Thermal degradation energetics of fentanyl and its analogues: furanyl fentanyl and <i>ortho</i>-fluoro fentanyl

Fentanyl is a synthetic opioid with higher potency compared to morphine and heroin, making it an essential drug for pain management and also an abused drug. Beyond fentanyl, derivatives, such as <i>o</i>-fluoro fentanyl and furanyl fentanyl, also possess similar potency and present a significant risk of misuse, but without medical utility. A major challenge for law enforcement is detecting fentanyl and its analogues in their degraded forms. While the degradation fragments of fentanyl are well-known, those of its analogues are not as well studied. Here, we investigated the thermal degradation pathways of fentanyl analogues using extensive <i>ab initio</i> molecular dynamics simulations combined with enhanced sampling techniques, including multiple walker metadynamics and umbrella sampling. We calculated the free energy profiles for each bond previously identified as a potential degradation site to map out the thermodynamic driving forces. Additionally, we estimated the forward attempt rate of each bond degradation reaction to gain insights into the kinetics of those degradation processes. Our results show that, despite high similarity in structure, the bond breaking pathways differ for the analogues compared with fentanyl. We also observed that traditional force fields with fixed charges are insufficient for studies of fentanyl and its analogues due to polarizability of the electronic structure. Distribution Statement A. Approved for Public Release. Distribution Unlimited.