Pyrroles dipyrromethenes

A mild procedure which does not involve strong adds, has to be used in the synthesis of pure isomers of unsymmetrically substituted porphyrins from dipyrromethanes. The best procedure having been applied, e.g. in unequivocal syntheses of uroporphyrins II, III, and IV (see p. 251f.), is the condensation of 5,5 -diformyldipyrromethanes with 5,5 -unsubstituted dipyrromethanes in a very dilute solution of hydriodic add in acetic acid (A.H. Jackson, 1973). The electron-withdrawing formyl groups disfavor protonation of the pyrrole and therefore isomerization. The porphodimethene that is formed during short reaction times isomerizes only very slowly, since the pyrrole units are part of a dipyrromethene chromophore (see below). Furthermore, it can be oxidized immediately after its synthesis to give stable porphyrins. 

Conjugated dipyrrolic pigments, the dipyrromethenes, are synthesized by add-catalyzed condensation of an a-formyl pyrrole and an a-unsubstituted pyrrole. They are readily protonated and deprotonated and are difficult to purify by chromatography. 

The pyridine-like nitrogen of the 2H-pyrrol-2-yiidene unit tends to withdraw electrons from the conjugated system and deactivates it in reactions with electrophiles. The add-catalyzed condensations described above for pyrroles and dipyrromethanes therefore do not occur with dipyrromethenes. Vilsmeier formylation, for example, is only successful with pyrroles and dipyrromethanes but not with dipyrromethenes. 

This reaction sequence is much less prone to difficulties with isomerizations since the pyridine-like carbons of dipyrromethenes do not add protons. Yields are often low, however, since the intermediates do not survive the high temperatures. The more reactive, faster but less reliable system is certainly provided by the dipyrromethanes, in which the reactivity of the pyrrole units is comparable to activated benzene derivatives such as phenol or aniline. The situation is comparable with that found in peptide synthesis where the slow azide method gives cleaner products than the fast DCC-promoted condensations (see p. 234). 

Aromatic species include the neutral molecules pyrrole, furan and thiophene (1 Z = NH, O, S) and the pyrrole anion (2). The radicals derived from these rings are named pyrryl, furyl and thienyl. The 2-furylmethyl radical is called furfuryl. Compounds in which two pyrrole nuclei are joined by a CH2 group are called dipyrromethanes when the linkage is by a CH group, they are named dipyrromethenes . The 2- (3) and 3-pyrrolenines (4) are isomeric with the pyrroles, but are nonaromatic as the ring conjugation is broken by an. s/r -hybridized carbon atom. 

Pure individual porphyrins such as (4)-(7) can, however, be synthesized using dipyrroles, and these approaches will be briefly discussed later in this section. If two dipyrrole units (8) and (9) with an appropriate future meso-carbon are reacted together with the intention of preparing porphyrin (10), there is actually a maximum of three possible products, (10) (12) (Scheme 3). This is because the two dipyrroles can either react with themselves, or (as required) with each other. If the dipyrroles do not possess attached (future) meso-carbon atoms (e.g., (13) and (14)) and also bear an unsymmetrical arrangement of substituents (indicated by the A and B labels on each pyrrole— oxidation levels, i.e., dipyrromethene or dipyrromethane, not defined), even greater mixtures can occur—in this case, porphyrins (15)-(20) (Scheme 4). Such symmetry problems are common with all so-called [2 + 2] syntheses. However, if a porphyrin synthesis involving two dipyrroles is to be attempted, the symmetry problems can often be overcome if one of the two dipyrroles is symmetrical about its interpyrrolic (5-) carbon atom (e.g., synthesis of (6) from (21) and (22), Scheme 5). 

Dipyrromethenes (e.g., (42)) with a symmetrical arrangement of substituents can be prepared by self-condensation of 2-unsubstituted pyrroles (43a) or the corresponding pyrrole-2-carboxylic acids (43b) in boiling formic acid containing hydrobromic acid (Scheme ll).27 The synthetically more useful unsymmetrically substituted dipyrromethene salts (e.g., (44)) are best obtained by the condensation of a 2-formylpyrrole (45) with a 2-unsubstituted pyrrole (46) in the presence of acid (usually HBr) (Scheme 12). Heating of 2-bromomethylpyrroles (47) with 2-bromopyrroles (48) (synthesized by bromination of 2-unsubstituted pyrroles, (49)) in presence of bromine also gives good yields of unsymmetrical dipyrromethene hydrobromides (50) (Scheme 13). 

The presence of an a-free pyrrole attached to the native HMBS was also demonstrated, both in Cambridge and Southampton, by treatment with Ehrlich s reagent, acidic p-dimethylaminobenzaldehyde [30, 33]. This initially gave the UV/visible absorbance at 564 nm, typical of the Ehrlich product from an a-free pyrrole, but the spectrum then changed to one at 495 nm, typical of a dipyrromethene, indicating that the cofactor is in fact a dipyrromethane (e. g. 32), as shown in Scheme 11 and tautomerisation of the initial product 33 occurs to give 34. 

Analogous condensations, but with a pyrrole aldehyde lead to mesomeric dipyrromethene cations, which play an important part in porphyrin synthesis. Thus, using formyldipyrromethane as the aldehyde and a second mole as the pyrrole component, with air as oxidant, porphine is formed directly, as its magnesium derivative, possibly via a dipyrromethene cationic intermediate. ... 

Barton-Zard pyrrole synthesis and its application to synthesis of porphyrins, polypyrroles and dipyrromethene dyes , Ono, N., Heterocycles, 2008, 75, 243. 

In a model synthesis <81CC524>, a nitro-Michael addition of the readily available nitroalkyl pyrrole 36 to mesityl oxide was used to introduce a geminally dimethylated structural element into an AD component rac-39 for the desired chlorin. Reduction of the nitro function in rac-37 leads to the desired AD dimer rac-38 which is combined in the presence hydrobromic acid with the well known a-bromo-a -bromomethyl dipyrromethene 40 after acid induced ester clevage and decarboxylation to yield the tetrapyrrolic biline rac-41. In the final step the linear tetrapyrrole rac-41 undergoes oxidation and cyclization in the presence of copper(II) acetate to give the copper chlorin. The cyclization occurs via the enamine tautomer of rac-41 by nucleophilic attack of the enamine structure on the bromo imine part of the linear tetrapyrrole. 

There are several routes to a,c-biladienes. One was mentioned at the start of this section of porphyrin synthesis, i.e. condensation of two dipyrromethenes (one of which has an unsubstituted 5-position). Another route, to symmetrically substituted a,c-biladienes in particular, is by condensation of dipyrrylmethane-5,5 -dicarboxylic acids with two moles of a 2-formyl-5-pyrrole. This method can be used to construct the most unsymmetric porphyrins, e.g. isocoproporphyrin. ... 

The synthetic world of porphyrins is extremely rich and its history began in the middle of 1930s. An enormous number of synthetic procedures have been reported until now, and the reason can be easily understood analysing the porphyrin skeleton. In principle, there are many chemical strategies to synthesized porphyrins, involving different building blocks, like pyrroles, aldehydes, dipyrromethanes, dipyrromethenes, tripyrranes and linear tetrapyrroles. 

Analogous condensations with a pyrrole aldehyde lead to mesomeric dipyrromethene cations, which play an important part in porphyrin synthesis. 

A second area of optoelectronic materials are the BODIPY (boron-dipyrromethene) fluorescent dyes. These materials are prepared by condensation of pyrroles with aldehydes, followed by complexation of boron. Attempts to prepare the mesityl-substituted pyrroles via the hindered mesitylketoximine 67 were unsuccessful due to difficulty in generating 67 under standard conditions (NH2OH HCI, heat). However, reaction of the mesityl Grignard reagent with proprionitrile followed by reaction with NH2OH HCI provided ketoximine 67, which was successfully converted to the corresponding pyrrole in 23% yield. The cesium salt of ketoximine 67 was also converted to the same pyrrole in 41%. ... 

BODIPY has a rigid structure, which can be formed by boron insertion with BF3 OEt2 into a dipyrromethene unit. Generally, the synthesis of BODIPY derivatives starts from the dipyrromethene precursor. It is relatively easy to construct the precursor using the well-known pyrrole condensation reaction. There are two common synthetic strategies, especially for symmetric and unsymmetric BODIPY cores, respeetively. 

A highly eleetrophilic carboxylie aeid derivative (aeid anhydride, acyl chloride or aldehyde) is usually used to generate the dipyrromethene precursor with two pyrrole units (Scheme 7.1). The synthetie proeedure introduces the... 

Recently, 2-mesityl-3-methylpyrrole, synthesized from mesityl ethyl ketone and acetylene via the Trofimov reaction, has been used for the preparation of sterically encumbered fluorophores of BODIPY family (Scheme 2.183) [222]. The fluoro-phore assembled in a one-pot manner through the following procedure the pyrrole is condensed with mesityl aldehyde (TFAA, CHjClj, 20°C-25 C, 24 h), dipyrro-methane is oxidized to dipyrromethene (DDQ, CHjClj, 20°C-25 C, 0.5 h), and the latter is treated with BF3-Et20 in the presence of diisopropylethylamine (CH2CI2, 20°C-25°C, 0.5 h). 

The reaction comprises the following steps reduction of 2-trifluoroacetylpyrroles, condensation of the alcohols formed with pyrroles to dipyrromethanes (Scheme 2.187, Table 2.18), their oxidation to dipyrromethenes, and complex formation of the latter with boron trifluoride. The last two stages proceed in a one-pot manner. 

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