Solvent Effects on the Reactions of Organo-Phosphorus Compounds with KF/Al₂O₃ Solid-Support

The effects solvents have on the fluoride-promoted heterogeneous hydrolysis and alcoholysis of various organo-phosphorus (OP) compounds on the surface of KF/Al₂O₃ were explored.^1,2 Solid-state magic angle spinning (MAS) NMR experiments of these reactions were conducted using different solvents at various amounts (3-90 wt %). Water, methanol and ethanol were chosen as representatives of polar protic solvents, heptane as a non-polar solvent and acetonitrile as a polar aprotic solvent. NMR analyses supported by scanning electron (SEM) microscopy data allowed us to determine that not only is the identity of the solvent important in these reactions but also its quantity. That is, minimal solvent amounts are favored and much more effective in such solid-supported reactions (and maybe generally) than those featuring solvent-free or excess solvent conditions. The addition of a minute quantity of the proper solvents (e.g., water or methanol/ethanol at 3-10 wt %) avoids fluoride leaching from the matrix, permits mobility (mass transport) of the reaction components and ensures their very high local concentration in close proximity to the solid-support large porous surface area. Accordingly, acceleration of reactions rates by orders of magnitude is obtained. This phenomena was observed with phosphonothioates, phosphonates and phosphates. Fascinatingly, even challenging phosphoesters with poor leaving groups, which were found to be very stable in the presence of solvent-free KF/Al₂O₃ or wetted with excess water, were efficiently hydrolyzed with a minute amount of this solvent.

1) Fridkin, G.; Columbus, I.; Saphier, S.; Yehezkel, L.; Goldvaser, M.; Marciano, D.; Ashkenazi, N.; Zafrani, Y. J. Org. Chem 2015, 80, 5176-5188.

2) Fridkin, G.; Yehezkel, L.; Columbus, I.; Zafrani, Y. J. Org. Chem 2016, 81, 2154-2158.