The Breaking and Mending of meso-Tetraarylporphyrins: Transmuting

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The Breaking and Mending of meso-Tetraarylporphyrins: Transmuting the Pyrrolic Building Blocks Christian Brückner* Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060, United States CONSPECTUS: Naturally occurring porphyrins and hydroporphyrins vary with respect to their ring substituents and oxidation states, but their tetrapyrrolic frameworks remain fully preserved across all kingdoms of life; there are no naturally occurring porphyrin-like macrocycles known that contain nonpyrrolic building blocks. However, the study of porphyrin analogues in which one or two pyrroles were replaced with nonpyrrolic building blocks might shed light on the correlation between structural modulation and ground and excited state optical properties of the “pigments of life”, unlocking their mechanisms of function. Also, porphyrinoids with strong absorbance and emission spectra in the NIR are sought after in technical (e.g., light-harvesting) and biomedical (e.g., imaging and photochemotherapy) applications. These porphyrin analogues, the so-called pyrrole-modified porphyrins (PMPs), are synthetically accessible using total syntheses. Alternativelyand most handilythey can also be formed by conversion of synthetic porphyrins. Guided by older reports of the fortuitous modifications of porphyrins into PMPs, our research program generalized the so-dubbed “Breaking and Mending of Porphyrins” approach toward PMPs. This method to convert a pyrrole in meso-tetraarylporphyrins to a nonpyrrolic building block with high precision relies on a number of distinct steps. Step 1: The porphyrin is functionalized in a way that activates one or two peripheral double bonds toward breakage; in all cases surveyed here, this step is an osmium tetroxide-mediated dihydroxylation to generate dihydroxychlorin and tetrahydroxybacteriochlorins. Step 2: The activated, dihydroxylated β,β′-bond is “broken”. Step 3: The functional groups resulting from the ring-cleavage reactions are utilized in subsequent “mending” steps to form the PMPs, that themselves may be subject to further modifications, Step 4. Thus, PMPs in which a pyrrole was degraded to an imine linkage, contracted to a four-membered ring, or expanded by oxygen, sulfur, carbon, or nitrogen atoms to form six-membered building blocks have become accessible. This approach also allowed the replacement of a single β-carbon atom by a nitrogen or oxygen atom. Depending on the ring size, conformation, conformational flexibility, the oxidation state of the pyrrole replacements, or the presence of substituents that π-extend the chromophores, the PMPs possess porphyrin- or hydroporphyrin-like optical spectra, or they show altogether unique electronic properties. Some PMP classes allow the fine-tuning of their absorption range; others exhibit panchromatic absorption spectra from the UV to the NIR. Several PMPs take up persistent chiral helimeric conformations that could be resolved. This Account summarizes the scopes of the “Breaking and Mending” methodology with a special focus on laying out the structural diversity of PMPs accessible from mesotetraarylporphyrins and highlighting their optical properties, with the aim of encouraging their further study and application.

1. INTRODUCTION

particular stability of the planar, strain-free tetrapyrrolic macrocycle architecture. Synthetic meso-tetraarylporphyrins are readily accessible, chemically stable, feature deep colors, bright fluorescence, high triplet yields, and chelate a wide variety of metal ions in their central cavity.2 They are therefore of wide-ranging utility in technical and biomedical applications. Some of them mimic the natural systems (e.g., in light harvesting and catalytic applications), others perform functions unknown to natural porphyrins (e.g., in bioimaging, information storage, or chemosensing). The ability to fine-tune the electronic properties of the porphyrins to the particular demands of their application is most desirable.

1.1. Tetrapyrrolic Structure of the “Pigments of Life”

Blood is red and grass is green because of the presence of porphyrins (the iron complex heme) and chlorins (the magnesium complex chlorophyll), respectively, the principal members of the “pigments of life”. Aside from these conspicuous forms, porphyrins and hydroporphyrins are found as prosthetic groups in a large variety of proteins in all kingdoms of life.1 Remarkably, while the peripheral substituents of natural porphyrins and chlorins may vary, their tetrapyrrolic frameworks enclosing an aromatic 18 π-electron system are fully preserved! There are no naturally occurring porphyrin-like macrocycles known that incorporate any other number than four pyrroles, or any nonpyrrolic building blocks. This lays testament to the © XXXX American Chemical Society

Received: January 26, 2016

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DOI: 10.1021/acs.accounts.6b00043 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research The electronics of the porphyrinic π-systems depend on their degree of saturation. The fully conjugated porphyrins and the hydroporphyrins, in which one or two of the cross-conjugated, pseudo-olefinic β,β′-double bonds are removed, all possess characteristic UV−vis spectra (Figure 1). The presence of

results from our graduate work,6,7 we began a program in the early 2000s to develop a general strategy for the conversion of porphyrins to PMPs, eventually formulating what would become known as the “Breaking and Mending of Porphyrins” strategy (Scheme 1).5,8 Step 1: Addition of a reagent to the β,β′-double bond of a (metallo)porphyrin converts it to a β-functionalized porphyrin ormore frequentlychlorin. In the approach championed by us, this step is an osmium tetroxide-mediated dihydroxylation of a meso-tetraarylporphyrin to generate the corresponding dihydroxychlorin or tetrahydroxybacteriochlorins. Step 2: The functionalization step provides a versatile synthetic handle for subsequent β,β′-bond cleavage reactions, generating a secochlorin. This could be isolable or an intermediate. Step 3: The functionalities generated in the ring cleavage reaction are then utilized in ring-closure reactions, generating a multitude of PMPs that may lend themselves to further derivatization, Step 4. This controlled approach avoids regioselectivity problems seen in the direct conversion of a nonactivated porphyrins into PMPs with more than one modified pyrrole.9−11 The “Breaking and Mending of Porphyrins” approach turned out to be astoundingly malleable.5 For brevity, we will survey here only the key PMP-forming reactions applied by us to mesotetraarylporphyrins, with the aim of presenting a cross section of the structural diversity of accessible PMPs. Unless PMP derivatizations result in the change of the framework of one PMP to another, they will not be reviewed. Where available, PMP single crystal X-ray structures will be presented to illustrate their structural similarities or differences to the parent porphyrin. We will briefly note the optical properties of the PMPs compared to those of regular meso-tetraphenylporphyrins or -hydroporphyrins, but will list their applications only in passing. Comprehensive reviews of the field of PMPs in the broadest sense are available.2,5,12−14

Figure 1. Principal classes of the “pigments of life” with the corresponding UV−vis spectra; bold lines indicate the aromatic 18 πelectron system, and the colors approximate their typical colors.

substituents that are in conjugation with the porphyrinic πsystem and the conformation of the chromophore are also important factors in the determination of their electronic properties.3 Broadly speaking, π-conjugated substituents and distortions of the porphyrinic chromophores from planarity result in a red-shift of their optical spectra. Nature uses all three modalities to fine-tune porphyrinic prosthetic groups.4

2. EARLY EXAMPLES OF THE CONVERSION OF A PORPHYRIN INTO A PMP In 1933, Fischer and Deželić realized that dilute ozone streams converted β-octaalkylporphyrins into chlorin-like chromophores of undetermined structures.15 The work was reproduced 44 years later by Shul’ga et al. using octaethylporphyrin 1 (Scheme 2).16 The chemically fragile main product was spectroscopically determined to be the oxazole-based PMP heptaethyloxazolochlorin 2. Thus, a β-carbon with attached ethyl group was replaced by an oxygen atom and the neighboring β′-carbon was hydroxylated. The formation of this chlorin analogue was rationalized by way of the formation of a primary β,β′-ozonide I that subsequently rearranged, hydrolyzed, and fragmented into the final product 2. The Shul’ga report therefore represents the first recognized case of the conversion of a porphyrin into a PMP!

1.2. Porphyrinoids with Altered Framework Structures

Will the electronic properties of derivatives in which a pyrrole is replaced by a nonpyrrolic heterocycle be porphyrin- or chlorinlike, or exhibit altogether unique characteristics? Will these derivatives hold desirable properties for any particular application? Will their study reveal fundamental relationships between porphyrinoid structure, conformation, conformational flexibility, and ground and excited state electronic properties relevant to the understanding of the “pigments of life”? These are some of the key questions that drive the investigation of porphyrin analogues.2 We will refer to “tetrapyrrolic” porphyrinoids containing one or two nonpyrrolic building blocks as pyrrole-modified porphyrins (PMPs).5 PMPs are accessible via total synthesis or by conversion of porphyrins.5 Informed by earlier reports and building on some

Scheme 1. Generalized “Breaking and Mending of Porphyrins” Strategy

B


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Accounts of Chemical Research Scheme 2. Ozonation of Octaethylporphyrin According to Shul’ga et al.16

Scheme 4. Oxidation of mesoTetrakis(pentafluorophenyl)porphyrin (8F) According to Gouterman et al.9

Nonetheless, the pioneering status of this work was long overlooked by us, and others.5 The expansion of a pyrrole to a six-membered 3-hydropyridine moiety was first described by Callot and Schaeffer in 1978 as a minor product of the thermally induced rearrangement of a porphyrin-N-propionate, a to this day singular reaction pathway toward PMPs.17 In 1984, Crossley and King reported on the attempts to prepare β,β′-dioxoporphyrin 3 by oxidation of mesotetraphenyl-2-amino-porphyrin 4 (Scheme 3).18 In a communi-

Scheme 5. Rational Syntheses of PMPs According to the Group of Bonnett19,20

Scheme 3. Oxidation Reactions of β-Aminoporphyrin 4 and Dione 3 According to Crossley and King18

his group reported the diol cleavage of octaethyldihydroxychlorin 9Ni to generate secochlorin 10Ni. This subsequently underwent an aldol condensation, forming pyrrole-expanded oxypyriporphyrin 11Ni.19,20 We regard this paper as the closest blueprint to our “Breaking and Mending of Porphyrin” strategy.

cation of striking brevity, they described three PMPs: One in which the porphyrin had lost a β-carbon (5), a second in which a β-carbon was replaced by an oxygen atom (6), and a third in which an oxygen atom was inserted into the porphyrin β,β′-bond (7). The report also presaged the option to convert one class of PMP to another. Generally, this paper was our primary inspiration for the development of the general “Breaking and Mending” strategy of the conversion of porphyrins into PMPs. Gouterman and co-workers reported in 1989 the fortuitous formation of porpholactones, such as 6F, that had formed during an attempt to insert silver into meso-tetrakis(pentafluorophenyl)porphyrin 8F (Scheme 4).9 Up to three β,β′-bonds were replaced with lactone moieties. This oxidation reaction constituted the first report of the direct conversion of a nonactivated mesoarylporphyrin to a PMP; the report also underscored the selectivity issues associated with this approach. The credit for the first rational and regioselective preparation of PMPs goes to the group of Bonnett (Scheme 5).19,20 In 1993,

3. “THE BREAKING AND MENDING OF meso-TETRAARYLPORPHYRINS” IN PRACTICE 3.1. The Activation of the Porphyrin β,β′-Bonds

Key to our work is the osmium tetroxide-mediated cisdihydroxylation of meso-tetraarylporphyrins (Scheme 6). The dihydroxylation of free base meso-tetraphenylporphyrin provides dihydroxychlorin 12 and regioselectively tetrahydroxybacteriochlorins 14, as a mixture of two stereoisomers.6,21,22 The introduction of the diol groups does not significantly distort the conformation of the macrocycles from planarity, though minor distortions are seen in the dihydroxypyrroline moieties as a result of the hydroxy groups assuming staggered conformations. Dihydroxylation of metallodihydroxychlorins provides regioselectively tetrahydroxymetalloisobacteriochlorins.22 Osmate esters of type 13 are intermediates in the reaction. The diol functionalities serve as versatile synthetic handles for the C


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Accounts of Chemical Research Scheme 6. OsO4-Mediated Dihydroxylation of meso-Tetraarylporphyrins6,21,23

Scheme 7. Preparation and Deformylation of Secochlorin Dialdehyde 15Ni7,23,25

in light of the natural degradation pathways of heme catabolism or chlorophyll senescence. The enzymatic oxidative ring degradations exclusively target the meso-positions of the porphyrins, leading to the formation of ring-opened tetrapyrroles.1

conversion of the pyrroline moieties in single or multiple steps into nonpyrrolic building blocks. While isobacteriochlorin-type PMPs are known,9,10,24 we have not much explored them. This is because we did not expect the isobacteriochlorins to feature optical advantages over the corresponding chlorins but requiring synthetic efforts that are complicated by many possible regio- and stereoisomers of the derived PMPs. The chemoselectivity of the oxidant osmium tetroxide (and that of ozone in Scheme 2)16 for the attack on the pseudo-olefinic β,β′-bonds is expected from a chemical point of view, but unusual

3.2. Pyrrole Cleavage and Degradation Reactions

The classic lead tetraacetate-induced cleavage of diols is also suitable to “break” meso-tetraphenyldihydroxychlorin 12Ni (Scheme 7).6,7,25 The presence of the central nickel ion proved to be a significant stabilizing factor for the resulting secochlorin dialdehyde 15Ni. The corresponding free base compound 15 is D


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Accounts of Chemical Research Scheme 8. Preparation of Indaphyrin Derivatives23,29−32

ruffled conformation and brings the meso-aryl groups into coplanarityand therefore in conjugationwith the porphyrinic chromophore. The conformational and electronic effects explain the much altered and red-shifted optical spectra of indaphyrins (Figure 2).29−31 The persistence of the ruffled conformations was shown by the separation of their P- and Mhelimeric enantiomers (Figure 3).30

also accessible by cleavage of chlorin diol 12 using sodium periodate, but this dialdehyde is very reactive.26 It is therefore best prepared in situ or immediately prior to its use (see, e.g., Schemes 8 or 13). Dialdehyde 15Ni behaves like a regular arylaldehyde in that it is susceptible to catalyzed deformylations, forming successively monoaldehyde 16Ni and chlorophin 17Ni.7,25 Ultimately, one pyrrole in meso-tetraphenylporphyrin nickel complex 12Ni was degraded to an imine linkage. Chlorophin 17Ni possesses metallochlorin-like optical properties, whereas the presence of formyl groups π-conjugated to the porphyrinic chromophore much perturb the electronics of 15Ni and 16Ni.7,25 The conformations of the ring-opened compounds are, enhanced by the substituents, strongly ruffled, an effect of the presence of the nickel.25 The diamagnetic Ni(II) ion is a little too small to fit perfectly into a porphyrin cavity, leading to unusually long Ni−N bond distances. In the drive to shorten the Ni−N bond distances, strain is introduced into the macrocycle, an effect generally recognized in porphyrin chemistry.3 Without altering the preferred square planar coordination mode of the central metal, a ruffling distortion shortens the Ni−N bond lengths.4 Removal of one β,β′-bond renders the porphyrinic framework a little more flexible and thus allows a larger degree of ruffling in alkylated chlorin 12Me2Ni. Cleavage of the β,β′-bond breaks the structural integrity of the porphyrin and the secochlorin framework collapses around the nickel ion, achieving near-ideal short Ni−N bond distances in 15Ni. This nickel-induced ruffling of Ni-porphyrinoids is also observed in other PMPs (see subsection 3.6).6,27,28 The reactivity of the carbonyl functionalities of the secochlorins make them key compounds in the “mending” step toward the preparation of multiple PMP classes.

Figure 2. UV−vis spectra (CH2Cl2) of the compounds indicated.29,31

The conversion of indapyrin 18 to bis-modified PMPs is also possible, as morpholine-derived indachlorin 19 demonstrates (Scheme 8) (see below for the description of the expansion of a pyrrole to a morpholine moiety). It possesses a unique panchromatic UV−vis spectrum in the range between 350 and ∼950 nm. The chlorin-like intensity enhancement of the λmax band is attributed to the removal of another β,β′-double bond from indaphyrin 18 (Figure 2). The dramatically altered optical properties of the indaphyrins compared to those of the corresponding porphyrins are also illustrated by the much redshifted absorption and emission spectra of their Pt(II) complexes (Figure 4).32 Interestingly, the insertion of platinum into 18 did not change the macrocycle conformation.31,32

3.3. Indaphyrins: Secochlorin Derivatives with Coplanar meso-Aryl Groups

Free-base secochlorin dialdehyde 15, prepared in situ by cleavage of diol 12 in the presence of trifluoroacetic acid (TFA), undergoes an intramolecular Friedel−Crafts-like acylation of the o-position of the flanking meso-aryl group, forming indanone moieties annulated to the central porphyrinic π-system (Scheme 8).29,30 This annulation forces indaphyrin 18 into a severely

3.4. Pyrrole Contraction Reactions

Monoaldehyde 16Ni lacking already a β-carbon is perceivably a suitable substrate for the preparation of PMPs incorporating ring-contracted frameworks. Indeed, acid treatment of 16Ni E


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Accounts of Chemical Research

chlorin 21Ni, a ring-contracted nickel chlorin analogue with only a slightly blue-shifted spectrum compared to that of the regular (and slightly ruffled) chlorin 12Ni (Figure 5).34

Figure 3. Experimental and computed CD spectra of resolved indaphyrins helimers, confirming their absolute stereostructure assignments.23,30

Figure 5. UV−vis spectra (CH2Cl2) of the compounds indicated.6,34

3.5. β-Atom Replacement Reactions

The oxidation of the chlorin diol 12 with permanganate (such as cetyltrimethylammonium permanganate, CTAP) likely forms a secochlorin dicarboxylic acid or anhydride 7. These putative intermediates are, however, never directly observed. Instead, they spontaneously decarboxylate and porpholactone 6 is isolated (Scheme 10).35 A considerable number of examples of oxidation reactions of porphyrins and chlorins that form porpholactones emerged over the years,5 suggestive that this product is a particularly stable PMP. Porpholactones serve as source for numerous other PMPs (see below). The lactone moiety mimicks very well the electronic properties of the β,β′-bond (see below).35 The situation is more complex when two lactone moieties are combined into a single chromophore.9,36,37 Our group,38−40 and others,36,37 demonstrated the utility of porpholactones in catalysis, photochemotherapy or chemosensing.5 Porpholactones can be reduced to the corresponding hemiacetal and further to oxoazolochlorin 22,35 while the porphyrin-like optical spectrum of the porpholactone gives way to typical chlorin spectra. The dihydroxylation → oxidation to lactone → lactone reduction sequence can be repeated on the same framework, or the lactone functionality can be alkylated, establishing a family of oxazolochlorins and bisoxazolobacteriochlorins, as exemplified by compounds 23, 24, and 25.41,42 Thus, the chromophore type can be varied and the λmax of their absorption (and emission) values shifted from 650 nm to past 800 nm by modification of the framework structure (Figure 6).35,41,42 Porpholactone 6 may also serve as starting material for PMPs containing a fifth ring nitrogen (Scheme 11):43 Reaction with hydrazine generates an N-aminolactam (and the chlorin analogues of porpholactone and porpho-N-aminolactam) that could reductively be converted to lactam 26. Further multistep reduction steps provided the parent free-base imidazoloporphyrin 27. Its nickel complex 27Ni is accessible via an independent route: Under the reaction conditions to convert secochlorin monoaldehyde 16Ni to its oxime, it spontaneously cyclizes to form 27Ni (Scheme 12).8 A fortuitous synthesis of 27Ni along yet another path is shown below (subsection 3.9).8 By virtue of the presence of the external basic nitrogen, imidazoloporphyrin 27Ni can be readily protonated, with an associated big shift in its optical spectrum. The presence of such external functionalities on the PMPs is generally the basis for their utilization as

Figure 4. UV−vis absorption (CH2Cl2) and emission (EtOH glass at 77 K) spectra and fluorescence emission quantum yields (ϕ) of the compounds indicated.32

results in an intramolecular ring-closure reaction, forming azeteonochlorin 20Ni (Scheme 9).25 First reported in Crossley’s Scheme 9. Preparation of Ring-Contracted PMPs25,33,34

paper,18 this PMP was also prepared by the group of Zaleski along an independent “Breaking and Mending”-type route.33 Its solid state structure revealed that the pyrrole contraction also reduced the central cavity size such that short Ni−N bonds lengths could be achieved without any macrocycle ruffling.33 Reaction of 16Ni with methylmagnesium bromide, followed by an intramolecular Friedel−Crafts alkylation, generates azeteoF


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Accounts of Chemical Research Scheme 10. Syntheses of Porpholactone, Oxazolochlorins, and Bisoxazolobacteriochlorins23,35,41,42

Figure 6. Accessible λmax values by various classes of oxazol-based PMPs.35,41,42

Scheme 11. Preparation of Free Base Imidazoloporphyrin 2723,43

Irrespective of the replacement of the β,β′-bond in tetraphenylporphyrin 8 by a lactone, lactam, or imine

chemosensors,5 though 27/27Ni have not yet found an application. G


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nucleophiles, such as hydride, can also induce the ring closure reaction, leading, after further dehydroxylation, to the parent unsubstituted morpholinochlorin 28.28 The variety of derivatives accessible helps to delineate the effects of the substituents on the conformation, conformational flexibility, and associated electronic properties of the PMP chromophore. All morpholinochlorin UV−vis spectra are red-shifted and broadened chlorinlike spectra that are modulated, like their conformations, by their substituents (Figure 8).28

Scheme 12. Preparation of Imidazoloporphyrin Nickel Complex 27Ni8

functionality, these PMPs all feature porphyrin-like UV−vis spectra (Figure 7).35,43 Thus, the replacement of a pyrrole β,β′-

Figure 8. UV−vis spectra (CH2Cl2) of the compounds indicated.28 Figure 7. UV−vis spectra (CH2Cl2) of the compounds indicated.35,43

The morpholinochlorin nickel complexes form similarly to their free base analogues from nickel dialdehyde 15Ni.6,27,28 Contrary to the corresponding free bases, however, they all possess near-identical nickel-induced ruffled conformations, irrespective of the presence, number, or bulk of morpholine substituents (Figure 9). As a consequence, their UV−vis spectra are also near-identical.6,28 Morpholinochlorins show an interesting correlation between the chirality of their ruffled conformation (M or P) and the chirality of the two morpholine sp3-carbons (R or S) that reduces the number of possible stereoisomers formed to a single pair of enantiomers.27,28 This stereoselectivity is the effect of the cooperative action of steric and stereoelectronic effects (Scheme 14).28 The two aldehyde functionalities of the ruffled secochlorin M-15Ni lie parallel and on top of each other.7,25 This alignment directs the attack by a nucleophile on the prochiral aldehyde centers to occur from an unshielded homotopic exo-side. The hemiacetal hydroxy group in IV subsequently attacks the second aldehyde intramolecularly from the endo-side, forming the

double bond by an X-sp2-β-carbon moiety (i.e., a lactone, lactam, or imine moiety) is spectroscopically equivalent the presence of a pyrrole. We attribute this to the retention of the sp2hybridization of at least one β-carbon and planarity of the macrocycle. However, the replacement of a pyrrole β,β′-double bond with O-sp3-β-carbon moiety mimicks the presence of a pyrroline (Figure 6). 3.6. Ring-Expansion Reactions: Insertion of an Oxygen Atom

Crossley and King demonstrated the Baeyer−Villiger oxidation of dione 3, forming oxygen-expanded PMP 7 possessing a porphyrin-like optical spectrum (Scheme 3).18 Formal reduction of the anhydride sp2-carbons generates the chlorin-like morpholinochlorins. They are formed by alcohol-induced double-acetal formation of secochlorin dialdehyde 15 (Scheme 13).6,27,28 Varying the reaction conditions, mono- and dialkoxy derivatives 28OEt and 28(OEt)2 became accessible.28 Other Scheme 13. Formation of Free-Base Morpholinochlorins23,28

H


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(Scheme 15), producing monomorpholinobacteriochlorin 29 and bismorpholinobacteriochlorin 30, respectively.45 The introduction of the morpholine moieties dramatically distorts the near-planar conformation of the parent bacteriochlorin framework (cf. to Scheme 6). Only one pair of enantiomers is observed for bismorpholinobacteriochlorin 30, indicating the tight coupling of five chiral elements. All bacteriochlorins possess an identical π-system but parallel to the degree of distortion of the chromophore, a drastic red-shift of their UV−vis spectra is observed (Figure 10). It thus follows that the modulation of the optical properties in these bacteriochlorin analogues is purely conformational. This is in contrast to, for example, the modulation of the optical properties of the oxazolochlorin series (Figure 6). 3.7. Ring-Expansion Reactions: Insertion of a Carbon or Sulfur Atom

β,β′-Dimethyl-trans-dihydroxychlorin 31Ni is accessible by double methylmagnesium bromide addition to dione 3 (itself prepared by oxidation of diol 13),46 followed by nickel insertion (Scheme 16).47 This metallochlorin is susceptible to diol cleavage, providing diketone secochlorin 32Ni. Its treatment with a non-nucleophilic base, such as 1,8-diazabicylo[5.4.0]undec-7-ene (DBU), induces an aldol condensation to form oxypyriporphyrin 33Ni.47 Secochlorins 32Ni and 33Ni are the meso-aryl analogues to Bonnett’s β-octaethylporphyrin-derived PMPs (Scheme 5). A cyclization of secochlorin diketone 32Ni can also be induced by Lawesson’s reagent, forming the thiomorpholine 34Ni carrying two exocyclic double bonds.47 The exocyclic methylene groups could perceivably be utilized for further framework manipulations.

Figure 9. Overlay of the crystal structures of morpholinochlorin nickel complexes.23,28

morpholine moiety. The anomeric effect favors the transconfiguration of the alkoxy/hydroxy groups in the ring-closed hemiacetal M-28OEt,OHNi, as well as the two alkoxy groups in final product M-28(OEt)2Ni. Importantly, the trans-configuration is also the sterically favored orientation of the alkoxy substituents as both alkoxides then point away from the flanking phenyl groups; it thus is also the thermodynamically favored product. As a result, the configurations of the two sp3-centers are fixed to be trans and homochiral: The M-conformer of dialdehyde M-15Ni leads exclusively to the M-R,R-configuration in product 28(OEt)2Ni; inversely, the P-conformer yields the P−S,S28(OEt)2Ni isomer. The chiral M- and P-helimers of 28(OEt)2 could be separated by HPLC on a chiral column and their stereochemical stability was tested.28 The presence of either a nickel center or morpholine substituents act as steric locks that prevent racemization. An electrochemical experiment indicated that this steric lock does not even allow morpholinochlorin complex 28(OMe)2 to relax the ruffled conformation sufficiently enough to allow the accommodation of the larger Ni(I) ion.44 The dihydroxypyrroline to dialkoxymorpholine conversion can also take place once or twice in tetrahydroxybacteriochlorins

3.8. Ring-Expansion Reactions: Insertion of a Nitrogen Atom

Monooxime 35Ni is susceptible to a Beckmann rearrangement, forming, after demetalation, free-base porphyrin-like imide 36 (Scheme 17).48 This reaction parallels the Baeyer−Villiger oxidation of dione 3 (Scheme 3).18 These reactions might suggest that other classic ring-expansion reactions are applicable to appropriately modified porphyrins, but this impression is deceiving as other classic reactions took unexpected turns when applied to conformationally restricted porphyrin frameworks (see also subsection 3.9).49 Ammonia can also be used to ring-close secochlorin dialdehyde 15, creating pyrazinoporphyrins, such as 37OEt (Scheme 18).44,50 The mechanism likely involves a nucleophilic attack of the amine on one aldehyde of 15 to form hemiaminal V.

Scheme 14. Stereoselective Formation of a Single Pair of Morpholinochlorin Enantiomers23,28

I


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Accounts of Chemical Research Scheme 15. Preparation of Mono- and Bismorpholinobacteriochlorins23,45

Scheme 17. Beckmann Rearrangement of Dioxoporphyrin Oxime 35Ni48

Figure 10. UV−vis spectra (CH2Cl2) of the compounds indicated.45

Scheme 16. Syntheses of Oxypyriporphyrin 33Ni and Thiomorpholinoporphyrin 34Ni47 Scheme 18. Synthesis of Pyrazinoporphyrin50

the pyrazine-based intermediate VI is formed; elimination of water and substitution with ethanol generates ethoxy-substituted pyrazinoporphyrin 37OEt. Similarly to anhydride 7, pyrazinoporphyrins display slightly red-shifted porphyrin-type UV−vis spectra, likely a combination of their assumed ruffled conformation and presence of sp2-hybridized β-carbon atoms.50 3.9. Attempts at the Generation of PMPs Containing a Seven-Membered Heterocycle

Only a single stable PMP is known that incorporates a sevenmembered ring, tropiporphyrin, a cycloheptatrienyl porphyrin analog made by total synthesis by the group of Lash.5,13 Based on the smooth reaction of alcohols and amines with secochlorin dialdehydes to provide six-membered rings (Schemes 13 and 18), we expected the reactions of secochlorin 15 with hydrazine or hydroxylamine to furnish seven-membered PMPs. However,

Two potential nucleophiles are then available for an intramolecular ring-closure reaction: an alcohol to form a morpholinochlorin or an amine to form a pyrazino-derivative. Evidently, the greater nucleophilicity of the amine wins over and J


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Accounts of Chemical Research Scheme 19. Reaction of Secochlorin 15 with Hydroxylamine8

Scheme 20. Reaction of Dialdehyde 15 with Hydrazine51

the “Breaking and Mending of Porphyrin” strategy to a closed loop.51

both reactions did not generate isolable seven-membered PMPs. To our surprise, reaction of free-base dialdehyde 15 with hydroxylamine led to the formation of a mixture of imidazoloporphyrin 27 and β-nitroporphyrin 38 (Scheme 19).8 Imidazoloporphyrin 27 may have formed by extrusion of carbon dioxide from the target oxadiazepinonoporphyrin VIII. The formation of nitroporphyrin 38 can also be straightforwardly derived: Formation of oxime VII is followed by an oxime-tonitroso tautomeric exchange. Nitroso IX oxidizes to the corresponding nitro compound X, which undergoes an intramolecular Henry reaction to form the final product 38. Similarly unexpected, reaction of dialdehyde 15 with hydrazine led to the formation of hydroxychlorin 39 and porphyrin 12 (Scheme 20).51 Chlorin 39 may form along a Wolff−Kishnertype reaction pathway, combined with an intramolecular aldoltype reaction. A loss of water from chlorin 39 results in the formation of porphyrin 12. Alternatively, the formation of the target 1,4,5-triazapinoporphyrin XII may take place but this PMP then extrudes elemental nitrogen. Neither of the reactions of dialdehyde 15 with hydroxylamine or hydrazine are synthetically useful. Nevertheless, they highlight in an impressive fashion the driving force for the formation of porphyrinsor at least porphyrin-like arrangements of four fivemembered ringsover the incorporation of a seven-membered ring. On a more poetic level, the reaction of secochlorin 15 with hydrazine mends the broken porphyrin and regenerates the ultimate starting material meso-tetraphenylporphyrin 8, bringing

4. CONCLUDING REMARKS The “Breaking and Mending of Porphyrins” methodology evolved in our hands to a controlled and versatile method to convert readily accessible meso-tetraarylporphyrins into PMPs containing one or two nonpyrrolic macrocycles. PMPs containing imine,7,25,29−32 azete,25,34 oxazole,26,35,41,42 imidazole,8,43 pyrazine,44,50 pyridinone,47 morpholine,6,27,28,31,45 and thiamorpholine47 moieties have thus become accessible. Some syntheses were straightforward, though some reactions held surprises as their expected outcomes were much altered by the structural confines of the porphyrinic macrocyle. Some syntheses formed known PMPs, but most chromophores were unprecedented.5 All PMPs possess central 18 π-electron systems with some featuring porphyrin-, chlorin-, or bacteriochlorin-like optical spectra that could be manipulated through framework adjustments, substituent- or central metal-induced conformational modulation, and the oxidation states of the β,β′-bond replacement(s). The broader significance of the work lies in the generation of porphyrinoids that enable further fundamental studies of the pigments of life, particularly with respect to the connections between chromophore connectivity, conformation, conformational flexibility, and electronic properties. As other research groups in academic or industrial settings will recognize the variety and unique chemical and electronic K


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Accounts of Chemical Research properties of PMPs accessible using the “Breaking and Mending Strategy”, we predict that the study of PMPs will expand. Given the high stability of some PMP classes and their porphyrin- and hydroporphyrin-like optical properties, we anticipate they will replace classic porphyrins/hydroporphyrins in some applications. Their panchromatic absorption spectra, facile modulation of their electronic properties, persistent conformational chirality, or the presence of functional groups at their chromophore periphery will likely drive their application in areas in which porphyrins have not been traditionally used.

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(9) Gouterman, M.; Hall, R. J.; Khalil, G. E.; Martin, P. C.; Shankland, E. G.; Cerny, R. L. Tetrakis(pentafluorophenyl)porpholactone. J. Am. Chem. Soc. 1989, 111, 3702−3707. (10) 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. (11) Yu, Y.; Lv, H.; Ke, X.; Yang, B.; Zhang, J.-L. Ruthenium-Catalyzed Oxidation of the Porphyrin ß-ß’-Pyrrolic Ring: A General and Efficient Approach to Porpholactones. Adv. Synth. Catal. 2012, 354, 3509−3516. (12) Arnold, L.; Müllen, K. Modifying the Porphyrin CoreA Chemist’s Jigsaw. J. Porphyrins Phthalocyanines 2011, 15, 757−779. (13) Lash, T. D. Carbaporphyrins, Porphyrin Isomers and the Legacy of Emanuel Vogel. J. Porphyrins Phthalocyanines 2012, 16, 423−433. (14) Szyszko, B.; Latos-Grażyński, L. Core Chemistry and Skeletal Rearrangements of Porphyrinoids and Metalloporphyrinoids. Chem. Soc. Rev. 2015, 44, 3588−3616. (15) Fischer, H.; Deželić, M. Ü ber die Einwirkung von Ozon auf Porphyrine. Hoppe-Seyler's Z. Physiol. Chem. 1933, 222, 270−278. (16) Shul’ga, A. M.; Byteva, I. M.; Gurinovich, I. F.; Grubina, L. A.; Gurinovich, G. P. Oxidation of Porphyrins. Structure of the Products of Octaethylporphine Ozonization. Biofizika 1977, 22, 771−776. (17) Callot, H. J.; Schaeffer, E. Homologation directe du cycle des porphyrines par les diazoalcanes. Tetrahedron 1978, 34, 2295−2300. (18) 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. (19) Adams, K. R.; Bonnett, R.; Burke, P. J.; Salgado, A.; Valles, M. A. The 2,3-Secochlorin-2,3-dione system. J. Chem. Soc., Chem. Commun. 1993, 1860−1861. (20) Adams, K. R.; Bonnett, R.; Burke, P. J.; Salgado, A.; Valles, 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. (21) 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. (22) Bruhn, T.; Brückner, C. Origin of the Regioselective Reduction of Chlorins. J. Org. Chem. 2015, 80, 4861−4868. (23) Molecular graphics images were produced from data from the references cited using Chimera (V. 1.10.2), Resource for Biocomputing, Visualization, and Informatics at UCSF, 2015. All ring sp2-hydrogens, or meso-aryl groups, disorder, and solvent atoms were removed for clarity. (24) Yu, Y.; Furuyama, T.; Tang, J.; Wu, Z.-Y.; Chen, J.-Z.; Kobayashi, N.; Zhang, J.-L. Stable Iso-Bacteriochlorin Mimics from Porpholactone: Effect of a β-Oxazolone Moiety on the Frontier π-Molecular Orbitals. Inorg. Chem. Front. 2015, 2, 671−677. (25) Brückner, C.; Hyland, M. A.; Sternberg, E. D.; MacAlpine, J.; Rettig, S. J.; Patrick, B. O.; Dolphin, D. Preparation of [mesoTetraphenylchlorophinato]Nickel(II) by Stepwise Deformylation of [meso-Tetraphenyl-2,3-diformylsecochlorinato]Nickel(II): Conformational Consequences of Breaking the Structural Integrity of Nickel Porphyrins. Inorg. Chim. Acta 2005, 358, 2943−2953. (26) Akhigbe, J.; Ryppa, C.; Zeller, M.; Brückner, C. Intramolecular Cannizzaro Reaction of meso-Tetraphenylsecochlorin Bisaldehyde. J. Org. Chem. 2009, 74, 4927−4933. (27) Daniell, H. W.; Brückner, C. Enantiomeric Resolution of a Ruffled Porphyrinoid. Angew. Chem., Int. Ed. 2004, 43, 1688−1691. (28) 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. (29) McCarthy, J. R.; Hyland, M. A.; Brückner, C. Synthesis of Indaphyrins: meso-Tetraarylsecochlorin-based Porphyrinoids Containing Direct o-Phenyl-to-β-linkages. Org. Biomol. Chem. 2004, 2, 1484− 1491.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biography Christian Brückner was born in São Paulo, Brazil, and raised in Mexico and Germany. He studied chemistry and biology at the RWTH Aachen, Germany (Dipl. Chem., 1991) before attending the University of British Columbia, Vancouver, Canada (Ph.D., 1996), where David Dolphin introduced him to porphyrin chemistry. After a postdoctoral appointment at UC Berkeley (with Kenneth N. Raymond), he joined the faculty of the University of Connecticut, where he is currently professor in the Department of Chemistry. His research interests lie in the chemistry of porphyrinoids and the design of imaging agents and chemosensors.

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ACKNOWLEDGMENTS The author expresses his deepest gratitude for the contributions of all research group members and collaborators, past and present. The work was supported over the years by the US National Science Foundation through grants CHE-0517782, CHE-1058846, and CHE-1465133.

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The Breaking and Mending of meso-Tetraarylporphyrins: Transmuting

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