Abstract
The regioselectivity of N-alkylation in unsymmetrical imidazoles was studied.
The ambident nature of imidazole was scrutinised in an examination of substrate (ie. substituent(s)), alkylating agent, and medium effects on the ratios of isomeric N-alkylated products obtained under standardised alkylation conditions. To this end various 4-mono- and 4-nitro-5-substituted-imidazoles were synthesised and subsequently treated with alkylating reagents in both "neutral" (ethanolic) and basic (aqueous sodium hydroxide) reaction media to produce isomeric products in proportions rigorously determined by 1H nmr analysis.
A number of factors were shown to affect the product ratios. It is generally accepted that the free base is methylated by an SE2' process while the imidazole anion obeys SE2cB kinetics. The ratios of 1-alkyl-4- : 1-alkyl-5-substituted products determined from reaction in basic medium depend largely on polar and steric factors. Electron-withdrawing groups in the 4(5)-position render the more remote nitrogen the least deactivated to electrophilic attack. Correlation of the results obtained is much better with ơ1 or ơm than with ơp substituent constants, indicating that the major effect of the substituent is inductive. Steric effects play a very significant role in the overall regiochemistry of alkylation. An increased preference for the less-hindered nitrogen is demonstrated as both the size of the substituent and the size of the incoming electrophile increases. In "neutral" conditions matters are more complex. Certainly steric effects can be seen, but the expected electronic effects are overcome by a dominant tautomeric effect when the substituent is an electron-withdrawing group. KT values were determined for a number of substrates and these demonstrate that the 4-substituted tautomer is dominant when the substituent is electron-withdrawing, and even though this is the less-reactive tautomer in an SE2' reaction, it still controls the product ratio,
leading to high proportions of 1-alkyl-5-substituted imidazole in the product
mixture.
Diazomethane methylation was also briefly examined. Substitution is predominantly at the nitrogen proximate to an electron-withdrawing group, and reaction yields are seen to be dependent on substrate acidity.