The first publication by Starks in 1971 in which he coined the term “phase-transfer catalysis” and defined the PTC extraction mechanism, cited cyanation as the first PTC reaction and it included clear cut kinetics to support the extraction mechanism. In that publication, Starks used 1.3 mole% phase-transfer catalyst for the cyanation.
In the PTC cyanation reported in the patent this month shown in the diagram, the inventors used 50 mole% phase-transfer catalyst. That is obviously overkill. To be fair, the focus of the invention is pharmaceutical compositions and compounds useful for the treatment of opioid dependence, alcohol dependence, alcohol use disorder, or the prevention of relapse. The focus of the invention has nothing to do with this cyanation reaction. Nevertheless, the conditions chosen provided a basis for discussion.
First, nucleophilic substitutions under PTC conditions should often be performed (when safe and when feasible) with high concentrations of the salt of the nucleophilic anion in the aqueous phase or using the solid salt of the nucleophilic anion. The reasons for this include minimizing hydration of the nucleophile that reduces nucleophilicity and to avoid unnecessarily wasting reactor volume with water. The reaction shown in the diagram used very dilute aqueous KCN. If they were ever to scale up, they would undoubtedly optimize the concentration of the cyanide.
The use of 50 mole% TBAB is surprising even for a small scale lab reaction. Screening reactions for proof-of-concept of new PTC applications usually start out with 5-20 mole% phase transfer catalyst, unless stoichiometric quat salt is required for special diagnostics.
The choice of methylene chloride by academics is not uncommon since it dissolves well both organic substrates and all common phase-transfer catalysts. The choice of methylene chloride by an industrial group is somewhat surprising. More importantly, methylene chloride has an active methylene with two electron-withdrawing leaving groups and can act as an alkylating agent in the presence of nucleophiles. A better choice would be an inert solvent such as toluene.
Again, the procedure described in the patent was not disclosed for scrutiny. But it does provide the opportunity to review some thoughts about choosing PTC reaction conditions.
Now contact Marc Halpern of PTC Organics to benefit from highly specialized expertise in industrial phase-transfer catalysis to achieve low-cost high-performance green chemistry.
