porphyrin under forcing conditions (DDQ in refluxing toluene), whereas more electron-rich porphyrins upon cycloaddition typically afford a mixture of the porphyrin (derived from adventitious dehydrogenation) and chlorin.368 The approach appears to be far-reaching given its simplicity and versatility. Here, a comprehensive treatment is provided, which extends earlier assessments reported by Cavaleiro and co-workCY


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ers.365,367−369,420 The Cavaleiro group has made at least three major accomplishments in this area, which are described as follows. The first major accomplishment by Cavaleiro and co-workers concerned the reaction of meso-tetraarylporphyrins with dienes derived from sulfone-extrusion processes. In this regard, an early demonstration entailed reaction of H2TPP with sulfone 12-7 to give the corresponding chlorin 12-H29 (Scheme 139).415

Scheme 140. Pyrrolo−Chlorin and Pyrrolo−Porphyrins

Scheme 139. meso-Tetraarylchlorins

Thermal extrusion of SO2 from sulfone 12-7 gives rise to obenzoquinodimethane (12-8), which reacted in a [4 + 2] cycloaddition to give the annulated chlorin 12-H29 (26% yield). The corresponding porphyrin also was obtained by autoxidation of the chlorin (not shown).415 Similar results were observed for Ar = 3-methoxyphenyl or 4-methoxyphenyl. The reaction with Ar = pentafluorophenyl (H2F20TPP), however, afforded the chlorin as well as two bacteriochlorins (cis and trans isomers; not shown). Vicente et al. extended the approach of Cavaleiro by reaction of pyrrole-fused 3-sulfolene 12-10 with various porphyrins.421 The reaction, which required elevated temperature to extrude SO2, was carried out by heating (240 °C) the solvent 1,2,4trichlorobenzene (1,2,4-TCB) containing molecular sieves. With H2TPP, the products included the chlorin 12-H211, pyrroloporphyrin 12-H212, isoindoloporphyrin 12-H213 (which is believed to be quite reactive and to give way to downstream products), and a trace of bacteriochlorin. Porphyrins 12-H212 and 12-H213 also could be formed upon quinone-mediated dehydrogenation of chlorin 12-H211 (Scheme 140). Application to H2F20TPP gave only the chlorin 12-H214 and bacteriochlorin 12-H215, which may not be surprising given the resistance toward oxidation imparted by the pentafluorophenyl groups (Scheme 141). On the other hand, attempts to use octaethylporphyrin H2OEP gave the chlorin 12-H216 (as a pair of enantiomers), albeit in quite low yield (Scheme 142). Note that 12-H211, 12-H214 and 12-H216 are each expected as a pair of enantiomers (not shown), although removal of the carboethoxy group would provide a single structure in each case.

A second major accomplishment by Cavaleiro and co-workers entailed the reaction of pentacene with H2F20TPP to give a “barrelene−chlorin” (Table 20).417 The reaction was carried out at 200 °C in 1,2,4-trichlorobenzene. In an initial study, the reaction was examined with several porphyrins. With mesotetraarylporphyrins, a sizable amount of porphyrin remained unreacted (entries 1−3), and the isolated yield of chlorin was 200 °C) have tended to result in the retro-cycloaddition process.425 Cavaleiro and co-workers examined the utility of microwave syntheses as a means to alleviate such problems of limited reaction, given that microwave reactions had proved fruitful in other difficult cycloaddition processes.425 Thus, the reaction of H2F20TPP and pentacene upon microwave heating (200 °C, sealed vessel) for ∼30 min gave the barrelene−chlorin in 83% yield, to be compared with 16% upon traditional convection heating (Table 20, entry 2).425 The microwave reaction afforded small quantities of bis-addition (i.e., bacteriochlorins and isobacteriochlorins), which were not observed by traditional convection heating. The application of microwave-assisted syntheses in tetrapyrrole chemistry has been reviewed by Pineiro.426

“long” axis of the molecule). In a metalloporphyrin, the two axes bisecting opposite pyrrole rings are equivalent (and in a free base porphyrin differ only slightly). The electronic interactions of a chlorin with neighboring entities (e.g., donors/acceptors of excitons or charge) are expected to be quite different depending on 3-dimensional location with regard to rings A, C versus ring B versus ring D. Accordingly, the ability to fix the location of such entities with respect to the pyrroline unit has many attractions in exploring chlorin photophysical properties. Architectural control in this manner is a phenomenon that accrues with chlorin chemistry, and is not present in porphyrin chemistry. DB


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positions; see Table 20)422 affords a symmetrical pair of appended naphthalene units as part of the bicyclic architecture, whereas napthacene has no such central unit for reaction. Accordingly, reaction with napthacene across the 6,11positions422 affords benzene and naphthalene units appended to the bicyclic architecture. In isomer 12-H223a, the appended benzene group projects above the π-face of the chlorin, whereas in isomer 12-H223b, the naphthalene face is so disposed. The reaction was carried out at 180 °C because higher temperatures gave the retro-cycloaddition process. A third major accomplishment by Cavaleiro and co-workers stemmed from the discovery that a wide variety of dipolar reactants could be used in cycloaddition reactions with porphyrins. An early demonstration concerned the reaction of H2F20TPP with the azomethine ylide 12-24 derived from paraformaldehyde and sarcosine (N-methyl glycine) as shown in Scheme 147.416 The reaction afforded the N-methylpyrrolidinefused chlorin 12-H225 in 61% yield. Unreacted porphyrin H2F20TPP was recovered (20%) and the isobacteriochlorins 12H226 (11%, expected as a pair of enantiomers as displayed) also were isolated; the putative isobacteriochlorin 12-H227 with both fused pyrrolidine groups on the same face of the macrocycle was not isolated. Prolonged reaction (40 h) of chlorin 12-H225 with precursors to 12-24 gave the following isolated products: 12H226 (37%), the isobacteriochlorin 12-H227 (5%), the two bacteriochlorin diastereomers 12-H 228(cis/trans) (trace amount), and a tris adduct (not shown).418 The reaction to form N-methylpyrrolidine-fused chlorin 12H225 and analogues has provided the foundation for further elaboration as required for photodynamic therapy studies.427 The cycloaddition also was carried out with the Pd(II) or Pt(II) chelate of H2F20TPP to give the corresponding metallochlorin

The microwave reaction of H2F20TPP and a polynuclear aromatic hydrocarbon was extended to naphthacene instead of pentacene. In this case, the microwave reaction at 180 °C (45 min) afforded the corresponding chlorin isomers upon cycloaddition whereas no reaction was observed upon traditional convection heating (Scheme 146).425 A key difference arises with Scheme 146. Barrelene−Chlorins Derived from Naphthacene

pentacene and naphthacene in cycloaddition chemistry: reaction with pentacene at the central benzo ring (across the 6,13Scheme 147. Azomethine-Derived Chlorins

DC


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(yield of 17 or 13%, respectively; not shown).428 Such metallochlorins are of interest given the high yield of intersystem crossing to form the triplet state, which sensitizes ground-state O2 in an essential step in photodynamic therapy. The role of the meso-aryl group in controlling the reaction rate and product distribution upon cycloaddition was examined with three porphyrins (Table 21).416,418 The reaction examined was Table 21. Effect of meso-Aryl Group on Cycloaddition with Azomethine Ylide418

The porphyrin is H2TPP bearing one β-nitro substituent (i.e., 4H216, in section 4). bNot observed. a

Figure 42. Absorption spectra of (1) porphyrin H2F20TPP (black dotted line) and chlorin 12-H225 (red line) in DMSO;429 (2) porphyrin PdF20TPP (black dotted line) and chlorin 12-Pd25 (red line) in chloroform;428 and (3) porphyrin PtF20TPP (black dotted line) and chlorin 12-Pt25 (red line) in chloroform.428

for sarcosine and paraformaldehyde in refluxing toluene, as in Scheme 147. The results show the marked increase in reactivity of the dipolarophile (i.e., the porphyrin) upon the presence of electron-withdrawing groups. For example, the yield of mesotetraarylchlorin was 61% with the presence of pentafluorophenyl groups (entry 1) versus 3% with 4-methoxyphenyl groups (entry 2). Yields intermediate between these extremes were observed for phenyl (12%, entry 3) and 2,6-dichlorophenyl (26%, entry 4), affording a coherent trend concerning electronic effects on the cycloaddition reaction. The absorption spectra of H2F20TPP and the palladium and platinum complexes thereof, PdF20TPP and PtF20TPP, are shown in Figure 42, along with those of chlorins derived therefrom, 12-H225, 12-Pd25, and 12-Pt25. The same approach for cycloadditionusing sarcosine and paraformaldehyde to generate 12-24 in refluxing toluenewas applied to an A3B-porphyrin containing electron-withdrawing meso-substituents (pentafluorophenyl, 4-pyridyl). The results are shown in Scheme 148.430 Reaction occurred at the two distinct β-pyrrole sites in the porphyrin 12-H229 to give the corresponding two chlorin isomers. The order of chromato-

graphic elution was as follows: recovered starting porphyrin 12H229, chlorin 12-H230a and then chlorin 12-H230b. Chlorins 12-H230a and 12-H230b are positional isomers, and each is expected to be racemic. A distinctly attractive feature of the use of H2F20TPP as a substrate for cycloaddition, apart from the facile reaction with the azomethine 12-24 derived from sarcosine, is the ability to substitute the p-fluoro group of the pentafluorophenyl moiety. While the thrust of this review generally eschews applications, silence about the versatility of this substitution process would be remiss. The reaction, first reported by Boyle and co-workers with pentafluorophenyl-substituted porphyrins,431,432 has been extended by Drain and co-workers to encompass porphyrins and hydroporphyrins (including chlorins).433−436 The most prominent nucleophile is an alkyl thiol, which affords essentially nonhydrolyzable conjugates. Other nucleophiles such as amines DD


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Scheme 148. Azomethine-Derived Chlorins

Scheme 149. Thioether-Derivatized Chlorins

and alcohols also have been employed to good effect, together rendering H2F20TPP as a versatile substrate or even a “platform” for facile elaboration.437 As one example, reaction of chlorin 12H225 with an alkyl thiol afforded the tetrakis(thioether)−chlorin conjugate 12-H231 (Scheme 149). Representative entities incorporated in this manner include S-carboranyl438 and diverse S-glycosyl428,435,439 groups. The absorption spectra of the parent chlorin and the thio-substituted chlorin (R = D-glucosyl) are shown in Figure 43. A further example of an electron-deficient tetrapyrrole macrocycle, but lacking beneficial features for (or adverse susceptibility to) derivatization by nucleophilic substitution, is tetraazaporphyrin. The reaction of octaphenyltetraazaporphyrin with sarcosine and paraformaldehyde afforded, via the reactive azomethine ylide 12-24, the corresponding octaphenyltetraazachlorin 12-H232 (Scheme 150).440 The long-wavelength absorption band of the chlorin appeared at 723 nm, to be compared with the parent octaphenyltetraazaporphyrin at 663 nm.441 A parallel comparison concerns the fully unsubstituted tetraazachlorin at 678 nm,442 and the fully unsubstituted tetraazaporphyrin at 617 nm (see section 14).442,443 The absorption spectra of octaphenyltetraazaporphyrin and octaphenyltetraazachlorin 12-H232 are shown in Figure 44. The conversion of porphyrins to chlorins by cycloaddition is compatible with diverse dipolar reactants. The precursors to the dipolar reactants, resulting dipolar reactants, and chlorins produced upon reaction with H2F20TPP are shown in Table 22.418,419 The use of paraformaldehyde and glycine afforded the pyrrolidine-fused chlorin in reasonable yield (entry 1). A slight amount of N,N-methylene-linked chlorin dimer was produced (not shown), which was cleaved in TFA to give additional chlorin

Figure 43. Absorption spectra in DMSO of chlorin 12-H225 (red line) and the thio-substituted chlorin 12-H231 (R = D-glucosyl, orange line).429

monomer; from both pathways together the total yield was 47%. Here, the pyrrolidine contains a free NH site to be compared with the N-methyl moiety produced upon reaction with sarcosine (vide supra). The reaction with L-proline gave the bis-aza-fused chlorin as a mixture of four stereoisomers, including two pairs of enantiomers (entry 2). On the other hand, (2S)(4R)-4-hydroxy-L-proline gave the bis-aza-fused chlorin, but only three chlorins were isolated (entry 3). A further study employed sarcosine with a variety of aldehydes in lieu of paraformaldehyde, which was expected to give the chlorin bearing an N-methyl group and a substituent at the adjacent methylene site. In each case, however, the porphyrin was recovered and no chlorin was observed (entry 4). The aldehydes examined in lieu of paraformaldehyde were benzaldehyde, pDE


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whereas the isobacteriochlorin was obtained in 66% yield. The absorption spectra of two N-benzyl substituted pyrrolidine-fused chlorins are shown in Figure 45. Even more elaborate ylides have been examined, giving rise to seven distinct heterocycles annulated with the pyrroline ring (Table 23). The reaction of a chloro−hydrazone in the presence of a base generated the iminonitrile by 1,3-elimination of HCl. The iminonitrile underwent [3 + 2] cycloaddition with H2F20TPP to give the corresponding pyrazoline-fused chlorins as shown in entries 1−5. The presence in the hydrazine aryl moiety of electron-withdrawing (by induction) substituents (e.g., methoxy, entries 3, 5) or sterically demanding substituents (entries 4, 5) resulted in decreased yields. Indeed, hydrazones derived from p-nitrophenylhydrazine gave no chlorin (not shown).445 The base-induced dehydrobromination of an ethyl arylhydrazono-α-bromoglyoxalate afforded the N-aryl-Cethoxycarbonylnitrile, which reacted to give the pyrazolochlorin (entry 6).446 The p-nitro-substituted arylhydrazono-α-bromoglyoxalate substrate did not afford any chlorin, however (not shown). In each case, a variety of reaction conditions was explored, encompassing variation in solvent (chloroform, 1,4dioxane, chlorobenzene, toluene), base (triethylamine, K2CO3, Cs2CO3) and temperature; the conditions that afforded the highest yield are indicated. Tetracyanoethylene oxide in refluxing toluene gave the carbonyl ylide, which with H2TPP gave the tetracyanotetrahydrofuranyl-fused adduct (entry 7); the latter could be hydrolyzed to the diester.447 Similarly, bis(chloromethyl)ether gave rise to the unsubstituted carbonyl ylide, which added to H2F20TPP to give the furan-fused chlorin (entry 8).447 The latter chlorin is the oxa-counterpart to the pyrrolidine-fused chlorin shown in Table 22 (entry 1). 2,6-Dichlorobenzonitrile oxide, which is an isolable dipolar reactant, gave the isoxazolinyl-fused chlorin with several mesotetraarylporphyrins (entries 9−15). In each case, bis-adducts (i.e., isobacteriochlorins and/or bacteriochlorins) were also observed. The reaction with the zinc chelate of meso-tetrakis(pchlorophenyl)porphyrin gave the chlorin in 10% yield (not shown), suggesting the central metal may deactivate the macrocycle toward the cycloaddition.448 Little difference in yield was noted upon reaction in refluxing benzene for 72 h versus refluxing toluene for 26−28 h (entries 9 and 10).448−450 The reaction with meso-tetrakis(p-methoxyphenyl)porphyrin was first reported to not afford any chlorin448 although a subsequent study did afford a low yield of chlorin (entry 13).450 The reaction was found to be compatible with the meso-thienyl group (entries 14 and 15).451 The reaction with the nitrile oxide derived from a nitroalkane gave the isoxazoline-fused chlorin; a large amount of unreacted porphyrin was recovered in each case for the various length alkanes despite the 50-h reaction period (entry 16).452 Further studies of modified reaction conditions did not improve the yield.460 An [8 + 2] cycloaddition with a diazafulvene methide under microwave conditions at 250 °C in 1,2,4-TCB afforded the corresponding tetrahydropyrazolo−chlorin in yields of 10−31% (entries 17−19). The yields shown are for the limiting diazafulvene given the use of 2 equiv of porphyrin. In each case, a substantial quantity of unreacted porphyrin could be recovered.453,454 Use of the m-methoxyphenyl substituent resulted in formation of atropisomers, which stemmed from hindered aryl ring rotation with the juxtaposed pyrazolo unit (entry 18).454

Scheme 150. Azomethine-Derived Tetraazachlorin

Figure 44. Absorption spectra of octaphenyltetraazaporphyrin (black dotted line, in dichloromethane,441 ε = 30 200 M−1 cm−1 at 666 nm in chloroform444) and octaphenyltetraazachlorin 12-H232 (red line, in 2methyltetrahydrofuran, ε = 95 500 M−1 cm −1 at 723 nm in dichloromethane).440

nitrobenzaldehyde, acetaldehyde, phenylacetaldehyde, and chloral hydrate. An alternative approach to the use of refluxing toluene in cycloadditions was examined. Thus, the reaction was carried out in dichloromethane at room temperature with N-benzyl-N(trimethylsilylmethyl)aminomethoxymethane, which in the presence of TFA gives the corresponding N-benzyl dipolar reactant (i.e., the N-benzyl analogue of the dipolar reactant derived from sarcosine). The reaction with H2F20TPP in dichloromethane containing TFA at room temperature gave a complex mixture of products. On the other hand, the nickel chelate of H2F20TPP (i.e., NiF20TPP) under the same conditions gave the N-benzyl substituted pyrrolidine-fused chlorin; however, only a small amount was obtained (entry 5, Table 22). The reaction was quite sensitive to the amount of Nbenzylazomethine ylide. With 5 equiv of the azomethine ylide precursor N-benzyl-N-(trimethylsilylmethyl)aminomethoxymethane, the products comprised recovered porphyrin (80%) and chlorin (10%); with 25 equiv, the products included porphyrin (37%), chlorin (46%), and isobacteriochlorin (12%); but with 30 equiv, neither porphyrin nor chlorin was obtained DF


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Table 22. Diverse Dipolar Reactants in Cycloaddition Reactions in Refluxing Toluene

a

With H2F20TPP and paraformaldehyde unless noted otherwise. bTrace amount of bis-adducts. cFour stereoisomers are expected. d1:1 ratio of endo/ exo diastereomers. eThree chlorins were isolated. fPorphyrin was recovered, and no chlorin was observed, for reactions with RCHO in lieu of paraformaldehyde (R = methyl, benzyl, phenyl; see text). gReaction was carried out with the nickel chelate NiF20TPP in dichloromethane containing TFA at room temperature, and without paraformaldehyde.

The reaction of diazomethane with H2F20TPP gave the pyrazoline-fused chlorin in 60% yield (entry 20). Thermolysis of the latter in refluxing mesitylene for 1 h, or irradiation (550−650 nm) at room temperature for 1 h, gave the cyclopropano− chlorin (not shown) in 96% or quantitative yield, respectively.455 The cyclopropano−chlorin prepared in this manner also can be formed by diazomethane treatment of a porphyrin-2-carboxaldehyde (vide infra). An N-methyl isoxazolidine−chlorin also was prepared by reaction with the ylide derived from N-methylhydroxylamine and paraformaldehyde (entry 21).456 The isoxazolidine moiety has proved to be a versatile scaffold for introduction of glycosyl moieties, where the N-position of the isoxazolidine unit has been utilized as a point of attachment. The introduction of sugars to create glyco−tetrapyrroles has been a longstanding pursuit in tetrapyrrole science. A clever method for constructing glycol−chlorins was developed by Cavaleiro and co-workers. Reaction of an acetonide-protected sugar nitrone with H2F20TPP gave smooth cycloaddition to form the isoxazolidine-fused chlorin, with the sugar attached at the

Figure 45. Normalized absorption spectra in chloroform of a free base N-benzyl substituted pyrrolidine-fused chlorin (red line; Table 22, entry 5) and the corresponding nickel complex (blue line, ε = 105 000 M−1 cm−1 at 408 nm; structure not shown).419

DG


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Table 23. Cycloaddition To Form Chlorinsa−s

DH


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Table 23. continued

DI


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Table 23. continued

DJ


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Table 23. continued

a A pair of enantiomers is expected for entries 1−6, and 9−21; four stereoisomers are possible for entries 22−26, 28, and 29. bConditions: Et3N, toluene, reflux, 45 h. cConditions: DABCO, cyclooctane, 150 °C, 6 h. dConditions: Et3N, toluene, reflux, 20 h. eConditions: K2CO3, toluene, reflux, 18 h. fConditions: toluene, reflux, 1 h. gConditions: Mn/PbCl2, NaI, THF, rt. hConditions: benzene, reflux, 72 h. iConditions: toluene, reflux, 24-50 h. jConditions: Et3N, PhNCO, benzene or 1,2,4-TCB, reflux, 50 h. kConditions: 1,2,4-TCB, MW, 250 °C, 20 min. lConditions: Et2O, rt, overnight. m Conditions: K2CO3, toluene, 60 °C, 30 h. nConditions: toluene, 60 °C, 4 days. oConditions: toluene, 60 °C, 5 days. pConditions: toluene, 100 °C, 10 h. qConditions: toluene, 80 °C, 2 days. rConditions: toluene, reflux, molecular sieves, ∼4 h. sConditions: K2CO3, toluene, reflux, 2 h.

isoxazolidine nitrogen atom in a configuration distal to the chlorin macrocycle. In this manner, acetonide-protected galactosyl, ribosyl, xylosyl, and lyxosyl moieties were installed upon formation of the chlorin (entries 22−25). In each case, some bacteriochlorin also was formed. The acetonide protecting group was readily cleaved with aqueous TFA to give the glycol−chlorin.457

A related approach toward glycol−chlorins relied on reaction of an acetonide-protected galactosyl-aldehyde with sarcosine to give the azomethine ylide (entry 26). Two diastereomeric chlorins derived from endo-cycloaddition were formed in 32 and 19% yield (51% total). In addition, loss of the sugar was observed and the N-methyl pyrrolidine-fused chlorin was formed (8% yield). To overcome these limitations, an alternative route DK


Chemical Reviews

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paraformaldehyde and a second tetrapyrrole as dipolarophile resulted in attachment of the latter (as a pyrrolidine-fused chlorin) to the former, resulting in the covalently linked porphyrin−chlorin dyad. With H2F20TPP as the porphyrin dipolarophile, the dyad 12-34 (nickel porphyrin, free base chlorin) or 12-35 (free base porphyrin, free base chlorin) was obtained (Schemes 151 and 152). With tetraazaporphyrin as the

preinstalled the sarcosine moiety, as it were, by reductive amination of glycine with the galactosyl-aldehyde. Reaction with paraformaldehyde generated the azomethine ylide, which gave the N-glycosyl pyrrolidine-fused chlorin in 19% yield; the unreacted porphyrin was recovered in 79% yield, attesting to the cleanliness of the reaction albeit not the efficient conversion (entry 27).458 Assorted other chlorin architectures also were created. Chlorins containing a spiro ring in the pyrroline unit were prepared by reaction of the azomethine ylide derived from sarcosine and isatin (entry 28) or N-benzylisatin (entry 29).459 In summary, the cycloaddition with porphyrins provides a powerful method for installing a substituted pyrroline ring, yet at a minimum, the choice of dipolar reactant is criticala pair of enantiomers is formed with entries 1−5 and 9−21; four stereoisomers can form with entries 22−26, 28 and 29; and achiral chlorins form only with entries 7, 8, and 27 (although entry 27 contains an appended chiral moiety). The absorption spectra of selected chlorins are shown in Figure 46. The versatility of the reaction of the azomethine ylide derived from sarcosine and paraformaldehyde is illustrated by the examples shown in Scheme 152.461 The N-methyl glycine moiety was attached to the β-position of meso-tetraphenylporphyrin as the free base (12-H233) or Ni chelate (12-Ni33). Reaction with

Scheme 151. Isoxazolino-Substituted Chlorin−Porphyrin Dyads

dipolarophile reacting with 12-Ni33, the dyad 12-36 (nickel porphyrin, free base tetraazachlorin) was obtained (Scheme 152). The reaction yields were ∼30−40%; such yields are excellent given the simultaneous joining of the two halves to form the dyad and conversion of the porphyrin to the chlorin. Moreover, this particular design is devoid of positional isomers or stereoisomers. The absorption spectra of porphyrin−chlorin dyad 12-34 and porphyrin−tetraazachlorin dyad 12-36 are shown in Figure 47. The use of porphyrins that bear nonidentical mesosubstituents in cycloaddition processes sets up the possible formation of positional isomers. Such an example is shown in Scheme 153.462 The reaction of 5-(4-methoxycarbonylphenyl)10,15,20-tri-p-tolylporphyrin (12-H237) with the dipolar reactant 2,6-dichlorobenzonitrile oxide afforded four chromatographically separable chlorins 12-H238a−d (each of which is expected as a pair of enantiomers). A set of bis-adducts also was isolated. Each chlorin was metalated with zinc and saponified to give the zinc chlorin−carboxylate for use in dye-sensitized solar cells.

Figure 46. Normalized absorption spectra of selected chlorins from Table 23: (1) free base chlorin (entry 1, red line, ε = 148 000 M−1 cm−1 at 409 nm) in chloroform,445 free base chlorin (entry 12, orange line, ε = 174 000 M−1 cm−1 at 419 nm) in chloroform,450 and free base chlorin (entry 17 (R = OMe), lavender line, ε = 200 000 M−1 cm−1 at 421 nm) in dichloromethane;454 (2) free base chlorin (entry 14, red dashed line, ε = 123 000 M−1 cm−1 at 424 nm), zinc chlorin (entry 14, aqua dashed line, ε = 204 000 M−1 cm−1 at 424 nm), free base chlorin (entry 15, red solid line, ε = 123 000 M−1 cm−1 at 430 nm), and zinc chlorin (entry 15, aqua solid line, ε = 87 100 M−1 cm−1 at 429 nm) in dichloromethane.451 DL


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Scheme 152. Isoxazolino-Substituted Tetraazachlorin−Porphyrin Dyad

Scheme 153. Isoxazolino-Substituted Chlorins

successful for Ar = pentafluorophenyl and R = medium or long chain alkyl (propyl, 16%; pentyl, 18%;) or R = carbomethoxy (34%) whereas R = a short chain alkyl (methyl or ethyl) gave 700 nm) versus the ~650 nm absorption band of the corresponding chlorin that lacks the π-expansion (12-H265). The location of a formyl group at the β-pyrrole position in meso-tetraphenylporphyrin-2-carboxaldehyde (12-H268) was investigated as a synthetic handle for creation of a pyrroline ring and simultaneous installation of a gem-dialkyl group. Thus, the reaction of 12-H268 with diazomethane afforded the acetylporphyrin 12-H269, acetonylporphyrin 12-H270, and the cyclopropano-fused acetylchlorin 12-H271 (Scheme 166, top panel).474 The formation of the chlorin was restricted to the reaction in dry chloroform; when the reaction was carried out in chloroform containing methanol or isopropanol (3:1), 12-H269 and 12-H270 were isolated but no chlorin was obtained. Chlorin 12-H271 is expected as a pair of enantiomers. A proposed mechanism for conversion of 12-H268 to 12-H271 entails addition of diazomethane to the carboxaldehyde followed by loss of N2 to give the betaine (Scheme 166, bottom panel).474 Two competing pathways to the porphyrin proceed via hydride shift to give 12-H269 or porphinyl shift to give the acetaldehyde− porphyrin. The latter adds a second equivalent of diazomethane and proceeds similarly (loss of N2, hydride shift) to give 12H270. Attempts to treat the acetylporphyrin 12-H269 with diazomethane failed to give the chlorin 12-H271, thereby casting

Figure 52. Absorption spectra in dichloromethane of 12-H260 (black dotted line) and 12-H261 (red line).471

toluene gave starting porphyrin 12-H254 (via retrocycloaddition) and methanochlorin 12-H264 via loss of nitrogen. Chlorins 12-H262 and 12-H264 are each expected as a pair of enantiomers. Yet another example of directed addition was reported by Ostrowski and Wyrebek.473 The reaction of o-xylyene and mononitroporphyrin 12-H254 occurred selectively at the most electron-deficient ring, namely that bearing the nitro group, thereby affording chlorin 12-H265 (Scheme 165). The facile loss of the nitro group by elimination afforded the corresponding naphthoporphyrin 12-H266, and addition of two o-xylyene units followed by double elimination resulted in the trans-dinaphthoporphyrin 12-H267. The simplicity of the strategy to form 12H265 (as a pair of enantiomers) is offset by the presence of the two accompanying porphyrins. The absorption spectra of chlorin 12-H265, naphthoporphyrin 12-H266, and dinaphthoporphyrin 12-H267 are shown in Figure 53. The long-wavelength absorption band of the π-expanded porphyrins (12-H266, 12DR


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occurs in a site-specific manner (Schemes 162 and 165), but the nitro group is typically installed by nitration of the intact porphyrin rather than having been preset in precursors to the tetrapyrrole macrocycle. The same phenomenon holds for the formyl group in Scheme 166. In many of the instances shown here, the ring specificity is an irrelevant concern because the porphyrin bears four identical meso-substituents (e.g., H2TPP). But to prepare chlorins with the architectural sophistication characteristic of chlorophyllswhere auxochromes70 are positioned at designated sites relative to the pyrroline ringor to prepare synthetic analogues with additional features not found in natural chlorophylls (e.g., tethers for bioconjugation or surface attachment; substituents to tune electronic features; isotopic substitution; intramolecular apical ligands), control over the location of the pyrroline ring would appear to be essential. One example of an attractive hybrid approach toward chlorin synthesis is shown in Table 24.475,476 Reaction of an aryl aldehyde with excess pyrrole in the presence of TFA afforded the corresponding tripyrrane 12-72. A “3 + 1” reaction of the tripyrrane 12-72 with a 3,4-dialkoxycarbonylpyrrole-2,5-dicarboxaldehyde (12-73) gave the 5,10-diaryl-17,18-dialkoxycarbonylporphyrin 12-H274. The porphyrin-forming process was carried out in a two-step one-flask process of condensation followed by oxidation. The porphyrin 12-H274 was thus set for reaction as a dipolarophile with an azomethine ylide. Indeed, the reaction with the ylide derived from sarcosine and formaldehyde gave, as planned, cycloaddition in the designated ring bearing the electron-withdrawing alkoxycarbonyl groups. In this manner, a 17,18-dialkyl-17,18-dicarboethoxychlorin 12-H275 was constructed. The reaction is tolerant of diverse meso-substituents. Use of the 5,10-A2-porphyrin is attractive due to the absence of stereoisomers formed upon cycloaddition. The chlorins 12-H275 exhibited typical chlorin absorption spectra, as shown in Figure 54. In summary, the synthesis in Table 24 provides an example of the installation of a bis(gem-dialkyl) motif to construct the pyrroline ring at a designated site on a porphyrin. The strategy thus represents one example to gain access to stable, “locked” chlorins in a rational manner without laborious synthesis. Yet, much further work is required to render this and other approaches compatible with all of the architectural control available by the (albeit more lengthy) de novo synthesis of gemdimethyl substituted chlorins.2 We now turn to more recent synthetic strategies that have provided entrée to an astonishingly diverse collection of pyrroline motifs.

Scheme 165. Directed Electrocyclization To Give a Chlorin

13. ALTERNATIVE PYRROLINE MOTIFS If the present review had been written 1−2 generations earlier (ca. 1975), the common substituents in the pyrroline ring that would have been discussed are shown in Scheme 167. Purpurins of the type developed by Woodward were known at that time but not substantially developed. In general, the scope of motifs delineated here was either unknown or a mere glimmer in the literature. Concerning the established motifs at that time, hydrogenation of a porphyrin was known to afford the corresponding chlorin.62,122,124 For a 17,18-dialkylporphyrin (e.g., H2OEP), the 17,18-cis-dialkyl pattern would result.62 The 17,18-trans-dialkyl configurationabundantly represented by chlorophyllscould be achieved as a racemic mixture by de novo synthesis as demonstrated for chlorin-e6 trimethyl ester10 or by reduction of a 17,18-dialkylporphyrin (e.g., H2OEP) with sodium in refluxing isoamyl alcohol.101,477 Vicinal dihydroxylation followed by pinacol−pinacolone-like rearrangement

Figure 53. Normalized absorption spectra in chloroform of chlorin 12H265 (red line), naphthoporphyrin 12-H266 (black dotted line), and dinaphthoporphyrin 12-H267 (olive dotted ine).473

doubt on a mechanism where 12-H269 is a precursor to the chlorin. A likely route to chlorin 12-H271 was suggested to proceed via conjugate addition of diazomethane at the 3-position of the 2-carboxaldehyde, followed by loss of N2 and collapse of the betaine to give the cyclopropane−carboxaldehyde. Diazomethane addition to the carboxaldehyde group thereby gives rise to the acetyl−chlorin 12-H271. A chief limitation for many of the approaches shown in this section, despite the rich examples provided, is the inability to control the particular pyrrole ring in the porphyrin to be converted to the pyrroline unit thereby yielding the chlorin. The reaction of an active methylene compound with a nitroporphyrin DS


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Scheme 166. Directed Reaction To Give a Chlorin

Upon writing a review of chlorin syntheses in 2015, the composition and substitution patterns available for the pyrroline ring have become so vast as to render almost quaint those five shown in Scheme 167. The diverse pyrroline motifs that have been created to date are listed in Table 25. Note that the pyrroline motifs in Table 25 are largely distinct from the pyrroline adducts shown in Table 23, which are derived by cycloaddition at a pyrrole ring in an intact porphyrin. Accompanying each structure in Table 25 is an identifying type number (chosen arbitrarily here), which is used herein to impart order in the numerous synthesis schemes that follow. In addition, the nomenclature or shorthand term for each motif also is provided. The question arises as to the suitability of such pyrroline substituents from the standpoints of synthesis and spectral features. Stability is an equally important feature, but

could be used to create the 18,18-gem-dialkyl-17-oxochlorin, from which the corresponding 18,18-dialkylchlorin could be obtained by deoxygenation (see section 5). De novo routes to the 18,18-geminal dimethyl pattern were not yet available.2 The five pyrroline motifs shown in Scheme 167 represented the chief targets of synthesis for the early period of chlorin chemistry. Yet even in the present era, much remains to be explored and significant areas of fundamental knowledge remain lacking. As one example, intuition suggests that stability toward adventitious dehydrogenation should increase in order along the following series: unsubstituted ≪ 17,18-cis-dialkyl, 17,18-transdialkyl ≪ 18,18-dimethyl, 17-oxo-18,18-dialkyl pyrroline motifs. Such comparative studies of stability toward various (or any) conditions have not been reported. DT


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Table 24. Concise Synthesis of “Locked” Chlorins

Scheme 167. Common Substitution Patterns of the Pyrroline Ring

13.1. Breaking and Mending Strategies yield (%) Porphyrin

Chlorin

entry

R1

12-H274

12-H275

time (h)a

b

3,4,5-trimethoxyphenyl 4-methoxyphenyl 2,4,6-trimethylphenyl phenyl 3-pyridyl 4-cyanophenyl 4-cyanophenyl 4-cyanophenyl C6F5 CF3

12 11 30 16 17 17 26 11 15 7

42 47 57 21 42 35 43 47 30 10

168 48 72 24 48 24 24 24 10 2

1 2b 3b 4b 5b 6c 7b 8d 9b 10b

The prior sections have delineated diverse chemistries for creating the pyrroline ring on an intact porphyrin. The approaches include hydrogenation, vicinal dihydroxylation, cycloadditions, and annulations with appended side chains (at the meso- or β-positions). In recent years, a far wider variety of substituents has been included in the pyrroline ring. The central strategy that has opened the door to diverse pyrroline motifs is an approach referred to as “breaking and mending” of the pyrrole ring.478 While the present review was in the final days of final revision, an account by Brückner of the “breaking and mending” approach was published.479 In the following, relevant absorption spectra are collected and displayed in section 13.2. 13.1.1. Synthesis of Chlorins via Oxidation of Porphyrins. Formation of chlorins by oxidation of porphyrins is a longstanding approach−indeed, treatment of a β-alkylporphyrin to an oxidant (e.g., H2O2/H2SO4 or OsO4) to give the vicinal dihydroxychlorin followed by pinacol−pinacolone-like rearrangement affords the 17-oxo-18,18-dialkylchlorin. Such an approach is inapplicable to β-unsubstituted porphyrins because the ostensible 17-oxo-18,18-dihydrochlorin would tautomerize to form the 17-hydroxyporphyrin (vide infra). Crossley and coworkers pursued an alternative route as shown in Scheme 168.480 Photooxidation of β-aminoporphyrin 13-H21 gave the 17-oxo18-iminochlorin 13-H22 (type B5), which upon hydrolysis on silica gel gave the 17,18-dioxochlorin 13-H23 (type B1). The dioxochlorin also is referred to as a porphyrindione. The dioxochlorin is thus derived from a porphyrin that lacks βsubstituents. The 17,18-dioxochlorin 13-H23 (type B1) undergoes annulation with diamines.480−486 Treatment of the β-aminoporphyrin 13-H21 or the 17-oxo-18iminochlorin 13-H22 (type B5) with m-chloroperbenzoic acid (m-CPBA) gave the 17-oxo-18-oxachlorin 13-H24 (type F1). The 17-oxo-18-oxachlorin is also referred to as a porpholactone. On the other hand, treatment of the 17,18-dioxochlorin 13-H23 (type B1) gave only a trace amount of the 17-oxo-18-oxachlorin 13-H24 (type F1). The 17-oxo-18-oxachlorins (type F1) possess porphyrin-like absorption spectra and fluorescence emission with a fluorescence quantum yield (Φf = 0.2; vide infra)487 that is quite strong for a tetrapyrrole macrocycle.30,65,67,70

a

Reaction time for chlorin formation. bR2 = ethyl. cR2 = methyl. dR2 = tert-butyl.

Figure 54. Absorption spectra in toluene of chlorins from Table 24: entry 5 (orange line), entry 9 (lavender line), and entry 10 (red line).475

data generally are not available in this regard. We now turn to a fundamentallly new approach for creating pyrroline motifs that encompass a very rich level of diversity. DU


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Table 25. Diverse Pyrroline Motifs

DV


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Table 25. continued

DW


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Table 25. continued

a

One stereoisomer shown.

The β-aminoporphyrins, prepared from reduction of the βnitro porphyrins, also proved to be good precursors for the 17,18-dioxochlorin (type B1). However, the β-aminoporphyrins were typically used without purification due to limited stability upon silica gel chromatography. The first step involved reduction of the nitro to the amino group with Pd/C or SnCl2, while the second step involved oxidation (entries 16−22).483,489−491 One exception was provided by entry 23.492 The 2,3-dinitroporphyrin has also been applied for the synthesis of the 17,18-dioxochlorin (type B1, entry 24).483 Routes to 17,18-dioxochlorins (type B1) via chlorin intermediates are shown in Schemes 169 and 170. The βsubstituted (hydroxy/acetoxy or amino/nitro) porphyrins are not always required for the preparation of the 17,18dioxochlorins (type B1). For example, meso-tetrakis(3,5-di-tertbutylphenyl)chlorin (13-H26), prepared by diborane reduction of meso-tetrakis(3,5-di-tert-butylphenyl)porphyrin (13-H25), was hydroxylated upon exposure to silica to give the 17hydroxychlorin 13-H27 in 67% yield (Scheme 169).484 Oxidation of 13-H27 with DMP afforded the 17,18-dioxochlorin 13-H28 (type B1).484 Treatment of the copper complex of 2nitro-meso-tetrakis(3-methoxyphenyl)porphyrin (13-Cu9a) with benzaldehyde oxime followed by demetalation afforded the 17-oxochlorin 13-H210 (type C1), which was oxidized with DMP to give the 17,18-dioxochlorin 13-H211 (type B1) (Scheme 170).493 Note that the putative 17-oxochlorin lacking any gem-disubstitution at the adjacent 18-position (e.g., 13H210) is expected to form the more stable 17-hydroxyporphyrin tautomer (not shown). Such tautomerization apparently does not affect the oxidation process here, as evidenced by the high yield of 17,18-dioxochlorin 13-H211. The synthesis of the 17-oxo-18-oxachlorin (type F1) shown in Scheme 168480 has been extended to encompass other starting 2aminoporphyrins bearing diverse meso-substituents. The original synthesis by Crossley, which employed meso-phenyl groups (Table 27, entry 1),480 was equally applicable to porphyrins with sterically encumbering meso-substituents (entries 2 and 3).494 The 17-oxo-18-oxachlorins (type F1) also were prepared directly from porphyrins that lack the 2-amino group. Treatment of the H2F20TPP with silver nitrate and oxalic acid dihydrate gave the free base 17-oxo-18-oxachlorin (type F1) in 15% yield (∼40% of the starting porphyrin was converted to type F1), together with the silver complex of H2F20TPP (entry 4).487

Scheme 168. Synthesis of a 17,18-Dioxochlorin (type B1) and a 17-Oxo-18-oxachlorin (type F1)

Porphyrins that bear hydroxy/acetoxy or amino/nitro substituents at the β-positions are readily available and are valuable precursors to the 17,18-dioxochlorin (type B1). A wide variety of oxidation conditions were examined for the conversion of such β-substituted porphyrins to the corresponding dioxochlorin (Table 26). In extending the chemistry shown in Scheme 168, Crossley and co-workers demonstrated that the 17,18-dioxochlorin (type B1) could be directly synthesized from the β-hydroxyporphyrin by use of Rose Bengal as photosensitizer or of SeO2 as an oxidant (entries 1 and 2).481 Burn and coworkers further examined reaction conditions including the following: (i) one-flask irradiation in the presence of silica (entries 3−5), and (ii) use of an oxidant such as CrO3, DDQ, or Dess-Martin periodinane (DMP) (entries 6−14). The reaction conditions were applicable for free base, zinc, and copper chelates.482 The 17,18-dioxochlorin (type B1) could be prepared from the β-acetoxyporphyrin in two steps (through the βhydroxyporphyrin, entry 15).488 DX


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Table 26. 17,18-Dioxochlorins (type B1) via Oxidation of β-Substituted Porphyrins

entry

R

M

Ar

via 2-hydroxy- or 2-acetoxyporphyrins (R = OH/OAc) 1 OH Cu phenyl 2 OH Cu phenyl 3 OH H, H 3,5-di-tert-butylphenyl 4 OH Zn 3,5-di-tert-butylphenyl 5 OH Cu 3,5-di-tert-butylphenyl 6 OH H, H 3,5-di-tert-butylphenyl 7 OH Zn 3,5-di-tert-butylphenyl 8 OH Cu 3,5-di-tert-butylphenyl 9 OH H, H 3,5-di-tert-butylphenyl 10 OH Zn 3,5-di-tert-butylphenyl 11 OH Cu 3,5-di-tert-butylphenyl 12 OH H, H 3,5-di-tert-butylphenyl 13 OH Zn 3,5-di-tert-butylphenyl 14 OH Cu 3,5-di-tert-butylphenyl 15 OAc (OH) H, H 2,4,6-trimethylphenyl via 2-amino- or 2-nitroporphyrins (R = NH2/NO2) 16 NO2 (NH2) H, H 3,5-di-tert-butylphenyl 17 NO2 (NH2) Zn 3,5-di-tert-butylphenyl 18 NO2 (NH2) Cu 3,5-di-tert-butylphenyl 19 NO2 (NH2) H, H 2,4,6-trimethylphenyl 20 NO2 (NH2) Cu 2,4,6-trimethylphenyl 21 NO2 (NH2) Pd 2,4,6-trimethylphenyl 22 NO2 (NH2) H, H phenyl 23 NH2 H, H 2,4,6-trimethylphenyl via a vicinal-dinitroporphyrin 24 NO2 (NH2) Zn 3,5-di-tert-butylphenyl

reagents (oxidant)

yield (%)

ref

Rose Bengal, hν, O2 SeO2 silica, hν, O2 silica, hν, O2 silica, hν, O2 CrO3 CrO3 CrO3 DDQ DDQ DDQ DMP DMP DMP (1) K2CO3, (2) DMP

39 58 94 28 10 63 53 43 30 32 65 79 57 76 15

481 481 482 482 482 482 482 482 482 482 482 482 482 482 488

(1) SnCl2·2H2O, (2) DMP (1) Pd/C, NaBH4, (2) DMP (1) Pd/C, NaBH4, (2) DMP (1) Pd/C, NaBH4, (2) hν, O2 (1) Pd/C, NaBH4, (2) hν, O2 (1) Pd/C, NaBH4, (2) hν, O2 (1) SnCl2, HCl, (2) microwave, (3) silica, hν, O2 DMP

52 20 37 80 55 80 78 37

483 483 483 489 490 489 491 492

(1) Pd/C, NaBH4, (2) DMP

78

483

Scheme 169. Synthesis of a 17,18-Dioxochlorin (type B1) via a Chlorin Intermediate

Scheme 170. Synthesis of a 17,18-Dioxochlorin (type B1) via a Chlorin Intermediate

In a similar manner, treatment of H2F20TPP with chloroauric acid in acetic acid gave the free base 17-oxo-18-oxachlorin (type

F1) in 6% yield, together with the gold complex of H2F20TPP and 2-chloro-meso-tetrakis(pentafluorophenyl)porphyrin (entry DY


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Table 27. 17-Oxo-18-oxachlorins (type F1) via Oxidation of Porphyrins

entry

R

M

Ar

reagents (oxidant)

yield (%)

ref

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

NH2 NO2(NH2) NO2(NH2) H H H H H H H H H H H H H H H H H H H

H, H H, H H, H H, H H, H H, H H, H H, H H, H H, H H, H H, H H, H H, H H, H H, H Ni Cu Zn Pd Pt Au

phenyl 2,4,6-trimethylphenyl 2,6-dichlorophenyl C6F5 C6F5 C6F5 4-(trifluoromethyl)phenyl 4-fluorophenyl 4-chlorophenyl phenyl 4-methoxyphenyl 3,5-difluorophenyl 3,5-difluorophenyll 3,5-dichlorophenyl 2,4,6-trimethylphenyl 2,6-dimethoxyphenyl C6F5 C6F5 C6F5 C6F5 C6F5 C6F5

m-CPBA (1) Pd/C, NaBH4, (2) m-CPBA (1) Pd/C, NaBH4, (2) m-CPBA AgNO3, oxalic acid HAuCl4, AcOH, reflux RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH RuCl3, 2,2′-bipyridine, Oxone, NaOH

55 72 44 15 6 85 72 67 65 55 40 71 79 75 65 78 85 83 78 80 30 0

480 494 494 487 495 496 496 496 496 496 496 496 496 496 496 496 496 496 496 496 496 496

5).495 However, when H2TPP was employed under identical conditions, AuTPP was isolated as the sole product; thus, the presence of electron-withdrawing group(s) appears essential for the formation of the 17-oxo-18-oxachlorin (type F1). Ruthenium-catalyzed oxidation of a porphyrin gave the 17oxo-18-oxachlorin (type F1), a process that showed compatibility toward a wide variety of electron-withdrawing groups, electron-donating groups, sterically hindered groups, bioconjugatable groups, and central metals (entries 6−22).496 It is noteworthy that H2TPP could be converted to the corresponding 17-oxo-18-oxachlorin (type F1) in 55% yield in a single step (entry 10). Oxidation of a β-aminoporphyrin with NaNO2 and sulfuric acid in hydrogen peroxide afforded the corresponding 17-oxo18-diazochlorin (type B2). The results for several metalloporphyrins are shown in Table 28.497 The resulting 17-oxo18-diazochlorins (type B2) are stable compounds and could be stored at room temperature for one month, and also did not show any decomposition in refluxing THF or chloroform for 48 h. In the course of studies concerning the synthesis of 17,18dioxochlorins (type B1) by oxidation of porphyrins (Table 26), Burn and co-workers examined the oxidation of β-hydroxyporphyrins with PbO2. The hydroxyporphyrins included free base 13-H212, zinc chelate 13-Zn12, and copper chelate 13Cu12. The corresponding 17-oxo-18,18-dialkoxychlorins 13H213, 13-Zn13, and 13-Cu13 (type B3) were obtained as shown in Scheme 171.482 Dehydration of a vicinal-dihydroxychlorin is illustrated in Scheme 172. The cis-17,18-dihydroxychlorin 13-H214 (type

Table 28. 17-Oxo-18-diazochlorins (type B2) via Oxidation of Porphyrins

entry

M

Ar

yield (%)

1 2 3

Cu Cu Ni

phenyl 4-n-hexylphenyl phenyl

54 24 30

Scheme 171. 17-Oxo-18,18-dialkoxychlorins (type B3) via Oxidation of Porphyrins

DZ


Chemical Reviews

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Scheme 172. Conversion of Chlorins to Porphyrins

Scheme 175. Interconversion of a Chlorin and a Porphyrin

give the 17-hydroxyporphyrin.498 Note that the 17-oxochlorin (type C1) has been described as an intermediate in Scheme 170.493 Similarly, the 17,17-dimethoxychlorin 13-Cu17 (type C2) underwent hydrolysis under mild conditions and in high yield to form the corresponding 17-methoxychlorin 13-Cu18a (Scheme 173).499,500 Treatment of the copper chelate of 18-nitroporphyrin 13Cu9b with sodium methoxide in DMF containing the oxidant nitrobenzene afforded a mixture of macrocyclesthe 17,17dimethoxy-18-nitrochlorin 13-Cu19 (type C3) in good yield, two 17-alkoxyporphyrins (13-Cu18a, 13-Cu18b) in trace amounts, and recovered starting porphyrin (Scheme 174).500 The same reaction in the absence of nitrobenzene afforded a generally similar profile albeit with only 18% yield of the desired chlorin 13-Cu19. Altenatively, reaction in the presence of nitrobenzene at increasing temperature (50, 80, 120, 153 °C) did not afford an increased yield of the desired chlorin; indeed, at the highest temperature the dominant product (49% yield) was CuTPP (lacking the nitro substituent of the starting material 13Cu9b). The room temperature reaction also was carried out with sodium benzyl oxide (R = PhCH2−), or the nickel chelate, whereupon a rather similar product distribution was obtained (not shown). Treatment of the 17-methoxy-18-nitroporphyrin 13-Cu18b with sodium methoxide in DMF gave the 17,17-dimethoxy-18nitrochlorin (type C3: 13-Cu19) in good yield. Conversely, the dimethoxychlorin upon exposure to aqueous acid gave the 17methoxy-18-nitroporphyrin 13-Cu18b (Scheme 175).500 The same interconversion process was also demonstrated with the benzyloxyporphyrin and dibenzyloxychlorin (R = PhCH2−, not shown).499,500 In short, a gem-dialkoxychlorin (unequipped with other stabilizing features) readily undergoes hydrolysis under mild acidic conditions to form the corresponding monoalkoxyporphyrin. 13.1.2. Derivatization of cis-17,18-Dihydroxychlorins (type A1). The cis-17,18-dihydroxychlorins (type A1) are versatile substrates and have been converted to other types of chlorins. This section chiefly concerns the conversion upon treatment with various oxidants. The general concept for such derivatizations is displayed in Scheme 176. Three key intermediates that appear repeatedly in subsequent chemistries are enclosed in boxes.

Scheme 173. Conversion of a Chlorin to a Porphyrin

Scheme 174. Conversion of a Porphyrin to a Chlorin

A1)196 was prepared by treatment of the porphyrin with OsO4 (see section 5 and Table 9, entry 1). The dihydroxychlorin was found to be stable in refluxing chloroform containing dilute HCl but underwent dehydration in the presence of perchloric acid to give the 17-hydroxyporphyrin 13-H215.196 In general, a 17oxochlorin lacking a flanking 18,18-dialkyl (or other blocking) motif, such as 13-H216 (type C1), undergoes tautomerization to EA


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Review

Scheme 176. Derivatization Flow Chart from cis-17,18Dihydroxychlorins (type A1)

Scheme 177. Synthesis of a 17,18-Dialkoxychlorin (type A2) and a 17,18-cis-Acetonide−Chlorin (type A3)

Scheme 178. Methylation of a cis-17,18-Dihydroxychlorin (type A1)

Treatment of the cis-17,18-dihydroxychlorin 13-H214 (type A1) with NaH followed by an alkyl iodide (e.g., MeI) afforded the corresponding cis-17,18-dialkoxychlorin 13-H221 (type A2, Scheme 177).501 Similar treatment with 7,8-dibromo-17,18dihydroxy-meso-tetraphenylchlorin gave 7,8-dibromo-17,18-dialkoxy-meso-tetraphenylchlorin in 88% yield (not shown).502 Also, cis-17,18-dihydroxychlorin 13-H214 (type A1) underwent acetal formation with acetone to give the cis-17,18-acetonide− chlorin 13-Zn23 (type A3) (Scheme 178).196 Similarly, reaction of cis-17,18-dihydroxychlorin 13-H220 (type A1) with NaH followed by MeI gave the corresponding 17,18-dimethoxychlorin 13-H222 (type A2). Note that the meso-substituent in this case was 3,4,5-trimethoxyphenyl, which is electron-rich and slightly bulky (Scheme 178). Oxidation of the cis-17,18-dihydroxychlorins 13-H214 and 13Ni14 (type A1) with DDQ afforded the 17,18-dioxochlorins 13H23 and 13-Ni3 (type B1) as shown in Scheme 179.485,486 The 17,18-dioxochlorins (type B1) could be reduced to form the cis17,18-dihydroxychlorins (type A1) by treatment with Zn−Hg/ H+ or Pd−C/H2 (details were not described).485 The oxidative conversion of a chlorin−diol (e.g., 13-H214) to a chlorin−dione (e.g., 13-H23), and the reductive reversal, on the face of it may be reminiscent of the redox interconversion of an o-hydroquinone and the corresponding o-quinone. Close inspection shows such an analogy to be misleading and inappropriate. The transformation of a quinone to a hydroquinone entails a 2e−/2H+ addition wherein the hybridization (sp2) of both oxygen-bearing carbons remains essentially unchanged. By contrast, the conversion of a chlorin−dione to a chlorin−diol entails a 4e−/ 4H+ addition wherein each carbonyl group is reduced and undergoes a hybridization change from sp2 to sp3. Said

differently, in the o-hydroquinone the hydroxy groups are phenolic in nature whereas in the chlorin−diol each hydroxy group is a secondary (benzylic-like) alcohol. The oxidized products, the o-quinone and the chlorin−dione, have similar structures; hence, the key (and interesting) difference in the analogy resides in the disparate reduction processes leading to the o-hydroquinone versus the chlorin−diol. Oxidation of the cis-17,18-dihydroxychlorins (type A1) with a permanganate source afforded the corresponding the 17-oxo-18oxachlorins (type F1) as shown in Table 29.200,503 The permanganate sources included KMnO4 in the presence of the EB


Chemical Reviews

Review

Scheme 180. 17-Oxo-18-oxachlorins (type F1) from cis-17,18Dihydroxychlorins (type A)

Scheme 179. Synthesis of 17,18-Dioxochlorins (type B1) from cis-17,18-Dihydroxychlorins (type A1)

phase transfer catalyst 18-crown-6, or cetyltrimethylammonium permanganate (CTAP). Table 29. 17-Oxo-18-oxachlorins (type F1) from cis-17,18Dihydroxychlorins (type A1)

Scheme 181. 16,19-Diformyl-seco-chlorins (type G1) from cis17,18-Dihydroxychlorins (type A1)

entry

M

Ar

yield (%)

ref

1 2 3 4 5 6 7 8 9 10

H, H Zn Ni H, H H, H H, H Ni H, H H, H H, H

phenyl phenyl phenyl 4-isopropylphenyl 4-tert-butylphenyl 3,4,5-trimethoxyphenyl 3,4,5-trimethoxyphenyl 4-methoxyphenyl 4-(trifluoromethyl)phenyl C6 F5

75 85 55 77 73 95 42 95 73 25−30

200, 503 200 200 200 200 200 200 200 200 200

Similar chemistry was also extended to obtain trans-A2chlorins. Oxidation of 5,15-diphenyl-17,18-dihydroxychlorin 13H224 (type A1) with CTAP afforded two positional isomers, 13H225a and 13-H225b (type F1), in 1:5 ratio. The less sterically hindered isomer 13-H225b, which contains the lactone carbonyl group positioned and pointed away from the meso-phenyl group, was the dominant isomer (Scheme 180).200 The cis-17,18-dihydroxychlorins 13-H214 and 13-Ni14 (type A1) underwent oxidation to give the corresponding 16,19diformyl-seco-chlorin 13-H226 and 13-Ni26 (type G1, Scheme 181). The oxidant for the free base chlorin was sodium periodate on silica gel503,504 whereas that for the nickel chlorin was Pb(OAc)4.505 The free base 16,19-diformyl-seco-chlorin 13H226 tended to decompose in solution (acidic or wet) or on silica gel within several hours; however, after completely dry, ample spectroscopic data (1H and 13C NMR, HRMS, and absorption spectra) were obtained, and the chlorin could be stored at −18 °C for several months.504 On the other hand, the nickel complex of 16,19-diformyl-seco-chlorin (13-Ni26) is more stable and could be purified by silica chromatography.505 The diformyl-seco-chlorins (type G1) exhibit absorption spectra that

are quite different from those of chlorins wherein an intact, allcarbon pyrroline ring is present (vide infra).504,505 The reactivity of the cis-17,18-dihydroxychlorin silver complex 13-Ag14 (type A1) toward periodate oxidation was different from that of the free base chlorin (vide supra). Oxidation of the cis-17,18-dihydroxychlorin silver complex 13-Ag14 (type A1) with periodate gave the 16,19-diformyl-seco-chlorin 13-Ag26 (type G1) and the 17-hydroxy-18-oxachlorin 13-Ag27 (type D5; i.e., a porpholactol) in 1:3 ratio and isolated yields of up to 20 and 50%, respectively (Scheme 182).506 The ratio varied depending on reaction conditions such as the amount of oxidant in the silica gel. Oxidation of the cis-17,18-dihydroxychlorin silver complex 13-Ag14 (type A1) with Pb(OAc)4 gave the 17-hydroxy-18oxachlorin 13-Ag27 (type D5) as a major product (up to 30% yield) and a trace amount of the 16,19-diformyl-seco-chlorin 13Ag26 (type G1). Regardless of the presence of the central metal, the silver complex 13-Ag26 was highly reactive (similar to that of the free base 13-H226) but nonetheless could be isolated. When EC


Chemical Reviews

Review

morpholinochlorin 13-Ag28 (type H3) is reversible, regenerating the 16,19-diformyl-seco-chlorin 13-Ag26 (type G1), which then converts to the 17-ethoxy-18-oxachlorin 13-Ag29 (type D6). The 17,18-dioxochlorins (type B1), the 16,19-diformyl-secochlorins (type G1), and the 17-oxo-18-oxachlorins (type F1) are key compounds for which further derivatizations are described in the following sections. 13.1.3. Derivatization of 17,18-Dioxochlorins (type B1). The 17,18-dioxochlorins (type B1) are versatile substrates for conversion to other types of chlorins. An overview for such derivatizations is displayed in Scheme 184. The chemistry for the various transformations is described in the following. Crossley and King first demonstrated that oxidation of a 17,18dioxochlorin (type B1) leads to a wide variety of oxygenincorporated porphyrinic macrocycles (types H1, F1, and L1).480,507 For example, treatment of a free base 17,18dioxochlorin (type B1) with m-CPBA proceeded via Baeyer− Villiger oxidation of the α-dione to give the free base anhydride (type H1) as a major product (64%); only a trace amount of the free base 17-oxo-18-oxachlorin (type F1) was detected (Table 30, entry 1). Alternatively, treatment of the free base 17,18dioxochlorin (type B1) with excess NaH in dichloromethane exposed to air for 16 h, followed by 3 M aqueous HCl, afforded the free base anhydride (type H1) in 80% yield together with the oxoazeteo species (type L1) in 4% yield. On the other hand, conversion of the 17,18-dioxochlorin (type B1) to the 17-oxo18-oxachlorin (type F1) was unsuccessful (entry 3). In 2006, Zaleski and co-workers reported that oxidation of the copper or nickel chelate of a 17,18-dioxochlorin (type B1) with benzeneselenic anhydride (BSA) afforded the oxoazeteo− chlorin (type L1) and the 17-oxo-18-oxachlorin (type F1) (Table 30, entries 4−7).508 The product ratio of type L1 and type F1 depended on the amount of BSA and the reaction time, given that the oxoazeto−chlorin (type L1) is a presumed initial oxidation product that subsequently proceeds to the 17-oxo-18oxachlorin (type F1) (vide infra). In a series of studies of porphyrin/chlorin N-oxides by Brückner and co-workers, the synthesis of the 17,18-dioxochlorin N-oxide 13-H23-I (type B1-N-oxide) was attempted from the corresponding 17,18-dioxochlorin 13-H23 (type B1). Use of methyltrioxorhenium-catalyzed hydrogen peroxide oxidation in the presence of pyrazole afforded multiple compounds (Table 30, entries 8 and 9; Scheme 185): the anhydride 13-H230 (type H1), the anhydride N-oxide 13-H230-I (type H1-N-oxide), the 17-oxo-18-oxachlorin 13-H24 (type F1), and the 17-oxo-18oxachlorin N-oxide 13-H24-I (type F1-N-oxide).509 Use of a smaller amount of catalyst and a shorter reaction time suppressed formation of the 17-oxo-18-oxachlorin 13-H24 (type F1), which implies that the oxidation proceeds in a stepwise manner: type B1 → type H1 → type F1. The absorption spectra of anhydride 13-H230 (type H1) and anhydride N-oxide 13-H230-I (type H1N-oxide) are shown in Figure 55. In contrast, oxidation of the 17,18-cis-dimethoxychlorin 13H221 (type A2) and the 17-oxo-18-oxachlorin 13-H24 (type F1) with catalysis by methyltrioxorhenium and hydrogen peroxide proceeded smoothly to give the corresponding chlorin N-oxides 13-H221-I and 13-H24-I in moderate yields (Scheme 186).510 In each case, the nitrogen atom in the pyrrole ring distal to the reduced pyrrole ring was oxidized (also see Schemes 39 and 40). Alternatively, a set of chlorin-N-oxides was synthesized directly from the corresponding free base porphyrin-N-oxide 13-H231 (Scheme 187).509 Treatment of 13-H231 with osmium

Scheme 182. Derivatization of the cis-17,18-Dihydroxychlorin Silver Complex (type A1)

periodate oxidation of 13-Ag14 was carried out in the presence of ethanol, the dialkoxy−morpholinochlorin 13-Ag28 (type H3), the 17-ethoxy-18-oxachlorin 13-Ag29 (type D6), and the 17oxo-18-oxachlorin 13-Ag4 (type F1) were isolated in yields up to 50, 50, and 20% respectively, depending on the reaction conditions (Scheme 183).506 Note that 13-Ag27, 13-Ag28, and 13-Ag29 are each expected as racemic mixtures. The formation of the 17-oxo-18-oxachlorin 13-Ag4 (type F1) was suppressed by purging oxygen from the reaction mixture. The amount of the 17-ethoxy-18-oxachlorin 13-Ag29 (type D6) increased with addition of oxidant and prolonged reaction time. These observations imply that the formation of the dialkoxy− Scheme 183. Derivatization of the cis-17,18-Dihydroxychlorin Silver Complex (type A1)

ED


Chemical Reviews

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Scheme 184. Derivatization Flow Chart from the 17,18-Dioxochlorins (type B1)

Table 30. Oxidation of the 17,18-Dioxochlorins (type B1)

yield (%)

a

entry

M

conditions

type H1

type F1

1 2 3 4 5 6 7 8 9

H, H H, H H, H Cu Cu Cu Ni H, H H, H

m-CPBA m-CPBA (1) NaH, O2, in CH2Cl2, 16 h (2) 3 M aq HCl BSA (8 equiv), in chlorobenzene, reflux, 5 h BSA (4 equiv), in chlorobenzene, reflux, 8 h BSA (4 equiv), in chlorobenzene, reflux, 18 h BSA (6 equiv), in chlorobenzene, reflux, 9 h MeReO3 (0.15 equiv), aq H2O2, pyrazole, CH2Cl2, rt, 15 h MeReO3 (0.25 equiv), aq H2O2, pyrazole, CH2Cl2

64% 39% 80%

trace

a

a

a

a

4% 6% 7% trace 19%

a a a a

82% 70% 75% 35%

a 39% 50% (type H1 + type F1)

type L1

a a

ref 480 507 480 508 508 508 508 509 509

Not reported.

EE


Chemical Reviews

Review

Scheme 186. Synthesis of Chlorin N-Oxides

Scheme 185. Oxidation of a 17,18-Dioxochlorin (type B1) Catalyzed by Methyltrioxorhenium

porphyrin-N-oxide 13-H231 in 37% yield. The chlorin−osmates 13-H232-I and 13-H232-II differ in the position of the osmate; apparently, the presence of the N-oxide in the pyrrole ring did not exert significant directional influence in which subsequent pyrrole rings were oxidized. The other two possible isomers (21N-oxide or 23-N-oxide) were not observed. The reductive cleavage of the chlorin−osmate 13-H232-I or 13-H232-II with H2S afforded the cis-17,18-dihydroxychlorin-22-N-oxide 13H214-I (type A1-N-oxide) or the cis-17,18-dihydroxychlorin24-N-oxide 13-H214-II (type A1-N-oxide) in 40 or 23% yield, respectively, together with the cis-17,18-dihydroxytetraphenylchlorin 13-H214 (not shown) due to N-oxide deoxygenation. Upon treatment of the chlorin−osmate 13-H232-I or 13-H232II with o-phenylenediamine as a putative nonreducing reagent, 13-H214-I or 13-H214-II was obtained in 50 or 70% yield, respectively.509 Oxidation with CTAP of the chlorin−osmate 13-H232-I or 13-H232-II showed disparate results; thus, chlorin−osmate 13H232-I gave the 17-oxo-18-oxachlorin-22-N-oxide 13-H24-I (type F1-N-oxide), while the chlorin−osmate 13-H232-II gave the 17,18-dioxochlorin-24-N-oxide 13-H23-II (type B1-Noxide). The presence of the N-oxide moiety apparently deactivates the attached pyrrole ring in 13-H232-II but not the distal ring in 13-H232-I. In other words, CTAP oxidation of the chlorin−osmate 13-H232-II stopped at the stage of the 17,18dioxochlorin-24-N-oxide 13-H23-II, whereas CTAP oxidation of chlorin−osmate 13-H232-I proceeded to the 17-oxo-18oxachlorin-22-N-oxide 13-H24-I. Moreover, CTAP oxidation of the chlorin−osmate 13-H232-II gave both 13-H23-II and 17,18-dioxochlorin-24-N-oxide 13-H24-II (type F1-N-oxide) as products depending on the reaction time (details were not discussed); regardless, the formation of both products supports the notion of deactivation by the N-oxide moiety. Similarly, CTAP oxidation of dihydroxychlorin 13-H214-II also gave 13H24-II, presumably via the intermediacy of 13-H23-II, because CTAP oxidation of 13-H23-II gave 13-H24-II. As described above, the 17-oxo-18-oxachlorins (type F1) may be the thermodynamic end points of the oxidation process in this series of compounds.509

Figure 55. Normalized absorption spectra in dichloromethane of anhydride 13-H230 (type H1, red line) and anhydride N-oxide 13H230-I (type H1-N-oxide, purple line).509

tetroxide at room temperature for 5 days afforded the cis-17,18dihydroxychlorin-22-N-oxide osmate 13-H232-I and the cis17,18-dihydroxychlorin-24-N-oxide osmate 13-H232-II in 35 and 25% yield, respectively, together with recovery of starting EF


Chemical Reviews

Review

Scheme 187. Preparation of Chlorin N-Oxide Positional Isomers

To gain access to the 17,18-dioxochlorin-22-N-oxide 13-H23-I (B1-N-oxide), Dess-Martin periodinane oxidation of 13-H214-I was carried out, whereupon 13-H23-I was obtained in 76% yield. Finally, CTAP oxidation of 13-H214-I or 13-H23-I afforded 17oxo-18-oxachlorin-22-N-oxide 13-H24-I. The absorption spectra of selected porphyrin/chlorin N-oxides are shown in Figure 56 together with their parent porphyrin/chlorins. The formation of 17-oxo-18-oxachlorins (type F1) was described earlier (e.g., Scheme 185). Hydrolysis of the tetrapyrrole−anhydride 13-H230 (type H1) with NaOH in aqueous DMF gave the 17-oxo-18-oxachlorin 13-H24 (type F1) in 94% yield (Scheme 188).480 Similarly, oxidation of the oxoazeteo species 13-Cu33 (type L1) with BSA afforded the 17oxo-18-oxachlorin 13-Cu4 (type F1) in 59% yield.508 The 17oxo-18-oxachlorins (type F1) are widely observed as a side product in the oxidation of porphyrins/chlorins, which again suggests that the macrocycle type F1 is a thermodynamic sink.503

Conversion between the 17,18-dioxochlorins (type B1), the 17-oxo-18,18-dialkoxychlorins (type B3), and the 17-oxo-18diazochlorins (type B2) is summarized in Table 31. The reaction of the 17,18-dioxochlorins (type B1) with primary alcohols in the presence of AgOTf afforded the corresponding 17-oxo-18,18dialkoxychlorins (type B3, entries 1−10).512 The presence of electron-withdrawing groups in the alcohol unit decreased the yields. Acetals of the resulting 17-oxo-18,18-dialkoxychlorins (type B3) were readily removed under acidic conditions (entries 11−14).512,513 The 17-oxo-18-diazochlorins (type B2, M = Zn, Cu, Ni) were prepared from the corresponding metal complexes of the 17,18-dioxochlorins (type B1) by treatment with pTsNHNH2 in the presence or absence of Zn(OAc)2 as a cocatalyst (entries 15−17).514,515 The 17-oxo-18,18-dialkoxychlorins (type B3) were also prepared from the 17-oxo-18diazochlorins (type B2) with alcohols in the presence of AgOTf (entries 18 and 19).512 EG


Chemical Reviews

Review

Figure 56. Absorption spectra of (1) H2TPP (black dotted line, in toluene)54,55 and N-oxide thereof 13-H231 (purple line, in dichloromethane);510 (2) cis-17,18-dihydroxychlorin 13-H214 (type A1, red line, in chloroform),196,200 cis-17,18-dihydroxychlorin-22-N-oxide 13-H214-I (type A1-N-oxide, purple line, in dichloromethane),510 and cis-17,18-dihydroxychlorin-24-N-oxide 13-H214-II (type A1-N-oxide, lavender line, in dichloromethane);509 (3) 17-oxo-18-oxachlorin 13-H24 (type F1, red line, in chloroform),200,511 17-oxo-18-oxachlorin-22-N-oxide 13-H24-I (type F1-N-oxide, purple line, in dichloromethane),510 and 17-oxo-18-oxachlorin-24-N-oxide 13-H24-II (type F1-N-oxide, lavender line, in dichloromethane);509 and (4) 17,18dioxochlorin 13-H23 (type B1, red line, in chloroform),485 17,18-dioxochlorin-22-N-oxide 13-H23-I (type B1-N-oxide, purple line, in dichloromethane),509 and 17,18-dioxochlorin-24-N-oxide 13-H23-II (type B1-N-oxide, lavender line, in dichloromethane).509

14%), the 17-oxo-18-alkoxychlorins (type B4, 6−10%), 2hydroxyporphyrin (i, R = H, 25−27% for copper, 1−2% for nickel), and 2-alkoxyporphyrin (i, R = alkyl, 26−28% for copper, 8−10% for nickel) (entries 1−6).513 The formation of the acylazeteochlorin (type L2) or the oxochlorin dimer (iii) was not reported. Zaleski and co-workers reinvestigated photolysis of the 17-oxo-18-diazochlorins (type B2) in the presence of methanol, which afforded the 17-oxo-18,18-dialkoxychlorins (type B3, 7− 32%), the 17-oxo-18-alkoxychlorins (type B4, 4−5%), the acylazeteochlorin (type L2, 6−16%), 2-hydroxyporphyrin (i, R = H, trace to 22%), and the oxochlorin dimer (iii, trace for nickel complex) (entries 7−9).515 The dimer (iii) may be present as a mixture of four stereoisomers. A follow-up study by Zaleski and co-workers showed sharply different results from prior studies (Table 32, entries 10−16).516 Photolysis of the free base 17-oxo-18-diazochlorin (type B2) in the presence of n-butanol gave the n-butoxycarbonyl-substituted azeteochlorin (type L2, 34%) and the oxochlorin dimer (iii, 10%) (entry 10). When a nucleophile was omitted from the photolysis reaction of the free base 17-oxo-18-diazochlorin (type B2), the oxochlorin dimer (iii) was obtained as the sole species in 42% yield. Under the identical photolysis conditions with nbutanol as the nucleophile, the copper and nickel chelates of 17oxo-18-diazochlorins (type B2) gave the n-butoxycarbonylsubstituted azeteochlorin (type L2, 14 and 16%), 2-hydroxyporphyrin (i, R = H, 43 and 29%), and the intramolecular exocyclic ring-contracted porphyrin (ii, 6 and 12%), without

Scheme 188. Oxidation to Form 17-Oxo-18-oxachlorin (type F1)

The results upon photolysis of the 17-oxo-18-diazochlorins (type B2) in the presence of a nucleophile are summarized in Table 32. Cavaleiro and co-workers first reported photolysis of the 17-oxo-18-diazochlorins (type B2) in the presence of an alcohol (methanol, ethanol, or, n-propanol) as a nucleophile, which afforded the 17-oxo-18,18-dialkoxychlorins (type B3, 11− EH


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well as a trace amount of the 17,18-bis(hydroxyimino)chlorin 13-H235 (type B7) in 5% yield (Scheme 189).517 Treatment of 13-H235 under dehydration conditions using p-toluenesulfonic acid gave the oxazole-contracted porphyrin 13-H236 (type B8) as a minor product (19% yield) together with annulated chlorins (vide inf ra).517 Treatment of the metal complexes of the 17,18-dioxochlorins (type B1: 13-Ni3, 13-Pd3, and 13-Pt3) with hydroxylamine hydrochloride (50 equiv) afforded the corresponding 17-oxo-18hydroxyiminochlorins 13-Ni34, 13-Pd34, and 13-Pt34 (type B6) in high yields (Scheme 190).518 The reactions proceeded without noticeable formation of the 17,18-bis(hydroxyimino)chlorins (type B7, Scheme 189). Further treatment of the 17oxo-18-hydroxyiminochlorins 13-Ni34, 13-Pd34, and 13-Pt34 (type B6) with p-toluenesulfonic acid under forcing conditions afforded the corresponding imido−chlorins 13-Ni37, 13-Pd37, and 13-Pt37 (type I1) in 70, 76, and 52% yield, respectively.518 Demetalation of 13-Ni37 in the standard way with strong acid (H2SO4) gave the free base imido−chlorin 13-H237 without affect on the imide moiety. N-Benzylation of the free base imido−chlorin 13-H237 (type I1) with benzyl bromide in the presence of sodium hydride gave the N-benzyl imido−chlorin 13-H238 (type I2) as a minor product (22% yield) and the Obenzyl enolimido−chlorin 13-H239 (type I3) as the major product (66% yield).518 A 17,18-dioxochlorin (type B1) upon reaction with a nucleophilic reagent [RLi, RMgBr, or (CH3)3SiCF3/TBAF] afforded the corresponding trans-17,18-dihydroxy-17,18-dialkylchlorin or trans-17,18-dihydroxy-17,18-diarylchlorin (type A4) depending on the nature of the nucleophile (Table 33).493,519,520 Selective formation of the trans isomers can be attributed to steric factors. Single-crystal X-ray structures of the trans-17,18dihydroxy-17,18-dimethylchlorins (type A4, M = H, H and Ni) established the stereochemistry.520 Each is expected as a racemic mixture. The trans-17,18-dihydroxy-17,18-dimethylchlorin 13-Ni40 (type A4) underwent oxidation with Pb(OAc)4 to give the 16,19-diacetyl-seco-chlorin 13-Ni41 (type G4, Scheme 191).520 Whereas many transformations at the pyrrole/pyrroline ring entail reduction or oxidation, the seco-chlorin (by definition) has suffered complete scission of the β,β′-bond. The 16,19-diacetylseco-chlorin 13-Ni41 (type G4) underwent DBU-mediated aldol condensation to give the oxypyriporphyrin 13-Ni42 (type K2),520 a general tetrapyrrole structure prepared earlier by Lash and Chaney.521 The oxypyriporphyrin has also been termed a homoporphyrinone. Reduction of 13-Ni42 with L-Selectride gave the oxypyrichlorin 13-Ni43 (type K1). The diastereotopic nature of the α-methylene protons (adjacent to the carbonyl) in 13-Ni43 was noted, but any enantioselectivity in the ene reduction by L-Selectride was not reported. On the other hand, treatment of the 16,19-diacetyl-seco-chlorin 13-Ni41 (type G4) with Lawesson’s reagent afforded the thiamorpholinochlorin with exocyclic methylidene groups 13-Ni44 (type J) (Scheme 192).520 One early antecedent of the “breaking and mending” approach was reported by Bonnett and co-workers, who treated trans17,18-dihydroxyoctaethylchlorin 13-Ni45 (type A4) with lead acetate. In so doing, the two hydroxy groups were converted to a dione with scission of the β,β′-bond, thereby affording a 16,19diacyl-seco-chlorin (Scheme 193).522,523 The resulting secodiacylchlorin 13-Ni46 (type G4) underwent ring closure to give the oxypyriporphyrin 13-Ni47 (type K2) upon exposure to a mild base. The 16,19-diacyl-seco-chlorin 13-Ni46 (type G4)

Table 31. Interconversion of Three Oxochlorin Derivatives

entry

M

1 2 3 4 5 6 7 8 9 10

Cu Cu Cu Cu Cu Cu Ni Ni Ni H, H

11 12 13 14

Cu Cu Cu Cu

15 16 17 18 19

R type B1 → type B3a n-propyl n-butyl n-pentyl 2-methoxyethyl 2-chloroethyl 2-methylpropyl n-butyl 2-methoxyethyl 2-chloroethyl 2-chloroethyl type B3 → type B1b,c methyl ethyl n-propyl n-butyl type B1 → type B2d

yield (%)

ref

79 80 90 64 25 89 70 59 27 35

512 512 512 512 512 512 512 512 512 512

62−75 62−75 62−75 70

513 513 513 512

Zn Cu Ni

68 73 64

514,515 514,515 514,515

Cu Ni

type B2 → type B3e n-butyl 34 n-butyl 60

512 512

a

AgOTf, ROH, dichloromethane, reflux, 3−8 h. b20% aqueous HCl, 65 °C, chloroform, 20 min. c10% aqueous HCl, 1,4-dioxane/n-butanol (1:4), 70 °C, 2 h. dp-TsNHNH2 (20 equiv), Zn(OAc)2 (1 equiv), dichloromethane, methanol, reflux, 35 to 90 min. eAgOTf, 1,4dioxane/n-butanol (1:4), reflux, 20 h.

observable formation of the dimer (iii; entries 11 and 12). When the nucleophile was omitted from the photolysis reaction of the nickel complex of 17-oxo-18-diazochlorins (type B2), the intramolecular exocyclic ring-contracted porphyrin (ii) was obtained as the sole species in 76% yield. The scope of nucleophiles was extended further to include p-TsNHNH2 and tetrahydrofurfuryl alcohol, which gave similar results (Table 32, entries 13−16). Condensation of the 17,18-dioxochlorin 13-H23 (type B1) with hydroxylamine hydrochloride (100 equiv) afforded the 17oxo-18-hydroxyiminochlorin 13-H234 (type B6) in 91% yield as EI


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Review

Table 32. Photolysis of the 17-Oxo-18-diazochlorin (type B2)

yield (%)

a

entry

M

R

conditions

type B3

typeB4

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Cu Cu Cu Ni Ni Ni Ni Cu Zn H, H Cu Ni Cu Ni Cu Ni

methyl ethyl n-propyl methyl ethyl n-propyl methyl methyl methyl n-butyl n-butyl n-butyl -NH-NH-Tsa -NH-NH-Tsa -OCH2-2-THFa -OCH2-2-THFa

hν, methanol, CHCl3, 5 to 10 h hν, ethanol, CHCl3, 5 to 10 h hν, n-propanol, CHCl3, 5 to 10 h hν, methanol, CHCl3, 5 to 10 h hν, ethanol, CHCl3, 5 to 10 h hν, n-propanol, CHCl3, 5 to 10 h hν, methanol, degassed CH2Cl2 hν, methanol, degassed CH2Cl2 hν, methanol, degassed CH2Cl2 hν, 1-butanol, degassed CH2Cl2, 9 h hν, 1-butanol, degassed CH2Cl2, 6 h hν, 1-butanol, degassed CH2Cl2, 9 h hν, p-TsNHNH2, degassed CH2Cl2, 6 h hν, p-TsNHNH2, degassed CH2Cl2, 9 h hν, tetrahydrofurfuryl alcohol, degassed CH2Cl2, 6 h hν, tetrahydrofurfuryl alcohol, degassed CH2Cl2, 9 h

11 14 12 14 13 14 32 10 7

5 6 6.5 10 10 9 5 4 4

b

b

b

b

b

b

b

b

b

b

b

b

b

b

type L2 b b b b b b

16 7 6 34 14 16 13 13 16 28

ref 513 513 513 513 513 513 515 515 515 516 516 516 516 516 516 516

The moiety given in the table stands for “OR” not R in structure type L2 in the above diagram. Not reported. b

day. The treatment of 13-H248 with base (10% DBU) or a catalytic amount of acid (TFA) afforded oxypyriporphyrin 13H247 (type K2). On the basis of these findings, oxypyriporphyrin 13-H247 (type K2) was prepared directly from cis-17,18dihydroxyoctaethylchlorin 13-H245 (type A4). The absorption spectra of 13-H245, 13-H247, and 13-H248 are shown in Figure 58. The spectrum of 13-H248 exhibits an enhanced longwavelength absorption band resembling that of chlorin 13-H245; both spectra are quite distinct from that of oxypyriporphyrin 13H247. The breaking and mending strategy was further applied with other β-alkyl-substituted porphyrinic macrocycles, such as octaethyloxochlorin 13-H249 (Scheme 195).526 Treatment of 13-H249 with excess hydroxylamine in pyridine gave the oxime 13-H250. Attempted Beckmann rearrangement of 13-H250 gave

gave a bis(2,4-dinitrophenylhydrazone), indicating characteristic reactivity of the two ketones, but the ketone 13-Ni47 (type K2) was quite unreactive. Indeed, expected derivatives were not obtained upon treatment with common carbonyl-reactive reagents, lithium dibutylcuprate, or 2,3-dimethylbuta-1,3-diene. The absorption spectra of octaethyl seco-chlorin 13-Ni46 (type G4) and homoporphyrin 13-Ni47 (type K2) are shown in Figure 57.522 Attempted cleavage of free base cis-17,18-dihydroxyoctaethylchlorin 13-H245 (type A4) with Pb(OAc)4 gave a complex mixture.522,523 Brückner and co-workers reinvestigated the reaction conditions (Scheme 194).524 Periodate oxidation of 13-H245 gave 16,19-diacyl-seco-chlorin 13-H246 (type G4, not isolated), which spontaneously afforded aldol product 13-H248. Aldol product 13-H248 readily decomposed in solution within 1 EJ


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Scheme 189. Amination of 17,18-Dioxochlorin (type B1)

Scheme 190. Derivatization from the 17-Oxo-18-hydroxyiminochlorins (type B6)

example includes the 16,19-bis(methoxycarbonyl)-seco-chlorin 13-H254 (type G4), which was obtained by photolysis of porphyrin 13-H253 with Rose Bengal in O2-saturated methanol (Scheme 196).527 Of the three distinct pyrrole rings in 13-H253, reaction occurred preferentially at the pyrrole bearing two methoxy substituents. The apparent directed nature of this process is reminiscent of the directed installation of alkyl groups in the pyrroline ring as described in Section 12.2. A second example includes the 16,19-dicyano-seco-chlorins 13-Zn57 and 13-Ni57 (type G5), which were obtained by oxidation of 17,18diaminoporphyrins 13-Zn56 and 13-Ni56 with (diacetoxyiodo)benzene (Scheme 197).528 Diaminoporphyrins 13-Ni56 and 13Zn56 in turn were obtained by reduction of the nitro group in the 17-amino-18-nitroporphyrins 13-Ni55 and 13-Zn55, respectively. A third example includes the 16-cyano-19-acyl-secochlorins 13-H259a and 13-H259b (type G6), which were obtained by direct photolysis of imidazoleporphyrins 13H258a528 and 13-H258b528 (Scheme 198). While the limited

the octaethyl-1,3-oxazinochlorin 13-H252 in 20% yield. The oxazinochlorin 13-H252 possesses a six-membered ring (1,3oxazine-6-one moiety), which is similar to the five-membered ring in a 17-oxo-18-oxachlorin (type F1). Note that 13-H252 is expected to form via Baeyer−Villiger oxidation of octaethyloxochlorin 13-H249, not via Beckmann rearrangement of oxime 13H250. Further investigation of the reaction revealed that the secochlorin 13-H251a was the precursor of 13-H252. The secochlorin 13-H251a was unstable, while the stable seco-chlorin 13H251b was obtained in low yield (9%) using methanol instead of aqueous ammonia, and was fully characterized. The absorption spectra of 13-H249, 13-H250, 13-H251b, and 13-H252 are shown in Figure 59. Among the four compounds, 13-H251b exhibits quite broad absorption bands while the other three give relatively sharp bands. Chlorins with pyrroline rings that have been modified by cleavage of the β,β′-pyrrole bond also have been prepared from porphyrins other than H2TPP or octaalkylporphyrins. One EK


Chemical Reviews

Review

Table 33. Synthesis of trans-17,18-Dihydroxy-17,18dialkylchlorins (type A4)

Scheme 191. Derivatization of a trans-17,18-Dihydroxy17,18-dialkylchlorin (type A4)

Entry

M

R

yield (%)

ref

1a 2b 3c 4d 5e 6f

H, H H, H H, H H, H H, H Ni

methyl n-hethyl 3,5-bis(trifluoromethyl)phenyl CF3 methyl methyl

50 53 44 78 61−78 g

519 493 493 493 520 520

a

Ar = mesityl. Conditions: CH3Li. bAr = 3-methoxyphenyl. Conditions: n-hexyl-MgBr, dry THF, − 45 °C, 3 h. cAr = 3methoxyphenyl. Conditions: 3,5-bis(trifluoromethyl)phenylmagnesium bromide, dry THF, − 45 °C, 3 h. dAr = 3methoxyphenyl. Conditions: (CH3)3SiCF3/TBAF, dry THF, − 40 °C, 8 h. eAr = phenyl. Conditions: (i) CH3MgBr, dry THF, rt, 5−10 min, (ii) 2% TFA, dichloromethane, followed by Et3N. fAr = phenyl. Conditions: CH3MgBr, dry THF. gNot reported.

number of examples here precludes wide generalization, a trend is that 1O2-mediated transformations have been employed with free base porphyrins, whereas (diacetoxyiodo)benzene has been employed with zinc or nickel chelates of the porphyrin. Considerable selectivity for reaction at a particular pyrrole ring has been observed. The absorption spectra of porphyrin 13H253 and seco-chlorin 13-H254 (type G4) are shown in Figure 60. The seco-chlorin 13-H254 exhibits quite broad absorption bands, akin to those of seco-chlorin 13-H251b shown in Scheme 59. Oxypyriporphyrins (type K2), which contain a six-membered ring in lieu of a pyrrole, could be prepared directly from the 17,18-dioxochlorin (type B1). The 17,18-dioxochlorin 13-H23 (type B1) upon exposure to a large excess of diazomethane gave a mixture composed of the 17-oxo-18-epoxychlorin 13-H260 (type C4) and two positional isomers of the oxypyriporphyrin, 13-H261a and 13-H261b (type K2) (Scheme 199).529 The positional isomers differ in the location (position 181 or 182) of the methoxy group with respect to the carbonyl in the oxypyriporphyrin. Many of the reactions considered herein have focused on the conversion of the 17,18-dioxochlorin, e.g., 13-H23 (type B1), to other chlorin-like molecules. It warrants mention, that the 17,18-dioxochlorin 13-H23 has also been employed as a platform for reaction with 1,2-diaminobenzene derivatives in the creation of cavitands (not shown).530 13.1.4. Derivatization of 16,19-Diformyl-seco-chlorins (type G1). The 16,19-diformyl-seco-chlorins (type G1) are valuable substrates for conversion to other types of chlorins. The general concept for such transformations is displayed in Scheme 200. The chemistry for the various transformations is described in the following. The synthesis of the dialkoxy−morpholinochlorins (type H3) from the 17,18-dihydroxychlorins (type A1) was first reported by Brückner and co-workers.505 The conversion takes place in a stepwise manner: type A1 → type G1 → type H4 → type H3. The chemistry has since been extensively investigated and

Scheme 192. Derivatization of a 16,19-Diacetyl seco-Chlorin (type G4)

optimized.503,531−533 Key intermediates in the series of reactions are the 16,19-diformyl-seco-chlorins (type G1), which react with EL


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Review

Scheme 193. Derivatization of a cis-17,18-Dihydroxy-17,18dialkylchlorin (type A4), Part 1

Scheme 194. Derivatization of a cis-17,18-Dihydroxy-17,18dialkylchlorin (type A4), Part 2

Figure 57. Absorption spectra in chloroform of octaethyl seco-chlorin 13-Ni46 (type G4, red line) and homoporphyrin 13-Ni47 (type K2, black dotted line).522

a wide variety of alcohols including primary alcohols (e.g., isopropanol, in the presence of triethylamine) or sterically bulky alcohols (e.g., tert-butyl alcohol, benzhydrol, cholesterol) in the presence of HCl or TFA vapor as an acid catalyst to give the monoalkoxy−morpholinochlorins (type H4, hemiacetal; presumably as a racemic mixture) (Scheme 201).505,532 The monoalkoxy−morpholinochlorins (type H4) were formed quantitatively; however, purification by silica chromatography tended to lead to side products. Thus, the crude compounds were typically used in the next step without further purification. The treatment of a monoalkoxy−morpholinochlorin (type H4) with alcohols under more forcing conditions led to the corresponding dialkoxy−morpholinochlorin (type H3, also expected as a racemic mixture). 505,532 An unsymmetric

Figure 58. Normalized absorption spectra in chloroform of 13-H245 (type A4, red line, ε = 170 000 M−1 cm−1 at 393 nm525), 13-H247 (type K2, lavender line, ε = 138 000 M−1 cm−1 at 424 nm), and 13-H248 (type K1, orange line).524

dialkoxy−morpholinochlorin (type H3) could be prepared by choosing different alcohols for the first step (type G1 → type H4) and the second step (type H4 → type H3).505,532 The symmetric dialkoxy−morpholinochlorins (type H3) could also EM


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Review

Scheme 195. Synthesis of Octaethyl-1,3-oxazinochlorin

Scheme 196. Photooxidation To Form a 16,19-Diester-secochlorin (type G4)

Scheme 197. Formation of a 16,19-Dicyano-seco-chlorin (type G5)

Figure 59. Absorption spectra in dichloromethane of 13-H249 (lavender line), 13-H250 (orange line), 13-H251b (red line), and 13H252 (black line).526

chlorins. Examples are provided here and in subsequent sections. As one example, the dimethoxy−morpholinochlorin (type H3, R = methyl) was found to undergo alkoxy exchange upon treatment with excess ethanol or isopropanol under acid catalysis at 65 °C, thereby forming the diethoxy−morpholinochlorin (type H3, R = ethyl) or diisopropoxy−morpholinochlorin (type H3, R = isopropyl).503 A dialkoxy−morpholinochlorin (type H3) typically is ruffled and crystallizes as a racemic

be prepared directly from the cis-17,18-dihydroxychlorin (type A1) or the 16,19-diformyl-seco-chlorin (type G1).503,505,531−533 The various morpholinochlorins shown in Scheme 201 have proved to be valuable intermediates in the preparation of diverse EN


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Review

Scheme 198. Photooxidation To Form a 16-Cyano-19-amidoseco-chlorin (type G6)

Scheme 199. Treatment of a 17,18-Dioxochlorin (type B1) with Diazomethane

13-H266, 13-Ni66, and 13-Ni68 is expected as a racemic mixture. The 16,19-diformyl-seco-chlorin (type G1) derived from NiTPP reacted with Wilkinson’s catalyst [(PPh3)3RhCl] in refluxing benzonitrile to give the 16-formyl-19-decarbo-secochlorin (type G2) and the 16,19-didecarbo-seco-chlorin (type G3) (Table 34, entry 1).531,535 The 16-formyl-19-decarbo-secochlorin is also known as chlorophin−monoaldehyde, and the 16,19-didecarbo-seco-chlorin is known as chlorophin. The hydroxyazeteochlorin (type L3) was obtained as a side product when the reaction temperature was increased and the reaction time was prolonged (entry 2).535 The first reported attempt to prepare chlorophins (type G3) was described by Crossley and co-workers.480 Vilsmeier formylation of the 16,19-didecarbo-seco-chlorin 13Ni69 (type G3) afforded the 16-formyl-19-decarbo-seco-chlorin 13-Ni70 (type G2) in moderate yield (30%,531 25−45%535), together with the hydroxyazeteochlorin 13-Ni71 (type L3) (Scheme 203).531 Distinct reactivity at the α-position and βpositions toward formylation was not observed; as a result, a mixture of the β-formylated 16,19-didecarbo-seco-chlorins (not isolated nor fully characterized) was obtained.531 The azeteo species (types L1, L2, and L3) were typically obtained as side products in low yield.480,508,515 On the other hand, the methylazeteochlorin (type L4) could be readily prepared as shown in Scheme 204.535 Thus, treatment of 16formyl-seco-chlorin 13-Ni70 (type G2) with MeMgBr afforded the α-hydroxyethyl substituent, which cyclized to give the methylazeteochlorin 13-Ni72 (type L4) in good yield (60− 75%). An attractive feature of the azeteochlorins, at least with the substitution pattern for 13-Ni72, is the absence of any stereoisomers.

Figure 60. Normalized absorption spectra in dichloromethane of porphyrin 13-H253 (black dotted line) and seco-chlorin 13-H254 (type G4, red line).527

mixture505,531,532 The dialkoxy−morpholinochlorins exhibit typical chlorin absorption spectra (vide infra).532 The 16,19-diformyl-seco-chlorins 13-H226 and 13-Ni26 (type G1) upon treatment with nucleophiles other than alcohols such as KCN or CH3MgBr afforded the morpholinochlorins 13Ni62a (type H6) and 13-Ni62b (type H7), respectively. Treatment of the resulting morpholinochlorins with acid gave the phenyl-fused morpholinochlorins 13-Ni63a and 13-Ni63b (Scheme 202).532 Reaction of the 16,19-diformyl-seco-chlorins 13-H226 and 13-Ni26 (type G1) with a borohydride source (NaBH4 or Et3SiH/TMSOTf) afforded the monohydroxy− morpholinochlorins 13-H264 and 13-Ni64 (type H5). The latter upon acid treatment underwent ring closure with the adjacent meso-phenyl group to give phenyl-fused morpholinochlorins 13H265 and 13-Ni65.532 Exposure of the monohydroxy− morpholinochlorins 13-H264 and 13-Ni64 (type H5) to acidic ethanol gave the monoethoxy−morpholinochlorins 13-H266 and 13-Ni66 (type H8) (Scheme 202).532 Reduction of the monohydroxy−morpholinochlorins 13-H264 and 13-Ni64 (type H5) further gave the unsubstituted morpholinochlorins 13-H267 and 13-Ni67 (type H2).532 The pyrazine-derived homoporphyrin 13-Ni68 (type I4) was prepared by reaction of the 16,19-diformyl-seco-chlorin 13-Ni26 (type G1) with NH4OH followed by methylation.534 Each member 13Ni62ab, 13-Ni63ab, 13-H264, 13-Ni64, 13-H265, 13-Ni65, EO


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Review

Scheme 200. Derivatization of a 16,19-Diformyl-seco-chlorin (type G1)

Scheme 201. Monoalkoxy-morpholinochlorins (type H4) and Dialkoxy-morpholinochlorins (type H3)

The 16,19-didecarbo-seco-chlorins 13-Ni69, 13-Ni74b, and 13-Ni74c (type G3) also could be prepared by degradation of the nickel 2,3,12,13-tetrabromo-meso-tetraarylporphyrins 13Ni73a, 13-Ni73b, and 13-Ni73c with E-benzaldoxime sodium salt and CuBr as a catalyst in DMSO at 100−200 °C (Scheme 205).536 Additional products formed under such conditions included the dibromo-16,19-didecarbo-seco-chlorins 13−Ni69Br2, 13-Ni74b-Br2, and 13-Ni74c-Br2 (all type G3), the monobromo-16,19-didecarbo-seco-chlorins 13−Ni69-Br, 13Ni74b-Br, and 13-Ni74c-Br (all type G3), and the 6,9,16,19tetradecarbo-seco-bacteriochlorins 13-Ni75a, 13-Ni75b, and 13Ni75c. The 6,9,16,19-tetradecarbo-seco-bacteriochlorins are also known as bacteriophins. The product distribution depended on the reaction temperature. High temperature (200 °C) was preferred for efficient formation of the 16,19-didecarbo-secochlorins (type G3), with products and yields as follows: 13-Ni69, 26%; 13-Ni74b, 26%, and 13-Ni74c, 12%. The 16,19-diformyl-seco-chlorins 13-H226 and 13-Ni26 (type G1) underwent Cannizarro reaction to give the 17-hydroxy-18-

oxachlorin 13-H227 (type D5), the 17-oxo-18-oxachlorin 13H24 (type F1), and the 17,17-ether linked 18-oxachlorin dimer 13-H276 (Scheme 206).504 Note that the 17-hydroxy-18oxachlorin is a hemiacetal. Similar reaction of the nickel 16,19diformyl-seco-chlorin 13-Ni26 (type G1) gave the 17-hydroxy18-oxachlorin 13-Ni27 (type D5) and the 17-oxo-18-oxachlorin 13-Ni4 (type F1), but no dimer was observed. Treatment of the 17-hydroxy-18-oxachlorins 13-H227 and 13-Ni27 (type D5) with methanol under acid catalysis afforded the corresponding 17-methoxy-18-oxachlorins 13-H229b and 13-Ni29b (type D6), which contain an acetal functional group in the pyrroline motif. Moroever, similar treatment of the oxachlorin dimer 13-H276 also gave the free base 17-methoxy-18-oxachlorin 13-H229b. The latter reaction is an example of transacetalization. The structure of dimer 13-H276, suggested by exciton coupling in the UV−vis absorption spectrum, was confirmed by single-crystal X-ray determination. As noted by Brückner,504 “dimer (13-H276) is chiral, containing two homochiral centers (both sp3 oxazolochlorin carbons) but crystallizes as a racemic mixture··· Evidently, establishment of the chirality of the first chiral center enforces the homochirality of the second. Molecular models show that a heterochiral linkage appears to cause more steric inhibition and does not allow for the observed cog-wheeled arrangement of the phenyl groups”. 13.1.5. Derivatization of 18-Oxachlorins (type F1). The 17-oxo-18-oxachlorins (type F1) have been used as substrates for the preparation of other types of chlorins. The general format for such derivatizations is displayed in Scheme 207. The chemistry for the various transformations is described in the following. EP


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Review

Scheme 202. Transformations of Morpholinochlorins

The 17-oxo-18-oxachlorins 13-H24, 13-H277b, 13-H277c, and 13-H277d (all type F1) underwent substitution with Lawesson’s reagent to give the corresponding 17-thio-18oxachlorins 13-H278a, 13-H278b, 13-H278c, and 13-H278d (all type F2). The 17-thio-18-oxachlorins 13-H278a and 13H278b were readily and quantitatively oxidized back to the 17oxo-18-oxachlorins 13-H24 and 13-H277b (both type F1) upon treatment with sodium hypochlorite (Scheme 208).511 The 17thio-18-oxachlorins (type F2) were found to possess very weak fluorescence, while the 17-oxo-18-oxachlorins (type F1) are bright fluorophores. The 17-thio-18-oxachlorins (type F2) thus were proposed as potential candidates as fluorescence chemodosimeters for hypochlorite detection. Reduction of the 17-thio18-oxachlorin 13-H278a (type F2) with Raney nickel gave a mixture of the 17-hydroxy-18-oxachlorin 13-H227 (type D5, 65%; expected as a racemic mixture), the 18-oxachlorin 13-H279 (type D1, 11%), and the 17-oxo-18-oxachlorin 13-H24 (type F1, 8%) (Scheme 209).511 The 17-oxo-18-oxachlorins 13-H24, 13-H280b, and 13-H280c (all type F1) underwent substitution with hydrazine to give the 17-oxo-18-aminoazachlorins 13-H281a, 13-H281b, and 13H281c (all type E2). Subsequent reduction with SmI2 gave the 17-oxo-18-azachlorins 13-H282a, 13-H282b, and 13-H282c (all type E1) (Scheme 210).537,538 The 17-oxo-18-azachlorins are also known as porpholactams. The 17-oxo-18-oxachlorins 13-Zn4 and 13-Zn80c (type F1) underwent addition with an alkylmagnesium bromide (or chloride) to give the 17-alkyl-17-hydroxy-18-oxachlorins 13-

H283a, 13-H283b, 13-H283c, 13-H283Fb, and 13-H283Fc (all type D3) (Scheme 211). Note that the macrocycles of type D3 are hemiketals. The “Fb” and “Fc” terminology conveys a 4trifluoromethylphenyl substituent (see inset in Scheme 211). Double-alkylation was achieved with an alkylmagnesium bromide (or chloride) in the presence of BF3·OEt2 (or TMSOTf) to give the 17,17-dialkyl-18-oxachlorins 13-H284a, 13-H284b, 13H284c, 13-H284Fb, and 13-H284Fc (all type D9).539,540 The 17,17-dialkyl-18-oxachlorins are gem-dialkylchlorins. The 17-alkyl-17-hydroxy-18-oxazalochlorins (type D3) underwent a number of reactions. Hydrodehydration occurred upon reaction with triethylsilane and BF3·OEt2 to give the 17-alkyl-18oxachlorins 13-H285a, 13-H285b, 13-H285c, 13-H285Fb, and 13-H285Fc (all type D2).539,540 The hydroxy group of hemiketal type D3 was replaced in the presence of methanol and acid catalysis to give the 17-methoxy-17-alkyl-18-oxazalochlorins 13H286c and 13-H286Fc (type D4), each of which is a ketal. The ketalization could be reversed to form the hemiketal (type D3) upon treatment with HCl.540 The 17,17-dialkyl-18-oxachlorin 13-H284c (type D9) also was prepared in stepwise fashion (type D3 → type D4 → type D9).540 The overall approach has been extended to meso-tetraarylporphyrins with diverse alkyl substituents540 for investigation as optical sensors.541−543 For a given 17-oxo-18-oxachlorin (type F1) starting material, the resulting gem-dialkyloxachlorin (type D9) is devoid of stereoisomers, which is not the case for structures of types D2, D3, and D4 (Scheme 211). EQ


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Table 34. Decarbonylation of a 16,19-Diformyl-seco-chlorin (type G1)

Scheme 204. Synthesis of a Methylazeteochlorin (type L4)

Scheme 205. Synthesis of 16,19-Didecarbo-seco-chlorins (type G3)

yield (%) entry 1a 2c

type G2

type G3

type L3

ref

12 9

59 45

b 7

531 535

a

4 equiv of (Ph3P)3RhCl, PhCN, reflux, 90 min. bNot reported. c1 + 0.5 + 0.5 equiv of (Ph3P)3RhCl, PhCN/C6H6 (1:1), reflux, 72 h.

Scheme 203. Vilsmeier Formylation of a 16,19-Didecarboseco-chlorin (type G3)

Reduction of the 17-oxo-18-oxachlorin 13-Zn4 (type F1) with DIBAL−H gave the 17-hydroxy-18-oxachlorin 13-Zn27 (type D5, expected to be racemic) (Scheme 212).200,486,544 The 17oxo-18-oxachlorin (type F1) has features common to both porphyrins and chlorins,494 yet exhibits an absorption spectrum more typical of a porphyrin; by contrast, the 17-hydroxy-18oxachlorin (type D5) is chlorin-like (vide inf ra).200 We note that there likely are several ways to prepare structures of type D5 ER


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Scheme 206. Cannizarro Reaction of the 16,19-Diformyl-secochlorins (type G1)

Scheme 207. Derivatization of 18-Oxachlorins (type F1)

including the following: (1) from type A1 in Scheme 182; (2) from type G1 in Scheme 206; and (3) by the method shown here in Scheme 212. The latter method appears to be the most efficient. Exposure of the 17-hydroxy-18-oxachlorins (type D5) to an alcohol in acidic media gave the corresponding ether (type D6), which also is expected to be racemic. The results for a wide variety of alcohols are shown in Table 35.200,504,506,544,545 The 17-hydroxy-18-oxachlorin 13-H227 (type D5, racemic) underwent reduction with triethylsilane to give the achiral 18oxachlorin 13-H279 (type D1). The latter was exquisitely sensitive to oxidation of the methylene unit (Scheme 213).200 The 17-hydroxy-18-oxachlorin 13-H227 (type D5) contains a hemiacetal functionality, which underwent exchange with N,Ndialkylamines to give the corresponding 17-dialkylamino-18oxachlorins 13-H287a and 13-H287b (type D7), which are hemiaminals. Similar exchange with thiols gave the 17-alkylthio18-oxachlorins 13-H288a and 13-H288b (type D8),200 which are hemithiooxaacetals. Each product of types D7 and D8 are expected to be racemic. An early study by Johnson and co-workers suggested that octadehydrocorrin 13-Ni89 (presumably racemic) underwent thermolysis to form a porphyrin−epoxide. Further investigation by Chang and co-workers revealed that the chief product derived

from oxidative ring opening underwent further structural alterations, thereby forming 13-Ni90 and the nickel porphyrin 13-Ni91 (Scheme 214).546 The structure 13-Ni90 has been referred to as a furochlorophin (where chlorophin refers to a 16,19-didecarbo-seco-chlorin; see Scheme 202) to denote the 18π chlorin-like structure and the annulated furan ring. The furochlorophin 13-Ni90 underwent demetalation in strong acid to form the free base macrocycle 13-H290 as well as putative macrocycle 13-H292. Other tautomers of 13-H292 are possible, and the one shown here, which preserves the 18π-electron pathway, differs from those displayed in the literature. The free base furochlorophin 13-H290 could be metalated with copper or zinc to give 13-Cu90 or 13-Zn90, respectively. Remetalation of free base furochlorophin 13-H290 with nickel gave 13-Ni90. The absorption spectrum of furochlorophin 13-H290 is shown in Figure 61. In summary, the “making and bending” strategy,478,547 largely developed by Brückner and co-workers, has been richly exploited to gain access to diverse macrocycles owing to the composition of the pyrroline ring β-atoms and substituents. There remain three ES


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Scheme 208. Synthesis of 17-Thio-18-oxachlorins (type F2)

Scheme 210. Synthesis of 17-Oxo-18-azachlorins (types E1 and E2)

Scheme 209. Derivatization of a 17-Thio-18-oxachlorin (type F2)

(2) Some of the products exhibit characteristic chlorin-like spectral properties whereas others are clearly porphyrinlike (e.g., the 17-oxo-18-oxachlorins, 17-thio-18-oxachlorins, and 16,19-diformyl-seco-chlorins). In-depth studies on many of the putative chlorin architectures have only just begun to address whether the “broken and mended macrocycle” behaves like a porphyrin, simple chlorin, or chlorophyllesque chlorin in terms of absorption spectra and photophysical properties.200,486,534 (3) Strategies have not yet been invented to incorporate structural motifs in chlorins with the exquisite architectural exactness enabled by de novo syntheses (vide infra). Hence, the jury remains out in most respects on the suitability (stability, photophysical properties, synthetic/ architectural versatility) of the pyrroline structural motifs for use as chlorophyll surrogates. Regardless, the collection of molecules described in this section constitutes a treasure-trove for physicochemical studies, which are expected to enrich our understanding of the essential structural and electronic features that engender chlorin photophysical properties. The spectral properties of the chlorins with diverse pyrroline motifs, most of which have been prepared via breaking and mending strategies, are described in the next section.

relatively undefined issues concerning the diverse motifs shown in Table 25: (1) Knowledge concerning the stability of the various pyrroline motifs toward diverse conditions is rather incomplete. ET


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Scheme 211. Synthesis of Mono- and Bis-alkyloxazolochlorins (types D2, D3, D4, and D9)

Scheme 212. Reduction of a 17-Oxo-18-oxachlorin (type F1)

Table 35. Derivatization of Hydroxy-18-oxachlorins (type D5)

13.2. Spectral Properties of Chlorins with Diverse “Pyrroline Rings”

The absorption spectra for 49 representative members of the collection of compounds described in Section 13.1, where available, have been assembled in Figure 62. The known molar absorption coefficients where available are listed in the legend to the Figure. In some cases, the spectrum was available in one solvent but the molar absorption coefficient was reported in a different solvent; such cases also are noted in the legend. Given that not all molar absorption coefficients are available, for consistency of display, the spectra have been normalized at the B bands. Visual inspection reveals that some spectra are “chlorinlike”, others are “porphyrin-like”, and yet others are distinct from both the canonical chlorin and porphyrin spectra. EU

entry

Ar

M

1 2 3 4 5 6 7 8 9 10 11 12

phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl C6F5 C6F5 C6F5

H, H Ni Ag H, H H, H Ni H, H H, H H, H Zn Zn Zn

R methyl methyl ethyl i-propyl t-butyl n-octyl cyclohexyl cholesteryl pregnenolonyl propargyl 2-azidoethyl 3-azido-2-(azidomethyl) propyl

yield (%)

ref

90 94 quant. 95 80 92 95 88 83 80 85 85

504 504 506, 544 200 200 200 200 200 200 545 545 545


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Scheme 213. Derivatization of a Hydroxy-18-oxachlorin

Scheme 214. Rearrangement of an Octadehydrocorrin to a Furochlorophin

13.3. Synthetic Applications of Breaking and Mending

13.3.1. Annulations of Modified Pyrroline Units. The availability of the diverse structural motifs shown in Table 25 presents wide, if not bewildering, opportunities in tetrapyrrole science. While the ramifications remain to be defined, a glimpse at how one such structure has been used to create a novel molecular architecture is illustrated in Scheme 215.199 Tetrapyrrole macrocycles containing meso-pentafluorophenyl groups (e.g., H2F20TPP) are known to be susceptible to nucleophilic replacement of the p-fluorine atoms; such reaction has been exploited as a convenient means of creating diverse substituted derivatives (see Scheme 149).437 The dihydroxychlorin 13-H293 (type A1) derived from H2F20TPP underwent further transformations: simple heating in DMF at reflux resulted in a single intramolecular cyclization, affording monoalcohol/ monoether 13-H294a. On the other hand, use of NaH and MeI in THF at room temperature gave the diether 13-H294b, whereas omission of MeI resulted in double cyclization to give 13-H295. Moreover, the monoalcohol/monoether 13-H294a could be converted by treatment with NaH in THF to give 13H295. The annulation caused the long-wavelength absorption band to shift bathochromically by 16 nm (13-H294a) and a further 8 nm upon installation of the second ether (13-H295). Compounds 13-H294a and 13-H294b are expected to be racemic. Because 2-benzopyrans are termed chromenes, 13H294a,b and 13-H295 are referred to as chromene−chlorins.199 The absorption spectra of dihydroxychlorin 13-H293, chro-

Figure 61. Absorption spectrum of furochlorophin 13-H290 in dichloromethane.546

mene−chlorin 13-H294a, and chromene−chlorin 13-H295 are shown in Figure 63. The seco-chlorin-dialdehyde 13-Ni26 (type G) is ruffled and hence exists as a mixture of conformational enantiomers (Scheme 216).548 Treatment of the diformylchlorin with an alcohol afforded the morpholinochlorin (e.g., see Scheme 183). Here, reaction with cholesterol afforded the corresponding hemiacetals, which transformed via presumed electrophilic aromatic substitution to the annulated morpholinochlorins 13Ni97-(+443)-Chol and 13-Ni97-(−443)-Chol. Given that EV


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Figure 62. continued

EW


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EX


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EY


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Figure 62. Absorption spectra of tetrapyrroles bearing diverse pyrroline motifs. The spectra have been normalized at the B bands. The color code is free base (red), nickel (blue), zinc (aqua), and copper (moss green). Ar = phenyl unless otherwise noted. The following list provides more in-depth information concerning the spectra displayed here: (1) Type A1 (cis-17,18-dihydroxy). Free base in dichloromethane200 (ε = 186 000 M−1 cm−1 at 408 nm in dichloromethane containing 0.5% methanol196), nickel chelate in dichloromethane containing 0.5% methanol (ε = 126 000 M−1 cm−1 at 416 nm),505 and zinc chelate in dichloromethane200 (ε = 257 000 M−1 cm−1 at 418 nm in dichloromethane containing 0.5% methanol196). (2) Type A2 (cis17,18-dialkoxy). Free base (R = methyl, ε = 141 000 M−1 cm−1 at 414 nm) in dichloromethane.501 (3) Type A4 (trans-17,18-dihydroxy-17,18-dialkyl). Free base (R = methyl, ε = 138 000 M−1 cm−1 at 417 nm) and nickel chelate (R = methyl, ε = 95 500 M−1 cm−1 at 418 nm, corrected from the literature) in dichloromethane.520 (4) Type B1 (17,18-dioxo). Free base (ε = 74 100 M−1 cm−1 at 403 nm) in chloroform, and nickel chelate (ε = 77 600 M−1 cm−1 at 413 nm) in dichloromethane.485 (5) Type B2 (17-oxo-18-diazo). Nickel chelate in dichloromethane.515 (6) Type B3 (17-oxo-18,18-dialkoxy). Cupper chelate (R = n-butyl) in dichloromethane.512 (7) Type B6 (17-oxo-18-hydroxyimino). Free base (ε = 234 000 M−1 cm−1 at 405 nm)517 and nickel chelate (ε = 316 000 M−1 cm−1 at 410 nm)518 in dichloromethane. (8) Type B7 [17,18-bis(hydroxyimino)]. Free base (ε = 129 000 M−1 cm−1 at 420 nm) in dichloromethane.517 (9) Type B8 (1,2,5-oxadiazole-fused). Free base (ε = 302 000 M−1 cm−1 at 418 nm) in dichloromethane.517 (10) Type D1 (18-oxa). Free base and zinc chelate in dichloromethane.200 (11) Type D2 (17-alkyl-18-oxa). Free base (R = i-propyl, ε = 186 000 M−1 cm−1 at 423 nm in chloroform) in dichloromethane.539 (12) Type D3 (17-alkyl-17-hydroxy-18-oxa). Free base (R = i-propyl, ε = 166 000 M−1 cm−1 at 420 nm in chloroform) in dichloromethane.539 (13) Type D5 (17-hydroxy-18-oxa). Free base504 (ε = 182 000 M−1 cm−1 at 416 nm506) and zinc chelate (ε = 234 000 M−1 cm−1 at 415 nm200) in dichloromethane. (14) Type D9 (17,17-dialkyl-18-oxa). Free base (R = i-propyl, ε = 115 000 M−1 cm−1 at 424 nm in chloroform) in dichloromethane.539 (15) Type E1 (17-oxo-18-aza). Free base (ε = 309 000 M−1 cm−1 at 421 nm) in dichloromethane.537 (16) Type E2 (17-oxo-18-aminoaza). Free base (ε = 295 000 M−1 cm−1 at 424 nm) in dichloromethane.537 (17) Type F1 (17-oxo-18-oxa). Free base511 (ε = 269 000 M−1 cm−1 at 423 nm in chloroform480) and zinc chelate (ε = 339 000 M−1 cm−1 at 422 nm) in dichloromethane.200 (18) Type F2 (17-thio-18-oxa). Free base (ε = 178 000 M−1 cm−1 at 453 nm) in dichloromethane.511 (19) Type G1 (16,19-diformyl-seco). Free base in chloroform,504 and nickel chelate in dichloromethane485 (ε = 60 300 M−1 cm−1 at 466 nm in chloroform505). (20) Type G2 (16-formyl-19-decarbo-seco). Nickel chelate (ε = 45 700 M−1 cm−1 at 448 nm) in dichloromethane.531 (21) Type G3 (16,19-didecarbo-seco). Nickel chelate531 (ε = 21 400 M−1 cm−1 at 422 nm) in dichloromethane.531 (22) Type G4 (16,19-diacyl-seco). Nickel chelate (R = methyl) in dichloromethane.520 (23) Type G5 (16,19-dicyano-seco). Ar = 3,5-di-tert-butylphenyl. Free base (ε = 162 000 M−1 cm−1 at 435 nm), nickel chelate (ε = 101 000 M−1 cm−1 at 451 nm), and zinc chelate (ε = 183 000 M−1 cm−1 at 443 nm) in dichloromethane.528 (24) Type H1 (anhydride). Free base in dichloromethane.509 (25) Type H3 (dialkoxy−morpholino). Free base (R = ethyl)203 (ε = 200 000 M−1 cm−1 at 419 nm503) and nickel chelate (R = methyl, ε = 64 600 M−1 cm−1 at 430 nm505) in dichloromethane. (26) Type I1 (imido). Free base (ε = 251 000 M−1 cm−1 at 432 nm) and nickel chelate (ε = 302 000 M−1 cm−1 at 439 nm) in dichloromethane.518 (27) Type I2 (N-benzylimido). Free base (ε = 148 000 M−1 cm−1 at 432 nm) in dichloromethane.518 (28) Type I3 (O-benzyl enol imido). Free base (ε = 102 000 M−1 cm−1 at 438 nm) in dichloromethane.518 (29) Type J (thiamorpholino). Nickel chelate (ε = 77 600 M−1 cm−1 at 442 nm) in dichloromethane.520 (30) Type K1 (oxypyri). Nickel chelate (R1 = H, R2 = methyl, ε = 60 300 M−1 cm−1 at 439 nm) in dichloromethane.520 (31) Type K2 [oxypyri(porphyrin)]. Nickel chelate (R1 = H, R2 = methyl, ε = 93 300 M−1 cm−1 at 453 nm) in dichloromethane.520 (32) Type L2 (acylazeteo). Free base, nickel chelate, and cupper chelate (R = butoxy) in dichloromethane.516 (33) Type L3 (hydroxyazeteo). Nickel chelate (ε = 37 400 M−1 cm−1 at 411 nm) in dichloromethane.535 (34) Type L4 (methylazeteo). Nickel chelate (ε = 52 500 M−1 cm−1 at 406 nm) in dichloromethane.535

Et exhibited opposite optical rotations (as expected) but absolute configurations could not be assigned. The absorption spectrum of morpholinochlorin 13-Ni97-(+443)-Chol is shown in Figure 64. The morpholinochlorin (e.g., type H3: 13-H228; one enantiomer is shown) was readily obtained upon treatment of

cholesterol is enantiomerically pure, the two products are diastereomers. Separation of the diastereomers on preparative thin layer chromatography was achieved, albeit with exchange, whereupon cholesterol was replaced with ethanol in the hemiacetal unit in an enantioretentive manner. The resulting chlorin enantiomers 13-Ni97-(+442)-Et and 13-Ni97-(−442)EZ


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Scheme 215. Annulation To Form “Chromene−Chlorins”

Scheme 216. Separation of Enantiomeric Morpholinochlorinsa

The ± signs indicate deformation that is outward/inward (with respect to the reader) of the ruffled conformers.

a

Figure 63. Absorption spectra in dichloromethane of chlorin−diol 13H293 (red line), chromene−chlorin 13-H294a (orange line), and chromene−chlorin 13-H295 (lavender line).199

give the diketo product. Indeed, periodate oxidation (on silica support) of the dihydroxychlorin 13-H214 (type A1) in the presence of mild acid gave the indaphyrin 13-H298 directly.549 The reaction proved to be compatible with the nickel chelate and aryl groups other than phenyl; the use of 3,4,5-trimethoxyphenyl groups gave rise to more rapid ring closure (minutes instead of hours) under milder acid conditions as expected for electrophilic substitution with the more electron-rich substrate. Moreover, when only a trace of acid was employed following the periodate oxidation, the intermediate monoindaphyrin monocarboxaldehyde 13-H299 could be isolated. The latter could be smoothly transformed to the indaphyrin 13-H298 with relatively stronger (but still modest) acid. The absorption spectra of indaphyrins 13-H298 and 13-H299 are shown in Figure 65.549

cis-17,18-dihydroxychlorin (type A1, 13-H214) with silicasupported NaIO4 in the presence of an alcohol and acid (Scheme 217).503 Exposure of morpholinochlorin 13-H228 to acid afforded the corresponding “indaphyrin” 13-H298.549,550 The term indaphyrin stems from the fusion of an indanone unit to the seco-chlorin framework. The reaction can be envisaged as proceeding via the seco-chlorin-dialdehyde, wherein the flanking phenyl groups undergo intramolecular electrophilic aromatic substitution at the ortho-positions with the neighboring formyl groups. The resulting benzylic alcohol must be oxidized in situ to FA


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Figure 64. Absorption spectrum of morpholinochlorin 13-Ni97(+443)-Chol in benzene.548

Figure 65. Absorption spectra in dichloromethane of indaphyrin 13H298 (red line) and 13-H299 (orange line).549

Scheme 217. Synthesis of an Indaphyrin

Scheme 218. Synthesis of Thiaindaphyrin

The synthetic method for preparing indaphyrins could be applied to other meso-aryl substituted dihydroxychlorins where an ortho-position is susceptible to electrophilic aromatic substitution. Periodate oxidation of the meso-tetrakis(4-methylthien-2-yl)dihydroxychlorin 13-H2100 (type A1) gave monothiaindanone monocarboxaldehyde 13-H2101 in 70% yield (Scheme 218); the latter was fully characterized despite limited stability in solution.551 Treatment of 13-H2101 with mild acid gave thiaindaphyrin 13-H2102. The absorption spectra of 13H2100, 13-H2101, and 13-H2102 are shown in Figure 66. The indaphyrins exhibit exceptionally broad absorption bands.

13.3.2. Doubly Fused Chlorins. A fused quinolino− porphyrin was prepared by beginning with the nickel mononitro tetraphenylporphyrin 13-Ni103552,553 as shown in Scheme 219. Treatment with triethyl phosphite (Cadogan reaction, via the nitrene) afforded the aza-fused porphyrin 13-Ni104.554 In one FB


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reaction pathway, Vilsmeier formylation of the enamine gave regioselective introduction of the formyl group at the adjacent carbon, affording 13-Ni105.554 Exposure to hot acid in excess gave the corresponding monoaza bis-fused product 13-Ni106.555 The latter was demetalated with TFA/H2SO4 to give the free base analogue 13-H2106.555 In a second pathway, the amine was protected as the carbamate 13-Ni107, which underwent smooth nitration again at the adjacent carbon to give 13-Ni108.556 Elevated temperature afforded ring closure to give the bis(azafused) macrocycle 13-Ni109, which was quantitatively demetalated with TFA/H2SO4 to give 13-H2109.556 The absorption spectra of the nickel-chelated macrocycles 13-Ni105, 13-Ni106, and 13-Ni109 and the free base doubly fused macrocycles 13H2106 and 13-H2109 are shown in Figure 67. A parallel series of reactions was carried out contemporaneously by Brückner and co-workers (Scheme 220).517 The synthesis of the mono-oxime 13-H234 (type B6) as well as a trace amount of the bis-oxime 13-H235 (type B7) was described

Figure 66. Absorption spectra in dichloromethane containing 0.1% triethylamine of 13-H2100 (red line), 13-H2101 (lavender line), and 13-H2102 (orange line).551

Scheme 219. Formation of Bis-Annulated Chlorins

FC


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Scheme 220. Formation of Bis-Annulated Chlorins

Figure 67. Absorption spectra in dichloromethane of (1) nickel chelates 13-Ni105 (black dotted line),554 13-Ni106 (orange line),555 and 13Ni109 (red line);556 and (2) free base doubly fused macrocycles 13H2106 (orange line)555 and 13-H2109 (red line).556

previously (Scheme 189) by condensation of 17,18-dioxochlorin 13-H23 with hydroxylamine. The resulting mono-oxime 13H234 under dehydrating acidic conditions gave the ring fusion product 13-H2110 bearing a single keto group; the latter also gave the oxime 13-H2111. Alternatively, treatment of the monooxime 13-H234 with DDQ gave the ring-fusion, N-oxide product 13-H2112. Further treatment with hydroxylamine gave 13H2111 due to reductive deoxygenation and formation of a second oxime. A second ring closure of 13-H2111 under dehydrating acidic conditions then gave the doubly fused bisimine 13-H2109 (identical to that in Scheme 219). The latter was metalated to give the nickel chelate 13-Ni109 (as well as the zinc and palladium chelates; not shown). Alternatively, exposure of 13-H2111 to DDQ gave the N-oxide of the bisimine macrocycle, 13-H2113. Treatment of the bisimine N-oxide macrocycle 13-H2113 with Ni(OAc)2 gave nickelation and deoxygenation to afford 13-Ni109 in 55% yield.557 Note that the bis-oxime 13-H235 (Scheme 189), although obtained as a minor byproduct, under dehydrating acidic conditions gave three products (scheme not shown): the monofused product 13H2110 (66%), the annulated oxadiazole 13-H236 (19%), and the bisimine 13-H2109 (12%). A reasonable question is whether the doubly fused macrocycles of Schemes 219 and 220 are chlorins. The 17,18-double bond is absent as is characteristic of chlorins, yet the absorption spectra generally lack the pronounced sharp Qy band of chlorins. While the answer requires further study (e.g., photophysical characterization, electronic structure calculations), the absorption spectra do exhibit long-wavelength absorption bands that

are enhanced compared with those of the parent porphyrin (Figure 68). Boyle and Dolphin examined cyclization of a copper 5,15diphenylporphyrin bearing a meso-acrolein group, 13-Cu114, with the expectation of forming a benzochlorin. The difference FD


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afforded 18-oxobenzochlorin 13-Cu115 and doubly fused chlorin 13-Cu116 (expected as a racemic mixture). The formation of both compounds is attributed to the susceptibility to oxidation of the doubly allylic site at position 18 in the pyrrolinic ring. No yields were reported. Polar morpholino−hemiacetals such as 13-Ni96a and 13Ni96b (type H4) form during the course of reaction leading to the corresponding dialkoxy−morpholinochlorins. Such hemiacetals also can be prepared directly from the chlorin− dialdehyde. Exposure of the hemiacetal 13-Ni96a or 13-Ni96b to catalytic quantities of acids (e.g., fumes from TFA or conc. HCl) resulted in the phenyl-fused monoalkoxy−morpholinochlorin 13-Ni97a or 13-Ni97b, respectively. Strong acid (excess TFA) and/or prolonged reaction gave rise to double ring closure, affording 13-Ni117 in ∼10% yield (Scheme 222).532 Each Scheme 222. Synthesis of a Doubly Fused Morpholinochlorin

Figure 68. Absorption spectra in dichloromethane of (1) annulated chlorins 13-H2110 (lavender line), 13-H2111 (orange line), and 13H2112 (red line);517 and (2) bis-annulated chlorins 13-H2109 (red line, also shown in Figure 67)555 and 13-H2113 (lavender line).517

between this route (Scheme 221) and those examined previously is the absence of β-pyrrolic substituents.558 The cyclization Scheme 221. Formation of a Bis-Annulated Chlorin

compound 13-Ni96a, 13-Ni96b, 13-Ni97a, 13-Ni97b, and 13Ni117 is expected as a racemic mixture. The doubly fused morpholinochlorin exhibited an absorption spectrum with a rather bathochromically shifted Soret band (452 nm) and an enhanced long-wavelength absorption band (639 nm). In summary, this section has displayed an extraordinarily rich collection of pyrroline motifs, most of which have become accessible only in the past 15 years. Many of the modified pyrroline motifs contain atom substitutions or other modifications at the 17- and 18-positions. Some of the pyrroline motifs enable substitution with groups that project outward from the macrocycle. We now turn inward to consider structural modifications, namely atom replacements, in the inner core of chlorins. FE


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14. CORE-MODIFIED CHLORINS A longstanding research effort in tetrapyrrole chemistry has focused on systematic replacement of skeletal atoms with other atoms, such as replacement of the four nitrogens with carbon, oxygen, sulfur, or selenium; replacement of the meso-carbons with atoms such as nitrogen; and combinations thereof.559−562 This aspect of porphyrin chemistry has hardly penetrated chlorin chemistry. In this section, a survey is provided of reports concerning synthesis of core-modified chlorins, of which a small subset contains geminal-dialkyl groups in the pyrroline ring.

the 17,18-dimethoxychlorin 14-3 (type A2); permanganate oxidation afforded the 17-oxo-18-oxachlorin 14-4 (type F1); and periodate oxidation in the presence of ethanol afforded the diethoxy−morpholinochlorin 14-5 (type H3).203 Among types A2, F1 and H3, only H3 contains stereoisomers (not shown). The absorption spectra of the parent dithiaporphyrin 14-1, the cis-17,18-dihydroxydithiachlorin 14-2, 17-oxo-18-oxadithiachlorin 14-4 and diethoxy−morpholinodithiachlorin 14-5 are shown in Figure 69.

14.1. Other Atoms in Place of Nitrogen

Brückner and co-workers treated meso-tetra-p-tolyl-21,23dithiaporphyrin 14-1 with OsO4 and found that vicinal dihydroxylation proceeded at the pyrrole rather than thiophene unit, affording the dihydroxychlorin 14-2 (Scheme 223).203,204 The selectivity of oxidation (pyrrole versus thiophene) was attributed to the least loss of resonance energy.203 Subsequent transformations of the vicinal hydroxy groups in the pyrroline ring enable the diversity derived therefrom in noncore-modified macrocycles, as shown in Table 25. Thus, methylation afforded Scheme 223. Synthesis of Dithiachlorins

Figure 69. Absorption spectra in dichloromethane of (1) dithiaporphyrin 14-1 (black dotted line) and cis-17,18-dihydroxydithiachlorin 142 (red line),203 and (2) 17-oxo-18-oxadithiachlorin 14-4 (red line) and diethoxy−morpholinodithiachlorin 14-5 (lavender line).203

A route to N-confused chlorins is shown in Scheme 224.563 The 1,3-dipolar cycloaddition of N-confused porphyrin 14-6 with 2,6-dichlorobenzonitrile oxide afforded a mixture of bisadducts, chlorins (monoadducts), and unreacted porphyrin. Four chlorin isomers 14-Ni7a−d were distinguishable by NMR spectroscopy in ratio of 55:27:13:5. Separation of the free base chlorins proved difficult; hence, the nickel chelates were prepared, affording a mixture of isomers in similar ratio of 57:27:9:7. Isomer 14-Ni7a was isolated by chromatography and demetalated with HCl to give the free base 14-H27a (not shown). The latter was identified unambiguously by singlecrystal X-ray crystallography. Further separation of the mixture of chlorins by chiral-phase chromatography led to a number of optically active fractions, as each chlorin displayed represents one member of a pair of enantiomers. The absorption spectra of Nconfused porphyrin 14-6 and of N-confused free base chlorin 14H27a are shown in Figure 70. An example of a route to carbachlorins has been provided by Hayes and Lash.565 The reaction entailed use of tripyrrane 14-8 and bicyclo[3.3.0]octanedialdehyde (14-9a) in a “3 + 1” route FF


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Scheme 224. Synthesis of N-Confused Chlorins by Cycloaddition

Scheme 225. De Novo Synthesis of a Carbachlorin

Scheme 226. De Novo Synthesis of a Carbachlorin

Scheme 227. Attempted Synthesis of a Carbachlorin

Figure 70. Absorption spectra in dichloromethane of N-confused porphyrin 14-6 (black dotted line)563,564 and N-confused chlorin 14H27a (free base of 14-Ni7a, red line).563

resembling the MacDonald-type route to porphyrins (Scheme 225). Acid-catalyzed condensation of 14-8 and 14-9a in dichloromethane containing TFA was followed by oxidation with DDQ in refluxing toluene. Ordinarily, DDQ in refluxing toluene effects dehydrogenation of a chlorin thereby forming the porphyrin;47 but here, the propano-carbachlorin 14-H210 was formed intact in 15% yield. The resistance to dehydrogenation must stem from the presence of the annulated propane unit. The carbachlorin 14-H210 afforded a bright green solution in organic solvents and a typical chlorin-like long-wavelength absorption

band at 650 nm. Similar reaction with dialdehyde 14-9b gave propeno−carbachlorin 14-H211 in 11% yield, presumably as a racemic mixture (Scheme 226). Attempts to use a cyclopentane-1,3-dicarboxaldehyde (14-9c), which lacks the bridging cycloalkane unit, in the same reaction FG


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Scheme 228. De Novo Synthesis of a Carbachlorin and Carbaporphyrin

Figure 71. Absorption spectra in dichloromethane (containing 1% triethylamine) of carbachlorin 14-H212 (red line) and carbaporphyrin 14-H213 (black dotted line).566

Scheme 229. De Novo Synthesis of a Dicarbachlorin

with tripyrrane 14-8 did not give the expected chlorin 14-H212 (Scheme 227).566 The failure of 14-9c prompted examination of a dialdehyde equivalent.566 Thus, acid-catalyzed condensation of 3-ethoxymethylenecyclopenten-1-carboxaldehyde (14-9d) and tripyrrane 14-8 followed by very brief exposure to oxidative conditions gave the corresponding carbachlorin 14-H212 (Scheme 228). The carbachlorin 14-H212, which is effectively hydrogenated in the “carbapyrroline” ring, provides the first example of a carbachlorin lacking β-substituents in the “carbapyrrole” ring. The carbachlorin was dehydrogenated with DDQ to give the carbaporphyrin 14-H213. Additional reactions (not shown) that carbachlorin 14-H212 underwent include (1) protonation at the pyrrolenine nitrogen, (2) metalation with Ag(I)acetate to give the Ag(III) chelate (31% yield), and (3) Nmethylation at one of the pyrrole nitrogens. The carbachlorin 14H212 also gave a slightly enhanced long-wavelength absorption band. The absorption spectra of 14-H212 and 14-H213 are shown in Figure 71. Lash extended the approach shown in Schemes 225−228 to the preparation of a dicarbachlorin. Thus, the reaction of dicyclopentadienylmethane 14-15 (mixture of isomers) and dipyrromethane 14-14 under basic conditions gave the dicarbachlorin as a mixture of tautomers 14-16a and 14-16b (Scheme 229).567 The putative tautomer 14-16c was ruled out on the basis of 1H NMR data, as was the putative tautomer dicarbaporphyrin 14-17 (in addition to mass spectrometric data). Single-crystal X-ray data confirmed the presence of dicarbachlorin 14-16a. The absorption spectrum of 14-16a is shown in Figure 72. Carbaporphyrins have recently been prepared from thiophene or furan reactants, wherein the β-position of the “confused ring” is substituted with a sulfur or oxygen atom. The βthiacarbaporphyrins and β-oxacarbaporphyrins have been

Figure 72. Absorption spectrum of 14-16a in chloroform containing 1% triethylamine.567 FH


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found to undergo transformations at the β′-carbon.568 Examples of the resulting products are shown in Scheme 230. Note that the

14.2. Heteroatoms in the Peripheral Skeleton

Investigation of the chemistry of phthalocyanines, which are meso-tetraaza-β-tetrabenzoporphyrins, began in earnest in the early 1930s573 and continues unabated at present. The analogues lacking the four benzo groupsknown as tetraazaporphyrins or porphyrazineswere first generally accessed in the early 1950s574 and have received comparatively less but still considerable attention.575 The structures of phthalocyanine, tetrabenzoporphyrin, tetraazaporphyrin (i.e., porphyrazine), and tetraazachlorin (i.e., 17,18-dihydroporphyrazine) are shown in Scheme 231. Tetraazaporphyrin and tetraazachlorin are

Scheme 230. Carbachlorins with Modified β-Positions of Ring D

Scheme 231. Three Tetraazatetrapyrroles and Tetrabenzoporphyrin

“carbapyrroline” motifs (left to right in the scheme) are analogues of pyrroline types F2, F1, D6 and D2, respectively. The synthesis and physicochemical properties of a large collection of carbaporphyrins with diverse “confused ring motifs” have been reviewed by Lash569 and by Pawlicki and LatosGrazynski.559 On the basis of the absorption spectra, 14-H218 and 14-H219 are chlorins in name only,570,571 as the characteristic strong longwavelength absorption band is not present, whereas 14-H220 and 14-H221 exhibit a long-wavelength band with only minutely enhanced absorption intensity (see section 13.2).572 The availability of diverse tetrapyrroles is expected to broaden our understanding of the roles of molecular composition and structure in giving rise to characteristic chlorin spectral features. The photochemical features of core-modified chlorins have in general been little studied. The absorption spectra of carbachlorins 14-H219, 14-H220, and 14-H221 are shown in Figure 73. Far more profound structural modifications are provided by substitution of the four meso-carbons with nitrogen atoms, a class of macrocycles to which we now turn.

analogues of porphine and chlorin, respectively. The reduced derivatives such as tetraazachlorin have until quite recently been comparatively unexamined. The absorption spectra of tetrabenzoporphyrin (free base and protonated), magnesium tetrabenzoporphyrin and Mn(II) tetrabenzoporphyrin are shown in Figure 74. For comparison, the absorption spectra of the fully unsubstituted porphyrazine and 17,18-dihydroporphyrazine are shown in Figure 75. Several reviews that treat “hydrogenated tetraazaporphyrins,”579 “low symmetry phthalocyanines,”580 and “asymmetric phthalocyanines”581 have appeared within the past decade. Formation of tetraazachlorins has parallels with chemistry established for nonaza-containing tetrapyrrole macrocycles, although there are far fewer examples and less extensive development. The review by Fukuda and Kobayashi covers the early approaches toward chlorin-like analogues of porphyrazines, which include hydrogenation, reductive derivatization, and cycloaddition with the porphyrazine.579 De novo syntheses, which are beyond the scope of the present review, are also treated. A subtopic apparently not treated in depth previously concerns seco-porphyrazines, which is covered in the following sections (hereafter we use the term porphyrazine, which is preferred by most practitioners). The reader is referred to the aforementioned reviews for full coverage of the literature. 14.2.1. seco-Porphyrazines. Barrett, Hoffman and coworkers performed a fairly standard porphyrazine synthesis by reaction of 2,3-bis(dimethylamino)maleonitrile (14-22) in the presence of magnesium propoxide in refluxing propanol (Scheme 232). The product was the magnesium porphyrazine 14-Mg23 along with a trace of a more polar pigment, the free

Figure 73. Absorption spectra in dichloromethane of carbachlorins 14H219 (red line),570 14-H220 (orange line),570 and 14-H221 (lavender line) (Ar5, Ar10 = p-tolyl; Ar15, Ar20 = phenyl).572 FI


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Scheme 232. A seco-Porphyrazine from a Symmetrical Porphyrazine

Figure 74. Normalized absorption spectra of (1) tetrabenzoporphyrin in chloroform (orange line), 5% pyridine/THF (red line; ε = 85 100 M−1 cm−1 at 427 nm), and 1% TFA/dichloromethane (lavender line);576 and (2) magnesium tetrabenzoporphyrin (lime line; ε = 331 000 M−1 cm−1 at 433 nm) in 5% pyridine/THF577 and manganese(II) tetrabenzoporphyrin (violet line) in DMF.578

Scheme 233. A seco-Porphyrazine by Oxidation of a Symmetrical Porphyrazine

Figure 75. Absorption spectra of tetraazaporphyrin (black dotted line, in n-octane;443 ε = 55 000 M−1 cm−1 at 617 nm in chloroform442) and tetraazachlorin [red line, in chloroform/methanol (6:1);443 ε = 53 700 M−1 cm−1 at 678 nm in chlorobenzene442].

base seco-porphyrazine 14-H224, zinc porphyrazine 14-Zn23 and zinc seco-porphyrazine 14-Zn24 are shown in Figure 76. The reaction of two distinct dicyanomaleonitriles typically affords a mixture of substituted macrocycles derived from either one or both of the parent maleonitriles. In principle, for A and B reactants, one expects the A4, A3B, cis-A2B2, trans-A2B2, AB3, and B4 products. In practice, Barrett and Hoffman and co-workers have found that appropriate adjustment of the ratio of A and B reactants so that A is in excess (and where A and B react at similar rates) chiefly affords two products, the A4 and A3B species. Upon surveying dicyanomaleonitriles for comparable kinetics of

base seco-porphyrazine 14-H224.582,583 Demetalation of 14Mg23 in the presence of air gave the free base seco-porphyrazine 14-H224 in 62% yield whereas demetalation under anaerobic conditions gave the free base porphyrazine 14-H223 in 69% yield. Alternatively, treatment of free base porphyrazine 14-H223 with MnO2 gave the free base seco-porphyrazine 14-H224 in nearly quantitative yield (Scheme 233).583 The same reaction on the zinc porphyrazine 14-Zn23, obtained by zincation of 14H223, gave the zinc seco-porphyrazine 14-Zn24 in 77% yield.583 The absorption spectra of free base porphyrazine 14-H223, free FJ


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conversion of reactants, chromatographic separation, and subsequent demetalation processes. Treatment of free base porphyrazine 14-H227 with KMnO4 gave the corresponding seco-porphyrazine 14-H228 in >90% yield (Scheme 234, top panel).583 Application of the same KMnO4-mediated oxidation with zinc porphyrazine 14-Zn27, obtained from 14-H227 via standard zincation conditions for porphyrins, afforded the zinc seco-porphyrazine 14-Zn28 also in >90% yield. In each case, the oxidation proceeded at the pyrrole ring bearing the most electron-rich substituents, namely the vicinal-dimethylamino groups rather than the propyl groups, despite the presence of three pyrroles with propyl substitution and only one pyrrole with dimethylamino substitution. This strategy of installing one electron-rich site to direct oxidation was extended to maleonitrile 14-29. Cocyclization with the dipropylmaleonitrile 14-26 followed by the standard chromatography and demetalation gave the free base porphyrazine 14H230 in 11% yield (Scheme 234, middle panel). Zincation followed by oxidation gave in 44% yield the zinc secoporphyrazine 14-Zn31 (which is stereoisomeric depending on the structure of the precursor 14-29).586 Application of this synthetic approachstatistical condensation followed by permanganate oxidation of the A3B-species− afforded the seco-porphyrazines 14-Zn32,587 14-H233,587 14Zn33,587 and 14-Zn34 (Scheme 234, bottom panel).588 secoPorphyrazine 14-Zn34 was found to be water-soluble and bioconjugatable.588 An insightful, conversational account of the discovery and elaboration of seco-porphyrazines by Barrett and Hoffman and co-workers is available.589 The absorption spectra of a number of free base or zinc porphyrazines are shown in Figures 77−79. Gonca and co-workers prepared a set of octaarylporphyrazines.590,591 The synthesis proceeded in fairly standard fashion, by reaction of a disubstituted maleonitrile with Mg turnings in a high-boiling alcohol (e.g., n-butanol) at reflux, whereupon the magnesium chelate was obtained. In attempting to demetalate the magnesium chelate with TFA, the product was not the expected free base porphyrazine; instead, the seco-porphyrazine17,18-dione was obtained. A series of seco-porphyrazines was prepared in this fashion (Table 36). This approach would appear to obviate the statistical cocyclization shown in the preceding schemes. The absorption spectra of magnesium octa(4methylphenyl)porphyrazine and free base octa(4-methylphenyl)-seco-porphyrazine-17,18-dione; magnesium octa(4biphenyl)porphyrazine and free base octa(4-biphenyl)-secoporphyrazine-17,18-dione; and magnesium octa(4-tertbutylphenyl)porphyrazine and free base octa(4-tert-butylphenyl)-seco-porphyrazine-17,18-dione are shown in Figure 80. The cocyclization of 2,5-diiminopyrrolidine 14-35 and 3,4bis(4-tert-butylphenyl)pyrroline-2,5-diimine 14-36 gave the expected mixture of macrocycles, as the magnesium chelates (Scheme 235).596 Chromatographic separation and demetalation with TFA gave the A3B-type porphyrazine 14-H237 in 17% overall yield. Porphyrazine 14-H237 contains three pyrroles with a full complement of β-substituents and one pyrrole that lacks such substituents. Treatment with OsO4 gave the dihydroxychlorin analogue 14-H238. Metalation of 14-H238 with nickel acetate resulted in scission of the pyrroline ring and oxidation to form the monoketo seco-porphyrazine 14-Ni39. The “seco” terminology is used a bit loosely here and throughout the remainder of this section; 14-Ni39 more exactly would be termed a 17,18-didecarbo-seco-porphyrazin-18-one. Alternatively, nickelation of 14-H237 to form 14-Ni37 followed by

Figure 76. Normalized absorption spectra in dichloromethane of (1) free base porphyrazine 14-H223 (black dotted line, ε = 37 200 M−1 cm−1 at 334 nm) and free base seco-porphyrazine 14-H224 (red line, ε = 57 500 M−1 cm−1 at 323 nm); and (2) zinc porphyrazine 14-Zn23 (black dotted line, ε = 49 000 M−1 cm−1 at 335 nm) and zinc secoporphyrazine 14-Zn24 (red line, ε = 63 100 M−1 cm−1 at 334 nm).583

reaction with the desired 2,3-bis(dimethylamino)maleonitrile (14-25), 2,3-dipropylmaleonitrile (14-26) was found to be a suitable reaction partner. Thus, cocyclization of 14-26 (A) and 14-25 (B) in 7:1 ratio under otherwise standard reaction conditions gave the A4 and A3B species, which were readily separated by chromatography given the difference in polarity of the propyl versus dimethylamino substituents (Scheme 234, top panel).584 The magnesium A3B-porphyrazine was treated with TFA to give the free base A3B-porphyrazine 14-H227 in overall 19% yield. Zincation of 14-H227 gave zinc A3B-porphyrazine 14Zn27. A comment about statistics in this context may be warranted. If statistics are obeyed, the A3B compound would constitute 25% of the total mixture upon a 1:1 ratio of A and B reactants, but 42.19% upon a 3:1 ratio of A and B reactants. Even higher ratios do not afford a greater fraction of the desired A3B species (in fact the fraction is less), but such ratios would diminish the amount of the more highly B-enriched species (i.e., A2B2, AB3, B4), which can facilitate purification. The overall yield of the A3B compound is the product of this statistical issue (i.e., binomial statistics that dictate the fraction of the total mixture) and the percentage of starting material that is converted to macrocycles (i.e., total macrocycle yield). Differences of reactivity of the A and B reactants would skew the expected statistical outcome. This analysis has been developed for porphyrin formation and applies equally to porphyrazines.41,47,585 Regardless, the overall yield of 19% for A3B-porphyrazine 14-H227 is quite excellent given the expected statistical nature of macrocycle formation, overall FK


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Scheme 234. seco-Porphyrazines from Unsymmetrical Porphyrazines

treatment with OsO4 gave the dihydroxychlorin analogue 14-

The reaction of diaryl-substituted 1,3-diiminoisoindoline 1440 in refluxing 2-(N,N-dimethylamino)ethanol containing NiCl2 or PdCl2 gave the expected metallophthalocyanine 14-Ni41 or 14-Pd41, respectively, in reasonable yield (Scheme 236).597 In addition, the metalated seco-tribenzoporphyrazine 14-Ni42 or 14-Pd42 was isolated in 2% yield in each case. The investigation

Ni38; the latter also could be prepared simply by anaerobic nickelation of 14-H238. The absorption spectra of nickel porphyrazine 14-Ni37, nickel dihydroxyporphyrazine 14-Ni38, and nickel seco-porphyrazinone 14-Ni39 are shown in Figure 81. FL


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Figure 79. Absorption spectra in toluene of (1) zinc seco-porphyrazine 14-Zn32 (arbitrary scale); and (2) zinc seco-porphyrazine 14-Zn33 (aqua line, ε = 44 700 M−1 cm−1 at 339 nm in dichloromethane) and free base seco-porphyrazine 14-H233 (red line, ε = 24 500 M−1 cm−1 at 375 nm in dichloromethane).587

Figure 77. Normalized absorption spectra in dichloromethane of (1) free base porphyrazine 14-H227 (black dotted line) and free base secoporphyrazine 14-H228 (red line, ε = 56 200 M−1 cm−1 at 348 nm); and (2) zinc porphyrazine 14-Zn27 (black dotted line, ε = 66 100 M−1 cm−1 at 341 nm) and zinc seco-porphyrazine 14-Zn28 (red line, ε = 49 000 M−1 cm−1 at 356 nm).583

Table 36. seco-Porphyrazines from Octaaryl Porphyrazines

Figure 78. Absorption spectra of zinc porphyrazine 14-Zn30 (black dotted line) and zinc seco-porphyrazine 14-Zn31 (red line) in dichloromethane.586

of other metal chlorides, solvents and precursors (e.g., phthalonitrile) gave only the metallophthalocyanine. Treatment of an intact metallophthalocyanine to the same reaction conditions did not afford the metalated seco-tribenzoporphyrazine, implying that the ring scission must occur during the reaction rather than after formation of the macrocycle. The absorption spectra of nickel porphyrazine 14-Ni41, nickel secoporphyrazine 14-Ni42, palladium porphyrazine 14-Pd41, and palladium seco-porphyrazine 14-Pd42 are shown in Figure 82. 14.2.2. Diazachlorins. A 5,15-diaryl-10,20-diazachlorin could be obtained by nucleophilic attack on the corresponding

entry

R

yield (%)

ref

1 2 3 4 5 6 7

4-methylphenyl 2-methylphenyl 4-biphenyl 4-tert-butylphenyl 1-naphthyl 3,5-bis(trifluoromethyl)phenyl C6 F 5

53 48 64 56 60 65 68

590 590 591 592 593 594 595

diazaporphyrin. The diazaporphyrin itself was prepared by reaction of dihalo−dipyrrins with azide.598 The nucleophiles employed were alkyllithium reagents. Thus, nucleophilic attack on trans-diazaporphyrin 14-Ni43 afforded the β-alkyl-5,15diaryl-10,20-diazaporphyrin 14-Ni44 and the desired β-alkyl5,15-diaryl-10,20-diazachlorin 14-Ni45. The results are shown in Table 37. A noteworthy feature of the reaction is the essentially complete regioselectivity wherein the alkyl group was installed adjacent to a meso-aza site. A mechanism proposed to account for these observations is shown in the diagram accompanying FM


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Scheme 235. seco-Porphyrazinone from an Unsymmetrical Porphyrazine

Figure 80. Absorption spectra in chloroform of selected compounds from Table 36: (1) magnesium octakis(4-methylphenyl)porphyrazine (black dashed line) and free base octakis(4-methylphenyl)-secoporphyrazine-17,18-dione (red line, entry 1);590 (2) magnesium octakis(4-biphenyl)porphyrazine (black dashed line) and free base octakis(4-biphenyl)-seco-porphyrazine-17,18-dione (red line, entry 3);591 and (3) magnesium octakis(4-tert-butylphenyl)porphyrazine (black dashed line) and free base octakis(4-tert-butylphenyl)-secoporphyrazine-17,18-dione (red line, entry 4).592

Table 37. The essential feature of the mechanism is coordination of the lithium to the nitrogen atom, thereby causing nucleophilic attack at the adjacent β-pyrrolic carbon. Such attack creates a stereocenter and hence a pair of enantiomers. In one example, treatment with DDQ caused dehydrogenation of the chlorin (entry 1, R = Me) to give the porphyrin.598 One benchmark chlorin was derived by diimide-mediated hydrogenation of 14Ni43, affording the diazachlorin 14-Ni45 where R = H (not shown). The absorption spectra of selected diazaporphyrins and diazachlorins are shown in Figure 83. This and the previous section have treated chlorins with core modification (i.e., atom replacement) and diverse pyrroline

Figure 81. Normalized absorption spectra in dichloromethane of nickel porphyrazine 14-Ni37 (black dotted line), nickel porphyrazine−diol 14-Ni38 (red line), and nickel seco-porphyrazinone 14-Ni39 (lavender line).596

motifs, respectively. In the next section, we consider a collection of molecules that contain contracted macrocycles, expanded macrocycles, or macrocycles with permuted pyrrole/pyrroline/ methene units. Each member of these various sections has features suggestive of a chlorini.e., each would seem to satisfy the infamous legal maxim600 “I know it when I see it”although FN


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Scheme 236. seco-Porphyrazine Byproduct

Table 37. Alkylation Products from a Diazaporphyrin

yield (%)

Figure 82. Absorption spectra in toluene of nickel porphyrazine 14Ni41 (black solid line), nickel seco-porphyrazine 14-Ni42 (red solid line), palladium porphyrazine 14-Pd41 (black dotted line), and palladium seco-porphyrazine 14-Pd42 (red dotted line).597

a

the resemblance may fall across the spectrum from strong to faint.

entry

R of RLi

Porphyrin 14-Ni44

Chlorin 14-Ni45

1 2 3 4 5 6

methyl n-butyl sec-butyl tert-butyl phenyl H

6 27 12 trace 18

42 12 17 48 trace a

Prepared by diimide hydrogenation of 14-Ni43.

Scheme 104 and accompanying text). Thus, Mahammed and Gross reported the diimide-mediated reduction of tris(pentafluorophenyl)corrole 15-H21 to give the corresponding dihydrocorrole 15-H22, dubbed a corrolin (Scheme 237). Subsequent treatment with AlMe3 and pyridine gave the dipyridyl complex of the aluminum(III) chelate 15-Al2. A noteworthy feature of the dihydrocorroles is the high fluorescence quantum yield (Φf = 0.36 for 15-H22; 0.62 for 15-Al2).601 The absorption spectra of corrolin 15-H22 and aluminum(III) corrolin 15-Al2 are shown in Figure 84. Osuka and Kim and co-workers reported the synthesis of subporphyrins by acid-catalyzed condensation of pyridine-tri-N-

15. WEIRD ANALOGUES OF CHLORINS The power of synthetic chemistry has enabled the creation of diverse molecules. Advances in tetrapyrrole science have led to the preparation of compounds that have structural features resembling chlorins but are quite different from the gardenvariety chlorin of which chlorophyll contains the canonical chromophore. Here, we consider a handful of representative examples. The first example concerns reduction of a corrole, which is an aromatic molecule with an A−D ring junction (see FO


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Figure 83. Absorption spectra in dichloromethane of diazaporphyrin 14-Ni44 (R = methyl, Table 37, entry 1, black solid line),598 diazaporphyrin 14-Ni43 (black dotted line),599 diazachlorin 14-Ni45 (R = methyl, Table 37, entry 1, red solid line),598 and diazachlorin 14Ni45 (R = H, Table 37, entry 6, red dotted line).598

Figure 84. Absorption spectra in toluene (+5% pyridine) of corrolin 15H22 (red line) and aluminum(III) corrolin 15-Al2 (blue line).601

Scheme 238. Ring-Contracted Chlorin Analogues

Scheme 237. Ring-Contracted Chlorin Analogues

expanded porphyrin bearing a single meso-aryl ring (15-H26). The conversion to a naphthochlorin is shown in Scheme 239. Reduction with LiAlH4 gave the trialcohol 15-H27, which upon treatment with strong acid gave the expanded naphthochlorin 15-H28. The approach for cyclization of 15-H27 to give naphthochlorin 15-H28 closely parallels that for preparation of benzochlorins (Scheme 93). Only in acidified solvent did the expanded naphthochlorin 15-H28 give a strong long-wavelength absorption band.604 The absorption spectra (long-wavelength region only) of the expanded chlorin 15-H28 and protonated derivatives thereof are shown in Figure 86. A longstanding research effort in tetrapyrrole chemistry has concerned permuting the order of the methine and pyrrolic units. One product that has emanated from this line of inquiry is a

pyrrolylborane 15-3 with an aryl aldehyde, whereupon a mixture of the corresponding subporphyrin 15-B4a−c and subchlorin 15-B5a−c was typically obtained (Scheme 238).602 Each subchlorin 15-B5a−c could be oxidized upon treatment of the crude reaction mixture with MnO2 to form additional subporphyrin 15-B4a−c. Alternatively, diimide-mediated reduction of subporphyrin 15-B4a−c gave the subchlorin 15-B5a−c in yields of 25−36%. A subporphyrin or subchlorin features a 14πelectron system, making these constructs of interest for fundamental studies of aromaticity. The absorption spectra of subporphyrin 15-B4a and subchlorin 15-B5a are shown in Figure 85. In an approach toward longer-wavelength absorbing tetrapyrrole analogues, Sengupta and Robinson prepared an FP


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Figure 85. Absorption spectra in dichloromethane of subporphyrin 15B4a (black dotted line)602,603 and subchlorin 15-B5a (red line).602

Figure 86. Absorption spectra at arbitrary scale of expanded chlorin 15H28 in the long-wavelength region.604 The spectra are assigned to the diprotonated form [dichloromethane/TFA (excess), lavender line]; monoprotonated form (dichloromethane containing trace acid, orange line); and free base form [dichloromethane/Et3N (excess), red line].

Scheme 239. Ring-Expanded Chlorin Analogues

Scheme 240. Hydrogenation of Porphycenes

porphycene,605 which contains two direct pyrrole−pyrrole linkages and two ethene linkages. Hydrogenation of porphycene (15-H29, analogous to porphine) afforded the dihydroporphycene (15-H210, analogous to chlorin) as shown in Scheme 240.606 Application of these most simple hydrogenation conditions to the tetrapropylporphycene 15-H211 or the nickel chelate 15-Ni11 did not afford the corresponding dihydroporphycene. Instead, dissolving metal reduction with Zn in aqueous HCl was employed, thereby affording the free base 15-H212 and nickel chelate 15-Ni12 of the dihydroporphycene.607 The absorption spectra of nickel porphycene 15-Ni11 and nickel dihydroporphycene 15-Ni12 are shown in Figure 87. A porphycene bearing an ethyl acrylate substituent (15-H213) was reduced to the alcohol 15-H214, which upon treatment with strong acid gave the corresponding benzochlorin analogue 15H215, dubbed a benzochloracene (Scheme 241). Here, the cyclization of the allylic alcohol in 15-H214 to give benzochlorin

15-H215 closely parallels reaction of the allylic ammonium group to form benzochlorins as shown in Scheme 75. Metalation with zinc acetate gave the zinc chelate 15-Zn15. The free base benzochloracene 15-H215 did not give a significant bathochromic shift relative to the corresponding octaethylbenzochlorin (see 10-H27, Scheme 74).608 The free base benzochloracene 15-H215 has been subjected to in-depth, comparative physicochemical studies.609 The absorption spectra of octaethylbenzochloracene 15-H215 and octaethylporphycene 15-H216 are shown in Figure 88. Osuka and co-workers also have prepared and extensively investigated the family of expanded porphyrins.612 One example is meso -o ct akis(pent afluorophenyl)[36]octaphyrin(1.1.1.1.1.1.1.1) 15-17. Treatment of 15-17 with the azomethine FQ


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Figure 87. Absorption spectra in dichloromethane of nickel porphycene 15-Ni11 (black dotted line) and nickel dihydroporphycene 15-Ni12 (red line).607

Figure 88. Normalized absorption spectra in dichloromethane of free base octaethylbenzochloracene 15-H215 (red line,609 ε = 29 300 M−1 cm−1 at 407 nm608) and free base octaethylporphycene 15-H216 (black dotted line,610 ε = 144 000 M−1 cm−1 at 385 nm611).

Scheme 241. Structure-Permuted Chlorin Analogues

Scheme 242. Cycloaddition with an Expanded Porphyrin

ylide derived from sarcosine and paraformaldehyde gave the monoadduct 15-18 (3%), the bis-adduct 15-19 (7%), recovered octaphyrin 15-17 (30%), and a reduced derivative of 15-17, [38]octaphyrin (not shown), in 26% yield. The structures of 1517, 15-18, and 15-19 are shown in Scheme 242.613 Use of excess reagents in the same reaction gave 15-19 in 34% yield without isolation of 15-18. Cycloaddition occurred in rings C and G to give 15-18 and 15-19, respectively; the β-pyrrole bonds in rings C and G do not formally participate in the 36π-electron circuit of the macrocycle. In terms of reduction level, the monoadduct 1518 is the chlorin analogue of porphyrin 15-17, whereas the bisadduct 15-19 is analogous to a bacteriochlorin. The introduction of the pyrroline unit creates stereoisomers. Moreover, the size and figure-eight structure of the octaphyrin skeleton are expected to afford a number of energetically accessible conformations. It is interesting that while meso-hexakis(pentafluorophenyl)[26]-

hexaphyrin(1.1.1.1.1.1) underwent Diels−Alder cycloadditions with o-xylylene (derived from benzosultine) followed by DDQmediated oxidation,614 octaphyrin 15-17 did not afford such cycloadditions with o-xylylene. The absorption spectra of [36]octaphyrin 15-17 and monoadduct 15-18 are shown in Figure 89. In summary, this section has covered compounds wherein the structures suggest some resemblance to chlorins. Such compounds may represent distant analogues of chlorins. Given the fuzzy nature of what constitutes a chlorin and the power of FR


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(6) acquiring an integrated database of spectral data (absorption, luminescence), photophysical data, electrochemical data, and accompanying theoretical calculations for a basis set of the chlorins and chlorin-like molecules described herein. The motivations for preparing a chlorin, while perhaps not always articulated in the literature, undoubtedly stem from a desire for the strong red-region absorption bandthe band that in conjunction with the blue-region, Soret band, imbues chlorophyll with its characteristic green color upon white light illumination. In this regard, the synthetic chlorins are largely accessible, tailorable surrogates for chlorophylls. The red-region absorption band enables solar coverage for artificial photosynthesis and relatively deep soft-tissue penetration in photomedicine, to name two exemplary fields where chlorins find unrelenting interest. In artificial photosynthesis, one key question is the extent to which the window of photosynthesis can be expanded, thereby broadening solar coverage while retaining the capability to convert sunlight to fuels.615 The rich body of work described herein provides synthetic routes and constituents that greatly enrich approaches to address this question. In particular, the work helps to establish the foundation for understanding how chlorin species can be tailored to achieve a given wavelength of absorption. The diversity of pyrroline motifs raises a fundamental question: what structural and electronic features are essential to engender chlorin properties? While chlorophyll might be regarded as “a “gestalt” object: a form so instantaneously familiar that it needs no description”616immediately eliciting the corresponding absorption spectrum among the cognoscenti the results here show that the pyrroline motif of chlorophylls (Scheme 1) hardly is unique in engendering chlorin-like spectral properties. Indeed, diverse structural motifs afford symmetryallowed red-region absorption bands, while somewhat related structural motifs afford porphyrin-like bands or even quite distorted absorption spectra. The relationship between structures and spectra is unidirectional and nonexclusive (what mathematicians would refer to as surjective): one structure gives rise to one spectrum, but a given spectrum could stem from a number of distinct structures. As one example, the spectrum of zinc(II) 3,13-diacetyl-10-mesityl-18,18-dimethylchlorin (16Zn1)67 very closely matches that of chlorophyll a (Figure 90), yet the metals are different, the pyrroline ring substituents are different, the β-pyrrole substituents are different, and the mesosubstituents are different. The photophysical characterization of the vast collection of compounds described herein can be expected to illuminate the scope to which chlorophylls can be emulated if not surpassed. The presentation of >250 absorption spectra of chlorins herein has been accompanied by comments on the position and intensity of the chlorin long-wavelength absorption (Qy) band. Knowledge of such parameters is of utmost importance, given that the position of the Qy band sets an upper limit on the energy of the first excited singlet state, and the intensity of absorption is directly related (by the Einstein coefficients) to the magnitude of the radiative rate constant.30,65,72 The latter in part determines the extent of fluorescence emission of the isolated chlorin, as well as the strength of through-space excited-state energy transfer with other molecules. For solar light-harvesting, the position and intensity of all of the absorption bandsincluding the B and the Qare relevant. The topic of light-harvesting, as one effort within the field of artificial photosynthesis, has received extensive attention, yet most efforts in this direction to employ tetrapyrrole

Figure 89. Absorption spectra in dichloromethane of [36]octaphyrin 15-17 (black dotted line) and monoadduct 15-18 (red line).613

synthesis to create diverse molecular architectures, this section undoubtedly does not constitute an exhaustive compilation.

16. OUTLOOK: SYNTHETIC CHLORINS AS SURROGATES FOR CHLOROPHYLLS The vast results described herein are a testament to the ambitions, creativity and persistence of several generations of chemists dedicated to the synthesis of chlorins. The conversion of a porphyrin to a chlorin is ostensibly simple given that the presence or absence of only one double bond distinguishes a porphyrin from a chlorin. The methods for conversion of porphyrins to chlorins, which at one point chiefly included hydrogenation and oxidation/rearrangement, now encompass a vast array of approaches. In parallel with the diverse synthetic methods is a commensurate diversity of pyrroline ring motifs; >50 distinct pyrroline motifs were described in section 13 alone. Indeed, a review on chlorin chemistry written 40 years ago would have included only a handful of pyrroline motifs (Scheme 167). The history of chlorin synthetic chemistry now spans a saeculum, given Fischer’s work as a reasonable point of inception,172,315,316 and the present review shows a remarkable and almost bewildering assortment of pyrroline motifs and synthetic approaches for installation of such motifs in a porphyrin substrate. Still, stepping back from this pointillist survey of the synthesis of >1000 chlorins, it is evident that much remains to be done. A future, more full flourishing of chlorin science would entail at least the following: (1) understanding the relationship between electron richness (electrochemical potential, orbital composition) of a porphyrin and the ease of cycloaddition with a given dipolar reagent; (2) developing synthetic methods to install the pyrroline motif in a regioselective manner at any one of the four pyrroles; (3) developing synthetic methods to install a pyrroline motif either without concomitant creation of stereocenters or in a highly stereoselective manner; (4) developing synthetic methods to install a given pattern of substituents at designated sites about the perimeter of the macrocycle in conjunction with a given method for installing the pyrroline motif; (5) understanding the relation between the molecular structure of the pyrroline motif and the absorption spectrum, particularly the nature (position, intensity, sharpness) of the long-wavelength (Qy) band; FS


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AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Phone: 919-515-6406. Fax: 919513-2830. Notes

The authors declare no competing financial interest. Biographies Masahiko Taniguchi studied pharmacology at the Science University of Tokyo, Japan. He obtained his Ph.D. under the guidance of Prof. Shuntaro Mataka (2000) in the Department of Molecular Science and Technology at Kyushu University, Japan. In 2000, he joined North Carolina State University as postdoctoral fellow and is now Research Professor. His research interests concern hydroporphyrin chemistry, photochemistry, and scientific software. In his spare time, he is an avid fisherman and devotee of all-things Americana. Jonathan S. Lindsey (b. 1956) grew up in Rockport, Indiana and did his undergraduate studies at Indiana University in Bloomington (1974− 1978) where he worked with Profs. Frank R. N. Gurd and Lawrence K. Montgomery. His graduate and postdoctoral studies (1978−1984) were at The Rockefeller University with Prof. David C. Mauzerall in the Laboratory of Photobiology. He was on the faculty at Carnegie Mellon University for 12 years before joining North Carolina State University in 1996. His passions concern the science and creation of tetrapyrrole macrocycles and their roles in photosynthesis and diverse photochemical phenomena. Figure 90. Normalized absorption spectra of chlorophyll a (lime line, in diethyl ether54,55) and zinc chlorin 16-Zn1 (red line, in toluene67).

ACKNOWLEDGMENTS The authors acknowledge funding from the Division of Chemical Sciences, Geosciences, and Biosciences, Office of Basic Energy Sciences of the U.S. Department of Energy (DE-FG0296ER14632). We thank Ms. Ann Norcross for valuable assistance with manuscript preparation.

macrocycles for biomimicry of natural photosynthesis have employed porphyrins rather than chlorins. In some key respects, porphyrins are inadequate surrogates for natural chlorophylls because the former lack the characteristically strong longwavelength (Qy) absorption band of the latter. The absence of the strong Qy band in porphyrins not only limits red-region absorption but also results in diminished vectorial electronic coupling with other molecules compared with that for chlorins.69 The position of auxochromes on the chlorin macrocycle also has a profound effect on spectral properties,70 more so than in porphyrins. Porphyrins also are harder to oxidize and easier to reduce than chlorins.67 The widespread reliance on porphyrins rather than chlorins in studies of artificial photosynthesis in the early years reasonably stemmed from greater ease of synthetic access, but in recent years may stem from unfamiliarity with the diverse synthetic approaches or perhaps even the virtues for preparing synthetic chlorins. In summary, this review has presented an extensive compendium of synthetic approaches for converting porphyrins to chlorins. Yet, the seminal importance of chlorophylls demands the continued development of even more versatile and simple synthetic approaches for preparing chlorins. Moreover, the acquisition of a knowledge base concerning the rational molecular design and rational synthesis of a best chlorin structure to give a desired spectrum (and photophysical properties) remains an unfulfilled but essential objective for the creation of a science of design in the tetrapyrrole field. Given the magnitude of such challenges, chlorin chemistry may still be in its infancy.

ABBREVIATIONS AgOTf silver(I) triflate AIBN azobis(isobutyronitrile) aq aqueous Bn benzyl BPD-MA benzoporphyrin derivative mono-carboxylic acid BSA benzeneselenic anhydride BSH mercaptoundecahydro-closo-dodecaborate CAS Chemical Abstracts Service CTAP cetyltrimethylammonium permanganate DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N-dicyclohexylcarbodiimide 1,2-DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DIAD diisopropyl azodicarboxylate DIBAL−H diisobutylaluminum hydride DMAC N,N-dimethylacetamide DMAP 4-(N,N-dimethylamino)pyridine DMF N,N-dimethylformamide DMP Dess−Martin periodinane DMSO dimethylsulfoxide EDC 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride HOBT 1-hydroxybenzotriazole FT


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(12) Smith, K. M. Chemistry of Chlorophylls: Synthesis. In Chlorophylls; Scheer, H., Ed.; CRC Press, Inc.: Boca Raton, FL, 1991; pp 115−143. (13) Hynninen, P. H. Chemistry of Chlorophylls: Modifications. In Chlorophylls; Scheer, H., Ed.; CRC Press, Inc.: Boca Raton, FL, 1991; pp 145−209. (14) Vicente, M. G. H. Reactivity and Functionalization of βSubstituted Porphyrins and Chlorins. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 1, pp 149−199. (15) Pandey, R. K.; Zheng, G. Porphyrins as Photosensitizers in Photodynamic Therapy. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 6, pp 157−230. (16) Pavlov, V. Y.; Ponomarev, G. V. Modification of the Peripheral Substituents in Chlorophylls a and b and Their Derivatives (Review). Chem. Heterocycl. Compd. 2004, 40, 393−425. (17) Balaban, T. S.; Tamiaki, H.; Holzwarth, A. R. Chlorins Programmed for Self-Assembly. Top. Curr. Chem. 2005, 258, 1−38. (18) Senge, M. O.; Wiehe, A.; Ryppa, C. Synthesis, Reactivity and Structure of Chlorophylls. In Chlorophylls and Bacteriochlorophylls: Biochemistry, Biophysics, Functions and Applications; Grimm, B., Porra, R. J., Rüdiger, W., Scheer, H., Eds.; Advances in Photosynthesis and Respiration, Vol. 25; Springer: Dordrecht, The Netherlands, 2006; pp 27−37. (19) Tamiaki, H.; Kunieda, M. Photochemistry of Chlorophylls and their Synthetic Analogs. In Handbook of Porphyrin Science; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; World Scientific Publishing Co. Pte. Ltd.: Singapore, 2011; Vol. 11, pp 223−290. (20) Yoon, I.; Demberelnyamba, D.; Li, J. Z.; Shim, Y. K. Ionic LiquidBased Chlorins and Type III Mechanism of Photodynamic Therapy (PDT). In Handbook of Porphyrin Science; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; World Scientific Publishing Co. Pte. Ltd.: Singapore, 2014; Vol. 33, pp 167−224. (21) Ryan, A. A.; Senge, M. O. How Green is Green Chemistry? Chlorophylls as a Bioresource from Biorefineries and their Commercial Potential in Medicine and Photovoltaics. Photochem. Photobiol. Sci. 2015, 14, 638−660. (22) Tamiaki, H.; Ariki, N.; Sugiyama, H.; Taira, Y.; Kinoshita, Y.; Miyatake, T. Synthesis of 3,20-Disubstituted Chlorophyll-a Derivatives and Reactivity of the Substituents. Tetrahedron 2013, 69, 8412−8421. (23) Sasaki, S.-i.; Mizoguchi, T.; Tamiaki, H. A Facile Synthetic Method for Conversion of Chlorophyll-a to Bacteriochlorophyll-c. J. Org. Chem. 2007, 72, 4566−4569. (24) Montforts, F.-P.; Zimmermann, G. Facile Entry to Geminally Dialkylated Chlorins. Angew. Chem., Int. Ed. Engl. 1986, 25, 458−459. (25) Willstätter, R. From My Life: The Memoirs of Richard Willstätter, Translated from the German; W. A. Benjamin: New York, 1965. (26) Treibs, A. On the Chromophores of Porphyrin Systems. Ann. N. Y. Acad. Sci. 1973, 206, 97−115. (27) Chisum, D. S.; Jacobs, M. A. Understanding Intellectual Property Law; Legal Text Series; Matthew Bender & Co., Inc.: New York, NY, 1992; pp 4−124−21. (28) Scheer, H. The Pigments. In Light-Harvesting Antennas in Photosynthesis; Green, B. R., Parson, W. W., Eds.; Advances in Photosynthesis and Respiration; Kluwer Academic Publishers: The Netherlands, 2003; Vol. 13, pp 29−81. (29) Chen, M. Chlorophyll Modifications and Their Spectral Extension in Oxygenic Photosynthesis. Annu. Rev. Biochem. 2014, 83, 317−340. (30) Yuen, J. M.; Harris, M. A.; Liu, M.; Diers, J. R.; Kirmaier, C.; Bocian, D. F.; Lindsey, J. S.; Holten, D. Effects of Substituents on Synthetic Analogs of Chlorophylls. Part 4: How Formyl Group Location Dictates the Spectral Properties of Chlorophylls b, d and f . Photochem. Photobiol. 2015, 91, 331−342. (31) Scheer, H. An Overview of Chlorophylls and Bacteriochlorophylls: Biochemistry, Biophysics, Functions and Applications. In Chlorophylls and Bacteriochlorophylls: Biochemistry, Biophysics, Functions and Applications; Grimm, B., Porra, R. J., Rüdiger, W., Scheer, H., Eds.;

HPLC HRP i-Pr IUPAC

high performance liquid chromatography horseradish peroxidase isopropyl International Union of Pure and Applied Chemistry mCPBA meta-chloroperoxybenzoic acid MEM 2-methoxyethoxymethyl Mes mesityl (2,4,6-trimethylphenyl) ODCB ortho-dichlorobenzene OMSH O-mesitylsulfonylhydroxylamine p-TsNHNH2 p-toluenesulfonyl hydrazide p-TsOH·H2O p-toluenesulfonic acid monohydrate PADA potassium azodicarboxylate PPSE trimethylsilyl polyphosphate PPTS pyridinium p-toluenesulfonate RP reversed phase rt room temperature SHb sulfhemoglobin SMb sulfmyoglobin t-Bu or tBu tert-butyl 1,2,4-TCB 1,2,4-trichlorobenzene TCNE tetracyanoethylene TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyranyl TMS trimethylsilyl TMSOTf trimethylsilyl triflate TosMIC p-toluenesulfonyl methylisocyanide TPSH 2,4,6-triisopropylphenylsulfonyl hydrazide Ts p-toluenesulfonyl

REFERENCES (1) Battersby, A. R. Tetrapyrroles: The Pigments of Life. Nat. Prod. Rep. 2000, 17, 507−526. (2) Lindsey, J. S. De Novo Synthesis of Gem-Dialkyl Chlorophyll Analogues for Probing and Emulating our Green World. Chem. Rev. 2015, 115, 6534−6620. (3) Seely, G. R. The Structure and Chemistry of Functional Groups. In The Chlorophylls; Vernon, L. P., Seely, G. R., Eds.; Academic Press: New York, 1966; pp 67−109. (4) Mass, O.; Taniguchi, M.; Ptaszek, M.; Springer, J. W.; Faries, K. M.; Diers, J. R.; Bocian, D. F.; Holten, D.; Lindsey, J. S. Structural Characteristics that Make Chlorophylls Green: Interplay of Hydrocarbon Skeleton and Substituents. New J. Chem. 2011, 35, 76−88. (5) Woodward, R. B.; Ayer, W. A.; Beaton, J. M.; Bickelhaupt, F.; Bonnett, R.; Buchschacher, P.; Closs, G. L.; Dutler, H.; Hannah, J.; Hauck, F. P.; Itô, S.; Langemann, A.; Le Goff, E.; Leimgruber, W.; Lwowski, W.; Sauer, J.; Valenta, Z.; Volz, H. The Total Synthesis of Chlorophyll. J. Am. Chem. Soc. 1960, 82, 3800−3802. (6) Woodward, R. B. Totalsynthese des Chlorophylls. Angew. Chem. 1960, 72, 651−662. (7) Woodward, R. B. The Total Synthesis of Chlorophyll. Pure Appl. Chem. 1961, 2, 383−404. (8) Woodward, R. B. Fundamental Studies in the Chemistry of Macrocyclic Systems Related to Chlorophyll. Ind. Chim. Belge 1962, 1293−1308. (9) Bonnett, R. Chlorophyll a Synthesis: A Prefatory Note. Tetrahedron 1990, 46, xi−xiii. (10) Woodward, R. B.; Ayer, W. A.; Beaton, J. M.; Bickelhaupt, F.; Bonnett, R.; Buchschacher, P.; Closs, G. L.; Dutler, H.; Hannah, J.; Hauck, F. P.; Itô, S.; Langemann, A.; Le Goff, E.; Leimgruber, W.; Lwowski, W.; Sauer, J.; Valenta, Z.; Volz, H. The Total Synthesis of Chlorophyll a. Tetrahedron 1990, 46, 7599−7659. (11) Jackson, A. H. Structure, Properties and Distribution of Chlorophylls. In Chemistry and Biochemistry of Plant Pigments, 2nd ed., Goodwin, T. W., Ed.; Academic Press: London, 1976; Vol. 1, pp 1−63. FU


Chemical Reviews

Review

Advances in Photosynthesis and Respiration; Springer: Dordrecht, The Netherlands, 2006; Vol. 25, pp 1−26. (32) van de Meent, E. J.; Kobayashi, M.; Erkelens, C.; van Veelen, P. A.; Amesz, J.; Watanabe, T. Identification of 81-Hydroxychlorophyll a as a Functional Reaction Center Pigment in Heliobacteria. Biochim. Biophys. Acta, Bioenerg. 1991, 1058, 356−362. (33) Mizoguchi, T.; Oh-oka, H.; Tamiaki, H. Determination of Stereochemistry of Bacteriochlorophyll gF and 81-Hydroxy-chlorophyll aF from Heliobacterium modesticaldum. Photochem. Photobiol. 2005, 81, 666−673. (34) Delwiche, C. F. Algae in the Warp and Weave of Life: Bound by Plastids. In Unravelling the Algae − The Past, Present, and Future of Algal Systematics; Brodie, J., Lewis, J., Eds.; CRC Press, Inc.: Boca Raton, FL, 2007; pp 7−20. (35) Field, C. B.; Behrenfeld, M. J.; Randerson, J. T.; Falkowski, P. Primary Production of the Biosphere: Integrating Terrestrial and Oceanic Components. Science 1998, 281, 237−240. (36) Huston, M. A.; Wolverton, S. The Global Distribution of Net Primary Production: Resolving the Paradox. Ecol. Monogr. 2009, 79, 343−377. (37) Gest, H. Discovery of the Heliobacteria. Photosynth. Res. 1994, 41, 17−21. (38) Patterson, A. M.; Capell, L. T.; Walker, D. F. The Ring Index, 2nd ed.; American Chemical Society: Washington, DC, 1960; p 959. (39) Moss, G. P. Nomenclature of Tetrapyrroles. Pure Appl. Chem. 1987, 59, 779−832. (40) Senge, M. O.; Ryan, A. A.; Letchford, K. A.; MacGowan, S. A.; Mielke, T. Chlorophylls, Symmetry, Chirality, and Photosynthesis. Symmetry 2014, 6, 781−843. (41) Taniguchi, M.; Lindsey, J. S. Enumeration of Isomers of Substituted Tetrapyrrole Macrocycles: From Classical Problems in Biology to Modern Combinatorial Libraries. In Handbook of Porphyrin Science; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; World Scientific Publishing Co. Pte. Ltd.: Singapore, 2012; Vol. 23, pp 1−80. (42) Oba, T.; Tamiaki, H. Asymmetry of Chlorophylls in Photosynthetic Proteins: From the Viewpoint of Coordination Chemistry. J. Porphyrins Phthalocyanines 2014, 18, 919−932. (43) Zapata, M.; Garrido, J. L.; Jeffrey, S. W. Chlorophyll c Pigments: Current Status. In Chlorophylls and Bacteriochlorophylls: Biochemistry, Biophysics, Functions and Applications; Grimm, B., Porra, R. J., Rüdiger, W., Scheer, H., Eds.; Advances in Photosynthesis and Respiration, Vol. 25; Springer: Dordrecht, The Netherlands, 2006; pp 39−53. (44) Chen, M.; Schliep, M.; Willows, R. D.; Cai, Z.-L.; Neilan, B. A.; Scheer, H. A Red-Shifted Chlorophyll. Science 2010, 329, 1318−1319. (45) Berezovskii, V. V.; Ishkov, Y. V.; Mazepa, A. V. Porphyrins and Their Derivatives: XXVI. Synthesis and Properties of 2-(3-Butenyl)5,10,15,20-tetraphenylporphyrin. Russ. J. Org. Chem. 2010, 46, 1409− 1413. (46) Harel, Y.; Manassen, J. 13C NMR Studies of Reduced Porphyrin Compounds. Aromatic Delocalization Pathways. Org. Magn. Reson. 1981, 16, 290−295. (47) Lindsey, J. S. Synthesis of meso-Substituted Porphyrins. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 1, pp 45−118. (48) Dolphin, D. Porphyrinogens and Porphodimethenes, Intermediates in the Synthesis of meso-Tetraphenylporphins from Pyrroles and Benzaldehyde. J. Heterocycl. Chem. 1970, 7, 275−283. (49) Whitlock, H. W.; Oester, M. Y. Behavior of Di- and Tetrahydroporphyrins under Alkaline Conditions. Direct Observation of the ChlorinPhlorin Equilibrium. J. Am. Chem. Soc. 1973, 95, 5738− 5741. (50) Burns, D. H.; Li, Y. H.; Shi, D. C.; Caldwell, T. M. The Rational Synthesis of Chlorins via Rearrangement of Porphodimethenes: Influence of β-Substituents on the Regioselectivity and Stereoselectivity of Pyrroline Ring Formation. J. Org. Chem. 2002, 67, 4536−4546. (51) Soret, J.-L. Analyse Spectrale: Sur le Spectre d’Absorption du Sang dans la Partie Violette et Ultra-Violette. C. R. Acad. Sci. 1883, 97, 1269− 1270.

(52) Okabe, M.; Ito, K. How to Make Figures and Presentations that are Friendly to Color Blind People 2002. http://jfly.iam.u-tokyo.ac.jp/ html/color_blind/index.html (accessed 3/24/16). (53) Jenny, B.; Kelso, N. V. Color Design for the Color Vision Impaired. Cartographic Persp. 2007, 58, 61−67. (54) Du, H.; Fuh, R.-C. A.; Li, J.; Corkan, L. A.; Lindsey, J. S. PhotochemCAD: A Computer-Aided Design and Research Tool in Photochemistry. Photochem. Photobiol. 1998, 68, 141−142. (55) Dixon, J. M.; Taniguchi, M.; Lindsey, J. S. PhotochemCAD 2: A Refined Program with Accompanying Spectral Databases for Photochemical Calculations. Photochem. Photobiol. 2005, 81, 212−213. (56) Jones, I. D.; White, R. C.; Gibbs, E.; Denard, C. D. Absorption Spectra of Copper and Zinc Complexes of Pheophytins and Pheophorbides. J. Agric. Food Chem. 1968, 16, 80−83. (57) Zass, E.; Isenring, H. P.; Etter, R.; Eschenmoser, A. Der Einbau von Magnesium in Liganden der Chlorophyll-Reihe mit (2,6-Di-t-butyl4-methylphenoxy)magnesiumjodid. Helv. Chim. Acta 1980, 63, 1048− 1067. (58) Keegan, J. D.; Stolzenberg, A. M.; Lu, Y.-C.; Linder, R. E.; Barth, G.; Moscowitz, A.; Bunnenberg, E.; Djerassi, C. Magnetic Circular Dichroism Studies. 60. Substituent-Induced Sign Variation in the Magnetic Circular Dichroism Spectra of Reduced Porphyrins. 1. Spectra and Band Assignments. J. Am. Chem. Soc. 1982, 104, 4305−4317. (59) Aravindu, K.; Kim, H.-J.; Taniguchi, M.; Dilbeck, P. L.; Diers, J. R.; Bocian, D. F.; Holten, D.; Lindsey, J. S. Synthesis and Photophysical Properties of Chlorins Bearing 0−4 Distinct Meso-Substituents. Photochem. Photobiol. Sci. 2013, 12, 2089−2109. (60) Kim, J. B.; Leonard, J. J.; Longo, F. R. A Mechanistic Study of the Synthesis and Spectral Properties of meso-Tetraarylporphyrins. J. Am. Chem. Soc. 1972, 94, 3986−3992. (61) Dorough, G. D.; Huennekens, F. M. The Spectra of α,β,γ,δTetraphenylchlorin and its Metallo-derivatives. J. Am. Chem. Soc. 1952, 74, 3974−3976. (62) Whitlock, H. W., Jr.; Hanauer, R.; Oester, M. Y.; Bower, B. K. Diimide Reduction of Porphyrins. J. Am. Chem. Soc. 1969, 91, 7485− 7489. (63) Smith, J. H. C.; Benitez, A. Chlorophylls: Analysis in Plant Materials. In Modern Methods of Plant Analysis; Paech, K., Tracey, M. V., Eds.; Springer-Verlag: Berlin, 1955; Vol. IV, pp 142−196. (64) Strain, H. H.; Svec, W. A. Extraction, Separation, Estimation, and Isolation of the Chlorophylls. In The Chlorophylls; Vernon, L. P., Seely, G. R., Eds.; Academic Press: New York, 1966; pp 21−66. (65) Kee, H. L.; Kirmaier, C.; Tang, Q.; Diers, J. R.; Muthiah, C.; Taniguchi, M.; Laha, J. K.; Ptaszek, M.; Lindsey, J. S.; Bocian, D. F.; Holten, D. Effects of Substituents on Synthetic Analogs of Chlorophylls. Part 1: Synthesis, Vibrational Properties and Excited-state Decay Characteristics. Photochem. Photobiol. 2007, 83, 1110−1124. (66) Meyer, M.; Scheer, H.; Breton, J. Probing Native-Like Orientation of Pigments in Modified Reaction Centers from Rhodobacter sphaeroides R26 by Linear Dichroism. FEBS Lett. 1996, 393, 131−134. (67) Kee, H. L.; Kirmaier, C.; Tang, Q.; Diers, J. R.; Muthiah, C.; Taniguchi, M.; Laha, J. K.; Ptaszek, M.; Lindsey, J. S.; Bocian, D. F.; Holten, D. Effects of Substituents on Synthetic Analogs of Chlorophylls. Part 2: Redox Properties, Optical Spectra and Electronic Structure. Photochem. Photobiol. 2007, 83, 1125−1143. (68) Mass, O.; Ptaszek, M.; Taniguchi, M.; Diers, J. R.; Kee, H. L.; Bocian, D. F.; Holten, D.; Lindsey, J. S. Synthesis and Photochemical Properties of 12-Substituted versus 13-Substituted Chlorins. J. Org. Chem. 2009, 74, 5276−5289. (69) Mass, O.; Pandithavidana, D. R.; Ptaszek, M.; Santiago, K.; Springer, J. W.; Jiao, J.; Tang, Q.; Kirmaier, C.; Bocian, D. F.; Holten, D.; Lindsey, J. S. De Novo Synthesis and Properties of Analogues of the SelfAssembling Chlorosomal Bacteriochlorophylls. New J. Chem. 2011, 35, 2671−2690. (70) Springer, J. W.; Faries, K. M.; Diers, J. R.; Muthiah, C.; Mass, O.; Kee, H. L.; Kirmaier, C.; Lindsey, J. S.; Bocian, D. F.; Holten, D. Effects of Substituents on Synthetic Analogs of Chlorophylls. Part 3: The Distinctive Impact of Auxochromes at the 7- versus 3-Positions. Photochem. Photobiol. 2012, 88, 651−674. FV


Chemical Reviews

Review

(71) Springer, J. W.; Taniguchi, M.; Krayer, M.; Ruzié, C.; Diers, J. R.; Niedzwiedzki, D. M.; Bocian, D. F.; Lindsey, J. S.; Holten, D. Photophysical Properties and Electronic Structure of Retinylidene− Chlorin−Chalcones and Analogues. Photochem. Photobiol. Sci. 2014, 13, 634−650. (72) Faries, K. M.; Diers, J. R.; Springer, J. W.; Yang, E.; Ptaszek, M.; Lahaye, D.; Krayer, M.; Taniguchi, M.; Kirmaier, C.; Lindsey, J. S.; Bocian, D. F.; Holten, D. Photophysical Properties and Electronic Structure of Chlorin−Imides: Bridging the Gap Between Chlorins and Bacteriochlorins. J. Phys. Chem. B 2015, 119, 7503−7515. (73) Vairaprakash, P.; Yang, E.; Sahin, T.; Taniguchi, M.; Krayer, M.; Diers, J. R.; Wang, A.; Niedzwiedzki, D. M.; Kirmaier, C.; Lindsey, J. S.; Bocian, D. F.; Holten, D. Extending the Short and Long Wavelength Limits of Bacteriochlorin Near-Infrared Absorption via Dioxo- and Bisimide-Functionalization. J. Phys. Chem. B 2015, 119, 4382−4395. (74) Rabinowitch, E. Spectra of Porphyrins and Chlorophyll. Rev. Mod. Phys. 1944, 16, 226−235. (75) Gouterman, M. Optical Spectra and Electronic Structure of Porphyrins and Related Rings. In The Porphyrins. Physical Chemistry, Part A; Dolphin, D., Ed.; Academic Press: New York, 1978; Vol. III, pp 1−165. (76) Tarbell, D. S.; Tarbell, A. T. Essays on the History of Organic Chemistry in the United States, 1875−1955; Folio Publishers: Nashville, TN, 1986; pp 181−194. (77) Chang, C. K. Paul Rothemund and S. Ferguson MacDonald, and their Namesake Reactions − The Influence of the Fischer School on my Life in Porphyrin Chemistry. Isr. J. Chem. 2016, 56, 130−143. (78) Rothemund, P. Formation of Porphyrins from Pyrrole and Aldehydes. J. Am. Chem. Soc. 1935, 57, 2010−2011. (79) Rothemund, P. A New Porphyrin Synthesis. The Synthesis of Porphin. J. Am. Chem. Soc. 1936, 58, 625−627. (80) Rothemund, P. Porphyrin Studies. III. The Structure of the Porphine Ring System. J. Am. Chem. Soc. 1939, 61, 2912−2915. (81) Aronoff, S.; Calvin, M. The Porphyrin-Like Products of the Reaction of Pyrrole with Benzaldehyde. J. Org. Chem. 1943, 8, 205−223. (82) Calvin, M.; Ball, R. H.; Aronoff, S. α,β,γ,δ−Tetraphenylchlorin. J. Am. Chem. Soc. 1943, 65, 2259. (83) Ball, R. H.; Dorough, G. D.; Calvin, M. A Further Study of the Porphine-like Products of the Reaction of Benzaldehyde and Pyrrole. J. Am. Chem. Soc. 1946, 68, 2278−2281. (84) Dorough, G. D.; Huennekens, F. M. The Spectra of α,β,γ,δTetraphenylchlorin and its Metallo-Derivatives. J. Am. Chem. Soc. 1952, 74, 3974−3976. (85) Miller, J. R.; Dorough, G. D. Pyridinate Complexes of Some Metallo-derivatives of Tetraphenylporphine and Tetraphenylchlorin. J. Am. Chem. Soc. 1952, 74, 3977−3981. (86) Dorough, G. D.; Miller, J. R. An Attempted Preparation of a Simple Tetrahydroporphine. J. Am. Chem. Soc. 1952, 74, 6106−6108. (87) Eisner, U.; Linstead, R. P. Chlorophyll and Related Substances. Part 1. The Synthesis of Chlorin. J. Chem. Soc. 1955, 3742−3749. (88) Eisner, U.; Linstead, R. P.; Parkes, E. A.; Stephen, E. Chlorophyll and Related Substances. Part III. The Synthesis of Octamethylchlorin. J. Chem. Soc. 1956, 1655−1661. (89) Eisner, U.; Lichtarowicz, A.; Linstead, R. P. Chlorophyll and Related Compounds. Part VI. The Synthesis of Octaethylchlorin. J. Chem. Soc. 1957, 733−739. (90) Eisner, U. Synthesis of mesoTetramethylchlorin. J. Chem. Soc. 1957, 854−858. (91) Ulman, A.; Gallucci, J.; Fisher, D.; Ibers, J. A. Facile Syntheses of Tetraalkylchlorin and Tetraalkylporphyrin Complexes and Comparison of the Structures of the Tetramethylchlorin and Tetramethylporphyrin Complexes of Nickel(II). J. Am. Chem. Soc. 1980, 102, 6852−6854. (92) Ulman, A.; Fisher, D.; Ibers, J. A. Synthesis of Some 5,10,15,20Tetraalkylchlorin and Tetraalkylporphyrin Complexes of Transition Metals. J. Heterocycl. Chem. 1982, 19, 409−413. (93) Suh, M. P.; Swepston, P. N.; Ibers, J. A. Direct Preparation of a Siroheme Model Compound: Synthesis and Structure of (5,10,15,20Tetramethylisobacteriochlorinato)nickel(II). J. Am. Chem. Soc. 1984, 106, 5164−5171.

(94) Serra, A. C.; Rocha Gonsalves, A. M. d. A. Controlled Porphyrinogen Oxidation for the Selective Synthesis of mesoTetraarylchlorins. Tetrahedron Lett. 2010, 51, 4192−4194. (95) Pinho e Melo, T. M. V. D. Professor António M. d’A. Rocha Gonsalves: A Tribute. Arkivoc 2010, 1−4. (96) Rocha Gonsalves, A. M. d. A.; Serrra, A. C.; Pineiro, M. The Small Stones of Coimbra in the Huge Tetrapyrrolic Chemistry Building. J. Porphyrins Phthalocyanines 2009, 13, 429−445. (97) Thomas, D. W.; Martell, A. E. Tetraphenylporphine and Some para-Substituted Derivatives. J. Am. Chem. Soc. 1956, 78, 1335−1338. (98) Fleischer, E. B. α,β,y,δ-Tetra-(4-pyridyl)-porphine and Some of its Metal Complexes. Inorg. Chem. 1962, 1, 493−495. (99) Badger, G. M.; Jones, R. A.; Laslett, R. L. Porphyrins. VII. The Synthesis of Porphyrins by the Rothemund Reaction. Aust. J. Chem. 1964, 17, 1028−1035. (100) Adler, A. D.; Longo, F. R.; Shergalis, W. Mechanistic Investigations of Porphyrin Syntheses. I. Preliminary Studies on msTetraphenylporphin. J. Am. Chem. Soc. 1964, 86, 3145−3149. (101) Schlesinger, W.; Corwin, A. H.; Sargent, L. J. Synthetic Chlorins and Dihydrochlorins. J. Am. Chem. Soc. 1950, 72, 2867−2871. (102) van Tamelen, E. E.; Dewey, R. S.; Timmons, R. J. The Reduction of Olefins by Means of Azodicarboxylic Acid in situ. J. Am. Chem. Soc. 1961, 83, 3725−3726. (103) Dewey, R. S.; van Tamelen, E. E. Reduction of Isolated Olefinic Bonds by Means of p-Toluenesulfonylhydrazine. J. Am. Chem. Soc. 1961, 83, 3729. (104) van Tamelen, E. E.; Dewey, R. S.; Lease, M. F.; Pirkle, W. H. Selectivity and Mechanism of Diimide Reductions. J. Am. Chem. Soc. 1961, 83, 4302. (105) Burns, D. H.; Lai, J.-J.; Smith, K. M. Syntheses of Chlorins from Unsymmetrically Substituted Iron Porphyrins. J. Chem. Soc., Perkin Trans. 1 1988, 3119−3131. (106) Senge, M. O.; Brandt, J. C. Temoporfin (Foscan®, 5,10,15,20Tetra(m-hydroxyphenyl)chlorin)A Second-generation Photosensitizer. Photochem. Photobiol. 2011, 87, 1240−1296. (107) Senge, M. O. mTHPC  A Drug on its Way From Second to Third Generation Photosensitizer? Photodiagn. Photodyn. Ther. 2012, 9, 170−179. (108) Mojzisova, H.; Bonneau, S.; Maillard, P.; Berg, K.; Brault, D. Photosensitizing Properties of Chlorins in Solution and in MembraneMimicking Systems. Photochem. Photobiol. Sci. 2009, 8, 778−787. (109) Rogers, L.; Sergeeva, N. N.; Paszko, E.; Vaz, G. M. F.; Senge, M. O. Lead Structures for Applications in Photodynamic Therapy. 6. Temoporfin Anti-Inflammatory Conjugates to Target the Tumor Microenvironment for In Vitro PDT. PLoS One 2015, 10, DOI: e012537210.1371/journal.pone.0125372. (110) Li, K.-L.; Guo, C.-C.; Chen, Q.-Y. Efficient One-Pot Regioselective Synthesis of 2,3-Dibromo-5,10,15,20-tetraarylporphyrins from 5,10,15,20-Tetraarylchlorins. Synlett 2009, 2867−2871. (111) Bonnett, R.; White, R. D.; Winfield, U.-J.; Berenbaum, M. C. Hydroporphyrins of the meso-Tetra(hydroxyphenyl)porphyrin Series as Tumour Photosensitizers. Biochem. J. 1989, 261, 277−280. (112) Banfi, S.; Caruso, E.; Caprioli, S.; Mazzagatti, L.; Canti, G.; Ravizza, R.; Gariboldi, M.; Monti, E. Photodynamic Effects of Porphyrin and Chlorin Photosensitizers in Human Colon Adenocarcinoma Cells. Bioorg. Med. Chem. 2004, 12, 4853−4860. (113) Sutter, T. P. G.; Hambright, P. Kinetic and Equilibrium Studies on Porphyrins, Chlorins, and Isobacteriochlorins: Basicities, Zinc Incorporation, and Acid-Catalyzed Solvolysis Reactions in Aqueous and Nonaqueous Solutions. Inorg. Chem. 1992, 31, 5089−5093. (114) Peng, C.-L.; Shieh, M.-J.; Tsai, M.-H.; Chang, C.-C.; Lai, P.-S. Self-Assembled Star-Shaped Chlorin-Core Poly(ε-Caprolactone)-Poly(Ethylene Glycol) Diblock Copolymer Micelles for Dual ChemoPhotodynamic Therapies. Biomaterials 2008, 29, 3599−3608. (115) Kyushin, S.; Saito, Y.; Yoshimura, K.; Horiuchi, H.; Hiratsuka, H. Synthesis and Properties of 5,10,15,20-Tetrakis(4′trimethylsilylphenyl)chlorin. Heteroat. Chem. 2014, 25, 514−517. (116) Ferreyra, D. D.; Spesia, M. B.; Milanesio, M. E.; Durantini, E. N. Synthesis and Photodynamic Properties of 5,10,15,20-Tetrakis[3-(NFW


Chemical Reviews

Review

ethyl-N-methylcarbazoyl)]chlorin and its Analogous Porphyrin in Solution and in Human Red Blood Cells. J. Photochem. Photobiol., A 2014, 282, 16−24. (117) Stolzenberg, A. M.; Simerly, S. W.; Steffey, B. D.; Haymond, G. S. The Synthesis, Properties, and Reactivities of Free-Base- and Zn(II)N-Methyl Hydroporphyrin Compounds. The Unexpected Selectivity of the Direct Methylation of Free-Base Hydroporphyrin Compounds. J. Am. Chem. Soc. 1997, 119, 11843−11854. (118) Murugesan, S.; Shetty, S. J.; Srivastava, T. S.; Samuel, A. M.; Noronha, O. P. D. Preparation and Biological Evaluation of the New Chlorin Photosensitizer T3,4BCPC for Detection and Treatment of Tumors. J. Photochem. Photobiol., B 2002, 68, 33−38. (119) Pineiro, M.; Carvalho, A. L.; Pereira, M. M.; Rocha Gonsalves, A. M. d.A.; Arnaut, L. G.; Formosinho, S. J. Photoacoustic Measurements of Porphyrin Triplet-State Quantum Yields and Singlet-Oxygen Efficiencies. Chem. - Eur. J. 1998, 4, 2299−2307. (120) Ozawa, S.; Watanabe, Y.; Morishima, I. Preparation and Characterization of a Novel Oxoiron(IV) Chlorin π-Cation Radical Complex. The First Model for Compound I of Chlorin-Containing Heme Enzymes. Inorg. Chem. 1992, 31, 4042−4043. (121) Pineiro, M.; Pereira, M. M.; Rocha Gonsalves, A. M. d.A.; Arnaut, L. G.; Formosinho, S. J. Singlet Oxygen Quantum Yields from Halogenated Chlorins: Potential New Photodynamic Therapy Agents. J. Photochem. Photobiol., A 2001, 138, 147−157. (122) Dąbrowski, J. M.; Arnaut, L. G.; Pereira, M. M.; Monteiro, C. J. P.; Urbańska, K.; Simões, S.; Stochel, G. New Halogenated WaterSoluble Chlorin and Bacteriochlorin as Photostable PDT Sensitizers: Synthesis, Spectroscopy, Photophysics, and in vitro Photosensitizing Efficacy. ChemMedChem 2010, 5, 1770−1780. (123) Dąbrowski, J. M.; Krzykawska, M.; Arnaut, L. G.; Pereira, M. M.; Monteiro, C. J. P.; Simões, S.; Urbańska, K.; Stochel, G. Tissue Uptake Study and Photodynamic Therapy of Melanoma-Bearing Mice with a Nontoxic, Effective Chlorin. ChemMedChem 2011, 6, 1715−1726. (124) Pereira, M. M.; Abreu, A. R.; Goncalves, N. P. F.; Calvete, M. J. F.; Simões, A. V. C.; Monteiro, C. J. P.; Arnaut, L. G.; Eusébio, M. E.; Canotilho, J. An Insight into Solvent-Free Diimide Porphyrin Reduction: A Versatile Approach for meso-Aryl Hydroporphyrin Synthesis. Green Chem. 2012, 14, 1666−1672. (125) Da Silva Arnaut Moreira, L. G.; Pereira, M. M.; Simões, S. J. F. S.; Simões, S. P. M.; Stochel, G.; Urbańska, K. Process for Preparing Chlorins and their Pharmaceutical Uses. U.S. Patent Appl. Publ. US 2011/0250143 A1, 2011. (126) Mikata, Y.; Onchi, Y.; Shibata, M.; Kakuchi, T.; Ono, H.; Ogura, S.-i.; Okura, I.; Yano, S. Synthesis and Phototoxic Property of Tetra- and Octa-Glycoconjugated Tetraphenylchlorins. Bioorg. Med. Chem. Lett. 1998, 8, 3543−3548. (127) Laville, I.; Figueiredo, T.; Loock, B.; Pigaglio, S.; Maillard, P.; Grierson, D. S.; Carrez, D.; Croisy, A.; Blais, J. Synthesis, Cellular Internalization and Photodynamic Activity of Glucoconjugated Derivatives of Tri and Tetra(meta-hydroxyphenyl)chlorins. Bioorg. Med. Chem. 2003, 11, 1643−1652. (128) Hirohara, S.; Obata, M.; Ogata, S.-i.; Ohtsuki, C.; Higashida, S.; Ogura, S.-i.; Okura, I.; Takenaka, M.; Ono, H.; Sugai, Y.; Mikata, Y.; Tanihara, M.; Yano, S. Cellular Uptake and Photocytotoxicity of Glycoconjugated Chlorins in HeLa Cells. J. Photochem. Photobiol., B 2005, 78, 7−15. (129) Senge, M. O.; Kalisch, W. W.; Runge, S. Conformationally Distorted Chlorins via Diimide Reduction of Nonplanar Porphyrins. Tetrahedron 1998, 54, 3781−3798. (130) Ikezaki, A.; Ono, J.; Ohgo, Y.; Fukagawa, M.; Ikeue, T.; Nakamura, M. Electronic Structure of Low-Spin Six-Coordinate Iron(III) meso-Tetrapropylchlorin Complexes. J. Porphyrins Phthalocyanines 2014, 18, 778−791. (131) Gravier, J.; Schneider, R.; Frochot, C.; Bastogne, T.; Schmitt, F.; Didelon, J.; Guillemin, F.; Barberi-Heyob, M. Improvement of metaTetra(hydroxyphenyl)chlorin-Like Photosensitizer Selectivity with Folate-Based Targeted Delivery. Synthesis and in Vivo Delivery Studies. J. Med. Chem. 2008, 51, 3867−3877.

(132) Abraham, R. J.; Plant, J. E.; Bedford, G. R. The NMR Spectra of the Porphyrins. 24The NMR Spectra of some Tetraarylchlorins. Org. Magn. Reson. 1983, 21, 745−756. (133) Mössler, H.; Wittenberg, M.; Niethammer, D.; Mudrassagam, R. K.; Kurreck, H.; Huber, M. EPR and ENDOR of Radicals of Chlorinand Bacteriochlorin-Quinone Model Compounds for Electron Transfer in Photosynthesis. Magn. Reson. Chem. 2000, 38, 67−84. (134) Laville, I.; Pigaglio, S.; Blais, J.-C.; Loock, B.; Maillard, P.; Grierson, D. S.; Blais, J. A Study of the Stability of Tri(glucosyloxyphenyl)chlorin, a Sensitizer for Photodynamic Therapy, in Human Colon Tumoural Cells: A Liquid Chromatography and MALDI-TOF Mass Spectrometry Analysis. Bioorg. Med. Chem. 2004, 12, 3673−3682. (135) Di Stasio, B.; Frochot, C.; Dumas, D.; Even, P.; Zwier, J.; Müller, A.; Didelon, J.; Guillemin, F.; Viriot, M.-L.; Barberi-Heyob, M. The 2Aminoglucosamide Motif Improves Cellular Uptake and Photodynamic Activity of Tetraphenylporphyrin. Eur. J. Med. Chem. 2005, 40, 1111− 1122. (136) Verhille, M.; Benachour, H.; Ibrahim, A.; Achard, M.; Arnoux, P.; Barberi-Heyob, M.; André, J.-C.; Allonas, X.; Baros, F.; Vanderesse, R.; Frochot, C. Photodynamic Molecular Beacons Triggered by MMP-2 and MMP-9: Influence of the Distance Between Photosensitizer and Quencher onto Photophysical Properties and Enzymatic Activation. Curr. Med. Chem. 2012, 19, 5580−5594. (137) Chouikrat, R.; Champion, A.; Vanderesse, R.; Frochot, C.; Moussaron, A. Microwave-assisted Synthesis of Zinc 5-(4-Carboxyphenyl)-10,15,20-triphenylporphyrin and Zinc 5-(4-Carboxyphenyl)10,15,20-triphenylchlorin. J. Porphyrins Phthalocyanines 2015, 19, 595− 600. (138) Varamo, M.; Loock, B.; Maillard, P.; Grierson, D. S. Development of Strategies for the Regiocontrolled Synthesis of meso5,10,20-Triaryl-2,3-chlorins. Org. Lett. 2007, 9, 4689−4692. (139) Li, D.; Li, P.; Lin, H.; Jiang, Z.; Guo, L.; Li, B. A Novel Chlorin− PEG−Folate Conjugate with Higher Water Solubility, Lower Cytotoxicity, Better Tumor Targeting and Photodynamic Activity. J. Photochem. Photobiol., B 2013, 127, 28−37. (140) Faustino, M. A. F.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S.; Neumann, M.; Brauer, H.-D.; Jori, G. Part 2. meso-Tetraphenylporphyrin Dimer Derivatives as Potential Photosensitizers in Photodynamic Therapy. Photochem. Photobiol. 2000, 72, 217−225. (141) Wang, T. Y.; Chen, J. R.; Ma, J. S. Diphenylchlorin and Diphenylbacteriochlorin: Synthesis, Spectroscopy and Photosensitising Properties. Dyes Pigm. 2002, 52, 199−208. (142) Banfi, S.; Caruso, E.; Buccafurni, L.; Murano, R.; Monti, E.; Gariboldi, M.; Papa, E.; Gramatica, P. Comparison between 5,10,15,20Tetraaryl- and 5,15-Diarylporphyrins as Photosensitizers: Synthesis, Photodynamic Activity, and Quantitative Structure−Activity Relationship Modeling. J. Med. Chem. 2006, 49, 3293−3304. (143) Zenkevich, E. I.; von Borczyskowski, C.; Shulga, A. M.; Bachilo, S.; Rempel, U.; Willert, A. Self-Assembled Nanoscale Photomimetic Models: Structure and Related Dynamics. Chem. Phys. 2002, 275, 185− 209. (144) Chernook, A. V.; Shulga, A. M.; Zenkevich, E. I.; Rempel, U.; von Borczyskowski, C. Complexation and Interchromophoric Interactions in Self-Organized Porphyrin and Chlorin Triads. J. Phys. Chem. 1996, 100, 1918−1926. (145) Ferrand, Y.; Bourré, L.; Simonneaux, G.; Thibaut, S.; Odobel, F.; Lajat, Y.; Patrice, T. Hydroporphyrins as Tumour Photosensitizers: Synthesis and Photophysical Studies of 2,3-Dihydro-5,15-di(3,5dihydroxyphenyl) Porphyrin. Bioorg. Med. Chem. Lett. 2003, 13, 833− 835. (146) Bourré, L.; Simonneaux, G.; Ferrand, Y.; Thibaut, S.; Lajat, Y.; Patrice, T. Synthesis, and in vitro and in vivo Evaluation of a Diphenylchlorin Sensitizer for Photodynamic Therapy. J. Photochem. Photobiol., B 2003, 69, 179−192. (147) Rocha Gonsalves, A. M. d.’A.; Botelho, M. F.; Serra, A. C.; Pineiro, M. Macrocyclic Tetrapyrrole Compound of the Family of Porphyrins, Chlorins and Bacteriochlorins as Photosensitizers for Photodynamic Therapy. Intl. Patent Appl. WO 2011/161065 A1, 2011. FX


Chemical Reviews

Review

(148) Gariboldi, M. B.; Ravizza, R.; Baranyai, P.; Caruso, E.; Banfi, S.; Meschini, S.; Monti, E. Photodynamic Effects of Novel 5,15-Diaryltetrapyrrole Derivatives on Human Colon Carcinoma Cells. Bioorg. Med. Chem. 2009, 17, 2009−2016. (149) Ahmad, S.; Yadav, K. K.; Singh, S. J.; Chauhan, S. M. S. Synthesis of 5,10,15,20-meso-Unsubstituted and 5,10,15,20-meso-Substituted21,23-Ditellura/Diselena Core-Modified Porphyrinogens: Oxidation and Detection of Mercury(II). RSC Adv. 2014, 4, 3171−3180. (150) Senge, M. O. Nucleophilic Substitution as a Tool for the Synthesis of Unsymmetrical Porphyrins. Acc. Chem. Res. 2005, 38, 733− 743. (151) Senge, M. O. Stirring the Porphyrin Alphabet Soup − Functionalization Reactions for Porphyrins. Chem. Commun. 2011, 47, 1943−1960. (152) Lindsey, J. S. Synthetic Routes to meso-Patterned Porphyrins. Acc. Chem. Res. 2010, 43, 300−311. (153) Yu, Q.; Rodriguez, E. M.; Naccache, R.; Forgione, P.; Lamoureux, G.; Sanz-Rodriguez, F.; Scheglmann, D.; Capobianco, J. A. Chemical Modification of Temoporfin − A Second Generation Photosensitizer Activated using Upconverting Nanoparticles for Singlet Oxygen Generation. Chem. Commun. 2014, 50, 12150−12153. (154) Berg, K.; Nordstrand, S.; Selbo, P. K.; Tran, D. T. T.; AngellPetersen, E.; Høgset, A. Disulfonated Tetraphenyl Chlorin (TPCS2a), a Novel Photosensitizer Developed for Clinical Utilization of Photochemical Internalization. Photochem. Photobiol. Sci. 2011, 10, 1637− 1651. (155) Cusack, N. J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B. 2,4,6Tri-Isopropylbenzenesulphonyl Hydrazide: A Convenient Source of DiImide. Tetrahedron 1976, 32, 2157−2162. (156) Lindsey, J. S.; Delaney, J. K.; Mauzerall, D. C.; Linschitz, H. Photophysics of a Cofacial Porphyrin−Quinone Cage Molecule and Related Compounds: Fluorescence Properties, Flash Transients, and Electron-Transfer Reactions. J. Am. Chem. Soc. 1988, 110, 3610−3621. (157) Chen, C.-Y.; Sun, E.; Fan, D.; Taniguchi, M.; McDowell, B. E.; Yang, E.; Diers, J. R.; Bocian, D. F.; Holten, D.; Lindsey, J. S. Synthesis and Physicochemical Properties of Metallobacteriochlorins. Inorg. Chem. 2012, 51, 9443−9464. (158) Lindsey, J. S.; Woodford, J. N. A Simple Method for Preparing Magnesium Porphyrins. Inorg. Chem. 1995, 34, 1063−1069. (159) Yang, S. I.; Li, J.; Cho, H. S.; Kim, D.; Bocian, D. F.; Holten, D.; Lindsey, J. S. Synthesis and Excited-State Photodynamics of Phenylethyne-Linked Porphyrin−Phthalocyanine Dyads. J. Mater. Chem. 2000, 10, 283−296. (160) O’Shea, D. F.; Miller, M. A.; Matsueda, H.; Lindsey, J. S. Investigation of the Scope of Heterogeneous and Homogeneous Procedures for Preparing Magnesium Chelates of Porphyrins, Hydroporphyrins, and Phthalocyanines. Inorg. Chem. 1996, 35, 7325−7338. (161) Pereira, M. M.; Monteiro, C. J. P.; Simões, A. V. C.; Pinto, S. M. A.; Arnaut, L. G.; Sá, G. F. F.; Silva, E. F. F.; Rocha, L. B.; Simões, S.; Formosinho, S. J. Synthesis and Photophysical Properties of Amphiphilic Halogenated Bacteriochlorins: New Opportunities for Photodynamic Therapy of Cancer. J. Porphyrins Phthalocyanines 2009, 13, 567−573. (162) Pereira, M. M.; Monteiro, C. J. P.; Simões, A. V. C.; Pinto, S. M. A.; Abreu, A. R.; Sá, G. F. F.; Silva, E. F. F.; Rocha, L. B.; Dąbrowski, J. M.; Formosinho, S. J.; Simões, S.; Arnaut, L. G. Synthesis and Photophysical Characterization of a Library of Photostable Halogenated Bacteriochlorins: An Access to Near Infrared Chemistry. Tetrahedron 2010, 66, 9545−9551. (163) Nascimento, B. F. O.; Rocha Gonsalves, A. M. d. A.; Pineiro, M. MnO2 instead of Quinones as Selective Oxidant of Tetrapyrrolic Macrocycles. Inorg. Chem. Commun. 2010, 13, 395−398. (164) de Souza, M. C.; Pedrosa, L. F.; Cazagrande, G. S.; Ferreira, V. F.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. From Porphyrin Benzylphosphoramidate Conjugates to the Catalytic Hydrogenation of 5,10,15,20-Tetrakis(pentafluorophenyl)porphyrin. Beilstein J. Org. Chem. 2014, 10, 628−633. (165) Crossley, M. J.; King, L. G. A New Method for Regiospecific Deuteration and Reduction of 5,10,15,20-Tetraphenylporphyrins:

Nucleophilic Reaction of Borohydride Ion with 2-Nitro-5,10,15,20tetraphenylporphyrins. J. Org. Chem. 1993, 58, 4370−4375. (166) Salhi, S.; Vernières, M.-C.; Pansu, R.; Bied-Charreton, C.; Faure, J. Study of Energy Transfer Between Porphyrin and Chlorin Grafted on Polystyrene. React. Funct. Polym. 1995, 26, 209−220. (167) Genady, A. R.; Gabel, D. Synthesis of Triazole- and PyridineBridged Porphyrin−Chlorin and Porphyrin Dimers. Tetrahedron Lett. 2003, 44, 2915−2917. (168) Dayan, F. E.; Duke, S. O.; Faibis, V.; Jacobs, J. M.; Jacobs, N. J. Horseradish Peroxidase-Dependent Oxidation of Deuteroporphyrin IX into Chlorins. Arch. Biochem. Biophys. 1998, 351, 27−34. (169) Pont, F.; Jacobs, N. J.; Montforts, F.-P. Formation of Chlorins by Oxidation of Deuteroporphyrin with Horseradish Peroxidase. Tetrahedron Lett. 1997, 38, 6383−6384. (170) Jacobs, N. J.; Kruszyna, H. G.; Hier, J. S. L.; Dayan, F. E.; Duke, S. O.; Pont, F.; Montforts, F. P. Glutathione-Dependent Oxidative Modification of Protoporphyrin and Other Dicarboxylic Porphyrins by Mammalian and Plant Peroxidases. Biochem. Biophys. Res. Commun. 1999, 259, 195−200. (171) Smith, K. M. Synthesis and Preparation of Porphyrin Compounds. In Porphyrins and Metalloporphyrins; Smith, K. M., Ed.; Elsevier Scientific Publishing Co.: Amsterdam, The Netherlands, 1975; pp 29−58. (172) Fischer, H.; Halbig, P.; Walach, B. Ü ber eine neue Porphyrinsynthese, Oxydation von Porphyrinen und einige kleinere Beobachtungen. Justus Liebigs Ann. Chem. 1927, 452, 268−302. (173) Bonnett, R.; Dolphin, D.; Johnson, A. W.; Oldfield, D.; Stephenson, G. F. The Oxidation of Porphyrins with Hydrogen Peroxide in Sulphuric Acid. Proc. Chem. Soc. London 1964, 371. (174) Bonnett, R.; Dimsdale, M. J.; Stephenson, G. F. The mesoReactivity of Porphyrins and Related Compounds. Part IV. Introduction of Oxygen Functions. J. Chem. Soc. C 1969, 564−570. (175) Inhoffen, H. H.; Nolte, W. Zur weiteren Kenntnis des Chlorophylls und des Hämins, XXIV. Oxidative Umlagerungen am Octaäthylporphin zu Geminiporphin-polyketonen. Liebigs Ann. Chem. 1969, 725, 167−176. (176) Inhoffen, H. H. Recent Progress in Chlorophyll and Porphyrin Chemistry. Pure Appl. Chem. 1968, 17, 443−460. (177) Flitsch, W. Hydrogenated Porphyrin Derivatives: Hydroporphyrins. Adv. Heterocycl. Chem. 1988, 43, 73−126. (178) Brückner, C.; Samankumara, L.; Ogikubo, J. Syntheses of Bacteriochlorins and Isobacteriochlorins. In Handbook of Porphyrin Science; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; World Scientific Publishing Co. Pte. Ltd.: Singapore, 2012; Vol. 17, pp 1−112. (179) Pandey, R. K.; Isaac, M.; MacDonald, I.; Medforth, C. J.; Senge, M. O.; Dougherty, T. J.; Smith, K. M. Pinacol−Pinacolone Rearrangements in vic-Dihydroxychlorins and Bacteriochlorins: Effect of Substituents at the Peripheral Positions. J. Org. Chem. 1997, 62, 1463−1472. (180) Chen, Y.; Medforth, C. J.; Smith, K. M.; Alderfer, J.; Dougherty, T. J.; Pandey, R. K. Effect of Meso-Substituents on the Osmium Tetraoxide Reaction and Pinacol−Pinacolone Rearrangement of the Corresponding vic-Dihydroxyporphyrins. J. Org. Chem. 2001, 66, 3930− 3939. (181) Chang, C. K.; Sotiriou, C. Migratory Aptitudes in Pinacol Rearrangement of vic-Dihydroxychlorins. J. Heterocycl. Chem. 1985, 22, 1739−1741. (182) Sotiriou, C. Synthesis and Properties of Heme d-, d1- and SulfurContaining Green Hemes. Ph.D. thesis; Michigan State University: Ann Arbor, MI, 1987. (183) Chang, C. K. Synthesis and Characterization of Alkylated Isobacteriochlorins, Models of Siroheme and Sirohydrochlorin. Biochemistry 1980, 19, 1971−1976. (184) Chang, C.-K.; Wu, W. Derivatives of Porphyrin Useful in Photodynamic Therapy. U.S. Patent 5,064,952, 1991. (185) Sotiriou, C.; Chang, C. K. Synthesis of the Heme d Prosthetic Group of Bacterial Terminal Oxidase. J. Am. Chem. Soc. 1988, 110, 2264−2270. FY


Chemical Reviews

Review

(186) Chang, C. K.; Sotiriou, C. C-Hydroxy- and C-Methylchlorins. A Convenient Route to Heme d and Bonellin Model Compounds. J. Org. Chem. 1985, 50, 4989−4991. (187) Araiso, T.; Dunford, H. B.; Chang, C. K. Horseradish Peroxidase. XXXVII. Compound I Formation from Reconstituted Enzyme Lacking Free Carboxyl Groups as Heme Side Chains. Biochem. Biophys. Res. Commun. 1979, 90, 520−524. (188) Bracete, A. M.; Kadkhodayan, S.; Sono, M.; Huff, A. M.; Zhuang, C.; Cooper, D. K.; Smith, K. M.; Chang, C. K.; Dawson, J. H. Iron Chlorin-Reconstituted Histidine-Ligated Heme Proteins as Models for Naturally Occurring Iron Chlorin Proteins: Magnetic Circular Dichroism Spectroscopy as a Probe of Iron Chlorin Coordination Structure. Inorg. Chem. 1994, 33, 5042−5049. (189) Andersson, L. A.; Sotiriou, C.; Chang, C. K.; Loehr, T. M. Facile Lactonization and Inversion of Vicinal Diols in Heme d-Type Chlorins: A Spectroscopic Study. J. Am. Chem. Soc. 1987, 109, 258−264. (190) Kunieda, M.; Mikata, Y.; Tamiaki, H. Regioselective Transformation of Octaethylporphyrin into a Phytoporphyrin Analogue. J. Org. Chem. 2007, 72, 7398−7401. (191) Osuka, A.; Marumo, S.; Maruyama, K.; Mataga, N.; Tanaka, Y.; Taniguchi, S.; Okada, T.; Yamazaki, I.; Nishimura, Y. Sequential Electron Transfer Leading to Long-Lived Charge Separated State in a Porphyrin−Oxochlorin−Pyromellitdimide Triad. Bull. Chem. Soc. Jpn. 1995, 68, 262−276. (192) Lederer, E. Sur L’Isolement et la Constitution Chimique de la Bonelline, Pigment Vert de Bonellia viridis. C. R. Acad. Sci. 1939, 209, 528−530. (193) Agius, L.; Ballantine, J. A.; Ferrito, V.; Jaccarini, V.; Murray-Rust, P.; Pelter, A.; Psaila, A. F.; Schembri, P. J. The Structure and Physiological Activity of Bonellin − A Unique Chlorin Derived from Bonellia viridis. Pure Appl. Chem. 1979, 51, 1847−1864. (194) Barkigia, K. M.; Chang, C. K.; Fajer, J. Molecular Structure of a Dihydroxychlorin. A Model of the Green Heme d and of a Photodynamic Therapy Sensitizer. J. Am. Chem. Soc. 1991, 113, 7445−7447. (195) Senge, M. O.; Hope, H.; Iakovides, P.; Smith, K. M. Aggregation of 2,3-Dihydroxy-Etiochlorin I. An Amphiphilic Model Compound for Photodynamic Therapy and Green Heme d. Photochem. Photobiol. 1993, 58, 748−752. (196) Brückner, C.; Dolphin, D. 2,3-vic-Dihydroxy-meso-tetraphenylchlorins from the Osmium Tetroxide Oxidation of meso-Tetraphenylporphyrin. Tetrahedron Lett. 1995, 36, 3295−3298. (197) Chang, C. K.; Sotiriou, C. A Novel Method of Functionalizing the Ethyl Chain of Octaethylporphyrin. J. Org. Chem. 1987, 52, 926− 929. (198) Macalpine, J. K.; Boch, R.; Dolphin, D. Evaluation of Tetraphenyl-2,3-dihydroxychlorins as Potential Photosensitizers. J. Porphyrins Phthalocyanines 2002, 6, 146−155. (199) Hyland, M. A.; Morton, M. D.; Brückner, C. meso-Tetrakis(pentafluorophenyl)porphyrin-Derived Chromene-Annulated Chlorins. J. Org. Chem. 2012, 77, 3038−3048. (200) Brückner, C.; Ogikubo, J.; McCarthy, J. R.; Akhigbe, J.; Hyland, M. A.; Daddario, P.; Worlinsky, J. L.; Zeller, M.; Engle, J. T.; Ziegler, C. J.; Ranaghan, M. J.; Sandberg, M. N.; Birge, R. R. mesoArylporpholactones and their Reduction Products. J. Org. Chem. 2012, 77, 6480−6494. (201) Aicher, D.; Wiehe, A.; Stark, C. B. W.; Albrechr, V.; Gräfe, S. Application of β-Functionalized Dihydroxy-chlorins for PDT. U. S. Patent 9,156,849, 2015. (202) Aicher, D.; Albrecht, V.; Gitter, B.; Stark, C. B. W.; Wiehe, A. Glyco-Substituted Dihydroxy-Chlorins and β-Functionalized Chlorins for Anti-Microbial Photodynamic Therapy U. S. Patent Appl. US 2012/ 0263625 A1, 2012. (203) Lara, K. K.; Rinaldo, C. R.; Brückner, C. meso-Tetraaryl-7,8-diol21,23-dithiachlorins and their Pyrrole-Modified Derivatives: A Spectroscopic Comparison to their Aza-analogues. Tetrahedron 2005, 61, 2529−2539.

(204) Lara, K. K.; Rinaldo, C. R.; Brückner, C. meso-Tetraaryl-7,8dihydroxydithiachlorins: First Examples of Heterochlorins. Tetrahedron Lett. 2003, 44, 7793−7797. (205) Wang, T. Y.; Liu, H. L.; Chen, J. R.; Liu, F. G.; Gu, Y.; Ma, J. S. Synthesis and Photodynamic Action of Diphenyl-2,3-dihydroxychlorin: A Potential Tumor Photosensitizer. Bioorg. Med. Chem. Lett. 2001, 11, 2049−2052. (206) Sutton, J. M.; Fernandez, N.; Boyle, R. W. Functionalized Diphenylchlorins and Bacteriochlorins: Their Synthesis and Bioconjugation for Targeted Photodynamic Therapy and Tumour Cell Imaging. J. Porphyrins Phthalocyanines 2000, 4, 655−658. (207) Beyzavi, M. H.; Nietzold, C.; Reissig, H.-U.; Wiehe, A. Synthesis of Functionalized trans-A2B2-Porphyrins Using Donor−Acceptor Cyclopropane-Derived Dipyrromethanes. Adv. Synth. Catal. 2013, 355, 1409−1422. (208) Zaitseva, S. V.; Zdanovich, S. A.; Koifman, O. I. Effect of Pyridine on the Reaction of ″Spanned″ Zinc Porphyrin with Organic Peroxides. Russ. J. Gen. Chem. 2007, 77, 1275−1283. (209) Pandey, S. K.; Gryshuk, A. L.; Graham, A.; Ohkubo, K.; Fukuzumi, S.; Dobhal, M. P.; Zheng, G.; Ou, Z.; Zhan, R.; Kadish, K. M.; Oseroff, A.; Ramaprasad, S.; Pandey, R. K. Fluorinated Photosensitizers: Synthesis, Photophysical, Electrochemical, Intracellular Localization, in vitro Photosensitizing Efficacy and Determination of Tumor-Uptake by 19 F in vivo NMR Spectroscopy. Tetrahedron 2003, 59, 10059−10073. (210) Choi, Y.; McCarthy, J. R.; Weissleder, R.; Tung, C.-H. Conjugation of a Photosensitizer to an Oligoarginine-Based CellPenetrating Peptide Increases the Efficacy of Photodynamic Therapy. ChemMedChem 2006, 1, 458−463. (211) Sutton, J. M.; Clarke, O. J.; Fernandez, N.; Boyle, R. W. Porphyrin, Chlorin, and Bacteriochlorin Isothiocyanates: Useful Reagents for the Synthesis of Photoactive Bioconjugates. Bioconjugate Chem. 2002, 13, 249−263. (212) McCarthy, J. R.; Bhaumik, J.; Merbouh, N.; Weissleder, R. HighYielding Syntheses of Hydrophilic Conjugatable Chlorins and Bacteriochlorins. Org. Biomol. Chem. 2009, 7, 3430−3436. (213) McCarthy, J. R.; Korngold, E.; Weissleder, R.; Jaffer, F. A. A Light-Activated Theranostic Nanoagent for Targeted Macrophage Ablation in Inflammatory Atherosclerosis. Small 2010, 6, 2041−2049. (214) Krattinger, B.; Callot, H. J. New Routes from Porphyrins to Stable Phlorins. Meso-Alkylation and Reduction of meso-Tetraphenyland Octaalkylporphyrins. Tetrahedron Lett. 1996, 37, 7699−7702. (215) Krattinger, B.; Callot, H. J. Addition of Sterically Hindered Organolithium Compounds to meso-Tetraphenylporphyrin. Tetrahedron Lett. 1998, 39, 1165−1168. (216) Sergeeva, N. N.; Shaker, Y. M.; Finnigan, E. M.; McCabe, T.; Senge, M. O. Synthesis of Hydroporphyrins Based on Comparative Studies of Palladium-Catalyzed and Non-Catalyzed Approaches. Tetrahedron 2007, 63, 12454−12464. (217) Sergeeva, N. N.; Senge, M. O. Palladium-Catalyzed Reactions for the Synthesis of Chlorins and 5,10-Porphodimethenes. Tetrahedron Lett. 2006, 47, 6169−6172. (218) Thamyongkit, P.; Speckbacher, M.; Diers, J. R.; Kee, H. L.; Kirmaier, C.; Holten, D.; Bocian, D. F.; Lindsey, J. S. Swallowtail Porphyrins: Synthesis, Characterization and Incorporation into Porphyrin Dyads. J. Org. Chem. 2004, 69, 3700−3710. (219) Carcel, C. M.; Laha, J. K.; Loewe, R. S.; Thamyongkit, P.; Schweikart, K.-H.; Misra, V.; Bocian, D. F.; Lindsey, J. S. Porphyrin Architectures Tailored for Studies of Molecular Information Storage. J. Org. Chem. 2004, 69, 6739−6750. (220) Thamyongkit, P.; Lindsey, J. S. Synthesis of SwallowtailSubstituted Multiporphyrin Rods. J. Org. Chem. 2004, 69, 5796−5799. (221) Fan, D.; Taniguchi, M.; Yao, Z.; Dhanalekshmi, S.; Lindsey, J. S. 1,9-Bis(N,N-dimethylaminomethyl)dipyrromethanes in the Synthesis of Porphyrins Bearing One or Two meso Substituents. Tetrahedron 2005, 61, 10291−10302. (222) Taniguchi, M.; Balakumar, A.; Fan, D.; McDowell, B. E.; Lindsey, J. S. Imine-substituted Dipyrromethanes in the Synthesis of Porphyrins Bearing One or Two meso Substituents. J. Porphyrins Phthalocyanines 2005, 9, 554−574. FZ


Chemical Reviews

Review

(223) Borbas, K. E.; Mroz, P.; Hamblin, M. R.; Lindsey, J. S. Bioconjugatable Porphyrins Bearing a Compact Swallowtail Motif for Water Solubility. Bioconjugate Chem. 2006, 17, 638−653. (224) Thamyongkit, P.; Muresan, A. Z.; Diers, J. R.; Holten, D.; Bocian, D. F.; Lindsey, J. S. Meso-13C-Labeled Porphyrins for Studies of Ground-State Hole Transfer in Multiporphyrin Arrays. J. Org. Chem. 2007, 72, 5207−5217. (225) Yao, Z.; Borbas, K. E.; Lindsey, J. S. Soluble Precipitable Porphyrins for Use in Targeted Molecular Brachytherapy. New J. Chem. 2008, 32, 436−451. (226) Borbas, K. E.; Kee, H. L.; Holten, D.; Lindsey, J. S. A Compact Water-Soluble Porphyrin Bearing An Iodoacetamido Bioconjugatable Site. Org. Biomol. Chem. 2008, 6, 187−194. (227) Borbas, K. E.; Chandrashaker, V.; Muthiah, C.; Kee, H. L.; Holten, D.; Lindsey, J. S. Design, Synthesis, and Photophysical Properties of Water-Soluble Chlorins. J. Org. Chem. 2008, 73, 3145− 3158. (228) Krattinger, B.; Callot, H. J. Alkylation and Reduction of Porphyrins and N-Substituted Porphyrins: New Routes to Chlorins and Phlorins. Eur. J. Org. Chem. 1999, 1999, 1857−1867. (229) Grigg, R.; Sweeney, A.; Dearden, G. R.; Jackson, A. H.; Johnson, A. W. N-Methylation of Octaethylporphyrin and Octaethylchlorin. J. Chem. Soc. D 1970, 1273−1274. (230) Grigg, R.; Shelton, G.; Sweeney, A.; Johnson, A. W. NMethylation and Electrophilic Substitution Reactions of Octa-alkylporphins, Octaethylchlorin, and Metalloporphins. J. Chem. Soc., Perkin Trans. 1 1972, 1789−1799. (231) Callot, H. J. Synthesis of N-Aminoporphyrins. Tetrahedron 1979, 35, 1455−1456. (232) Pandey, R. K.; Zheng, X.; Dobhal, M. P.; Smith, K. M. Formation of Chlorins and meso-Substituted Porphyrins through Intramolecular Nitrogen-Carbon Migration of N-Substituted Porphyrins. J. Porphyrins Phthalocyanines 2008, 12, 131−141. (233) Müller, G.; Deeg, R.; Gneuss, K. D.; Gunzer, G. On the Methylation Process in Cobyrinic Acid Biosynthesis. In Vitamin B12, Proceedings of the Third European Symposium on Vitamin B12 and Intrinsic Factor; Zagalak, B., Friedrich, W., Eds.; Walter de Gruyter: Berlin, 1979; pp 279−291. (234) Imfeld, M.; Arigoni, D.; Deeg, R.; Müller, G. Factor I ex Clostridium tetanomorphum: Proof of Structure and Relationship to Vitamin B12 Biosynthesis. In Vitamin B12, Proceedings of the Third European Symposium on Vitamin B12 and Intrinsic Factor; Zagalak, B., Friedrich, W., Eds.; Walter de Gruyter: Berlin, 1979; pp 315−316. (235) Timkovich, R. The Family of d-Type Hemes: Tetrapyrroles with Unusual Substituents. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2003; Vol. 12, pp 123−156. (236) Montforts, F.-P.; Meier, A.; Scheurich, G.; Haake, G.; Bats, J. W. Chlorins Designed for Photodynamic Tumor Therapy and as Model Systems for Photosynthesis. Angew. Chem., Int. Ed. Engl. 1992, 31, 1592−1594. (237) Kusch, D.; Töllner, E.; Lincke, A.; Montforts, F.-P. A Simple, Chirogenic, Enantioselective Synthesis of Chlorins and Isobacteriochlorins. Angew. Chem., Int. Ed. Engl. 1995, 34, 784−787. (238) Kusch, D.; Montforts, F.-P. Synthesis of Enantiomerically Pure Hydroxyethylporphyrins and Their Transformation into Optically Active Chlorin Derivatives. Liebigs Ann. 1996, 83−86. (239) Kusch, D.; Meier, A.; Montforts, F.-P. Synthesis and Characterization of Amphiphilic Chlorins for Photodynamic Tumor Therapy (PDT). Liebigs Ann. 1995, 1027−1032. (240) Höper, F.; Montforts, F.-P. A Simple Synthesis of Functionalized rac-Chlorins via Allylboration of Porphyrin Aldehydes. Liebigs Ann. 1995, 1033−1038. (241) DiNello, R. K.; Chang, C. K. Isolation and Modification of Natural Porphyrins. In The Porphyrins. Structure and Synthesis, Part A; Dolphin, D., Ed.; Academic Press: New York, 1978; Vol. I, pp 289−339. (242) Brockman, H., Jr.; Bliesener, K.-M.; Inhoffen, H. H. Formyl- und Acetyl-substituierte Deuteroporphyrine. Liebigs Ann. Chem. 1968, 718, 148−161.

(243) Clezy, P. S.; Diakiw, V.; Webb, N. W. Synthetic 2- and 4Monoacetyldeuteroporphyrin IX. J. Chem. Soc., Chem. Commun. 1972, 413−414. (244) Haake, G.; Meier, A.; Montforts, F.-P.; Scheurich, G.; Zimmermann, G. Synthese von Chlorinen aus dem roten Blutfarbstoff Hämin. Liebigs Ann. Chem. 1992, 325−336. (245) Smith, K. M.; Fujinari, E. M.; Langry, K. C.; Parish, D. W.; Tabba, H. D. Manipulation of Vinyl Groups in Protoporphyrin IX: Introduction of Deuterium and Carbon-13 Labels for Spectroscopic Studies. J. Am. Chem. Soc. 1983, 105, 6638−6646. (246) Pandey, R. K.; Shiau, F.-Y.; Dougherty, T. J.; Smith, K. M. Regioselective Syntheses of Ether-Linked Porphyrin Dimers and Trimers Related to Photofrin-II®. Tetrahedron 1991, 47, 9571−9584. (247) Parker, K. A.; Resnick, L. N,N-Dimethylacetamide Dimethyl Acetal. In E-EROS Encyclopedia of Reagents for Organic Synthesis: 2009; Wiley Online Library, John Wiley & Sons, Inc. DOI: 10.1002/ 047084289X. (248) Williams, D. R.; Fultz, M. W. N,N-Dimethylacetamide Dimethyl Acetal: First Update. In E-EROS Encyclopedia of Reagents for Organic Synthesis: 2009; Wiley Online Library, John Wiley & Sons, Inc. DOI: 10.1002/047084289X. (249) Montforts, F.-P.; Meier, A.; Haake, G.; Hoper, F. A Taylor Made Lipophilic Chlorin for Photodynamic Tumor Therapy. Tetrahedron Lett. 1991, 32, 3481−3482. (250) Szurko, A.; Rams, M.; Sochanik, A.; Sieroń-Stołtny, K.; Kozielec, A. M.; Montforts, F.-P.; Wrzalik, R.; Ratuszna, A. Spectroscopic and Biological Studies of a Novel Synthetic Chlorin Derivative with Prospects for Use in PDT. Bioorg. Med. Chem. 2009, 17, 8197−8205. (251) Erbacher, M.; Montforts, F.-P. Synthesis of Novel Porphyrin and Chlorin Phosphonic Acids and their Immobilization on Metal Oxides. J. Porphyrins Phthalocyanines 2011, 15, 1070−1077. (252) Bats, J. W.; Haake, G.; Meier, A.; Montforts, F.-P.; Scheurich, G. Synthesis of Oxochlorins from the Red Blood Pigment Heme and Their Transformation into Potentially Biologically Active Chlorin Derivatives. Liebigs Ann. 1995, 1617−1631. (253) Pavlov, V. Y. Modern Aspects of the Chemistry of Protoporphyrin IX. Russ. J. Org. Chem. 2007, 43, 1−34. (254) Montforts, F.-P.; Gerlach, B.; Höper, F. Discovery and Synthesis of Less Common Natural Hydroporphyrins. Chem. Rev. 1994, 94, 327− 347. (255) Turner, S. P. D.; Block, M. H.; Sheng, Z.-C.; Zimmerman, S. C.; Battersby, A. R. Syntheses Relevant to Vitamin B12 Biosynthesis: Synthesis of (±)Faktor-I Octamethyl Ester. J. Chem. Soc., Chem. Commun. 1985, 583−585. (256) Gerlach, B.; Montforts, F.-P. Azachlorins: Synthesis of a Novel Type of Hydroporphyrins from the Bile Pigment Bilirubin. Liebigs Ann. 1995, 1509−1514. (257) Collier, G. L.; Jackson, A. H.; Kenner, G. W. A Novel Conversion of Porphyrins into Chlorins. Chem. Commun. 1966, 299−300. (258) Collier, G. L.; Jackson, A. H.; Kenner, G. W. Pyrroles and Related Compounds. Part XI. Synthesis of Two Acetamidoethyl Porphyrins and their Conversion into Vinyl Porphyrins and Chlorins. J. Chem. Soc. C 1967, 66−72. (259) Smith, K. M.; Baptista de Almeida, J. A. P.; Lewis, W. M. Studies of Spiro-chlorin Formation Using Porphyrin Amides. J. Heterocycl. Chem. 1980, 17, 481−487. (260) Chang, Y.; Clezy, P. S.; Morell, D. B. The Chemistry of Pyrrolic Compounds. VI. Chlorins and Related Compounds. Aust. J. Chem. 1967, 20, 959−968. (261) Gunter, M. W.; Tang, H.; Warrener, R. N. Porphodimethylidenes from Porphyrin-Fused 3-Sulfolenes − Versatile Porphyrin Dienes for Cycloadditions. Chem. Commun. 1999, 803−804. (262) Banala, S.; Sintic, P.; Kräutler, B. A Functionalized Spiro[chlorinporphyrin]-Type ‘Dimer’ Dizinc Complex from Rapid [4 + 2] Selfcycloaddition of a Conjugated [β,β′-Bis(methylene)porphyrinato]zinc. Helv. Chim. Acta 2012, 95, 211−220. (263) Harvey, P. D. Recent Advances in Free and Metalated Multiporphyrin Assemblies and Arrays; A Photophysical Behavior and Energy Transfer Perspective. In The Porphyrin Handbook; Kadish, K. M., GA


Chemical Reviews

Review

Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2003; Vol. 18, pp 63−250. (264) Harvey, P. D.; Stern, C.; Guilard, R. Bio-inspired Molecular Devices Based on Systems Found in Photosynthetic Bacteria. In Handbook of Porphyrin Science; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; World Scientific Publishing Co. Pte. Ltd.: Singapore, 2011; Vol. 11, pp 1−179. (265) Tanaka, T.; Nakamura, Y.; Osuka, A. Bay-Area Selective Thermal [4 + 2] and [4 + 4] Cycloaddition Reactions of Triply Linked ZnII Diporphyrin with o-Xylylene. Chem. - Eur. J. 2008, 14, 204−211. (266) Ptaszek, M.; Lahaye, D.; Krayer, M.; Muthiah, C.; Lindsey, J. S. De Novo Synthesis of Long-Wavelength Absorbing Chlorin-13,15Dicarboximides. J. Org. Chem. 2010, 75, 1659−1673. (267) Thomson, R. H. Naturally Occurring Quinones, 2nd ed.; Academic Press: London, 1971; pp 407−408. (268) Conant, J. B.; Moyer, W. W. Studies in the Chlorophyll Series. III. Products of the Phase Test. J. Am. Chem. Soc. 1930, 52, 3013−3023. (269) Treibs, A. Das Leben und Wirken von Hans Fischer; Hans Fischer Gesellschaft: Munich, 1971. (270) Fleming, I. In Selected Organic Syntheses; John Wiley & Sons: London, 1973; pp 112−124. (271) Lwowski, W. The Synthesis of Chlorophyll a. In The Chlorophylls; Vernon, L. P., Seely, G. R., Eds.; Academic Press: New York, NY, 1966; pp 119−143. (272) Fuhrhop, J.-H.; Li, G. In Organic Synthesis − Concepts and Methods; Wiley VCH: Weinheim, 2003; pp 285−287. (273) Nicolau, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century. Angew. Chem., Int. Ed. 2000, 39, 44−122. (274) Witte, L.; Fuhrhop, J.-H. Preparation and Reactivity of Sterically Crowded Porphyrins. Angew. Chem., Int. Ed. Engl. 1975, 14, 361−363. (275) Arnold, D.; Gaete-Holmes, R.; Johnson, A. W. Cyclisations Involving meso-Substituents of Crowded Porphyrins. J. Chem. Soc., Chem. Commun. 1978, 73−74. (276) Arnold, D. P.; Gaete-Holmes, R.; Johnson, A. W.; Smith, A. R. P.; Williams, G. A. Wittig Condensation Products From Nickel mesoFormyl-octaethyl-porphyrin and -aetioporphyrin I and Some Cyclisation Reactions. J. Chem. Soc., Perkin Trans. 1 1978, 1660−1670. (277) Morgan, A. R.; Tertel, N. C. Observations on the Synthesis and Spectroscopic Characteristics of Purpurins. J. Org. Chem. 1986, 51, 1347−1350. (278) Morgan, A. R.; Rampersaud, A.; Garbo, G. M.; Keck, R. W.; Selman, S. H. New Sensitizers for Photodynamic Therapy: Controlled Synthesis of Purpurins and Their Effect on Normal Tissue. J. Med. Chem. 1989, 32, 904−908. (279) Gunter, M. J.; Robinson, B. C. A Synthesis of Purpurin Derivatives Substituted at the 6,16-meso Positions. Tetrahedron Lett. 1990, 31, 285−288. (280) Gunter, M. J.; Robinson, B. C. Purpurins Bearing Functionality at the 6,16-meso-Positions: Synthesis from 5,15-Disubstituted meso-[β(Methoxycarbonyl)vinyl]porphyrins. Aust. J. Chem. 1990, 43, 1839− 1860. (281) Gunter, M. J.; Robinson, B. C.; Gulbis, J. M.; Tiekink, E. R. T. 5,15-Diaryl Substituted Benzochlorins - Synthesis and Structure. Tetrahedron 1991, 47, 7853−7868. (282) Forsyth, T. P.; Nurco, D. J.; Pandey, R. K.; Smith, K. M. Synthesis and Structure of a 5,15-Bis(4-pyridyl)purpurin. Tetrahedron Lett. 1995, 36, 9093−9096. (283) Macpherson, A. N.; Liddell, P. A.; Kuciauskas, D.; Tatman, D.; Gillbro, T.; Gust, D.; Moore, T. A.; Moore, A. L. Ultrafast Energy Transfer from a Carotenoid to a Chlorin in a Simple Artificial Photosynthetic Antenna. J. Phys. Chem. B 2002, 106, 9424−9433. (284) Gould, S. L.; Kodis, G.; Liddell, P. A.; Palacios, R. E.; Brune, A.; Gust, D.; Moore, T. A.; Moore, A. L. Artificial Photosynthetic Reaction Centers with Carotenoid Antennas. Tetrahedron 2006, 62, 2074−2096. (285) Johnson, A. W.; Oldfield, D. meso-Substitution Products of Ætioporphyrin I. J. Chem. Soc. C 1966, 794−798.

(286) Callot, H. J. Réaction de Wittig sur les Formylporphyrines. Un Cas de Déformylation Particulièrement Facile. Bull. Soc. Chim. Fr. 1973, 3413−3416. (287) Higuchi, H.; Shimizu, K.; Takeuchi, M.; Ojima, J.; Sugiura, K.-i.; Sakata, Y. Synthesis and Properties of Tris(octaethylporphyrin)s Connected with Vinylene Groups. Bull. Chem. Soc. Jpn. 1997, 70, 1923−1933. (288) Rosenthal, J.; Hodgkiss, J. M.; Young, E. R.; Nocera, D. G. Spectroscopic Determination of Proton Position in the Proton-Coupled Electron Transfer Pathways of DonorAcceptor Supramolecule Assemblies. J. Am. Chem. Soc. 2006, 128, 10474−10483. (289) Arnold, D. P.; Johnson, A. W.; Mahendran, M. Some Reactions of meso-Formyloctaethylporhyrin. J. Chem. Soc., Perkin Trans. 1 1978, 366−370. (290) Macpherson, A. N.; Kessel, D.; Morgan, A. R.; Munro, I.; Truscott, T. G. A Photophysical Study of Some Purpurins. J. Chem. Soc., Faraday Trans. 1990, 86, 3081−3085. (291) Fuhrhop, J.-H.; Witte, L.; Sheldrick, W. S. Darstellung, Struktur und Reaktivität hochsubtituierter Porphyrine. Liebigs Ann. Chem. 1976, 1537−1559. (292) Robinson, B. C.; Morgan, A. R. Cyanopurpurins; Synthesis from meso-(2-Cyanovinyl)porphyrins. Proc. SPIE 1996, 2675, 191−199. (293) Poriel, C.; Kessel, D.; Vicente, M. G. H. Stability of Tin Etiopurpurin. Photochem. Photobiol. 2005, 81, 149−153. (294) Morgan, A. R.; Garbo, G. M.; Keck, R. W.; Selman, S. H. New Photosensitizers for Photodynamic Therapy: Combined Effect of Metallopurpurin Derivatives and Light on Transplantable Bladder Tumors. Cancer Res. 1988, 48, 194−198. (295) Sanders, J. K. M.; Bampos, N.; Clyde-Watson, Z.; Darling, S. L.; Hawley, J. C.; Kim, H.-J.; Mak, C. C.; Webb, S. J. Axial Coordination Chemistry of Metalloporphyrins. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 3, pp 1−48. (296) Gunter, M. J.; Mander, L. N. Synthesis and Atropisomer Separation of Porphyrins Containing Functionalization at the 5,15Meso Positions: Application to the Synthesis of Binuclear Ligand Systems. J. Org. Chem. 1981, 46, 4792−4795. (297) Senge, M. O. Highly Substituted Porphyrins. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 1, pp 239−347. (298) Gust, D.; Moore, T. A.; Moore, A. L. Mimicking Photosynthetic Solar Energy Transduction. Acc. Chem. Res. 2001, 34, 40−48. (299) Maggini, M.; Scorrano, G.; Prato, M. Addition of Azomethine Ylides to C-60: Synthesis, Characterization, and Functionalization of Fullerene Pyrrolidines. J. Am. Chem. Soc. 1993, 115, 9798−9799. (300) Morgan, A. R.; Skalkos, D.; Maguire, G.; Rampersaud, A.; Garbo, G.; Keck, R.; Selman, S. H. Observations on the Synthesis and in vivo Photodynamic Activity of Some Benzochlorins. Photochem. Photobiol. 1992, 55, 133−136. (301) Vicente, M. G. H.; Smith, K. M. Vilsmeier Reactions of Porphyrins and Chlorins with 3-(Dimethylamino)acrolein To Give meso-(2-Formylvinyl)porphyrins: New Syntheses of Benzochlorins, Benzoisobacteriochlorins, and Benzobacteriochlorins and Reductive Coupling of Porphyrins and Chlorins Using Low-Valent Titanium Complexes. J. Org. Chem. 1991, 56, 4407−4418. (302) Mettath, S.; Li, G.; Srikrishnan, T.; Mehta, R.; Grossman, Z. D.; Dougherty, T. J.; Pandey, R. K. Effect of Substituents in Directing the Formation of Benzochlorins and Isobacteriochlorins in Porphyrin and Chlorin Systems. Org. Lett. 1999, 1, 1961−1964. (303) Li, G.; Mehta, R.; Srikrishnan, T.; Nurco, D. J.; Tabaczynski, W. A.; Alderfer, J. L.; Smith, K. M.; Dougherty, T. J.; Pandey, R. K. A Novel Synthetic Route to Fused Propenochlorin and Benzochlorin Photodynamic Therapy Probes. Chem. Commun. 2002, 1172−1173. (304) Li, G.; Pandey, S. K.; Graham, A.; Dobhal, M. P.; Mehta, R.; Chen, Y.; Gryshuk, A.; Rittenhouse-Olson, K.; Oseroff, A.; Pandey, R. K. Functionalization of OEP-Based Benzochlorins To Develop Carbohydrate-Conjugated Photosensitizers. Attempt To Target β-GalactosideRecognized Proteins. J. Org. Chem. 2004, 69, 158−172. GB


Chemical Reviews

Review

Reactions). In The Porphyrins. Structure and Synthesis, Part B; Dolphin, D., Ed.; Academic Press: New York, NY, 1978; Vol. II, pp 131−159. (325) Ragsdale, S. W. Biochemistry of Methyl-CoM Reductase and Coenzyme F430. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2003; Vol. 11, pp 205−228. (326) Ishkov, Y. V. Porphyrins and Their Derivatives: XXII. A New Product of Intramolecular Cyclization of 5,10,15,20-Tetraphenyl-2formylporphyrin Copper Complex. Russ. J. Org. Chem. 2001, 37, 288− 290. (327) Callot, H. J.; Schaeffer, E.; Cromer, R.; Metz, F. Unexpected Routes to Naphtoporphyrin Derivatives. Tetrahedron 1990, 46, 5253− 5262. (328) Barloy, L.; Dolphin, D.; Dupré, D.; Wijesekera, T. P. Anomalous Double Cyclization Reactions of β-Formylporphyrins. J. Org. Chem. 1994, 59, 7976−7985. (329) Kirby, J. P.; van Dantzig, N. A.; Chang, C. K.; Nocera, D. G. Formation of Porphyrin Donor-Acceptor Complexes via an AmidiniumCarboxylate Salt Bridge. Tetrahedron Lett. 1995, 36, 3477−3480. (330) van der Haas, R. N. S.; Tang, S.-H.; Hernandez, B. A.; de Jong, R. L. P.; Erkelens, C.; Liu, Y.; Gast, P.; Smijs, T. G. M.; Schuitmaker, H. J.; Lugtenburg, J. Synthesis of the Dimethyl Ester of 2′-Cyano-8′-formylN′-methyl-1′,1a′,5a′,6′-tetrahydroacrido[4,5,5a,6-bcd]-Annulated 2,3Dihydromesoporphyrin − A Novel System with Outstanding Properties as Basis for Photodynamic Therapy in the Far-Red Region of the Visible Spectrum. Eur. J. Org. Chem. 2005, 2005, 3813−3824. (331) Kohli, D. H.; Morgan, A. R. Preparation of Substituted Chlorins and Benzochlorins. Bioorg. Med. Chem. Lett. 1995, 5, 2175−2178. (332) Mak, N.-K.; Li, K.-M.; Leung, W.-N.; Wong, R. N.-S.; Huang, D. P.; Lung, M. L.; Lau, Y.-K.; Chang, C. K. Involvement of Both Endoplasmic Reticulum and Mitochondria in Photokilling of Nasopharyngeal Carcinoma Cells by the Photosensitizer Zn−BC− AM. Biochem. Pharmacol. 2004, 68, 2387−2396. (333) Skalkos, D.; Hampton, J. A. Iminium Salt Benzochlorins as Potential Photosensitizers in Photodynamic Therapy. Med. Chem. Res. 1992, 2, 276−281. (334) Johnson, C. K.; Dolphin, D. Syntheses of Chlorins Possessing Fused Nitrogen-Containing Rings. Tetrahedron Lett. 1998, 39, 4619− 4622. (335) Johnson, C. K.; Dolphin, D. Synthesis of a Fused Bis-Chlorin. Tetrahedron Lett. 1998, 39, 4753−4756. (336) Clezy, P. S.; Lim, C. L.; Shannon, J. S. Chemistry of Pyrrolic Compounds. XXVII. Some Aspects of the Mass Spectra and Chemistry of meso-Substituted Porphyrins. Aust. J. Chem. 1974, 27, 1103−1120. (337) Speckbacher, M.; Yu, L.; Lindsey, J. S. Formation of Porphyrins in the Presence of Acid-Labile Metalloporphyrins: A New Route to Mixed-Metal Multiporphyrin Arrays. Inorg. Chem. 2003, 42, 4322− 4337. (338) Maillard, P.; Hery, C.; Momenteau, M. Synthesis, Characterization and Photocytotoxicity of a Glycoconjugated meso-Monoarylbenzochlorin. Tetrahedron Lett. 1997, 38, 3731−3734. (339) Sengupta, D.; Robinson, B. C. Synthesis of Chlorins Possessing a Fused Naphthalene Ring. Tetrahedron 2002, 58, 5497−5502. (340) Robinson, B. C.; Sengupta, D.; Phadke, A. Chlorins Possessing Fused Ring Systems Useful as Photoselective Compounds for Photodynamic Therapy. U.S. Patent 6,794,505, 2004. (341) Vicente, M. G. H.; Rezzano, I. N.; Smith, K. M. Efficient New Syntheses of Benzochlorins, Benzoisobacteriochlorins, and Benzobacteriochlorins. Tetrahedron Lett. 1990, 31, 1365−1368. (342) Woodward, R. B.; Škarić, V. A New Aspect of the Chemistry of Chlorins. J. Am. Chem. Soc. 1961, 83, 4676−4678. (343) Morgan, A. R.; Garbo, G. M. Biomedical Application of Porphyrin Photosensitizers. Trends Photochem. Photobiol. 1991, 2, 229− 236. (344) Robinson, B. C.; Morgan, A. R. Barbituric Acid Functionalized Porphyrins and Chlorins. Tetrahedron Lett. 1993, 34, 3711−3714. (345) Sahoo, A. K.; Mori, S.; Shinokubo, H.; Osuka, A. Facile Peripheral Functionalization of Porphyrins by Pd-Catalyzed [3 + 2] Annulation with Alkynes. Angew. Chem., Int. Ed. 2006, 45, 7972−7975.

(305) van der Haas, R. N. S.; de Jong, R. L. P.; Noushazar, M.; Erkelens, K.; Smijs, T. G. M.; Liu, Y.; Gast, P.; Schuitmaker, H. J.; Lugtenburg, J. The Synthesis of the Dimethyl Ester of Quino[4,4a,5,6-efg]-Annulated 7-Demethyl-8-deethylmesoporphyrin and Three of Its Isomers with Unprecedented peri-Condensed Quinoline Porphyrin Structures. Molecules with Outstanding Properties as Sensitizers for Photodynamic Therapy in the Far-Red Region of the Visible Spectrum. Eur. J. Org. Chem. 2004, 2004, 4024−4038. (306) Basavaiah, D.; Veeraraghavaiah, G. The Baylis-Hillman Reaction: A Novel Concept for Creativity in Chemistry. Chem. Soc. Rev. 2012, 41, 68−78. (307) Osuka, A.; Ikawa, Y.; Maryuyama, K. Synthesis of Benzochlorin Monomer, Dimer, and Porphyrin−Benzochlorin Heterodimer From 5Aryl- and 5,15-Diaryl-octaethylporphyrins. Bull. Chem. Soc. Jpn. 1992, 65, 3322−3330. (308) Taniguchi, M.; Ptaszek, M.; McDowell, B. E.; Boyle, P. D.; Lindsey, J. S. Sparsely Substituted Chlorins as Core Constructs in Chlorophyll Analogue Chemistry. Part 3: Spectral and Structural Properties. Tetrahedron 2007, 63, 3850−3863. (309) Kobayashi, M.; Akiyama, M.; Kano, H.; Kise, H. Spectroscopy and Structure Determination. In Chlorophylls and Bacteriochlorophylls: Biochemistry, Biophysics, Functions and Applications; Advances in Photosynthesis and Respiration; Springer: Dordrecht, The Netherlands, 2006; Vol. 25, pp 79−94. (310) Watanabe, T.; Machida, K.; Suzuki, H.; Kobayashi, M.; Honda, K. Photoelectrochemistry of Metallochlorophylls. Coord. Chem. Rev. 1985, 64, 207−224. (311) Gurinovich, G. P.; Sevchenko, A. N.; Solov’ev, K. N. Spectroscopy of Chlorophyll and Related Compounds; National Technical Information Service, U.S. Department of Commerce: Springfield, VA, 1971; pp 134− 204. (312) Yashunsky, D. V.; Ponomarev, G. V.; Moskovkin, A. S.; Arnold, D. P. Chemistry of meso-Dimethylaminopropenyl-porphyrins and -bisporphyrins: the Synthesis of Australochlorin, a Benzochlorin Isomer. Aust. J. Chem. 1997, 50, 487−493. (313) Phadke, A. S.; Robinson, B. C.; Barkigia, K. M.; Fajer, J. Synthesis of Benzochlorins and Rhodinobenzochlorins. Tetrahedron 2000, 56, 7661−7666. (314) Clezy, P. S.; Mirza, A. H.; Ravi, B. N.; van Thuc, L. The Chemistry of Pyrrolic Compounds. LIV. The Chemistry of Rhodins, Verdins and Related Compounds. Aust. J. Chem. 1984, 37, 143−154. (315) Fischer, H.; Treibs, A. Zur Kenntnis der Chlorophylle. I. Ü ber Ä tioporphyrine aus Blatt- und BlutfarbstoffPorphyrinen. Justus Liebigs Ann. Chem. 1928, 466, 188−242. (316) Fischer, H.; Treibs, A.; Helberger, H. Ü ber Rhodine und Verdine. Justus Liebigs Ann. Chem. 1928, 466, 243−264. (317) Fischer, H. Chlorophyll. Chem. Rev. 1937, 20, 41−68. (318) Morgan, A. R.; Rampersaud, A.; Keck, R. W.; Selman, S. H. Verdins: New Photosensitizers for Photodynamic Therapy. Photochem. Photobiol. 1987, 46, 441−444. (319) Lemberg, R.; Legge, J. W. In Hematin Compounds and Bile Pigments; Interscience Publishers, Inc.: New York, 1949; pp 113−118. (320) Terry, M. J. Biosynthesis and Analysis of Bilins. In Heme, Chlorophyll, and Bilins: Methods and Protocols; Smith, A. G., Witty, M., Eds.; Humana Press: NJ, 2002; pp 273−291. (321) Balch, A. L.; Latos-Grażyński, L.; Noll, B. C.; Olmstead, M. M.; Szterenberg, L.; Safari, N. Structural Characterization of Verdoheme Analogs. Iron Complexes of Octaethyloxoporphyrin. J. Am. Chem. Soc. 1993, 115, 1422−1429. (322) Webster, M. D. Verdin (Auriparus f laviceps). In The Birds of North America; Poole, A., Gill, F., Eds.; The Birds of North America, Inc.: Philadelphia, PA, 1999; No. 470, pp 1−20. (323) Wee, A. G. H.; Shu, A. Y. L.; Bunnenberg, E.; Djerassi, C. Magnetic Circular Dichroism Studies. 66. Synthesis of Demethyl Monosubstituted Porphyrins. The Effect of Substituent Conformation on the Magnetic Circular Dichroism Spectra of Ethoxycarbonyl Porphyrins. J. Org. Chem. 1984, 49, 3327−3336. (324) Fuhrhop, J.-H. Irreversible Reactions on the Porphyrin Periphery (Excluding Oxidations, Reductions, and Photochemical GC


Chemical Reviews

Review

(346) Tokuji, S.; Takahashi, Y.; Shinmori, H.; Shinokubo, H.; Osuka, A. Synthesis of a Pyridine-Fused Porphyrinoid: Oxopyridochlorin. Chem. Commun. 2009, 1028−1030. (347) Kadish, K. M.; van Caemelbecke, E.; Royal, G. Electrochemistry of Metalloporphyrins in Nonaqueous Media. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 8, pp 1−114. (348) Bell, F. A.; Ledwith, A.; Sherrington, D. C. Cation-Radicals Tris-(p-bromophenyl)amminium Perchlorate and Hexachloroantimonate. J. Chem. Soc. C 1969, 2719−2720. (349) Jayaraj, K.; Gold, A.; Ball, L. M.; White, P. S. NPorphyrinylamino and -amido Compounds by Addition of an Amino or Amido Nitrogen to a Porphyrin Meso Position. Inorg. Chem. 2000, 39, 3652−3664. (350) Callot, H. J. Nouvelles Voies d’Accès aux Vinylporphyrines. Tetrahedron 1973, 29, 899−901. (351) Faustino, M. A.; Neves, M. G. P. M. S.; Vicente, M. G. H.; Silva, A. M. S.; Cavaleiro, J. A. S. New Naphthochlorins from the Intramolecular Cyclization of β-Vinyl-meso-Tetraarylporphyrins. Tetrahedron Lett. 1995, 36, 5977−5978. (352) Krattinger, B.; Nurco, D. J.; Smith, K. M. Novel Synthesis and New Chemistry of Naphthochlorins. Chem. Commun. 1998, 757−758. (353) Fouchet, J.; Jeandon, C.; Ruppert, R.; Callot, H. J. Locked πExpanded Chlorins in Two Steps from Simple Tetraarylporphyrins. Org. Lett. 2005, 7, 5257−5260. (354) Jeandon, C.; Ruppert, R.; Callot, H. J. Acylation of Nickel mesoTetraarylporphyrins: Porphyrin to Corrole Ring Contraction and Formation of seco-Porphyrins. J. Org. Chem. 2006, 71, 3111−3120. (355) Jeandon, C.; Ruppert, R.; Callot, H. J. Porphyrin Ring Contraction: A One-Pot Reaction Leading to Divalent Corroles. Chem. Commun. 2004, 1090−1091. (356) Paolesse, R. Syntheses of Corroles. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 2, pp 201−232. (357) Erben, C.; Will, S.; Kadish, K. M. Metallocorroles: Molecular Structure, Spectroscopy and Electronic States. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 2, pp 233−300. (358) Deans, R. M.; Mass, O.; Diers, J. R.; Bocian, D. F.; Lindsey, J. S. Serendipitous Synthetic Entrée to Tetradehydro Analogues of Cobalamins. New J. Chem. 2013, 37, 3964−3975. (359) Lindsey, J. S.; Wagner, R. W. Investigation of the Synthesis of Ortho-Substituted Tetraphenylporphyrins. J. Org. Chem. 1989, 54, 828−836. (360) Lindsey, J. S. The Synthesis of meso-Substituted Porphyrins. In Metalloporphyrins Catalyzed Oxidations; Montanari, F., Casella, L., Eds.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 1994; pp 49−86. (361) Yang, J.; Jiang, J.; Fang, W.; Kai, X.; Hu, C.; Yang, Y. One-Pot Synthesis of 5-(8-Ethoxycarbonyl-1-naphthyl)-10,15,20-triphenyl porphyrin (ENTPP) and Spontaneous Resolution upon Crystallization. J. Porphyrins Phthalocyanines 2011, 15, 197−201. (362) Kai, X.; Jiang, J.; Hu, C. Facile One-Pot Synthesis of Unprecedented β,β′-linked Porphyrin−Chlorin Heterodimers. Chem. Commun. 2012, 48, 4302−4304. (363) Morozova, Y. V.; Yashunsky, D. V.; Maksimov, B. I.; Ponomarev, G. V. Chemistry of Oximes of meso-Porphyrin Metal Complexes. Synthesis of Chlorine with Fused 1,2-Oxazocine Ring. Chem. Heterocycl. Compd. 2003, 39, 388−389. (364) Morozova, Y. V.; Yashunsky, D. V.; Starikova, Z. A.; Ponomarev, G. V. Chemical Transformation of 1,2-oxazinochlorin Derivatives; Synthesis and X-Ray Crystal Structure of a Novel Porphyrin-Porphyrin Dimer with a Condensed Cyclohexane Ring. J. Porphyrins Phthalocyanines 2007, 11, 31−41. (365) Vicente, M. G. H.; Smith, K. M. Porphyrins with Fused Exocyclic Rings. J. Porphyrins Phthalocyanines 2004, 8, 26−42. (366) Fox, S.; Boyle, R. W. Synthetic Routes to Porphyrins Bearing Fused Rings. Tetrahedron 2006, 62, 10039−10054.

(367) Silva, A. M. G.; Cavaleiro, J. A. S. Porphyrins in Diels-Alder and 1,3-Dipolar Cycloaddition Reactions. In Prog. Heterocycl. Chem.; Gribble, G. W., Joule, J. A., Eds.; Elsevier: Amsterdam, 2008; Vol. 19, pp 44−69. (368) Cavaleiro, J. A. S.; Neves, M. G. P. M. S.; Tomé, A. C. Cycloaddition Reactions of Porphyrins. Arkivoc 2003, 14, 107−130. (369) Tomé, A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. Porphyrins and Other Pyrrolic Macrocycles in Cycloaddition Reactions. J. Porphyrins Phthalocyanines 2009, 13, 408−414. (370) Inhoffen, H. H.; Bliesener, C.; Brockmann, H., Jr. Zur Weiteren Kenntnis des Chlorophylls und des Hämins, VIII. Umwandlung von Protoporphyrin IX Ü ber Photoprotoporphyrin in Spirographis- und Isospirographisporphyrin. Tetrahedron Lett. 1966, 7, 3779−3785. (371) Brault, D.; Aveline, B.; Delgado, O.; Martin, M. T. Chlorin-Type Photosensitizers Photochemically Derived from Vinyl Porphyrins. Photochem. Photobiol. 2001, 73, 331−338. (372) Cox, G. S.; Bobillier, C.; Whitten, D. G. Photooxidation and Singlet Oxygen Sensitization by Protoporphyrin IX and its Photooxidation Products. Photochem. Photobiol. 1982, 36, 401−407. (373) Dolphin, D.; Sivasothy, R. The Preparation of Porphyrin S-411 (Dehydrocoproporphyrin) and Harderoporphyrin from Protoporphyrin IX. Can. J. Chem. 1981, 59, 779−785. (374) Aveline, B.; Delgado, O.; Brault, D. Reaction of Singlet Oxygen with Vinyl-substituted Porphyrins. A Kinetic Study by Laser Flash Photolysis. J. Chem. Soc., Faraday Trans. 1992, 88, 1971−1976. (375) Brault, D.; Aveline, B.; Delgado, O.; Vever-Bizet, C. Chlorin-type Photosensitizers Derived from Vinyl Porphyrins. Proc. SPIE. Photodynamic Therapy of Cancer II 1994, 2325, 40−46. (376) Inhoffen, H. H.; Brockman, H., Jr.; Bliesener, K.-M. Zur weiteren Kenntnis des Chlorophylls und des Hämins, XXX. Photoprotoporphyrine und ihre Urnwandlung in Spirographis-sowie Isospirographisporphyrin. Justus Liebigs Ann. Chem. 1969, 730, 173−185. (377) Jackson, A. H.; Kenner, G. W.; Wass, J. Rational Syntheses of Chlorocruoroporphyrin (Spirographis Porphyrin) and Pemptoporphyrin. Chem. Commun. 1967, 1027−1029. (378) Nakae, Y.; Fukusaki, E.-i.; Kajiyama, S.-i.; Kobayashi, A.; Nakajima, S.; Sakata, I. Syntheses and Screening Tests of New Chlorin Derivatives as Photosensitizer. J. Photochem. Photobiol., A 2005, 174, 187−193. (379) Asano, R.; Nagami, A.; Fukumoto, Y.; Yazama, F.; Ito, H.; Sakata, I.; Tai, A. Synthesis and Biological Evaluation of New Chlorin Derivatives as Potential Photosensitizers for Photodynamic Therapy. Bioorg. Med. Chem. 2013, 21, 2298−2304. (380) Asano, R.; Nagami, A.; Fukumoto, Y.; Miura, K.; Yazama, F.; Ito, H.; Sakata, I.; Tai, A. Synthesis and Biological Evaluation of New BSHConjugated Chlorin Derivatives as Agents for Both Photodynamic Therapy and Boron Neutron Capture Therapy of Cancer. J. Photochem. Photobiol., B 2014, 140, 140−149. (381) Asano, R.; Nagami, A.; Fukumoto, Y.; Miura, K.; Yazama, F.; Ito, H.; Sakata, I.; Tai, A. Synthesis and Biological Evaluation of New BoronContaining Chlorin Derivatives as Agents for Both Photodynamic Therapy and Boron Neutron Capture Therapy of Cancer. Bioorg. Med. Chem. Lett. 2014, 24, 1339−1343. (382) Bonnett, R.; Cornell, P.; McDonagh, A. F. The meso-Reactivity of Porphyrins and Related Compounds. Part VII. Benzoyloxylation of Phenylpyrroles and of Octaethylporphyrin. J. Chem. Soc., Perkin Trans. 1 1976, 794−800. (383) Iakovides, P.; Smith, K. M. Syntheses of Oxygen Analogues of Sulfhemes-A and -C. Tetrahedron 1996, 52, 1123−1148. (384) Bonnett, R.; Campion-Smith, I. H.; Kozyrev, A. N.; Mironov, A. F. Bromination and Iodination of Porphyrins. J. Chem. Res.-S 1990, 1015−1043. (385) Boutorine, A. S.; Brault, D.; Takasugi, M.; Delgado, O.; Hélène, C. Chlorin-Oligonucleotide Conjugates: Synthesis, Properties, and Red Light-Induced Photochemical Sequence-Specific DNA Cleavage in Duplexes and Triplexes. J. Am. Chem. Soc. 1996, 118, 9469−9476. (386) Vever-Bizet, C.; Boutorine, A. S.; Delgado, O.; Brault, D.; Hélène, C. Targeting of HIV gp120 by Oligonucleotide-Photosensitizer Conjugates. Light-Induced Damages. FEBS Lett. 1999, 462, 467−471. GD


Chemical Reviews

Review

(387) Boutorine, A. S.; Grimm, G. N.; Hélène, C. Methods of Attaching Unprotected Oligonucleotides to DNA-binding, Fluorescent, or Reactive Ligands for Synthesis of Antisense or Gene-directed Agents and Probes. Mol. Biol. 2000, 34, 804−813. (388) Ward, B.; Chang, C. K.; Young, R. Spectral Shifts Upon Reversible Modifications of CHO Peripheral Substituents in Porphyrin, Chlorin, and Bacteriochlorin. A Phenomenological Explanation for the Red Shift of Protonated Schiff Base. J. Am. Chem. Soc. 1984, 106, 3943− 3950. (389) Chatfield, M. J.; La Mar, G. N.; Lecomte, J. T. J.; Balch, A. L.; Smith, K. M.; Langry, K. C. Identification of the Altered Pyrrole in Sulfmyoglobin and an Extractable “Sulfhemin”: Participation of the 4Vinyl Group in the Saturation of the Pyrrole in One Form of Sulfmyoglobin. J. Am. Chem. Soc. 1986, 108, 7108−7110. (390) Ríos-González, B. B.; Román-Morales, E. M.; Pietri, R.; LópezGarriga, J. Hydrogen Sulfide Activation in Hemeproteins: The Sulfheme Scenario. J. Inorg. Biochem. 2014, 133, 78−86. (391) Iakovides, P.; Smith, K. M. Synthesis of Oxygen Analogs of the Sulfchlorins. Tetrahedron Lett. 1990, 31, 3853−3856. (392) Arasasingham, R. D.; Balch, A. L.; Olmstead, M. M. Synthesis and Structural Characterization of Octaethyl-17-Thiochlorin and Octaethyl-7,17-Dithioisobacteriochlorin. Heterocycles 1988, 27, 2111− 2118. (393) Hempenius, M. A.; Koek, J. H.; Lugtenburg, J. Spectroscopy and Reactivity of Zinc 20-Oxaporphyrin-IX Dimethyl Ester. Recl. Trav. Chim. Pays-Bas 1987, 106, 105−112. (394) Grigg, R.; Johnson, A. W.; Sweeney, A. Diels−Alder Additions to Protoporphyrin IX Dimethyl Ester. Chem. Commun. 1968, 697. (395) Callott, H. J.; Johnson, A. W.; Sweeney, A. Additions to Porphins Involving the Formation of New Carbon−Carbon Bonds. J. Chem. Soc., Perkin Trans. 1 1973, 1424−1427. (396) Morgan, A. R.; Pangka, V. S.; Dolphin, D. Ready Syntheses of Benzoporphyrins via Diels−Alder Reactions with Protoporphyrin IX. J. Chem. Soc., Chem. Commun. 1984, 1047−1048. (397) Pangka, V. S.; Morgan, A. R.; Dolphin, D. Diels−Alder Reactions of Protoporphyrin IX Dimethyl Ester with Electron-Deficient Alkynes. J. Org. Chem. 1986, 51, 1094−1100. (398) DiNello, R. K.; Dolphin, D. Reactions of Protoporphyrin with Tetracyanoethylene. J. Org. Chem. 1980, 45, 5196−5204. (399) Morgan, A. R.; Kohli, D. H. Diels-Alder Reactions of Protoporphyrin IX Dimethyl Ester. Tetrahedron Lett. 1995, 36, 7603− 7606. (400) Uchoa, A. F.; de Oliveira, K. T.; Baptista, M. S.; Bortoluzzi, A. J.; Iamamoto, Y.; Serra, O. A. Chlorin Photosensitizers Sterically Designed To Prevent Self-Aggregation. J. Org. Chem. 2011, 76, 8824−8832. (401) dos Santos, F. A. B.; Uchoa, A. F.; Baptista, M. S.; Iamamoto, Y.; Serra, O. A.; Brocksom, T. J.; de Oliveira, K. T. Synthesis of Functionalized Chlorins Sterically-Prevented From Self-Aggregation. Dyes Pigm. 2013, 99, 402−411. (402) de Oliveira, K. T.; Silva, A. M. S.; Tomé, A. C.; Neves, M. G. P. M. S.; Neri, C. R.; Garcia, V. S.; Serra, O. A.; Iamamoto, Y.; Cavaleiro, J. A. S. Synthesis of New Amphiphilic Chlorin Derivatives From Protoporphyrin-IX Dimethyl Ester. Tetrahedron 2008, 64, 8709−8715. (403) Cavaleiro, J. A. S.; Jackson, A. H.; Neves, M. G. P. M. S.; Rao, K. R. N. Diels−Alder Reactions of Protoporphyrin Dimethyl Esters with Nitrosobenzenes: A Novel Degradation to Formyl Porphyrins. J. Chem. Soc., Chem. Commun. 1985, 776−777. (404) Meunier, I.; Pandey, R. K.; Senge, M. O.; Dougherty, T. J.; Smith, K. M. Benzoporphyrin Derivatives: Synthesis, Structure and Preliminary Biological Activity. J. Chem. Soc., Perkin Trans. 1 1994, 961−969. (405) Pandey, R. K.; Smith, K. M.; Dougherty, T. J. Porphyrin Dimers as Photosensitizers in Photodynamic Therapy. J. Med. Chem. 1990, 33, 2032−2038. (406) Pandey, R. K.; Shiau, F.-Y.; Ramachandran, K.; Dougherty, T. J.; Smith, K. M. Long Wavelength Photosensitizers Related to Chlorins and Bacteriochlorins for Use in Photodynamic Therapy. J. Chem. Soc., Perkin Trans. 1 1992, 1377−1385.

(407) Faustino, M. A. F.; Neves, M. G. P. M. S.; Vicente, M. G. H.; Silva, A. M. S.; Cavaleiro, J. A. S. Diels-Alder Reactions of Ni(II) β-Vinylmeso-Tetraarylporphyrins. Tetrahedron Lett. 1996, 37, 3569−3570. (408) Matsumoto, K.; Kimura, S. Diels-Alder Reaction of Ni(II) βVinyl-meso-Tetraphenylporphyrin with Dimethyl Acetylenedicarboxylate and N-Phenyl Maleimide. Heterocycl. Commun. 2000, 6, 31−34. (409) Matsumoto, K.; Kimura, S.; Morishita, T.; Misumi, Y.; Hayashi, N. Diels-Alder Reaction of Ni(II) β-Vinyl-meso-tetraphenylporphyrin; A General Method for Synthesis of Functionalized Porphyrins. Synlett 2000, 233−235. (410) Kai, S.; Suzuki, M. Formation of Novel Spirochlorin and Allylidenechlorin by the Reaction of Bromovinylporphyrin with Tetracyanoethylene. Tetrahedron Lett. 1996, 37, 5931−5934. (411) Vicente, M. G. H.; Smith, K. M. Functionalizations of the Alkyl Substituents in Octa-Alkylporphyrins. Tetrahedron 1991, 47, 6887− 6894. (412) Callot, H. J. Stereochimie de l’Addition de Carbenes sur la mesoTetraphenylporphine. Tetrahedron Lett. 1972, 13, 1011−1014. (413) Callot, H. J. Addition de Carbènes sur la méso-Tétraphénylphorphine. Bull. Soc. Chim. Fr. 1972, 4387−4391. (414) Gomes, A. T. P. C.; Leão, R. A. C.; da Silva, F. C.; Neves, M. G. P. M. S.; Faustino, M. A. F.; Tomé, A. C.; Silva, A. M. S.; Pinheiro, S.; de Souza, M. C. B. V.; Ferreira, V. F.; Cavaleiro, J. A. S. Synthesis of New Glycoporphyrin Derivatives Through Carbohydrate-Substituted αDiazoacetates. J. Porphyrins Phthalocyanines 2009, 13, 247−255. (415) Tomé, A. C.; Lacerda, P. S. S.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. meso-Arylporphyrins as Dienophiles in Diels−Alder Reactions: A Novel Approach to the Synthesis of Chlorins, Bacteriochlorins and Naphthoporphyrins. Chem. Commun. 1997, 1199−1200. (416) Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.; Cavaleiro, J. A. S. meso-Tetraarylporphyrins as Dipolarophiles in 1,3Dipolar Cycloaddition Reactions. Chem. Commun. 1999, 1767−1768. (417) Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. Novel Barrelene-fused Chlorins by Diels−Alder Reactions. Tetrahedron Lett. 2000, 41, 3065−3068. (418) Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.; Cavaleiro, J. A. S. 1,3-Dipolar Cycloaddition Reactions of Porphyrins with Azomethine Ylides. J. Org. Chem. 2005, 70, 2306−2314. (419) de Souza, J. M.; de Assis, F. F.; Carvalho, C. M. B.; Cavaleiro, J. A. S.; Brocksom, T. J.; de Oliveira, K. T. Synthesis of Non-aggregating C h l o r in s a n d I s o b a c te r i o c h lo r i ns fr o m m e s o- T e t r a k i s (pentafluorophenyl)porphyrin: A Study using 1,3-Dipolar Cycloadditions under Mild Conditions. Tetrahedron Lett. 2014, 55, 1491− 1495. (420) Cavaleiro, J. A. S.; Neves, M. G. P. M.; Tomé, A. C.; Silva, A. M. S.; Faustino, M. A. F.; Lacerda, P. S.; Silva, A. M. G. Porphyrin Derivatives: Synthesis and Potential Applications. J. Heterocycl. Chem. 2000, 37, 527−534. (421) Vicente, M. G. H.; Cancilla, M. T.; Lebrilla, C. B.; Smith, K. M. Cruciform Porphyrin Pentamers. Chem. Commun. 1998, 2355−2356. (422) Fox, R. B.; Powell, W. H. Nomenclature of Organic Compounds − Principles and Practice, 2nd ed.; Oxford University Press: Oxford, 2001. (423) Makarova, E. A.; Korolyova, G. V.; Tok, O. L.; Lukyanets, E. A. New Synthesis of Tetraazachlorins and Tetraazabacteriochlorins by Diels−Alder Reaction of Tetraazaporphine. J. Porphyrins Phthalocyanines 2000, 4, 525−531. (424) Kuzmitsky, V. A.; Makarova, E. A.; Pershukevich, P. P.; Shushkevich, I. K.; Solovyov, K. N.; Tusov, V. B. Electronic Structure and Photophysics of the Aza-Analogues of Hydroporphyrins. Chem. Phys. 2004, 298, 1−16. (425) Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S.; Kappe, C. O. Porphyrins in Diels−Alder Reactions. Improvements on the Synthesis of Barrelene-Fused Chlorins Using Microwave Irradiation. Tetrahedron Lett. 2005, 46, 4723−4726. (426) Pineiro, M. Microwave-Assisted Synthesis and Reactivity of Porphyrins. Curr. Org. Synth. 2014, 11, 89−109. (427) Costa, D. C. S.; Gomes, M. C.; Faustino, M. A. F.; Neves, M. G. P. M. S.; Cunha, A.; Cavaleiro, J. A. S.; Almeida, A.; Tomé, J. P. C. Comparative Photodynamic Inactivation of Antibiotic Resistant GE


Chemical Reviews

Review

Tetraazaporphin and Tetraazachlorin Molecules. J. Appl. Spectrosc. 2004, 71, 35−41. (444) Chizhova, N. V.; Khelevina, O. G.; Berezin, B. D. Synthesis of Sulfonyl Chlorides Based on Octaphenyltetraazaporphin. Russ. J. Org. Chem. 1993, 29, 1834−1836. (445) Wyrębek, P.; Ostrowski, S. An Approach to Pyrazoline-Fused Chlorins by Dipolar [3 + 2]-Cycloaddition of Iminonitriles to mesoTetrakis(pentafluorophenyl)porphyrin: Synthesis of New PDT Photosensitizers. Bull. Chem. Soc. Jpn. 2012, 85, 1167−1174. (446) Moura, N. M. M.; Giuntini, F.; Faustino, M. A. F.; Neves, M. G. P. M. S.; Tomé, A. C.; Silva, A. M. S.; Rakib, E. M.; Hannioui, A.; Abouricha, S.; Röder, B.; Cavaleiro, J. A. S. 1,3-Dipolar Cycloaddition of Nitrile Imines to meso-Tetraarylporphyrins. Arkivoc 2010, 24−33. (447) Flemming, J.; Dolphin, D. Carbonyl Ylide 1,3-Dipolar Cycloadditions with Porphyrins. Tetrahedron Lett. 2002, 43, 7281− 7283. (448) Li, X.; Zhuang, J.; Li, Y.; Liu, H.; Wang, S.; Zhu, D. Synthesis of Isoxazoline-Fused Chlorins and Bacteriochlorins by 1,3-Dipolar Cycloaddition Reaction of Porphyrin with Nitrile Oxide. Tetrahedron Lett. 2005, 46, 1555−1559. (449) Liu, X.; Feng, Y.; Chen, X.; Li, F.; Li, X. Porphyrins as Dipolarophiles in 1,3-Dipolar Cycloaddition Reactions with Nitrile Oxide. Synlett 2005, 1030−1032. (450) Xingang, L.; Yaqing, F.; Xiaofen, H.; Xianggao, L. Synthesis of Novel Isoxazole-Fused Chlorins and Bacteriochlorins via 1,3-Dipolar Cycloaddition Reactions of Nitrile Oxides with Porphyrins. Synthesis 2005, 2005, 3632−3638. (451) Momo, P. B.; Pavani, C.; Baptista, M. S.; Brocksom, T. J.; de Oliveira, K. T. Chemical Transformations and Photophysical Properties of meso-Tetrathienyl-Substituted Porphyrin Derivatives. Eur. J. Org. Chem. 2014, 2014, 4536−4547. (452) Ostrowski, S.; Wyrębek, P.; Mikus, A. Synthesis of Isoxazolinefused Chlorins By 1,3-Dipolar Cycloaddition Reaction of Porphyrins with Alkyl Nitrile Oxides. Heterocycles 2006, 68, 885−888. (453) Pereira, N. A. M.; Serra, A. C.; Pinho e Melo, T. M. V. D. Novel Approach to Chlorins and Bacteriochlorins: [8π+2π] Cycloaddition of Diazafulvenium Methides with Porphyrins. Eur. J. Org. Chem. 2010, 2010, 6539−6543. (454) Pereira, N. A. M.; Fonseca, S. M.; Serra, A. C.; Pinho e Melo, T. M. V. D.; Burrows, H. D. [8π+2π] Cycloaddition of meso-Tetra- and 5,15-Diarylporphyrins: Synthesis and Photophysical Characterization of Stable Chlorins and Bacteriochlorins. Eur. J. Org. Chem. 2011, 2011, 3970−3979. (455) Desjardins, A.; Flemming, J.; Sternberg, E. D.; Dolphin, D. Nitrogen Extrusion from Pyrazoline-substituted Porphyrins and Chlorins using Long Wavelength Visible Light. Chem. Commun. 2002, 2622−2623. (456) Aguiar, A.; Leite, A.; Silva, A. M. N.; Tomé, A. C.; Cunha-Silva, L.; de Castro, B.; Rangel, M.; Silva, A. M. G. Isoxazolidine-fused mesoTetraarylchlorins as Key Tools for the Synthesis of Mono- and Bisannulated Chlorins. Org. Biomol. Chem. 2015, 13, 7131−7135. (457) Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.; Cavaleiro, J. A. S.; Perrone, D.; Dondoni, A. Porphyrins in 1,3Dipolar Cycloaddition Reactions with Sugar Nitrones. Synthesis of Glycoconjugated Isoxazolidine-fused Chlorins and Bacteriochlorins. Tetrahedron Lett. 2002, 43, 603−605. (458) Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S.; Perrone, D.; Dondoni, A. Porphyrins in 1,3-Dipolar Cycloadditions with Sugar Azomethine Ylides. Synthesis of Pyrrolidinoporphyrin Glycoconjugates. Synlett 2005, 857−859. (459) Saravanan, P.; Babu, A. R. S.; Raghunathan, R. Synthesis of Chlorin-Fused Monospirooxindolopyrrolidines Through a Facile [3 + 2]-Cycloaddition of Azomethine Ylides. Synth. Commun. 2010, 40, 2329−2335. (460) Wyrębek, P.; Mikus, A.; Ostrowski, S. 1,3-Dipolar Cycloaddition Reaction in Porphyrin Systems with Functionalized Alkyl Nitrile Oxides − Synthesis of Isoxazoline-Fused Chlorins. Heterocycles 2012, 85, 57− 64.

Bacteria by First and Second Generation Cationic Photosensitizers. Photochem. Photobiol. Sci. 2012, 11, 1905−1913. (428) Obata, M.; Hirohara, S.; Tanaka, R.; Kinoshita, I.; Ohkubo, K.; Fukuzumi, S.; Tanihara, M.; Yano, S. In Vitro Heavy-Atom Effect of Palladium(II) and Platinum(II) Complexes of Pyrrolidine-Fused Chlorin in Photodynamic Therapy. J. Med. Chem. 2009, 52, 2747−2753. (429) Hirohara, S.; Obata, M.; Alitomo, H.; Sharyo, K.; Ando, T.; Tanihara, M.; Yano, S. Synthesis, Photophysical Properties and SugarDependent in vitro Photocytotoxicity of Pyrrolidine-Fused Chlorins bearing S-glycosides. J. Photochem. Photobiol., B 2009, 97, 22−33. (430) Maestrin, A. P. J.; Ribeiro, A. O.; Tedesco, A. C.; Neri, C. R.; Vinhado, F. S.; Serra, O. A.; Martins, P. R.; Iamamoto, Y.; Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. A Novel Chlorin Derivative of Meso-tris(pentafluorophenyl)-4-pyridylporphyrin: Synthesis, Photophysics and Photochemical Properties. J. Braz. Chem. Soc. 2004, 15, 923−930. (431) Shaw, S. J.; Elgie, K. J.; Edwards, C.; Boyle, R. W. Mono(pentafluorophenyl)porphyrins − Useful Intermediates in the Regioselective Synthesis of Multifunctionalised Porphyrins. Tetrahedron Lett. 1999, 40, 1595−1596. (432) Shaw, S. J.; Edwards, C.; Boyle, R. W. Regioselective Synthesis of Multifunctionalised Porphyrins − Coupling of Mono(pentafluorophenyl)porphyrins to Electrophiles. Tetrahedron Lett. 1999, 40, 7585−7586. (433) Pasetto, P.; Chen, X.; Drain, C. M.; Franck, R. W. Synthesis of Hydrolytically Stable Porphyrin C- and S-Glycoconjugates in High Yields. Chem. Commun. 2001, 81−82. (434) Samaroo, D.; Vinodu, M.; Chen, X.; Drain, C. M. mesoTetra(pentafluorophenyl)porphyrin as an Efficient Platform for Combinatorial Synthesis and the Selection of New Photodynamic Therapeutics using a Cancer Cell Line. J. Comb. Chem. 2007, 9, 998− 1011. (435) Singh, S.; Aggarwal, A.; Thompson, S.; Tomé, J. P. C.; Zhu, X.; Samaroo, D.; Vinodu, M.; Gao, R.; Drain, C. M. Synthesis and Photophysical Properties of Thioglycosylated Chlorins, Isobacteriochlorins, and Bacteriochlorins for Bioimaging and Diagnostics. Bioconjugate Chem. 2010, 21, 2136−2146. (436) Aggarwal, A.; Thompson, S.; Singh, S.; Newton, B.; Moore, A.; Gao, R.; Gu, X.; Mukherjee, S.; Drain, C. M. Photophysics of Glycosylated Derivatives of a Chlorin, Isobacteriochlorin and Bacteriochlorin for Photodynamic Theragnostics: Discovery of a Two-photon-absorbing Photosensitizer. Photochem. Photobiol. 2014, 90, 419−430. (437) Costa, J. I. T.; Tomé, A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. 5,10,15,20-Tetrakis(pentafluorophenyl)porphyrin: A Versatile Platform to Novel Porphyrinic Materials. J. Porphyrins Phthalocyanines 2011, 15, 1116−1133. (438) Hao, E.; Friso, E.; Miotto, G.; Jori, G.; Soncin, M.; Fabris, C.; Sibrian-Vazquez, M.; Vicente, M. G. H. Synthesis and Biological Investigations of Tetrakis(p-carboranylthio-tetrafluorophenyl)chlorin (TPFC). Org. Biomol. Chem. 2008, 6, 3732−3740. (439) Sakuma, S.; Otake, E.; Torii, K.; Nakamura, M.; Maeda, A.; Tujii, R.; Akashi, H.; Ohi, H.; Yano, S.; Morita, A. Photodynamic Therapy with Glycoconjugated Chlorin Photosensitizer. J. Porphyrins Phthalocyanines 2013, 17, 331−342. (440) Pershukevich, P. P.; Volkovich, D. I.; Gladkov, L. L.; Dudkin, S. V.; Stupak, A. P.; Kuzmitsky, V. A.; Makarova, E. A.; Solovyov, K. N. The Fluorescence and Electronic Structure of Phenyl-substituted Tetraazachlorin Molecules. Opt. Spectrosc. 2014, 117, 722−740. (441) Ivanova, S. S.; Moryganova, Y.; Hamdoush, M.; Koifman, O. I.; Sal’nikov, D. S.; Stuzhin, P. A. Phosphorus(V) Tetrapyrazinocorrolazines  First Corrolazine Derivatives with Fused Heterocyclic Rings. J. Porphyrins Phthalocyanines 2014, 18, 875−883. (442) Makarova, E. A.; Koroleva, G. V.; Luk’yanets, E. A. Phthalocyanines and Related Compounds: XXXVI. Synthesis of Tetraazachlorin and Tetraazaporphine from Succinonitrile. Russ. J. Gen. Chem. 1999, 69, 1306−1311. (443) Arabei, S. M.; Solov’ev, K. N.; Makarova, E. A. Effect of the Electron-Vibrational Interaction on the Second Electron Transition of GF


Chemical Reviews

Review

(461) Silva, A. M. G.; Lacerda, P. S. S.; Tomé, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.; Cavaleiro, J. A. S.; Makarova, E. A.; Lukyanets, E. A. Porphyrins in 1,3-Dipolar Cycloaddition Reactions. Synthesis of New Porphyrin−Chlorin and Porphyrin−Tetraazachlorin Dyads. J. Org. Chem. 2006, 71, 8352−8356. (462) Liu, X.; Li, C.; Peng, X.; Zhou, Y.; Zeng, Z.; Li, Y.; Zhang, T.; Zhang, B.; Dong, Y.; Sun, D.; Cheng, P.; Feng, Y. Performance of Four Artificial Chlorin-type Sensitizers with Different Stereostructures in Dye-sensitized Solar Cells. Dyes Pigm. 2013, 98, 181−189. (463) Ebrahim, M. M.; Moreau, M.; Senge, M. O. Silyl Nitronate 1,3Dipolar Cycloaddition Reactions with Meso-Tetraarylporphyrins. Heterocycles 2011, 83, 627−630. (464) Mesquita, M. Q.; Menezes, J. C. J. M. D. S.; Neves, M. G. P. M. S.; Tomé, A. C.; Cavaleiro, J. A. S.; Cunha, A.; Almeida, A.; Hackbarth, S.; Röder, B.; Faustino, M. A. F. Photodynamic Inactivation of Bioluminescent Escherichia coli by Neutral and Cationic PyrrolidineFused Chlorins and Isobacteriochlorins. Bioorg. Med. Chem. Lett. 2014, 24, 808−812. (465) Mesquita, M. Q.; Menezes, J. C. J. M. D. S.; Pires, S. M. G.; Neves, M. G. P. M. S.; Simões, M. M. Q.; Tomé, A. C.; Cavaleiro, J. A. S.; Cunha, A.; Daniel-da-Silva, A. L.; Almeida, A.; Faustino, M. A. F. Pyrrolidine-fused Chlorin Photosensitizer Immobilized on Solid Supports for the Photoinactivation of Gram Negative Bacteria. Dyes Pigm. 2014, 110, 123−133. (466) de Assis, F. F.; de Souza, J. M.; Assis, B. H. K.; Brocksom, T. J.; de Oliveira, K. T. Synthesis and Photophysical Studies of a Chlorin Sterically Designed to Prevent Self-Aggregation. Dyes Pigm. 2013, 98, 153−159. (467) Shea, K. M.; Jaquinod, L.; Smith, K. M. Dihydroporphyrin Synthesis: New Methodology. J. Org. Chem. 1998, 63, 7013−7021. (468) Jaquinod, L.; Gros, C.; Khoury, R. G.; Smith, K. M. A Convenient Synthesis of Functionalized Tetraphenylchlorins. Chem. Commun. 1996, 2581−2582. (469) Luguya, R.; Fronczek, F. R.; Smith, K. M.; Vicente, M. G. H. Synthesis of Novel Carboranylchlorins with Dual Application in Boron Neutron Capture Therapy (BNCT) and Photodynamic Therapy (PDT). Appl. Radiat. Isot. 2004, 61, 1117−1123. (470) Shea, K. M.; Jaquinod, L.; Khoury, R. G.; Smith, K. M. Functionalization of 2,3-Disubstituted-2,3-dihydro-5,10,15,20-tetraphenylporphyrins. Tetrahedron 2000, 56, 3139−3144. (471) Pereira, A. M. V. M; Alonso, C. M. A.; Neves, M. G. P. M. S.; Tomé, A. C.; Silva, A. M. S.; Paz, F. A. A.; Cavaleiro, J. A. S. A New Synthetic Approach to N-Arylquinolino[2,3,4-at]porphyrins from βArylaminoporphyrins. J. Org. Chem. 2008, 73, 7353−7356. (472) Silva, A. M. G.; Tomé, A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. Porphyrins in 1,3-Dipolar Cycloaddition Reactions: Synthesis of a Novel Pyrazoline-fused Chlorin and a Pyrazole-fused Porphyrin. Synlett 2002, 1155−1157. (473) Ostrowski, S.; Wyrębek, P. The First Example of Diels−Alder Cycloaddition of ortho-Xylylenes to meso-Tetraarylporphyrins Containing Electron-Deficient β,β-Double Bonds. Tetrahedron Lett. 2006, 47, 8437−8440. (474) Ishkov, Y. V.; Vodzinskii, S. V.; Kirichenko, A. M.; Mazepa, A. V. Porphyrins and Their Derivatives: XXV. Reaction of 2-Formyl5,10,15,20-tetraphenylporphyrin with Diazomethane. Russ. J. Org. Chem. 2008, 44, 1072−1076. (475) Gałęzowski, M.; Gryko, D. T. Synthesis of Locked meso-βSubstituted Chlorins via 1,3-Dipolar Cycloaddition. J. Org. Chem. 2006, 71, 5942−5950. (476) Gryko, D. T.; Gałęzowski, M. Simple Approach to “Locked” Chlorins. Org. Lett. 2005, 7, 1749−1752. (477) Corwin, A. H.; Collins, O. D. III Reduction of Tin Porphyrins to Tin Chlorins. J. Org. Chem. 1962, 27, 3060−3062. (478) Akhigbe, J.; Peters, G.; Zeller, M.; Brückner, C. Unexpected Hydroxylamine-induced Ring-Closure Reactions of meso-Tetraphenylsecochlorin Bisaldehyde. Org. Biomol. Chem. 2011, 9, 2306−2313. (479) Brückner, C. The Breaking and Mending of meso-Tetraarylporphyrins: Transmuting the Pyrrolic Building Blocks. Acc. Chem. Res. 2016, 49, 1080−1092.

(480) Crossley, M. J.; King, L. G. Novel Heterocyclic Systems from Selective Oxidation at the β-Pyrrolic Position of Porphyrins. J. Chem. Soc., Chem. Commun. 1984, 920−922. (481) Crossley, M. J.; Burn, P. L.; Langford, S. J.; Pyke, S. M.; Stark, A. G. A New Method for the Synthesis of Porphyrin-α-diones that is Applicable to the Synthesis of Trans-annular Extended Porphyrin Systems. J. Chem. Soc., Chem. Commun. 1991, 1567−1568. (482) Beavington, R.; Rees, P. A.; Burn, P. L. A Study on the Oxidation of 2-Hydroxyporphyrins to Porphyrin-α-diones. J. Chem. Soc., Perkin Trans. 1 1998, 2847−2851. (483) Promarak, V.; Burn, P. L. A New Synthetic Approach to Porphyrin-α-diones and a −2,3,12,13-tetraone: Building Blocks for Laterally Conjugated Porphyrin Arrays. J. Chem. Soc., Perkin Trans. 1 2001, 14−20. (484) Wicks, M. N.; Burn, P. L. A Short Route To Chlorin-α-diones. J. Porphyrins Phthalocyanines 2005, 9, 444−450. (485) Daniell, H. W.; Williams, S. C.; Jenkins, H. A.; Brückner, C. Oxidation of meso-Tetraphenyl-2,3-dihydroxychlorin: Simplified Synthesis of β,β′-Dioxochlorins. Tetrahedron Lett. 2003, 44, 4045−4049. (486) Brückner, C.; McCarthy, J. R.; Daniell, H. W.; Pendon, Z. D.; Ilagan, R. P.; Francis, T. M.; Ren, L.; Birge, R. R.; Frank, H. A. A Spectroscopic and Computational Study of the Singlet and Triplet Excited States of Synthetic β-Functionalized Chlorins. Chem. Phys. 2003, 294, 285−303. (487) Gouterman, M.; Hall, R. J.; Khalil, G.-E.; Martin, P. C.; Shankland, E. G.; Cerny, R. L. Tetra(pentafluorophenyl)porpholactone. J. Am. Chem. Soc. 1989, 111, 3702−3707. (488) Hayashi, H.; Touchy, A. S.; Kinjo, Y.; Kurotobi, K.; Toude, Y.; Ito, S.; Saarenpäa,̈ H.; Tkachenko, N. V.; Lemmetyinen, H.; Imahori, H. Triarylamine-substituted Imidazole- and Quinoxaline-fused Push−Pull Porphyrins for Dye-Sensitized Solar Cells. ChemSusChem 2013, 6, 508− 517. (489) Matlachowski, C.; Schwalbe, M. Synthesis and Characterization of Mono- and Dinuclear Phenanthroline-extended Tetramesitylporphyrin Complexes as well as UV-Vis And EPR Studies on their OneElectron Reduced Species. Dalton Trans. 2013, 42, 3490−3503. (490) Vannelli, T. A.; Karpishin, T. B. Neocuproine-Extended Porphyrin Coordination Complexes. 2. Spectroscopic Properties of the Metalloporphyrin Derivatives and Investigations into the HOMO Ordering. Inorg. Chem. 2000, 39, 340−347. (491) Lin, R.-S.; Li, M.-R.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Bimetallic Complexes of Porphyrinphenanthroline: Preparation and Catalytic Activities. Inorg. Chim. Acta 2010, 363, 3523−3529. (492) Eu, S.; Hayashi, S.; Umeyama, T.; Matano, Y.; Araki, Y.; Imahori, H. Quinoxaline-Fused Porphyrins for Dye-Sensitized Solar Cells. J. Phys. Chem. C 2008, 112, 4396−4405. (493) Aicher, D.; Gräfe, S.; Stark, C. B. W.; Wiehe, A. Synthesis of βFunctionalized Temoporfin Derivatives for an Application in Photodynamic Therapy. Bioorg. Med. Chem. Lett. 2011, 21, 5808−5811. (494) Jayaraj, K.; Gold, A.; Austin, R. N.; Ball, L. M.; Terner, J.; Mandon, D.; Weiss, R.; Fischer, J.; DeCian, A.; Bill, E.; Müther, M.; Schünemann, V.; Trautwein, A. X. Compound I and Compound II Analogues From Porpholactones. Inorg. Chem. 1997, 36, 4555−4566. (495) Lv, H.; Yang, B.; Jing, J.; Yu, Y.; Zhang, J.; Zhang, J.-L. Dual Facet of Gold(III) in the Reactions of Gold(III) and Porphyrins. Dalton Trans. 2012, 41, 3116−3118. (496) Yu, Y.; Lv, H.; Ke, X.; Yang, B.; Zhang, J.-L. RutheniumCatalyzed Oxidation of the Porphyrin β,β′-Pyrrolic Ring: A General and Efficient Approach to Porpholactones. Adv. Synth. Catal. 2012, 354, 3509−3516. (497) Cavaleiro, J. A. S.; Gerdan, V. M.; Hombrecher, H. K.; Neves, M. G. P. M. S.; Silva, A. M. S. Synthesis and Characterisation of New 2Diazo-3-oxo-5,10,15,20-tetraphenylchlorins. Heterocycl. Commun. 1997, 3, 253−261. (498) Crossley, M. J.; Harding, M. M.; Sternhell, S. Tautomerism in 2Hydroxy-5,10,15,20-tetraphenylporphyrin: An Equilibrium between Enol, Keto, and Aromatic Hydroxyl Tautomers. J. Org. Chem. 1988, 53, 1132−1137. GG


Chemical Reviews

Review

(518) Akhigbe, J.; Brückner, C. Expansion of a Pyrrole in mesoTetraphenylporphyrin to a Pyrazine Imide Moiety Using a Beckmann Rearrangement. Eur. J. Org. Chem. 2013, 2013, 3876−3884. (519) Jayaraj, K.; Gold, A.; Austin, R. N.; Mandon, D.; Weiss, R.; Terner, J.; Bill, E.; Müther, M.; Trautwein, A. X. Compound I and II Analogs of a Chlorin. J. Am. Chem. Soc. 1995, 117, 9079−9080. (520) Banerjee, S.; Zeller, M.; Brückner, C. meso-Tetraphenylporphyrin-derived Oxypyriporphyrin, Oxypyrichlorin, and Thiomorpholinochlorin, as their Ni(II) Complexes. J. Porphyrins Phthalocyanines 2012, 16, 576−588. (521) Lash, T. D.; Chaney, S. T. Oxypyriporphyrin, the First Fully Aromatic Porphyrinoid Macrocycle with a Pyridine Subunit. Chem. Eur. J. 1996, 2, 944−948. (522) Adams, K. R.; Bonnett, R.; Burke, P. J.; Salgado, A.; Vallés, M. A. The 2,3-Secochlorin-2,3-dione System. J. Chem. Soc., Chem. Commun. 1993, 1860−1861. (523) Adams, K. R.; Bonnett, R.; Burke, P. J.; Salgado, A.; Vallés, M. A. Cleavage of (Octaethyl-2,3-dihydroxychlorinato)nickel(II) to give the Novel 2,3-Dioxo-2,3-secochlorin System. J. Chem. Soc., Perkin Trans. 1 1997, 1769−1772. (524) Ryppa, C.; Niedzwiedzki, D.; Morozowich, N. L.; Srikanth, R.; Zeller, M.; Frank, H. A.; Brückner, C. Stepwise Conversion of Two Pyrrole Moieties of Octaethylporphyrin to Pyridin-3-ones: Synthesis, Mass Spectral, and Photophysical Properties of Mono and Bis(oxypyri)porphyrins. Chem. - Eur. J. 2009, 15, 5749−5762. (525) Adams, K. R.; Berenbaum, M. C.; Bonnett, R.; Nizhnik, A. N.; Salgado, A.; Vallés, M. A. Second Generation Tumour Photosensitisers: The Synthesis and Biological Activity of Octaalkyl Chlorins and Bacteriochlorins with Graded Amphiphilic Character. J. Chem. Soc., Perkin Trans. 1 1992, 1465−1470. (526) Meehan, E.; Li, R.; Zeller, M.; Brückner, C. Octaethyl-1,3oxazinochlorin: A β-Octaethylchlorin Analogue Made by Pyrrole Expansion. Org. Lett. 2015, 17, 2210−2213. (527) Sessler, J. L.; Shevchuk, S. V.; Callaway, W.; Lynch, V. A OneStep Synthesis of a Free Base Secochlorin From a 2,3-Dimethoxy Porphyrin. Chem. Commun. 2001, 968−969. (528) Lo, M.; Lefebvre, J.-F.; Marcotte, N.; Tonnelé, C.; Beljonne, D.; Lazzaroni, R.; Clément, S.; Richeter, S. Synthesis of Stable Free Base Secochlorins and their Corresponding Metal Complexes from mesoTetraarylporphyrin Derivatives. Chem. Commun. 2012, 48, 3460−3462. (529) Kozyrev, A. N.; Alderfer, J. L.; Dougherty, T. J.; Pandey, R. K. Synthesis of Mono- and Di(oxopyri)porphyrins: A New Approach through Ring Enlargement with Diazomethane. Angew. Chem., Int. Ed. 1999, 38, 126−128. (530) Starnes, S. D.; Rudkevich, D. M.; Rebek, J., Jr. Cavitand−Porphyrins. J. Am. Chem. Soc. 2001, 123, 4659−4669. (531) Brückner, C.; Hyland, M. A.; Sternberg, E. D.; MacAlpine, J. K.; Rettig, S. J.; Patrick, B. O.; Dolphin, D. Preparation of [mesoTetraphenylchlorophinato]nickel(II) by Stepwise Deformylation of [meso-Tetraphenyl-2,3-diformyl-secochlorinato]nickel(II): Conformational Consequences of Breaking the Structural Integrity of Nickel Porphyrins. Inorg. Chim. Acta 2005, 358, 2943−2953. (532) Brückner, C.; Götz, D. C. G.; Fox, S. P.; Ryppa, C.; McCarthy, J. R.; Bruhn, T.; Akhigbe, J.; Banerjee, S.; Daddario, P.; Daniell, H. W.; Zeller, M.; Boyle, R. W.; Bringmann, G. Helimeric Porphyrinoids: Stereostructure and Chiral Resolution of meso-Tetraarylmorpholinochlorins. J. Am. Chem. Soc. 2011, 133, 8740−8752. (533) Ogikubo, J.; Worlinsky, J. L.; Fu, Y.-J.; Brückner, C. A Two-Step, One-Pot Route to Swap the Pyrroline Moiety in meso-Tetraaryldihydroxy-Chlorins with an O/N-Substituted Oxazoline. Tetrahedron Lett. 2013, 54, 1707−1710. (534) Campbell, C. J.; Rusling, J. F.; Brückner, C. Nickel(II) mesoTetraphenyl-Homoporphyrins, -secochlorins, and -chlorophin: Control of Redox Chemistry by Macrocycle Rigidity. J. Am. Chem. Soc. 2000, 122, 6679−6685. (535) Banerjee, S.; Hyland, M. A.; Brü c kner, C. [2Methylazeteochlorinato]Ni(II): A Pyrrole Ring-Contracted Chlorin Analogue. Tetrahedron Lett. 2010, 51, 4505−4508.

(499) Catalano, M. M.; Crossley, M. J.; King, L. G. Efficient Synthesis of 2-Oxy-5,10,15,20-tetraphenylporphyrins from a Nitroporphyrin by a Novel Multi-step Cine-substitution Sequence. J. Chem. Soc., Chem. Commun. 1984, 1537−1538. (500) Crossley, M. J.; King, L. G. Reaction of Metallo-2-nitro5,10,15,20-tetraphenylporphyrins with Oxyanions. Temperature-Dependent Competition Between Nucleophilic Addition and SingleElectron Transfer Processes. J. Chem. Soc., Perkin Trans. 1 1996, 1251− 1260. (501) Samankumara, L. P.; Zeller, M.; Krause, J. A.; Brückner, C. Syntheses, Structures, Modification, and Optical Properties of mesoTetraaryl-2,3-dimethoxychlorin, and Two Isomeric meso-Tetraaryl2,3,12,13-tetrahydroxybacteriochlorins. Org. Biomol. Chem. 2010, 8, 1951−1965. (502) Chen, J.; Li, K.-L.; Guo, Y.; Liu, C.; Guo, C.-C.; Chen, Q.-Y. Design and Synthesis of β-Multi-substituted Push−Pull Porphyrins. RSC Adv. 2013, 3, 8227−8231. (503) McCarthy, J. R.; Jenkins, H. A.; Brückner, C. Free Base mesoTetraaryl-morpholinochlorins and Porpholactone from meso-Tetraaryl2,3-dihydroxy-chlorin. Org. Lett. 2003, 5, 19−22. (504) Akhigbe, J.; Ryppa, C.; Zeller, M.; Brückner, C. Oxazolochlorins. 2. Intramolecular Cannizzaro Reaction of meso-Tetraphenylsecochlorin Bisaldehyde. J. Org. Chem. 2009, 74, 4927−4933. (505) Brückner, C.; Rettig, S. J.; Dolphin, D. Formation of a mesoTetraphenylsecochlorin and a Homoporphyrin with a Twist. J. Org. Chem. 1998, 63, 2094−2098. (506) McCarthy, J. R.; Melfi, P. J.; Capetta, S. H.; Brückner, C. Use of Ag(II) as a Removable Template in Porphyrin Chemistry: Diol Cleavage Products of [meso-Tetraphenyl-2,3-cis-diolchlorinato]silver(II). Tetrahedron 2003, 59, 9137−9146. (507) Crossley, M. J.; Hambley, T. W.; King, L. G. Conversion of a Porphyrin into a 5,6-Dihydroporphyrin. Synthesis and X-Ray Crystal Structure of (5RS,6SR)-5,6-Dihydro-6-(methoxycarbonyl)-8-oxo5,10,15,20-tetraphenyl-8H-7-oxaporphyrin. Bull. Soc. Chim. Fr. 1996, 133, 735−742. (508) Kö pke, T.; Pink, M.; Zaleski, J. M. Elucidation of the Extraordinary 4-Membered Pyrrole Ring-contracted Azeteoporphyrinoid as an Intermediate in Chlorin Oxidation. Chem. Commun. 2006, 4940−4942. (509) Banerjee, S.; Zeller, M.; Brü ckner, C. OsO4-Mediated Dihydroxylation of meso-Tetraphenylporphyrin N-Oxide and Transformation of the Resulting Diolchlorin N-Oxide Regioisomers. J. Org. Chem. 2010, 75, 1179−1187. (510) Banerjee, S.; Zeller, M.; Brückner, C. MTO/H2O2/PyrazoleMediated N-Oxidation of meso-Tetraarylporphyrins and -chlorins, and S-Oxidation of a meso-Tetraaryldithiaporphyrin and -chlorin. J. Org. Chem. 2009, 74, 4283−4288. (511) Yu, Y.; Czepukojc, B.; Jacob, C.; Jiang, Y.; Zeller, M.; Brückner, C.; Zhang, J.-L. Porphothionolactones: Synthesis, Structure, Physical, and Chemical Properties of a Chemodosimeter for Hypochlorite. Org. Biomol. Chem. 2013, 11, 4613−4621. (512) Köpke, T.; Pink, M.; Zaleski, J. M. Efficient Silver-Mediated Acetalation of β,β′-Functionalized Chlorins. Synlett 2008, 1882−1888. (513) Hombrecher, H. K.; Gerdan, V. M.; Cavaleiro, J. A. S.; Neves, M. G. P. M. S. Photoinduced Reaction of 2-Diazo-3-oxo-5,10,15,20tetraphenylchlorins with Alcohols. Heterocycl. Commun. 1997, 3, 453− 460. (514) Köpke, T.; Pink, M.; Zaleski, J. M. A Facile Synthesis of 2-Diazo3-oxochlorins by Lewis Acid Activation: Selective Modification of πElectron Conjugated Macrocycles. Synlett 2006, 2183−2186. (515) Köpke, T.; Pink, M.; Zaleski, J. M. Photochemical Preparation of Pyrrole Ring-contracted Chlorins by the Wolff Rearrangement. Org. Biomol. Chem. 2006, 4, 4059−4062. (516) Köpke, T.; Pink, M.; Zaleski, J. M. Expansion by Contraction: Diversifying The Photochemical Reactivity Scope Of Diazo-oxochlorins toward Development of in Situ Alkylating Agents. J. Am. Chem. Soc. 2008, 130, 15864−15871. (517) Akhigbe, J.; Zeller, M.; Brückner, C. Quinoline-Annulated Porphyrins. Org. Lett. 2011, 13, 1322−1325. GH


Chemical Reviews

Review

(536) Li, K.-L.; Guo, C.-C.; Chen, Q.-Y. Unprecedented Degradation of Nickel(II) 2,3,12,13-Tetrabromo-5,10,15,20-tetraarylporphyrins by the Anion of E-Benzaldoxime: A Novel Approach to Nickel(II) Chlorophins and Bacteriophins. Org. Lett. 2009, 11, 2724−2727. (537) Akhigbe, J.; Haskoor, J.; Zeller, M.; Brückner, C. Porpholactams and Chlorolactams: Replacement of a β,β′-Double Bond in mesoTetraphenyl-porphyrin and -chlorin by a Lactam Moiety. Chem. Commun. 2011, 47, 8599−8601. (538) Akhigbe, J.; Haskoor, J.; Krause, J. A.; Zeller, M.; Brückner, C. Formation, Structure, and Reactivity of meso-Tetraaryl-chlorolactones, -porpholactams, and -chlorolactams, Porphyrin and Chlorin Analogues Incorporating Oxazolone or Imidazolone Moieties. Org. Biomol. Chem. 2013, 11, 3616−3628. (539) Ogikubo, J.; Brückner, C. Tunable meso-Tetraphenyl-alkyloxazolo-chlorins and -bacteriochlorins. Org. Lett. 2011, 13, 2380−2383. (540) Ogikubo, J.; Meehan, E.; Engle, J. T.; Ziegler, C. J.; Brückner, C. meso-Aryl-3-alkyl-2-oxachlorins. J. Org. Chem. 2012, 77, 6199−6207. (541) Khalil, G. E.; Daddario, P.; Lau, K. S. F.; Imtiaz, S.; King, M.; Gouterman, M.; Sidelev, A.; Puran, N.; Ghandehari, M.; Brückner, C. meso-Tetraarylporpholactones as High pH Sensors. Analyst 2010, 135, 2125−2131. (542) Worlinsky, J. L.; Zarate, G.; Zeller, M.; Ghandehari, M.; Khalil, G.; Brückner, C. Oxazolochlorins 11: Tuning the Dynamic High pH Sensing Range of [meso-Tetraarylporpholactonato]M(II) Complexes by Variation of the Central Metal Ion, the Aryl Substituents, and Introduction of a β-Nitro Group. J. Porphyrins Phthalocyanines 2013, 17, 836−849. (543) Worlinsky, J. L.; Halepas, S.; Brückner, C. PEGylated mesoArylporpholactone Metal Complexes as Optical Cyanide Sensors in Water. Org. Biomol. Chem. 2014, 12, 3991−4001. (544) Zeller, M.; Hunter, A. D.; McCarthy, J. R.; Capetta, S. H.; Brückner, C. Crystal and Molecular Structure of [5,10,15,20-Tetrakisphenyl-2-ethoxy-3-oxa-chlorinato]Ag(II). J. Chem. Crystallogr. 2005, 35, 935−942. (545) Ke, X.-S.; Tang, J.; Chen, J.-J.; Zhou, Z.-Y.; Zhang, J.-L. β-Ionic Conjugated Chlorin-Type Photosensitizers Based on Porpholactone: Synthesis, Photophysical Properties, and Photodynamic Activity. ChemPlusChem 2015, 80, 237−252. (546) Chang, C. K.; Wu, W.; Chern, S.-S.; Peng, S.-M. First Example of a Chlorophin from an Unexpected Oxidative Ring-Opening of an (Octadehydrocorrinato)nickel(II) Salt. Angew. Chem., Int. Ed. Engl. 1992, 31, 70−72. (547) Akhigbe, J.; Samankumara, L. P.; Brückner, C. The Breaking and Mending of Porphyrins: Reductive Coupling of Secochlorin Bisaldehydes. Tetrahedron Lett. 2012, 53, 3524−3526. (548) Daniell, H. W.; Brückner, C. Enantiomeric Resolution of a Ruffled Porphyrinoid. Angew. Chem., Int. Ed. 2004, 43, 1688−1691. (549) McCarthy, J. R.; Hyland, M. A.; Brückner, C. Synthesis of Indaphyrins: meso-Tetraarylsecochlorin-based Porphyrinoids Containing Direct ο-Phenyl-to-β-Linkages. Org. Biomol. Chem. 2004, 2, 1484− 1491. (550) McCarthy, J. R.; Hyland, M. A.; Brückner, C. Indaphyrin, a mesoTetraphenylsecochlorin-derived Chromophore Incorporating o-Phenylto-β-Linkages. Chem. Commun. 2003, 1738−1739. (551) Lau, K. S. F.; Zhao, S.; Ryppa, C.; Jockusch, S.; Turro, N. J.; Zeller, M.; Gouterman, M.; Khalil, G. E.; Brückner, C. Synthesis, Structure, and Optical Properties of the Platinum(II) Complexes of Indaphyrin and Thiaindaphyrin. Inorg. Chem. 2009, 48, 4067−4074. (552) Gros, C. P.; Jaquinod, L.; Khoury, R. G.; Olmstead, M. M.; Smith, K. M. Approaches to β-Fused Porphyrinoporphyrins: Pyrroloand Dipyrromethanoporphyrins. J. Porphyrins Phthalocyanines 1997, 1, 201−212. (553) Catalano, M. M.; Crossley, M. J.; Harding, M. M.; King, L. G. Control of Reactivity at the Porphyrin Periphery by Metal Ion Coordination: A General Method for Specific Nitration at the β-Pyrrolic Position of 5,10,15,20-Tetraarylporphyrins. J. Chem. Soc., Chem. Commun. 1984, 1535−1536. (554) Richeter, S.; Jeandon, C.; Gisselbrecht, J.-P.; Graff, R.; Ruppert, R.; Callot, H. J. Synthesis of New Porphyrins with Peripheral

Conjugated Chelates and Their Use for the Preparation of Porphyrin Dimers Linked by Metal Ions. Inorg. Chem. 2004, 43, 251−263. (555) Jimenez, A. J.; Jeandon, C.; Gisselbrecht, J.-P.; Ruppert, R. Synthesis, Characterization, and Electrochemical Studies of New πExtended Metalloporphyrins. Eur. J. Org. Chem. 2009, 2009, 5725− 5730. (556) Jeandon, C.; Ruppert, R. A Porphyrin with Two Coordination Sites: The Biquinoline Ligand as a New Potential External Chelate. Eur. J. Org. Chem. 2011, 2011, 4098−4102. (557) Akhigbe, J.; Luciano, M.; Zeller, M.; Brückner, C. Mono- and Bisquinoline-Annulated Porphyrins from Porphyrin β,β′-Dione Oximes. J. Org. Chem. 2015, 80, 499−511. (558) Boyle, R. W.; Dolphin, D. 5,15-Diphenyl-7-oxobenzochlorins. Novel Long-wavelength Absorbing Photosensitizers for Photodynamic Therapy. J. Chem. Soc., Chem. Commun. 1994, 2463−2464. (559) Pawlicki, M.; Latos-Grażyński, L. CarbaporphyrinoidsSynthesis and Coordination Properties. In Handbook of Porphyrin Science; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; World Scientific Publishing Co. Pte. Ltd.: Singapore, 2010; Vol. 2, pp 103−192. (560) Lash, T. D. Carbaporphyrins and Related Systems. Synthesis, Characterization, Reactivity and Insights into Porphyrinoid Aromaticity. In Handbook of Porphyrin Science; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; World Scientific Publishing Co. Pte. Ltd.: Singapore, 2012; Vol. 16, pp 1−329. (561) Gupta, I.; Ravikanth, M. Recent Developments in Heteroporphyrins and their Analogues. Coord. Chem. Rev. 2006, 250, 468−518. (562) Singh, K.; Sharma, A.; Sharma, S. Heteroporphyrins: Synthesis and Structural Modifications. Adv. Heterocycl. Chem. 2012, 106, 111− 184. (563) Li, X.; Liu, B.; Yu, X.; Yi, P.; Yi, R.; Chmielewski, P. J. 1,3-Dipolar Cycloaddition of 2,6-Dichlorobenzonitrile Oxide to 2-Methyl-Nconfused Porphyrin. Regio- and Stereoselective Synthesis and Structural Characterization of 2-Aza-21-carbabacteriochlorin and Resolution of 2Aza-21-carbachlorin Enantiomers. J. Org. Chem. 2012, 77, 2431−2440. (564) Chmielewski, P. J.; Latos-Grażyński, L. N-Methyltetraphenylporphyrin with an Inverted N-Methylpyrrole Ring: The First Isomer of N-Methyltetraphenylporphyrin. J. Chem. Soc., Perkin Trans. 2 1995, 503−509. (565) Hayes, M. J.; Lash, T. D. Carbachlorins. Chem. - Eur. J. 1998, 4, 508−511. (566) Li, D.; Lash, T. D. Synthesis and Reactivity of Carbachlorins and Carbaporphyrins. J. Org. Chem. 2014, 79, 7112−7121. (567) Lash, T. D.; AbuSalim, D. I.; Ferrence, G. M. adj-Dicarbachlorin, the First Free Base Carbaporphyrinoid System with an Internal Methylene Unit. Chem. Commun. 2015, 51, 15952−15955. (568) Pawlicki, M.; Latos-Grażyński, L. O-Confusion Approach in Construction of Carbaporphyrinoids. Chem. Rec. 2006, 6, 64−78. (569) Lash, T. D. Benziporphyrins, a Unique Platform for Exploring the Aromatic Characteristics of Porphyrinoid Systems. Org. Biomol. Chem. 2015, 13, 7846−7878. (570) Pawlicki, M.; Latos-Grażyński, L. O-Confused Oxaporphyrin An Intermediate in Formation of 3-Substituted 2-Oxa-21-Carbaporphyrins. J. Org. Chem. 2005, 70, 9123−9130. (571) Sprutta, N.; Latos-Grażyński, L. A Tetraphenylthiaporphyrin with an Inverted Thiophene Ring. Tetrahedron Lett. 1999, 40, 8457− 8460. (572) Pawlicki, M.; Latos-Grażyński, L. Pyrrole-Appended Derivatives of O-Confused Oxaporphyrins and Their Complexes with Nickel(II), Palladium(II), and Silver(III). Chem. - Eur. J. 2003, 9, 4650−4660. (573) Linstead, R. P. Discoveries among Conjugated Macrocyclic Compounds. J. Chem. Soc. 1953, 2873−2884. (574) Linstead, R. P.; Whalley, M. Conjugated Macrocycles. Part XXII. Tetraazaporphin and its Metallic Derivatives. J. Chem. Soc. 1952, 4839− 4846. (575) Rodríguez-Morgade, M. S.; Stuzhin, P. A. The Chemistry of Porphyrazines: An Overview. J. Porphyrins Phthalocyanines 2004, 8, 1129−1165. (576) Uno, H.; Shimizu, Y.; Uoyama, H.; Tanaka, Y.; Okujima, T.; Ono, N. Thermal Behavior of Free-Base and Core-Modified GI


Chemical Reviews

Review

Bicyclo[2.2.2]octadiene-Fused Porphyrins. Eur. J. Org. Chem. 2008, 2008, 87−98. (577) Koehorst, R. B. M.; Kleibeuker, J. F.; Schaafsma, T. J.; de Bie, D. A.; Geurtsen, B.; Henrie, R. N.; van der Plas, H. C. Preparation and Spectroscopic Properties of Pure Tetrabenzoporphyrins. J. Chem. Soc., Perkin Trans. 2 1981, 1005−1009. (578) Sheinin, V. B.; Chizhov, N. V.; Romanova, A. O. Synthesis and S pe c t r al C ha r a c t e r i s t i c s o f ( T e t r a b e n z op o r p hy r i n a t o )chloromanganese(III). Russ. J. Gen. Chem. 2010, 80, 351−356. (579) Fukuda, T.; Kobayashi, N. Hydrogenated Tetraazaporphyrins Old but New Core-modified Phthalocyanine Analogues. Dalton Trans. 2008, 4685−4704. (580) Mack, J.; Kobayashi, N. Low Symmetry Phthalocyanines and Their Analogues. Chem. Rev. 2011, 111, 281−321. (581) Nemykin, V. N.; Dudkin, S. V.; Dumoulin, F.; Hirel, C.; Gürek, A. G.; Ahsen, V. Synthetic Approaches to Asymmetric Phthalocyanines and Their Analogues. Arkivoc 2014, 142−204. (582) Mani, N. S.; Beall, L. S.; White, A. J. P.; Williams, D. J.; Barrett, A. G. M.; Hoffman, B. M. Serendipitous Desymmetrisation during Porphyrazine Synthesis: An X-Ray Crystallographic Study of 2,3,7,8,12,13,17,18-Octakis(dimethylamino)-2-secoporphyrazine-2,3dione. J. Chem. Soc., Chem. Commun. 1994, 1943−1944. (583) Montalban, A. G.; Lange, S. J.; Beall, L. S.; Mani, N. S.; Williams, D. J.; White, A. J. P.; Barrett, A. G. M.; Hoffman, B. M. SecoPorphyrazines: Synthetic, Structural, and Spectroscopic Investigations. J. Org. Chem. 1997, 62, 9284−9289. (584) Lange, S. J.; Nie, H.; Stern, C. L.; Barrett, A. G. M.; Hoffman, B. M. Peripheral Palladium(II) and Platinum(II) Complexes of Bis(dimethylamino)porphyrazine. Inorg. Chem. 1998, 37, 6435−6443. (585) Staley, S. W.; Eliasson, B.; Kearney, P. C.; Schreiman, I. C.; Lindsey, J. S. Synthesis and Electron-Transfer Studies of Conjugated πElectron Systems. Model Systems for Molecular Computation Studies. In Molecular Electronic Devices; 3rd ed.; Carter, F. L., Siatkowski, R. E., Wohltjen, H., Eds.; Elsevier: North Holland, 1988; pp 543−554. (586) Baum, S. M.; Trabanco, A. A.; Montalban, A. G.; Micallef, A. S.; Zhong, C.; Meunier, H. G.; Suhling, K.; Phillips, D.; White, A. J. P.; Williams, D. J.; Barrett, A. G. M.; Hoffman, B. M. Synthesis and Reactions of Aminoporphyrazines with Annulated Five- and SevenMembered Rings. J. Org. Chem. 2003, 68, 1665−1670. (587) Sakellariou, E. G.; Montalban, A. G.; Beall, S. L.; Henderson, D.; Meunier, H. G.; Phillips, D.; Suhling, K.; Barrett, A. G. M.; Hoffman, B. M. Novel Peripherally Functionalized seco-Porphyrazines: Synthesis, Characterization and Spectroscopic Evaluation. Tetrahedron 2003, 59, 9083−9090. (588) Guinchard, X.; Fuchter, M. J.; Ruggiero, A.; Duckworth, B. J.; Barrett, A. G. M.; Hoffman, B. M. Multigram Synthesis of a WaterSoluble Porphyrazine and Derived seco-Porphyrazine Labeling Agents. Org. Lett. 2007, 9, 5291−5294. (589) Montalban, A. G.; Baum, S. M.; Barrett, A. G. M.; Hoffman, B. M. Studies on seco-Porphyrazines: A Case Study on Serendipity. Dalton Trans. 2003, 2093−2102. (590) Gonca, E.; Baklacı, U. G.; Dinçer, H. A. Seco-Porphyrazines with Eight (p-tolyl) and (o-tolyl) Units. J. Porphyrins Phthalocyanines 2008, 12, 116−122. (591) Gonca, E.; Baklacı, U. G.; Dinçer, H. A. Synthesis and Spectral Properties of Novel seco-Porphyrazines with Eight 4-Biphenyl Groups. Polyhedron 2008, 27, 2431−2435. (592) Gonca, E.; Keskin, B. Synthesis and Characterization of Soluble seco-Porphyrazines with Bulky Substituents. J. Coord. Chem. 2009, 62, 2875−2882. (593) Nazlı, A.; Gonca, E.; Gül, A. Partially Oxidized Porphyrazines. J. Porphyrins Phthalocyanines 2006, 10, 996−1002. (594) Altunkaya, M.; Gonca, E. Synthesis and Characterization of New Soluble Fluorinated seco-Porphyrazines. Polyhedron 2011, 30, 1035− 1039. (595) Kayaköy, S.; Gonca, E. Synthesis and Characterization of New Soluble Polyfluorinated seco-Porphyrazines. Inorg. Chem. Commun. 2012, 21, 28−31.

(596) Nie, H.; Stern, C. L.; Barrett, A. G. M.; Hoffman, B. M. Decapitation of Dihydroporphyrazinediol Derivatives: Synthesis and XRay Structure of a Novel seco-Porphyrazine. Chem. Commun. 1999, 703−704. (597) Sugita, I.; Shimizu, S.; Fukuda, T.; Kobayashi, N. Nickel and Palladium Complexes of seco-Tribenzoporphyrazines Derived from One-Pot Condensation of 1,3-Diiminoisoindoline. Tetrahedron Lett. 2013, 54, 1599−1601. (598) Yamaji, A.; Hiroto, S.; Shin, J.-Y.; Shinokubo, H. Carbolithiation of meso-Aryl-Substituted 5,15-Diazaporphyrin Selectively Provides 3Alkylated Diazachlorins. Chem. Commun. 2013, 49, 5064−5066. (599) Horie, M.; Hayashi, Y.; Yamaguchi, S.; Shinokubo, H. Synthesis of Nickel(II) Azacorroles by Pd-Catalyzed Amination of α,α′Dichlorodipyrrin NiII Complex and Their Properties. Chem. - Eur. J. 2012, 18, 5919−5923. (600) Gewirtz, P. On “I Know It When I See It”. Yale Law Journal 1996, 105, 1023−1047. (601) Mahammed, A.; Gross, Z. Aluminum Corrolin, a Novel Chlorophyll Analogue. J. Inorg. Biochem. 2002, 88, 305−309. (602) Tsurumaki, E.; Saito, S.; Kim, K. S.; Lim, J. M.; Inokuma, Y.; Kim, D.; Osuka, A. Synthesis and Characterization of meso-Aryl-Substituted Subchlorins. J. Am. Chem. Soc. 2008, 130, 438−439. (603) Inokuma, Y.; Yoon, Z. S.; Kim, D.; Osuka, A. meso-ArylSubstituted Subporphyrins: Synthesis, Structures, and Large Substituent Effects on Their Electronic Properties. J. Am. Chem. Soc. 2007, 129, 4747−4761. (604) Sengupta, D.; Robinson, B. Synthesis of a Bis-vinylogous Chlorin Possessing a Fused Naphthalene Ring. Tetrahedron 2002, 58, 8737− 8741. (605) Lash, T. D. Carbaporphyrins, Porphyrin Isomers and the Legacy of Emanuel Vogel. J. Porphyrins Phthalocyanines 2012, 16, 423−433. (606) Vogel, E.; Köcher, M.; Balci, M.; Teichler, I.; Lex, J.; Schmickler, H.; Ermer, O. 2,3-Dihydroporphycene − an Analog of Chlorin. Angew. Chem., Int. Ed. Engl. 1987, 26, 931−934. (607) Okawara, T.; Hashimoto, K.; Abe, M.; Shimakoshi, H.; Hisaeda, Y. Hydrogenation Effects in Metalloporphycenes: Synthesis and Redox Behavior of Ni(II)-Tetra(n-propyl)dihydroporphycene. Chem. Commun. 2012, 48, 5413−5415. (608) Masuno, M. N.; Robinson, B. C.; Phadke, A. S. A New Porphycene-Derived Ring Structure: Octaethylbenzochloracene. J. Porphyrins Phthalocyanines 2001, 5, 177−180. (609) Barkigia, K. M.; Robinson, B. C.; Renner, M. W. Molecular Structure and Spectroscopic Properties of Octaethylbenzochloracene, the Porphycene Analog of a Benzochlorin. J. Porphyrins Phthalocyanines 2005, 9, 864−871. (610) Fowler, C. J.; Sessler, J. L.; Lynch, V. M.; Waluk, J.; Gebauer, A.; Lex, J.; Heger, A.; Zuniga-y-Rivero, F.; Vogel, E. Metal Complexes of Porphycene, Corrphycene, and Hemiporphycene: Stability and Coordination Chemistry. Chem. - Eur. J. 2002, 8, 3485−3496. (611) Vogel, E.; Koch, P.; Hou, X.-L.; Lex, J.; Lausmann, M.; Kisters, M.; Aukauloo, M. A.; Richard, P.; Guilard, R. New Porphycene Ligands: Octaethyl- and Etioporphycene (OEPc and EtioPc)Tetra- and Pentacoordinated Zinc Complexes of OEPc. Angew. Chem., Int. Ed. Engl. 1993, 32, 1600−1604. (612) Saito, S.; Osuka, A. Expanded Porphyrins: Intriguing Structures, Electronic Properties, and Reactivities. Angew. Chem., Int. Ed. 2011, 50, 4342−4373. (613) Hata, H.; Kamimura, Y.; Shinokubo, H.; Osuka, A. Synthesis of Pyrrolidine-Fused [34]- and [36]Octaphyrins via 1,3-Dipolar Cycloaddition. Org. Lett. 2006, 8, 1169−1172. (614) Hata, H.; Shinokubo, H.; Osuka, A. Anthracene-Bridged ZShaped [26]Hexaphyrin(1.1.1.1.1.1.1) Dimer from the Regioselective Diels−Alder Reaction of a Hexaphyrin with Bis-o-xylylene Equivalents. Angew. Chem., Int. Ed. 2005, 44, 932−935. (615) Chen, M.; Blankenship, R. E. Expanding the Solar Spectrum used by Photosynthesis. Trends Plant Sci. 2011, 16, 427−431. (616) Hoptman, L. In The Forever Now: Contemporary Painting in an Atemporal World; The Museum of Modern Art: New York, 2014; p 45.

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