I am trying to do a simple methylation of a carboxylic acid, using base to deprotonate the carboxylic acid and then adding the MeI while refluxing. The reactions did form the desired product but with extremely low yields. It is as if the reaction does not want to proceed to completion. Any suggestions?
What base and solvent did you use? Those will have a huge effect on the reaction. It might be better to isolate the carboxylates first, then heat with MeI, so that you don't compete with the base reacting with MeI.
Kyle
Can you use acid as catalst and reflux in MeOH? If you compound is stable to acid(such as HCl, H2SO4).
GX is right, generally methyl esters are easier and safer to prepare using acid-catalysis in methanol. Look in very early volumes or Organic Syntheses or any organic chem lab book.
For one thing, methyl iodide is carcinogenic* and very volatile, while methanol is cheap, relatively harmless and comes off easily on a rotary evaporator. One convenient trick is to use strong cation exchange resin in methanol solvent. The advantage is that the catalyst is removed by filtration, so no neutralization or extraction is needed. Keep in mind that SCX-catalyzed esterifications are a lot slower than the corresponding reactions with soluble acid like H2SO4 or TsOH, so your first try should be with refluxing methanol. If you use a soluble acid, only heat the mixture if it fails to react at room temp.
Some carboxyl groups are surprisingly resistant to acid esterification, such as when there is conjugation to an electron-donating group. (E.g. R1R2NCR3=CR4CO2H) Only if it's REALLY resistant to acid-catalyzed esterification should you bother with nucleophilic esterification. Use 1 eq of KOH, Cs2CO3 or for hard cases Bu4N+-OH and in all cases use polar aprotic solvent - CH3CN if possible but you are likely stuck with DMF or DMSO.
*When working with alkylating agents like CH3I, keep a plastic tub with a lid nearby (preferably in a fume hood), filled with a mixture of diluted cheap alcohol (2-propanol, denatured EtOH) and some concentrated ammonia. Put each piece of glassware in this immediately when you are done with it and let them sit in the ammonia bath for a few hours before washing.
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