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Density Functional Investigation of the Mitsunobu Reaction
journal contribution
posted on 2005-09-14, 00:00 authored by Stephan Schenk, Jennie Weston, Ernst AndersIn this article we performed an extensive density functional [BP86/6-311++G(3df,3pd) level]
investigation of the hypersurface of the Mitsunobu reaction. Reaction of a phosphine with a dialkyl
azodicarboxylate (first step in the Mitsunobu conversion) leads to either a five-membered oxadiazaphosphole
ring (more stable) or a betaine. The subsequent formation of two stable intermediates, a dialkoxyphosphorane and an acyloxyalkoxyphosphorane, constitutes the second step in the mechanism. These
intermediates are in equilibrium with each other (under exchange of alkoxy and acyloxy ligands), and both
can undergo an acid-induced decomposition to yield the alkoxy- and/or acyloxyphosphonium salts. The
alkoxyphosphonium salt generates the desired ester via a SN2 mechanism (inversion product). Alternatively,
the phosphorus atom in a mixed acyloxyalkoxyphosphorane species can easily undergo Berry pseudorotation. A subsequent intramolecular substitution leads to the final ester via a retention mechanism. The
hypersurface is much more complicated than previously assumed, and the Mitsunobu reaction is
fundamentally capable of running under either inversion or retention. The possibility of selective stereocontrol
is discussed. Side reactions include the formation of a degradation product and an anhydride.