J. Am. Chem. Soc. 133, 13894–13897 (2011)

The α-effect is the empirical observation that nucleophiles with a second lone-pair-bearing atom adjacent (α) to the nucleophilic centre exhibit anomalously high reactivity. Generally, the reactivity within a series containing the same nucleophilic atom correlates well with basicity, but some nucleophiles, such as hydroperoxide and hydrazine, do not fit the pattern well. Experimental studies of the α-effect can be difficult to interpret because a number of different phenomena that can enhance or attenuate it can be convoluted. There has, therefore, been much debate as to whether the α-effect is an intrinsic result of structure or just a solvent-induced phenomenon.

Now, Veronica Bierbaum and co-workers from the University of Colorado have performed gas-phase studies that compared the reactivity of an α-nucleophile (hydroperoxide, HOO−) with a series of related normal oxygen nucleophiles (HO−, CH3O−, C2H5O− and i-C3H7O−) with three different electrophiles (methyl fluoride, anisole and 4-fluoroanisole). A gas-phase study eliminates any solvent effect, but more importantly this study also investigates reactions with relatively small enthalpy changes (large enthalpy changes can mask the α-effect) and takes into account the different reaction pathways that can be followed.

Even in the simplest system — comparing the reactions of methoxide or hydroperoxide with methyl fluoride — Bierbaum and co-workers observe a rate enhancement of 3.7 when using the α-nucleophile. In these reactions both nucleophiles have similar proton affinities, the reactions involve similar enthalpy changes, and only one reaction pathway (SN2) is possible, so the measured rate enhancement confirms that the α-effect is intrinsic to the nucleophile structure.