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The Conjugate Acid Is A Better Leaving Group

One of the key factors that determines whether a nucleophilic substitution reaction will happen or not is the identity of the leaving group. Previously, we’ve seen that good leaving groups are weak bases. That means that if you see a halogen (Cl, Br, or I) or a tosylate (OTs) or mesylate (OMs) on your molecule, these are all good candidates to be leaving groups, since Cl(–), Br(–), I(–), TsO(–), and MsO(–) are all weak bases.

Here’s the problem. What if we have a functional group on a molecule that we’d like to involve in a substitution reaction, but it isn’t a good leaving group like the ones listed above? For instance, the reactions listed below don’t work, because the leaving group (HO-) is a strong base and thus a poor leaving group.

What can we do to involve OH (and other similar groups) so that they can participate in substitution reactions? Well, we need our leaving group to be a weaker base. How do we make it a weaker base? By removing some of its electron density. The best way to do this is to treat it with acid. This will make the conjugate acid of our leaving group, which will be a weaker base. And then these reactions will proceed nicely.

Here’s an SN2 example:


To put some numbers on it, if you look at a pKa table, you’ll see that the pKa of H2O (water) is about 16 (15.7). Its conjugate base is HO(–). When we add acid, water becomes H3O(+), which has a pKa of –1.7. It’s a much stronger acid, in other words, and therefore its conjugate base (water, H2O) is much weaker. In other words, by adding acid, we’ve made it a better leaving group.

This is a general phenomenon, by the way – the conjugate acid will always be a better leaving group. 

It applies not only to OH, but other functional groups as well. For example, ethers (R–O–R) are some of the most unreactive species you’ll meet. However, if you add a very strong acid to an ether, you can break it open to give an alcohol and an alkyl halide:

We can take advantage of this to make halogens better leaving groups too. Halogens don’t react with H+ as readily as alcohols and ethers do, but they do react with certain Lewis acids [remember – a Lewis acid accepts a lone pair]. One Lewis acid that gets a lot of attention with halides is Ag+ (silver ion). You might see it as AgNO3 or AgBF4  (the counter-ion NO3(-) or BF4(-) is just a spectator here). When Ag+ combines with a halogen such as Cl, the resulting species R-Cl-Ag (+) has a considerably weaker C-Cl bond, meaning it can better participate in substitution reactions. With secondary or tertiary alkyl halides, the result is usually formation of a carbocation. One neat trick is that silver halides are insoluble in water, so if water is chosen as solvent, loss of AgCl is irreversible. The carbocation is then trapped by the water solvent.

In the end, it’s still the same phenomenon here. Whether we use a Brønsted acid or a Lewis acid, the conjugate acid is always a better leaving group, and acid can be helpful for getting substitution reactions to proceed at a much faster rate than they would otherwise.

In the next post, let’s compare the SN1 and SN2 reactions.

Next Post: Comparing The SN1 and SN2 Reactions

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