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A method for the preparation of an α-formylated pyrrole or dipyrromethane which contains an electron-withdrawing β-acetyl is described. Formylation proceeds directly from the corresponding acid pyrrole or dipyrromethane without the need of the usual two-step acid decarboxylation/formylation procedure. The acid is first transformed into its acid chloride with oxalyl chloride, followed by reduction to the aldehyde with the mild reducing agent sodium triacetoxyborohydride, in a one-pot reaction. The non-basic acylating reagent PR₃ is necessary both for acyl chloride formation and for the reduction to succeed.

Optimized syntheses of 5,15-diphenylporphyrin (DPP, 1) and its dipyrrolic precursors are described. A novel procedure for the synthesis of dipyrromethane (2), prepared by hydrodesulfurization of the corresponding di-2-pyrrolylthione (8), is presented, as well as an improved method to isolate large quantities of 5-phenyldipyrromethane (4), prepared by the acid-catalysed condensation of pyrrole with benzaldehyde. These dipyrromethanes are key reagents in two high-yield (2+2)-type syntheses of DPP. 5-Phenyldipyrromethane was formylated to provide 1-formyl- (11) and 1,9-diformyl-5-phenyldipyrromethane (12), and reduction of 11 provided the corresponding hydroxymethyl compound 13. These compounds (11-13), however, were much less efficient precursors to DPP. Two polypyrrolic compounds, 1,1,2,2-dipyrrolylethane (9) and 5,10-diphenyltripyrrane (10), potentially useful for the synthesis of porphyrinic macrocycles, were isolated as side-products during the dipyrromethane and 5-phenyldipyrromethane syntheses.

The successful use of dipyrromethanecarbinols in rational routes to porphyrinic macrocycles requires catalysis conditions that enable irreversible condensation, thereby avoiding substituent scrambling and formation of undesired porphyrin products. Previously, successful conditions of trifluoroacetic acid (TFA) (30 mM) in acetonitrile were identified following a lengthy survey of TFA and BF₃-etherate catalysis in diverse solvents. In this study, focus was placed on the acid catalyst by examining 17 acids in CH₂Cl₂, the traditional solvent for two-step, one-flask porphyrin syntheses. In the self-condensation of the carbinol derived from 1-(4-methylbenzoyl)-5-phenyldipyrromethane, porphyrin yields of 9–55% were obtained from the various acids, compared to 20% under TFA catalysis in acetonitrile. A number of catalytic conditions that produce little to no porphyrin in reactions of pyrrole + benzaldehyde afforded good yields of porphyrin and the suppression of scrambling in reactions of dipyrromethanecarbinols. The four best acid catalysts (InCl₃, Sc(OTf)₃, Yb(OTf)₃, and Dy(OTf)₃) initially identified were then examined with dipyrromethanecarbinols bearing challenging substituents (alkyl, pyridyl, or no substituent). The greatest improvement was obtained with the pyridyl substrates. Selected reactions performed on a preparative scale (115 to 460 mg of isolated porphyrin) verified the results of the analytical-scale experiments and revealed the more facile isolation of the porphyrin from reactions performed in CH₂Cl₂ rather than acetonitrile. This study provides alternatives to the use of TFA/acetonitrile that offer advantages in terms of yield and isolation of the porphyrin without sacrificing suppression of scrambling. Furthermore, the finding that poor catalysts for the benzaldehyde + pyrrole reaction can be excellent catalysts for dipyrromethanecarbinols provides guidance for the identification of other catalysts for use with reactive precursors in porphyrin-forming reactions.

The stability towards acidolysis of intermediates used in the preparation of core-modified porphyrinic macrocycles was examined. Experiments were performed using analogs of 5-phenyldipyrromethane in which one of the two pyrrole rings was modified (XPM). The XPMs utilized in these studies had X = 2-furyl (OPM), 2-thienyl (SPM), 2-selenyl (SePM), or 3-pyrrolyl (^NCPPM). The XPMs possess a potentially labile linkage to a heteroatom-modified ring as well as a potentially labile linkage to a pyrrole ring. The stability of the two types of linkages was examined under acid catalysis conditions commonly used in the preparation of porphyrinic macrocycles. The methodology employed enabled characterization of the stability of the XPM (GC analysis), the yield of porphyrin (UV-vis absorption), and the composition of porphyrinic species (laser-desorption mass spectrometry, LD-MS) formed upon acidolysis of the XPM. These experiments showed that (1) the linkage to the heteroatom-modified ring is fairly stable in the presence of a linkage to pyrrole, and (2) the linkage to pyrrole is much more stable in the XPMs than is the case in 5-phenyldipyrromethane. Additional experiments with analogs of 5-phenyldipyrromethane having both rings modified (X₂M), where X = 2-furyl (O₂M), 2-thienyl (S₂M), or 2-selenyl (Se₂M) confirmed that linkages to furyl, thienyl, and selenyl rings are stable towards acidolysis. Taken together, the observations concerning stability of various linkages provide a foundation for understanding the types and yields of core-modified porphyrinic macrocycles formed in reactions with reactants that are not direct precursors to the isolated products.

A new, unsymmetrically substituted 5,15-diarylporphyrin has been synthesized following a stepwise approach. The tetrapyrrolic precursor for the porphyrin is a 10-aryl substituted a,c-biladiene dihydrobromide. The preparation of the starting pyrrolic compounds has been optimized with respect to the previously reported methods.

Attachment of functional groups at the designated β-pyrrolic positions in asymmetrically substituted porphyrins is important in building customized model systems. We have developed a synthetic method of mono-functionalized dipyrromethanes at one of the β-pyrrolic positions. Synthesis of β-mono-brominated AB₂C and ABCD type porphyrins was achieved by “2+2” condensation therefrom.

Reported here is the synthesis and characterization of a new class of macrocycle that represents a hybrid between texaphyrin and calixpyrrole. These polypyrrolic macrocycles were prepared in one step by the acid-catalyzed condensation between diformyl dipyrromethanes and o-phenylenediamines in high yields. The X-ray crystal structure of one of these new “chimeras” was solved. It reveals that the diprotonated Schiff-base macrocycle has a V-shape in which one chloride anion is bound. Isothermal titration calorimetry (ITC) studies served to confirm the ability of the hybrid macrocycles to bind chloride anion in acetonitrile solution. These compounds may be useful as easy-to-make anion receptors.

Novel asymmetrically meso-substituted porphyrins bearing amino groups have been synthesized as precursors of cationic photodynamic agents. The amphiphilic character of these porphyrins was increased by the presence of a high lipophilic trifluoromethyl group. Different patterns of porphyrin structures were obtained from meso-4-[(3-N,N-dimethylaminopropoxy)phenyl] dipyrromethane 1, which was formed by the condensation of 4-(3-N,N-dimethylaminopropoxy) benzaldehyde with a large excess of pyrrole. This reaction takes place at high temperature with a yield of 59%. This reaction was also attempted under acid-catalyzed condensation at room temperature. However, under these conditions, the amino group reduces the catalyst and the reaction does not take place. To obtain porphyrins, dipyrromethane 1 was condensed with aldehydes in the presence of trifluoroacetic acid (TFA) under different conditions. First, 1 reacted with 4-(3-N,N-dimethylaminopropoxy)benzaldehyde in dichloromethane catalyzed by TFA (∼4 times TFA/1 molar ratio) to obtain 6.2% of 5,10,15,20-tetrakis(4-[3-N,N-dimethylaminopropoxy]phenyl)porphyrin (A₄-porphyrin). Under similar conditions, reaction of 1 with 4-(trifluoromethyl)benzaldehyde produces 5,15-di(4-[3-N,N-dimethylaminopropoxy]phenyl)-10,20-di(4-trifluoromethylphenyl)porphyrin (A₂B₂-porphyrin) with a 4.8% yield. This procedure also yields a mixture of porphyrins, which were formed due to acidolysis of 1. When a minor amount of TFA was used in acetonitrile, the yield of A₂B₂-porphyrin was very poor (∼0.4%). On the other hand, condensation of 1 with 4-trifluoromethylbenzaldehyde and 4-(3-N,N-dimethylaminopropoxy)benzaldehyde catalyzed by TFA (∼2 times TFA/1 molar ratio) in acetonitrile yields 9.3% of 5-(4-trifluoromethylphenyl)-10,15,20-tris(4-[3-N,N-dimethylaminopropoxy]phenyl)porphyrin (A₃B-porphyrin). A₂B₂ and A₄ porphyrins were also isolated with 6.0 and 2.0%, respectively. Finally, exhaustive methylation of amino porphyrins produces cationic sensitizers (>94% yield). Absorption and fluorescence spectroscopic studies of these sensitizers were compared in N,N-dimethylformamide. In these porphyrins, the cationic centers are isolated from the porphyrin ring by a propoxy bridge. Thus, the cationic charges have minimal influence on the photophysical properties of the sensitizers. In addition, this chain provides a higher mobility of the charge, which could facilitate interaction with the outer membrane of the Gram-negative bacteria. These amphiphilic cationic porphyrins are promising photosensitizers with potential applications in bacterial inactivation by photodynamic therapy.

5,15-substituted porphyrins are valuable compounds in bioorganic and materials chemistry. A new synthesis has been developed that employs 1,9-diformylation of a dipyrromethane, conversion of the diformyldipyrromethane to the bis(imino) derivative, and reaction of the bis(imino)dipyrromethane + a dipyrromethane to give the zinc-porphyrin bearing trans-AB-substituents. 1,9-diformylation was achieved via Vilsmeier reaction. Imination was achieved by treatment of the 1,9-diformyldipyrromethane with excess amine under neat conditions at room temperature. The porphyrin-forming reaction was carried out over 2 h in refluxing ethanol containing zinc acetate exposed to air. Oxidation of the intermediate porphyrinogen occurs aerobically. A complex composed of two bis(imino)dipyrromethanes and two zinc atoms was observed to form reversibly during the course of the reaction. A set of zinc-porphyrins with trans-AB-, A₂-, or A-substituents has been prepared in yields of ~30% (without detectable scrambling) with straightforward purification. The reaction is applicable to A/B substituent combinations of aryl/aryl, aryl/alkyl, and aryl/H.

Novel palladium(II) complexes with α,α'-bis(phenylimino)- and α,α'-bis(picolyl)-substituted meso-H-dipyrromethanes have been prepared. The complexes are able to react with dioxygen upon activation with potassium tert-butoxide. Reactions with dioxygen afford C-N or C-C self-bond cleavage producing α-pyrrole-carboxylate or α-hydroxypyrrole residues, respectively. According to DFT calculations the deprotonation of meso-hydrogen leads to the redistribution of electron density between ligand and metal, thus formally forming dipyrromethene-palladium(0) anionic complex. Possible reactive oxygen-containing intermediates have been suggested on the basis of calculations.

Porphyrins bearing a single bioconjugatable group and a single water-solubilization motif in a trans-AB-architecture (with no other substituents) provide a compact design of value for studies in diverse disciplines. Established synthetic methods have been employed to prepare four new free base porphyrins and one Mn(III) chelate. The hydrophilic motif includes 4-N-methylpyridinium, 2,4,6-tris(carboxymethoxy)phenyl, 2,6-bis(phosphonomethoxy)phenyl, and carboxy; the bioconjugatable unit includes carboxy, maleimido, and N-hydroxysuccinimido (NHS) ester. Bioconjugation experiments with a protected porphyrin-diphosphate or unprotected porphyrin-diphosphonate were examined in organic solution or water, respectively. Both approaches were employed to conjugate to the ε-amino group of Lys¹¹ in AcKPV-NH₂, a tripeptide fragment [Ac-α-MSH(11-13)-NH₂] of melanocyte stimulating hormone, yielding porphyrin-peptide conjugates.

meso-Aryl dipyrromethanes are important building blocks to create various practical molecules, and the electron-withdrawing effect of the meso-aryls can play an important role in improving/controlling their reactivities in further reactions: meso-Pentafluorophenyl and meso-(2,6-dichlorophenyl) substituted dipyrromethanes towards the associating dipyrrins and other derivatives have been investigated, in which coordination with different transition metals followed by the dissociation of the metal coordination by interruption of proton and halide ions have been verified. Furthermore, simple DDQ-oxidations of the dipyrromethanes have afforded DDQ-dipyrrin adducts which were delivered to distinctly advanced molecular rearrangements in the presence of acid and base. Vinylene bisdipyrrin compounds, obtained in the reactions of DDQ-dipyrrin adducts with a Lewis base triethylamine, have produced expanded porphyrinoid bis-nickel complexes during the metalation procedure with nickel acetate, while a cobalt metalation of the vinylene bisdipyrrin compounds resulted in an isolation of diamagnetic octahedral cobalt(III) complex. Moreover, meso-pentafluorophenyl and meso-(2,6-dichlorophenyl) dipyrromethanes have been useful platforms to accomplish size-controlled series of meso-aryl-substituted expanded porphyrins and easy separation/purification of selective meso-aryl expanded porphyrins, in which advanced metal complexes and various fascinating properties and reactivities admitting moderate functional molecules have arisen.

The synthesis of dipyrromethanes from pyrrole and arylglyoxylic acids in the presence of K₂S₂O₈at 90 ${}^{\circ }$C is reported affording dipyrromethanes in very good yields. Unlike an excess pyrrole traditionally used in dipyrromethane synthesis, the current method uses a stoichiometric amount of pyrrole avoiding any use of Brønsted or Lewis acid. A gram scale synthesis of 5-phenyldipyrromethane is also achieved demonstrating potential scale up of dipyrromethanes using this method feasible. Subsequently, dipyrromethanes were converted to A₄-tetraarylporphyrins also in the presence of K₂S₂O₈at 90${}^{\circ }$C. A direct synthesis of A₄-tetraphenylporphyrin from excess pyrrole and phenylglyoxylic acid in the presence of K₂S₂O₈ at 90${}^{\circ }$C is also reported.

Pyrrole C-glycosylated in either the 2- or the 3-position could be prepared by the acid-catalyzed reaction between trichloroacetimidate glycosyl donors and pyrrole, or $N$-phenyl-tri?uoroacetimidate glucosyl donor and $N$-TIPS pyrrole, respectively. Pyrroles carrying glucose, mannose, galactose and lactose in the 2-position, and glucose in the 3-position were obtained. The configurations of the products could be assigned using a combination of 1D and 2D NMR spectroscopy. A number of undesired background reactions yielding a variety of stereo- and regioisomers were identified; in several cases these could be eliminated. Glycosylpyrroles could be incorporated into mono- and diglycosylated dipyrromethanes, a diglycosylated BODIPY dye, and a monoglycosylated Zn(II) porphyrin without damaging the sugar unit.

Tetrapyrrole building blocks are invaluable constituents in the construction of molecular architectures for use in biomimicry, functional materials, and biomedicine. The reaction of dipyrromethane and the triisopropylsilyl-protected 3,5-diethynylbenzaldehyde afforded the corresponding trans-${\mathrm{\text{A}}}_2$-porphyrin (free base) bearing four ethynes. Subsequent meso-bromination, Suzuki coupling, and protecting group removal afforded a porphyrin building block bearing four ethynes and one benzylamine. The reaction of dipyrromethane and 3,5-bis(propargyloxy)benzaldehyde afforded the corresponding trans-${\mathrm{\text{A}}}_2$-porphyrin (free base) bearing four ethynes. The reaction of 5-(3,5-bis(propargyloxy)phenyl)dipyrromethane and the Eschenmoser (1,9-dimethylaminomethyl) derivative of a 5-($p$-substituted aryl)dipyrromethane was used to create two trans-AB-porphyrins (zinc chelates). The $p$-substituent of the aryl group was cyano or an acetal moiety. Hydrolysis of the acetal and a click reaction with m-PEG24-azide gave the bis(PEGylated)porphyrin-carboxaldehyde. The porphyrins present readily derivatizable functional groups in a compact architecture.