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. 2013 Apr 19;78(8):4037-48.
doi: 10.1021/jo400350v. Epub 2013 Mar 22.

Enhanced reactivity in dioxirane C-H oxidations via strain release: a computational and experimental study

Lufeng Zou  1 , Robert S Paton, Albert Eschenmoser, Timothy R Newhouse, Phil S Baran, K N Houk
Affiliations

Enhanced reactivity in dioxirane C-H oxidations via strain release: a computational and experimental study

Lufeng Zou et al. J Org Chem. .

Abstract

The site selectivities and stereoselectivities of C-H oxidations of substituted cyclohexanes and trans-decalins by dimethyldioxirane (DMDO) were investigated computationally with quantum mechanical density functional theory (DFT). The multiconfiguration CASPT2 method was employed on model systems to establish the preferred mechanism and transition state geometry. The reaction pathway involving a rebound step is established to account for the retention of stereochemistry. The oxidation of sclareolide with dioxirane reagents is reported, including the oxidation by the in situ generated tBu-TFDO, a new dioxirane that better discriminates between C-H bonds on the basis of steric effects. The release of 1,3-diaxial strain in the transition state contributes to the site selectivity and enhanced equatorial C-H bond reactivity for tertiary C-H bonds, a result of the lowering of distortion energy. In addition to this strain release factor, steric and inductive effects contribute to the rates of C-H oxidation by dioxiranes.

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Figures

Figure 1
Figure 1
Transition state geometries for DMDO and isobutane reaction.
Figure 2
Figure 2
Reaction pathway in DMDO oxidations. Energies in kcal/mol.
Figure 3
Figure 3
Optimized TSs for the reactions of DMDO with equatorial (2-eq-TS) and axial (2-ax-TS) C-H bonds. Energies in kcal/mol with respect to the corresponding reactants. Individual components of distortion energies (alkane distortion, dioxirane distortion) are given in parentheses.
Figure 4
Figure 4
Optimized TSs for the reactions of DMDO with (a) cis-1,4-dimethylcyclohexanes at the equatorial (3-eq-TS) and axial C-H bonds (3-ax-TS); (b) cis-1,2-dimethylcyclohexanes at the equatorial (4-eq-TS) and axial (4-ax-TS) C-H bonds. Energies in kcal/mol with respect to the corresponding reactants. Individual components of distortion energies (alkane distortion, dioxirane distortion) are in parentheses.
Figure 5
Figure 5
Optimized reactant and transition state geometries for the reaction of DMDO with substituted cyclohexanes. Energies are in kcal/mol. Individual components of distortion energies (alkane distortion, dioxirane distortion) are in parenthesis.
Figure 6
Figure 6
Optimized reactant and transition state geometries for the reaction of TFDO with (a) 8 and (b) 9. R = -C(O)NHCH2CF3. The iPr substituents on the decalin rings of 8′ and 9′ were omitted for simplicity. Energies are in kcal/mol. Individual components of distortion energies (alkane distortion, dioxirane distortion) are in parenthesis. Energies with dichloromethane solvation correction are in square brackets.
Figure 7
Figure 7
Optimized reactant and transition state geometries for the reaction of TFDO with sclareolide 10. Energies are in kcal/mol. Individual components of distortion energies (alkane distortion, dioxirane distortion) are in parenthesis. Energies with acetonitrile solvation correction are in square brackets.
Figure 8
Figure 8
Optimized reactant and transition state geometries for the reaction of tBu-TFDO with sclareolide 10. Energies are in kcal/mol. Individual components of distortion energies (alkane distortion, dioxirane distortion) are in parenthesis. The prime labels on TS distinguish the transition states for tBu-TFDO oxidation with those with DMDO. Energies with acetonitrile solvation correction are in square brackets.
Scheme 1
Scheme 1
Selective C-H oxidation. Only one of the five tertiary C-H bonds is oxidized
Scheme 2
Scheme 2
Reaction products in a competition reaction
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