Recently I posted on a dinosaur of a development compound in which we used an extractive esterification to prepare a methyl ester of a benzoic acid derivative. A reader asked me to explain this in a little more detail, so here we go.
This is nothing more than a normal Fischer esterification carried out in a two phase system. So we used about 500Kg of the benzoic acid, 320Kg methanol, 715Kg heptane and added while stirring rapidly 240Kg of 98% sulphuric acid, this is exothermic. The mixture is heated to 90°C for 5 or so hours, or until the reaction is complete, cooled and diluted with 530Kg water and the phases separated. The heptane is washed with 120Kg, 4wt% NaHCO3 solution and the layers separated (CO2 formation). The pH of the aqueous phase is checked and needs to reach about 6.5. So one just repeats the wash until this is reached. Just remove the heptane and you have your methyl ester in about 97% yield corrected for traces of heptane, around 2-3%. This product can be used directly in any further steps. The heptane can be re-used with monitoring to ensure that no side products accumulate.
So basically this reaction happens at the solvent/solvent interface and extremely efficient stirring is required, a magnetic stirring bar (for lab preps) is not sufficient, use a mechanical stirrer. Effectively, as the ester is formed it is removed from the hostile conditions of hot 98% sulphuric acid by extraction into the heptane. Also you don’t need vast quantities of base to neutralise the sulphuric, quantities which may hydrolyse your ester. Dilution with water also helps push the ester remaining in the methanol to the heptane phase.
About the scope, well obviously good for benzoic acids. In fact as long as your ester is simple, methyl, ethyl, futile, and heptane soluble this is a great method. You also need to be able to remove the heptane from the ester, so the BPt. difference should be large. It will work for most aromatics, as long as the esters are heptane soluble or the aromatic substituents are not worried by 98% sulphuric. It also works for aliphatic esters, again with the proviso that are soluble in and they can be separated from the heptane. I used this sort of procedure on a variety of compounds and can recommend it
Watch out for dimethyl ether or diethyl ether formation if doing this on scale. Also earth the system if doing on scale (static discharge). Some of the aromatic esters may crystallise out from the heptane when the solution becomes concentrated enough, an added bonus.
Otherwise the reaction is not a great problem. So I hope this answers the question asked. Happy esterification.
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