Azuliporphyrins and Related Carbaporphyrinoid Systems - American

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Out of the Blue! Azuliporphyrins and Related Carbaporphyrinoid Systems Timothy D. Lash* Department of Chemistry, Illinois State University, Normal, Illinois 61790-4160, United States

CONSPECTUS: First reported in 1997, azuliporphyrins have proven to be a truly remarkable family of porphyrin analogues. In this system, although the porphyrin framework is retained, one of the pyrrolic moieties has been replaced by an azulene unit. Azulene favors electrophilic substitution at the 1,3-positions, which are structurally analogous to the α-positions in pyrrole, and this property facilitates the construction of azulene-containing porphyrinoid systems. Azuliporphyrins were first prepared from tripyrranes and 1,3-azulenedicarbaldehyde using a “3 + 1” variant on the MacDonald reaction. Subsequently, azulenes were shown to react with acetoxymethylpyrroles under acidic conditions to generate azulitripyrranes that could be utilized in a back-tofront “3 + 1” methodology to form azuliporphyrins and related heteroporphyrinoids. In addition, the favorability of azulenes toward 1,3-substitution was applied to one-pot syntheses of tetraarylazuliporphyrins and calix[4]azulenes. Azuliporphyrins have significant diatropic character that is greatly enhanced upon protonation. They have been shown to form organometallic complexes with Ni(II), Pd(II), Pt(II), Ir(III), Rh(III), and Ru(II) and undergo selective oxidations at the internal carbon with copper(II) or silver(I) salts to afford 21-oxyazuliporphyrins. In addition, oxidative ring contractions readily occur under basic conditions in the presence of peroxides to give benzocarbaporphyrins, and this reactivity provides access to tetraarylbenzocarbaporphyrins and their organometallic derivatives. A diazulenylmethane dialdehyde has been shown to react with dipyrrylmethanes in the presence of HCl or HBr to give diazuliporphyrins that were isolated in a monoprotonated form, and metalation with palladium(II) acetate afforded a stable zwitterionic palladium(II) complex. Equally intriguing dicarbaporphyrinoids incorporating indene and azulene rings have been reported, and these systems exhibit significant aromatic character. Recent studies have demonstrated that calixazulenes form supramolecular complexes with quaternary ammonium salts and afford a 1:1 complex with C60. In addition, conjugated structures have been prepared from calixazulenes that are structurally related to quatyrin, the theoretically important hydrocarbon analogue of the porphyrins. Examples of expanded azuliporphyrinoids have also been described. These azulene-containing porphyrinoids exhibit unique and complex reactivity that compares favorably with better studied porphyrin analogue systems such as the N-confused porphyrins, and azuliporphyrin derivatives show promise in the development of new catalytic systems. science,12 it is of great interest to explore related structures. The introduction of carbocyclic subunits in place of one or more of the pyrrolic rings provides the means by which the properties of these macrocycles can be altered. Azuliporphyrins, which incorporate an azulene subunit, are a particularly intriguing family of porphyrin analogues.10,13 This system generally exhibits intermediary aromatic properties, possesses unique reactivity, and has unusual spectroscopic characteristics.

1. INTRODUCTION Carbaporphyrinoid systems, porphyrin analogues that place one or more carbon atoms within the macrocyclic cavity, have been widely investigated over the last 20 years.1,2 These conjugated macrocycles include the so-called N-confused porphyrins (1),3,4 true carbaporphyrins (such as 2 and 3),5−7 benziporphyrins (4),8 tropiporphyrins (5),9 and azuliporphyrins (6) (Figure 1).10 Carbaporphyrinoids exhibit a wide range of properties1,2 and may exist as fully aromatic species such as 1−3,5−7 nonaromatic structures such as 4,8 or even antiaromatic compounds.11 Given the multitude of applications for porphyrins that range from medicine to catalysis to material © XXXX American Chemical Society

Received: November 28, 2015

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DOI: 10.1021/acs.accounts.5b00523 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

2. SYNTHESES AND SPECTROSCOPIC PROPERTIES OF AZULIPORPHYRINS The first example of an azuliporphyrin was prepared by the application of a “3 + 1” variant on the MacDonald reaction (Scheme 1).10,22 Azulene dialdehyde 7a, which is easily Scheme 1. MacDonald “3 + 1” Syntheses and Protonation of Azuliporphyrins

Figure 1. Selected carbaporphyrinoid systems.

Azulene is a well studied isomer of naphthalene which exhibits a significant dipole moment that has been attributed to dipolar resonance contributors with cyclopentadienyl anionic and tropylium cationic character (Figure 2).14 The deep blue

Figure 2. Dipolar character of azulene.

color of azulene also attests to its distinctive electronic structure. Azulene strongly favors electrophilic substitution at the 1,3-positions that structurally resemble the α-positions of pyrrole, and this attribute makes this system an ideal precursor for the construction of carbaporphyrinoids (Figure 3).15−18

Figure 3. Favored sites for electrophilic substitution in pyrrole and azulene.

Virtually all porphyrin syntheses rely on the reactivity of the electron-rich pyrrole moieties toward electrophilic substitution at the α-positions to generate the carbon−carbon bonds needed to construct the tetrapyrrolic macrocycle.19 Because azulene shares this property, at least in a structural sense, it can be used to create similar systems incorporating this bicyclic hydrocarbon unit. In this Account, synthetic strategies for generating azuliporphyrins are discussed. The unusual properties of this system are detailed, including its ability to generate organometallic derivatives under mild conditions, and the synthesis of related azulene-containing porphyrinoid structures is described. This body of work provides insights into the nature of aromaticity in porphyrin-like systems20,21 and reveals novel strategies for modifying these important macrocyclic structures.

prepared by the Vilsmeier−Haack formylation of azulene, was reacted with tripyrrane 8 in the presence of trifluoroacetic acid in dichloromethane, and following oxidation with 2,3-dichloro5,6-dicyano-p-benzoquinone (DDQ), the porphyrin analogue was generated in 28% yield.10 In later work, azuliporphyrins have been prepared by using this approach in up to 77% yield.23 Azuliporphyrin 9a was only sparingly soluble in most organic solvents and gave a poor quality proton NMR spectrum,10 although the data indicated that the macrocycle possesses a moderate diatropic ring current. Unfortunately, the internal CH B


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ppm. Tropylium-containing contributors such as 9′H22+ and 9″H22+ now aid in charge delocalization and this favors the aromatic conjugation pathways present in these species. An alternative “back-to-front” “3 + 1” strategy for preparing azuliporphyrins has also been developed (Scheme 2).15 By

resonance could not be identified with confidence in these spectra. Subsequently, more soluble azuliporphyrins were prepared from 6-tert-butyl or 6-phenylazulene dialdehydes 7b and 7c, and these showed the inner CH resonance at 3 ppm.24 This value is approximately 5 ppm upfield from the equivalent 2-H resonance for azulene, confirming the presence of a diamagnetic ring current. Nevertheless, the effect is substantially reduced compared with the upfield shifts observed for carbaporphyrins 2 and 3 where the internal CH shows up near −7 ppm.5,6 Nucleus independent chemical shifts (NICS) also confirm the presence of a moderate aromatic ring current.25 The presence of an azulene ring in 7 introduces an element of cross-conjugation that would be expected to disrupt macrocyclic aromaticity. It was proposed that dipolar resonance contributors such as 10 introduce a degree of porphyrinoid aromaticity while simultaneously taking on tropylium character.10,13 However, this species only contributes to a limited extent due to the necessity for charge separation. The diatropic character exhibited by azuliporphyrins is somewhat solvent dependent, and significant downfield shifts for the external protons were noted when NMR spectra were run in polar solvents such as pyridine-d5, acetone-d6, and DMSO-d6.13,24 This was attributed to stabilization of dipolar canonical forms that possess 18π electron delocalization pathways. The X-ray crystal structure for 9f showed that the overall macrocycle was essentially planar, although the azulene ring was tilted by 7.4° from the mean macrocyclic plane.24 An analysis of the bond lengths suggested that the 17-atom 18π electron delocalization pathway shown in structure 10′ is responsible for the aromatic characteristics of the system.24 The UV−vis spectra for azuliporphyrins show four moderate sized peaks between 350 and 500 nm and a broad absorption at higher wavelengths (Figure 4).10,13,24 The absence of a strong

Scheme 2. Back-to-Front “3 + 1” Syntheses of Azuliporphyrins

taking advantage of azulene’s ability to undergo facile electrophilic substitution at the 1,3-positions, azulene was reacted with acetoxymethylpyrroles 11 in the presence of acetic acid and refluxing 2-propanol to give azulitripyrrane 12a.13,15 6tert-Butyl- and 6-phenylazulene reacted similarly to give the related azulitripyrranes 12b and 12c.24 Cleavage of the tertbutyl ester protective groups with TFA, followed by condensation with pyrrole dialdehyde 13 and oxidation with DDQ, gave azuliporphyrins 14 in 36−51% yield.13,15,24 This approach has been adapted for the preparation of benzoazuliporphyrins such as 15.25 The azuliporphyrins were initially generated with fused bicyclooctadiene units, for example, structure 16, and upon heating to 200 °C, retro-Diels−Alder elimination of ethylene afforded the targeted benzoazuliporphyrins.25 A “2 + 2” synthesis of azuliporphyrin 17 has also been reported where dipyrrylmethane 18 was condensed with azulenylmethylpyrrole dialdehyde 19 in the presence of HCl (Scheme 3).

Figure 4. UV−vis spectra of azuliporphyrin 9f in 1% Et3N−CHCl3 (free base, green line) and 1% TFA−CHCl3 (dication 9fH22+, purple line).

Scheme 3. MacDonald “2 + 2’ Synthesis of an Azuliporphyrin

Soret band and defined Q absorptions indicate that the electronic structure of azuliporphyrins is quite different from porphyrins or carbaporphyrins. Addition of trifluoroacetic acid (TFA) to solutions of azuliporphyrins resulted in the formation of dicationic species 9H22+ that gave substantially altered UV− vis spectra with a strong Soret-like band near 500 nm together with several Q bands at higher wavelengths (Figure 4).10,13,24 The proton NMR spectra for 9H22+ in TFA-CDCl3 showed that the diatropicity of the system has been greatly enhanced as the meso-protons are shifted downfield to between 9.4 and 10.5 ppm, while the internal CH moved upfield to approximately −3 C


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Accounts of Chemical Research One-pot syntheses of calix[4]azulenes (vide infra)18 and tetraarylazuliporphyrins 20 (Scheme 4) have been intro-

structures are reversible, 22 gradually accumulated and upon oxidation afforded azuliporphyrin 20a. A series of aromatic aldehydes were investigated in these studies and 4-halobenzaldehydes gave superior results producing azuliporphyrins 20b−d in 18−22% yield.17 Similar results were also obtained using 6tert-butyl- and 6-phenylazulene.26

Scheme 4. Lindsey−Rothemund Synthesis of mesoTetraarylazuliporphyrins

3. REACTIVITY OF AZULIPORPHYRINS Addition of pyrrolidine to solutions of azuliporphyrin 9a resulted in the formation of a new carbaporphyrinoid species that exhibited a strong diatropic ring current.31 This was due to the formation of a pyrrolidine adduct, 23, that resulted from nucleophilic attack onto the seven-membered ring (Scheme 5).31 The adduct no longer has a cross-conjugated azulene Scheme 5. Oxidative Ring Contractions to Benzocarbaporphyrins

duced.16,17,26 The approaches applied to prepare these systems again make use of azulene’s ability to selectively undergo electrophilic substitution at the 1,3-positions. In the Rothemund reaction, pyrrole and aldehydes react together to give meso-tetrasubstituted porphyrins, and this strategy has been improved upon by Lindsey who carried out the initial condensation using a suitable acid catalyst such as boron trifluoride etherate to generate the macrocycle and then oxidized the porphyrinogen intermediate to form the fully conjugated porphyrin.27 Lindsey’s conditions were adapted to react azulene, benzaldehyde, and pyrrole in a 1:4:3 molar ratio in the presence of BF3·Et2O and under optimized conditions; following oxidation with DDQ, tetraphenylazuliporphyrin 20a was isolated in 13% yield together with tetraphenylporphyrin.16,17 The reaction was solvent dependent. Chloroform gave superior results, whereas virtually no 20a was formed in dichloromethane. This appears to be due to the presence of ethanol, which is used as a stabilizer in CHCl3, presumably due to modifications resulting from coordination to the Lewis acid catalyst.16,17 This phenomenon had previously been observed in the synthesis of sterically hindered porphyrin structures such as tetramesitylporphyrin,28 meso-tetraaryltetraacenaphthoporphyrins,29 and tetraphenanthroporphyrins.30 When the reaction was carried out at room temperature for 1 h, the only isolatable macrocyclic product was tetraphenylporphyrin, but after 16 h, significant quantities of 20a were formed.16,17 It was suggested that pyrrole and benzaldehyde rapidly react to generate porphyrinogen 21, while azuliporphyrinogen 22 forms relatively slowly. However, because the steps leading to these

subunit, and the macrocycle takes on a carbaporphyrin-type conjugation with an 18π electron delocalization pathway. Although 23 predominates in solution, it cannot be isolated because it reverts to azuliporphyrin upon removal of the excess pyrrolidine. Similar adducts were observed for tetraphenylazuliporphyrin 20a with pyrrolidine, thiophenol, benzylamine, and hydrazine.21 It was speculated that reaction of 9a with peroxide anions could provide a route to tropone-fused carbaporphyrins 24 (Scheme 5).31 However, treatment of 9a with tert-butyl hydroperoxide under basic conditions failed to generate the tropone-containing system and instead afforded benzocarbaporphyrins 25a−c (Scheme 6).13,31 It is worth noting that benzocarbaporphyrins are commonly observed as byproducts in D


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Although tropone-fused carbaporphyrin 24 could not be obtained from azuliporphyrin 9a, an alternative synthesis of this system was recently reported.34 6-Methoxyazulene (32) reacted with acetoxymethylpyrrole 11 in refluxing acetic acid−ethanol to give azulitripyrrane 33 (Scheme 8). Subsequent treatment

Scheme 6. Conversion of Azuliporphyrins to Benzocarbaporphyrins

Scheme 8. Synthesis of Tropone-Fused Carbaporphyrins

the synthesis of azuliporphyrins.32 The formation of these products was rationalized by the mechanism shown in Scheme 5.13,31 Initial nucleophilic attack at the 23-position of the azulene subunit would afford the peroxide adduct 26, but instead of elimination of tert-butyl alcohol to give 24, a Cope rearrangement appears to take place to afford the norcaradienefused carbaporphyrin 27. Elimination of tert-butyl alcohol could either give the benzocarbaporphyrin aldehyde 25b or cyclopropanone 28. The latter compound can then extrude carbon monoxide to produce 25a. The formation of the minor aldehyde product 25c can be explained if initial nucleophilic attack occurs at the 22-position.13 Similar carbaporphyrin products 29 were obtained for tetraarylazuliporphyrins 20a and 20b, and indeed this route provides the only known method for preparing tetraarylcarbaporphyrins (Scheme 7)16,17 Scheme 7. Ring Contractions for 23-Substituted and Tetraaryl Substituted Azuliporphyrins

with TFA and condensation with pyrrole dialdehyde 13, followed by oxidation with aqueous ferric chloride, gave the tropone-containing porphyrinoid 24 in 32% yield. It was speculated that methoxyazuliporphyrin 34 was initially generated, but this species underwent a spontaneous SN2 displacement of the methyl group to generate the tropone product (Scheme 8). Although 24 has a fully conjugated carbaporphyrin core, the UV−vis spectrum appears to be a hybrid of the spectra observed for azuliporphyrins and carbaporphyrins. Specifically, the Soret band region between 350 and 500 nm shows several absorptions of medium intensity similar to those seen for 9, while a series of porphyrin-like Q bands show up between 500 and 750 nm. The proton NMR spectrum of 24 in CDCl3 demonstrated that this porphyrinoid has strongly diatropic properties and the internal NH and CH resonances appear at −4.47 and −7.64 ppm. Addition of TFA gave the related dication 24H22+, while DBU deprotonated the system to give the anionic species [24-H]−, both of which retained highly diatropic characteristics (Scheme 8). In addition, 24 behaves as a trianionic ligand reacting with

and their organometallic derivatives.33 The presence of 23substituents did not prevent the oxidative ring contractions and phenyl or tert-butyl substituted azuliporphyrins 9f,h and 20e−h gave related carbaporphyrin products 30 and 31, respectively (Scheme 7). 24,26 The formation of these substituted carbaporphyrins can easily be explained using the same mechanistic rationales. E


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Accounts of Chemical Research silver(I) acetate to afford the related silver(III) complex 35. A tropone-fused thiacarbaporphyrin 36 was also prepared by reacting 33 with 2,5-thiophenedicarbaldehyde.34 Azuliporphyrins act as dianionic ligands and readily form stable organometallic derivatives. Reaction of 9a or 20a with nickel(II) acetate or palladium(II) acetate gave the related metalated azuliporphyrins 37 and 38, respectively, in good yields (Schemes 9 and 10).24,26,35,36 Platinum(II) chloride also

Scheme 10. Metalation and Oxidation of Tetraarylazuliporphyrins

Scheme 9. Metalation of Azuliporphyrins

that the macrocycle is near planar with the methylbenzoyl ligand lying at right angles to the macrocyclic system.38 [Rh(CO)2Cl]2 also reacted with azuliporphyrin 14a to give related rhodium(III) complexes 40, although in these derivatives the xylene solvent was incorporated as a methylbenzyl ligand.39 The o-, m-, and p-xylene derived complexes were characterized by single crystal XRD, and these results again demonstrated that the azuliporphyrin system is near planar while the benzylic ligand is placed orthogonally to the ring system.39 When the reaction was carried out in acetonitrile and the unidentified intermediary species was then treated with acetone and basic alumina, a 2-oxopropyl rhodium(III) derivative, 41, was generated.39 Reaction of 20a with 1 equiv or less of Ru2(CO)12 gave the ruthenium(II) complex 42, but further reaction took place in the presence of an excess of the reagent to give the π-coordinated Ru4(CO)9 cluster complex 43a.40 Ru3(CO)12 also reacted with nickel(II), palladium(II), and platinum(II) azuliporphyrins 38 to give the related bimetallic complexes 43b−d.40 Hence, azuliporphyrins demonstrate the ability to form a wide range of organometallic derivatives. Reaction of tetraphenylazuliporphyrin 20a or the related tetrakis(4-chlorophenyl) compound 20b with copper(II) acetate led to an oxidative metalation process that afforded moderate yields of the corresponding copper(II) complexes 44.41 The X-ray crystal structure of 44a showed that the ring system is highly distorted with the azulene subunit being tilted by 53° relative to the mean macrocyclic plane. Treatment of 44a and 44b with 10% TFA in chloroform gave the demetalated 21-oxyazuliporphyrins 45.41 It was subsequently shown that porphyrinoids 45 could be more efficiently synthesized by refluxing tetraarylazuliporphyrins 20 with silver(I) acetate in chloroform-acetonitrile.42 In principle, oxyazuliporphyrins 45 have a 20π electron delocalization

reacted under these conditions, but the resulting platinum(II) complexes 37c and 38c were only isolated in 22−27% yield.36 The proton NMR spectra for these metallo-azuliporphyrins showed downfield shifts for the meso-protons indicating slightly enhanced diatropic character, particularly in the case of the palladium complexes. The X-ray crystal structure of palladium(II) complexes 38b and a related tert-butyl substituted complex demonstrated that the porphyrinoid macrocycle is reasonably planar, although the azulene subunit is significantly twisted,36,37 but nickel(II) complex 37a is somewhat distorted favoring a ruffled conformation.35,36 Azuliporphyrin 9a and the related tert-butyl substituted compound 9f were found to react with bis(1,5-cyclooctadiene)diiridium(I) dichloride in refluxing o-, m-, or p-xylene to give low yields of iridium(III) azuliporphyrins 39 (Scheme 9).38 These reactions are notable in that two metal−carbon bonds have been generated and a solvent molecule has been incorporated as an axial ligand. It was speculated that the xylene unit was initially introduced as a methylbenzyl group and that subsequent oxidation by molecular oxygen led to the formation of the observed benzoyl ligands. Single crystal X-ray diffraction analysis of 39 showed F


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Accounts of Chemical Research pathway, but there is no evidence for antiaromatic character in this system.41,42 Although the azulene protons are shifted upfield in the proton NMR spectrum of 45a, the pyrrolic protons gave relatively downfield peaks, and these results indicate that the seven-membered ring is nonaromatic while the remaining macrocycle retains significant diatropic characteristics. DFT calculations confirmed these observations and indicated that the dipolar contributor 45x is responsible for these properties.42 The X-ray crystal structure for 45a showed that the azulene subunit is rotated by nearly 40° relative to the mean macrocyclic plane and also confirmed the presence of the carbonyl moiety.42 Reaction of oxyazuliporphyrins 45 with nickel(II) acetate, palladium(II) acetate, or platinum(II) chloride gave the metallo-derivatives 46, demonstrating that this system can act as a dianionic ligand.42 Related ruthenium(II) complexes were also reported recently.43

Scheme 12. Synthesis of Dimesityl Thia- and Selenaazuliporphyrins

KOH to give thia- and selenacarbaporphyrins 54a,b by analogy to the chemistry previously discussed for azuliporphyrins.13 In an attempt to inhibit the ring contraction for heteroazuliporphyrins, 23-tert-butyl and phenyl substituted azuliporphyrinoids 47b,c and 48b,c were prepared in 45−55% yield from the corresponding azulitripyrranes 12b and 12c.45 However, as had been observed for substituted azuliporphyrins, the presence of the 23-substituents did not inhibit the ring contraction reactions and a series of benzoheterocarbaporphyrins 54c−f were generated (Scheme 11).45 Reaction of azulitripyrranes 12a−c with TFA and furan dicarbaldehyde, followed by oxidation with aqueous ferric chloride solutions, initially appeared to give no heteroazuliporphyrin products. However, when the aqueous solutions were saturated with sodium chloride, oxaazuliporphyrins 49a−c precipitated out, and following purification, the related dihydrochloride salts could be isolated in 41−57% yield.45 Oxaazuliporphyrin hydrochlorides 49·2HCl exhibited strong diamagnetic ring currents in their proton NMR spectra, but as expected these shifts were considerably reduced for the free base structures in DBU−CDCl3. Unlike thia- and selenaazuliporphyrins, the free base forms of the oxaazuliporphyrins proved to be somewhat unstable. X-ray crystal structures of 47b and 48b were obtained, and these demonstrated that the structures are essentially planar. An analysis of the bond lengths again indicated that the 17-atom 18π electron delocalization pathway shown in structure 55 is responsible for the aromatic properties observed for these heteroanalogues.45

4. HETEROAZULIPORPHYRINS Thia-, selena-, and oxaazuliporphyrins 47−49, respectively, have been described. The first example of a thiaazuliporphyrin 47a was prepared in 33% yield by reacting azulitripyrrane 12a with thiophene dialdehyde 50a and TFA, followed by oxidation with DDQ (Scheme 11).15 However, furan dialdehyde 50c Scheme 11. “3 + 1” Syntheses of Heteroazuliporphyrins

5. DI- AND TETRACARBAPORPHYRINOID SYSTEMS INCORPORATING AZULENE SUBUNITS Carbaporphyrinoid systems with more than one internal carbon atom are less well studied but a number of azulene-containing macrocycles of this type have been described. Condensation of diazulenylmethane dialdehyde 56 with dipyrrylmethanes 18 and 37 in the presence of HCl or HBr, followed by oxidation with ferric chloride, gave 43−56% yields of the corresponding diazuliporphyrins 57 (Scheme 13).46 These were isolated as the monoprotonated salts 57H+, although addition of TFA to solutions of these compounds afforded the diprotonated dications 57H22+. The proton NMR spectrum for 57·HBr in CDCl3 afforded an upfield resonance for the internal CHs at −0.05 ppm, while the meso-protons shifted downfield, demonstrating that this system possesses a significant amount of diatropic character. The results for dication 57H22+ were similar, showing the inner methine protons upfield at +0.8 ppm and the meso-protons downfield between 8.4 and 10.7 ppm.46 Reaction of 57a·HBr with palladium(II) acetate gave palladium(II) complex 58 in 26% yield (Scheme 13).46 The X-ray structure for this species showed that the macrocycle is slightly saddled. The proton NMR spectrum for the palladium complex

afforded a mixture of benzocarbaporphyrin products 51a−c due to ring contraction of the seven-membered ring. Chandrashekar and co-workers prepared dimesityl 23-heteroazuliporphyrins 52 by reacting thia- or selenatripyrranes 53 with azulene dialdehyde 7a in the presence of TFA, followed by oxidation with DDQ (Scheme 12).44 The NMR spectra for 47a, 52a, and 52b indicated that the heteroanalogues have similar diatropic characteristics to regular azuliporphyrins. Selenaazuliporphyrin 48a was subsequently prepared in 27% yield by reacting 12a with selenophene dialdehyde 50b (Scheme 11).13 Heteroazuliporphyrins 47a and 48a underwent oxidative ring contractions in the presence of tert-butyl hydroperoxide and G


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Accounts of Chemical Research Scheme 13. Synthesis of Diazuliporphyrins

Scheme 15. Synthesis of a 23-Carbaazuliporphyrin

azulene, and pyrrole protons showed up at 0.52, 1.25, and 1.99 ppm. Addition of TFA initially afforded the monocation 63H+, but further addition of acid gave the C-protonated dication 63H22+. Both of the protonated species showed enhanced diatropic character.15 An isomeric dicarbaporphyrinoid system 64 was subsequently prepared using a fulvene dialdehyde strategy.49 Azulene dicarbaldehydes 7a,b reacted with 1 equiv of indene enamine 65 in the presence of di-n-butylboron triflate to give the required fulvene dialdehyde intermediates 66 (Scheme 16).49,50 Acid catalyzed MacDonald condensation of 66 with dipyrrylmethanes 18 and 37 gave the 22-carbaazuliporphyrins 64 in 19−80% yield. These adj-dicarbaporphyrinoids proved to be far more stable than opp-isomer 63 but showed comparable diatropic characteristics.49,50 Addition of TFA again led to the formation of monoprotonated and diprotonated species 64H+ and 64H22+. Dicarbaporphyrinoid 64b underwent oxidation rather than metalation with silver(I) acetate in alcohol solvents to give nonaromatic dialkoxy derivatives 67.50 Considerable interest has been directed toward the synthesis of quatyrin 68, the hydrocarbon analogue of the porphyrins.7,51 Given the ease with which azulene units can be incorporated into porphyrinoid systems, efforts were directed toward the preparation of calix[4]azulenes 69 (Scheme 17) that possess the same carbon skeleton as the elusive but theoretically important quatyrin system.18 Azulene reacted with paraformaldehyde at room temperature in the presence of florisil to give calixazulene 69a in 74% yield.18 Similarly, 6-tert-butylazulene afforded 69b in 68% yield and 6-methylazulene gave the related calixazulene 69c in 17% yield, although 6-phenylazulene gave a complex mixtures of products.52,53 Calix[4]azulene 69a has recently been shown to form 1:1 supramolecular complexes with several tetraalkylammonium salts,54 while 69b afforded a 1:1 supramolecular complex with C60.55 Calix[4]azulene 70 was later obtained by reacting 6-tert-butylazulene with ferrocenecarbaldehyde in acetic acid,56 while aryl substituted calix[4]azulenes 71 (mixed isomers) were formed when azulene and aromatic aldehydes were reacted in the presence of boron trifluoride etherate (Scheme 18).57 Treatment of calix[4]azulene 69b with triphenylcarbenium hexafluorophosphate gave a deep blue colored porphodimethene analogue 72 (Scheme 17).52 Tetraarylcalix[4]azulenes 71 were also oxidized with excess DDQ to give the tetracationic species 73.57 Although these structures can be considered to be didehy-

was consistent with an aromatic porphyrinoid system. This species, which must exist as a zwitterionic structure, proved to be quite polar, and 1% methanol−chloroform was required to elute it from a silica column. Heterodiazuliporphyrins have also been reported. Using the principles previously applied to the synthesis of tetraarylazuliporphyrins 20,16,17 azulene was reacted with furan or thiophene dicarbinols 59 in the presence of boron trifluoride etherate, and following oxidation with DDQ, the neutral macrocycles 60 were generated (Scheme 14).47,48 Further oxidation afforded aromatic dications 61, but these could be reduced back to 60 with tin(II) chloride.47,48 Several examples of carbaazuliporphyrins have been reported. Azulitripyrrane 12a was treated with TFA and further condensed with indene dialdehyde 62 (Scheme 15).15 Following oxidation with ferric chloride, the 23-carbaazuliporphyrin 63 was isolated in 9.4% yield. This system proved to have significant aromatic character because the internal indene, Scheme 14. Heterodiazuliporphyrins

H


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Accounts of Chemical Research Scheme 16. Synthesis of adj-Dicarbaporphyrinoids Incorporating an Azulene Subunit

Scheme 18. meso-Tetraarylcalix[4]azulenes and a Tetracation Derived Therefrom

Scheme 17. Synthesis of Calix[4]azulenes

6. EXPANDED AZULIPORPHYRINOIDS Currently, there are few expanded porphyrinoid systems that incorporating azulene subunits, but they offer intriguing possibilities for future research. Azulene dialdehyde 7a reacted with tetrapyrrole dicarboxylic acid 74 in the presence of TFA to give, following oxidation with FeCl3 and protonation with hydrochloric acid, azulisapphyrin dication 75H22+ (Scheme 19).58 The UV−vis spectrum for this expanded azuliporphyrin closely resembled the spectra observed for free base azuliporphyrins 9, showing a series of bands between 420 and 511 nm and a broad absorption at 742 nm, although azulisapphyrin 75H22+ exhibits a strong diamagnetic ring current.58 Addition of DBU afforded the free base form, but Scheme 19. Synthesis of an Azulisapphyrin

droquatyrins (see resonance contributor 73′), DFT calculations indicate that the macrocycles are severely distorted, and this system appears to be nonaromatic rather than antiaromatic.57 Hence, the conversion of calix[4]azulenes to true quatyrins has not yet been achieved, although 72 can be considered to be a dihydroquatyrin.52 I



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this proved to be very unstable.58 In addition, evidence for the formation of a pyrrolidine adduct 76 was presented, but this species was also very unstable (Scheme 19). Acid catalyzed condensation of azulene diacrylaldehyde 77 with dipyrrylmethane 18 led to the formation of a nonaromatic diazulihexaphyrin 78 in 64% yield (Scheme 20).59 Addition

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Funding

The author’s work in this area has received virtually continuous support from the National Science Foundation over the last 25 years, most recently under Grant No. CHE-1465049. Additional support has been received from the Petroleum Research Fund, administered by the American Chemical Society.

Scheme 20. Synthesis of a Diazulihexaphyrin

Notes

The authors declare no competing financial interest. Biography Timothy Lash obtained his B.Sc. (Hon.) from the University of Exeter in 1975 and completed his Ph.D. degree in 1979 at the University of Wales, College of Cardiff, under the direction of Prof. A. H. Jackson. He joined the Department of Chemistry at Illinois State University in 1984 as an Assistant Professor, and was promoted to full Professor in 1993. In 2000, he was awarded the title of Distinguished Professor. His research has focused on the synthesis, aromaticity, reactivity, biochemistry, geochemistry, and spectroscopy of porphyrins and related conjugated macrocycles.

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REFERENCES

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of TFA led to C-protonation to form a tetracationic species.59 Clearly, the possibilities for preparing expanded porphyrinoids of this type remain underdeveloped, but this area holds promise for future discoveries.

7. CONCLUSIONS AND FUTURE PROSPECTS Azulene is an ideal substitute for pyrrole in the construction of carbaporphyrinoid systems. Azulene’s propensity to react at the 1,3-positions, which are structurally equivalent to the αpositions in pyrrole, enable the formation of useful intermediates such as azulitripyrranes and can facilitate macrocycle formation as has been demonstrated in the onepot syntheses of tetraarylazuliporphyrins and calix[4]azulenes. The reactivity of azuliporphyrins has also proven to be intriguing, and stable organometallic derivatives with the catalytically important transition metal ions Ni(II), Pd(II), Pt(II), Ir(III), Rh(III), and Ru(II) have been demonstrated. Azuliporphyrins also readily undergo oxidative ring contractions to yield benzocarbaporphyrins providing an alternative route to these important aromatic porphyrin analogues. Furthermore, selective oxidation at the internal azulene carbon allows the formation of 21-oxyazuliporphyrins that can act as dianionic ligands for transition metal ions. Azulene has also been incorporated into a number of dicarbaporphyrinoid systems that show equally fascinating reactivity as well as significant aromatic characteristics. Inroads into the synthesis of expanded azuliporphyrins have also been made. The striking results already reported for these porphyrinoid systems indicate that there is far more to learn about azulene-containing porphyrin analogues, and this work will no doubt lead to equally important discoveries in the future. J


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(33) Lash, T. D.; Colby, D. A.; Szczepura, L. F. New Riches in Carbaporphyrin Chemistry: Silver and Gold Organometallic Complexes of Benzocarbaporphyrins. Inorg. Chem. 2004, 43, 5258−5267. (34) Lash, T. D.; Gilot, G. C.; AbuSalim, D. I. Tropone-Fused Carbaporphyrins. J. Org. Chem. 2014, 79, 9704−9716. (35) Graham, S. R.; Ferrence, G. M.; Lash, T. D. Organometallic Chemistry of Carbaporphyrinoids: Synthesis and Characterization of Nickel(II) and Palladium(II) Azuliporphyrins. Chem. Commun. 2002, 38, 894−895. (36) Lash, T. D.; Colby, D. A.; Graham, S. R.; Ferrence, G. M.; Szczepura, L. F. Organometallic Chemistry of Azuliporphyrins: Synthesis, Spectroscopy, Electrochemistry and Structural Characterization of Nickel(II), Palladium(II) and Platinum(II) Complexes of Azuliporphyrins. Inorg. Chem. 2003, 42, 7326−7338. (37) Ferrence, G. M.; Lash, T. D. (23-tert-Butyl-5,10,15,20tetraphenylazuliporphyrinato)-palladium(II) Dichloromethane Solvate. Acta Crystallogr., Sect. E: Struct. Rep. Online 2007, 63, m1351− m1353. (38) Lash, T. D.; Pokharel, K.; Zeller, M.; Ferrence, G. M. Iridium(III) Azuliporphyrins. Chem. Commun. 2012, 48, 11793− 11795. (39) Stateman, L. M.; Ferrence, G. M.; Lash, T. D. Rhodium(III) Azuliporphyrins. Organometallics 2015, 34, 3842−3848. (40) Bialek, M.; Latos-Grazynski, L. Merging of Inner and Outer Ruthenium Organometallic Coordination Motifs Within an Azuliporphyrin Framework. Chem. Commun. 2014, 50, 9270−9272. (41) Colby, D. A.; Ferrence, G. M.; Lash, T. D. Oxidative Metalation of Azuliporphyrins with Copper(II) Salts: Formation of a Porphyrin Analogue System with a Unique Fully Conjugated Nonaromatic Azulene Subunit. Angew. Chem., Int. Ed. 2004, 43, 1346−1349. (42) Lash, T. D.; Colby, D. A.; El-Beck, J. A.; AbuSalim, D. I.; Ferrence, G. M. Preparation, Structural Characterization, Assessment of Potential Antiaromaticity and Metalation of 21-Oxyazuliporphyrins. Inorg. Chem. 2015, 54, 9174−9187. (43) Bialek, M. J.; Bialonska, A.; Latos-Grazynski, L. Oxidation and Oxygenation of Carbonyl Ruthenium(II) Azuliporphyrin. Inorg. Chem. 2015, 54, 6184−6194. (44) Venkatraman, S.; Anand, V. G.; PrabhuRaja, V.; Rath, H.; Sankar, J.; Chandrasekar, T. K.; Teng, W.; Senge, K. R. First Structural Characterization of Core Modified 10,15-meso Aryl Azuliporphyrins: Observation of C−H···π Interaction between Pyrrole β-CH and Mesityl Ring. Chem. Commun. 2002, 38, 1660−1661. (45) Lash, T. D.; El-Beck, J. A.; Ferrence, G. M. Synthesis, Structural Characterization and Reactivity of Heteroazuliporphyrins. Org. Biomol. Chem. 2014, 12, 316−329. (46) Zhang, Z.; Ferrence, G. M.; Lash, T. D. adj-Diazuliporphyrins, a New Family of Dicarbaporphyrinoids with Unprecedented Mesoionic Characteristics. Org. Lett. 2009, 11, 101−104. (47) Sprutta, N.; Swiderska, M.; Latos-Grazynski, L. Dithiadiazuliporphyrin: Facile Generation of Carbaporphyrinoid Cation Radical and Dication. J. Am. Chem. Soc. 2005, 127, 13108−13109. (48) Sprutta, N.; Siczek, M.; Latos-Grazynski, L.; Pawlicki, M.; Szterenberg, L.; Lis, T. Dioxadiazuliporphyrin: A Near-IR Redox Switchable Chromophore. J. Org. Chem. 2007, 72, 9501−9509. (49) Lash, T. D.; Colby, D. A.; Idate, A. S.; Davis, R. N. Fulvene Dialdehyde Strategy for adj-Dicarbaporphyrinoid Synthesis: Preparation of a 22-Carbaazuliporphyrin. J. Am. Chem. Soc. 2007, 129, 13800− 13801. (50) Lash, T. D.; Lammer, A. D.; Idate, A. S.; Colby, D. A.; White, K. Preparation of Azulene-Derived Fulvenedialdehydes and their Application to the Synthesis of Stable adj-Dicarbaporphyrinoids. J. Org. Chem. 2012, 77, 2368−2381. (51) Lash, T. D.; Romanic, J. L.; Hayes, M. J.; Spence, J. D. Towards Hydrocarbon Analogues of the Porphyrins: Synthesis and Spectroscopic Characterization of the First Dicarbaporphyrin. Chem. Commun. 1999, 35, 819−820. (52) Lash, T. D.; El-Beck, J. A.; Colby, D. A. Synthesis of a Tetraazulene Porphodimethene Analogue. J. Org. Chem. 2009, 74, 8830−8833. K


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Accounts of Chemical Research (53) Although a multistep synthesis of 2,2′,2″,2‴-tetramethoxycalix[4]azulene from 2-methoxyazulene had been reported earlier, this work did not inspire the later one-pot syntheses of calix[4]azulenes. See: Asao, T.; Ito, S.; Morita, N. Synthesis of [1.1.1.1](1,3)-2Methoxyazulenophane: Azulene Analogue of Calixarenes. Tetrahedron Lett. 1988, 29, 2839−2842. (54) Rahman, S.; Zein, A.; Dawe, L. N.; Shamov, G.; Thordarson, P.; Georghiou, P. E. Supramolecular Host−Guest Complexation of Lash’s Calix[4]azulene with Tetraalkylammonium Halides and Tetrafluoroborate Salts: Binding and DFT Computational Studies. RSC Adv. 2015, 5, 54848−54852. (55) Georghiou, P. E.; Schneider, C.; Shamov, G.; Lash, T. D.; Rahman, S.; Giddings, S. Mechanochemical Formation of a 1:1 C60:tert-Butylcalix[4]azulene Supramolecular Complex: Solid-State NMR and DFT Computational Studies. Supramol. Chem. 2016, DOI: 10.1080/10610278.2015.1108416. (56) Shoji, T.; Higashi, J.; Ito, S.; Toyota, K.; Iwamoto, T.; Morita, N. Synthesis and Properties of Ferrocenylmethylene-Bridged Calix[4]azulene and a New Example of Bis(1-azulenyl)ferrocenylmethylium Ion. Eur. J. Org. Chem. 2009, 2009, 5948−5952. (57) Sprutta, N.; Mackowiak, S.; Kocik, M.; Szterenberg, L.; Lis, T.; Latos-Grazynski, L. Tetraazuliporphyrin Tetracation. Angew. Chem., Int. Ed. 2009, 48, 3337−3341. (58) Richter, D. T.; Lash, T. D. Synthesis of Sapphyrins, Heterosapphyrins and Carbasapphyrins by a “4 + 1” Approach. J. Org. Chem. 2004, 69, 8842−8850. (59) Zhang, Z.; Ferrence, G. M.; Lash, T. D. MacDonald-Type Reactions Using Bis-Acrylaldehydes: Synthesis of an Expanded Sapphyrin and Vinylogous Hexaphyrins. Org. Lett. 2009, 11, 1249− 1252.

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