Pyrrole, alkylation substitution

A comparison of the relative basicities of pyrrole, furan and thiophene may be made by comparing the pK values of their 2,5-di-t-butyl derivatives, which were found to be -1.01, —10.01 and —10.16, respectively. In each case protonation was shown by NMR to occur at position 2. The base-strengthening effect of alkyl substitution is clearly apparent by comparison of pyrrole and its alkyl derivatives, e.g. A-methylpyrrole has a pKa. for a-protonation of -2.9 and 2,3,4,5-tetramethylpyrrole has a pK of 4-3.7. In general, protonation of a-alkylpyrroles occurs at the a -position whereas /3-alkylpyrroles are protonated at the adjacent a-position. As expected, electron-withdrawing groups are base-weakening thus A-phenylpyrrole is reported to have a p/sTa of -5.8. The IR spectrum of the hydrochloride of 2-formylpyrrole indicates that protonation occurs mainly at the carbonyl oxygen atom and only to a limited extent at C-5. 

Complex reactions occur on the autoxidation of pyrroles (see Section 3.05.1.4) predictably, susceptibility to autoxidation increases with increasing alkyl substitution, llie photosensitized reaction of pyrrole and oxygen yields 5-hydroxy-A -pyrrolin-2-one, probably by way of an intermediate cyclic peroxide (Scheme 28) (76JA802). 

The alkyl substitution forced adjacent pyrrole units on the same chain out-of-plane by at least 40°. A consequence of this was that the authors could only evaluate their data at higher temperatures (including room temperature), in terms of the assumption that interchain electronic hopping was the dominant factor in determining the macroscopically measureable electronic conductivity, rather than in/rachain hopping. Under these conditions, the... 

Mannich reaction Pyrrole and alkyl substituted furan undergo the Man-nich reaction. Thiophene also undergoes this reaction, but, instead of acetic acid, hydrochloric acid is used. 

Ranu, B.C. and Hajra, A., Synthesis of alkyl-substituted pyrroles by three-component coupling of carbonyl compound, amine and nitro-alkane/alkene on a solid surface of silica gel/alumina under microwave irradiation, Tetrahedron, 2001, 57, 4767-4773. 

Another variant of this reaction has also been described51. In this case, carbonyl compounds were coupled with amines and a,[3-unsaturated nitroalkanes to form 1,3,4,5-alkyl substituted pyrroles on AI2O3 as the solid support, Scheme 5.32. After 15 min irradiation, the products were obtained in 71—86% yield. It was found that substitution at the a-position of the nitroalkane was essential for the reaction. While... 

Thiophene, alkyl-substituted furans, and especially pyrrole, undergo Mannich reactions. 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

Substitution in aromatic hydrocarbon naturally shifts the wavelength of fluorescence in agreement with the effect of the same substitution on the absorption spectrum. Alkyl substitution has little effect. Chlorine and bromine weaken the florescence and iodine completely inhibits it. The simplest aromatic heterocyclics, pyridine, pyrrole, furan and thiophene do not show fluorescence. 

Recently, FI. Mayr et al. (08EJO2369) estimated the nucleophilicities of pyrrole and its alkyl-substituted derivatives. The second-order rate... 

Porphyrins dissolved in SDS micelles have also been applied towards the determination of pKa values of the central atoms, which are around 5.5 for alkyl substituted porphyrins, but drop to 4.8 for divinyl substituted protoporphyrin dimethyl ester and to 3.0 for porphyrins with two p-pyrrolic carbethoxy or formyl substituents. 

Fig. 33. Isomeric distribution of alkyl substituted pyrroles at low pressure (20-50 Torr) [81CC1177 82JA7084 83JCS(P2)1491].

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