Structure and electric field gradients in three fentanyl salt forms: insights from first-principles calculations and solid-state NMR

Fentanyl is the leading driver of overdose deaths owing to its ease of manufacture, extreme potency, and high addictiveness. The ability to rapidly detect fentanyl compounds is therefore a priority, yet prevailing approaches based on chemical assays or mass spectrometry require direct sample access, which is time-consuming and hazardous. Nuclear quadrupole resonance (NQR) was recently shown to detect the aniline 14N in fentanyl hydrochloride through opaque packaging, offering a low-cost, high-throughput route to stand-off screening. Here we combine first-principles density functional theory (DFT), solid-state nuclear magnetic resonance (NMR), and NQR to predict and measure quadrupolar interaction parameters for the aniline and piperidine 14N sites in three forms of fentanyl: freebase, citrate, and hydrochloride. We compare how the quadrupolar coupling constant, CQ, and associated resonance frequencies vary with local bonding, at ambient temperature. In particular, CQ for the piperidine nitrogen is substantially reduced by protonation and/or proximal hydrogen bonding in the citrate and hydrochloride salts relative to the neutral free-base crystal, whereas all three compounds exhibit comparable CQ values for the aniline nitrogen. These results establish robust spectral fingerprints across multiple fentanyl formulations and provide a mechanistic basis for finding unknown NQR frequencies for rapid, non-contact detection in real-world screening scenarios.