Carboxylic Acid Derivatives

By James Ashenhurst

Simplifying the reactions of carboxylic acid derivatives (part 1)

Last updated: February 3rd, 2020 |

I’ve had a fair number of emails over the past week or two from students who say that they are having a hard time keeping track of all the reactions of carboxylic acids and their derivatives.

It can get pretty overwhelming, this is true.

Today we’ll talk about the simple principle that lies behind the reactions of carboxylic acid derivatives with basic (i.e. negatively charged) nucleophiles.  If you remember this one principle, you will save yourself a lot of memorization.

Fortunately it’s a principle that you should have learned back in Org 1.

Here it is: acid base reactions always favor formation of the weaker base (and weaker acid, of course).

how do we tell if an acid base reaction will happen - stronger acid plus stronger base gives weaker acid and weaker base

You might recall that good leaving groups are weak bases.

Just like in acid base reactions, reactions of carboxylic acid derivatives also favor formation of the weaker base.  Let’s look at two examples: reactions of anhydrides with alkoxides (deprotonated alcohols) to form esters, and reactions of amides with halides (such as Cl-) to form acid halides.


favorable and unfavorable reactions of carboxylic acid derivatives

Note how in the first reaction, the formation of the ester is favored, since we’re going from a stronger base (alkoxide) to a weaker base (carboxylate). However, in the second reaction we’re going from a weak base (chloride) to a much stronger base (NR2(-)). This isn’t favored at all – in fact, were any acid halide to form at all, it would immediately react with the NR2(-) to regenerate the amide.

A quick refresher, just in case these relative base strengths aren’t immediately coming to mind for you: we measure basicity (and conversely, acidity) through a factor referred to pKa. This measures the equilibrium between the acid and its conjugate base (that’s what’s left over when the acid loses a proton). The stronger the acid, the weaker the conjugate base. The weaker the base, the better the leaving group!

ranking acyl groups according to leaving group ability

Note how leaving group ability goes Cl (-) > RCOO (-) > RO (-) > NR2 (-) > O(2-) > H (-) > R(-)

This ranking gives us a guide as to which reactions are favored and which are not. In short, if the leaving group is a weaker base than the nucleophile, then the reaction should be favored. (again – this is for negatively charged cases only!).

nucleophilic acyl substitution using negatively charged nucleophiles - principles

We can use this information to put together a little “league table” to guide us. Omitting nucleophiles with R and H for now (e.g. Grignards, organolithiums, LiAlH4 and so on) because their reactions are a bit more complicated, we come up with this table.

table of reactions between carboxylic acid derivatives with nucleophiles

Note that this is a smaller and more manageable version of information that can be found in the big freaking grid, aka summary sheet #3.

Three notes:

1) Carboxylic acids are… well, acids. This means that instead of adding to the carbonyl, negatively charged nucleophiles will tend to remove the proton instead. This leaves behind the conjugate base, (the “carboxylate”) which is much worse at reacting with negatively charged nucleophiles. If you think about it for a second, the leaving group from addition/elimination on the carboxylate would have to be O 2- . That’s not a happy leaving group.

why don't carboxylic acids participate in nucleophilic acyl substitution - poor leaving group

2) You can exchange one ester for another if you use a different RO(-) group. Since the basicity of the nucleophile and the leaving group will be very similar, the equilibrium between the two esters will be similar. In order to favor formation of one product, we usually swamp it with a large excess of nucleophile, which drives the equilibrium to the desired direction.

3) Note that HO(-) is a weaker base than NR2(-), but we can still turn an amide into a carboxylic acid. It’s not favorable, but if they’re heated together at very high temperatures, it can happen. What’s likely happening here is that the leaving group is not actually NR2(-) but picks up a proton to become HNR2, which is a weaker base (and better leaving group!).


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