Pyrroles electrophilic substitution, relative reactivity

Electrophilic Aromatic Substitution. The Tt-excessive character of the pyrrole ring makes the indole ring susceptible to electrophilic attack. The reactivity is greater at the 3-position than at the 2-position. This reactivity pattern is suggested both by electron density distributions calculated by molecular orbital methods and by the relative energies of the intermediates for electrophilic substitution, as represented by the protonated stmctures (7a) and (7b). Stmcture (7b) is more favorable than (7a) because it retains the ben2enoid character of the carbocycHc ring (12). 

It is also of significance that in the dilute gas phase, where the intrinsic orientating properties of pyrrole can be examined without the complication of variable phenomena such as solvation, ion-pairing and catalyst attendant on electrophilic substitution reactions in solution, preferential /3-attack on pyrrole occurs. In gas phase t-butylation, the relative order of reactivity at /3-carbon, a-carbon and nitrogen is 10.3 3.0 1.0 (81CC1177). 

The thiophene ring can be elaborated using standard electrophilic, nucleophilic, and organometallic chemistry. A variety of methods have been developed to exploit the tendency for the thiophene ring (analogous to that of furan and pyrrole) to favor electrophilic substitution and metallation at its a-carbons. Substitution at the p-carbons is more challenging, but this problem can also be solved by utilizing relative reactivity differences. 

Electrophilic substitution in furan, thiophene, selenophene and pyrrole has, up to 1970, been comprehensively reviewed by Marino.66 Italian workers have determined the relative reactivities of selenophene and thiophene as well67 relative rates are given in Table I. Including furan, the order of reactivity is furan > selenophene > thiophene. 

The reactivity of five-membered rings with one heteroatom to electrophilic reagents has been quantitatively compared. Table 1 shows that the rates of substitution for (a) formylation by phosgene and V,iV-dimethylformamide, (b) acetylation by acetic anhydride and tin(IV) chloride, and (c) trifluoroacetylation with trifluoroacetic anhydride (71AHC(13)235) are all in the sequence furan > tellurophene > selenophene > thiophene. Pyrrole is still more reactive as shown by the rate for trifluoroacetylation, by the relative rates of bromination of the 2-methoxycarbonyl derivatives (pyrrole > furan > selenophene > thiophene), and by the rate data on the reaction of the iron tricarbonyl-complexed carbocation [C6H7Fe(CO)3]+ (Scheme 5) (2-methylindole ss V-methylindole > indole > pyrrole > furan > thiophene (73CC540)). 

Thiophene is far more reactive than benzene in electrophilic substitution reactions. Reaction with bromine in acetic acid has been calculated to be 1.76 x 109 times faster than with benzene (72IJS(C)(7)6l). This comparison should, of course, be treated with circumspection in view of the fact that the experimental conditions are not really comparable. Benzene in the absence of catalysts is scarcely attacked by bromine in acetic acid. More pertinent is the reactivity sequence for this bromination among five-membered aromatic heterocycles, the relative rates being in the order 1 (thiophene) and 120 (furan) or, for trifluoroacetylation, 1 (thiophene), 140 (furan), 5.3 xlO7 (pyrrole) (B-72MI31300, 72IJS(C)(7)6l). Among the five-membered heteroaromatics, thiophene is definitely the least reactive. 

A DFT study of the reactivity of pyridine and the diazabenzenes towards electrophilic substitution, assuming frontier orbital control of the reactions, predicts their low reactivity as the HOMOs of these substrates are not n-orbitals.5 For pyridine-N-oxide, however, the HOMO is an aromatic orbital. DFT studies giving Fukui indices predict6 the preferred sites of electrophilic attack on pyrrole, furan, and thiophene and calculation of the local softness of the reactive sites rationalizes relative reactivities. 

The relative reactivities of all four unsubstituted rings have been subsequently determined in another electrophilic substitution trifluoroacetylation by trifluoroacetic anhydride in dichloroeth-ane.142 143 The relative rates, obtained by a competitive procedure, are in good agreement with the bromination data (Table V) and confirm, in particular, the big jump in reactivity from furan to pyrrole. The great reactivity of pyrrole cannot be ascribed to a reaction involving the anion C4H4N, since V-methylpyrrole is still more reactive than pyrrole by a factor of about 2. 

In pyrrole the a /3 reactivity ratio is much smaller than in the other 5-membered rings (see Section III,A, 2) here the formation of a relatively larger amount of 3-substituted isomer could be expected. Actually, the 5-substituted 2-alkyl derivative appears to be the main product in all the electrophilic substitutions of the 2-alkylpyrroles3 in some cases, as in the reactions with trifluoroacetic anhydride and acetyl trifluoroacetate,147 the 5-substituted isomer is apparently the only product formed. 

In many ways the chemistry of indole is that of a reactive pyrrole ring with a relatively unreactive benzene ring standing on one side—electrophilic substitution almost always occurs on the pyrrole ring, for example. But indole and pyrrole differ in one important respect. In indole, electrophilic substitution is preferred in the 3-position with almost all reagents. Halo-genation, nitration, snlfonation,... 

The data considered confirm the reactivity sequence pyrrole furan > selenophene > thiophene for substrate selectivity on electrophilic substitution (71 AHC(13)235) and show that the positional selectivity is reduced in the series furan > selenophene > thiophene > pyrrole, which correlate with that for the relative stability of the onium states of the elements (O < Se < S " < N" ") in agreement with the hypothesis proposed previously (79MI2,80KGS1587), not including selenophene and its derivatives. 

These substitutions are facilitated by electron release from the heteroatom pyrroles are more reactive than furans, which are in turn more reactive than thiophenes. Quantitative comparisons of the relative reactivities of the three heterocycles vary from electrophile to electrophile, but for trifluoroacetylation, for example, the pyrrole furan thiophene ratio is 5 x 10 1.5 x 10 I " in formylation, furan is 12 times more reactive than thiophene, and for acetylation, the value is 9.3. In hydrogen exchange (deuteriodeproton-ation), the partial rate factors for the a and p positions of A-methylpyrrole are 3.9 x 10 ° and 2.0 x 10 ° respectively for this same process, the values for furan are 1.6 x 10 and 3.2 x l(f and for thiophene, 3.9 X 10 and 1.0 x 10 respectively, and in a study of thiophene, a P ratios ranging from 100 1 to 1000 1 were found for different electrophiles. Relative substrate reactivity parallels positional selectivity i.e. the a P ratio decreases in the order furan > thiophene > pyrrole. ° Nice illustrations of these relative reactivities are found in acylations of compounds containing two different systems linked together. ... 

The relative reactivity of benzene and the three heterocycles in electrophilic substitutions is the result of contributions from the aromaticity of the respective rings and the stabilization of the intermediate cations. It increases in the order benzene thiophene < furan < pyrrole. 

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