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Kinetic Effects of Sulfur Oxidation on Catalytic Nitrile Hydration: Nitrile Hydratase Insights from Bioinspired Ruthenium(II) Complexes

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journal contribution
posted on 01.12.2014 by Davinder Kumar, Tho N. Nguyen, Craig A. Grapperhaus
Kinetic investigations inspired by the metalloenzyme nitrile hydratase were performed on a series of ruthenium­(II) complexes to determine the effect of sulfur oxidation on catalytic nitrile hydration. The rate of benzonitrile hydration was quantified as a function of catalyst, nitrile, and water concentrations. Precatalysts LnRuPPh3 (n = 1–3; L1 = 4,7-bis­(2′-methyl-2′-mercapto-propyl)-1-thia-4,7-diazacyclononane; L2 = 4-(2′-methyl-2′-sulfinatopropyl)-7-(2′-methyl-2′-mercapto-propyl)-1-thia-4,7-diazacyclononane; L3 = 4-(2′-methyl-2′-sulfinatopropyl)-7-(2′-methyl-2′-sulfenato-propyl)-1-thia-4,7-diazacyclononane) were activated by substitution of triphenylphosphine with substrate in hot dimethylformamide solution. Rate measurements are consistent with a dynamic equilibrium between inactive aqua (LnRu–OH2) and active nitrile (LnRu–NCR) derivatives with K = 21 ± 1, 9 ± 0.9, and 23 ± 3 for L1 to L3, respectively. Subsequent hydration of the LnRu–NCR intermediate yields the amide product with measured hydration rate constants (k’s) of 0.37 ± 0.01, 0.82 ± 0.07, and 1.59 ± 0.12 M–1 h–1 for L1 to L3, respectively. Temperature dependent studies reveal that sulfur oxidation lowers the enthalpic barrier by 27 kJ/mol, but increases the entropic barrier by 65 J/(mol K). Density functional theory (DFT) calculations (B3LYP/LanL2DZ (Ru); 6-31G­(d) (all other atoms)) support a nitrile bound catalytic cycle with lowering of the reaction barrier as a consequence of sulfur oxidation through enhanced nitrile binding and attack of the water nucleophile through a highly organized transition state.