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Deciding SN1/SN2/E1/E2 (2) – The Nucleophile/Base

Last time I talked about the process of deciding if a reaction goes through SN1, SN2, E1, or E2 as asking a series of questions. I call it The Quick N’ Dirty Guide To SN1/SN2/E1/E2. This is the second instalment.

Once we’ve looked at a reaction and recognized that it has the potential for proceeding through SN1/SN2/E1/E2 – that is, is it an alkyl halide, alkyl sulfonate (abbreviated as OTs or OMs) or alcohol – and asked whether the carbon attached to the leaving group is primary, secondary, or tertiary, we next can look at the reagent for the reaction.

In substitution reactions, a nucleophile forms a new bond to carbon, and a bond between the carbon and the leaving group is broken. In elimination reactions, a base forms a new bond with a  proton from the carbon, the C-H bond breaks,  a C-C π bond forms, and a bond between carbon and leaving group is broken.

There’s a lot of confusion from students on this point. “How do I know what’s a nucleophile and what’s a base?”.

Whether something is a nucleophile or a base depends on the type of bond it is forming in the reaction. Take a species like NaOH. It’s both a strong base and a good nucleophile. When it’s forming a bond to hydrogen (in an elimination reaction, for instance), we say it’s acting as a base. Similarly, when it’s forming a bond to carbon (as in a substitution reaction) we say it’s acting as a nucleophile. 

In other words, it’s a relationship. For instance, when I’m interacting with my wife, I’m interacting with her as a husband. When I’m talking to my mom, I’m interacting with her as a son. I’m the same person, but depending on whom I’m interacting with, our relationship has different names.

Anyway. All this is prelude to making the key determination for today, which is:

  1. Charged bases/nucleophiles will tend to perform SN2/E2 reactions.
  2. Reactions where neutral bases/nucleophiles are involved tend to go through carbocations (i.e. they tend to be SN1/E1).
Again: Quick N’ Dirty is an 80/20 set of principles. There are exceptions!!! But this framework will help us in most situations.

Charged Nucleophiles/Bases

Let’s talk about charged nucleophiles first. It’s important to be able to recognize charged nucleophiles. The charges are often not written in, but “implied”. For example, NaOEt (sodium ethoxide) actually has an ionic bond between Na(+)  and (-)OEt, even though the charges themselves aren’t written in (us chemists are lazy that way). So if you see Na, K, or Li, for instance, you’re looking at a charged nucleophile/base. Whether it’s K, Na, or Li doesn’t matter for our purposes – these are just spectator ions.

In both the SN2 and E2 pathways the reaction is “concerted” – that is, the nucleophile/base forms a bond as the C-LG bond is broken. Since there is significant bond-breaking occurring in the transition state, the energy barrier for this step is higher than in the (second) step of the E1 or SN1; we’re going to require a stronger nucleophile/base to perform these reactions. Recall that the conjugate base is always a stronger nucleophile. Negatively charged species have a higher electron density and are more reactive than their neutral counterparts.

Quick N’ Dirty Rule #3:

If you see a charged nucleophile/base, you can rule out carbocation formation (i.e. rule out SN1/E1). In other words, the reaction will be SN2/E2. 

We can break things down even more, depending on how strong a base the charged species is; go to the section at the bottom of this post for some examples where we can use base strength to rule out E2.

Reactions of Neutral Bases/Nucleophiles

Neutral bases/nucleophiles tend to be weaker than negatively charged bases/nucleophiles. In order for them to participate in substitution or elimination reactions, generally the leaving group must depart first, giving a carbocation.

Quick N’ Dirty Rule #4: If you don’t see a charged species present, you’re likely looking at a reaction that will go through a carbocation (i.e. an SN1 or E1).

One special case worth noting is if you see a strong acid such as H2SO4 or HCl with an alcohol as a substrate. Unless you’re looking at a primary alcohol (where carbocations are very unstable) the reactions in these cases will almost always proceed through carbocations.

It’s not uncommon to see a neutral nucleophile in the presence of a charged one (see example 2, below). In that case it’s likely acting as the solvent. We’ll talk about solvents next. 

Here’s a chart where we evaluate this second question for deciding if a reaction is SN1, SN2, E1, or E2 (below).

What’s the biggest weakness of the Quick N’ Dirty approach? It’s an oversimplification. To conclude that a reaction “proceeds SN2” or “proceeds E2” might give the impression that it gives 100% SN2 or 100% E2, and that is surely not the case! Often, these reactions compete with each other, and can therefore give mixtures products. When I say “SN2” , for instance, I mean mostly SN2. There are likely other products in there.  

The key lesson here is to understand the concepts – “what conditions favor each reaction?” and then to be able to apply the rules you know about each reaction to draw the proper product.

Next Post: The Role of Solvent


Elaboration: Good Nucleophiles That Are Weak Bases

Some charged nucleophiles are actually poor bases. Here’s a good rule of thumb: if the conjugate acid of the base/nucleophile is less than 12, an E2 reaction will be extremely unlikely. So if you see a nucleophile like NaCl, NaBr, KCN, and so on, it will favor SN2 over E2.

(This is a more rigorous way of saying that weak bases don’t perform E2 reactions).

In contrast, the bulky base below (tert-butoxide ion) is a strong base but a poor nucleophile due to its great steric hindrance, so an E2 reaction is much more likely than SN2.

Exception: Neutral Nucleophiles in SN2 and E2 Reactions

One class of neutral nucleophiles/bases that readily perform E2 reactions (and SN2) are amines. For example, the tertiary alkyl halide below will undergo elimination through E2 here, although the Quick N’ Dirty rules call for SN1/E1. Amines are generally not the most useful nucleophiles for doing SN2 however because they lead to over-alkylation and ammonium salt formation. [See: Alkylation of Amines (Sucks!)]

Finally, there are also neutral species which are good nucleophiles (and poor bases) such as PPh3, below.

Exception: Charged Nucleophiles In SN1 Reactions

It’s also possible to use charged nucleophiles in SN1 reactions under certain conditions. If you have, for instance a tertiary alkyl halide in the presence of a high concentration of a  good nucleophile (but weak base) such as those above, the carbocation that forms can be intercepted by that nucleophile. For example:

Here, the good nucleophile (cyanide ion), if present in large excess, can overpower the weak nucleophile  (solvent). Of course the ultimate arbiter of such statements are actual experiments.

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