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 voila – you have your ester.

1-AcidCat

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:

protontransfer_2

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.*

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! 

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{ 13 comments… read them below or add one }

vipul

catalyst

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dara

LOL, you’re hilarious!! Thanks for the help!!

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am

Why is the carbonyl oxygen the most nucleophilic site?

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James

The carbonyl oxygen is more electron-rich, especially when you consider that it is in conjugation with the OH. Imagine a resonance form where the OH donates a pair of electrons to form a double bond, resulting in O- where the carbonyl is.

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chris

Was wondering if you could talk more about the equilibrium of the reaction… isn’t each step reversible? Or do you just end up with a bunch of ester and an equal number of H2O molecules?

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James

True – each step is reversible. To drive the reaction to completion, the choice of solvent is critical. For the Fischer esterification [carb acid plus alcohol –> ester + H2O], for example, one uses the alcohol as the solvent. Since the concentration of alcohol will vastly outnumber the concentration of water formed in the process, the reaction will go to the right.
Another way to do it is to remove or trap the water that is formed by using an apparatus known as a Dean Stark trap.

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Alex

Great Stuff! Might I suggest adding and diving more into the topic of lewis acid catalyst like (ZnCl2, AlCl3)?

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Andrew

If a solid acid catalyst, capable of protonating and de-protonating, is added to an ester(EVA for example) and there is no free moisture in the system, is the water that is formed from the reaction of the catalyst producing H2O?

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James

Not 100% sure what you’re asking, but if you take polymeric ethylene vinyl acetate (EVA) [which contains ester linkages] and treat with an acid catalyst, nothing will happen beyond protonation UNLESS water is added. In that case, then the ester will be hydrolyzed to give carboxylic acids. [edit: changed deprotonation to protonation]

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Victoria Provost

Hi! I understood/loved the diagrams and explanations, but the way the diagram is written line to line (for the order of the steps) is confusing in my opinion….i went straight to product step on the next line and was so confused because the product didn’t have a step number assigned to it, i assumed it was the next step.

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Athirah nasuha

Could you explain in a very simple words what is the function of acid catalyst in friedel craft acylation

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dale

how strong of an acid would we have to use to do this? hcl has a pka of -7 and a protonated ketone is at around -7.3. is this difference in magnitude enough to protonate a percentage of ketones/aldehydes or do we need a stronger acid like maybe hbr?

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James

A good rule of thumb is about 8 pKa units up. So in order for the protonated ketone (pKa -7) to be accessible via equilibrium, you could use an acid with a pKa of 1 or below. Acetic acid (pKa 4) would be too weak, but H2SO4 (-3) is just fine.

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