(426f) Implementation of a Vapor-Liquid Equilibrium and Vapor Purge Model for Scale-up of a Transfer Hydrogenation

Scale-up of hydrogenation reactions can uncover mixing sensitivities due to heterogeneous catalyst use or catalyst deactivation by impurity adsorption. This presentation will describe the control of carbon dioxide (CO2) formed as a by-product during a palladium-on-carbon catalyzed transfer hydrogenation reaction. At small scale, CO2 was adequately purged via nitrogen sparging to ensure sufficient mass transfer of reagents to the catalyst. This resulted in a first-order kinetic model with respect to the limiting reactant. However, during an initial 5x scale-up, zeroth-order reaction kinetics were obtained and were attributed to CO2 inhibition of the catalyst. The reaction had been scaled to maintain nitrogen mass transfer rate coefficient (kLa) through adjustment of agitation and reactor configuration. While this achieved the desired kLa, the headspace turnover time (i.e. headspace volume over nitrogen flow rate) was much longer on-scale. This resulted in increased CO2 concentrations in the headspace and, therefore, the batch. Utilizing Process Analytical Technology and data from scale-down experiments, a coupled kinetic and mass transfer model was developed to account for CO2 generation, vapor-liquid equilibrium, and headspace purge. The kLa and headspace turnover requirements predicted by the model were then successfully demonstrated at scale. This model allows accurate prediction of reaction times and should be considered for other reactions where catalyst inhibition is a risk.