Carfentanil structural analogs found in street drugs by paper spray mass spectrometry and their characterization by high-resolution mass spectrometry.

Carfentanil is one of the most potent synthetic opioids ever developed, with an estimated analgesic potency approximately 20-100 times that of fentanyl and 10,000 times that of morphine. Carfentanil has been appearing in the illicit drug supply in many regions and has been linked to fatal overdose events. A subset of 59 street drug samples obtained in Victoria, B.C., that were confirmed to contain carfentanil were analyzed by mass spectrometry for this study. Carfentanil quantitation by paper spray mass spectrometry ranged from 0.05 to 2.95 w/w% (median = 0.32%) in the original drug sample. Paper spray mass spectrometry analysis also detected two unknown peaks at m/z 380.2 and 381.2 in 31 of these 59 samples (53%). Initial tandem mass spectrometry experiments revealed structural similarities between these unknown compounds and carfentanil, suggesting they were potential structural analogs, possibly arising from incomplete purification during synthesis. High-resolution mass spectrometry determined the chemical formulas of these compounds as C23 H29 N3 O2 (m/z 380.2333) and C23 H29 N2 O3 (m/z 381.2137). Literature and tandem mass spectrometry results were used to determine the identity of these potential new psychoactive substances, C23 H29 N3 O2 as desmethylcarfentanil amide and C23 H29 N2 O3 as desmethylcarfentanil acid. µ-Opioid receptor binding modeling determined that the binding poses of these analogs were nearly identical to that of carfentanil with relative binding energy calculations of 0.544 kJ/mol (desmethylcarfentanil amide) and -0.171 kJ/mol (desmethylcarfentanil acid); these data suggest they may share the toxic effects of carfentanil and have similar potencies.

Isotope Quantum Effects in the Metallization Transition in Liquid Hydrogen.

Quantum effects in condensed matter normally only occur at low temperatures. Here we show a large quantum effect in high-pressure liquid hydrogen at thousands of Kelvins. We show that the metallization transition in hydrogen is subject to a very large isotope effect, occurring hundreds of degrees lower than the equivalent transition in deuterium. We examined this using path integral molecular dynamics simulations which identify a liquid-liquid transition involving atomization, metallization, and changes in viscosity, specific heat, and compressibility. The difference between H_{2} and D_{2} is a quantum mechanical effect that can be associated with the larger zero-point energy in H_{2} weakening the covalent bond. Our results mean that experimental results on deuterium must be corrected before they are relevant to understanding hydrogen at planetary conditions.

Understanding high pressure molecular hydrogen with a hierarchical machine-learned potential.

The hydrogen phase diagram has several unusual features which are well reproduced by density functional calculations. Unfortunately, these calculations do not provide good physical insights into why those features occur. Here, we present a fast interatomic potential, which reproduces the molecular hydrogen phases: orientationally disordered Phase I; broken-symmetry Phase II and reentrant melt curve. The H2 vibrational frequency drops at high pressure because of increased coupling between neighbouring molecules, not bond weakening. Liquid H2 is denser than coexisting close-packed solid at high pressure because the favored molecular orientation switches from quadrupole-energy-minimizing to steric-repulsion-minimizing. The latter allows molecules to get closer together, without the atoms getting closer, but cannot be achieved within in a close-packed layer due to frustration. A similar effect causes negative thermal expansion. At high pressure, rotation is hindered in Phase I, such that it cannot be regarded as a molecular rotor phase.

Theoretical volume profiles for conformational changes: Application to internal rotation of benzene ring in 1,12-dimethoxy-[12]-paracyclophane.

Identification of the transition state is an important step in the study of reaction kinetics and mechanisms. However, for non-rigid chemical systems where multiple viable reaction pathways may exist, enumeration of all possible transition states quickly becomes computationally expensive, if at all feasible. As an alternative approach, we recently proposed a methodology where the volumetric properties of a flexible reaction system are used to locate its transition state ensemble through a comparison of its theoretically determined volume profile and experimental activation volumes derived from high pressure kinetic data. In this work, we apply this method to internal rotation of the benzene ring in 1,12-dimethoxy-[12]-paracyclophane. For this system, the transition state ensemble was found to be the state with the lowest volume, where the benzene ring and the flexible methylene tether are coplanar. This result was verified by comparison with a Gibbs free energy profile obtained via umbrella sampling.