Challenges in the identification process of phenidate analogues in LC‐ESI‐MS/MS analysis: Information enhancement by derivatization with isobutyl chloroformate

Yamin, Tamar Shamai; Prihed, Hagit; Weissberg, Avi

doi:10.1002/jms.4327

Cited by 11 publications

(10 citation statements)

References 24 publications

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“…The resulting carbamate derivatives can yield different mass spectral fragmentation patterns and may provide additional structural information about the precursory secondary amine. The isobutyl formate derivatives of phenidate analogues provided the best results among chosen phenidate derivatives containing secondary amines, yielding unique product ions for improved structural information 18 . Preliminary results demonstrated that both isobutyl chloroformate and 2,2,2‐trichloro‐1,1‐dimethylethyl chloroformate (TCDMEDF) derivatizing agents were found to react efficiently with local anesthetic drugs that possess secondary amines, reducing their proton affinity.…”

Section: Resultsmentioning

confidence: 99%

Structural elucidation of amino amide‐type local anesthetic drugs and their main metabolites in urine by LC‐MS after derivatization and its application for differentiation between positional isomers of prilocaine

et al. 2020

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The demand for clinical toxicology analytical methods for identifying drugs of abuse and medicinal drugs is steadily increasing. Structural elucidation of amino amide‐type local anesthetic drugs and their main metabolites by GC‐EI‐MS and LC‐ESI‐MS/MS is of great analytical challenge. These compounds exhibit only/mostly fragments/product ions representing the amine‐containing residue, while the aromatic amide moiety remains unidentified. This task becomes even more complicated when discrimination between positional isomers of such compounds is required. Here, we report the development of a derivatization procedure for the differentiation and structural elucidation of a mixture of local anesthetic drugs and their metabolites that possess tertiary and secondary amines in water and urine. A method based on two sequential “in‐vial” instantaneous derivatization processes at ambient temperature followed by LC‐ESI‐MS/MS analysis was developed. 2,2,2‐Trichloro‐1,1‐dimethylethyl chloroformate (TCDMECF) was utilized to selectively convert the secondary amines into their carbamate derivatives, followed by hydrogen peroxide addition to produce the corresponding tertiary amine oxides. The resulting derivatives exhibited rich fragmentation patterns, enabling improved structural elucidation of the original compounds. The developed method was successfully applied to the differentiation and structural elucidation of prilocaine and its four positional isomers, which all possess similar GC and LC retention times and four of them exhibit almost identical EI‐MS and ESI‐MS/MS spectra, enabling their structural elucidation in a single LC‐ESI‐MS/MS analysis. The developed technique is fast and simple and enables discrimination between isomers based on different diagnostic ions/fragmentation patterns.

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Section: Resultsmentioning

confidence: 99%

Structural elucidation of amino amide‐type local anesthetic drugs and their main metabolites in urine by LC‐MS after derivatization and its application for differentiation between positional isomers of prilocaine

et al. 2020

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“…20 Recently, we demonstrated how derivatization of tertiary and secondary amines can be used not only for sensitivity enhancement but also for the structural elucidation of several illicit drugs, pharmaceuticals, and proline-based dipeptides. [21][22][23][24][25] In the present study, we investigated the fragmentation behaviors of applied to the structural elucidation of a variety of dipeptides even in a complex matrix such as urine. To the best of our knowledge, this is the first report on the use of sodium adduct ions [M + Na] + and derivatization as an attractive approach to solving a problem related to the structural elucidation of dipeptides.…”

Section: Introductionmentioning

confidence: 99%

Structural elucidation of dipeptides displaying limited mass spectral information by liquid chromatography–electrospray ionization–tandem mass spectrometry

Madmon

Weissberg

2021

J Mass Spectrom

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Small peptides, such as dipeptides, have attracted attention in many research fields because of their important biological functions and potential roles as disease biomarkers. However, the identification of many of them by implementation of liquid chromatography–electrospray ionization–tandem mass spectrometry (LC–ESI–MS/MS) is a challenging task. This is because many dipeptides display limited mass spectral information in LC–ESI–MS/MS analyses, which leads to unavoidable ambiguity in determinations of their structures. In this study, two useful analytical techniques were developed for the structural elucidation of 10 representative dipeptides exhibiting a dominant/single product ion in the ESI–MS/MS spectra of the protonated molecules [M + H]+. Structural elucidation was obtained instantaneously through LC–ESI–MS/MS fragmentation of the accompanying sodium adducts [M + Na]+ or alternatively by “in‐vial” chemical derivatization with isobutyl chloroformate. The sodium adducts and the resulting carbamate derivatives altered the charge distribution occurring during ESI–MS/MS fragmentation, enabling detailed structural elucidation and unambiguous identification of such dipeptides at ng/ml levels. These quick, simple, and easy techniques can be implemented to identify various dipeptides or confirm their identities without the need for complex sample handling.

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“…Chemical derivatization that allows sensitivity enhancement for G‐type nerve agents in various matrices was reported by Weissberg et al, 12–14 Blanca et al, 15 Madmon and Weissberg, 16 and Mach et al 17 employing 2‐[(dimethylamino)methyl]phenol (2‐DMAMP). In recent years, we have demonstrated how derivatization can be employed not only for sensitivity enhancement, but also for the structural elucidation of several illicit drugs, pharmaceuticals and other related compounds 18–22 . This study aims to develop a facile and easy technique for the structural elucidation of V‐type nerve agents based on chemical derivatization at trace levels.…”

Section: Introductionmentioning

confidence: 99%

Oxidative derivatization of V‐type nerve agents as a tool for their structural elucidation by liquid chromatography/tandem mass spectrometry

Yamin

Madmon

Prihed

et al. 2021

Rapid Comm Mass Spectrometry

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Rationale The identification of V‐type nerve agents poses an analytical challenge. Their spectra obtained by electron ionization mass spectrometry (EI‐MS) and electrospray ionization tandem mass spectrometry (ESI‐MS/MS) are dominated by ions originating from the N,N‐dialkylaminoethyl moiety, while ions representative of the alkyl phosphonothiolate part are absent from the spectra or present at negligible abundance. Hence, analogs or isomers with the same amine residue exhibit similar mass spectral patterns, leading to unavoidable ambiguity in their identification. Methods Chemical derivatization was utilized for the structural elucidation of a series of five V‐type nerve agents, including O‐ethyl S‐(2‐diisopropylamino)ethyl methylalkyl phosphonothiolate (VX), O‐isobutyl S‐(2‐diethylamino)ethyl methylalkyl phosphonothiolate (RVX) and O‐ethyl S‐(2‐diethylamino)ethyl methylalkyl phosphonothiolate (VM). The procedure consisted of “in‐vial” oxidation of the tertiary amine group with 3‐chloroperbenzoic acid (m‐CPBA) at ambient temperature followed by liquid chromatography (LC)/Orbitrap‐ESI‐MS/MS analysis with no other sample preparation. Results The generated N‐oxide of the V‐type nerve agents altered the charge distribution occurring during fragmentation and produced informative ESI‐MS/MS spectra characteristic of the alkyl phosphonothiolate structure, enabling a higher degree of certainty in their identification. Moreover, two VX isomers possessing an identical tertiary amine moiety that coeluted at practically the same retention time and displayed high mass spectral similarity were easily differentiated, and their structures elucidated once derivatized. Conclusions In contrast to the ESI‐MS/MS spectra of the V‐type nerve agents, which exhibited mostly/only information on the amine‐containing residue, the ESI‐MS/MS spectra of the V‐type nerve agent N‐oxides revealed ions indicative of both the alkyl phosphonothiolate and the amine parts, enabling their reliable structural elucidation.

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Challenges in the identification process of phenidate analogues in LC‐ESI‐MS/MS analysis: Information enhancement by derivatization with isobutyl chloroformate

Cited by 11 publications

References 24 publications

Structural elucidation of amino amide‐type local anesthetic drugs and their main metabolites in urine by LC‐MS after derivatization and its application for differentiation between positional isomers of prilocaine

Structural elucidation of amino amide‐type local anesthetic drugs and their main metabolites in urine by LC‐MS after derivatization and its application for differentiation between positional isomers of prilocaine

Structural elucidation of dipeptides displaying limited mass spectral information by liquid chromatography–electrospray ionization–tandem mass spectrometry

Oxidative derivatization of V‐type nerve agents as a tool for their structural elucidation by liquid chromatography/tandem mass spectrometry

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