Three Candidates, Two Peaks: Addressing Conflicting Assignments of Fentanyl Protomers with DMS-UVPD
Bibliographic record
Abstract
Fentanyl and its analogs, many of which share the piperidine-4-carboxamide core, consistently exhibit two distinct peaks when detected as the protonated ion on the various low-field IMS platforms (one major, one minor). These peaks, widely presumed to arise from prototropic isomers (i.e., protomers, which are isomers differing by the site of protonation), are generally agreed to originate from protonation at the piperidine nitrogen for the major feature, the most basic site in both the solution and gas phases. However, the origin of the minor feature remains unresolved, with prior studies attributing it to protonation either at the amide nitrogen or at the carbonyl oxygen, despite theoretical predictions placing the amide- N protomer roughly 35 kJ/mol higher in energy than its O -protonated counterpart. To resolve this, we combine differential mobility spectrometry (DMS), ultraviolet photodissociation (UVPD), tandem mass spectrometry (DMS-MS 2 /MS 3 ), and quantum chemical calculations to interrogate the protomer landscape of ten fentanyl analogs. Mapping of fragmentation pathways using DMS-MS 2 /MS 3, along with DMS-MS-UVPD supported by in silico vertical-gradient Franck–Condon (VG|FC) simulations of UV absorption spectra, indicates that the major feature arises from piperidine- N protonation while the minor feature corresponds to amide carbonyl- O protonation. Collision cross section (CCS) measurements further corroborate these assignments, with calculated CCSs matching experimental values within 1% (on average) for both the N - and O -protomers, while calculated CCSs for the amide- N protomers deviate by an average of 7%. Microsolvation studies reveal that serial solvation progressively narrows the energy gap between the piperidine- N and O -protomers via the formation of a solvent bridge between the two sites, suggesting that rapid desolvation during electrospray ionization can kinetically trap a fraction of the ensemble in the higher-energy O -protonated form.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".