Elucidation of the fluorine substitution position on the phenyl ring of synthetic cannabinoids by electron ionization-triple quadrupole mass spectrometry

Abstract

We present herein a practical methodology for elucidating the o-, m-, or p‰uorine substitution pattern of indazole-type synthetic cannabinoids containing a ‰uorobenzyl group at the N-1 position and a carbonyl group at the C-3 position via electron ionization-triple quadrupole mass spectrometry. We synthesized, as model compounds of the synthetic cannabinoids, the o-, m-, and p-‰uorine positional isomers: 1-[1-(2-, 3-, and 4-‰uorobenzyl)-1H-indazol-3-yl]ethanone (o-, m-, and p-FUBINAE). Mass spectral analyses showed that the three isomers diŠered signiˆcantly in the logarithmic values of the abundance ratios of the product ion at m/z 109 to the precursor ion at m/z 253 (ln(A 109 /A 253 )), following the order of meta＜ortho＜para. In addition, the relationships between ln(A 109 /A 253 ) and collision energy were linear with high correlation coe‹cients. Comparing the ln(A 109 /A 253 ) plots of the FUBINAE isomers versus collision energy with similar plots of AB-FUBINACA and its o-and m-‰uorobenzyl isomers showed that the three AB-FUBINACA isomers behaved as the FUBINAE isomers did with the same ‰uorine substitution pattern on the phenyl ring. Moreover, other synthetic cannabinoids with a p-‰uorobenzyl group (ADB-FUBINACA, FUB-AMB, FUB-APINACA, FUB-NPB-22, and FU-PX-2) also exhibited behavior similar to p-FUBINAE. These results indicated that the ‰uorine substitution position on the phenyl ring can be diŠerentiated by collating the model compounds according to the logarithmic plots of their mass spectral abundance ratios as a function of the collision energy.

Differentiation of AB-FUBINACA and its five positional isomers using liquid chromatography–electrospray ionization-linear ion trap mass spectrometry and triple quadrupole mass spectrometry

“…Lastly, the logarithmic values of the abundance ratios of m / z 109 to 253 [ ln ( A 109 / A 253 )] for AB-FUBINACA, isomer- 1 , and isomer- 2 showed a significant relationship of isomer- 2 < isomer- 1 < AB-FUBINACA in the CE range of 20–50 eV (Fig. 5 d, Table S4), which agrees with our previous analyses using GC–EI-QqQ-MS, although the internal energies of the precursor ions differed on account of the difference of ionization techniques employed [ 22 , 23 ]. The logarithmic values of the abundance ratios for the five isomers, except isomer- 5 , revealed a linear relationship with the CE with high correlation coefficients (Fig.…”

“…Thus far, several research groups have differentiated positional isomers of other abused drugs using LIT-MS and/or QqQ-MS combined with gas chromatography (GC) or liquid chromatography (LC) [ 13 – 16 ]. Previously, we developed the method of distinguishing the 2-, 3-, and 4-fluorine substitution positions on the phenyl ring in SCs containing a fluorobenzyl group, such as AB-FUBINACA and its 2- and 3-fluorobenzyl isomers, based on the so-called energy-resolved mass spectrometry (ERMS) strategy [ 17 – 21 ] using GC–electron ionization (EI)-QqQ-MS [ 22 , 23 ]. We speculated that the methodology should be used in combination with other chromatographic and ionization techniques.…”

Energy‐resolved mass spectrometry for differentiation of the fluorine substitution position on the phenyl ring of fluoromethcathinones

“…The differentiation method presented herein should be applicable to all ring‐fluorinated synthetic cathinones, because the fluorophenyl and fluorobenzoyl ions are common fragment ions in their full scan and product ion scan spectra . Furthermore, including our previous studies on synthetic cannabinoids, the ERMS methodology could simply and clearly differentiate almost all ring‐fluorinated positional isomers in major classes of NPSs. Therefore, we believe that this approach would provide reliable and unambiguous structural identification for forensic drug analysis.…”

“…Herein, we present an alternative new and practical method to distinguish between them using electron ionization (EI)‐triple quadrupole mass spectrometry. Previously, we have reported a procedure for the differentiation of the fluorine substitution position on the phenyl ring in synthetic cannabinoids by “energy‐resolved mass spectrometry (ERMS),” which was based on the difference in the abundance ratios of the product ions as a function of the collision energy (CE) . We expected that this approach could also be applied to the differentiation of the FMC positional isomers.…”

Liquid chromatography–mass spectrometry studies on the isomeric 1-fluorobenzyl-3-naphthoyl-indoles: FUB-JWH-018 and five isomers

“…with frequent displacement of a functional group or substituent [5][6][7][8][9][10][11][12][13][14][15]. Such regioisomeric compounds possess mass spectral equivalency, and similar physicochemical and chromatographic properties in many cases, causing specific identification with complete differentiation from regioisomeric derivatives to be difficult.…”