Ferrocenoyl-adenines: substituent effects on regioselective acylation

A series of N ⁶-substituted adenine-ferrocene conjugates was prepared and the reaction mechanism underlying the synthesis was explored. The S_N2-like reaction between ferrocenoyl chloride and adenine anions is a regioselective process in which the product ratio (N7/N9-ferrocenoyl isomers) is governed by the steric property of the substituent at the N ⁶-position. Steric effects were evaluated by using Charton (empirical) and Sterimol (computational) parameters. The bulky substituents may shield the proximal N7 region of space, which prevents the approach of an electrophile towards the N7 atom. As a consequence, the formation of N7-isomer is a kinetically less feasible process, i.e., the corresponding transition state structure increases in relative energy (compared to the formation of the N9-isomer). In cases where the steric hindrance is negligible, the electronic effect of the N ⁶-substituent is prevailing. That was supported by calculations of Fukui functions and molecular orbital coefficients. Both descriptors indicated that the N7 atom was more nucleophilic than its N9-counterpart in all adenine anion derivatives. We demonstrated that selected substituents may shift the acylation of purines from a regioselective to a regiospecific mode.