Yamaguchi esterification

I love the name of this one, it reminds me of the Tamagotchi toys I used to play with as a kid (reference for anyone’s personal interest in the game: http://en.wikipedia.org/wiki/Tamagotchi). It’s basically the oldest form of Neopets that’s been around since 1996, lol. Anyways, the Yamaguchi esterification is the reaction of an aliphatic carboxylic acid with the Yamaguchi reagent, which is 2,4,6-trichlorobenzoyl chloride, under basic conditions.

Here is a mechanistic look at it.

The most common use of base is triethylamine (both smelly and ubiquitous). From there, the formed anhydride reacts with an alcohol and stoichiometric amounts of DMAP (4-dimethylaminopyridine) and apparently heated conditions to give an ester. The scope of this reaction is quite large in that different kinds of aliphatic carboxylic acids and alcohols can be used to create highly functionalized esters. However, substituents on either reactant shouldn’t be base- or heat-sensitive, since this reaction does occur in triethylamine. Because the first step is essentially an acid-base reaction followed by SN2, it should go quickly and have very limited side reactions. Once the anhydride forms, some rearrangement of the electrons in DMAP makes the nitrogen of pyridine nucleophilic enough to attack the electrophilic carbon of the carbonyl that is less hindered (or less sterically demanding than the carbonyl originally from the benzoyl chloride, as having two aromatic groups very close to each other is a no-no). After this SN2 reaction, the resulting molecule reacts with alcohol to produce the final product, an ester. I am not sure why heat is necessary for the reaction with DMAP, but I think it has something to do with elimination of the proton from alcohol. This method also provides a convenient way of making lactones (cyclic esters) if the starting carboxylic acid has a terminal alcohol, and unique esters if the aliphatic acid and/or alcohol had some crazy substitutions to begin with.