Thermal Degradation Energy Landscapes of Fluorofentanyls: Probing the Mechanisms and Energetics of Bond Breaking

Despite its utility in managing extreme pain, fentanyl is also one of the major drugs responsible for death because of its abuse and overuse. Not only is fentanyl a problem, but so are its analogues, including fluorofentanyls like ortho-, para-, and meta-fluorofentanyl. These analogues represent only minor modifications of the origi- nal fentanyl structure. To aid in the detection of fluorofentanyls, which degrade with exposure to heat such as during consumption by smoking, it is essential to understand the potential degradation products. However, the degradation products of fluorofen- tanyls are not well characterized. In this study, we investigated the thermal degradation pathways of fluorofentanyls using a combination of ab initio molecular dynamics simu- lations and enhanced sampling techniques, multiple walker metadynamics and umbrella sampling. We estimated the free energy profiles for each bond identified as a poten- tial degradation site to elucidate the thermodynamic driving forces. Additionally, we predicted the forward attempt rate for each bond degradation reaction to assess its likelihood of breaking. We also demonstrated that the vibrational frequencies reflect the stability of the bonds. Our findings indicate that, despite the structural similarities, fluorofentanyls differ in their degradation pathways