Chromium Additive Boosts Sensitivity of 1,1-ADEQUATE NMR Fourfold

Chemists at Merck & Co. have reported a simple way to make one of NMR spectroscopy’s most information-rich experiments faster and more sensitive: adding a paramagnetic salt to the sample. In a preprint posted on 26 October 2026 and currently under review at the journal Magnetic Resonance, Adam J. DiCaprio, Ryan D. Cohen and Mikhail Reibarkh, based at the company’s Pharmaceutical Analysis & Digital Technologies group in Rahway, New Jersey, show that chromium(III) ions at a concentration of 10 mM act as an excellent paramagnetic relaxation enhancement (PRE) agent for 1,1-ADEQUATE NMR. Across several test compounds, the additive improved signal-to-noise by up to 4.5-fold compared with ordinary diamagnetic conditions, allowing data of comparable quality to be collected in about one quarter of the usual experiment time.

The 1,1-ADEQUATE experiment occupies a special place in small-molecule structure elucidation because it detects two-bond proton-carbon correlations through carbon-carbon magnetization transfers, producing spectra that are relatively easy to interpret. Its Achilles heel is sensitivity. The technique depends on the natural abundance of carbon-13, and the abstract notes that this low abundance drastically reduces the efficacy of the experiment because of its reliance on carbon-carbon magnetization transfers. As a result, 1,1-ADEQUATE spectra of unlabelled small molecules can demand long acquisition times, which limits how often chemists can turn to the experiment when a structure is genuinely difficult.

The authors’ strategy attacks the problem from the relaxation side of the experiment. As they describe it, a reduction of the T1 and T2 relaxation times via paramagnetic relaxation enhancement represents an opportunity to improve sensitivity and reduce experiment times by facilitating a reduction in the recycle delays between scans. Shorter relaxation times mean less waiting between successive scans, so more scans fit into the same wall-clock time and the signal that is accumulated grows accordingly.

To identify the best additive, the team screened four paramagnetic co-solutes for their ability to enhance signal-to-noise in 1,1-ADEQUATE measurements. Chromium(III) at 10 mM emerged as the standout. Applied to the analysis of limonene, camphor, amoxapine and quinidine, four small molecules with quite different structural features, the PRE approach demonstrated signal-to-noise improvements of up to 4.5-fold over diamagnetic conditions. In practical terms, the short summary accompanying the preprint notes that quality data collection became possible in roughly one quarter of the time, a gain large enough to move 1,1-ADEQUATE toward a more routine option.

One of the most useful patterns in the reported results is that the benefits were not distributed evenly across a molecule’s carbon atoms. The gains were greatest for carbon atoms without attached hydrogen, the non-protonated carbons that are often the hardest to pin down in structure elucidation and for which 1,1-ADEQUATE correlations are particularly valuable evidence. However, the enhancement varied between molecules, so the authors’ screening of multiple paramagnetic co-solutes and multiple test compounds reflects the reality that a single set of conditions will not optimize every sample in the same way.

For the intended audience, the appeal of the method is its simplicity. The authors suggest that this approach could help assign difficult molecular structures for both specialist and non-specialist NMR users, a relevant point in pharmaceutical analysis, where chemists who are not NMR experts still need reliable connectivity information for compounds under development.

Some caveats follow directly from the reported results. Because the enhancement varied between limonene, camphor, amoxapine and quinidine, the benefit is compound-dependent rather than universal. The 4.5-fold figure is an upper bound observed across the tested compounds, not a guaranteed gain for every sample, and the concentration of 10 mM reflects what the authors found to be an excellent operating point rather than a fixed prescription for all analytes.

It is also worth keeping the status of the work in view. The report is a preprint distributed under the Creative Commons Attribution 4.0 License on the Magn. Reson. Discuss. discussion forum, received on 20 October 2026 and opened for public discussion on 26 October 2026, and it is currently under review for the journal Magnetic Resonance; the findings have not yet completed peer review. If the results hold up, the approach would offer a relaxation-based sensitivity tactic for an experiment whose carbon-13 dependence has historically made it one of the most expensive tools in the small-molecule toolkit. For structures that resist assignment by conventional two-dimensional spectra, a sensitivity boost of up to 4.5-fold that also cuts acquisition time to about a quarter could change how often chemists reach for 1,1-ADEQUATE in the first place.

Subject of Research: Paramagnetic relaxation enhancement with chromium(III) to improve the sensitivity of 1,1-ADEQUATE NMR for small-molecule structure analysis

Article Title: Paramagnetic Relaxation Enhancement to Improve Sensitivity of 1,1-ADEQUATE NMR

Article References: DiCaprio, A. J., Cohen, R. D., & Reibarkh, M. (2026). Paramagnetic Relaxation Enhancement to Improve Sensitivity of 1,1-ADEQUATE NMR. https://doi.org/10.5194/mr-2026-11

Image Credits: AI Generated

DOI: 10.5194/mr-2026-11

Keywords: NMR spectroscopy, 1,1-ADEQUATE, paramagnetic relaxation enhancement, chromium(III), small-molecule structure elucidation, signal-to-noise, relaxation times, carbon-13, analytical chemistry, preprint, Paramagnetic, Relaxation