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Technical Note The Characterization of 4-Methoxy-N-ethylamphetamine Hydrochloride John F. Casale*, Patrick A. Hays, Trinette K. Spratley, and Pamela R. Smith ABSTRACT: The synthesis, analysis, and characterization of 4-methoxy-N-ethylamphetamine hydrochloride is presented. Analytical data (gas chromatography/mass spectrometry, Fourier transform infrared spectroscopy, and proton nuclear magnetic resonance spectroscopy) are presented. KEYWORDS: 4-Methoxy-N-ethylamphetamine, Phenethylamine, Synthesis, Analysis, Forensic Chemistry Introduction In late 2004, this laboratory received a white crystalline substance submitted as an unknown suspected phenethylamine (seizure exhibit) for identification and characterization. It was thought that this compound might be one of the many esoteric phenethylamine “designer drugs” described in PIHKAL (1). Preliminary screening indicated that the sample contained a single component and was relatively pure. Utilizing proton nuclear magnetic resonance (1H-NMR) spectroscopy and a computerized structural elucidation program, the compound was tentatively identified as 4-methoxy-N-ethylamphetamine hydrochloride (Figure 1). Surprisingly, this compound is not detailed in PIHKAL, and furthermore has few literature citations, including on websites dedicated to drug abuse. It therefore constitutes a new phenethylamine-type “designer drug.” For this reason, and also to confirm the tentative identification via direct spectral comparisons, it was synthesized and fully characterized via gas chromatography/mass spectrometry (GC/MS), Fourier transform infrared spectroscopy (FTIR), and 1H-NMR spectroscopy.
Experimental Chemicals, Reagents, and Materials: All solvents were distilled-in-glass products of Burdick and Jackson Laboratories (Muskegon, MI). All other chemicals were of reagent-grade quality and products of Aldrich Chemical (Milwaukee, WI). 4-Methoxyamphetamine HCl (the starting material for the synthesis) was acquired from the reference collection of this laboratory. Gas Chromatography/Mass Spectrometry (GC/MS): Analyses were performed using an Agilent (Palo Alto, CA) Model 5973 quadrupole mass-selective detector (MSD) interfaced with an Agilent (Palo Alto, CA) Model 6890 gas chromatograph. The MSD was operated in the electron ionization (EI) mode with an ionization potential of 70 eV, a scan range of 34 - 700 mass units, and at 1.34 scans/second. The GC was fitted with a 30 m x 0.25 mm ID fused-silica capillary column coated with 0.25 μm DB-1 (J & W Scientific, Rancho Cordova, CA). The oven temperature was programmed as follows: Initial temperature, 100 °C; no hold, program rate, 6 °C/min; final temperature, 300 °C; final hold, 5.67 min. The injector was operated in the split mode (21.5:1) and at a temperature of 280 °C. The auxiliary transfer line to the MSD was operated at 280 °C. Infrared Spectroscopy (FTIR-ATR): Spectra were obtained on a Nexus 670 FTIR equipped with a single bounce attenuated total reflectance (ATR) accessory. Spectra were collected using 32 scans between 4000 cm-1 and 400 cm-1 at a resolution of 4 cm-1. Proton Nuclear Magnetic Resonance Spectroscopy (1H-NMR): Spectra were obtained on a Varian Mercury 400 MHz NMR using a 5 mm Varian Nalorac indirect detection, variable temperature, pulse field gradient probe with PulseTune® (Varian, Palo Alto, CA). The compound was dissolved in deuterium oxide (D2O) containing 0.05 percent (by weight) 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid, sodium salt (TSP) as a 0 ppm reference and 5 mg/mL maleic acid as the quantitative internal standard. The temperature of the sample was maintained at 25 °C. Standard Varian pulse sequences were used to acquire proton, proton-decoupled carbon, and gradient versions of COSY, HSQC, and HMBC. Processing of data was performed using software from Varian and Applied Chemistry Development (ACD/Labs, Toronto, Canada). Structural elucidation was performed manually and by using ACD/Labs Structure Elucidator® software. Syntheses: 4-Methoxy-N-ethylamphetamine HCl: A flame-dried 1-liter round bottom flask fitted with an addition funnel and water-cooled condenser was charged with 100 mL diethyl ether containing 1.0 M LiAlH4 (100 mmol). Approximately 75 mL of anhydrous diethyl ether containing 4-methoxy-N-acetylamphetamine (5.0 grams, 24.2 mmol) was added dropwise over 30 minutes, followed by an additional 125 mL of anhydrous diethyl ether, and the mixture was refluxed overnight. The reaction was quenched slowly, in sequence, with 4.0 mL of water, 4.0 mL of 15 percent aqueous NaOH, and 12 mL of water, and was then stirred for approximately 30 minutes. The lithium and aluminum salts were removed via suction filtration through a Celite pad, which was washed with an additional 100 mL diethyl ether. The filtrate was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give a clear oil. The oil was reconstituted in 35 mL isopropanol, treated with isopropanolic HCl until pH 5, and then diluted to approximately 800 mL with diethyl ether. The resulting precipitate was collected via suction filtration, washed with additional diethyl ether to remove traces of excess HCl, and desiccated under vacuum to remove residual solvent to give 4-methoxy-N-ethylamphetamine HCl as a white crystalline powder (3.22 grams, 58 percent yield). Results and Discussion Independent synthesis, spectral characterization, and comparison of authentic 4-methoxy-N-ethylamphetamine HCl to the submitted unknown confirmed its identity. The infrared spectrum (Figure 2) displays an absorbance pattern that is consistent with a secondary amine halogen (HCl) ion-pair and a para disubstituted aromatic ring. The mass spectrum (Figure 3) gives fragments at m/z 72 (base peak), 121, and 192, all consistent with a methoxy-substituted-N-ethylamphetamine. The 1H-NMR spectrum (Figure 4) exhibited two doublets at 7.0 and 7.3 ppm, integrating to 2 protons each, typical of a para substituted benzene. The singlet at 3.8 ppm integrates to 3 protons and corresponds to the methoxy group (supported by 13C-NMR (not shown)). The multiplet at 3.5 ppm integrates to 1 proton and corresponds to the methine (which is bonded to the methyl group (a doublet at 1.2 ppm integrating to 3 protons), the methylene group (2 doublet of doublets at 2.8 and 3.1 ppm integrating to 1 proton each), and the nitrogen). The methylene proton chemical shifts (2.8 and 3.1 ppm) confirm that they are bonded to the benzene ring. The remaining proton peaks (the multiplet at 3.2 ppm integrating to 2 protons and the triplet at 1.3 ppm integrating to 3 protons) are of the N-ethyl group. The spectrum peaks below 3.6 ppm are, as expected, nearly identical to those of MDEA (Figure 5). The starting material used in this synthesis (4-methoxyamphetamine, also known as “PMA”) is itself a controlled substance that is abused worldwide (especially in North America and Europe); therefore, it is quite unlikely that the synthetic procedure described herein was utilized by the original clandestine chemist - nor is it likely to be utilized in the future by any clandestine chemists. The choice of this synthetic route was based on convenience, since 4-methoxyamphetamine was available from this laboratory’s reference collection. Although not investigated, the clandestine chemist in this case probably started his synthesis from 4-methoxyphenyl-2-propanone. It is doubtful whether he intended to make 4-methoxy-N-ethylamphetamine, as comments made in PIHKAL concerning the homologous compound 4-methoxy-N-methylamphetamine (also known as 4- methoxymethamphetamine, PMMA) would suggest that 4-methoxy-N-ethylamphetamine is only a moderate stimulant with minimal (if any) hallucinogenic properties. In addition, both PMA and PMMA are toxic compounds that have been implicated in numerous deaths over the past four decades, and it is likely that 4-methoxy-N-ethylamphetamine would display similar toxicity. Conclusions The gas chromatography and infrared and mass spectra of 4-methoxy-N-ethylamphetamine are expected to be similar to its 2- and 3-methoxy substituted analogs. 1H-NMR provides unequivocal identification. Although quite unlikely, if this compound becomes more common in illicit markets, the acronym “PMEA” is an obvious choice. References 1. Shulgin A, Shulgin A. PIHKAL: A Chemical Love Story, Transform Press, Berkeley, CA, 1991. - - - - - - - - - -
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