There have been various explanations posited for the α-effect. The α-effect refers to a phenomenon wherein nucleophiles with lone pairs on atoms adjacent (i.e., in the α- position) to the atom bearing the reacting lone pair sometimes exhibit dramatically higher reactivity than similar nucleophiles without α-electrons. This effect is especially adduced when no associated increase in Brønsted basicity occurs. For example, hydroperoxide ($\ce{HOO-}$) experimental reaction rate constants are orders of magnitude greater[1] those of hydroxide ($\ce{HO-}$) with various electrophilic substrates, despite the former exhibiting lower Brønsted basicity. There is also a thermodynamic α-effect, in which equilibrium constants are enhanced[2]. It is currently on the list of unsolved problems in chemistry on Wikipedia, but, due to a lack of references to that effect, I'm not entirely convinced it really should be listed there. Here's the summary of my research on the topic thus far:
- I read Ren, Y. & Yamataka, H.[3], "The alpha-effect in gas-phase SN2 reactions revisited". In it, they claim that explanations based on ground-state destabilization (presumably due to repulsion between the electrons of the nucleophilic atom and the α-electrons) are not correct. Their reasoning is that this would result in a difference in the $\Delta G$ between reactants and products, leading to thermodynamic equilibrium effects. They argue that a correct explanation should be one exclusively involving stabilization of the transition state (i.e., minimization of $\Delta G^{\ddagger}$), and go on to offer some explanation for how this may occur (along with experimental data). Intuitively, their conclusion seems reasonable to me, and it also (at least to my naive comprehension) seems eminently testable. I don't know whether equilibrium effects consistent with ground-state destabilization have actually been observed or not; however, if they haven't, shouldn't that put the nail in the coffin of that theory? Or is it simply that the authors are searching for a purely kinetic α-effect, so that a distinction between a thermodynamic one needs to be made?
- Fleming devotes a section to the effect in his book, Molecular Orbitals and Organic Chemical Reactions. He notes that the presence of the α-lone pair should raise the energy of the HOMO of the nucleophile, but also points that experimental results don't correlate sufficiently well with the HOMO energies of various α-nucleophiles. In particular, certain soft electrophiles (per HSAB theory), such as alkyl halides, apparently show an anomalous low preference for α-nucleophiles. In the context of SET mechanisms, Fleming says that the higher energy of the HOMO and the availability of α-electrons (which can stabilize a radical intermediate) ought to have a highly favorable effect on the rate of reaction, and notes that experimental results have borne this out. My interpretation of this is that, while the picture is perhaps murky for anionic mechanisms, transition-state stabilization clearly seems to be operative in SET mechanisms.
I've also read the original 1962 paper by Pearson and Edwards[4], which also largely argued for transition-state stabilization as the primary explanatory mechanism.
Overall, from my reading thus far, it seems that transition-state stabilization has been most consistently invoked and has the largest wealth of evidence and the most plausible arguments supporting it. What I'd like to ask is, (a) are there flaws in my reasoning or understanding of the material, and (b) is this truly a fundamentally unsolved problem, or is there actually some emerging consensus among experts?
Notes and References
Fleming provides a small table with relative rates ($k_\mathrm{rel} = k_{\ce{HOO-}}/k_{\ce{HO-}}$) in his book. For example, he gives $k_\mathrm{rel} \approx 10^5$ for reaction with $\ce{PhCN}$ and $k_\mathrm{rel} \approx 50$ for $\ce{PhCH2Br}$, while $k_\mathrm{rel} \approx 10^{-4}$ for reaction with $\ce{H3O+}$. The rate of reaction correlates in the expected way with Brønsted basicity only in the case of proton transfer.
Again, citing Fleming, he gives the example of the reaction of N-acetylimidazole with hydroxylamines, in which both rate and equilibrium constants are positively affected. Qualitatively, he explains this by noting that the α-electrons raise the energy of the lone pair conjugated to the π-system, making overlap of said lone pair with the π* LUMO more effective. Additionally, he claims both ground-state stabilization and transition-state destabilization as being factors in the reduced electrophilicity of oximes and hydrazones relative to (most) other standard imines.
Ren, Y.; Yamataka, H. The α-Effect in Gas-Phase SN2 Reactions Revisited. Org. Lett. 2006, 8 (1), 119–121. DOI: 10.1021/ol0526930.
Edwards, J. O.; Pearson, R. G. The Factors Determining Nucleophilic Reactivities. J. Am. Chem. Soc. 1962, 84 (1), 16–24. DOI: 10.1021/ja00860a005.
