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Characterization of the “Indanylamphetamines” John F. Casale,* Timothy D. McKibben, Joseph S. Bozenko, and Patrick A. Hays Presented in part at the Clandestine Laboratory Investigating Chemists Association 14th ABSTRACT: Spectroscopic and chromatographic data are provided for 5-(2-aminopropyl)-2,3-dihydro-1H-indene 1 (the indane analog of 3,4-methylenedioxyamphetamine 2), 4-(2-aminopropyl)-2,3-dihydro-1H-indene 3 (the aromatic ring positional isomer of 1), and their respective synthetic intermediates. The data allow the identification and differentiation of 1 and 2 in illicit drug exhibits. KEYWORDS: Indanylamphetamine, Amphetamine Analogs, Designer Drugs, Chemical Analysis, Forensic Chemistry.
Introduction Clandestine laboratory operators have synthesized so-called “designer” or “analog” drugs for many years in efforts to avoid prosecution under existing statutes, and/or to produce more powerful drugs or drugs with alternate central nervous system (CNS) and/or psychoactive properties. The production (and use) of such compounds are the focus of a wide variety of texts, literature articles, and websites. The best known texts in this field, including extensive syntheses of designer/analog drugs along with detailed reports of their CNS and/or psychoactive activity levels based on self-experimentation, are PIHKAL (Phenethylamines I Have Known And Loved) and TIHKAL (Tryptamines I Have Known And Loved) by Shulgin and Shulgin [1,2]. Currently, the methylenedioxyamphetamines (3,4-methylenedioxyamphetamine (MDA, 2), 3,4-methylenedioxymethamphetamine (MDMA), etc.) are the most popular and widely used CNS-active, psychoactive drugs on the illicit markets. Virtually all of the common MDA’s are controlled under U.S. and international statutes, encouraging the production and use of designer/analog drugs. Additional encouragement occurred in late 2000, when the seizure of the world’s largest-ever lysergic acid diethylamide (LSD) synthesis laboratory, and the disruption of its associated distribution network [3], resulted in a major decline in LSD supplies worldwide, and an elevated demand for alternate hallucinogens. These have included traditional and well known substances such as psilocybin mushrooms, but also some unusual substances such as Salvia divinorum and many of the psychoactive phenethylamines and tryptamines featured in PIHKAL and TIHKAL. Since about 2003, the indanyl analog of MDA, that is, 5-(2-aminopropyl)-2,3-dihydro-1H-indene 1 (also known as 1-(5-indanyl)-2-aminopropane, commonly abbreviated as 5-IAP or IAP (Figure 1)) has been submitted to forensic laboratories in the U.S., usually as suspected ecstasy (MDMA). 5-IAP is also commonly - but incorrectly - referred to as “indanylamphetamine” (probably a misinterpretation of the meaning of “IAP”). 5-IAP was first reported by the Nichols group in 1993 [4], and again in 1998 [5], in two studies focusing on its pharmacological activity. Although the Nichols group does not so state, the synthesis of 5-IAP invariably produces a lesser quantity of its aromatic ring positional isomer, 4-(2-aminopropyl)-2,3-dihydro-1H-indene (4-IAP) 3. Although 4-IAP is not known (or expected) to have significant CNS stimulant activity (and therefore has minimal abuse potential), its close structural similarity to 5-IAP, and its likely presence in exhibits containing illicitly prepared 5-IAP, merits detailed spectroscopic and chromatographic delineation of the two compounds. Experimental Chemicals and Reagents Instrumentation Infrared Spectroscopy (FTIR-ATR) - Infrared spectra were obtained on a Nexus 670 FTIR equipped with a single bounce attenuated total reflectance (ATR) accessory. Nuclear Magnetic Resonance Spectroscopy (NMR) - Proton (1H), carbon (13C), and 2-dimensional NMR spectra were obtained on a Varian Inova 600 MHz NMR using a 5 mm Varian Nalorac Z-Spec broadband variable temperature, pulse field gradient probe (Varian, Palo Alto, CA). All compounds were dissolved in deuterochloroform (CDCl3) containing 0.03 percent v/v tetramethylsilane (TMS) as the 0 ppm reference compound. The sample temperature 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. Data processing was performed using software from Varian and Applied Chemistry Development (ACD/Labs, Toronto, Canada). Prediction of proton and carbon spectra was accomplished using ACD/Labs HNMR and CNMR Predictors. Syntheses Results and Discussion The synthetic procedure described by Nichols et al. is the most convenient route to 5-IAP, but as previously noted it produces both 4-IAP and 5-IAP (see Figure 2). To summarize, indane 4 is formylated with SnCl4 and dichloromethyl methyl ether to give a mixture of the aldehydes 5 and 6 in about a 15:85 ratio. If desired, the aldehydes can be separated via alumina column chromatography. Condensation of the aldehydes with nitroethane gave the nitropropenes 7 and 8. Nitropropene 8 can be isolated from 7 by recrystallization from n-hexane at -76 °C. 4-IAP 3 and 5-IAP 1 are obtained from their respective nitropropenes 7 and 8 via LiAlH4 reduction. If the intermediate products are not purified, the resulting final product will contain both 4-IAP 3 and 5-IAP 1 in about a 15:85 ratio.
GC retention time data for the respective compounds are presented in Table 1. The amines were injected as their free bases since the hydrochloride ion-pairs of some phenethylamines undergo thermally induced degradation and chromatograph poorly [6]. 4-IAP and 5-IAP (15:85) are baseline resolved under the chromatographic conditions utilized (Figure 3). Table 1: Gas Chromatographic Retention Times (min) for the “Indanylamphetamines” and their Synthetic Precursors. a
a Conditions given in Experimental Section. Figure 3. Partial Reconstructed Total Ion Chromatogram of a Mixture of 4-IAP and 5-IAP. The IR spectra for 4-IAP and 5-IAP are illustrated in Figure 4. Comparison of the hydrochloride ion pairs reveals similar absorption patterns with the most prominent, yet subtle, differences in the C-H out-of-plane bending frequencies between 700 - 900 cm-1. However, since the spectra are quite similar, additional or supplementary spectroscopic methods should be utilized for definitive identification. Figure 4. Infrared Spectra (FTIR-ATR) of 4-IAP HCl (upper) and 5-IAP HCl (lower). Mass spectra for 4-IAP and 5-IAP, nitropropenes 7 and 8, and aldehydes 5 and 6, are presented in Figures 5 - 7, respectively (top and bottom traces). 4-IAP and 5-IAP each gave a base peak at m/z 44, but were easily distinguished by the relative abundances of ions at m/z 115 and 117 and also at m/z 128 and 131 (Figure 5). Both gave weak fragment ions as well as a weak molecule ion at m/z 175. The nitropropene intermediates 7 and 8 each gave base peak at m/z 115, but were easily distinguished by the relative abundances of ions at m/z 115 and 117 and also at m/z 141 and 145 (Figure 6). The aldehyde intermediates 5 and 6 each gave base peak at m/z 146, and were easily distinguished by the relative abundances of ions at m/z 145 and 146 (Figure 7). The proton and carbon chemical shifts and splitting patterns for 4-IAP, 5-IAP, and their respective intermediates are presented in Tables 2 and 3, respectively. Assignments were based on proton and carbon chemical shift values, proton splitting patterns and coupling constants, and correlations between proton and carbon using the HSQC (directly bonded carbon-to-proton) and HMBC (2, 3, or 4 bond correlations between carbon and proton) experiments. The proton and carbon spectra for each structure were predicted using ACD/Labs HNMR and CNMR Predictors as an additional check. The substituent position on the indane ring was very easily determined using the aromatic proton splitting patterns. Substitution at carbon 4 resulted in 3 adjacent protons, giving a doublet, triplet, and doublet splitting pattern for the 5, 6, and 7 hydrogens, respectively. Substitution at carbon 5 resulted in a broad singlet (H-4) and two broad doublets (H-6 and H-7). The broadness of the singlet and the H-6 doublet is caused by a coupling constant less than one Hertz, typical of meta protons. Conclusions Analytical data is presented to assist delineating 4-IAP from 5-IAP, as well as their respective synthetic intermediates. Characterization is best achieved by GC/MS or NMR. Due to their similarities, the FTIR spectra should be supplemented with another spectroscopic method for definitive identification. References 1. Shulgin A, Shulgin A. PIHKAL: A Chemical Love Story, Transform Press, Berkeley, CA, 1991. 2. Shulgin A, Shulgin A. TIHKAL: The Continuation, Transform Press, Berkeley, CA, 1997. 3. Intelligence Brief: Wamego Kansas LSD Laboratory - Finale. Microgram Bulletin 2004;37(2):33-34 (Reprinted from the NDIC Narcotics Digest Weekly 2003;2(52):3). 4. Monte AP, Marona-Lewicka D, Cozzi NV, Nichols DE. Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogues of 3,4-methylenedioxyamphetamine. Journal of Medicinal Chemistry 1993;36:3700-3706. 5. Parker MA, Marona-Lewicka D, Kurrasch D, Shulgin AT, and Nichols DE. Synthesis and pharmacological evaluation of ring-methylated derivatives of of 3,4-methylenedioxyamphetamine (MDA). Journal of Medicinal Chemistry 1998;41:1001-1005. 6. Casale JF, Hays PA, Klein RFX. Synthesis and characterization of the 2,3-methylenedioxyamphetamines. Journal of Forensic Sciences 1995;40(3):391-400. * * * * * * Figure 5. Electron Ionization Mass Spectra of (a) 4-IAP HCl and (b) 5-IAP HCl. * * * * * * Figure 6. Electron Ionization Mass Spectra of (a) 4-[1-(nitropropenyl)]-2,3-dihydro-1H-indene 7 and (b) 5-[1-(nitropropenyl)]-2,3-dihydro-1H-indene 8. * * * * * * Figure 7. Electron Ionization Mass Spectra of (a) 2,3-dihydro-1H-indene-4-carboxaldehyde 5 and (b) 2,3-dihydro-1H-indene-5-carboxaldehyde 6. * * * * * * Table 2: NMR Proton Chemical Shifts (in ppm) and Splitting Patterns of 4-IAP HCl, 5-IAP HCl, and Related Compounds. Samples Run in CDCl3 with TMS as the Reference Compound for 0 ppm.
bd = broad doublet, bs = broad singlet, d = doublet, dd = doublet of doublets, m = multiplet, p = pentet, s = singlet, t = triplet . * * * * * * Table 3: NMR Carbon Chemical Shifts (in ppm) of 4-IAP HCl, 5-IAP HCl, and Related Compounds. Samples Run in CDCl3 with TMS as the Reference Compound for 0 ppm.
** = chemical, shift determined using HMBC experiment. Peak not visible in direct carbon experiment. * * * * * |
