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Assessment of the metabolic stability of the methyl groups in heterocyclic compounds using CH bond dissociation energies: Effects of diverse aromatic groups on the stability of methyl radicals
Author(s) -
Zhao SuWen,
Liu Lei,
Fu Yao,
Guo QingXiang
Publication year - 2005
Publication title -
journal of physical organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.325
H-Index - 66
eISSN - 1099-1395
pISSN - 0894-3230
DOI - 10.1002/poc.856
Subject(s) - chemistry , methyl group , aromatization , radical , heteroatom , bond dissociation energy , dissociation (chemistry) , medicinal chemistry , thiophene , stereochemistry , group (periodic table) , organic chemistry , ring (chemistry) , catalysis
The CH 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 CH 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 CH 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 ∼10 12 ‐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 CH BDEs than C ‐methyl groups. NH, O and S groups have similar effects on the benzylic CH 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 CH BDEs. A methyl group at the β‐position relative to N has a lower CH BDE than that at the α‐position. There is a special aromatization effect associated with 1‐methyl‐2 H ‐isoindole, 1‐methylisobenzofuran, 1‐methylbenzo[ c ]thiophene and related compounds. This aromatization effect dramatically decreases the benzylic CH BDEs. Finally, an interesting QSAR model has been developed. This model not only can successfully predict the benzylic CH BDEs of diverse heterocyclic compounds, but also can clearly and quantitatively reveal the mechanisms for the variation of the CH BDEs. Copyright © 2004 John Wiley & Sons, Ltd.