Safety Evaluation of the Copper-Mediated Cross-Coupling of 2-Bromopyridines with Ethyl Bromodifluoroacetate

The potential safety hazards associated with the copper-mediated cross-coupling of 2-bromopyridines with ethyl bromodifluoroacetate were evaluated. Thermal stability evaluation of the postreaction mixture of 50.6 mmol of 2-bromopyridine with 1.3 equiv of ethyl bromodifluoroacetate in the presence of 2.1 equiv of copper in 40 mL of dimethyl sulfoxide (DMSO) indicated a significant decomposition event with an onset temperature of 115.5 °C by accelerating rate calorimetry, which was significantly lower than that of neat DMSO. In contrast, the reaction mixture in N,N-dimethylformamide did not show any exothermic decomposition up to 400 °C by differential scanning calorimetry. Reaction calorimetry evaluation of this reaction in DMSO revealed a heat output (ΔH) of −13.5 kJ and an adiabatic temperature rise (ΔTad) of 129.5 °C, resulting in a maximum temperature of a synthesis reaction (MTSR) of 189.5 °C. The predicted heat of reaction using density functional theory with the BLYP functional was in good agreement with the experimental data. The scope studies with a variety of substituted 2-bromopyridines revealed similar magnitudes of ΔH and ΔTad compared to 2-bromopyridine when reacted at the same concentration. In all of the studied cases, the MTSR was significantly higher than the onset temperature of reaction mixture decomposition, indicating that in the absence of active cooling the system could quickly trigger the decomposition of the reaction mixture, resulting in a runaway reaction.