Managing Competing Reactions

The yield of a sought-after transformation in an organic synthesis sequence can often be reduced by the loss of a portion of the starting material in a competing reaction.

To overcome this,  the most common strategy is to vary the reaction conditions including, the reaction time. Frequently, it is changing the reaction solvent or the reaction temperature that contributes massively to that success.  That each different reaction is likely to respond differently to such changes and so a good chance exists to find conditions where the desired reaction is even more favored.  A change in the solvent seeks to alter the difference in the free energies of activation between the different reactions. A change in reaction temperature aims to change the ratio of reaction rates as a function of temperature without changing the actual difference in free energies of activation.

Other, less obvious, but potentially effective targets also exist. If catalyzed versions of the desired reaction, as opposed to the undesired competing reaction are known, or can be conceived, addition of a catalyst can accelerated the desired change. Addition of a catalyst is the most dramatic way to change one free energy of activation relative to another. Furthermore, because catalytic mechanisms are so specific, it is very unlikely that both reactions would be affected to the same degree.

A much, much less frequent situation arises where the less favored reaction can be inhibited.

Such a situation has been described in the paper, Effect of Amines on O-Benzyl Group Hydrogenolysis,[ Bronislaw P. Czech and Richard A. Bartsch, J. Org. Chem. 1984, 49, 4076-4078 ]. In an example, a substance with a monosubstituted olefin and an alkyl benzyl ether was treated with hydrogen gas and Pd/C in alcohol with the addition of a catalytic amount of a non-aromatic amine. In the presence of the added amine only olefin reduction occurred. Benzyl n-nonyl ether as investigated as a test substrate. Using the same conditions but in one case in the presence of 5 mol % n-butylamine and in the other in its absence, the first case gave complete debenzylation and the latter case gave none. This may be a fairly common case in the situation of competing reactions on heterogeneous catalysts. If different sites are responsible for the catalysis of the two reactions one group of sites can be selectively poisoned. Thus we could understand the different activities of a catalyst prepared with different protocols.

How would one create larger differences in the product ratios arising from differing fates of a common intermediate?

This is the most troublesome situation because there is a common free energy of activation going to the shared intermediate, so changing that activation energy will not change a product mixture. Also, any subsequent free energies of activation passing from the high energy common intermediate to the transition states can be expected to be small and the difference between these two even smaller. It is the rate of quenching of the activated common intermediate that may be crucial here. Take the example of the 5-hexenyl radical intermediate. After only a brief existence the material trapped will arise from the cyclopentyl methyl radical.