Factors Influencing the Thermodynamics of Zinc Alkoxide Formation by Alcoholysis of the Terminal Hydroxide Complex, [Tp^But,Me]ZnOH:  An Experimental and Theoretical Study Relevant to the Mechanism of Action of Liver Alcohol Dehydrogenase

Abstract

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 [Tp RR′ ]-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.

Synthesis and crystal structure of [Zn6Br4(C9H18NO)4(OH)4]·2C3H6O2

“…Hence, zinc alkoxides are an important species in the human body for example for the liver alcohol dehydrogenase or the CO 2 transport through the circulatory system by carbonate anhydrase (Clegg et al, 1988;Siek et al, 2016). Liver alcohol dehydrogenase is an enzyme that catalyses the biological oxidation of alcohols to aldehydes and ketones (Bergquist et al, 2000). As part of this reaction, a tetrahedral zinc alkoxide complex is formed and after that, a formal hydride transfer occurs from the alkoxide to the oxidized form of NAD + (see Fig.…”

The Insertion of Heterocumulenes into Zn−H and Zn−OH Bonds of Pyrazolylborate−Zinc Complexes

“…However, initial replacement of OH by OR to form Tp Ph,Me ZnϪOR as the species which is then subjected to insertion, cannot be ruled out with complete certainty. Although the alkoxides Tp*ZnϪOR exist only in extremely low concentrations as equilibrium species of Tp*ZnϪOH in alcohol solvents, [29] they might be the precursors of the product complexes 7 and 8.…”

Simple phosphinate ligands access zinc clusters identified in the synthesis of zinc oxide nanoparticles

“…The formation of 3A is unexpected; the isolation and characterization of well-defined Zn-hydroxide complexes is usually challenging, often requiring the use of bulky, multi-dentate ligands for stabilization 46 49 . Zinc-hydroxy species are of interest in a range of contexts, including as putative intermediates during ZnO nanoparticle synthesis and as models for a range of zinc-dependent metalloenzymes 11 45 46 47 50 51 52 53 54 .…”