Negative kinetic temperature effect on the hydride transfer from NADH analogue BNAH to the radical cation of N-benzylphenothiazine in acetonitrile

Article abstract of DOI:10.1021/jo061145c

The reaction rates of 1-(p-substituted benzyl)-1,4-dihydronicotinamide (G-BNAH) with N-benzylphenothiazine radical cation (PTZ^?+) in acetonitrile were determined. The results show that the reaction rates (k _obs) decreased from 2.80 × 10⁷ to 2.16 × 10⁷ M^-1 s^-1 for G = H as the reaction temperature increased from 298 to 318 K. The activation enthalpies of the reactions were estimated according to Eyring equation to give negative values (-3.4 to -2.9 kcal/mol). Investigation of the reaction intermediate shows that the charge-transfer complex (CT-complex) between G-BNAH and PTZ ^?+ was formed in front of the hydride transfer from G-BNAH to PTZ^?+. The formation enthalpy of the CT-complex was estimated by using the Benesi-Hildebrand equation to give the values from -6.4 to -6.0 kcal/mol when the substituent G in G-BNAH changes from CH₃O to Br. Detailed thermodynamic analyses on each elementary step in the possible reaction pathways suggest that the hydride transfer from G-BNAH to PTZ^?+ occurs by a concerted hydride transfer via a CT-complex. The effective charge distribution on the pyridine ring in G-BNAH at the various stages-the reactant G-BNAH, the charge-transfer complex, the transition-state, and the product G-BNA⁺-was estimated by using the method of Hammett-type linear free energy analysis, and the results show that the pyridine ring carries relative effective positive charges of 0.35 in the CT-complex and 0.45 in the transition state, respectively, which indicates that the concerted hydride transfer from G-BNAH to PTZ^?+ was practically performed by the initial charge (-0.35) transfer from G-BNAH to PTZ^?+ and then followed by the transfer of hydrogen atom with partial negative charge (-0.65). It is evident that the present work would be helpful in understanding the nature of the negative temperature effect, especially on the reaction of NADH coenzyme with the drug phenothiazine in vivo.