If, as a synthetic chemist, you want to invert the configuration of an alcohol in which the OH group is at a chiral centre, then the Mitsunobu reaction has been a stalwart for many years. Now a catalytic version has been published, [1] along with a proposed mechanism. Here I apply computation as a reality check to see what the energetics of this mechanism might be.
The chosen computational procedure was B3LYP+GD3BJ dispersion, Def2-TZVPP basis and SCRF=toluene as solvent and for the alcohol, R1=R2=Me. Data is at DOI: 10.14469/hpc/6186
Molecule | ΔΔG, kcal/mol |
---|---|
1 | 0.0 |
2 | 25.4 |
3 | 15.0 |
TS | 36.8 |
4 | +4.5 |
In the mechanism above, the proton transfers have not been included in the modelling, with the presumption that the step involving the inversion at carbon is rate limiting.
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