Factors influencing the thermodynamics of zinc alkoxide formation by alcoholysis of the terminal hydroxide complex, [TpBut,Me]ZnOH:: An experimental and theoretical study relevant to the mechanism of action of liver alcohol dehydrogenase

The factors that influence the formation of a tetrahedral alkoxide complex related to a critical intermediate of the catalytic cycle of liver alcohol dehydrogenase have been probed by a combined experimental and computational investigation of the reactions of the tris(pyrazolyl)hydroborato zinc hydroxide complexes [Tp(RR')]ZnOH with alcohols. The study demonstrates that zinc alkoxide formation is electronically favored by incorporation of electron-withdrawing substituents in the alcohol but is sterically disfavored for bulky alkoxides. A computational analysis indicates that these trends are a result of homolytic Zn-OR and Zn-OAr BDEs being more sensitive to the nature of R and Ar than are the corresponding H-OR and H-OAr BDEs. Thus, electron-withdrawing substituents increase Zn-OAr bond energies to a greater extent than H-OAr bond energies, while bulky substituents decrease Zn-OR bond energies to a greater extent than H-OR bond energies. With the exception of derivatives of acidic alcohols (e.g., nitrophenol), the zinc alkoxide complexes [TpRR'] ZnOR are very unstable toward hydrolysis, This hydrolytic instability of simple zinc alkoxide complexes suggests that the active site environment of LADH plays an important role in stabilizing the alkoxide intermediate, possibly via hydrogen-bonding interactions.