Testing Catalysts and Inhibitors to Change the Ratio of a Desired Product and an Undesired Coproduct

Suppose you are working with a reaction step that is providing, rather cleanly, a mixture of two products-- the desired one and an undesired byproduct. Perhaps modifications of conditions are not beneficially changing this product ratio. Perhaps a change in the relative rates of the reactions that give rise to these two compounds can change the final product ratio. Below is a list of molecules that in more than one instance have been found to either speed up a desired reaction or slow down an undesirable one: HMPA, water, N, N-dimethylformamide, N, N, N’, N’-tetramethylurea, urea, dimethylsulfoxide, pyridine oxide, 2-pyridone, N-methyl-2- pyridone, polyethylene glycols, DDQ,  antioxidants, dimethylformamide acetals, 4-dimethylaminopyridine, DBN, DBU,  beta-glycine, EDTA, transition metal salts,  phase transfer catalysts.

For any particular reaction you are trying to improve, most of these additives will have no impact at all. When one of them does exert its effect it can be expected to be effective at low concentrations. For that reason, they can be tested at low concentrations and for this same reason, small groupings of them can likely be tested together.  Any small packet of these additives should be chosen so they do not belong to the same general types. If a group of additives shows some activity in changing the important products ratio only then do experiments need to be done to deconvolute the group to discover which cause the improvement.

For example, I have divided the potential catalysts into five groups, any group of which could be included at a low level in a trial reaction to look for any significant change in the product: byproduct ratio.

A: EDTA, N-methyl-s-pyridone, polyethylene glycol, pyridine oxide

B: DBU, N, N-dimethylformamide, 2-pyridone, transition metal salt

C: Antioxidant, 4-dimethylamino pyridine, dimethylformamide dimethyl acetal, urea

D: beta glycine, N, N, N', N'-tetramethylurea, tetrabutylammonium chloride, water

E: DDQ, DMSO, DBN, HMPA

Probably a better idea is for the experimentalist should consider possible modes of catalysis and choose a group made up of the most likely candidates.

When trying to improve a procedure, improving a method using an additive needs to be considered as much as completely replacing that reaction.