Thank you to Brian Tarbit for bringing to our attention a very interesting article written by Dr. Johanna Templ and Prof. Michael Schnürch in Chemistry Europe entitled: “Strategies for using Quaternary Ammonium Salts as Alternative Reagents in Alkylations” available at https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202400675?af=R.
An example of this concept is that quaternary ammonium cations can be viewed as alkylated trialkylamines in which the alkyl group can be displaced by a nucleophile to form the alkylated product and liberate trialkylamine as the leaving group. For example, one might replace toxic dimethyl sulfate or methyl iodide with phenyl trimethyl ammonium chloride. One could then perform a methyl etherification, N-methylation or other nucleophilic substitution that would liberate phenyl dimethyl amine as the leaving group instead of methyl sulfate or iodide.
Phenyl trimethyl ammonium chloride is used as a methylating agent for the O-alkylation of alkaloids. For example, dextromethorphan, (9α,13α,14α)-3-methoxy-17-methylmorphinane (23.2.1), is synthesized from (±)-3-hydroxy-N-methylmorphinane by methylating the phenol hydroxyl group using phenyl trimethyl ammonium chloride and sodium methoxide in methanol.
In another example, morphine can be selectively mono-O-alkylated to produce codeine using phenyl trimethyl ammonium chloride as the methylating agent.
In our course “Industrial Phase-Transfer Catalysis,” we teach a PTC application that forms a specialty benzyl quat as a benzylating agent from trimethyl amine and 4-ethyl benzyl bromide. The quat benzylating agent is used for the C-alkylation of a sterically hindered aldehyde. See http://phasetransfercatalysis.com/ptc_reaction/ptc-c-alkylation-2/.
If you have been following the PTC literature since the 1960’s (like I have since 1976), you may wonder how benzylated quats are widely used for PTC reactions such as the hundred or so reports by Makosza using benzyl triethyl ammonium chloride for a wide variety of C-alkylations.
In fact, on the negative side, when using benzyl quats for PTC nucleophilic substitutions, there is usually observed at least some undesired benzylated side product. About 30 years ago, I was shocked to discover that a pharmaceutical company was using a benzylated quat for a PTC esterification of a penicillin derivative at high temperature and when I suggested that they may be inadvertently forming benzyl ester byproducts, they used LC-MS (that started to be affordable at that time) to detect the byproduct. I made the recommendation to replace the benzylated quat with a different phase-transfer catalyst that would be more stable at that temperature. I usually recommend against using benzylated quats as phase-transfer catalysts for nucleophilic substitutions unless you are purposely trying to benzylate the nucleophile.
In summary, if you are trying to benzylate, allylate or methylate nucleophiles, you can consider using the corresponding quats of those alkylating agents. If not and if you are working at high temperature and want to use such a quat as a phase-transfer catalyst, be aware that you may form undesired byproduct by the attack of the nucleophile on a potentially labile alkyl group on the quat.
