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I know this question has been asked many times but I need to confirm this doubt which has been pestering me for the past few days.

Suppose in an $\mathrm{S_N2}$ reaction (in polar aprotic solvent) we have two nucleophiles:

  • ethoxide $(\ce{EtO-})$ ion;
  • ethyl thiolate $(\ce{EtS-})$ ion.

Now, since we know fluoride $(\ce{F-})$ is stronger nucleophile than iodide $(\ce{I-})$ in polar aprotic solvent, i.e. nucleophilicity parallels basicity. We should expect the alkoxide ion to be more nucleophilic than thiolate since alcohols are weaker acids than thiols.

But my book says the opposite. Is this a exceptional case? If so, could it be predicted in advance that thiolates are better than alkoxide even though fluoride is stronger than iodide?

Any help would be much appreciated.

andselisk
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LM2357
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  • There is not a direct correlation between pKa and nucleophilic strength; pKa is mostly used for leaving group ability. Since the nucleophilic attack occurs via overlap of the nucleophile's HOMO with the p orbital of a carbon atom in the alkyl halide, the major factor in determining the nucleophilicity is how high the HOMO is (higher HOMO --> more nucleophilic). Since S has lower nuclear charge than O, the HOMO in the EtS- ion is higher than that in the EtO- ion (electrons less bound by nuclear charge). Thus, EtS- is more nucleophilic. – Ethiopius Feb 04 '19 at 19:26
  • Predicting nucleophilicity is often a non-trivial task due to the large number of factors to be considered (e.g. thermodynamics of the interaction, orbital interactions, solvent interactions, etc.). – Tan Yong Boon Feb 05 '19 at 00:02

2 Answers2

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Please remember that nucleophilic substitution at a saturated carbon atom does not directly correlate with pKa.

The pKa of a substance (in the Bronsted-Lowry definition) relates to the substance's ability to have strong interactions with $\ce{H^+}$. Thus, this interaction is mainly electrostatic in nature; since $\ce{H^+}$ is a very small, weakly polarizable ion, according to hard-soft acid base theory, strong interactions with this ion are largely electrostatic in nature, i.e. proportional to charge density.

However, nucleophilic substitution at a saturated carbon atom occurs mainly through orbital interactions, not through electrostatic interactions. Namely, the highest occupied molecular orbital (HOMO) of the nucleophile interacts with the LUMO (sigma antibonding orbital) of the substrate (usually alkyl halide).

enter image description here

Since higher energy HOMOs interact better with LUMOs, molecules or ions with higher energy HOMOs are more nucleophilic.

With the specific case that you gave ($\ce{EtO-}$ and $\ce{EtS-}$), consider that sulfur is a larger atom, and the electrons in HOMO in $\ce{EtS-}$ are going to be less tighly held by nuclear charge than electrons in the HOMO in $\ce{EtO-}$. Alternatively, you can consider that the highest energy level orbital in S is 3p while that of oxygen is 2p --> electrons are more tighly held and lower in energy in $\ce{EtO-}$ --> $\ce{EtO-}$ is less nucleophilic.

enter image description here

Thus, if you consider the relative energy levels HOMOs in related molecules and ions, you get the general trend below:

enter image description here

References

Clayden, J., Greeves, N., Warren, S. Organic chemistry, 2nd ed.; Oxford University Press: New York, 2012.

Ethiopius
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  • So why us the halide trend reversed in polar aprotic solvent? – LM2357 Feb 05 '19 at 06:13
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    This is likely due to the absence of hydrogen-ion interactions in aprotic solvent. In protic solvents, the high charge density fluoride ion is solvated while the lower halides are not. This solvation is absent in aprotic solvents. In this case, the solvent effects blur the general trend that we observe just considering the energy level of the HOMO. Just remember that there are several factors other than HOMO energy (such as solvent effects and substrate character) that influence nucleophilicty. Given a reaction, you need to consider these effects together. – Ethiopius Feb 05 '19 at 13:20
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It has been established here that basicity and nucleophilicity are distinct concepts. Why then is basicity often used as a measure of nucleophilicity?

To answer this question, we have to consider the several factors that affect nucleophilicity, which is a kinetic concept (i.e. it is related to the activation energy required for the reaction to take place). My answer here has very clearly put out the factors that affect nucleophilicity. Chiefly, they are the thermodynamics of the interaction (think of the bond energies of bonds being formed and broken), orbital interactions (primarily, a kinetic consideration) and of course, there are the usual steric and solvent considerations.

Being a thermodynamic concept, basicity is related to how strong are the bonds being formed between the nucleophile and the substrate carbon atom. It is essentially the thermodynamic factor which I have mentioned above. The generalisation "more basic means more nucleophilic" has been made as it has been observed that basicity is a good measure of nucleophilicity in most cases. However, it is important to note that consideration of basicity neglects other factors I have highlighted, particularly orbital interactions.

Although thiolates fall behind alkoxides on the thermodynamics factor, they win on the kinetics factor and that seems to be the reason for their higher relative nucleophilicity. The more highest occupied MO of the sulfur atom seems to be closer in energy to the lowest unoccupied MO of the substrate. This results in rather favourable orbital interactions. For more information on this, you can take a look at the portion on Klopman-Salem equation here.

Tan Yong Boon
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  • So, are you saying that the 'thermodynamic' factor (strength of carbon-halide) bond is responsible for the halides trend and the 'kinetic' factor is responsible for the thiolate and alkoxide trend?...By the way in one of your references it is written that, methoxide is better nucleophile than methyl thiolate..Why is that? – LM2357 Feb 05 '19 at 05:50
  • The two factors (thermodynamics and kinetics) are always at play. However, in some cases, one outweighs the other. Yes, that particular reference cites that based on intrinsic nucleophilicities (i.e. solvent-free nucleophilicity). You are considering a polar aprotic solvent, thus solvent factors would come into play, and this could change the relative nucleophilicity order. – Tan Yong Boon Feb 05 '19 at 06:27
  • Are the solvent factors responsible for changed trend in methoxide and thiolate? If yes, how so? I thought that polar aprotic solvent didn't affect the nucleophiles and they were relatively free as opposed to polar protic...By the way, your previous answers were very helpful.. – LM2357 Feb 05 '19 at 07:15
  • I am not entirely sure myself because solvent effects are often not straightforward. The category "polar aprotic solvents" itself is a very broad one with solvents with quite different properties. I am uncertain of how polar aprotic solvents can influence the nucleophilicity order in this case but clearly, there is some sort of influence. That's all I can help you with. – Tan Yong Boon Feb 05 '19 at 07:35