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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Cheers for elaborating on this, I appreciate it.
Given that it is a two phase system, I’m guessing alcohols miscible with heptane probably won’t work (so well)? I’m quite suprised you can maintain a reaction temperature of 90 *C with all that methanol in there, especially as n-heptane and methanol form a positive azeotrope. It looks like you’re using a ratio of approx 1 eq. acid : 2.5 eq. alcohol : 0.6 eq. sulfuric, with 1.4 ish volumes of heptane (relative to acid)
Does the acid need to be completely in solution at the start of the reaction, or will a solid-liquid-liquid phase reaction also work well?
The alcohols cannot be soluble in heptane. In this case the reaction mixture was milky-white, a suspension of the acid. This is not a problem as it dissolves upon reaction and at the end you have two clear phases.
Thats what I was expecting, so you’re pretty much limited to methyl, ethyl and propyl alcohols. Butanol is apparently miscible with heptanes (in some proportion). In terms of non-polar solvent, I guess its possible to use hexane/cyclohexane or decane in order to vary bp difference with product to facilitate isolation?
Yes it is limited to lower alcohols. As you say fiddling with the non-polar solvent may extend the range of useful alcohols.
I would also think that the dissolution of the carboxylic acid may lower the solubility of the alcohol somewhat. But that would have to be examined. Halogenated alkanes, trifluoromethyl, fluorocarbons may also be viable (thinking of fluorous chemistry here).
Fluorous chemistry, although is a great principle, is not going to be practical on scale. Perfluorocarbon solvents are extremely expensive, do not really dissolve many things. I used to work for one of the guys who discovered this chemistry, most of the things that dissolved in perfluorocarbons (most often perfluoro methylcyclohexane) have a massive aliphatic fluorine content (aprox. 50% by weight).
Thanks for the comment. Yes, I realise that fluorous chemistry won’t be any good on scale, I assumed the other poster would not be carrying out this reaction on anything but a much smaller scale than I did.
On checking some data tables it appears that only methanol is immiscible with heptanes; the other alcohols are miscible. As you say, dissolution of the acid could promote phase separation, and I suspect the sulfuric acid would be pretty good at creating an alcohol-rich phase (seeing how washes with conc. sulfuric acid are used to remove alcohols from alkyl halides and hydrocarbons).
It’s certainly something I’ll give a go when I next have need to. Thanks for your time to provide details.