Thermal characterization of highly exothermic flash chemistry in a continuous flow calorimeter

A key parameter for reactor design and safety evaluation is the reaction enthalpy (ΔH_r). Flash chemistry is a field of chemical synthesis where fast reactions are performed in a precise manner to produce desired compounds with high selectivity. In this paper, we demonstrate that robust calorimetric data for highly exothermic, rapid reactions can be obtained within a modular 3D printed continuous flow calorimeter. This data would be difficult, or impossible, to reliably measure within a batch calorimeter. Initially, the reaction of n-hexyllithium (HexLi) with ethanol was studied using different solvent compositions, with the average enthalpy determined to be −297.6 kJ mol⁻¹. Furthermore, the undesired reaction between HexLi and 2-methyltetrahydrofuran was avoided in continuous flow. Subsequently, the reaction between di-tert-butyldicarbonate and HexLi was conducted. This reaction forms a tert-butyl ester as the desired product and an alcohol as an undesired overreaction product. The influence of mixing efficiency on conversion and product selectivity within the microstructured continuous flow calorimeter was investigated through computational fluid dynamics (CFD) simulations. A tert-butyl ester and alcohol were synthesized with high selectivity after a design of experiments (DoE) study and the reaction enthalpies for generation of these two products were deconvoluted successfully. A lithium-halogen exchange and iodine (I₂) quench were also investigated in the continuous flow calorimeter, which demonstrated that the I₂ quench step is more exothermic than the lithiation step. Overall, the temporal resolution of these organolithium reactions was showcased on a length scale, which corresponded to residence times of seconds (1.1 to 8.9 s).