Carboxylic Acid Derivatives
The Power of Acid Catalysis
Last updated: May 24th, 2021 |
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!
catalyst
LOL, you’re hilarious!! Thanks for the help!!
Why is the carbonyl oxygen the most nucleophilic site?
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.
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?
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.
Great Stuff! Might I suggest adding and diving more into the topic of lewis acid catalyst like (ZnCl2, AlCl3)?
Does the amount of catalyst matter in the reaction, or is it just the fact that it is present?
Can vary, but about 5-10 mol% is a good rule of thumb.
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?
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]
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.
Aha. Let me fix that…thanks for the feedback.
Could you explain in a very simple words what is the function of acid catalyst in friedel craft acylation
Here’s a post I wrote about it. https://www.masterorganicchemistry.com/2018/05/17/friedel-crafts-alkylation-acylation/
If you distill off the excess amount of alcohol after refluxing the mixture, wouldn’t it facilitate hydrolysis of the ester, due to the presence of acid (which act as a catalyst and as such is not consumed)?
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?
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.
Can you give some examples of catalysts that can be used for this reaction other than sulfuric acid
Why carbonyl oxygen is more nucleophilic in carboxylic acid
Look at the second-most important resonance form. Where’s the negative charge? That gives you a clue about what element is most nucleophilic.
do nitric acid follow this same principle, or this is just for sulphuric acid ?. if no can you cite an example on how nitric acid catalyzes reactions
Nitric acid would, yes, but people tend to shy away from using it due to the fact that it can act as an oxidant (NO2+) to a lot of functional groups. H2SO4 and H3PO4 are much more innocuous.
Is it okay to do the esterification in the air, not at the nitrogen atmosphere?
I will use DCC as the catalyst for the reaction.
Yes, the reaction will not be affected by air.
Concentrated sulfuric acid is added as a catalyst in the esterification process of forming methyl benzoate from benzoic acid. Why is the sulfuric acid necessary even though another acid (benzoic acid) is one of the organic reagents used?
Benzoic acid has a pKa of about 4, which makes it a pretty weak acid. In order to get the Fischer esterification going at a reasonable rate
you need a stronger acid that is going to give you a decent concentration of the conjugate acid of the carboxylic acid (add H+ to the carbonyl).
IN any acid base reaction you go from “stronger acid + stronger acid —> weaker acid and weaker base”. Since the conjugate acid of the carboxylic acid has a pKa of at least -2 (if not lower) it’s very thermodynamically disfavored for the benzoic acid (pKa = 4) to give that species.
The reaction needs a kick in the pants in the form of a strong acid like H2SO4 (pKa values differ according to source, but vary from -2 to -8). Protonation of the carboxylic acid by H2SO4 is easy and facilitates both addition of methanol to protonated carboxylic acid and also loss of water in the elimination step.
Why can’t Fischer Esterification occur under basic catalysis
Esterification can occur under basic conditions (e.g. transesterification) but the Fischer specifically refers to esterification under acidic conditions.