Carboxylic Acid Derivatives
By James Ashenhurst
The Power of Acid Catalysis
Last updated: March 27th, 2019
When I talked about 10 key concepts in carbonyl chemistry a few weeks ago, there was one subject that I wanted to talk about in more depth but left out. That subject is acid catalysis, and any discussion of carbonyls would be remiss without it. Let’s get back to the subject by taking a really straightforward reaction that you’ve probably done in your labs. It’s called the Fischer esterification and it illustrates two of the key roles that acids can play in assisting chemical reactions.
The Fischer esterification is the reaction between a carboxylic acid and an alcohol to give an ester. You typically run the reaction by dissolving the carboxylic acid in the alcohol you want to make the ester with (e.g. ethanol to make the ethyl ester). The reason you do this is that it’s an equilibrium reaction: your product is water, so by using your alcohol as solvent, you effectively drown out the reverse reaction, which is hydrolysis of the ester to give you back the acid. The final step of setting up the reaction is the addition of a strong acid (like HCl or tosic acid) and commencing heating. After an hour or two at reflux, you strip off the solvent, and voilá – you have your ester.
Factor #1: Acids Increase Electrophilicity
Here’s observation #1. Without the acid catalyst, the reaction is painfully slow. You could let this heat for a week and the reaction would barely go anywhere. How do we best explain this? Well, there are two reasons. Let’s look at the mechanism in detail:
You’ll notice that the first step of the reaction is protonation of the carbonyl oxygen by the strong acid. Mechanistically, it might be tempting to protonate the OH, because we know that’s the group that’s going to leave. Actually, the carbonyl oxygen is protonated first because it is the most nucleophilic site. Now, when the carbonyl is protonated, some of the electron density on oxygen that was available for donation to the carbonyl carbon is taken up by the new O-H bond. The net effect of protonation is thus to weaken the carbon oxygen π bond. That leads us to this: Protonation of the carbonyl makes the carbonyl carbon a stronger electrophile. [This is true for all carbonyls, by the way, not just carboxylic acids.] This means it will react more quickly with whatever nucleophiles might be present in solution; in our case, the alcohol.
Note, though, that in our reaction, we’re using methanol, which is a pretty weak nucleophile. This is important. For a reaction involving acid catalysis, it’s really important to use a nucleophile that will protonate reversibly under the reaction conditions. For instance, if we tried using a Grignard or even an amine in this reaction, the acid would (irreversibly) hit the juicy lone pairs of those nucleophiles instead of the carbonyl oxygen and our nucleophile would be toast. Result: no reaction at the carbonyl. So if we want to take advantage of acid catalysis, we have to keep this in mind.*
Factor #2: Acid Makes Better Leaving Groups
Let’s look at the second factor which makes acid catalysis effective. In part 3 of the mechanism, after the alcohol attacks, we’re left with 3 carbon-oxygen bonds. Now as you well know, Nature abhors the hydroxyl ion OH¯ as a leaving group under most circumstances. When an acid catalyst is present, however, that OH is easily protonated to OH2 and our leaving group becomes water, which is a wonderful leaving group. So here’s the second principle: Acid greatly facilitates elimination of the leaving group. Let’s put this in perspective: the pKa of H2O is about 16. That’s the equilibrium between H2O and OH¯ – i.e., a good measure of OH¯ as a leaving group. Compare that to the pKa of H3O(+), which is -1.7. Essentially what I’m saying is that water is a better leaving group than OH¯ by about 10 to the power of 17. [This is your cue to say “Holy f*ck!”]. That’s the power of acid catalysis.
Without the addition of acid, the carboxylic acid and alcohol would just stare at each other in the reaction flask, bump into one another by accident, and continue on with their lives unchanged. The acid catalyst is the special ingredient that transforms a really lame party into something burned into your long-term memory. Inhibitions suddenly disappear. Barriers are lowered. Suddenly, chemistry happens!