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

Structure and electric field gradients in three fentanyl salt forms: insights from first-principles calculations and solid-state NMR | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Structure and electric field gradients in three fentanyl salt forms: insights from first-principles calculations and solid-state NMR Daniel Rehn, kamal wagle, Adam Altenhof, Madelyn Crotzer, Marc Alvarez, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8706028/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract 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. Physical sciences/Chemistry/Materials chemistry Physical sciences/Materials science/Theory and computation Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SI.pdf Structure and electric field gradients in three fentanyl salt forms: insights from first-principles calculations and solid-state NMR Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8706028","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":582601045,"identity":"19d69e01-c9e2-4467-8b6e-06b057d3635e","order_by":0,"name":"Daniel 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forms: insights from first-principles calculations and solid-state NMR","description":"","filename":"SI.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8706028/v1/c8a758bba10c88adbba7ee8c.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Structure and electric field gradients in three fentanyl salt forms: insights from first-principles calculations and solid-state 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Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8706028/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8706028/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Fentanyl is the leading driver of overdose deaths owing to its ease of manufacture,\r\nextreme potency, and high addictiveness. The ability to rapidly detect fentanyl\r\ncompounds is therefore a priority, yet prevailing approaches based on chemical assays\r\nor mass spectrometry require direct sample access, which is time-consuming and\r\nhazardous. Nuclear quadrupole resonance (NQR) was recently shown to detect the\r\naniline 14N in fentanyl hydrochloride through opaque packaging, offering a low-cost,\r\nhigh-throughput route to stand-off screening. Here we combine first-principles density\r\nfunctional theory (DFT), solid-state nuclear magnetic resonance (NMR), and NQR to\r\npredict and measure quadrupolar interaction parameters for the aniline and piperidine\r\n14N sites in three forms of fentanyl: freebase, citrate, and hydrochloride. We compare how the quadrupolar coupling constant, CQ, and associated resonance\r\nfrequencies vary with local bonding, at ambient temperature. In particular, CQ for\r\nthe piperidine nitrogen is substantially reduced by protonation and/or proximal hydrogen\r\nbonding in the citrate and hydrochloride salts relative to the neutral free-base\r\ncrystal, whereas all three compounds exhibit comparable CQ values for the aniline nitrogen.\r\nThese results establish robust spectral fingerprints across multiple fentanyl formulations\r\nand provide a mechanistic basis for finding unknown NQR frequencies for rapid,\r\nnon-contact detection in real-world screening scenarios.","manuscriptTitle":"Structure and electric field gradients in three fentanyl salt forms: insights from first-principles calculations and solid-state NMR","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-02 06:02:53","doi":"10.21203/rs.3.rs-8706028/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-chemistry","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commschem","sideBox":"Learn more about [Communications Chemistry](http://www.nature.com/commschem/)","snPcode":"","submissionUrl":"","title":"Communications Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"53de5fd4-2af0-4155-95e6-e44de930cec7","owner":[],"postedDate":"February 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":61985975,"name":"Physical sciences/Chemistry/Materials chemistry"},{"id":61985976,"name":"Physical sciences/Materials science/Theory and computation"}],"tags":[],"updatedAt":"2026-02-23T10:12:54+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-02 06:02:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8706028","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8706028","identity":"rs-8706028","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}