Thermal safety upgrading: Batch-to-flow transition of acid-catalyzed tert-butyl peroxypivalate synthesis

Traditional batch peroxyester synthesis processes pose a significant risk due to the presence of thermally unstable substances and highly exothermic nature of the reactions, highlighting the urgent need for a shift toward greener processes. With the aim to enhance safety of this process, a batch-to-flow transition was conducted, taking acid-catalyzed acylation of pivalic anhydride (PAn) with tert -butyl hydroperoxide (TBHP) to synthesize tert -butyl peroxypivalate (TBPP) as a case study. The acylation mechanism was investigated through density function theory calculation as well as in situ IR characterization. It was demonstrated that PAn first reacts with sulfuric acid to form pivalic acid sulfate, which subsequently undergoes nucleophilic attack by TBHP, yielding the corresponding peroxyester. The effects of process conditions, including reaction temperature, dosing rate, stirring rate and molar ratio, on thermal hazards in the semi-batch reactor was assessed. Under this mode, the processes which gained high yields (>90 %) showed unacceptable thermal runaway hazards. Then, the reaction was carried out under flow conditions. The process was optimized based on multi-objective Bayesian optimization. Through the batch-to-flow transition, it was showcased that the thermal runaway hazard could be reduced from severe (Class V) to moderate (Class II) along with a 74-fold increase in space-time yield. Furthermore, to distinguish the thermal risks quantitatively under different conditions in flow, a risk factor (R-factor) was proposed for the first time as a safety metric. With the application of R-factor, safety-oriented optimization in flow was made possible and sustainable synthesis processes could be realized.