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The alpha effect refers to the increased nucleophilicity of an atom due to the presence of an adjacent (alpha) atom with lone pair electrons. This first atom does not necessarily exhibit increased basicity compared with a similar atom without an adjacent electron donating atom, resulting in a deviation from the classical Brønsted-type reactivity-basicity relationship. The effect is well established with many theories to explain the effect but without a clear winner. The effect is illustrated by the high nucleophilicity of hydroperoxide (HO2−) and hydrazine (N2H4).

Experiment
The effect was first observed by Jencks and Carriuolo in 1960 in a series of chemical kinetics experiments involving the reaction of the ester p-nitrophenyl acetate with a range of nucleophiles. Regular nucleophiles such as the fluoride anion, aniline, pyridine, ethylene diamine and the phenolate ion were found to have pseudo first order reaction rates corresponding to their basicity as measured by their pKa. Other nucleophiles however reacted much faster than expected based on this criterion alone. These include hydrazine, hydroxylamine, the hypochlorite ion and the hydroperoxide anion.

α-effect
In 1962 Edwards and Pearson (the latter of HSAB theory) introduced the phrase alpha effect for this anomaly. He offered the suggestion that the effect was caused by a transition state (TS) stabilization effect: on entering the TS the free electron pair on the nucleophile moves away from the nucleus, causing a partial positive charge which can be stabilized by an adjacent lone pair as for instance happens in any carbocation.

Theory
Over the years, many additional theories have been put forward attempting to explain the effect. The ground state destabilization theory proposes that the electron-electron repulsion between the alpha lone-pair and nucleophilic electron pair destabilize each other by electronic repulsion (filled–filled orbital interaction) thereby decreasing the activation barrier by increasing the ground state energy and making it more reactive. This explains the higher reactivity of α-nucleophiles, however, this electronic mechanism should also increase the basicity and, therefore, cannot fully explain the α-effect. Stabilization of the transition state is possible by assuming some TS free radical character or assuming that the TS has more advanced nucleophile-substrate bond formation. The polarizability of the nucleophile or involvement of intramolecular catalysis also plays a role. Another in silico study did find a correlation between the alpha effect and the so-called deformation energy, which is the electronic energy required to bring the two reactants together in the transition state.

Solvent-induced effects
The alpha effect is also dependent on solvent but not in a predictable way: it can increase or decrease with solvent mix composition or even go through a maximum. At least in some cases, the alpha effect has been observed to vanish if the reaction is conducted in the gas phase, leading some to conclude that it is primarily a solvation effect.

Pauli repulsion and HOMO-LUMO overlap
In 2021, Hansen and Vermeeren proposed the two requirements for an α-nucleophile to present the α-effect. The two proposed requirements were (1) minimization of steric Pauli repulsion via small HOMO lobes on the nucleophilic center and (2) small HOMO-LUMO orbital energy gap that ensures orbital overlap with the substrate. It was proposed that both of these two requirements should be fulfilled to have an α-effect, otherwise, the nucleophiles would show no or inverse α-effect. In this recent work, the six normal nucleophiles (HO-, CH3O-, H2N-, CH3HN-, CH3S-, HS-) followed the Brønsted-type correlation. α-nucleophiles with O, HN, S in the α position were classified into three groups according to their degree and pattern of deviation from the Brønsted-type correlation. First, the α-nucleophiles with downward deviation, in other words, higher reactivity shown considering the basicity or lower basicity given the reactivity, were grouped as nucleophiles showing α-effect. The second group had nucleophiles with small or no deviation from the line plotted by six normal nucleophiles. Lastly, the third group had nucleophiles showing inverse α-effect, meaning that they are above the plotted line or having less reactivity considering their high basicity. Relative density functional theory, activation strain model, energy decomposition analysis, and Kohn-Sham molecular orbital analysis the three groups had distinction in HOMO lobes and HOMO-LUMO gaps.

Using ethyl chloride as the substrate, Bronsted-type correlation was six normal nucleophiles (HO-, CH3O-, H2N-, CH3HN-, CH3S-, HS-)