Mechanism of the Swern Oxidation: Significant Deviations from Transition State Theory

Abstract

Deprotonation of the alkoxysulfonium intermediate has been shown to be rate-determining in the Swern oxidation of benzyl alcohol. Directly following this rate-determining step is the intramolecular syn-β-elimination of the ylide. In the present study, intramolecular 2 H kinetic isotope effects (KIEs) are used to gain insight into this syn-β-elimination step. As a result of the stereogenic sulfur center in the ylide intermediate, two diastereomeric transition states (endo-TS1 and exo-TS1) must be assumed to contribute to the intramolecular KIE. The intramolecular 2 H KIE determined at -78 °C is 2.82 ± 0.06. Attempts to reproduce this measurement computationally using transition state theory and a Bell tunneling correction yielded a value (1.58) far below that determined experimentally. Computational analysis is complicated by the existence of two distinct transition structures owing to the stereogenic center. Two extremes of Curtin-Hammett kinetics are explored using energies, vibrational frequencies, and moments of inertia from computed transition structures. Neither Curtin-Hammett scenario can reproduce the observed KIE to any acceptable degree of fidelity. Evidence based upon previous kinetics measurements and calculations upon a model system suggest that the stereogenic sulfur center is not likely to undergo inversion to a significant degree at the temperatures at which the Swern oxidation is performed here. Proceeding under the assumption of no stereoinversion at the sulfur center, calculations predict a nearly linear Arrhenius plot for the KIE -even with the inclusion of a 1-dimensional tunneling correction. By contrast, the experimentally-determined temperature dependence shows a significant concave upward curvature indicative of the influence of tunneling. Notably, KIEs measured in CCl 4 , CHCl 3 , CH 2 Cl 2 , dichloroethane, and chlorobenzene at -23 °C showed little Correspondence to: Matthew P. Meyer, mmeyer@ucmerced.edu. Supporting Information Available: Details of the experimental and computational methods, derivations of eqs. 1-6, and Cartesian coordinates for all computed structures. This material is available free of charge via the Internet at http://pubs.acs.org. variance. This finding discounted the possible influence from dynamical effects due to incomplete vibrational relaxation. An ad hoc amplification of the imaginary frequencies corresponding to the first order saddle points corresponding to endo-TS1 and exo-TS1 allowed us to reproduce the experimental temperature dependence of the KIE using only two adjustable parameters applied to a kinetic scenario that involves four isotopomeric transition states. The cumulative data and computational modeling strongly suggest that, even though the intramolecular 2 H KIE observed in these experiments is small, this reaction requires a multi-dimensional description of the tunneling phenomenon to accurately reproduce experimental trends. NIH Public AccessAuthor Manuscript J Org Chem. Author manuscript; available in PMC 2011 December 3.

Atom Tunneling in Chemistry

“…These reactions are influenced by tunneling,e ven at room temperature,t hereby raising the reaction rate constants.F or Claisen rearrangements it was necessary to computationally include am odel of tunneling through ap arabolic barrier to explain the experimental 13 CK IEs, [162][163][164] and in aS wern oxidation, multidimensional tunneling had to be included in computations to reproduce the experimental results. [165] Several studies on the tautomerization of small or medium-sized molecules show the impact of tunneling on Scheme 1. Reaction of 2,4,6-tri-tert-butylphenyl to form 3,5-di-tert-butylneophyl.…”

“…These reactions are influenced by tunneling, even at room temperature, thereby raising the reaction rate constants. For Claisen rearrangements it was necessary to computationally include a model of tunneling through a parabolic barrier to explain the experimental 13 C KIEs, and in a Swern oxidation, multidimensional tunneling had to be included in computations to reproduce the experimental results …”

“…For Claisen rearrangements it was necessary to computationally include a model of tunneling through a parabolic barrier to explain the experimental 13 C KIEs [162][163][164] and in a Swern oxidation, multidimensional tunneling had to be included in computations to reproduce the experimental results. [165] Several studies of the tautomerization of small or medium-sized molecules show the impact of tunneling on proton shifts. Tunneling decay of particular conformers of glycine, [166,167] alanine, [168] cytosine, [169] and other small molecules with relevance to biology [170,171] was observed as well as the tunneling-accelerated tautomerization of tetrazole acetic acid.…”

Der Tunneleffekt von Atomen in der Chemie

“…Auch bei Raumtemperatur werden diese Reaktionen vom Tunneleffekt beeinflusst, was zu erhöhten Reaktionsgeschwindigkeitskonstanten führt. Für eine Claisen‐Umlagerung war es notwendig, in den Simulationen ein Modell zu verwenden, das Tunneln durch eine Parabel beinhaltet, um den experimentellen 13 C‐KIE zu erklären, und in einer Swern‐Oxidation musste mehrdimensionales Tunneln berücksichtigt werden, um die experimentellen Werte zu reproduzieren …”

Synthetic methods Part (II): oxidation and reduction methods

“…133 Finally, a notable theoretical study concerning the mechanism of the Swern oxidation has been disclosed by the Meyer group. 134 2 Reduction reactions…”