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Rationale: Tramadol (T) is a strong painkiller drug that belongs to the opioid analgesic group. Several accidental intoxication cases after oral administration of T have been reported in the past decade. Tramadol, its derivatives, and metabolites present information‐limited mass spectra with one prominent peak representing the amine‐containing residue; therefore, their structural determination based on both electron impact mass spectrometry (EI‐MS) and ESI‐MS/MS spectra could be misleading. Methods: A novel analytical method for the structural elucidation of tramadol, its four homologs, and its two main phase I metabolites (N‐desmethyltramadol and O‐desmethyltramadol) was developed using chemical modification and liquid chromatography–high‐resolution tandem mass spectrometry (LC‐HR‐MS/MS) with Orbitrap technology. Results: After chemical derivatization, each of the investigated T series exhibited informative mass spectra that enabled better exposition of their structures. The developed method was successfully implemented to explicitly identify the structures of tramadol and its N‐desmethyltramadol metabolite in urine samples at low ng/mL levels. Conclusions: An efficient derivatization‐aided strategy was developed for rapidly elucidating the structure of tramadol‐like compounds. The method is intended to assist forensic chemists in better diagnosing T and its analogs and metabolites in clinical or forensic toxicology laboratories. [ABSTRACT FROM AUTHOR]

Rationale: Sodium azide (NaN3) is a toxic chemical agent to humans by ingestion and inhalation with a growing number of intentional exposures and accidental cases over the last few decades. Due to its low molecular weight and lack of any chromophore, its retention and detection by reverse‐phase liquid chromatography–ultraviolet–mass spectrometry methods are a challenging task. Methods: To be able to confirm azide exposure, we have developed a method to identify azide in both beverages and bodily fluids. The identification of azide (N3−) is based on derivatization with N‐(2‐(bromomethyl)benzyl)‐N,N‐diethylethanaminium bromide (CAX‐B) at 25°C for 15 min followed by LC/ESI‐MS/MS analysis, with no other sample preparation. Results: The azide after derivatization (CAX‐N3) was stable, retainable by LC and sensitively detected by selected reaction monitoring. The ESI‐MS/MS fragmentation of the M+ precursor ion produced characteristic product ions at m/z 118, 100, 91 and 86. The calibration curves for CAX‐N3 showed linearity over two orders of magnitude with R2 value of 0.99. Low limits of identification of 0.1–0.5 ng/mL were obtained in all investigated matrices (drinking water, tea, orange juice, plasma and urine). Conclusions: Compared with previously reported chromatography‐based methods, this method that was based on derivatization and LC/ESI‐MS/MS analysis was substantially more sensitive, simpler and faster. The method can be used for forensic investigation to confirm azide exposure from fatal use to much smaller intoxication dose. [ABSTRACT FROM AUTHOR]

Fluorine atoms play an important role in all branches of chemistry and accordingly, it is very important to study their unique and varied effects systematically, in particular, the structure‐physicochemical properties relationship. The present study describes exceptional physicochemical effects resulting from a H/F exchange at the methylene bridge of gem‐difunctional compounds. The Δlog P(CF2‐CH2) values, that is, the change in lipophilicity, observed for the CH2/CF2 replacement in various α,α‐phenoxy‐ and thiophenoxy‐esters/amides, diketones, benzodioxoles and more, fall in the range of 0.6–1.4 units, which for most cases, is far above the values expected for such a replacement. Moreover, for compounds holding more than one such gem‐difunctional moiety, the effect is nearly additive, so one can switch from a hydrophilic compound to a lipophilic one in a limited number of H/F exchanges. DFT studies of some of these systems revealed that polarity, conformational preference as well as charge distributions are strongly affected by such hydrogen to fluorine atom substitution. The pronounced effects described, are a result of the interplay between changes in polarity, H‐bond basicity and molecular volume, which were obtained with a very low 'cost' in terms of molecular weight or steric effects and may have a great potential for implementation in various fields of chemical sciences. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

V-nerve agents present information-poor spectra, both in GC-EI-MS and LC-ESI-MS/MS, with dominant fragments/product ions corresponding to the amine-containing residue. Hence, derivatives/isomers with the same amine residue exhibit similar mass spectral patterns, leading to ambiguity in the phosphonate structure. We present a simple approach for their structural elucidation based on two complementary experiments: ESI-MS/MS of the original compound, which provides information about the amine moiety, and ESI-MS/MS of the phosphonic acid hydrolysis products generated by N-iodosuccinimide, which provides ions' characteristic of the phosphonate structure. This approach enables the structural elucidation of the original V-agents with a higher degree of certainty. [ABSTRACT FROM AUTHOR]

A novel analytical technique for the structural elucidation of compounds bearing a tertiary amine side chain via "in vial" instantaneous oxidation and liquid chromatography mass spectrometry (LC-MS) was developed. A series of lidocaine homologs and benzimidazole derivatives with a major/single amine representative base peak in both their EI-MS and ESI-MS/MS spectra were subjected to oxidation by a 0.1% solution of hydrogen peroxide (including several 16O/18O exchange experiments), followed by LC-ESI-MS/MS analysis. The N-oxide counterparts promoted extensive fragmentation with complete coverage of all parts of the molecule, enabling detailed structural elucidation and unambiguous identification of the unoxidized analytes at low nanogram per milliliter levels. [ABSTRACT FROM AUTHOR]

Fluorine atoms play an important role in all branches of chemistry and accordingly, it is very important to study their unique and varied effects systematically, in particular, the structure-physicochemical properties relationship. The present study describes exceptional physicochemical effects resulting from a H/F exchange at the methylene bridge of gem-difunctional compounds. The Δlog P (CF2-CH2) values, that is, the change in lipophilicity, observed for the CH 2 /CF 2 replacement in various α,α-phenoxy- and thiophenoxy-esters/amides, diketones, benzodioxoles and more, fall in the range of 0.6-1.4 units, which for most cases, is far above the values expected for such a replacement. Moreover, for compounds holding more than one such gem-difunctional moiety, the effect is nearly additive, so one can switch from a hydrophilic compound to a lipophilic one in a limited number of H/F exchanges. DFT studies of some of these systems revealed that polarity, conformational preference as well as charge distributions are strongly affected by such hydrogen to fluorine atom substitution. The pronounced effects described, are a result of the interplay between changes in polarity, H-bond basicity and molecular volume, which were obtained with a very low 'cost' in terms of molecular weight or steric effects and may have a great potential for implementation in various fields of chemical sciences., (© 2022 Wiley-VCH GmbH.)