Publication Date

5-2019

Advisor(s)

Albert J. Fry; Stewart Novick

Department

Chemistry

Abstract

The superoxide-facilitated cleavage of α-substituted 1,1-diphenyl ketones was investigated. Substituted ketones were synthesized by a pinacol condensation reduction of alkyl phenyl ketones using aluminum chloride and zinc in acetonitrile in high yields. It was demonstrated that reactions involving authentic superoxide with the synthesized ketones afforded 1,1-diphenyl alkanes as the major product. While superoxide can react with 1,1-diphenylacetone (α = H) via proton abstraction or nucleophilic attack of the carbonyl, substituted diphenyl ketones (α = R where R ≠ H) can only react with superoxide via the latter pathway. Density Functional Theory computational calculations using dispersion-corrected B3LYP-D3BJ and M062X-D3 hybrid functionals, modest augmented basis sets 6-31+G(d) and MIDIY+, and implicit PCM-based solvation models revealed initial formation of a stable pre-reaction complex between anion radical and substituted ketones (α = R where R = alkyl) followed by favorable addition of superoxide to the carbonyl group as the RDS and subsequent highly exergonic α- cleavage of the acyl group to oxidation products. Furthermore, general structure and energetic properties of 1,1-diphenylacetone, along with thorough examinations of various peroxidemediated reaction pathways, were also investigated computationally. In contrast to the substituted diphenyl ketones, attack of the carbonyl carbon for 1,1-diphenylacetone only occurs with in situ generated hydroperoxy anion because superoxide, unlike the aforementioned anion, does not readily form a stable pre-reactive (e.g. hydrogen-bonded) complex. Rather, addition of hydroperoxy anion to the carbonyl group leads to favorable Baeyer-Villiger step resulting in the formation of benzhydryl acetate and expulsion of hydroxyl radical. Contrary to what was previously assumed for decades in the literature, another equivalent of superoxide then displaces the carboxylate moiety via an Sn2 reaction at the benzylic α-carbon that is significantly more favorable than nucleophilic attack at the ester carbonyl. Interestingly, when the concentration of superoxide far exceeds that of hydroperoxy anion species, nucleophilic attack of the carbonyl is still overshadowed by another more favorable process: superoxide-facilitated hydrogen abstraction of the α-benzylic C–H group. For this class of reactions, the geometrical and energetic results are entirely dependent on chosen density functionals and implicit solvation techniques yet rather insensitive to basis set size; meaning, geometries can alternate wildly between gas-phase versus solution-phase optimizations and thermochemical determinations can differ significantly between B3LYP and M062X. The substantial structural transformations afforded by the superoxide reactions discussed here offer a high yielding, one-pot protocol with powerful synthetic capabilities. Additionally, a computational, NMR, and X-ray crystallographic study of substituted cyclohexane compounds revealed that synthesized α-substituted ketones with R = Cyclohexyl have larger Gibbs free energy differences between axial and equatorial conformers (A-values) than almighty tbutyl-cyclohexane.

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