Selectivity and enantioselectivity in the palladium catalysed hydrogenation of pyrazine and some substituted pyrazines

Carroll, John Robert

Abstract

The palladium catalysed hydrogenation of pyrazine and some substituted pyrazines has been investigated over a range of reaction conditions.
This thesis reports and discusses work in three areas. The first being the hydrogenation of pyrazine over Pd/C, second the hydrogenation of some monosubstituted pyrazines also over Pd/C and finally, the enantioselective hydrogenation of methyl pyrazine-2- carboxylate over different chirally modified catalysts.
The hydrogenation of pyrazine over Pd/C and some other platinum group metal (PGM) catalysts has given an insight into its reactivity and selectivity. The interaction of pyrazine with the catalyst surface has been examined by use of deuterium-exchange which indicates pyrazine adsorbs in a co-planar manner to the surface. This has been verified experimentally by interpreting results obtained from the rates of hydrogenation for a range of aromatic N-heterocycles.
The hydrogenation of methyl pyrazine-2-carboxylate and 2-pyrazinecarbonitrile (2- PCN) over Pd/C has given an insight into the effects of substituents on the reactivity of the aromatic heterocyclic ring. In the case of methyl pyrazine-2-carboxylate, hydrogenation occurs in two distinct stages. The first stage is the rapid uptake of two moles hydrogen, followed by no further hydrogenation. Investigation of the compound formed after this two-mole uptake has shown 1, 4, 5, 6-tetrahydro methyl pyrazine-2- carboxylate as the product. On an electronic level, this compound is very stable and resists further reaction due to its conjugation and is in fact an a, p-unsaturated ester having a carbamate-like structure.
The unmodified hydrogenation of 2-PCN gave different results. It became evident that this compound, like methyl pyrazine-2-carboxylate before, is only partially hydrogenated because reaction stops after a two-mole hydrogen uptake. Further investigation showed the cyano substituent is being partially hydrogenated as well as the ring. However, the degree of ring/substituent hydrogenation is affected by the pH ot the reaction solvent, and the mechanism of hydrogenation is not complying with traditional observations.
The major aim of this project i.e. achieving the enantioselective hydrogenation of methyl pyrazine-2-carboxylate, has been fulfilled. An enantioselective outcome has been achieved over several differently modified catalysts. This is of particular importance to the industrial collaborator in this project, Zeneca Specialities.
The action of an adsorbed chiral modifier onto Pd/C is to induce the preferential formation of methyl piperazine-2-carboxylate in a typical enantiomeric excess of 2- 25%; the highest value being obtained using a cinchonidine-modified catalyst.
The presented results indicate the first ever example of direct enantioselective hydrogenation of an aromatic N-heterocycle.
Mechanisms for the reaction predicting the experimental observations are given.

Citation

Carroll, J. R. (2000). Selectivity and enantioselectivity in the palladium catalysed hydrogenation of pyrazine and some substituted pyrazines. (Thesis). University of Hull. Retrieved from https://hull-repository.worktribe.com/output/4240018

• Thesis Type: Thesis
• Deposit Date: Mar 14, 2023
• Publicly Available Date: Mar 14, 2023
• Keywords: Chemistry
• Public URL: https://hull-repository.worktribe.com/output/4240018
• Additional Information: Department of Chemistry, The University of Hull
• Award Date: 2000-09