Ferrocenoyl-adenines: substituent effects on regioselective acylation.

A series of -substituted adenine-ferrocene conjugates was prepared and the reaction mechanism underlying the synthesis was explored. The S2-like reaction between ferrocenoyl chloride and adenine anions is a regioselective process in which the product ratio (7/9-ferrocenoyl isomers) is governed by the steric property of the substituent at the -position. Steric effects were evaluated by using Charton (empirical) and Sterimol (computational) parameters. The bulky substituents may shield the proximal 7 region of space, which prevents the approach of an electrophile towards the 7 atom. As a consequence, the formation of 7-isomer is a kinetically less feasible process, i.e., the corresponding transition state structure increases in relative energy (compared to the formation of the 9-isomer). In cases where the steric hindrance is negligible, the electronic effect of the -substituent is prevailing. That was supported by calculations of Fukui functions and molecular orbital coefficients. Both descriptors indicated that the 7 atom was more nucleophilic than its 9-counterpart in all adenine anion derivatives. We demonstrated that selected substituents may shift the acylation of purines from a regioselective to a regiospecific mode.