Indoles electrophilic substitution, relative reactivity

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,... 

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). 

Kinetics of reacting I R = H, OMe with nucleophiles such as the enol of pentan-2,4-dione aromatic amines , phosphorus derivatives and some reactive aromatic compounds , and relative rates with substituted (cyclohexadienyl)Fe(GO)3 cation have been examined. These behave as classically expected, but in contrast to 1-or 2-OMe, a 3-OMe increases rate through its inductive effect. The kinetics agree with electrophilic substitution with the possible intermediacy of n complexes " . Because aryl (N-diene)Fe(CO)3 complexes can rearrange by dissociation into C-aryl derivatives", intermediates could also involve reaction with an N of an indole or a MeO (oxonium cation) of MeO-aromatics. 

Indolizine, pA a 3.9, is much more basic than indole (pA a -3-5) and the implied relative stability of the cation makes it less reactive and thus indolizines resistant to acid-catalysed polymerisation cf. Section 17.1.9). Indolizine protonates at C-3, but 3-methylindolizine protonates mainly (79%) at C-1 the delicacy of the balance is further illustrated by 1,2,3-trimethyl- and 3,5-dimethylindolizines, each of which protonate exclusively at C-3. Electrophilic substitutions such as acylation," Vilsmeier formylation, and diazo-coupling all take place at C-3. 

There has also been considerable interest in the theoretical analysis of the relative reactivity of the position on the indole ring. One of the quantities that can be calculated is the condensed Fukui function [f ], which, in the context of density function theory, provides a measure of respruise to an approaching electrophile [8]. For indole, the 1-, 2-, and 3-positi(Mis are calculated as 0.08, 0.05, and 0.18, consistent with the observed preference for substitution at C-3 [9]. 

Many of the common electrophilic aromatic substitution reactions can be conducted on indole. CompHcations normally arise either because of excessive reactivity or the relative instabiUty of the substitution product. This is the case with halogenation. 

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)). 

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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