Furans electrophilic substitution, relative reactivity

Rate data are also available for the solvolysis of l-(2-heteroaryl)ethyl acetates in aqueous ethanol. Side-chain reactions such as this, in which a delocalizable positive charge is developed in the transition state, are frequently regarded as analogous to electrophilic aromatic substitution reactions. In solvolysis the relative order of reactivity is tellurienyl> furyl > selenienyl > thienyl whereas in electrophilic substitutions the reactivity sequence is furan > tellurophene > selenophene > thiophene. This discrepancy has been explained in terms of different charge distributions in the transition states of these two classes of reaction (77AHC(21)119>. 

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. 

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. 

While there are no extensive reports on the relative aromaticity of the heterocycles covered in this chapter, the general reactivity of these systems can be predicted based on first principles. By assuming that these fused systems are comprised of a five-membered rc-excessive heterocyclic system and a five-membered -deficient heterocyclic system, electrophilic agents are expected to react on the n-excessive subunit. Ab initio calculations on the thienothiazoles and furothiazoles predicted that electrophilic substitutions should occur exclusively on the furan or thiophene subunit with the regioselectivity being a function of the resonance-stabilization of the reactive intermediates <76KGS1202>. A priori, C-H deprotonation by a nonnucleophilic base should occur preferentially on the -deficient heterocyclic component. 

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. ... 

Electrophilic substitution in benzo[f>] thiophene has been compared with that in thiophene, furan, and benzo[h]furan.235 The fusion of a thiophene ring with a benzene ring lowers the reactivity of the 2-position in thiophene by a factor of 10 and raises that of the 3-position by a factor of 180.222 The general order of relative reactivities is 3-position in thiophene 3-position in furan < 3-position in benzo[b]furan 2-position in benzo[6]thiophene < 3-position in benzo[h]thiophene x 2-position in benzo[6]furan 2-2-position in thiophene 2-position in furan.236... 

The reactivity of thiophen has also been compared with that of seleno-phen and the relative reactivities in five electrophilic substitutions have been determined by kinetic or competitive procedures. The results have been compared with those available in the literature for furan. In all the reactions examined, selenophen exhibited a reactivity intermediate between those of furan and thiophen. p-Constants for electrophilic substitution of substituted thiophens are usually smaller than in the benzene series. A comparison of the trifluoroacetylation of a series of substituted thiophens and furans yielded p-values of — 7.4 and — 10.7 respectively. The observed order of substrate selectivity in the trifluoroacetylation (furan > thiophen) thus parallels the positional selectivity in electrophilic substitution, the oi ratio always being larger in furans than in thiophens. The relative importance of primary steric effects in benzene and thiophen has been investigated by determination of the isomer distributions in the acetylations of 2- and 3-methylthiophen, 2- and 3-t-butylthiophen, and toluene and t-butylbenzene. Steric hindrance is less significant in the thiophen series owing to the more favourable geometry. - ... 

Electrophilic Substitution.—The isomer distributions and the rates relative to those of the parent heterocyclic compounds for acetylation, benzoylation, chlorination, and bromination of benzo[Z>]thiophen and benzo[6]furan have been determined. It was found that although the orientation of substitution in the two bicyclic systems is different, the effect caused by annelation on the reactivity of the a- and jS-positions is substantially the same in the two rings the reactivity of the a-position is always decreased by a similar factor, and the reactivity of the j8-position is increased (with some exceptions) in both systems. The different orientation observed in the... 

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. 

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)). 

For the so-called jt-excessive heterocycles, furan, pyrrole, and thiophene, where the heteroatom contributes two electrons to the aromatic sextet, the HOMO is of relatively high energy, compared to that in benzene, which fact confers the familiar high reactivity of these species toward electrophiles. Correspondingly, ionization to give cation-radicals is facile however, such species are not persistent without stabilizing substitution or annelation (see Section III,D,3). Anion-radicals are also known, particularly for thiophene-containing systems (see Part Two this Series, Volume 27, in press). 

The scope of this reaction is limited to electron-rich arenes and heteroarenes such as thiophenes, pyrroles, furans, indoles, and alkoxybenzenes as nucleophilic partners, corresponding to a Mayr ir-nucleophilicily parameter N>-1 [75-78], Electron-neutral to electron-deficient iodo(hetero)arenes are suitable electrophilic partners. Aryl halides or pseudohalides that are less reactive towards oxidative addition (Br, Cl, OTf) are not sufficiently reactive partners in this reaction. The reactivity of sterically hindered and/or ortho substituted iodoarenes has not been demonstrated. However biaryls bearing one ortho substituent of relatively small steric demand (e.g., from methoxybenzene or /V-mcthylindole) have been prepared. 

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