Forensic Science International 152 (2005) 175184 www.elsevier.

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Determination of synthesis method of ecstasy based on the basic impurities

M. Swista,*, J. Wilamowskib, A. Parczewskia,c
a

Department of Analytical Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland b Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland c Institute of Forensic Research, Westerplatte 9, 31-033 Krakow, Poland Received 6 April 2004; received in revised form 30 July 2004; accepted 2 August 2004 Available online 25 September 2004

Abstract MDMA was prepared by ve different synthesis routes, i.e. by dissolving metal reduction (Al/Hg), cyanoborohydride reduction (NaBH3CN), borohydride reduction in low temperature (NaBH4), Leuckart reaction and safrole bromination. MDP-2P was prepared by two different synthesis methods, i.e. by isosafrole oxidation and MDP-2-nitropropene reduction. Each of the synthesis routes was repeated three times in order to establish variation in qualitative composition of route specic impurities between different batches. The analysis of impurities in MDP-2-nitropropene, MDP-2-P, bromosafrole and MDMA was performed with GC-MS. GC/MS was used also in the analysis of impurities in starting materials: safrole, isosafrole and piperonal. As a result of our study the way of determination of MDMA synthesis route determination based on qualitative composition of impurities is proposed. # 2004 Elsevier Ireland Ltd. All rights reserved.
Keywords: MDMA; Reductive amination; Leuckart method; Safrole bromination; Route specic impurities

1. Introduction The increasing number of ecstasy tablets seized by European law-enforcement agencies dealing with drugs, such as the police, customs, border guards, special drug agencies, etc., shows that illegal production of ecstasy, a synthetic derivative of amphetamine, has been risen during last decades. Western Europe is now recognized as the primary source of the worlds ecstasy. But illegal production of ecstasy is not only a problem of the European. Clandestine laboratories are seized all over the world, in Africa, Asia, North and South America.

* Corresponding author. Tel.: +48 12 633 6377x2014; fax: +48 12 634 0515. E-mail address: brozek@chemia.uj.edu.pl (M. Swist).

In illegal production of ecstasy (MDMA) the most popular synthesis method is reductive amination of MDP2-P (PMK) [15]. Within this method diversity of approaches exists because different reducing agents can be used. The most often encountered are borohydride (NaBH4) reduction in low temperature, dissolving metal reduction (Al/Hg) and cyanoborohydride reduction (NaBH3CN) (Fig. 1). Apart from these methods Leuckart reaction (Fig. 2) and safrole bromination (Fig. 3) are also used. It is worth while to mention that in illegal production of amphetamine Leuckart reaction is used predominantly [6]. Each sample of synthetic drug has its own, characteristic composition of impurities dependent on the way of its production and preparation for distribution. This enables comparative analysis of the drugs seizures. Moreover, there is also possibility of identication of synthesis method on the base of by-products and intermediates, as well as precursors,

0379-0738/$ see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.forsciint.2004.08.003

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Fig. 1. The scheme of reductive amination methods.

i.e. starting materials, which are at the source of many byproducts. Some studies devoted to route specic impurities of MDMA and MDA have already been done [713], but in most cases impurities were identied in reaction mixtures. The precipitate of MDMAHCl was very rarely investigated.

ether, toluene, isopropanol, hydrogen peroxide ($33%), sulfuric acid (95%) (all POCh, Poland, analytical grade), piperonal (99%, Aldrich), isosafrole (97%, Aldrich), safrole (97%, Aldrich), nitroethane (96%, Aldrich), cyclohexylamine (99%, Aldrich), ethyl formate (97%, Aldrich), hydrobromic acid (62%, Aldrich), methylamine solution (33% in abs. ethyl alcohol) methylamine aqueous solution (40%, Aldrich), diethyl ether (anhydrous, >99%, A.C.S. Reagent), methanol (HPLC grade, Merck), NaBH4 (Aldrich, for synthesis), NaBH3(CN) (Aldrich, for synthesis). In impurity proling experiments the following reagents were used: carbonate buffer pH 10 (10.7 ml 0.1 M NaOH, 50 ml 0.05 M NaHCO3, 39.3 ml H2O), n-heptane (Aldrich, HPLC grade), diphenylamine (Supelco, used as internal standard). 2.2. Syntheses The following synthesis methods of MDP-2-P and MDMA have been chosen by the authors according to the preferences of the clandestine laboratories. The physical and spectral (IR, NMR) properties of all synthesized compounds were identical with the data reported formerly [14].

2. Materials and methods 2.1. Chemicals and reagents In synthesis the following reagents were used: formic acid (98%), hydrochloric acid (3638%), methylene chloride, sodium hydroxide, acetic acid (99.5%), acetone, diethyl

Fig. 2. The scheme of Leuckat method.

Fig. 3. The scheme of MDMA synthesis by safrole bromination followed by methylamine substitution.

Fig. 4. The scheme of MDP-2-P synthesis by isosafrole oxidation.

Fig. 5. The scheme of MDP-2-P synthesis by MDP-2-nitropropene reduction.

 M. Swist et al. / Forensic Science International 152 (2005) 175184 Table 1 Variation in qualitative composition of route specic impurities between different batches Compound number Compound structure The number of synthesis repetition L 1 1 2 3 4 0 (++) (+) (++) 2 0 (++) (+) (++) 3 0 (++) (+) (++) B 1 0 0 0 0 2 0 0 0 0 3 0 0 0 0 R 1 0 (++) (+) (+++) 2 0 (++) (+) (+++) 3 0

177

(++) (+) (+++)

(+++)

(+++)

(+++)

(+)

(+)

(+)

(++)

(++)

(++)

(+)

(+)

(+)

(+)

(+++)

(+++)

(+++)

(+++)

(+++)

(+++)

(+++)

(+++)

(+++)

(+)

(+)

(+)

10 11

0 0

0 0

0 0

(+++) (+++)

(+++) (+++)

(+++) (+++)

0 0

0 0

0 0

12

(++)

(++)

(++)

(++)

(++)

(++)

(+)

(+)

(+)

13

(+)

(+)

(+)

L: Leuckart method, B: safrole bromination, R: borohydride reduction in low temperature; 0: absent in impurity prole; (+): percentage of total area <0.05%; (++): percentage of total area >0.05% and <1%; (+++): percentage of total area >1%.

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MDP-2-P was synthesized by two different routes, i.e. by oxidizing isosafrole in an acid medium (Fig. 4) and by reduction of 1-(3,4-methylenedioxyphenyl)-2-nitropropene, which was previously prepared by condensation of piperonal and nitroethane (Fig. 5). The syntheses were performed according to the procedures described by Al. Shulgin and A. Shulgin [15]. 2.2.1. MDMA prepared by reductive amination This is the most popular synthesis route of MDMA in illegal production. However, within this method diversity of approaches exists because of possibility of application various reducing agents. We have synthesized MDMA according to the following approaches (Fig. 1):  Dissolving metal reduction using aluminiummercury amalgam. This synthesis was performed according to the procedure described by Al. Shulgin and A. Shulgin [15].  Borohydride (NaBH4) reduction. This synthesis was performed according to the following procedure: aqueous solution (40%) of methylamine (2 ml) was added to a cold mixture of MDP-2-P (1.51 g) in MeOH (5 ml). The mixture was cooled to 20 8C and then NaBH4 (30 mg) was slowly added. After dissolving of reductive agent, reaction mixture was left at 20 8C for 2 h. The addition of NaBH4 was repeated three times, in portions of 30, 30 and 40 mg, and reaction mixture was left at 20 8C for 24 h. Methanol was evaporated, 10% HCl (10 ml) was added to a residue, and the solution was washed with CH2Cl2 (3 ml 8 ml). The organic solution was extracted

with 10% HCl, combined aqueous layers were alkalized with 25% NaOH ($10 ml) and extracted with CH2Cl2 (3 10 ml). Combined extracts were dried over MgSO4, evaporated, a residue was dissolved in Et2O (18 ml) and dry HCl was passed through the solution. Precipitate of MDMAHCl was ltered off and dried.  Cyanoborohydride (NaBH3CN) reduction. This synthesis was performed according to the modied MDA synthesis procedure described by Al. Shulgin and A. Shulgin [15]. 2.2.2. MDMA prepared by Leuckart method This synthesis was performed according to the modied MDA synthesis procedure described by Elks and Hey [16] (Fig. 2). 2.2.3. MDMA prepared by safrole bromination This synthesis was performed according to the procedure described by Biniecki and Krajewski [17] (Fig. 3). 2.3. Sample preparation Safrole (0.015 g), piperonal (0.015 g), isosafrole (0.015 g), MDP-2-nitropropene (0.015 g), MDP-2-P (0.015 g) and bromosafrole (0.015 g) were dissolved in 200 ml of Et2O and analyzed using GC/MS. Extraction of impurities was performed as follows: a portion of 200 mg of MDMAHCl was dissolved in 2 ml of carbonate buffer (pH 10), the solution was then vigorous shaken (25 min) following by addition of 200 ml of nheptane containing diphenylamine as an internal standard

Fig. 6. Some differences and similarities in impurity composition in MDMA samples prepared by different synthesis methods.

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Fig. 7. One of the side-reaction occurring during reductive amination and Leuckart method.

Fig. 8. One of the side-reaction occurring during safrole bromination method.

(35 mg/l), and then again shaken (25 min). The extracts were subjected to GC/MS analysis and impurity proles were obtained. 2.4. Apparatus GC/MS analysis was carried out on Hewlett-Packard 6890 series gas chromatograph coupled to 5984B mass spectrometer. HP5-MS fused silica capillary column (30 m 0.25 mm 0.25 mm) was applied and helium 6.0 was used as a carrier gas (1.0 ml/min). The injection (2 ml) was made splitless by the autosampler. The following temperature program was applied: 50 8C maintained for

1 min, then ramped at 10 8C/min up to 150 8C, maintained 5.5 min, and again increased to 280 8C at 10 8C/min ramp, and maintained for the nal 10 min. Mass spectrometer was operated in positive electron ionization mode (EI). A fullscan mass spectra 40500 amu were obtained.

3. Results and discussion Synthesis according to each given method was repeated three times according to the same procedure in order to establish variation in qualitative composition of route specic impurities between different batches. The results are

Fig. 9. The mass spectrum of N-methyl-N-[1-methyl-2-(3,4-methylenedioxyphenyl)-ethyl)]-3-(3,4-methylenedioxyphenyl)-propaneamine.

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Fig. 10. The proposed fragmentation of N-methyl-N-[1-methyl-2-(3,4-methylenedioxyphenyl)-ethyl)]-3-(3,4-methylenedioxyphenyl)-propaneamine.

presented in Table 1. Generally, the qualitative composition of route specic impurities does not change between different batches of the same synthetic route. But we found that some of these impurities may emerge unexpectedly in other methods. Therefore, instead of individual compounds, the groups of markers should be always considered for determination of synthetic route. Diagram in Fig. 6 shows how to identify synthesis method of ecstasy on the base of the basic impurities. As can be seen in this diagram each synthesis method has its own characteristic group of impurities. Identication of one of this group in impurity proles of MDMA is equivalent with the identication of synthesis method. It appears that majority of impurities included in this diagram occur in MDMAHCl in higher concentration as compare to other impurities. Some of them are common for not more than two methods although the mechanisms of their formation are sometimes different. This concerns compounds 8 and 9 which emerge in Leuckart reaction as well as safrol bromination. In the case of common impurities of Leuckart and reductive amination methods the mechanism of their formation is the same, i.e. compounds 2 and 3 emerge during reaction of methylamine impurities and piperonal, as was reported formerly [2] and compound 5 is a product of reaction of N-methyl-3,4-methylenedioxybenzylamine with MDP-2-P (Fig. 7). The compound 4 is a product of reaction of impurity of MDP-2-P, 1-methoxy-1-(3,4methylenodioxyphenyl)-2-propanone, with methylamine, so it is not only the marker of Leuckart and reductive amination but also synthesis of MDP-2-P by isosafrole

oxidation. The other compounds are characteristic for only one method, although compound 6 is sometimes found in MDMA samples prepared by safrole bromination. Compound 7 is produced in reaction of camphor (which has its source in isosafrole) with methylamine. In the case of synthesis marker of reductive amination (compound 1) we found that it might not be present in impurity proles if the synthesis is performed with good yield, as it was in case of borohydride reduction in low temperature (Table 1) and dissolving metal reduction. Only in cyanoborohydride reduction this compound was identied in impurity proles. The markers of safrole bromination, compounds 10

Fig. 11. The formation of N-methyl-2-methyl-1-(3,4-methylenedioxyphenyl)-ethaneamine (compound 12) in safrole bromination method and Leuckart method.

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Fig. 12. The mass spectrum of 1-(3,4-methylenedioksyphenyl)-1-propanone.

and 11 were found only in samples prepared by this method (Fig. 8). The mass spectrum of compound 11 is presented in Fig. 9 and proposed fragmentation pattern of this compound is present in Fig. 10. Moreover, in identication of synthesis method the following information could be used. During MDMA synthesis

by Leuckart method as well as safrole bromination the compound 12 (Table 1) is produced. In case of Leuckart method compound 12 arise in reaction of MDP-2-P impurity, 1-(3,4-methylenedioxyphenyl)-1-propanone, and methylamine (Fig. 11). The mass spectra of both subtract and product of this reaction are presented in Figs. 12 and 13.

Fig. 13. The mass spectrum of N-methyl-2-methyl-1-(3,4-methylenedioxyphenyl)-ethaneamine (compound 12).

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Fig. 14. The mass spectrum of N-methyl-1-(3,4-methylenedioxyphenyl)-ethaneamine (compound 13).

But in case of safrole bromination compound 12 is produced in reaction of 1-bromo-1-(3,4-methylenedioxyphenyl)propane. In reductive amination compound 12 is present in impurity proles of ecstasy but at a very low concentration in comparison to other impurities and this fact facilitates

the discrimination of Leuckart reaction from reductive amination. In discrimination the Leuckart reaction from safrole bromination could be used fact, that compound 13 (Table 1, Fig. 14) is not produced during safrole bromination.

Fig. 15. The mass spectrum of 2-(dimethylamino)-2-methyl-3-(3,4-methylenedioxyphenyl)-propanenitrile.

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Fig. 16. The mechanism of 2-(dimethylamino)-2-methyl-3-(3,4-methylenedioxyphenyl)-propanenitrile formation in cyanoborohydride reduction.

Fig. 17. The mass spectrum of N-methyl-2-methoxy-1-methyl-2-(3,4-methylenedioxyphenyl)-ethaneimine.

Fig. 18. The ways of formation of PMMA from impurity in safrole, 1-methoxy-4-(2-propenyl)-benzene.

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M. Swist et al. / Forensic Science International 152 (2005) 175184 methylenedioxymethamphetamine (MDMA) tablets, Forensic Sci. Int. 127 (2002) 144. F. Palhol, S. Boyer, N. Naulet, M. Chabrillat, Impurity proling of seized MDMA tablets by capillary gas chromatography, Anal. Bioanal. Chem. 374 (2002) 274281. A.M.A. Verweij, Clandestine manufacture of 3,4-methylenedioxymethylamphetamine (MDMA) by low pressure reductive amination. A mass spectrometric study of some reaction mixtures, Forensic Sci. Int. 45 (1990) 9196. A. Allen, T.S. Cantrell, Synthetic reductions in clandestine amphetamine and methamphetamine laboratories: a review, Forensic Sci. Int. 42 (1989) 183199. W. Krawczyk, Proling of drugs, Central Forensic Laboratory of Police, Warszawa (in Polish), 1998. T. Lukaszewski, Spectroscopic and chromatographic identication of precursors, intermediates, and impurities of 3,4methylenedioxyamphetamine, J. Assoc. Off. Anal. Chem. 61 (1978) 951967. R.J. Renton, J.S. Cowie, M.C.H. Oon, A Study of the precursors, intermediates and reaction by-products in the synthesis of 3,4-methylenedioxymethamphetamine and its application to forensic drug analysis, Forensic Sci. Int. 60 (1993) 189202. F.T. Noggle, C.R. Clark, J. DeRuiter, Gas chromatographic and mass spectrometric analysis of N-methyl-1-aryl-2-propanamines synthesized from the substituted allylbenzenes present in sassafras oil, J. Chromatogr. Sci. 29 (1991) 267 271. F.T. Noggle, C.R. Clark, J. DeRuiter, Gas chromatographic and mass spectrometric analysis of samples from a clandestine laboratory involved in the synthesis of ecstasy from sassafras oil, J. Chromatogr. Sci. 29 (1991) 168173. M. Bohn, G. Bohn, G. Blaschke, Synthesis markers in illegally manufactured 3,4-methylenedioxyamphetamine and 3,4methylenedioxymethamphetamine, Int. J. Leg. Med. 106 (1993) 1923. C.R. Clark, J. DeRuiter, S. Andurkar, F.T. Noggle, Analysis of 3,4-methylenedioxyphenyl-2-propanone and 3,4-methylenedioxyamphetamine prepared from isosafrole, J. Chromatogr. Sci. 32 (1994) 393402. R.J. Lewis, D. Reed, A.G. Service, A.M. Langford, The identication of 2-chloro-4,5-methylenedioxymethylamphetamine in an illicit drug seizure, J. Forensic Sci. 45 (2000) 1119 1125. T.A. Dal Cason, The characterization of some 3,4-methylenedioxyphenylisopropylamine (MDA) analogs, J. Forensic Sci. 34 (1989) 928961. Al. Shulgin, A. Shulgin, PIHKAL A Chemical Love Story, Transform Press, Berkeley, 1991. J. Elks, H. Hey, b-3:4-Methylenedioxyphenylisopropylamine, J. Chem. Soc. 55 (1943) 1516. S. Biniecki, E. Krajewski, Production of D,L-N-methyl-b-(3,4methylenedioxyphenyl)-isopropylamine and D,L-N-methyl-b(3,4-dimethoxyphenyl)-isopropylamine, Acta Poloniae Pharm. XVII (1960) 421425.

We found that different variants of reductive amination might be also discriminated. For example we identied marker of cyanoborohydride reduction (NaBH3CN), 2(dimethylamino)-2-methyl-3-(3,4-methylenedioxyphenyl)propanenitrile. Mass spectrum of this compound is presented in Fig. 15 and the mechanism of its formation is presented in Fig. 16. In impurity proles of MDMA samples prepared by this method we also identied an imine corresponding to compound 4, which mass spectrum is presented in Fig. 17. All these compounds were identied only in this method. GC/MS analysis of commercially available safrole and isosafrole proved that 1-methoxy-4-(2-propenyl)-benzene is only present in safrole (Fig. 18). Because of the fact that even its isomer, 1-methoxy-4-(1-propenyl)-benzene, is not present in isosafrole, there is a possibility to nd out whether synthesis of MDMA was started from safrole or isosafrole on the basis of presence or absence of PMMA (p-methoxymethamphetamine) in impurity proles. If commercially available safrole was used as a starting material to produce isosafrole (via isomerization reaction) or bromosafrole, then it should results in presence of PMMA in impurity proles of MDMA The absence of PMMA in impurity proles of MDMA indicates that probably commercially available isosafrole was used as a starting material.

[3]

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[5]

[6] [7]

[8]

[9]

[10]

4. Conclusions The route specic impurities were identied in impurity proles of MDMA prepared by ve different synthesis methods. Some of them have not been reported formerly. The way of synthesis route determination based on qualitative composition of impurities is proposed. Additionally, variation in qualitative composition of route specic impurities between different batches is evaluated. Acknowledgments This study was supported by a grant OT 00C 01024 from the Committee for Scientic Research, Poland. References
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