Last month we asked your help in understanding what appears to be a phase-transfer catalyzed reaction of thionyl chloride. Following are the high quality answers provided by our loyal, creative and intelligent readers.
Special thanks to Scott Sherwood, Danny Levin, Peter Wuts, Dan Henton, Maria Nieves Perez Payan and Jeffrey Marra, who provided excellent thought processes from which the entire PTC community benefits!
There seems to be consensus for the formation of a mixed anhydride-sulfonyl chloride as an intermediate that is promoted by the quat chloride.
Scott Sherwood wrote:
I have a possible explanation for the role of the quaternary ammonium chloride in the carboxylic acid => [acid chloride] => ester reaction scheme.
The quaternary ammonium chloride is a source of “naked” chloride to allow for the decomposition of the thionyl chloride adduct of the carboxylic acid to the acid chloride, sulfur dioxide, and HCl.
With DMF, the following sequence occurs (I am not showing all of the mechanistic steps for convenience):
The DMF byproduct then repeats the reaction with additional thionyl chloride to prepare the Vilsmeier reagent as the source of “naked” chloride.
As you can see, the quaternary ammonium chloride route is much more efficient. In the case of DMF catalysis, the carboxylic acid has a choice of two electrophilic reagents for reaction.
Additionally, the Vilsmeier reagent has a propensity to generate tars and/or become less soluble as the reaction proceeds towards completion.
Thank you to Dr. Sherwood for providing such a detailed explanation with structure diagrams!
Danny Levin wrote:
The reaction of carboxylic acid with thionyl chloride proceeds via an initial coupling step to give a mixed acid anhydride intermediate which then decomposes to the desired acid chloride plus sulfur dioxide plus HCl.
RCOOH + SOCl2 -> RCO-O-SO-Cl
This intermediate needs to react with chloride nucleophile to cause decomposition to RCOCl + SO2.
Cl- + RC(O)-O-S(O)-Cl -> RC(O)Cl + SO2 + Cl-
The PTC quat presumably enhances the reactivity of the chloride nucleophile in its reaction with the mixed acid anhydride intermediate.
In the absence of the PTC quat the chloride is less nucleophilic as it is tied up with proton as covalent HCl.
The PTC helps to make the chloride more available as unbound and hence more reactive chloride ion (paired by PTC cation) to enhance its reactivity as a nucleophile with the aliphatic acid carbonyl present in the mixed anhydride intermediate (chloride no doubt also reacts with the sulfur but that takes us back to starting material so this is an pre-equilibrium reaction):
PTC + Cl- + RC(O)-O-S(O)-Cl -> RC(O)Cl + SO2 + Cl- PTC+
Peter Wuts wrote:
There are 2 ways to took at this. First the presumed intermediate mixed anhydride reacts faster with the Quat salt because the chloride is free of a proton and is more nucleophilic than HCl with its proton.
The other could be that the acid in in equilibrium with the Quat salt to form HCl and the carboxylate which now would be expected to react much faster with thionyl chloride than the protonated acid. The release of Cl- then would be expected to react with the mixed anhydride faster like in the first scheme. Even though the amount of the ammonium salt might be small, Le Chatelier’s principle will take care of the rest.
So, in essence both the first step and the second could be accelerated with the Quat salt.
Dan Henton wrote:
My guess is that having a soluble source of chloride ion in the reaction mixture allows for more rapid breakdown of the mixed sulfite – carboxylic acid anhydride intermediate to the acid chloride and sulfur dioxide. Chloride is no doubt a better nucleophile than HCl or NN-DMF.
Jeffrey Marra wrote:
Don’t know if there is any sound evidence, but I’ve always thought that the nucleophilic attack of chloride on the mixed carboxylic sulfoxyl ‘anhydride’ was the rate limiting step. If you increase the concentration and/or the reactivity of chloride ions in the reaction mixture, the acid chloride forms more effectively. The only reference I can think of that supports this is from WAY back. In the original paper by Mosher for the use of his chiral acid to form chiral esters for enantiomeric analysis, he reports the addition of (I think) 5 equivalents of sodium chloride the reaction to form the Mosher acid chloride from the acid and thionyl chloride.
Maria Nieves Perez Payan wrote:
I am presuming that the quat chloride is improving the solubility of the dicarboxylic acid in the organic phase as bis-quaternary salt.
I want to thank all of you who contributed these high quality explanations and I commend you on paying such close attention to the surprising performance of phase-transfer catalysis. When you make such contributions, you are proving your high value to the PTC community and that is greatly appreciated by all of us!
