Density functional investigation of the Mitsunobu reaction.
In 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.
Schenk
Stephan
S
Institut für Organische Chemie und Makromolekulare Chemie der Friedrich-Schiller-Universität, Humboldtstrasse 10, D-07743 Jena, Germany.
Weston
Jennie
J
Anders
Ernst
E
D001391:Azo Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D010720:Phosphines / Q000737:chemistry*
D001391:Azo Compounds; D010720:Phosphines