CN- vs. CH3OH in terms of nucleophilicity

[deleted647690]

"Which of the following reactions is most likely to proceed by an Sn2 mechanism?

CN- + .......some electrophile
CH3OH + .....same electrophile"

So it is comparing the nucleophile strengths. The answer was that the CN- reaction would be more likely, because CN- is a stronger nucleophile.

However, if you look at the conjugate acids, isn't CH3OH2 + a stronger acid than HCN because of the + charge? And that would imply that the conjugate base (the nucleophile in the question, CH3OH) is more stable, and thus a better nucleophile?

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[aldol16]

However, if you look at the conjugate acids, isn't CH3OH2 + a stronger acid than HCN because of the + charge? And that would imply that the conjugate base (the nucleophile in the question, CH3OH) is more stable, and thus a better nucleophile?

You're mixing two phenomena here. There is an easier way of explaining your confusion and we will get to that later, but nucleophilicity vs. basicity is an important chemical concept. Nucleophilicity is a kinetic phenomenon. It relates to how fast something can donate a pair of electrons to something else. Basicity is a thermodynamic phenomenon. It is a measure of the equilibrium between a base and its conjugate acid. In other words, basicity is a specific subset of nucleophility. That is, basicity is when a nucleophile donates its electron pair to a proton. Nucleophilicity in general involves donation of that electron pair to any electrophile.

So what's the difference? Well, because donation of an electron pair to proton is easily reversible - that is, deprotonation can occur with a sufficiently similar rate as protonation - we can characterize this reaction as a thermodynamic equilibrium. This allows us to measure the "nucleophilicity" of a base via thermodynamics. However, most nucleophilic reactions are not easily reversible and thus you can't easily measure nucleophilicity by simple thermodynamic considerations.

Now in this specific case, let's imagine the simple case of "electrophile" being H+. This allows us to apply a thermodynamics as a measure of basicity here (which should not be applied generally because of the difference between nucleophilicity and basicity). Okay. Now if the electrophile = H+, then the relevant thermodynamic equilibria are here:

(1) -CN + H+ ----> HCN

(2) MeOH + H+ ----> MeOH2+

So now the task has been reduced to figuring out which one has an equilibrium that lies farther to the right. A rightward-lying equilibrium says that the forward reaction, namely donation of an electron pair from the base to the proton, is favored. In other words, this is what the question is asking for if you take "electrophile" to be the simple case of H+. So as you say, MeOH2+ would be a stronger acid than HCN because it would want to lose that positive charge. Indeed, the pKa of the former is -2.2 whereas the latter is 9.2 Therefore, (2) would have an equilibrium that favors the lefthand side whereas (1) has an equilibrium that favors the righthand side more. Since we're talking about nucleophilicity here, or the donation of an electron pair to an electrophile, this means that (1) would result in better donation of the electron pair from the nucleophile to the electrophile to result in HCN.

Now, to complete the picture. Since we're talking about nucleophilicity here, which is a kinetic phenomenon, we also must take into account things like sterics and solvent. There's no solvent given here so let's make sure the steric picture also points towards the same answer. SN2 reactions take place by backside attack and are governed by sterics. In other words, we have to consider nucleophile size because its approach is relevant to the transition state. Had the question been asking about SN1, nucleophilicity and nucleophile size wouldn't have mattered. -CN is certainly smaller than MeOH. Therefore, one would predict that -CN approaches the electrophile easier and therefore does SN2 faster than MeOH.

 

[deleted647690]

You're mixing two phenomena here. There is an easier way of explaining your confusion and we will get to that later, but nucleophilicity vs. basicity is an important chemical concept. Nucleophilicity is a kinetic phenomenon. It relates to how fast something can donate a pair of electrons to something else. Basicity is a thermodynamic phenomenon. It is a measure of the equilibrium between a base and its conjugate acid. In other words, basicity is a specific subset of nucleophility. That is, basicity is when a nucleophile donates its electron pair to a proton. Nucleophilicity in general involves donation of that electron pair to any electrophile.

So what's the difference? Well, because donation of an electron pair to proton is easily reversible - that is, deprotonation can occur with a sufficiently similar rate as protonation - we can characterize this reaction as a thermodynamic equilibrium. This allows us to measure the "nucleophilicity" of a base via thermodynamics. However, most nucleophilic reactions are not easily reversible and thus you can't easily measure nucleophilicity by simple thermodynamic considerations.

Now in this specific case, let's imagine the simple case of "electrophile" being H+. This allows us to apply a thermodynamics as a measure of basicity here (which should not be applied generally because of the difference between nucleophilicity and basicity). Okay. Now if the electrophile = H+, then the relevant thermodynamic equilibria are here:

(1) -CN + H+ ----> HCN

(2) MeOH + H+ ----> MeOH2+

So now the task has been reduced to figuring out which one has an equilibrium that lies farther to the right. A rightward-lying equilibrium says that the forward reaction, namely donation of an electron pair from the base to the proton, is favored. In other words, this is what the question is asking for if you take "electrophile" to be the simple case of H+. So as you say, MeOH2+ would be a stronger acid than HCN because it would want to lose that positive charge. Indeed, the pKa of the former is -2.2 whereas the latter is 9.2 Therefore, (2) would have an equilibrium that favors the lefthand side whereas (1) has an equilibrium that favors the righthand side more. Since we're talking about nucleophilicity here, or the donation of an electron pair to an electrophile, this means that (1) would result in better donation of the electron pair from the nucleophile to the electrophile to result in HCN.

Now, to complete the picture. Since we're talking about nucleophilicity here, which is a kinetic phenomenon, we also must take into account things like sterics and solvent. There's no solvent given here so let's make sure the steric picture also points towards the same answer. SN2 reactions take place by backside attack and are governed by sterics. In other words, we have to consider nucleophile size because its approach is relevant to the transition state. Had the question been asking about SN1, nucleophilicity and nucleophile size wouldn't have mattered. -CN is certainly smaller than MeOH. Therefore, one would predict that -CN approaches the electrophile easier and therefore does SN2 faster than MeOH.

Thank you for the really in depth explanation! I enjoy all the help you and others provide on this board.

After reading your explanation, and thinking about how I thought through the problem again, I think I found where I was confused. I have been supplementing with Klein's Organic as a Second Language, and I believe I confused what constitutes a good leaving group vs. what is a good nucleophile.

In his book, he talks about how the best leaving groups will be stable bases, and thus have stronger conjugate acids. I should have just seen right away from this problem that CN- has a negative charge, which automatically trumps the MeOH since it has an excess of electrons to donate.

In addition, that makes sense that, since
The conjugate acid of CN- has a higher pKa than the conjugate acid of CH3OH
Thus, the conjugate acid of CH3OH is a stronger acid
Thus, the nucleophilic base, CH3OH is more stable and weaker than CN-.
Thus, CN- is a stronger nucleophile.


I hope I am not incorrect with the phrase "nucleophilic base". That is a term that my organic I teacher always used.


I was also curious, what are the main reasons that CN- is certainly smaller than MeOH? You could say that CN-, being an anion, is smaller/electron cloud is held more tightly?

 

[deleted647690]

Edit:

In reference to my question about whether it is okay to use the phrasing, "nucleophilic base", I just wanted to make sure because of the distinction you wrote about between bases and nucleophiles.

To add, there is another question in berkeley review that asks about the strength of a nucleophile, and they use the reasoning that, "HCl is a stong acid while methanol is a weak acid, so methoxide is a stronger base than chloride. This means that methoxide is more willing ot donate electrons than chloride, and therefore methoxide is the better nucleophile."


So does base = nucleophile only when referring to reactions with protons acting as electrophiles (IE, acid/base reactions)? That is what you were saying I suppose.

I can't really think of nucleophile/electrophile chemistry in any context other than acid/base equilibria

 

[aldol16]

I was also curious, what are the main reasons that CN- is certainly smaller than MeOH? You could say that CN-, being an anion, is smaller/electron cloud is held more tightly?

It's mainly a simple steric picture/argument. You only have two atoms that are held fairly close together (sp carbon) in -CN whereas MeOH is just bigger. You can try building it with a model kit if you're having trouble visualizing it.

In reference to my question about whether it is okay to use the phrasing, "nucleophilic base", I just wanted to make sure because of the distinction you wrote about between bases and nucleophiles.

All bases are nucleophilic because bases are just a subset of the broader class of nucleophiles, so I don't see the point in saying "nucleophilic base."

To add, there is another question in berkeley review that asks about the strength of a nucleophile, and they use the reasoning that, "HCl is a stong acid while methanol is a weak acid, so methoxide is a stronger base than chloride. This means that methoxide is more willing ot donate electrons than chloride, and therefore methoxide is the better nucleophile."

They are blurring the line between nucleophilicity and basicity and that is a bad thing. Their conclusion isn't incorrect, but remember, acidity is a thermodynamic measure of the ability to donate a lone pair to a proton whereas nucleophilicity is a kinetic measure of the ability to donate a lone pair in general. The difference is that because donation of a lone pair to a proton is reversible, you can talk about equilibrium which is a thermodynamic measure. This, in turn, permits you to talk about stability when you're talking about the nucleophilicity of a base (i.e. basicity). But you have to realize that you can't do this in general when talking about nucleophiles.

And here's the problem. t-butoxide is quite a strong base. In fact, you use it a lot when doing carbonyl chemistry and trying to make enolates. That means that t-butoxide is quite willing to donate a lone pair to a proton. However, t-butoxide is a terrible nucleophile! Because nucleophilicity involves donation of a lone pair to any other species, t-butoxide is a terrible nucleophile because it's too big to get close to the electrophile. So you don't want to use t-butoxide when you're doing something like an SN2. You'll end up with mainly E2 products. Sterics, solvent interactions, etc. matter for nucleophilicity and not so much for basicity because bases are concerned only with nucleophilic attack upon proton and protons are quite small.

So does base = nucleophile only when referring to reactions with protons acting as electrophiles (IE, acid/base reactions)? That is what you were saying I suppose.

Therefore, given the above, yes.

I can't really think of nucleophile/electrophile chemistry in any context other than acid/base equilibria

Think about carbonyl chemistry. Or nucleophilic substitutions. Or any type of organic C-X bond formation. Acid-base chemistry is actually a very small subset of nucleophile chemistry. Most of organic chemistry is based on nucleophile chemistry in contexts other than acid-base chemistry.