Assessment of the metabolic stability of the methyl groups in heterocyclic compounds using CH bond dissociation energies: Effects of diverse aromatic groups on the stability of methyl radicals

Abstract

AbstractThe CH bond dissociation energies (BDEs) of the methyl groups attached to a large number of heterocyclic compounds are calculated using a carefully calibrated B3LYP method. These CH bond dissociation energies are important for evaluating the metabolic stability of the methyl groups in heterocyclic compounds that may be used as drug candidates. It is found that the CH BDEs of the methyl groups attached to diverse heterocycles can dramatically vary from ca 80 to ca 100 kcal mol−1 (1 kcal = 4.184 kJ). Therefore, the benzylic positions of different heterocycles may have remarkably different metabolic stabilities varying by ∼1012‐fold. The heteroatoms in the aromatic rings vary the benzylic BDEs either by delocalizing the spin or by changing the charge carried by the radical center. N‐Methyl groups have systematically higher CH BDEs than C‐methyl groups. NH, O and S groups have similar effects on the benzylic CH BDEs. A methyl group at the α‐position relative to the NH, O and S groups usually has a lower BDE than that at the β‐position. On the other hand, the N group has a different effect on the benzylic CH BDEs. A methyl group at the β‐position relative to N has a lower CH BDE than that at the α‐position. There is a special aromatization effect associated with 1‐methyl‐2H‐isoindole, 1‐methylisobenzofuran, 1‐methylbenzo[c]thiophene and related compounds. This aromatization effect dramatically decreases the benzylic CH BDEs. Finally, an interesting QSAR model has been developed. This model not only can successfully predict the benzylic CH BDEs of diverse heterocyclic compounds, but also can clearly and quantitatively reveal the mechanisms for the variation of the CH BDEs. Copyright © 2004 John Wiley & Sons, Ltd.