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Phosphate esters are key compounds in important biological reactions. One family of enzymes, PTPases, catalyze the dephosphorylation of tyrosine residues from other proteins by a cystein side-chain nucleophilic attack at tyrosin phosphate. Very little is known about the intrinsic reactivity of thiol nucleophiles with phosphorus centers. To explore this important reaction, we have performed ab initio calculations on the trimethyl phosphate ester (TMP) thiolysis by (CH 3 S) -. Results in the gas phase indicate that attack at TMP carbon is essentially predominant over phosphorus. Mechanisms are A n D n and exoergic for reaction at carbon and A n + D n with large activation barriers and endoergic reaction for attack on phosphorus. A trigonal-bipyramid intermediate was formed upon (CH 3 S)reaction at phosphorus and two different and competitive pathways were found for the elimination of methoxide from this intermediate. One of the elimination pathways is positioned in-line to the thiol group, as proposed in the enzymatic mechanism. If PTPases work by the same mechanism as the gas-phase reaction, these enzymes should drastically lower the activation barriers for attack at phosphorus.

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