(497a) The E-Factor of the Thin Film and Its Characterization to Understand Why Water Influences a Heck Alkynylation

This presentation will highlight our discoveries recently reported^[1] on why water influences cationic deprotonation, anionic deprotonation, and the ionic mechanism of a Heck alkynylation. Classical chemical reaction engineering theory was applied to characterize mass transfer in the aqueous-organic system. Estimation of Hatta modulus values < 0.02 enabled analyses of Gibbs free energies for all three mechanisms. It was discovered that water potentially switches the rate-determining steps of cationic and anionic deprotonation. Oxidative addition of organohalide to form a Pd-complex, coordination of the alkyne with the oxidative addition adduct, or ligand substitution could govern either catalytic cycle. Hydrogen-bonding is one possible explanation. Molecular-level process intensification has the potential to broadly impact the continuous-flow manufacture of fine chemicals and pharmaceuticals.

Synthesis in batch and continuous-flow were also studied by defining the E-factor in terms of the characteristics of the aqueous-organic interfacial film. First-principle calculations, where ligand substitution is infinitely fast with respect to the diffusive flux, predicted less chemical waste in continuous-flow than batch operation. Interestingly, the concentration of hydrophilic phosphine ligand influenced mass transport limitations and the E-factor of the thin film. Increasing the ligand concentration beyond a critical value increased the E-factor of the thin film above its minimum, and it also introduced mass-transfer-limitations. Finite changes in the ligand concentration could explain ambiguous results when performing aqueous-phase catalyzed Heck alkynylations, and potentially Pd-catalyzed C-C cross-couplings in general. The reactivity of useful ligands could be masked during discovery and mass transport limitations introduced during manufacture. Our understanding of the E-factor of the thin film broadly impacts the sustainable discovery and manufacture of fine chemicals, materials, natural products, and pharmaceuticals.�

[1] Hu, C., Shaughnessy, K.H., and Hartman, R.L. â??Influence of water on the deprotonation and the ionic mechanisms of a Heck alkynylation and its resultant E-factorsâ?, Reaction Chemistry & Engineering, 1 (2016) 65-72.