Fragmentation Pathways of Trifluoroacetyl Derivatives of Methamphetamine, Amphetamine, and Methylenedioxyphenylalkylamine Designer Drugs by Gas Chromatography/Mass Spectrometry
Methamphetamine (MA), amphetamine (AM), and the methylenedioxyphenylalkylamine designer drugs, such as 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), 3,4-methylenedioxyamphetamine (MDA), and 3,4-(methylenedioxyphenyl)-2-butanamine (BDB), are widely abused as psychedelics. In this paper, these compounds were derivatized with trifluoroacetic (TFA) anhydride and analyzed by gas chromatography/mass spectrometry using electron ionization in positive mode. Gas chromatographic separation for TFA derivatives of all compounds was successfully resolved using an Equity-5 fused silica capillary column with a poly (5% diphenyl-95% dimethylsiloxane) stationary phase. Base peaks or prominent peaks of MA, AM, MDMA, MDEA, MBDB, MDA, and BDB appeared at m/z 154, 140, 154, 168, 168, 135, and 135, respectively. These occurred due to α-cleavage from the amide nitrogen, splitting into the TFA imine species and benzyl or methylenedioxybenzyl cations. Further prominent fragment ions at m/z 118 for MA and AM, m/z 162 for MDMA, MDEA, and MDA, and m/z 176 for MBDB and BDB were produced by cleavage of the phenylpropane or methylenedioxypropane hydrocarbon radical cation via a hydrogen rearrangement. These fragmentation pathways for the TFA derivatives of all the compounds are summarized and illustrated in this paper. 1. Introduction In recent years, extensive attention in clinical and forensic toxicology has focused on the increasing abuse of methamphetamine (MA), amphetamine (AM), and methylenedioxyphenylalkylamine derivatives, such as 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), 3,4-methylenedioxyamphetamine (MDA), and 3,4-(methylenedioxyphenyl)-2-butanamine (BDB). A number of severe and even fatal intoxications attributable to these drugs have been reported [1–4]. Consequently, detection and identification analyses for these compounds are routinely performed in clinical and forensic laboratories. Several gas chromatographic methods to analyze MA, AM, MDMA, MDEA, MBDB, MDA, and BDB in doping control and toxicological analysis have been reported [5–8]. Because of their relatively low molecular weights, high polarity, and volatility, derivatization is necessary when using gas chromatography (GC) [9]. Acylation is one of the most popular derivatization reactions for primary and secondary amines and converts compounds into derivatives that are more easily separated or give an enhanced
References
[1]
V. Fineschi, F. Centini, E. Mazzeo, and E. Turillazzi, “Adam (MDMA) and Eve (MDEA) misuse: an immunohistochemical study on three fatal cases,” Forensic Science International, vol. 104, no. 1, pp. 65–74, 1999.
[2]
N. Carter, G. N. Rutty, C. M. Milroy, and A. R. W. Forrest, “Deaths associated with MBDB misuse,” International Journal of Legal Medicine, vol. 113, no. 3, pp. 168–170, 2000.
[3]
R. García-Repetto, E. Moreno, T. Soriano, C. Jurado, M. P. Giménez, and M. Menéndez, “Tissue concentrations of MDMA and its metabolite MDA in three fatal cases of overdose,” Forensic Science International, vol. 135, no. 2, pp. 110–114, 2003.
[4]
J. L. Pilgrim, D. Gerostamoulos, O. H. Drummer, and M. Bollmann, “Involvement of amphetamines in sudden and unexpected death,” Journal of Forensic Sciences, vol. 54, no. 2, pp. 478–485, 2009.
[5]
P. R. Paetsch, G. B. Baker, L. E. Caffaro, A. J. Greenshaw, G. A. Rauw, and R. T. Coutts, “Electron-capture gas chromatographic procedure for simultaneous determination of amphetamine and N-methylamphetamine,” Journal of Chromatography, vol. 573, no. 2, pp. 313–317, 1992.
[6]
P. Marquet, E. Lacassie, C. Battu, H. Faubert, and G. Lachatre, “Simultaneous determination of amphetamine and its analogs in human whole blood by gas chromatography-mass spectrometry,” Journal of Chromatography B, vol. 700, no. 1-2, pp. 77–82, 1997.
[7]
F. T. Peters, S. Schaefer, R. F. Staack, T. Kraemer, and H. H. Maurer, “Screening for and validated quantification of amphetamines and of amphetamine- and piperazine-derived designer drugs in human blood plasma by gas chromatography/mass spectrometry,” Journal of Mass Spectrometry, vol. 38, no. 6, pp. 659–676, 2003.
[8]
F. Moriya, “Accumulation of intravenously administered methamphetamine in stomach contents,” Forensic Toxicology, vol. 28, no. 1, pp. 43–46, 2010.
[9]
G. Frison, L. Tedeschi, D. Favretto, A. Reheman, and S. D. Ferrara, “Gas chromatography/mass spectrometry determination of amphetamine-related drugs and ephedrines in plasma, urine and hair samples after derivatization with 2,2,2-trichloroethyl chloroformate,” Rapid Communications in Mass Spectrometry, vol. 19, no. 7, pp. 919–927, 2005.
[10]
D. R. Knapp, Handbook of Analytical Derivatization Reactions, Wiley & Sons, New York, NY, USA, 1979.
[11]
J. T. Cody and R. L. Foltz, “GC/MS analysis of body fluids for drugs of abuse,” in Forensic Applications of Mass Spectrometry, J. Yinon, Ed., pp. 2–59, CRC Press, Boca Raton, Fla, USA, 1995.
[12]
W. Weinmann, M. Renz, S. Vogt, and S. Pollak, “Automated solid-phase extraction and two-step derivatisation for simultaneous analysis of basic illicit drugs in serum by GC/MS,” International Journal of Legal Medicine, vol. 113, no. 4, pp. 229–235, 2000.
[13]
M. Pujadas, S. Pichini, S. Poudevida et al., “Development and validation of a gas chromatography-mass spectrometry assay for hair analysis of amphetamine, methamphetamine and methylenedioxy derivatives,” Journal of Chromatography B, vol. 798, no. 2, pp. 249–255, 2003.
[14]
J. L. Villamor, A. M. Bermejo, P. Fernández, and M. J. Tabernero, “A new GC-MS method for the determination of five amphetamines in human hair,” Journal of Analytical Toxicology, vol. 29, no. 2, pp. 135–139, 2005.
[15]
C. Hasegawa, T. Kumazawa, X. P. Lee et al., “Pipette tip solid-phase extraction and gas chromatography-mass spectrometry for the determination of methamphetamine and amphetamine in human whole blood,” Analytical and Bioanalytical Chemistry, vol. 389, no. 2, pp. 563–570, 2007.
[16]
S. Lee, Y. Park, W. Yang et al., “Development of a reference material using methamphetamine abusers' hair samples for the determination of methamphetamine and amphetamine in hair,” Journal of Chromatography B, vol. 865, no. 1-2, pp. 33–39, 2008.
[17]
K. Kudo, T. Ishida, W. Hikiji et al., “Construction of calibration-locking databases for rapid and reliable drug screening by gas chromatography-mass spectrometry,” Forensic Toxicology, vol. 27, no. 1, pp. 21–31, 2009.
[18]
C. R. Clark, J. DeRuiter, A. K. Valaer, and F. T. Noggle, “GC-MS analysis of acylated derivatives of methamphetamine and regioisomeric phenethylamines,” Journal of Chromatographic Science, vol. 33, no. 9, pp. 485–492, 1995.
[19]
C. R. Clark, J. DeRuiter, and F. T. Noggle, “Chromatographic and mass spectrometric methods for the differentiation of N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine from regioisomeric derivatives,” Journal of Chromatographic Science, vol. 34, no. 5, pp. 230–237, 1996.
[20]
B. Lindeke and A. K. Cho, “Specifically deuterated 1-phenyl-1-isopropylamines. Synthesis of deuterium ( )-amphetamine, ( )-α-methyltyramine,” Acta Pharmaceutica Suecica, vol. 9, no. 4, pp. 363–372, 1972.
[21]
D. B. Repke, D. K. Bates, and W. J. Ferguson, “Synthesis of dextroamphetamine sulfate and methamphetamine hydrochloride from D-phenylalanine,” Journal of Pharmaceutical Sciences, vol. 67, no. 8, pp. 1167–1168, 1978.
[22]
A. T. Shulgin and A. Shulgin, PiHKAL: A Chemical Love Story, Transform Press, Berkeley, Calif, USA, 1991.
[23]
J. Y. Kim, K. S. Jung, M. K. Kim, J. I. Lee, and M. K. In, “Simultaneous determination of psychotropic phenylalkylamine derivatives in human hair by gas chromatography/mass spectrometry,” Rapid Communications in Mass Spectrometry, vol. 21, no. 11, pp. 1705–1720, 2007.
[24]
C. Brede, I. Skjevrak, and H. Herikstad, “Determination of primary aromatic amines in water food simulant using solid-phase analytical derivatization followed by gas chromatography coupled with mass spectrometry,” Journal of Chromatography A, vol. 983, no. 1-2, pp. 35–42, 2003.
[25]
H. Kataoka, “Derivatization reactions for the determination of amines by gas chromatography and their applications in environmental analysis,” Journal of Chromatography A, vol. 733, no. 1-2, pp. 19–34, 1996.
[26]
D. G. I. Kingston, J. T. Bursey, and M. M. Bursey, “Intramolecular hydrogen transfer in mass spectra. II. The McLafferty rearrangement and related reactions,” Chemical Reviews, vol. 74, no. 2, pp. 215–242, 1974.
[27]
K. Zaitsu, M. Katagi, H. T. Kamata, A. Miki, and H. Tsuchihashi, “Discrimination and identification of regioisomeric β-keto analogues of 3,4-methylenedioxyamphetamines by gas chromatography-mass spectrometry,” Forensic Toxicology, vol. 26, no. 2, pp. 45–51, 2008.
