The alpha effect. A review

Abstract

Instances of high reactivity (as signaled by a positive Br6nsted deviation) by nucleophiles bearing one or more unshared pairs of electrons on an atom adjacent to the nucleophilic center (the alpha effect) are surveyed in the context of possible explanations for this phenomenon.However, four factors (ground-state destabilization of the nucleophile, transition-state stabilization, solvent effect differences for alpha and nonalpha nucleophiles, and product stability) may be. involved in contributory roles. The response to proton basicity of a substrate is probably not related to its susceptibility to the alpha effect. Carbon electrophiles seem to be receptive to the alpha effect in the order digonal > trigonal > tetrahedral. The inconsistent behavior of alpha nucleophiles makes the prediction of alpha effects rather risky and confirms the complicated nature of nucleophilic substitutions.No single cause appears to account satisfactorily for all the data.

Unexpected reactivity and mechanism of carboxamide activation in bacterial N-linked protein glycosylation

“…Owing to the alpha effect, compound 6 (hydroxamate) is a better nucleophile than the Hse-containing compound 5 (ref. 23), even though the positioning of the hydroxyl group of Asp(NHOH) in the active site is not optimal (similar to glutamine).…”

“…By contrast, upon replacing an amide proton with a hydroxyl group (resulting in the hydroxamate Asp(NHOH, compound 6), we observed a sizeable binding affinity, suggesting that both the remaining proton and the hydroxyl group must form stabilizing interactions with PglB, in line with carboxamide twisting. For glycosylation, however, the hydroxamate does not need to be rotated, as the terminal hydroxyl group represents a highly reactive nucleophile because of the alpha effect 23 . This results in an unusual O-linked glycosylation reaction, as demonstrated by our NMR studies.…”

Alternative bases in the RNA world: The prebiotic synthesis of urazole and its ribosides

“…This is attributed to hydrazine being an o~-effect nucleophile whose enhanced reactivity is particularly marked with nitriles (Grekov and Veslov 1978;Fina and Edwards 1973).…”

G2(+) Investigation on the α‐Effect in the SN2 Reactions at Saturated Carbon

“…[1,2] The origin of the a-effect has been a matter of debate for many years. There are several proposed explanations for the origin of a-effect, including 1) groundstate destabilization of the nucleophile due to the lone-pair repulsion, [3][4][5] 2) transition-state (TS) stabilization due to the favorable interaction between the a-atom and the positively charged reaction center, [6][7][8] and 3) solvent effect differences between a normal nucleophile and the corresponding a-nucleophile, [9][10][11] for example, HO À is more solvated than HOO À in the case of aqueous reactions.…”