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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

  1. 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.

  2. 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.

  3. Ren, Y.; Yamataka, H. The α-Effect in Gas-Phase SN2 Reactions Revisited. Org. Lett. 2006, 8 (1), 119–121. DOI: 10.1021/ol0526930.

  4. Edwards, J. O.; Pearson, R. G. The Factors Determining Nucleophilic Reactivities. J. Am. Chem. Soc. 1962, 84 (1), 16–24. DOI: 10.1021/ja00860a005.

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    $\begingroup$ I really like your question and the research you have done. I also think your reasoning is quite solid. However, as the definition is quite vague and attempt on finding a 'true'explanation can also only be vague. I agree with you that transition state stabilisation might be the strongest clue so far, but I am also afraid, that it remains an rather unsolved question so far. (Anyway, I'd be delighted if you could post doi or isbn into your question.) $\endgroup$ – Martin - マーチン May 12 '14 at 10:12
  • $\begingroup$ Transition state stabilization is mentioned in couple of new papers published about alpha-effect: 1 "solvent interactions for HOO– are quite different from those with the normal nucleophiles at the transition state, indicating that differential solvation may well contribute to the α-effect." And 2 " Differential solvation effects have been suggested to be responsible for the α-effect in this study," $\endgroup$ – Mikael Jumppanen Apr 22 '15 at 21:05
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    $\begingroup$ This is the n-th time I've read this question, first time commenting. What does the literature say (if anyting) about quantum chemistry simulations of the alpha effect? If first-principles quantum calculations don't capture the alpha effect, then I would think it is truly an unsolved problem in chemistry. If they do however, then it's more a question of which hand-wavey heuristic theory/approximation to QM you want to invoke to "explain" it. If no one has tried modern compuchem methods on the problem, I guess its still unsolved, but seems like a good problem to work on. $\endgroup$ – Curt F. Jun 16 '15 at 2:18
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I am not a kineticist, and my quantum chemistry is long, long out of date, but what I was about to say was that I'd guess the reason the "effect" is "unsolved" is that it's not real.

That is, it is not a property of a single reactant while disregarding its environment (gas phase, solvent interactions). Then I saw that the two recent articles both were about solvation, so my comment is redundant (and certainly only a partially/inadequately educated guess). I'd also comment that comparing $\ce{HO-}$ with $\ce{HOO-}$ is apples and oranges. You should compare it with a species with an alpha atom which is electronegative but doesn't have a lone pair.

If it doesn't really have a published DFT model, then it might be good for an MS student to work on. I suspect answering it is like "curing cancer", it doesn't have just one 'reason', rather the cures depend on the exact nature of the reaction (including solvation).

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