The origin of the alpha effect, which gives some nucleophiles an unusually high reactivity in substitution reactions, is one of the unsolved mysteries of chemistry. Now computational chemists have discovered a largely overlooked mechanism that provides answers to the problem. “Our breakthrough was the formulation of a causal relationship between the electronic structure of the alpha nucleophiles and their intrinsic reactivity,” says lead researcher Trevor Hamlin from Vrije University in Amsterdam, Netherlands.
The alpha effect was first described in 1962 as the increased nucleophilicity of an atom – often oxygen, nitrogen, or sulfur – due to the presence of a neighboring (alpha) atom with a lone pair of electrons. In the hydroperoxide (OOH–) and hydroxylamine (H2NO–) Anions, for example, “significantly increases reactivity without affecting general basicity,” explains Joaquín Barroso-Flores, a computational chemist at the National Autonomous University of Mexico who was not involved in the study. But “the electronic origin of the alpha effect has challenged chemists for many decades,” he says.
Hamlin argues that previous explanations could not explain the alpha effect because they only focused on the repulsion between the lone electron pairs on the nucleophile and the alpha atom. “This mechanism should also increase the basicity and therefore cannot fully explain the alpha effect,” he says.
His team’s calculations use quantum mechanics to reveal a missing link. “Nucleophiles that exhibit the alpha effect are less likely to have destabilizing steric repulsions with the substrate,” says Hamlin.
Normally, interactions between two occupied orbitals have a destabilizing effect. However, the researchers’ simulations suggest that alpha nucleophiles have significantly smaller orbital lobes in their homo (highest occupied molecular orbital). “The alpha heteroatom polarizes homo in the nucleophilic center, reduces its size and reduces steric repulsion,” explains Barroso-Flores. “It also increases the energy of the homo of the nucleophile, … promotes more efficient overlap, which ultimately leads to increased reactivity.”
“This work provides a thought-provoking conceptual explanation of the origins of the alpha effect,” says Igor Alabugin, an expert on structure and reactivity at Florida State University, USA. “However, the theoretical analysis is simplified by … looking only at the anionic alpha nucleophiles,” he comments. “One can expect that the analysis of neutral systems, in which the alpha effect is only activated for certain geometries, would be more complicated.”
Barroso-Flores is also careful. ‘[The authors] found a very clear relationship between the structure of the nucleophile and the intensity of the alpha effect, but we have to be careful when establishing a causal relationship, ”he says.
Nevertheless, both experts appreciate the contribution of this work to the understanding of the alpha effect. ‘[It] presents a thorough systematic analysis of the alpha effect in a wide range of anionic systems at the same theoretical level and clearly shows [this] Effect is not a general phenomenon, ”explains Alabugin. In addition, the study establishes a classification for different nucleophiles: some have the alpha effect, others do not and a third type has an inverse alpha effect – a phenomenon in which neighboring heteroatoms reduce nucleophilicity.
“The physical principles provided enable a qualitative prediction of whether a nucleophile has the alpha effect solely on the basis of its intrinsic electronic structure,” says Hamlin. ‘Therefore, [this] has the potential to enable chemists to better predict the reactivity of fundamental reactions. ‘