Meso-Formyl, Vinyl, and Ethynyl Porphyrins—Multipotent Synthons for Obtaining a Diverse Array of Functional Derivatives

Abstract

This review presents a strategy for obtaining various functional derivatives of tetrapyrrole compounds based on transformations of unsaturated carbon-oxygen and carbon-carbon bonds of the substituents at the meso position (meso-formyl, vinyl, and ethynyl porphyrins). First, synthetic approaches to the preparation of these precursors are described. Then diverse pathways for the transformations of the multipotent synthons are discussed, revealing a variety of products of such reactions. The structures, electronic, and optical properties of the compounds obtained by the methods under consideration are analyzed. In addition, there is an overview of the applications of the products obtained. Biomedical use of the compounds is among the most important. Finally, the advantages of using the reviewed synthetic strategy to obtain dyes with targeted properties are highlighted.

1. Introduction

The production of porphyrin materials with target-specific structures is based on various methodologies, differing in that natural or synthetic porphyrins are used. Naturally derived porphyrins are substituted at β-pyrrolic position and usually with free-from substitution meso-carbons. The synthetic porphyrin core can be easily obtained by tetrapyrrole condensation, and the most popular way is condensation of easily available unsubstituted pyrrole with aldehydes to give meso-substituted porphyrins [1]. Thus, two main alternative porphyrin types are used as starting materials in synthesis: (1) β-substituted-meso-unsubstituted; and (2) β-unsubsituted-meso-substituted (Figure 1). Most of the synthetically obtained porphyrins are meso-arylporphyrins, like meso-tetraphenylporphyrin (TPP) and meso-diphenylporphyrin (DPP). The most popular synthetic porphyrin resembling natural porphyrins is β-octaethylporphyrin (OEP). The starting basic tetrapyrroles then need to be functionalized to impart the required properties to the porphyrin molecule [2,3,4]. The tetrapyrrolic macrocycle can be functionalized by a variety of methods, among which formylation is especially prolific due to the well-developed, very efficient, and easy-to-use formylation methods [5]. The advantage of this functionalization methodology is based on the fact that the aldehyde group is rich in the possibilities of further transformations leading to the addition of functional fragments. The vinyl group is also useful for further functionalizations, and it can be obtained by the Wittig reaction of the formyl-substituted substrate. The acetylenyl group is among the most commonly used for making multichromophore molecules due to its rich coupling possibilities. Thus, formyl, vinyl, and ethynyl groups are magic functions that lead to a variety of products from further transformations, including conversions between them (formyl <=> ethenyl <=> ethynyl). The products obtained through the transformations of these three main synthons are used in a wide variety of applications, including optical sensors [6] and photosensitizers [7,8,9]. The role of β-formyl and β-vinyl-porphyrins in the synthesis of various porphyrin derivatives was summarized in the review [10]. The β-position is more easily accessible to reagents compared to the meso position, and there were a wide variety of products synthesized from β-formyl and β-vinyl-porphyrins. The meso position is sterically hindered by the neighboring β-carbon atoms and their substituents, so the reactions of meso groups proceed harder. This obstacle is responsible for fewer reported works dealing with meso versus β functionalizations and transformations. However, the meso-substitution affects the electronic system and spectral properties of the tetrapyrrole macrocycle more strongly. Particularly, the meso push-pull substituted porphyrins are the most efficient organic photosensitizers for dye-sensitized solar cells (DSSC) [11]. Thus, it is important to develop meso functionalization and transformation methodologies, and the formyl, vinyl, and ethynyl groups present excellent opportunities for primary functionalization and further transformations at the meso position.

2. Meso-Formylporphyrins

Insertion of the formyl group into porphyrins is a primary functionalization of the tetrapyrrole ring, opening opportunities for further transformations including, but not limited to, Wittig [12,13,14], Grignard [14,15,16], McMurry [17], cycloaddition [18], Knoevenagel [19] reactions, and Schiff bases preparation [20]. Ponomarev made a considerable contribution to the chemistry of formylporphyrins and published a corresponding review about 30 years ago, summarizing works reported up to that date [5].

2.1. Preparation of Meso-Formylporphyrins

One of the strategies for the preparation of functionalized porphyrins is the utilization of the correspondingly functionalized precursors in the synthesis of the porphyrin core. The formyl group is actively involved in the condensation reaction during tetrapyrrole ring construction, and it needs to be protected. Formylporphyrins were obtained by the usual macrocyclization route to the porphyrins from the masked formyl-containing precursors: 2-formyl-1,3-dithiolane was converted to 5-(1,3-dithian-2-yl)dipyrromethane and mixed MacDonald [2 + 2] condensation with 5-mesytyldipyrromethane and p-tolualdehyde led to 5-(1,3-dithian-2-yl)-15-mesytyl-10,20-di(4-tolyl)porphyrin 1 which gave the corresponding 5-formyl-15-mesytyl-10,20-di(4-tolyl)porphyrin 2 after deprotection with DDQ/BF₃(OEt₂) (Scheme 1) [21].

Similar methods of preparation of formylporphyrins from 1,3-dithiane were proposed by Lindsey [22] and Senge [23]. These methods open opportunities for obtaining 5-, 5,10-, 5,15-, 5,10,15,20-thianyl substituted porphyrins (Scheme 2), which can easily be deprotected to the corresponding formylporphyrins with quantitative yield.

The insertion of the formyl group into the already assembled tetrapyrrole macrocycle can be realized both by electrophilic and nucleophilic substitution reactions. 1,3-dithiolane as an umpolung formyl synthon, developed by Seebach and Corey [24], was used to insert formyl via nucleophilic addition of the corresponding lithium salt to the porphyrin. Senge investigated the reaction of the addition of 1,3-dithiane, deprotonated with n-butyllithium, in the presence of N,N,N,N-tetramethylethylenediamine (TMEDA), to porphyrins [23]. The products of the nucleophilic addition of the 1,3-dithianyl anion to the 5,15-diphenylporphyrin (DPP) 3, 5,15,20-triphenylporphyrin (TrPP) 4, and their nickel complexes (3Ni and 4Ni) were protonated, and the corresponding porphyrinogens were oxidized with DDQ. Subsequent deprotection of the formyl group was carried out with DDQ but in the presence of BF₃ etherate to give the corresponding meso-formyl DPP and TrPP derivatives 5 and 6 (Scheme 3). However, low yields and functional group intolerance of the method limit its use.

Takanami developed a more efficient and functional group-tolerant method of nucleophilic formyl group insertion using 2-(trimethylsilyl)pyridine. The reaction proceeded via nucleophilic addition of (2-pyridylmethylsilyl)lithium to DPP 3, followed by protonation of the intermediate anion and oxidation of the porphyrinogen back to the aromatic porphyrin ring to give DPP-CHO 5 (Scheme 4) [25,26]. It should be noted that mild oxidation of the meso-silyl porphyrinogen by air led to the meso-(hydroxymethyl)porphyrins 7 [27].

The reaction proceeds under mild conditions, and it is applicable to aryl- and alkyl-substituted porphyrins as well as their metal complexes. In addition to monoformyl derivatives, this method makes it possible to obtain diformyl derivatives, as well as more complex aldehydes with high yields. To confirm the mechanism, reactions were carried out with the addition of various electrophiles, such as acyl chloride, methyl chloroformate, isocyanates, and enones, resulting in the corresponding formyl derivatives 8, variously substituted at the opposite formyl meso position [28].

Osuka obtained porphyrin Grignard reagents for the first time using metal-iodine exchange between meso-iodoporphyrins and iPrMgCl. The utilization of the meso-magnesiumporphyrins in reaction with DMF led to the formation of the meso-formyl derivatives (Scheme 5) [29].

Reactions of electrophilic substitution have found the greatest application in the chemistry of porphyrins as electron-rich aromatics. More reactive meso positions are usually attacked by electrophiles. The electrophilic formylation can easily be performed using the Vilsmeier–Haack reaction. The synthesis of meso-formyl-β-octaalkylporphyrins using Vilsmeier–Haack formylation was first reported more than half a century ago [30,31]. To date, this reaction has become one of the most popular and efficient for obtaining meso-formylporphyrins.

Porphyrin metal complexes resistant to HCl, released during the reaction, are substrates for formylate. It is known that the rate of formylation decreases with increasing electron acceptor ability of the metal cation in the series M(II) > M(III) > M(IV) and among M(II) in the series Ni(II) > Cu(II) > Pd(II) > Pt(II). Of the numerous variants of the reaction, the Vilsmeier reagent made from DMF/POCl₃ is usually used in porphyrin chemistry. The mechanism of the reaction is as follows: at the first stage, the electrophilic Vilsmeier reagent attacks the nucleophilic meso position of porphyrin, resulting in the formation of the iminium salt, which is the so-called “phosphorus complex”. Subsequent treatment of the phosphorus complex with water leads to the hydrolysis of the iminium salt, resulting in the formation of formylporphyrin (Scheme 6).

2.2. Reactions of Meso-Formylporphyrins with Nitrogen Nucleophiles

Ponomarev investigated the Vilsmeier–Haack formylation of a number of Cu(II), Ni(II), and Pd(II) complexes of β-octaalkylporphyrins and chlorins and the subsequent transformations of the meso-formyl derivatives [5,32]. As an electrophile, the formyl group can react with a variety of nucleophiles, including organometallic reagents, CH-acids, heteroatom nucleophiles (amines, thiols), electron-rich aromatic cycles, and heterocycles. The reaction of formylporphyrins with amines leads to azomethines or Schiff bases, and the corresponding studies up to the mid-1990s were summarized in the review of Ponomarev [20]. Meso-formyl porphyrins react with amines to give the corresponding imines; hydroxylamines give oximes; and hydrazines produce hydrazones. The Vilsmeier–Haack formylation of β-octaalkylporphyrin 13 produces the stable phosphorus complex 14 due to the sterical hindrances retarding hydrolysis of the complex. Ponomarev isolated phosphorus complexes of various porphyrins and used them instead of formylporphyrins for the preparation of Schiff bases [20]. The iminium group of the phosphorus complex is more active to nucleophilic attack compared to the formyl group. Azomethine derivatives of nickel and palladium complexes of various porphyrinoids, including OEP, tetraalkyl esters of coproporphyrins I and II, mesoporphyrin IX, and mesochlorin e6, were obtained by direct interaction of “phosphorus complexes” with amines (Scheme 7) [33,34,35].

Azomethine substitution at the meso position noticeably shifts the UV-Vis absorption spectra of porphyrins to long wavelengths, thus making their metal complexes potential photosensitizers [34]. Schiff bases also impart basic properties to the porphyrins, and the corresponding Pt(II) and Pd(II) complexes of azomethine derivatives of OEP and tetramethyl coproporphyrin I were investigated as sensor dyes for measuring proton and oxygen concentrations using an optical noninvasive method [36,37]. The corresponding phosphorescent probe, based on the Pt(II) complex of meso-(N-methylimino)-OEP for cellular diagnostics using dual oxygen and pH measurements in living cells, has been reported [38].

The imino group, which can be obtained by interacting the formyl group with an amine, was used as a linker to bond two tetrapyrrole chromophores into a dyad. The interaction of Zn(II) complexes of meso-formyltriphenylporphyrin 6Zn and meso-aminotriphenylporphyrin 17, catalyzed by Lewis acid ZnBr₂, led to the corresponding dimer of TrPP 18 (Scheme 8) [39]. The TrPP macrocycles are not coplanar in dimer 18 and consequently not conjugated. Nevertheless, there is some interchromophore communication, and dimer 18 features increased two-photon absorption, which can be used in PDT, providing deeper and more targeted treatment [40].

Schiff bases are useful synthons, as they can be subjected to further transformations. Elimination of meso-oximes led to meso-cyanoporphyrins [41]. Intramolecular cyclization was observed when meso-oxime 19Zn was vigorously stirred for a few hours in methylene chloride with a small amount of water. The probable intermediate chlorin with the fused 1,2-oxazin ring underwent hydroxylation via a peroxide mechanism to form stable hydroxychlorin 20Zn. The use of an oxidant, lead tetraacetate, gave the product the same fused 1,2-oxazin but with a vinyl group instead of ethyl and hydroxyl (Scheme 9) [42,43]. Apparently, the difference between products 20 and 21 is in the water molecule, which was probably eliminated in the case of 21. The UV-Vis spectra of the 1,2-oxazin annulated porphyrinoids 20 and 21 possess strong absorption bands in the red region.

Treatment of the Ni(II) complex of meso-(N-methylimino)-OEP 15Ni with t-BuOK led to the formation of the corresponding meso-nitrile 22, meso-amide 23, and meso-hydroxy 24 derivatives (Scheme 10). The latter was demetalated with sulfuric acid, resulting in phlorin 25 with strong light absorption in the region of 700 nm [35].

Thermolysis of meso-alkylimines of β-substituted metal porphyrins led to the formation of cyclopentane-fused derivatives (Scheme 11) [44,45,46]. The meso-imines of the tetraalkyl ester of coproporphyrin I (26 and 27) were transformed into a mixture of cyclopentane and cyclopentane-lactam bicycle fused derivatives (28–30) [35].

Meso-hydrazones of nickel and palladium complexes of OEP and coproporphyrin I ethyl esters were obtained as a mixture of E- and Z-isomers by the reaction of the corresponding meso-formyl derivatives with hydrazines catalyzed by trifluoroacetic acid (Scheme 12) [47].

N-tosylhydrazones 31 and 33 reacted with bases, generating an in situ porphyrin derivative of diazomethane, which released nitrogen molecules to give meso-carbene derivatives of porphyrins. Subsequent intramolecular insertion of the carbene into the CH bond of the neighboring β-substituent led to the corresponding fused cyclopentane (32 and 34) [48]. The cyclopentane fused products obtained were the same as in the thermolysis of azomethine 26; however, the second product in the carbene-based reaction of 33 was cyclohexane fused product 35 instead of bicyclic lactam 29 obtained in the thermolysis of azomethine 26 [35], and yields of the products in the carbene-based cyclization were appreciably higher compared to the thermolysis (Scheme 13).

Unsubstituted meso-hydrazones of OEP 36 and also β-octaethylchlorin (OEC) were used in the preparation of dyads 37 and 38 bridged with the azine group [49]. Derivatives of the natural chlorins, methyl pyropheophorbide-a (PPPa) and methyl pyropheophorbide-d (PPPd), reacted with the meso-hydrazones of OEP and OEC, leading to the formation of the corresponding porphyrin-chlorin and chlorin-chlorin dyads (Scheme 14) [49]. Upon irradiation of the dyads, the energy of the excited state was efficiently transferred from the OEP (OEC) components to the pyropheophorbide chromophore. However, the chromophores weakly interacted in the ground state; therefore, the azine group was regarded as a conjugation switch, usually in the off state but capable of being turned on with a sufficiently strong driving force.

One-pot meso-formylation, hydrazone, and azine formation were performed for meso-(trifluoroacetamido)-OEP 39 [50]. Under the conditions of formylation, the amide group was unexpectedly partially oxidized to form hydroxamic acid 42 (Scheme 15). The combined influence of trifluoroacetamide and arylazine groups in the products 41–43 led to strongly increased absorption near 500 nm and considerably red-shifted Q-bands up to 650 nm. Azine-bridged porphyrin-chlorin dyad 44 was obtained from meso-(trifluoroacetamido)-OEP 40a and PPPd (Scheme 15). The dyad features substantial growth in the Q-band intensity as well as a red-shifting Soret band compared to the similar dyad without the trifluoroacetamido substituent.

The meso-formyl group of porphyrins can be transformed to azomethine ylide by interaction with N-methylglycine. 1,3-dipolar cycloaddition of the intermediate azomethine ylide to the double bond leads to porphyrins with meso-fused heterocycles. The porphyrin—fullerene conjugate 46 was obtained this way from meso-formyltriarylporphyrin 45, N-methylglycine, and C₆₀ fullerene (Scheme 16) [18]. The irradiation of the dyad led to the formation of the exciplex due to the strong interaction between the porphyrin and C₆₀ chromophores at short distances.

Porphyrins functionalized with meso-fused 2-imidazolyl heterocycles were synthesized from the 5-formyl-10,20-diarylporphyrins and phenanthrene- or phenanthroline-5,6-dione in the presence of ammonium acetate (Scheme 17) [51]. The ruthenium phenanthroline complex of the free base porphyrin-imidazo[4,5-f]phenanthroline conjugate showed good binding ability to DNA and was capable of DNA photocleavage, which allows us to regard the complex as a potential photosensitizer for PDT [52].

2.3. Reactions of Meso-Formylporphyrins with Miscellaneous Nucleophiles

A family of push-pull quinoidal porphyrins was obtained from a meso-formyl porphyrin 48 through the attachment of 1,3-dithiolane (benzo-1,3-dithiolane) and malononitrile fragments at the opposite meso positions of the 5,15-diarylporphyrin (Scheme 18) [53].

Directly linked porphyrin-corrole dyads 52a–c were formed during condensation of the meso-formyltriarylporphyrin 51 with dipyrromethane (Scheme 19) [54]. A similar corrole-porphyrin-corrole triad was obtained when the 5,15-bisformylporphyrin was placed into the reaction. The strong exciton coupling between closely placed chromophores and reversible energy transfer were shown to exist in the dyad [55]. Directly meso-meso-linked porphyrin dimers and oligomers were obtained using condensation of meso-formylated porphyrins with pyrrole [21]. Such porphyrin dimers and oligomers were shown to act as prospective photosensitizers [56].

2.4. Reactions of Meso-Formylporphyrins with Organometallic Reagents

Among organometallic reagents, Grignard reagents were usually employed in the reactions for meso-formylporphyrins. Alkyllithium reagents gave the expected products of addition to the carbonyl group only with less hindered β-formyl derivatives [15]. Grignard reagents interact with meso-formylporphyrins, leading to the formation of the corresponding secondary alcohols, but due to steric factors and perhaps other causes, this reaction proceeds somewhat slowly. Especially retarding is the presence of β-alkyl substituents. For example, Ponomarev reported the formation of the Mg complex of the formylporphyrin without significant formation of the target meso-(1-hydroxyethyl)-OEP upon treatment of meso-formyl-OEP (OEP-CHO) with MeMgI under heating [57]. Smith carried out a similar reaction with a free base of OEP-CHO and a Zn(II) complex of OEP-CHO (ZnOEP-CHO), which resulted in 15-alkylated products, and the formyl group remained intact (Scheme 20) [58]. However, when Johnson and Arnold used the Ni(II) complex of OEP-CHO in the same reaction, Ni(II) 5-(1-hydroxyethyl)-OEP was obtained, as expected [16]. Water was easily eliminated, yielding Ni(II) 5-vinyl-OEP 54 (Scheme 21). The Wittig reaction is cleaner and more efficient, as well as tolerating various functional groups such as esters. Various Wittig regents interacted with the meso-formyl group of β-substituted porphyrins to form meso-vinyl 54 (Scheme 21), 2-(ethoxycarbonyl)ethenyl 59, 2-cyanoethenyl 56 (Scheme 22), and other alkenyl groups [5,14]. meso-formylporphyrins with meso-aryl groups without β-substituents were transformed to the corresponding meso-vinylporphyrins [59]. The products of the Wittig alkenylation can further be cyclized; for example, the methyl ester of coproporphyrin I was converted to the corresponding derivative of copropurpurin I 60 (Scheme 22). Purpurins and benzochlorins have an additional annealed cycle through meso positions and β-positions, which affect the π-electron system, leading to a bathochromic shift of the absorption bands. These annelated porphyrins and chlorins are more stable compared to other chlorins and have comparable electron-optical properties suitable for PDT. They have a higher efficiency than meso tetraphenylporphyrin and higher absorption in the longer wavelength region. The benzochlorins were shown to be of low dark toxicity towards Chinese Hamster ovary cells, whereas in the presence of light, total cell killing was observed at concentrations of the photosensitizer below 1 μg/mL [60]. These promising properties of the annelated porphyrin derivatives attract the attention of medical researchers [61]. One of the representatives of this type of compound, tin etiopurpurin complex 64, was used as a photosensitizer for PDT in human clinical trials. The drug was obtained from nickel etioporphyrin, which was formylated and reacted with a Wittig reagent, yielding meso-acrylate derivative 62, which was cyclized in acid to give etiopurpurin 63. The latter was metalated with tin(IV) chloride to give the drug for PDT (Scheme 23) [62]. The selectivity for the cyclization proceeding exclusively towards the carbon carrying the ethyl group vs. the carbon carrying the methyl group.

There are several published papers devoted to the synthesis of benzochlorin derivatives based on octaethylporphyrin and hematoporphyrin IX, as well as the study of their properties as photosensitizers [63,64,65,66]. In particular, the preparation of variously substituted benzochlorins containing fluorinated or alkyl groups has been reported [64].

The formyl group can be transformed to the 2-haloethenyl group in one step using two different reactions. The Wittig reaction of NiOEP-CHO 53 with bromomethyltriphenylphorphonium bromide led to meso-(2-bromoethynyl)NiOEP 65 as a major (E)-isomer with a 55% yield [67]. However, the side metal-halogen exchange reaction led to the formation of lithiated methylene ylide and subsequently the formation of meso-vinyl byproduct 54, which was hard to separate. The use of potassium t-butoxide in THF avoided contamination and produced a 53% yield (Scheme 24) [68]. Alternatively, the Takai reaction with iodoform catalyzed by CrCl₂ led to the formation of meso-(2-iodoethynyl)porphyrin 66 (Scheme 25). The obtained 2-haloethenyl derivatives were used as substrates of the cross-coupling reactions and precursors for the preparation of meso-ethynylporphyrins.

Transformation of the formylporphyrins into dimers bonded with an ethene bridge can be performed using low-valent titanium, which is called the McMurry reaction [17]. Cu(II) and Ni(II) complexes of OEP-CHO were dimerized under the action of TiCl₃ and Zn/Cu to form the corresponding complexes of dimers linked with the ethylene bridge in the form of a mixture of cis and trans isomers (Scheme 26) [69].

The similar dimerization of the Ni(II) meso-formyltriarylporphyrin 45 Ni was observed as a side reaction of coupling with tetraphenylzirconacyclopentadiene in the presence of AlCl₃, along with products of cross-coupling: porphyrin—cyclopentene 69, 70, and cyclopentadiene 68 hybrids (Scheme 27) [70].

2.5. The Reaction of Meso-Formylporphyrins with CH Acids

The Knoevenagel reaction allows for the transformation of formylporphyrins into the corresponding acrylic acid derivatives. The CH acid nucleophiles were introduced into the reaction with meso-formylporphyrins, leading to the formation of substituted meso-ethenyl porphyrin derivatives. Meso-formyl-diarylporphyrin 71 reacted with nitromethane, dimethylmalonate, and malononitrile in a mixture of piperidine, acetic acid, and toluene, leading to the corresponding substituted meso-(2-nitroethylene) 72 and meso-methylenemalonate 73 derivatives (Scheme 28) [71]. The meso-cyanoacrylate derivative 74 of Zn(II) meso-formyl-triarylporphyrin was obtained by heating in a mixture of piperidine and methanol for 16 h [72]. The product 75 of the reaction of meso-formyldiarylporphyrin with malononitrile containing a meso-dicyanovinyl group was shown to act as a fluorescence ‘‘turn-on’’ cyanide probe [73]. The meso-nitroethylene derivative 72 was utilized as fluorescence turn-on probes for biothiols as it exhibited fast fluorescence enhancement and high selectivity towards thiols based on the Michael addition mechanism [71]. It was also successfully applied to fluorescent cell imaging in the NIR wavelength range.

NiOEP-CHO 53 was much less reactive in the Knoevenagel reaction compared to β-unsubstituted porphyrins due to the sterical hindrances and was gradually degraded under basic reaction conditions. In order to activate the formyl group against the attack of CH acid nucleophiles, Lewis acid TiCl₄ was used in pyridine. The Lewis acid promoted the Knoevenagel reaction of the NiOEP-CHO 53 with malonic ester and heterocyclic CH acids [19]. The heterocyclic derivatives of porphyrins 77–79 linked with an exocyclic C=C double bond were obtained both by cyclization of the Knoevenagel product 76 from the reaction with malonic ester (Scheme 29) and by the Knoevenagel condensation of formylporphyrin with thiohydantoin and thiobarbituric acid (Scheme 30) [74].

The UV-Vis spectra of the heterocyclic conjugates contain new bands that arose from the interaction of the conjugated chromophores as well as bathochromically shifted original absorption bands. Particularly dramatic changes were observed in the UV-Vis spectrum of the porphyrin conjugate with thiobarbituric acid, which exhibited substantial absorption enhancement in the visible spectral range due to the considerable π-electron conjugation between tetrapyrrole and heterocyclic chromophores.

To sum up, meso-functionalization of porphyrins with the formyl group provides a powerful tool for the development of diverse porphyrin derivatives possessing valuable properties. In particular, promising photosensitizers with strong, red-shifted absorption bands, including NIR bands, were obtained from the meso-formyl porphyrins via the formation of annulated cycles such as benzochlorins and dibenzobacteriochlorins. Meso-imino derivatives were applied as sensor dyes in the multi-modal, multi-analyte optochemical sensing platform for cell diagnostics. Easily formed with the help of the formyl group, porphyrin conjugates with heterocycles can be used as biologically active compounds and in sensing applications. Imino- and azino-bridges represent two alternatives for bonding porphyrins into dyads, utilizing various pathways for energy transfer between the chromophores. Currently, the post-derivatization of the meso-formylporphyrins is under intense development.

3. Meso-Vinylporphyrins

Vinyl-substituted porphyrins are direct derivatives of formyl porphyrins, usually being obtained from the latter via the Wittig reaction. The vinyl group is a versatile nucleophilic synthon complementing electrophilic formyl. The electrophilic addition/substitution reactions and the modern catalytic cross-coupling and direct CH-functionalization methods are inherent to the vinyl group. The vinyl substituent can further be converted to the ethynyl group.

3.1. Preparation of Meso-Vinylporphyrins

Meso-vinyl substituted porphyrins can be obtained from the meso-formylporphyrins using the Grignard and Wittig reactions as described in a previous section [14,16]. However, the efficient Vilsmeier–Haack porphyrin formylation reaction is limited to certain metal complexes and cannot be used for free bases or more labile zinc complexes. The alternative formyl preparation methods are based on palladium-catalyzed cross-coupling reactions, which are tolerant to other functional groups but require primary halogenation of the porphyrin core. Heck and Stille reactions with meso-bromoporphyrins led to the corresponding meso-alkenylporphyrins [59]. Starting meso-bromo derivatives can easily be obtained by bromination of meso-di(tri)arylporphyrins with NBS [75,76]. Meso-vinylporphyrins were synthesized from meso-bromoporphyrins by the Pd-catalyzed Stille reaction with vinyltributyltin (Scheme 31) [59,75,77].

3.2. Transformations of Meso-Vinylporphyrins

The carbon-carbon double bond of the vinyl group is susceptible to electrophilic addition. However, bromination of the meso-vinyl-NiOEP 54 with pyridinium tribromide led to the product of electrophilic substitution: the 2-bromoethenyl derivative 65 as a mixture of (E) and (Z) isomers (Scheme 32) [16]. Bromination of meso-vinyl-TrPP proceeded similarly [78]. Possibly, the sterical hindrances at the meso position hamper the second bromine atom addition. The bromination product meso-(2-bromoethenyl)porphyrin 65 can serve as a substrate in palladium-catalyzed cross-coupling reactions and as a precursor of meso-ethynylporphyrin. Cross-coupling of iodo derivatives proceeds easily, and this was the reason for the exchange of bromine for iodine via palladation/iodination (Scheme 33). The subsequent Suzuki coupling of the meso-(2-iodoethenyl)-TrPP 82 with meso-pinacolboronyl-TrPP 83 led to the TrPP dimer 84 being bridged by an ethene linker (Scheme 34) [78]. The dimer 84 exists in solution in a number of conformations differing in dihedral angles between the porphyrin and alkene planes. More coplanar conformers have appreciable π-electron conjugation and interchromophore interaction across the bridge.

The meso-vinyl group participated in electrophilic substitution reactions not only during bromination but also during formylation in Vilsmeier–Haack conditions. Meso-vinyl-NiOEP 54 was transformed to the corresponding meso-acroleinic derivative 85 by treatment with the Vilsmeier reagent DMF/POCl₃ in 1,2-dichloroethane (Scheme 35) [79]. This compound can also be obtained using a short method by vinylogous formylation of NiOEP 13Ni with N,N-dimethylaminoacroleine/POCl₃ [69]. The treatment of the meso-acroleine derivative 85 with concentrated sulfuric acid led to cyclization involving ethyl migration to give benzochlorin 86 (Scheme 36) [69,79].

The octaethylbenzochlorin possesses significant red-light absorption, which makes it a potential photosensitizer for PDT [8,9,80,81]. Some benzochlorin derivatives can cause significant tumor regression at doses as low as 0.5 mg/kg body weight [82]. The product of the double cyclization of meso-bis-acroleinyl-OEP 87 is dibenzobacteriochlorin 89 [69], which possesses a strong absorption band in the region of 752 nm, thus fully corresponding to the tissue transparency window (Scheme 37) [8,82]. The conjugates of similar benzochlorin with carbohydrates were screened using the galectin-binding-ability assay and exhibited an enhancement of about 300–400-fold compared to lactose. All conjugates were also shown to possess good photosensitizing efficacy with fibrosarcoma tumor cells [65].

Arnold studied the functionalization of porphyrins using the Heck reaction [59]. The Heck coupling of 5-vinyl-10,15,20-triphenylporphyrinatonickel(II) 80Ni with 50 eq. iodobenzene was performed using a 20 mol% Pd(OAc)₂ catalyst with triphenylphosphine ligand K₂CO₃ as a base in a mixture of DMF and toluene heated to 105 °C for 48 h. As a result of the reaction, two major regioisomers were formed: trans-1,2-disubstituted ethene 90 with a 54% yield and 1,1-substituted product 91 with a 20% yield. It should be noted that 1,1-substitution with a very bulky porphyrin substituent is not usual in the Heck reaction. However, an even more curious result was obtained in the reaction with 5-vinyl-10,20-diphenylporphyrinatonickel(II) 92Ni, where additionally the β-substituted E-(2-phenylethenyl)porphyrin 94b was formed (Scheme 38).

2-subsituted ethenyl porphyrins were alternatively obtained using the Heck coupling of the meso-bromoporphyrins 95 and 97 with substituted ethene (usually with an electron acceptor group) [59]. The Heck coupling of 5-bromo-TrPP 95 and 5,15-dibromo-10,20-diarylporphyrin 97, as well as their Ni(II) and Zn(II) complexes with large excesses of methyl acrylate, styrene, and acrylonitrile, led to the corresponding mono- and dialkenyl functionalized porphyrins (Scheme 39). E-isomers were obtained predominantly, but some amount of Z-isomer was also formed in the case of less sterically demanded acrylonitrile. Partial debromination was observed during the reaction. The free-base porphyrins were partially metalated with palladium. Zinc complexes were less stable compared to nickel complexes and were slightly demetalated and transmetalated.

The Heck reaction was used to produce a porphyrin dimer bound by ethene. However, a large excess of one substrate over the other cannot be used in coupling two porphyrin substrates, as was used in reactions with small molecules, because both coupling compounds are very precious. Consequently, the reaction was too slow, side reactions rose, and debromination of the bromoporphyrins occurred predominantly. The coupling of meso-bromo-TrPP 95 with meso-vinyldiarylporphyrinatonickel 92Ni did not give the target meso-ethenyl-linked dimer but rather meso, β-ethenyl-linked dyad 102 (Scheme 40). Free-base bromoporphyrin, Ni(II), and Zn(II) complexes gave the corresponding dyad yields of 23, 33, and 15%, respectively. The electronic absorption spectra of the dyads revealed a modest degree of interchromophore interaction via a partially conjugated bridge. This was explained by two factors: twisting of the ethene bridge at meso position with respect to the tetrapyrrole plane reduces π–π conjugation, and linkage through the β-carbon has smaller orbital coefficients and consequently less influence on the π–electron system. The meso-meso-linked meso-arylporphyrin dimers were obtained by several other transition metal-mediated methods: the Suzuki reaction of the meso-(2-iodoethenyl)porphyrin with meso-pinacolboronylporphyrin, described above [78]; the Stille coupling of 1,2-di(tributyltin)ethene with meso-bromoporphyrin [83]; meso-iodoporphyrin [39]; and the McMurry coupling of meso-formylporphyrin, described above in the formyl section [84].

The meso-vinyl group can also be functionalized via catalytic direct CH-functionalization reactions. The direct C-H borylation of the meso-vinyl group in NiOEP 54 was performed with Cu(II) complex as a catalyst, yielding the meso-(2-pinacolboronylethenyl)porphyrin 103Ni, which was shown to act as a nucleophilic partner in the Suzuki cross-coupling leading to porphyrin derivatives 104 and 105 with an extended π-conjugation through the carbon double bond [85]. The oxidative homocoupling of the borylporphyrin 103Pd produced the dimer 106 (Scheme 41) [86]. Thus, this strategy of meso-vinyl transformations allows for the attachment of various chromophores through the unsaturated bridges. The products of couplings possess some degree of conjugation across the bridge and interchromophore interaction, which induces a bathochromic shift of absorption bands.

The meso-vinyl group in porphyrins differs in properties from β-vinyl and other vinyl-substituted aromatics. The sterical hindrances at the meso position decrease the reactivity of the vinyl group and change the results of reactions. For example, interaction with electrophiles led to electrophilic substitution instead of addition, like in aromatics. The Heck reactions proceeded harder. Probably, this was one of the reasons for quite a small amount of work devoted to the transformations of meso-vinyl groups, especially compared to the β-analogs. The rich potential of the meso-vinyl function is to be revealed.

4. Meso-Ethynylporphyrins

Due to the absence of the sterically interacting extra substituents at the linking carbon, the meso-acetylenyl group is coplanar with the macrocycle ring and fully π-electronically conjugated to the tetrapyrrole aromatic system in contrast to other meso-attached unsaturated groups like vinyl, phenyl, etc. [87,88,89,90,91]. The acetylene linker has been shown to allow efficient π-conjugation and strong electronic communication between chromophores [92,93,94]. This advantage of the triple bond linker is used when one needs to create extended conjugated systems.

Synthesis of Meso-Ethynylporphyrins

There are several ways to obtain meso-acetylenylporphyrins, including classical functional group transformations and modern catalytic cross-coupling reactions. The oldest route utilized alkynyl-substituted precursors in the assembly of the porphyrin core. MacDonald [2 + 2] condensation of dipyrromethane with trimethylsilylpropynal led to the 5,15-bis(trimethylsilylethynyl)porphyrin 107 in 11% yield, which was deprotected and converted to the Ni(II) 5,15-bisacetylenylporphine 108 (Scheme 42A) [95]. In some cases, the product of the reduction of one triple bond can occur. 5-alkenyl-15-alkynyl-porphyrin 108 and 5,15-dialkynyl-porphyrin 109 were formed selectively depending on the choice of solvent (Scheme 42B) [96]. The alkenyl group arises from a protonation followed by intramolecular 1,2-hydride transfer from the methine position of porphyrinogen [96].

The classical way to obtain alkyne is through the elimination of hydrogen halide from halo-vinyl. The first meso-(2-bromoethenyl)-NiOEP 65 was obtained using the Wittig reaction of NiOEP-CHO 53 with bromomethyltriphenylphosphonium bromide. Then the Wittig product 65 was treated with dimsyl sodium, yielding meso-acetylenyl-NiOEP 110Ni with an 86% yield (Scheme 43) [95,97].

The most common way to insert an acetylenyl group into porphyrins is based on the Sonogashira reaction [97]. However, the Sonogashira reaction can be accompanied by some side reactions. The most common complication is the oxidative dimerization of the terminal alkynes [98]. Trialkylsilyl-protected acetylenes are often used, like trimethylsilyl- and triisopropylsilylacetylene, instead of gaseous acetylene, so the products are not able to dimerize. Meso-acetylenylporphyrin 112 was prepared in 82% yield by the Sonogashira coupling of meso-bromo-porphyrin 111 with a 2.5 eq. excess of triisopropylsilylacetylene catalyzed by 20 mol% Pd(PPh₃)₂Cl₂ and 3 eq. CuI in THF with triethylamine (Scheme 44) [99].

When the less bulky trimethylsilyl protection group instead of triisopropylsilyl was used in the Sonogashira reaction of 5-iodo-10,15,20-tris(3,5-di(tert-butyl))porphyrin 113 with an excess of trimethylsilylacetylene, the byproduct of the addition of the second acetylene molecule 114b to the triple bond was obtained (Scheme 45) [100].

The most popular transformation of the meso-acetylenylporphyrins is also the Sonogashira coupling, leading to the triple bond linked dyad of the porphyrin with another fragment. Linking electron donors or acceptors to the porphyrin ring through the C≡C triple bond significantly affects the tetrapyrrole aromatic system. For example, to attach the salicylic acid anchor to the DPP 3, the latter was first brominated at the meso position followed by zinc metalation and catalytic coupling with triisopropylsilylacetylene. Metalated porphyrins are usually applied as substrates in transition metal-catalyzed reactions instead of free bases to prevent scavenging of the catalytic metal by coordination with the macrocycle. Silyl protection is removed with TBAF, and the meso-acetylenyl porphyrin was next coupled with an iodo derivative of the salicylic acid, yielding the product 115, with the anchoring group being conjugated to the porphyrin through the triple bond (Scheme 46) [99].

Strong electronic communication was observed between the triarylamine donors and porphyrin ring in the compound obtained by the Sonogashira reaction of meso-diacetylenylporphyrin with iodophenyldiarylamines (Scheme 47) [101]. The UV-Vis absorption spectra are considerably bathochromically shifted relative to the starting meso-arylporphyrin and exhibit a broad Soret band and an intense Q band.

With the help of Sonogashira coupling, a new photochromic porphyrin-perinaphthothioindigo dyad 117 was prepared (Scheme 48). One of the iodine atoms of the diiodo-perinaphthothioindigo reagent was reduced during the reaction, which led to the predominantly mono-substituted product. A small amount of the bisporphyrin-substituted triad was also obtained. Due to the extended conjugated system, the dyad 117 exhibited efficient two-photon absorption properties and clear photochromic switching between cis and trans isomers [102]. The two photon absorption cross-section maxima for both isomers appeared around 850 nm, with values of 2000 GM for trans and 700 GM for cis isomers.

The dyad 119 of PtOEP with di(p-acetylenylphenyl)anthracene was obtained using Sonogashira and Suzuki coupling of the components. The efficient triplet energy transfer with nearly quantitative quantum efficiency was shown to proceed upon excitation from the porphyrin unit to the anthracene unit (Scheme 49) [103].

Especially dramatic influence is exerted by so-called push-pull, both donor and acceptor substituted porphyrins. Electron donor N,N-dimethylaniline and electron acceptor nitrobisthiophene-substituted acetylenes were attached to the opposite positions of the porphyrin via Sonogashira coupling (Scheme 50). Such dipolar functionalized porphyrins possess considerable molecular hyperpolarizability and can be used for electro-optic applications [104,105].

Push-pull porphyrins have become the most efficient tetrapyrrole photosensitizers for dye-sensitized solar cells (DSSC). The dye with the donor diarylamino group and acceptor carboxyphenyl group, linked at the opposite meso positions with an ethyne bridge, outperformed all other porphyrins [106,107]. The synthetic strategy is similar to the examples given above. The Sonogashira coupling of meso-bromoporphyrin with trimethylsylylacetylene was carried out first, then the free meso position was brominated, followed by Buchwald amination with diarylamine, and after removing the trimethylsilyl protecting group, the second Sonogashira coupling with iodobenzoic acid was performed (Scheme 51).

A large range of 5,15-bisalkynyl substituted porphyrin derivatives were obtained by Sonogashira coupling meso-dibromo-di(carboxyphenyl)porphyrins, which were shown to be suitable for the synthesis of surface-anchored MOF thin films [108].

The conjugated dimer and trimer with di- and triethynylbenzene bridges were obtained by the Sonogashira coupling of meso-ethynylporphyrin with di- and triiodobenzene. Whereas nonconjugated oligomers were obtained with tetrakis(4-iodophenyl)methane and tetrakis(4-iodophenyl)porphyrin (Scheme 52) [109]. Different types of oligomers with diphenylacetylene bridges were obtained as a result of the Sonogashira coupling of meso-(4-ethynylphenyl)porphyrin with meso-(4-iodophenyl)porphyrin [110] and meso-bis(4-iodophenyl)porphyrin [111]. It is worth noting that the directly attached aryl group at meso position is not conjugated with the macrocycle because it turned almost perpendicular owing to the sterical interactions, and the dimers linked through the meso-phenyl [112], including the meso-diphenylacetylene bridge [111], are not conjugated [113].

The fully conjugated porphyrin dimer 131, directly linked by acetylene at meso position was obtained using Stille-type coupling of bis-1,2-stannylacetylene with 5-halo-TrPP with a 43% yield (Scheme 53) [39]. The electron absorption spectrum of the dimer 131 showed considerable changes compared to the monomer, which can be attributed to the extensive conjugation and strong interchromophore communication.

The DPP dimers and trimers bridged by ethyne linkers were obtained by the Sonogashira coupling of meso-ethynylporphyrin 132 and 134 with meso-bromo-porphyrin 111 (Scheme 54) [92]. The dimers with diethynylarene bridges 137–140 were obtained by the Sonogashira coupling of partially protected meso-diethynylporphyrin 136 with diiodoarenes (Scheme 55) [114]. The thiophene linker provided more conjugation than phenylene but less than anthracene, which allowed even more electronic communication than the simple butadiyne. All meso-arylporphyrin dimers with triple bond linkers possess high cross-sections of two-photon absorption, which makes them the most promising candidates for photosensitizers in two-photon-induced PDT. Efficient singlet oxygen generation was demonstrated both in one- and two-photon excitation of these dimers [115].

Further transformations of the acetylenylporphyrins include oxidative coupling, 1,3-dipolar cycloaddition, and nucleophilic addition. Glaser oxidative coupling of meso-acetylenylporphyrins was used to obtain porphyrin dimers as well as conjugates with other acetylenyl substituted compounds, but the yields of the oxidative cross-coupling are generally low due to the homocouplings. For example, 5,15-bisacetylenylporphine 141 was coupled with an excess of meso-acetylenyl-OEP, leading to the porphyrin triad 142 linked by butadiyne bridges with a 25% yield, along with a larger amount of the OEP dimer 143 formed by homocoupling (Scheme 56) [95]. The conjugation in the triad led to the splitting of the Soret band of OEP into two main bands with clear maxima at 429 and 481 nm and a bathochromic shift of the Q band to 670 nm. Furthermore, a dramatic bathochromic shift of the Q-band by 70 nm was observed in pyridine compared to that in chloroform, probably due to the coordination of the pyridine molecule as an axial ligand onto the Ni cation, though Ni porphyrinates do not usually coordinate extra ligands.

The butadiyne-linked meso-diarylporphyrin dimer 148 functionalized with hydrophilic groups was obtained using a sequence of Sonogashira and Glaser-type oxidative coupling reactions. First, meso-di(trihexylsilylacetylenyl)-diarylporphyrin was obtained from easily accessible meso-dibromodiarylporphyrin 144 and trihexylsilylacetylene using the classical Sonogashira reaction. The partial deprotection of the triple bond with TBAF proceeded with a low 29% yield. The half-protected bisacetylenylporphyrin 145 was dimerized using oxidative coupling in modified conditions catalyzed by Pd(PPh₃)₄, CuI, and 1,4-benzoquinone as an oxidant. These conditions provided a high 94% yield of dimer 146 bridged by butadiyne linkers. The presence of two meso-trihexylsilylacetylenyl groups in the dimer allowed for further functionalization using Sonogashira coupling with iodo-substituted hydrophilic fragments (Scheme 57) [116]. The obtained dyes possess red-shifted absorption bands in a region of 700–800 nm and a high two-photon absorption cross-section. These properties are important for application in PDT, and the porphyrin dimer dyes were studied as photosensitizers and were found to be more effective than the commercial drug Visudyne^® in two-photon PDT [40].

A series of bisporphyrins linked by bithiophene and butadiyne groups were obtained using oxidative cross-coupling of meso-acetylenyl-OEP with bisacetylenylbithiophene and oligomeric bithiophenes [97]. The coupling was carried out in the presence of copper(II) acetate in a mixture of pyridine and methanol. Yields of cross-coupled products were 15–20%, together with 20–30% yields of the diacetylene-bridged OEP dimer (Scheme 58). The position of the hexyl substituents in bisthiophene determines the relative orientation of thiophene rings, which plays an important role in electronic communications between the two terminal OEP rings.

A series of meso-diarylporphyrin dimers linked by oligoacetylenes were obtained using Glaser coupling of meso-(oligoethynyl)porphyrins [94]. The similar coupling of the 5,10-diethynyl-15,20-diarylporphyrin 153 led to the formation of the square-shaped porphyrin tetramer 154 (Scheme 59) [117]. The positions of both the Soret (503) and Q (659 nm) bands were bathochromically shifted by about 2900 cm⁻¹ relative to the monomer but remained similar to those of the corresponding linear tetramer [118].

A square cyclic porphyrin dodecamer 158 with ethynyl linkers was obtained via the tetramerization of a T-shaped trimer 157 using Glaser oxidation coupling [119]. The synthesis of the trimer was based on the Sonogashira reaction of 5,10-diethynyl-15,20-porphyrin 156 with 5-iodo-15-bromo-10,20-diarylporphyrin 157 (Scheme 60). The molecule was easily visualized using STM. The round-shaped octamer with butadiyne linkers 161 was synthesized via oxidative coupling of the 5,15-diethynyl-10,20-diarylporphyrin 159 using a template with palladium/copper catalysts and iodine as an oxidant to give the cyclooctamer 161 with a 14% yield (Scheme 61) [120]. A similar cyclohexamer was obtained with a smaller template by oxidizing trimerization of the corresponding dimer [121]. Absorption and emission spectra showed that π-conjugation and interchromophore communication in the nanoring are stronger than in its linear analog and angled square-shaped macrocycles. The giant porphyrin cyclooligomers can be applied as artificial light-harvesting antennas. The similarity between these nanorings and the natural chlorophyll-based LH2 light-harvesting system [122] allows us to model the photosynthetic center with these artificial molecules [123]. Middle-sized, angled cycles like square porphyrin tetramer and dodecamer are host compounds that can coordinate suitable guest molecules, including fullerenes.

Most of the porphyrin dimers, trimers, and oligomers, linked by carbon-carbon triple bonds, were synthesized using either Glaser type oxidative coupling or Sonogashira coupling reactions. The considerable bathochromic shifts of the absorption and emission bands were observed for all multiporphyrin compounds compared to the precursor monomers. The Qy absorption bands of the porphyrin dimers are even longer in wavelength than those of the chlorin monomers, reaching up to 720 nm, making them promising photosensitizers for PDT and other optical applications such as optical sensors, NLO materials, etc. [124,125].

A copper-catalyzed 1,3-dipolar cycloaddition of azides to alkynes, called the “click” reaction, was used to create meso-1,2,3-triazole substituted porphyrin (Scheme 62A). The porphyrin self-assembles to form a slipped cofacial dimer 164 by the coordination of the triazole nitrogen atom to the zinc center of a second porphyrin moiety (Scheme 62B) [126].

The triazole group was also applied as a linker between porphyrin rings. Odobel obtained directly meso-meso triazole bridged dyads by the click reaction of Ni(II) and Zn(II) complexes of meso-ethynyltriarylporphyrin 166 with Ni(II) meso-azidotriarylporphyrin 165 (Scheme 63) [127]. Both Ni-Ni and Ni-Zn dyads were obtained, but the yield of the heterometallic dyad 167Zn was notably lower (18%) compared to the yield of the Ni-Ni dyad 167Ni (41%). The reaction proceeded for quite a long time (50 h) in DMF with copper sulfate as a catalyst and ascorbic acid. Asymmetrical β-meso-triazole-linked dyad 169 was synthesized from nickel complexes of 5-ethynyl-10,20-diphenylporphyrin 132Ni and β-azido-meso-tetraphenylporphyrin 168 [128]. The reaction was carried out in the same conditions but proceeded much faster, being completed for 1.5 h with a high 98% yield (Scheme 63). It should be noted that in the case of the opposite reagent couple, namely 5-azido-10,20-diphenylporphyrin and β-ethynyl-meso-tetraphenylporphyrin, no reaction occurred under similar conditions.

The nucleophilic addition of alkynyl porphyrins to carbonyl compounds was used to prepare a series of porphyrin-dimer tertiary alcohols. Treatment of these alcohols with acid gave conjugated carbocations with three to nine carbon atoms bridging between the porphyrins (Scheme 64). All these carbocations show strong absorption in the near-IR region between 1000 and 1800 nm [129].

5. Conclusions

Formyl, vinyl, and ethynyl are simple substituents that can easily be inserted into a tetrapyrrole macrocycle, providing suitable building blocks for the construction of porphyrin materials. The substitution at the meso position significantly affects the electron and optical properties of the porphyrins, and for this reason, it was the meso-derivatives that were considered. The reviewed works showed the rich potential of these synthons, opening the way to a variety of novel dyes with considerably modified properties that can be tuned by a choice of specific transformations of the starting building blocks. The products of such transformations are dyes for solar cells, light-harvesting antennas, photosensitizers for PDT, optical sensors, components for supramolecular ensembles, porous materials for storage and catalysis, etc. Particularly valuable are the biomedical applications of the tetrapyrrolic derivatives.