Chemical Reaction Shutdown

Mitch Jacoby’s Science & Technology article states that “now scientists have uncovered the molecular-level origins of [the] mechanistic inhibition” of S_N2 reactions in water by finding that “just two or three water molecules can shut down S_N2 reactions” (C&EN, Feb. 25, page 34).

Actually, this has been known for a long time from theoretical work reported more than 20 years ago by Susan C. Tucker and me (J. Am. Chem. Soc., DOI: 10.1021/ja00165a014) and by Xin Gui Zhao et al. (J. Chem. Phys., DOI: 10.1063/1.463698). We calculated that one water molecule slows down the chloride-methyl chloride S_N2 reaction by a factor of 7,000 and a second water molecule by another factor of 300, for a total slowdown of a factor of 2 million. Furthermore, we presented transition-state structures explaining the slowdown in molecular detail.

In short, upon proceeding to the transition state, the negative charge delocalizes over both the nucleophile and the nucleofuge, leading to several kilocalorie per mole weaker hydrogen bonds at the transition state than for reactants.

Donald G. Truhlar
Minneapolis