smuv
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Counterion: effect upon alkylations in polar protic solvents
Lately I have resumed an old project, investigating MeONO2 as a methylating agent for phenols. In order to optimize conditions, I have been doing a
lot of reading about substrate, solvent and base effects upon SN2 reactions. The problem is, all the studies I have read exclusively deal with polar
aprotic solvents.
I am wondering if anyone has a source or experience addressing the effects of counterions on SN2 reactions in polar protic (specifically lower
alcohols) solvents. I suspect the effect is negligible, but I would really like something to base this on.
Thanks
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spirocycle
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In class we learned that SN1 reactions become favorable in protic solvents, because the solvent can easily protonate your nucleophile before the
reaction occurs
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Nicodem
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The counterion does have a huge effect on kinetics of SN2 in non-aqueous solvents, as well as some effect on the chemoselectivity of SN2 reactions on
ambident nucleophiles. Both effects are explained by the HSAB theory* coupled with solvation theory. Both theoretic principles act together and can
often cancel each other (ironically, the solvation theory actually relies on HSAB principles in many of its aspects).
Therefore, the more acidic the cation, the slower the reaction; but like already said, solvation can cancel this. The more protic and polar the
solvent, the less marked is the influence on the kinetics. For example, in water, the use of lithium, sodium, potassium or caesium as counterions for
the phenoxide has practically no influence on the kinetics of its alkylation. But in aprotic solvents (DMF, DMSO, THF, etc.) it has a huge influence.
You can imagine that in aprotic nonpolar solvents (like toluene) the reaction of the lithium phenoxide would be several magnitudes slower than the
analogous reaction of the caesium phenoxide (solubility issues ignored).
The influence on the chemoselectivity is similarly practically absent in highly protic solvents like water, methanol, formic acid or formamide where
ion pairing with the counterion is inhibited due to solvation of the nucleophile (H-bonds) and the cation (ion-dipole interactions). In the solvents
where there can still be lots of ion pairing (e.g., DMF, THF) or where the salt exists practically only as tight ion pairs (e.g., in toluene), the
influence on the chemoselectivity can be from small to strong, though rarely extreme. In the above hypothetical example of lithium vs. cesium
phenoxide in toluene, you can expect less selectivity for O-alkylation in the case of lithium counterion (soft acid electrophiles like allyl bromide
are known to generally give even up to 10% C-allylation in their reaction with sodium or potassium phenoxides already in the more polar and even
protic solvents).**
Regarding ambident nucleophiles (phenols are such), the HSAB theory free interpretation says that the harder acid the counterion is, the more tightly
it will sit on the harder basic site of nucleophile, thus making the softer basic site of the nucleophile freer to attack the electrophile. But this
effect has its limitation. For a practical example, even in THF, you cannot expect a lithium enolate*** to selectively give only C-methylation and the
ceasium enolate to give only O-methylation when using a hard acid electrophile like dimethyl sulfate. But you can expect an improved C- vs.
O-methylation for the lithium enolate at the cost of a considerably slower reaction. However for a truly selective C-methylation one will nevertheless
have to resort to a softer acid electrophile like methyl iodide for methylation of enolates in which case you can use sodium or potassium enolate and
still get a pretty good C-methylation selectivity and better kinetics.
PS: Do not confuse the effect of the counterion with the effect of bases used under heterogeneous conditions (for example, alkali carbonates, K3PO4,
etc.). While the chemoselectivity effect is still there in such reaction mixtures, the kinetics can be more influenced by solubility and dissolution
kinetics. Not only the solubility, but obviously also the basicity of bases dramatically influences the kinetics (for example Na2CO3 is, besides
generally less soluble, also less basic than K2CO3 or Cs2CO3 in organic solvents - this can again be explained by HSAB principles!).
* Some references on the hard soft acids bases (HSAB) principles:
Chemical Reviews, 75 (1975) 1-20. (review)
Tetrahedron, 58 (2002) 1017-1050. (review)
J. Org. Chem., 34 (1969) 1969-1973. (“O vs. C Alkylation of Ethyl Acetoacetate”, an interesting study on the chemoselectivity in regard
to HSAB)
http://www.meta-synthesis.com/webbook/43_hsab/HSAB.html
** Methyl nitrate should be a hard acid according to HSAB concepts. It should be as hard as or harder than dimethyl sulfate.
*** Enolates are ambident nucleophiles where the oxygen anion is the harder base position (in HSAB concepts) and the double bond is the softer base
position. Both positions are nucleophilic in the classical concepts, but their hardness-softness is quite different thus giving rise to
chemoselectivity differences in the reaction with electrophiles of different hardness-softness (ignoring steric factors). Other ambident nucleophiles
(nitrite, sulfite, cyanate, sulfoxides, enamines, phenols, etc.) behave similarly.
[Edited on 26/1/2011 by Nicodem]
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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smuv
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Nicodem, It looks like you put quite some thought into that post, and I want to thank you. I had been reading extensively about HSAB concepts (it was
something that was really not covered as much as it should have been in lectures), and in one post you pretty much delivered what I had gathered from
a bunch of reviews and a lot of research, plus a little more (I especially liked the O/C phenolate alkylation part)
Other than the chem rev. paper and the meta-synthesis page, I have only had time to skim the other two articles. Still though, as I see it, there are
a lot of allusions and things that could be readily inferred about the counterion effects in protic solvents, but I have never actually seen a study
directly testing this in a polar protic solvent (only aprotics). I guess this is because the effects are supposed to be trivial, and wouldn't make
for an interesting paper...
In the end, finding such study wouldn't change much; even if I found a paper saying the rate increase was nil, I'd probably still compare the yields
between sodium and potassium phenolates anyways...just to see.
Time will tell.
Edit: I suppose this thread could not be complete without mentioning, Chemical Hardness by Peasrson. Download link: http://ebookee.org/Chemical-Hardness-Applications-from-Molec...
[Edited on 1-30-2011 by smuv]
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