Theoretical aspects of palladium-catalyzed direct arylations of heterocycles
Date
2017
Authors
Blignaut, Jacques Philip
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Abstract
In this work, commercially relevant palladium catalysed direct arylation reactions, in which the
molecule oxazole is coupled to toluene were investigated computationally. These involve the
Pd(II)/Pd(0) manifold. Each of the three hydrogen atoms of oxazole can be replaced by a toluene
molecule, and as both mono- and di-substitution occurs there are 6 possible products.
Experimental results, using the catalyst Pd(OAc)2 in DMA solvent, show that both the presence
and quantity of tri-tertiary butyl phosphine (PtBu3) ligand has a significant impact on the observed
product distributions. The aims of this study were to discover why and to ascertain the rate
determining step (RDS) of the catalytic cycle under various conditions.
All geometry optimisation and frequency calculations were conducted using the TPSSh hydrid DFT
functional in conjunction with the Def2-SVP basis set. Single point energy benchmarks at the
DLPNO-CCSD(T)/Def2-TZVP level of theory revealed that the double hybrid (DH) functional DSDPBEP86
in conjunction with the Def2-TZVP basis set was the best compromise between accuracy
and efficiency for the systems at hand.
The generally accepted concerted metallation deprotonation(CMD) mechanism was investigated
under phosphine free conditions, where a DMA solvent molecule was modelled bound to the
palladium centre. The results correctly predicted the experimental product distibutions for both
mono- and di-substitution.
The CMD mechanism was also investigated under conditions of 1 equivalent of PtBu3 ligand. In this
case a PtBu3 molecule was modelled bound to the palladium centre. The results correctly predicted
the major mono-substituted experimental product and from the data formation of the major disubstituted
product was readily rationalized.
Finally, oxidative addition (OA) was investigated under both conditions. It was found that the
COSMO solvation model had a dramatic impact on OA reaction Gibbs energies. It was discovered
that the presence of PtBu3 ligand significantly reduced the total Gibbs energy required for OA. In
the absence of PtBu3, no DMA is coordinated to the palladium centre during OA. Regeneration of
the active Pd(II) catalyst via deprotonation was the modelled completing the entire catalytic cycle.
The RDS under phosphine free conditions was calculated to the CMD transition state (TS). Under
condition of 1 equivalent of PtBu3 ligand the RDS was a mixture of both the CMD TS as well as
coordination of oxazole to the active Pd(II) catalyst.
Description
Thesis (M.Sc.)--University of the Witwatersrand, Faculty of Science, School of Chemistry, 2017.
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Citation
Blignaut, Jacques Philip (2017) Theoretical aspects of palladium-catalyzed direct arylations of heterocycles, University of the Witwatersrand, Johannesburg, <http://hdl.handle.net/10539/24983>