Synthesis and determination of analytical characteristics and differentiation of positional isomers in the series of N‐(2‐methoxybenzyl)‐2‐(dimethoxyphenyl)ethanamine using chromatography–mass spectrometry

N‐(2‐Methoxybenzyl)‐2,5‐dimethoxyphenethylamines (NBOMes) are synthetic phenethylamine derivatives emerging on the global drug market and reported to be associated with untoward effects in people who use drugs. Its action involves agonism at serotonin 5‐HT_2A receptors, affecting cognitive and behavioral processes. However, certain isomers of NBOMes may not show any psychoactive effects. They are not controlled by legislation and can be tested as pharmaceutical drugs. This study deals with the differentiation among positional isomers of 25H‐NBOMe differing in the position of the two methoxy groups in the phenylethyl moiety of the molecule, using chromatography–mass spectrometry methods. The gas chromatography analysis showed that the isothermal mode was more efficient than the usually applied temperature‐programming mode for the separation of the mentioned isomers. Electron ionization mass spectra of 25H‐NBOMe isomers were highly similar, often resulting in a high probability of erroneous identification. However, mass spectra of their trifluoroacetyl or pentafluoropropanoyl derivatives were easily identified as they contained fragments with many significant differences. The proposed analysis using liquid chromatography–tandem mass spectrometry could distinguish the isomers of 25H‐NBOMe without the need for any derivatization.     

Differentiation of methoxybenzoylpiperazines (OMeBzPs) and methylenedioxybenzylpiperazines (MDBPs) By GC-IRD and GC-MS

The designer drug 3,4-methylenedioxybenzylpiperazine (3,4-MDBP), its positional isomer 2,3-methylenedioxybenzylpiperazine (2,3-MDBP) and three regioisomeric ring-substituted methoxybenzoylpiperazines (OMeBzPs) have identical elemental composition and no marked differences in their mass spectra with only the three methoxybenzoylpiperazine regioisomers showing one unique major fragment ion at m/z 152. Perfluoroacylation of the secondary amine nitrogen of these isomeric piperazines gave mass spectra with differences in the relative abundance of some fragment ions but did not alter the fragmentation pathway to provide unique ions for discrimination among these isomers. Exact mass determination using gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF-MS) did not provide any discrimination among these compounds since the main fragment ions are of identical elemental composition. Gas chromatography coupled to infrared detection (GC-IRD) provides direct confirmatory data for the identification of the carbonyl containing compounds and the differentiation of the psychoactive designer drug 3,4-MDBP from its direct (2,3-MDBP) and indirect (OMeBzPs) regioisomers. The mass spectra in combination with the vapour phase infrared spectra provide for specific confirmation of each of the isomeric piperazines. The underivatized and perfluoroacyl derivative forms of the five piperazines involved in this study were resolved on a stationary phase of 100% trifluoropropyl methyl polysiloxane (Rtx-200).     

Syntheses and analytical characterizations of novel (2‐aminopropyl)benzo[b]thiophene (APBT) based stimulants

Two groups of amphetamine‐like drugs with psychostimulant properties that were first developed during the course of scientific studies and later emerged as new psychoactive substances (NPS) are based on the (2‐aminopropyl)indole (API) and (2‐aminopropyl)benzofuran (APB) structural scaffolds. However, sulfur‐based analogs with a benzo[b]thiophene structure (resulting in (2‐aminopropyl)benzo[b]thiophene (APBT) derivatives) have received little attention. In the present investigation, all six racemic APBT positional isomers were synthesized in an effort to understand their structure–activity relationships relative to API‐ and APB‐based drugs. One lesson learned from the NPS phenomenon is that one cannot exclude the appearance of such substances on the market. Therefore, an in‐depth analytical characterization was performed, including various single‐ and tandem mass spectrometry (MS) and ionization platforms coupled to gas chromatography (GC) and liquid chromatography (LC), nuclear magnetic resonance spectroscopy (NMR), and solid phase and GC condensed phase infrared spectroscopy (GC‐sIR). Various derivatizations have also been explored; it was found that all six APBT isomers could be differentiated during GC analysis after derivatization with heptafluorobutyric anhydride and ethyl chloroformate (or heptafluorobutyric anhydride and acetic anhydride) under non‐routine conditions. Discriminating analytical features can also be derived from NMR, GC‐EI/CI‐ single‐ and tandem mass spectrometry, LC (pentafluorophenyl stationary phase), and various infrared spectroscopy approaches (including GC‐sIR). Availability of detailed analytical data obtained from these novel APBT‐type stimulants may be useful to researchers and scientists in cases where forensic and clinical investigations are warranted.     

GC-MS and GC-IRD studies on brominated dimethoxyamphetamines: regioisomers related to 4-Br-2,5-DMA (DOB)

A series of regioisomeric bromodimethoxyamphetamines have mass spectra essentially equivalent to the controlled drug substance 4-Br-2,5-dimethoxyamphetamine (4-Br-2,5-DMA; DOB); all have molecular weight of 274 and major fragment ions in their electron ionization mass spectra at m/z 44 and m/z 230/232. The trifluoroacetyl, pentafluoropropionyl and heptafluorobutryl derivatives of the primary regioisomeric amines were prepared and evaluated in gas chromatography-mass spectrometry (GC-MS) studies. The mass spectra for these derivatives did not show unique fragment ions for specific identification of individual isomers. However, the mass spectra do serve to divide the compounds into three groups, depending on their base peak. Gas chromatography with infrared detection (GC-IRD) provides direct confirmatory data for the identification of the designer drug 4-bromo-2,5-dimethoxyamphetamine from the other regioisomers involved in the study. The perfluoroacylated derivatives of the six regioisomeric bromodimethoxyamphetamines were successfully resolved on non-polar stationary phases such as a 100% dimethylpolysiloxane stationary phase (Rtx-1) and 50% phenyl - 50% methyl polysiloxane (Rxi-50).     

Differentiation of methylbenzylpiperazines (MBPs) and benzoylpiperazine (BNZP) using GC-MS and GC-IRD

Three-ring substituted methylbenzylpiperazines (MBPs) and their isobaric benzoylpiperazine (BNZP) have equal mass and many common mass spectral fragment ions. The mass spectrum of BNZP yields a unique benzoyl-group containing fragment at m/z 122 and an additional major fragment at m/z 69 that allows its discrimination from the three MBP regioisomers. Perfluoroacylation of the secondary amine nitrogen of these isomeric piperazines gave mass spectra with differences in relative abundance of some fragment ions but acylation does not alter the fragmentation pathway and did not provide additional MS fragments of discrimination among these isomers. Gas chromatography coupled with infrared detection (GC-IRD) provides direct confirmatory data for the structural differentiation between the four isomers. The mass spectra in combination with the vapour phase IR spectra provide for specific confirmation of each of the isomeric piperazines. The underivatized and perfluoroacyl derivatives of these four piperazines were resolved on a stationary phase of 100% trifluoropropyl methyl polysiloxane (Rtx-200). Gas chromatography coupled with time-of-flight mass spectrometry provides an additional means of differentiating between the isobaric MBP and BNZP which have equivalent nominal masses but are different in their elemental composition and exact masses.     

GC‐MS and GC‐IRD studies on the six‐ring regioisomeric dimethoxybenzylpiperazines (DMBPs)

Gas chromatography with infrared detection (GC‐IRD) provides direct confirmatory data for the differentiation between the six regioisomeric aromatic ring substituted dimethoxybenzylpiperazines (DMBPs). These regioisomeric substances are resolved by GC and the vapour‐phase infrared spectra clearly differentiate among the six dimethoxybenzyl substitution patterns. The mass spectra for these regioisomeric substances are almost identical. With only the 2,3‐dimethoxy isomer showing one unique major fragment ion at m/z 136. Thus mass spectrometry does not provide for the confirmation of identity of any one of these compounds to the exclusion of the other isomers. Perfluoroacylation of the secondary amine nitrogen for each of the six regioisomers gave mass spectra showing some differences in the relative abundance of fragment ions without the appearance of any unique fragments for specific confirmation of structure. Gas chromatography coupled with time‐of‐flight mass spectrometric detection (GC‐TOF) provided an additional means of confirmation of the elemental composition of the major fragment ions in the mass spectra of these compounds. Copyright © 2013 John Wiley & Sons, Ltd.     

Analytical characterization of three hallucinogenic N‐(2‐methoxy)benzyl derivatives of the 2C‐series of phenethylamine drugs

This publication reports analytical properties of three new hallucinogenic substances identified in blotter papers seized from the drug market, namely 25D‐NBOMe [2‐(2,5‐dimethoxy‐4‐methylphenyl)‐N‐(2‐methoxybenzyl)ethanamine], 25E‐NBOMe [2‐(4‐ethyl‐2,5‐dimethoxyphenyl)‐N‐(2‐methoxybenzyl)ethanamine] and 25G‐NBOMe [2‐(2,5‐dimethoxy‐3,4‐dimethylphenyl)‐N‐(2‐methoxybenzyl)ethanamine]. These substances are N‐(2‐methoxy)benzyl derivatives of the 2C‐series of phenethylamine drugs. The applied procedure covered a variety of analytical methods, including gas chromatography with electron impact mass spectrometry (GC‐EI‐MS; without derivatization and after derivatization with trifluoroacetic anhydride (TFAA)), liquid chromatography‐electrospray ionization‐quadrupole time of flight mass spectrometry (LC‐ESI‐QTOF‐MS), Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR), which made it possible to identify the active components unequivocally. The GC‐MS spectra of analyzed compounds were very similar, with dominant ions observed at m/z = 150, 121, and 91. The remaining ions were analogous to those observed for parent substances, namely 2C‐D, 2C‐E, 2C‐G, but their intensities were low. Derivatization allowed determination of molecular masses of the investigated substances. Their exact masses and chemical formulas were confirmed by LC‐QTOF‐MS experiments and the fragmentation patterns of these compounds following ESI were determined. The tandem mass spectrometry (MS/MS) experiments confirmed that the studied substances were N‐(2‐methoxy)benzyl derivatives of the 2C‐series compounds. Final elucidation of the structures was performed by NMR spectroscopy. The substances were also characterized by FTIR spectroscopy to corroborate the identity of the compounds. Copyright © 2012 John Wiley & Sons, Ltd.     

Syntheses and analytical characterizations of N‐alkyl‐arylcyclohexylamines

The rise in new psychoactive substances that are available as 'research chemicals’ (RCs) remains a significant forensic and legislative challenge. A number of arylcyclohexylamines have attracted attention as RCs and continue to be encountered, including 3‐MeO‐PCP, 3‐MeO‐PCE and 3‐MeO‐PCPr. These compounds are commonly perceived as ketamine‐like dissociative substances and are believed to act predominantly via antagonism of the N‐methyl‐D‐aspartate (NMDA) receptor. To aid in the identification of newly emerging substances of abuse, the current studies were performed. The syntheses of fifteen N‐alkyl‐arylcyclohexylamines are described. Analytical characterizations were performed via gas chromatography and high performance liquid chromatography coupled to multiple forms of mass spectrometry as well as nuclear magnetic resonance spectroscopy, ultraviolet diode array detection and infrared spectroscopy. The series consisted of the N‐alkyl derivatives (N‐methyl, N‐ethyl, N‐propyl) of phenyl‐substituted and isomeric 2‐, 3‐ and 4‐methoxy phenylcyclohexylamines, as well as the N‐alkyl derivatives obtained from 3‐methylphenyl and 2‐thienyl moieties. In addition to the presentation of a range of previously unreported data, it was also found that positional isomers of aryl methoxyl‐substituted arylcyclohexylamines were readily distinguishable under a variety of analytical conditions. Copyright © 2015 John Wiley & Sons, Ltd.     

Test purchase,synthesis, and characterization of 2‐methoxydiphenidine (MXP) and differentiation from its meta‐ and para‐substituted isomers

The structurally diverse nature of the 1,2‐diphenylethylamine template provides access to a range of substances for drug discovery work but some have attracted attention as ‘research chemicals’. The most recent examples include diphenidine, i.e. 1‐(1,2‐diphenylethyl)piperidine and 2‐methoxydiphenidine, i.e. 1‐[1‐(2‐methoxyphenyl)‐2‐phenylethyl]piperidine (MXP, methoxyphenidine, 2‐MXP) that have been associated with uncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist activity. Analytical challenges encountered during chemical analysis include the presence of positional isomers. Three powdered samples suspected to contain 2‐MXP were obtained from three Internet retailers in the United Kingdom and subjected to analytical characterization by gas chromatography (GC) and high performance liquid chromatography (HPLC) coupled to various forms of mass spectrometry (MS). Nuclear magnetic resonance spectroscopy, infrared spectroscopy and thin layer chromatography were also employed. This was supported by the synthesis of all three isomers (2‐, 3‐ and 4‐MXP) by two different synthetic routes. The analytical data obtained for the three purchased samples were consistent with the synthesized 2‐MXP standard and the differentiation between the isomers was possible. Distinct stability differences were observed for all three isomers during in‐source collision‐induced dissociation of the protonated molecule when employing detection under HPLC selected‐ion monitoring detection, which added to the ability to differentiate between them. Furthermore, the analysis of a 2‐MXP tablet by matrix assisted inlet ionization Orbitrap mass spectrometry confirmed that it was possible to detect the protonated molecule of 2‐MXP directly from the tablet surface following addition of 3‐nitrobenzonitrile as the matrix. Copyright © 2015 John Wiley & Sons, Ltd.     

Qualitative analysis of seized synthetic cannabinoids and synthetic cathinones by gas chromatography triple quadrupole tandem mass spectrometry

Designer drugs are analogues or derivatives of illicit drugs with a modification of their chemical structure in order to circumvent current legislation for controlled substances. Designer drugs of abuse have increased dramatically in popularity all over the world for the past couple of years. Currently, the qualitative seized‐drug analysis is mainly performed by gas chromatography‐electron ionization‐mass spectrometry (GC‐EI‐MS) in which most of these emerging designer drug derivatives are extensively fragmented not presenting a molecular ion in their mass spectra. The absence of molecular ion and/or similar fragmentation pattern among these derivatives may cause the equivocal identification of unknown seized‐substances. In this study, the qualitative identification of 34 designer drugs, mainly synthetic cannabinoids and synthetic cathinones, were performed by gas chromatography‐triple quadrupole‐tandem mass spectrometry with two different ionization techniques, including electron ionization (EI) and chemical ionization (CI) only focusing on qualitative seized‐drug analysis, not from the toxicological point of view. The implementation of CI source facilitates the determination of molecular mass and the identification of seized designer drugs. Developed multiple reaction monitoring (MRM) mode may increase sensitivity and selectivity in the analysis of seized designer drugs. In addition, CI mass spectra and MRM mass spectra of these designer drug derivatives can be used as a potential supplemental database along with EI mass spectral database. Copyright © 2014 John Wiley & Sons, Ltd.     

Analysis of highly potent synthetic opioid nitazene analogs and their positional isomers

Four nitazenes (metonitazene, etonitazene, protonitazene, and isotonitazene), highly potent benzimidazole synthetic opioids, and their four nitro group positional isomers (isonitazenes) were synthesized and analyzed using infrared (IR) spectroscopy, gas chromatography/mass spectrometry (GC/MS), and liquid chromatography/mass spectrometry (LC/MS). In addition, the agonistic activity of all compounds at the human μ-opioid receptor was measured using a cell-based assay system. In the IR spectra, characteristic peaks for nitazenes and isonitazenes were observed. In GC/MS, all compounds were well separated on the chromatogram, although distinguishing nitazenes from the corresponding isonitazenes by electron ionization mass spectra was difficult. In LC/MS, all compounds were detected in both positive and negative modes of electrospray ionization. Characteristic fragment ions were observed in the product ion spectra of isonitazenes, enabling nitazenes to be distinguished from isonitazenes. All nitazenes tested demonstrated higher agonistic activity at the human μ-opioid receptors than the synthetic opioid fentanyl. The agonistic activities of isonitazenes were 11–35 times lower than those of the corresponding nitazenes. However, iso-etonitazene and iso-isotonitazene showed moderate activity similar to that of fentanyl, indicating that these drugs could cause poisoning at a comparable level as fentanyl, if these drugs are abused in the future.     

The role of diode array ultraviolet detection for the identification of synthetic cathinones

The utility of diode array ultraviolet (UV) detection for aiding in the identification of synthetic cathinones, including different sub‐classes and positional isomers is presented. For 35 synthetic cathinones, unique UV spectra are obtained for seven sub‐classes, including mostly beta ketones, where position and type of substitution on benzene rings give rise to differences in UV maxima and relative intensity of the spectral bands. This aspect is key to distinguishing positional isomers that contain differences in R substitution (mono and di) around the benzene ring, which provides complementary information to electron ionization mass spectrometry, where the latter technique cannot distinguish between these types of positional isomers. In addition, it is possible to ascertain the substitution position based on the UV spectra. For ten sets of positional isomers, it was possible to distinguish most of the positional isomers within a set. For ultra‐high performance supercritical fluid chromatography (UHPSFC) versus reversed phase ultra‐high performance liquid chromatography (UHPLC), there was at least a 10 nm blue shift in UV maximum (shift to shorter wavelengths). This highlights the importance of taking in account the effect of mobile phase on the UV maximum when performing method development in UHPSFC. Copyright © 2017 John Wiley & Sons, Ltd.     

Separation of positional isomers of nine 2‐phenethylamine‐derived designer drugs by liquid chromatography–tandem mass spectrometry

The synthesis of positional isomers of designer drugs is a common way of bypassing legal restrictions. For forensic case work, and especially for the legal assessment of cases, there is a need for screening methods capable of the unequivocal identification of positional isomers. The presented liquid chromatography–electrospray ionization–tandem mass spectrometry (LC–ESI–MS/MS) method facilitates separation of positional isomers of 9 2‐phenethylamine‐derived designer drugs in different matrices including seized materials, hair, serum, and urine specimens. Chromatographic separation was achieved on a biphenyl phase using gradient elution with a total runtime of 26 minutes. The limit of detection was 25 pg/mg for hair samples and ranged from 0.1 ng/mL to 0.5 ng/mL for serum and from 0.2 ng/mL to 1.2 ng/mL for urine samples. The method proved to be selective and sensitive and showed good chromatographic resolution (R ≥ 1.2). The method was successfully applied to routine case samples.     

Development of a two-dimensional liquid chromatography system for isolation of drug metabolites

The separation, isolation and identification of drug metabolites from complex endogenous matrices like urine, plasma and tissue extracts are challenging tasks. Metabolites are usually first identified by mass spectrometry and tentative structures proposed from product ion spectra. In many cases mass spectrometry cannot be used to determine positional isomers and metabolites have to be fractionated in microgram amounts for analysis by NMR. To overcome the difficulties associated with separation and isolation of drug metabolites from biological matrices, a new two-dimensional liquid chromatography system has been developed.     

Rapid screening of 2-benzylbenzimidazole nitazene analogs in suspect counterfeit tablets using Raman,SERS, DART-TD-MS,and FT-IR

Developing methods to rapidly screen for novel synthetic 2-benzylbenzimidazole opioids, also known as nitazenes, has become increasingly important due to their high potency. These compounds have potency comparable or exceeding that of fentanyl by up to 10 times and have been implicated in approximately 5% of all drug overdose deaths in the United States in 2021. This paper details the authenticity determination of suspect tablets and the identification of three nitazene analogs (N-pyrrolidino etonitazene, isotonitazene, and etodesnitazene) in suspect tablets seized at a mail facility using Raman and surface-enhanced Raman scattering (SERS) with handheld devices, portable Fourier transform infrared spectrometer (FT-IR), and a direct analysis in real-time ambient ionization coupled to a thermal desorption unit and a mass spectrometer (DART-TD-MS). These methods are rapid and excellent for screening opioids in suspect tablets but could not fully determine the exact structure of some of the nitazene analogs present due to spectral similarities or similar fragmentation patterns. Liquid chromatography–mass spectrometry (LC–MS) confirmed the presence of these nitazene compounds in addition to other opioids/drugs that were in trace quantities. The quantitative high-performance liquid chromatography coupled with ultraviolet (HPLC-UV) detection experiments determined that the suspect tablets contained an average of 0.817 mg of N-pyrrolidino etonitazene per tablet. The results obtained reveal that the simultaneous deployment of these complementary and orthogonal portable analytical techniques as part of a workflow allows suspect tablets to be screened and nitazene-type drugs to be identified in suspect counterfeit tablets at remote sampling sites.     

Derivate des 2-Amino-1,2,3,4-tetrahydronaphthalins, 6. Mitt. IR-Spektroskopische Konformationsermittlung einiger 2-Amino-3-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthaline

Derivatives of 2-Amino-1,2,3,4-tetrahydronaphthalene, VI: IR-Spectroscopic Determination of the Conformational Equilibrium of Some 2-Amino-3-hydroxy-1,2,3,4-tetrahydronaphthalenes. The conformational characteristics of cis- and trans-2-amino-3-hydroxy-5,8-dimethoxytetralins and some N-substituted derivatives were investigated by analysing their IR spectra. A high degree of hydrogen bonding for the trans compounds and a preferred diequatorial conformation were established. The spectra of the cis isomers show the presence of a larger population of the rotamer with axial OH group. The scheme for the synthesis of cis-AT is presented.     

Stereospecific hydroxylation of nortriptyline in man in relation to interindividual differences in its steady-state plasma level

Summary Thecis andtrans isomers of 10-hydroxynortriptyline (10-OH-NT), the major metabolite of nortriptyline (NT) in man, have been separated and quantitated in urine from 6 healthy volunteers who received NT orally, 0.4 mg/kg body weight, three times daily. The isomers were separated by preparative thin layer chromatography and quantitatively determined by gas chromatography as the 10,11-dehydronortriptyline heptafluorobutyryl derivative. The structure of these derivatives producedin vitro was confirmed by gas chromatography — mass spectrometry. Less than 1% of totally excreted 10-OH-NT was accounted for as 10,11-dehydronortriptyline. — Despite interindividual differences in the mean steady-state plasma concentration of NT, the ratio between the two isomers was constant in all subjects (1:4–5). The isomers were both optically active and circular dichroism spectra showed that the asymmetric carbon atoms in the two compounds have different configurations. — It is concluded that NT undergoes stereospecific hydroxylation in man and that there is no correlation between the mean steady-state plasma concentration of NT and the proportion of thecis andtrans isomers formed.     

Metabolism of amphetamines. Identification of N-oxygenated products by gas chromatography and mass spectrometry

A sensitive method for the isolation and identification of N-oxygenated metabolites and metabonates of medicinal amines is described. A combination of gas chromatography and mass spectrometry is effective in separating and identifying secondary hydroxylamines, oximes and nitrones, all of which are N-oxygenated products of secondary amines. These products give mass spectra containing diagnostic fragment ions which are of great value in identification. Primary hydroxylamines are oxidized on column to oximes and can be separated and identified as such. This oxidation is avoided if the primary hydroxylamine is introduced by direct inlet into the mass spectrometer. Secondary hydroxylamines are more stable during gas chromatographic examination although some decomposition to nitrone and secondary amine does occur. In contrast, oximes and nitrones show no tendency to decompose when gas chromatographed.     

Structure-activity relationships in cinnamamides. 1. Synthesis and pharmacological evaluation of some (E)- and (Z)-N-alkyl-alpha,beta-dimethylcinnamamides.

Two series of (E)- and (Z)-N-alkyl-alpha,beta-dimethylcinnamamide derivatives were prepared and the biological activity of these compounds was investigated in a series of pharmacological tests. All compounds tested had clear activity on the CNS; generally, this was depressant with E isomers, while Z isomers always caused marked stimulation (tremors and convulsions). Some of the E isomers also had a clear-cut anticonvulsant activity as shown by the antagonistic effect on pentylenetetrazole-induced seizures in the mouse. The NMR spectra of these compounds, which confirm their configurations, are discussed.     

Syntheses and analytical characterizations of the research chemical 1‐[1‐(2‐fluorophenyl)‐2‐phenylethyl]pyrrolidine (fluorolintane) and five of its isomers

A number of substances based on the 1,2‐diarylethylamine template have been investigated for various potential clinical applications whereas others have been encountered as research chemicals sold for non‐medical use. Some of these substances have transpired to function as NMDA receptor antagonists that elicit dissociative effects in people who use these substances recreationally. 1‐[1‐(2‐Fluorophenyl)‐2‐phenylethyl]pyrrolidine (fluorolintane, 2‐F‐DPPy) has recently appeared as a research chemical, which users report has dissociative effects. One common difficulty encountered by stakeholders confronting the appearance of new psychoactive substances is the presence of positional isomers. In the case of fluorolintane, the presence of the fluorine substituent on either the phenyl and benzyl moieties of the 1,2‐diarylethylamine structure results in a total number of six possible racemic isomers, namely 2‐F‐, 3‐F‐, and 4‐F‐DPPy (phenyl ring substituents) and 2”‐F‐, 3”‐F‐, and 4”‐F‐DPPy (benzyl ring substituents). The present study reports the chemical syntheses and comprehensive analytical characterizations of the two sets of three positional isomers. These studies included various low‐ and high‐resolution mass spectrometry platforms, gas‐ and liquid chromatography (GC and LC), nuclear magnetic resonance (NMR) spectroscopy and GC‐condensed phase and attenuated total reflection infrared spectroscopy analyses. The differentiation between each set of three isomers was possible under a variety of experimental conditions including GC chemical ionization triple quadrupole tandem mass spectrometric analysis of the [M + H – HF]⁺ species. The latter MS method was particularly helpful as it revealed distinct formations of product ions for each of the six investigated substances.