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Organic impurity profiling of 3,4-methylenedioxymethamphetamine (MDMA) synthesised from catechol
Forensic Science International 248 (2015) 140–147
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Organic impurity profiling of 3,4-methylenedioxymethamphetamine (MDMA) synthesised from catechol Erin Heather, Ronald Shimmon, Andrew M. McDonagh * Centre for Forensic Science, University of Technology Sydney, Sydney, NSW 2007, Australia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 23 June 2014 Received in revised form 18 December 2014 Accepted 19 December 2014 Available online 31 December 2014
This work examines the organic impurity profile of 3,4-methylenedioxymethamphetamine (MDMA) that has been synthesised from catechol (1,2-dihydroxybenzene), a common chemical reagent available in industrial quantities. The synthesis of MDMA from catechol proceeded via the common MDMA precursor safrole. Methylenation of catechol yielded 1,3-benzodioxole, which was brominated and then reacted with magnesium allyl bromide to form safrole. Eight organic impurities were identified in the synthetic safrole. Safrole was then converted to 3,4-methylenedioxyphenyl-2-propanone (MDP2P) using two synthetic methods: Wacker oxidation (Route 1) and an isomerisation/peracid oxidation/acid dehydration method (Route 2). MDMA was then synthesised by reductive amination of MDP2P. Thirteen organic impurities were identified in MDMA synthesised via Route 1 and eleven organic impurities were identified in MDMA synthesised via Route 2. Overall, organic impurities in MDMA prepared from catechol indicated that synthetic safrole was used in the synthesis. The impurities also indicated which of the two synthetic routes was utilised. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Illicit drugs 3,4-Methylendioxymethamphetamine MDMA Safrole Chemical synthesis Chemical profiling
1. Introduction The active ingredient in the drug colloquially referred to as ‘ecstasy’ is the amphetamine-type stimulant 3,4-methylenedioxymethamphetamine (MDMA), Fig. 1. First patented as ‘methylsafrylamin’ in 1912 as a precursor for blood-clotting agents [1,2], the recreational use of MDMA gained popularity during the mid-1980s and it has since become a prevalent drug of choice [1,3]. MDMA is an illicit substance in many jurisdictions around the world and is under international control through its inclusion to the United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances 1988. There has been a significant amount of research into the organic impurity profiles of MDMA synthesised from the most common precursors: 3,4-methylenedioxyphenyl-2-propanone (MDP2P), safrole, isosafrole and piperonal [3]. These precursors, however, are controlled or regulated substances in many jurisdictions. The use of uncontrolled precursors therefore offers clandestine laboratory operators a strategy to reduce the risk associated with detection.
* Corresponding author at: University of Technology Sydney, P.O. Box 123, Broadway, NSW 2007, Australia. Tel.: +61 2 95141035. E-mail address: [email protected] (A.M. McDonagh). http://dx.doi.org/10.1016/j.forsciint.2014.12.021 0379-0738/ß 2015 Elsevier Ireland Ltd. All rights reserved.
Catechol (Scheme 1) is a common chemical reagent that is synthesised on an industrial scale with applications in the synthesis of fragrances, pesticides, drugs and dyes [4]. Diversion of catechol into illicit activities is therefore highly feasible. Safrole, a common starting material for MDMA production, is a natural product obtained from sassafras oil and is also used for the industrial production of fragrances, flavours and some insecticides [5]. The synthesis of safrole from synthetic precursors, including catechol, has been investigated as a means to reduce the reliance upon variable natural sources [5,6]. Thus, with such precedent as well as available literature, it is unsurprising that this route has been reported for the synthesis of MDMA in literature readily available to the clandestine laboratory operator [7]. The techniques and procedures for the synthesis of MDMA from uncontrolled precursors, including catechol, are described in detail in numerous freely available documents on the internet [7]. There is, however, only limited information available regarding the organic impurity profiles that arise when these synthetic routes are utilised [8]. Organic impurities in MDMA can result from precursors, intermediates or reaction by-products [3] and their identification can therefore provide valuable information about synthetic methods currently in use. Of course, adulterants are a further source of impurities however these will not be addressed here. This paper presents the results of organic impurity profiling of MDMA synthesised from catechol via the reaction pathways
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16 acquisitions, 8012.8 Hz spectral width, 4.089 s acquisition time, 1.0 s relaxation delay and 60.0 degree pulse. Spectra are available in the supplementary data files. Fig. 1. Chemical structure of MDMA.
2.2. Chemicals
2. Materials and methods
Catechol, diisobutylaluminium hydride (DIBAH, 1.5 M solution in cyclohexane), allyl bromide, magnesium, anhydrous tetrahydrofuran, p-benzoquinone, formic acid and nitromethane were purchased from Sigma–Aldrich. Diethyl ether, dichloromethane, methanol, acetone, toluene, hydrogen peroxide (30%), ammonium chloride and sodium hydroxide were purchased from ChemSupply. Dimethyl sulfoxide, mercuric chloride and hydrobromic acid (46–49%) were obtained from UNILAB. Glacial acetic acid, hydrochloric acid (36%) and sodium bicarbonate were purchased from Labscan. Sulphuric acid was purchased from BDH Chemicals. Anhydrous sodium sulphate was purchased from AJAX Finechem. Sodium bisulfite was obtained from the Mallinckrodt Chemical Works. Chloroform-D was purchased from Cambridge Isotope Laboratories, Inc.
2.1. General experimental
2.3. Synthesis
Each reaction was performed at minimum in duplicate. Gas chromatography–mass spectrometry (GC–MS) analysis was performed using an Agilent 6890 Series Gas Chromatographic System coupled to an Agilent 5973 Network Mass Selective Detector. Samples were prepared using diethyl ether as solvent at a concentration of 5–10 mg/mL. The column was a Zebron ZB-5ms 5% polysilarylene-95% (5%-phenyl-95%-dimethylpolysiloxane) with a length of 30 m, diameter of 250 mm and a film thickness of 0.25 mm. The front inlet was at a temperature of 250 8C and had a split injection, with a 1.0 mL injection volume and a 50:1 split ratio. The transfer line was at a temperature of 280 8C. Helium was used as a carrier gas at a rate of 1.2 mL/min. The temperature programme had an initial oven temperature of 50 8C for 2 min, followed by a ramp of 10 8C/min until 290 8C where it was held for 4 min. The scan parameters enabled collection of a mass range of 45–450 amu with an abundance threshold of 100. The data were analysed using MSD Chem Station software. Proton nuclear magnetic resonance (1H NMR) spectroscopy was performed using an Agilent Technologies 500 MHz NMR instrument. Samples were dissolved in deuterated chloroform (CDCl3) and the solvent residual chemical shift of 7.26 ppm was used as an internal standard to calibrate the spectra. The 1H NMR spectra were collected at 25 8C with the following acquisition parameters:
Synthesis of 1,3-benzodioxole: Catechol (20.0 g, 182 mmol) and an aqueous solution of sodium hydroxide (30 mL, 19.4 M, 582 mmol) were dissolved in 200 mL of dimethyl sulfoxide. The resultant green solution was heated to 90–100 8C. Dichloromethane (40 mL, 626 mL) was added drop wise to the solution, which was heated under reflux at 90–100 8C for 4 h. The mixture was allowed to cool and 200 mL of water was added. The mixture was decanted and the product was extracted with diethyl ether (3 200 mL). The diethyl ether extracts were washed with 3 200 mL of water, dried over anhydrous sodium sulphate and decanted. Solvent was removed with a rotary evaporator, producing a light brown oil. Yield: 14.8 g (66.7%). 1H NMR: Fig. S1. GC–MS: Fig. S9. Synthesis of 5-bromo-1,3-benzodioxole: 1,3-Benzodioxole (6.00 mL, 52.2 mmol) was dissolved in a mixture of glacial acetic acid (2.6 mL, 45 mmol), 16 mL of methanol, and 2 mL of water. Hydrobromic acid (6.0 mL, 8.9 M, 53 mmol) was then added dropwise to the solution ensuring that the temperature remained below 25 8C. The solution was heated to approximately 35 8C, and hydrogen peroxide (6.0 mL, 9.9 M, 59 mmol) was added drop wise, ensuring that the temperature did not exceed 50 8C. The resulting solution was stirred at 40–50 8C for 3 h and allowed to cool. The red organic layer was extracted with diethyl ether (1 40 mL) and
shown in Scheme 1. As the organic impurity profile is dependent on synthetic route, the synthesis of MDP2P from safrole was performed via the two most common methods used in clandestine laboratories – Wacker oxidation of safrole (Route 1) and the isomerisation of safrole and peracid oxidation and acid dehydration of isosafrole (Route 2) [3,9,10]. We show that the organic impurity profile of MDMA synthesised from catechol can indicate if synthetic safrole (from catechol) was used. Importantly, numerous impurities arise from these methods that are not reported in the significant amount of literature describing impurities in MDMA synthesised from commercially available safrole [3,9–11].
Scheme 1. Synthesis of MDMA from catechol. (i) CH2Cl2, NaOH. (ii) HBr, H2O2, CH3COOH. (iii) 1: Mg, DIBAH; 2: allyl bromide. (iv) p-benzoquinone, PdCl2. (v) KOH. (vi) 1: H2O2, HCOOH; 2: H2SO4. vii CH3NO2, Al(Hg).
E. Heather et al. / Forensic Science International 248 (2015) 140–147
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Synthesis of MDP2P (Route 2): A solution containing hydrogen peroxide (2.0 mL, 9.9 M, 20 mmol) and formic acid (10 mL, 23.6 M, 240 mol) was stirred at room temperature for 30 min. Isosafrole (800 mg, 4.93 mmol) in 6 mL of acetone was added to the solution and stirred at room temperature for 16 h. The volatile components of the resulting solution were removed in vacuo, leaving a red residue. The residue was redissolved in 10 mL of methanol and 10 mL of 2.8 M sulphuric acid was added. The resulting solution was heated under reflux for 3 h and allowed to cool. The product was extracted with 3 40 mL of diethyl ether and washed with 40 mL of water and 40 mL of saturated sodium bicarbonate solution. The ether extracts were dried over anhydrous sodium sulphate, decanted and the solvent removed with a rotary evaporator, producing a brown oil. Yield: 538 mg (61.2%). 1H NMR: Fig. S6. GC–MS: Fig. S13. Synthesis of MDMA: Aluminium foil (280 mg, 10.4 mmol), cut in approximate 1 cm 1 cm squares, was added to a solution of mercuric chloride (80.0 mg, 295 mmol) in 10 mL of methanol. The mixture was heated under reflux until the aluminium foil turned a dark grey and bubbles formed on the surface. Then, a solution of MDP2P (200 mg, 1.12 mmol) and nitromethane (0.20 mL, 3.7 mmol) in 5 mL of methanol was added [note: this procedure was performed using MDP2P synthesised by Route 1 and also with MDP2P synthesised by Route 2]. The resulting mixture was heated under reflux for 4 h and allowed to cool. An 8.8 M sodium hydroxide solution was added to the mixture until the majority of amalgam had dissolved. The mixture was filtered and the product extracted from the filtrate with toluene (3 20 mL). The solvent was removed with a rotary evaporator, producing a light brown oil. Yield: 136 mg (62.7%). 1H NMR: Figs. S7–S8. GC–MS: Figs. 3–4.
washed with 10 mL of aqueous 10% sodium bisulfite solution. The ether extracts were dried over anhydrous sodium sulphate, decanted and the solvent removed with a rotary evaporator, producing an orange oil. Yield: 8.95 g (85.2%). 1H NMR: Fig. S2. GC– MS: Fig. S10. Synthesis of safrole: The following Grignard reaction was conducted using dry glassware under nitrogen. Magnesium (0.60 g, 25 mmol), 5-bromo-1,3-benzodioxole (0.40 mL, 3.3 mmol) and a 1.5 M solution of DIBAH in cyclohexane (0.10 mL, 150 mmol) were stirred in 20 mL of anhydrous THF. Additional 5-bromo-1,3benzodioxole (2.60 mL, 21.5 mmol) was added drop wise and the mixture was stirred for 2 h. The solution was removed via syringe and added dropwise to allyl bromide (4.0 mL, 46 mmol) contained in an ice bath. The solution was stirred for 24 h and reaction quenched by the addition of 20 mL of water and 20 mL of saturated ammonium chloride. The product was extracted into 3 80 mL of diethyl ether and washed with 3 100 mL of water. The ether extracts were dried over anhydrous sodium sulphate, decanted, and the solvent removed with a rotary evaporator, producing a brown oil. Yield: 3.30 g (82.1%). 1H NMR: Fig. S3. GC–MS: Fig. 2. Synthesis of MDP2P (Route 1): Safrole (1.00 g, 6.17 mmol) was dissolved in 1 mL of methanol and added dropwise to a mixture of palladium (II) chloride (12 mg, 68 mmol), p-benzoquinone (0.85 g, 7.9 mmol), 5 mL of methanol and 0.5 mL of water. The resulting mixture was stirred for 3 h and filtered. To the filtrate, 10 mL of 3.2 M hydrochloric acid was added. The product was extracted with 3 20 mL of dichloromethane and washed with 2 20 mL of a saturated sodium bicarbonate solution, 2 20 mL of 1.3 M sodium hydroxide and 2 20 mL of brine. The organic extracts were dried over anhydrous sodium sulphate, decanted and the solvent removed with a rotary evaporator, producing a brown oil. Yield: 857 mg (78.0%). 1H NMR: Fig. S4. GC–MS: Fig. S11. Synthesis of isosafrole (Route 2): Safrole (1.40 g, 8.63 mmol) was dissolved in a 3 M solution of potassium hydroxide in 1-butanol (10 mL, 30 mmol). The resulting solution was heated under reflux for 3 h and allowed to cool. To the solution, 10 mL of a 1.6 M hydrochloric acid solution was added. The product was extracted with 3 40 mL of diethyl ether and washed with 3 40 mL of water. The organic extracts were dried over anhydrous sodium sulphate, decanted, and the solvent removed with a rotary evaporator, producing a brown oil. Yield: 1.19 g (85.0%). 1H NMR: Fig. S5. GC–MS: Fig. S12.
3. Results and discussion The synthetic methods described here were chosen such that they could be feasibly performed in a moderately equipped clandestine laboratory. Elaborate product purification techniques were not used so as to mimic the procedures that may be expected in relatively unsophisticated clandestine laboratories. As such, there were some variations in the concentration of organic impurities that were detected across series of repeat synthesises. The products from each step in the reaction pathway were analysed using GC–MS and 1H NMR spectroscopy. Organic
50 45 40
Abundance (×105)
35 30 25
20 15 10 5 0 4
6
8
10
12
14
16
18
20
22
24
Time (min) Fig. 2. Gas chromatogram of safrole synthesised from catechol.
26
28
30
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18 16 14
Abundance (×105)
12 10
8 6 4 2 0
4
6
8
10
12
14
16 18 Time (min)
20
22
24
26
28
30
Fig. 3. Gas chromatogram of MDMA synthesised from catechol via Route 1.
impurities were identified based on the fragmentation pattern of their mass spectrum. The identification of these organic impurities was also confirmed by 1H NMR spectroscopy when impurities were of a sufficient concentration to produce distinct NMR signals. 3.1. Safrole from catechol Safrole was synthesised from catechol in three steps: the methylenation of catechol, the bromination of 1,3-benzodioxole and a Grignard reaction using 5-bromo-1,3-benzodioxole and allyl bromide. The gas chromatogram of safrole synthesised from catechol is shown in Fig. 2 and the eight impurities identified unambiguously are listed in Table 1. Compounds 4, 5, and 8 arose during the methylenation of catechol (Step 1, Scheme 1). Compound 4 was formed through the cyclisation of two catechoxide dianions with dichloromethane while compound 8 was synthesised via a similar reaction involving the cyclisation of three catechoxide dianions with dichloro-
methane. The formation of compound 5 involves methylenation across the aromatic rings of two 1,3-benzodioxole molecules. Compounds 1 and 2 are intermediates in the synthesis of safrole from catechol. Their presence indicates that the reactions ii–iii (Scheme 1) did not proceed to completion. Compound 1, however, is also a reaction by-product in the Grignard reaction (Step 3, Scheme 1) whereby the Grignard reagent, formed through the reaction of 5-bromo-1,3-benzodioxole and magnesium, reacts with water to form 1,3-benzodioxole (1), as shown in Scheme 2. This decomposition could occur due to water contamination in the reactant setup or result from an incomplete reaction at the time when the reaction mixture was quenched. Compound 6 is also a reaction by-product of the Grignard reaction, as shown in Scheme 2, arising from the reaction of the Grignard reagent with 5-bromo-1,3-benzodioxole [12]. Compounds 3 and 7 are synthesised by Grignard reactions of the bromination reaction by-product, 5,6-dibromo-1,3-benzodioxole, via the reaction schemes shown in Scheme 3.
25
Abundance (×105)
20
15
10
5
0 4
6
8
10
12
14
16
18
20
22
24
26
Time (min) Fig. 4. Gas chromatogram of MDMA synthesised from catechol via Route 2.
28
30
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Table 1 Organic impurities identified in safrole synthesised from catechol. Impurity name
m/z
1
1,3-Benzodioxole
122/121, 63
2
5-Bromo-1,3-benzodioxole
202/200, 121, 63
3
5-Bromo-6-(2-propenyl)-1,3-benzodioxole
242/240, 199, 131, 103, 77
4
1,3-Benzodioxole dimer
244, 135, 122/121, 63
5
5,50 -Methylenebis-1,3-benzodioxole
256, 135, 77
6
5,50 -Bi-1,3-benzodioxole
242, 126, 121/120, 63
7
5-Allyl-6-(1,3-benzodioxol-5-yl)-1,3-benzodioxole
282, 267, 237, 209, 165, 139
8
1,3-Benzodioxole trimer
366, 244, 135, 122/121
No.
Impurity structure
H2O
Scheme 2. Synthesis of 1,3-benzodioxole (1) and 5,50 -bi-1,3-benzodioxole (6).
Mg
2Br 2Mg
Scheme 3. Synthesis of 5-bromo-6-(2-propenyl)-1,3-benzodioxole (3) and 5-allyl-6-(1,3-benzodioxol-5-yl)-1,3-benzodioxole (7).
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Table 2 Organic impurities identified in MDMA synthesised from catechol via Route 1 and Route 2. Impurity name
m/z
Synthetic route
1
1,3-Benzodioxole
122/121, 63
1
2
5-Bromo-1,3-benzodioxole
202/200, 121, 63
1 and 2
4
1,3-Benzodioxole dimer
244, 135, 122/121, 63
1 and 2
5
5,50 -Methylenebis-1,3-benzodioxole
256, 135, 77
1 and 2
6
5,50 -Bi-1,3-benzodioxole
242, 126, 121/120, 63
1 and 2
8
1,3-Benzodioxole trimer
366, 244, 135, 122/121
1
10
cis and trans isosafrole
162, 131, 104/103, 77, 44
1
11
5-(1-Methoxypropyl)-1,3-benzodioxole
194, 165, 150/149, 135, 77
1
12
5-(1,3-Dimethoxypropyl)-1,3-benzodioxole
224, 192, 161, 135, 75
1
13
MDP2P dimethyl acetal
224, 193, 135, 89
1 and 2
14
5-(3,3-Dimethoxypropyl)-1,3-benzodioxole
224, 192, 161, 135, 75
1
15
1-[6-(1,3-Benzodioxol-5-yl)-1,3-benzodioxol-5-yl]-Nmethyl-propan-2-amine
256, 58, 44
1
16
1,3-Benzodioxole-5-carboxylic acid
166, 150/149, 135, 121, 77
2
No.
Impurity structure
E. Heather et al. / Forensic Science International 248 (2015) 140–147
146 Table 2 (Continued )
Impurity name
m/z
Synthetic route
17
MDP2P methyl hemiacetal
196, 165, 150/149, 135, 121, 63
2
18
1-(1,3-Benzodioxol-5-yl)-1-methoxy-propan-2-ol
210, 165, 150/149, 135, 77
2
19
2,4-Dimethyl-3,5-bis(3,4-methylenedioxyphenyl) tetrahydrofuran
340, 296, 281, 207, 44
2
No.
Impurity structure
3.2. MDMA from safrole MDMA was synthesised by reductive amination of MDP2P. Two methods were used to synthesise MDP2P; Wacker oxidation of safrole (Route 1) and an isomerisation/peracid oxidation/acid dehydration method (Route 2). The gas chromatograms of MDMA synthesised from catechol via Route 1 and Route 2 are shown in Fig. 3 and Fig. 4, respectively. The organic impurities identified in MDMA, and the synthetic routes from which they arose, are listed in Table 2. Compounds 1, 2, 4–6 and 8 found in MDMA synthesised via Route 1 were identified as impurities in safrole (Table 1) and have been carried over, unchanged, in subsequent reactions. Compound 15 arose from compound 7 (identified in safrole) via an analogue route to MDMA, as shown in Scheme 4. Compounds 2, 4, 5 and 6 were also identified in MDMA synthesised via Route 2. Compounds 1, 8 and 5-(1,3-benzodioxol5-yl)-6-prop-1-enyl-1,3-benzodioxole (isomerisation product of compound 7 identified in safrole) were found in isosafrole. However, these impurities were not detected in MDP2P and MDMA as they were removed during the peracid oxidation and acid dehydration of isosafrole. With the exception of 1,3-benzodioxole (1), compounds 2, 4–6 and 8 and 15 have not been previously identified in sassafras oil or MDMA prepared from sassafras oil [11,13]. Furthermore, they have not been identified in MDMA synthesised from commercially
available MDP2P, safrole, isosafrole and piperonal [3]. The identification of compounds 2–6, 8 and 15 therefore indicates the use of safrole, synthesised from catechol, as a precursor to MDMA. Thus, elements of the organic impurity profile of MDMA synthesised from catechol via both Route 1 and Route 2 unambiguously indicate the use of synthetic, catechol-derived safrole (as discussed below). Compounds 4, 5 and 8 are characteristic of the methylenation of catechol; the detection of any of these impurities therefore indicates that catechol was the precursor utilised. The presence of compound 2 is indicative of the bromination reaction used in the second step of the synthetic pathway. The Grignard reaction, used in the final step of the synthesis of safrole, can be inferred by the presence of compounds 6 and/or 15, which are characteristic impurities formed when the Grignard reagent is prepared from 5-bromo-1,3-benzodioxole (2). The synthesis of MDP2P from safrole via Route 1 or Route 2 can also be differentiated based upon the organic impurity profile of MDMA. Compounds 11, 12 and 14 are characteristic impurities for the Wacker oxidation of safrole when methanol is used as a solvent [10] and, therefore, their identification in MDMA is indicative of synthesis via Route 1. Similarly, compounds 18 and 19 are characteristic for the peracid oxidation and acid dehydration of isosafrole [9] and their identification in MDMA is indicative of synthesis via Route 2. There are two diasteroisomers identified
PdCl2
CH3NO 2 Al(Hg)
Scheme 4. Synthesis of 1-[6-(1,3-benzodioxol-5-yl)-1,3-benzodioxol-5-yl]-N-methyl-propan-2-amine (15).
[O]
Scheme 5. Synthesis of 1,3-benzodioxole-5-carboxylic acid (16).
[O]
E. Heather et al. / Forensic Science International 248 (2015) 140–147
of both compounds 18 and 19, however, the stereoconfiguration of these cannot be determined without isolation of the impurity. Isosafrole (10) is also a reaction by-product of the Wacker oxidation of safrole that was synthesised via the palladiumcatalysed isomerisation of safrole. Compound 16 was synthesised through the oxidation of isosafrole, as shown in Scheme 5, during the peracid oxidation and acid dehydration of isosafrole. Isosafrole can be detected in MDMA samples as a result of a reaction byproduct, an intermediate or a precursor in a synthetic route. The identification of isosafrole, or impurities stemming from isosafrole, in MDMA is therefore not indicative of a particular synthetic route. Compounds 13 and 17 are by-products of the reductive amination of MDP2P, synthesised through the reaction of MDP2P with the reaction solvent, methanol [8]. The MDMA synthesised via Route 2 contains both of these impurities, whereas the MDMA synthesised via Route 1 contains only impurity 13 in a significantly lower concentration. This demonstrates that there can be large variation in the organic impurity profiles of reaction products when synthesised in a clandestine laboratory environment. In such an environment, these variations could be introduced due to an imperfect reaction setup, variations in reaction conditions or variations in the technique of different chemists performing the reaction. 4. Conclusions Safrole was synthesised from catechol, a common industrial chemical, via a three-step synthetic pathway that could be feasibly performed in a moderately equipped clandestine laboratory. The synthesis involved the methylenation of catechol, the bromination of 1,3-benzodixole and a Grignard reaction using 5-bromo-1,3benzodioxole and allyl bromide. Eight organic impurities were identified in the synthetic safrole and, of these impurities, only one (1,3-benzodioxole) has previously been identified in safrole obtained from natural sassafras oil. The synthesis of MDP2P from safrole was performed via two common synthetic methods: Wacker oxidation (Route 1) and an isomerisation/peracid oxidation/acid dehydration method (Route 2). MDMA was then synthesised by reductive amination of MDP2P in both of these synthetic routes. Thirteen organic impurities were identified in MDMA synthesised via Route 1 and eleven organic impurities were identified in MDMA synthesised via Route 2.
147
The organic impurity profile of MDMA synthesised from catechol via both Route 1 and Route 2 indicated that synthetic, catechol-derived safrole was used. The organic impurities identified also indicated which of the two synthetic routes was utilised. We conclude, therefore, that the organic impurities identified in MDMA indicated the precursor and the reaction pathway used to synthesise MDMA from catechol. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.forsciint.2014.12.021. References ¨ xler, S. Bernschneider-Reif, The origin of MDMA (ecstasy) [1] R.W. Freudenmann, F. O revisited: the true story reconstructed from the original documents, Addiction 101 (2006) 1241–1245. [2] R.J.H. Waddell-Smith, A review of recent advances in impurity profiling of illicit MDMA samples, J. Forensic Sci. 52 (2007) 1297–1304. [3] N. Stojanovska, et al., A review of impurity profiling and synthetic route of manufacture of methylamphetamine, 3,4-methylenedioxymethylamphetamine, amphetamine, dimethylamphetamine and p-methoxyamphetamine, Forensic Sci. Int. 224 (2013) 8–26. [4] H. Fiege, et al., Phenol derivatives, in: Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH Verlag GmbH & Co. KGaA, 2000. [5] J. Coppen, Flavours and Fragrances of Plant Origin, 1995 Available from: http:// www.fao.org/docrep/v5350e/v5350e00.HTM. [6] B. Lin, X. Yang, Research on the Synthesis for Safrole, vol. 30, Guangdong Huagong, 2003, pp. 6–7. [7] Rhodium Drug Chemistry Archive, 2004 Available from: http://www.erowid.org/ archive/rhodium/chemistry/index.html or http://www.drugs-forum.com/ chemistry/chemistry/index.html. [8] R. Gallagher, R. Shimmon, A.M. McDonagh, Synthesis and impurity profiling of MDMA prepared from commonly available starting materials, Forensic Sci. Int. 223 (2012) 306–313. [9] M. Cox, et al., Chemical markers from the peracid oxidation of isosafrole, Forensic Sci. Int. 179 (2008) 44–53. [10] M. Cox, G. Klass, Synthesis by-products from the Wacker oxidation of safrole in methanol using r-benzoquinone and palladium chloride, Forensic Sci. Int. 164 (2006) 138–147. [11] P. Gimeno, et al., A study of impurities in intermediates and 3,4-methylenedioxymethamphetamine (MDMA) samples produced via reductive amination routes, Forensic Sci. Int. 155 (2005) 141–157. [12] J.F. Garst, M.P. Soriaga, Grignard reagent formation, Coord. Chem. Rev. 248 (2004) 623–652. [13] M. Scha¨ffer, et al., Forensic profiling of sassafras oils based on comprehensive twodimensional gas chromatography, Forensic Sci. Int. 229 (2013) 108–115.
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Organic impurity profiling of 3,4-methylenedioxymethamphetamine (MDMA) synthesised from catechol Erin Heather, Ronald Shimmon, Andrew M. McDonagh * Centre for Forensic Science, University of Technology Sydney, Sydney, NSW 2007, Australia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 23 June 2014 Received in revised form 18 December 2014 Accepted 19 December 2014 Available online 31 December 2014
This work examines the organic impurity profile of 3,4-methylenedioxymethamphetamine (MDMA) that has been synthesised from catechol (1,2-dihydroxybenzene), a common chemical reagent available in industrial quantities. The synthesis of MDMA from catechol proceeded via the common MDMA precursor safrole. Methylenation of catechol yielded 1,3-benzodioxole, which was brominated and then reacted with magnesium allyl bromide to form safrole. Eight organic impurities were identified in the synthetic safrole. Safrole was then converted to 3,4-methylenedioxyphenyl-2-propanone (MDP2P) using two synthetic methods: Wacker oxidation (Route 1) and an isomerisation/peracid oxidation/acid dehydration method (Route 2). MDMA was then synthesised by reductive amination of MDP2P. Thirteen organic impurities were identified in MDMA synthesised via Route 1 and eleven organic impurities were identified in MDMA synthesised via Route 2. Overall, organic impurities in MDMA prepared from catechol indicated that synthetic safrole was used in the synthesis. The impurities also indicated which of the two synthetic routes was utilised. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Illicit drugs 3,4-Methylendioxymethamphetamine MDMA Safrole Chemical synthesis Chemical profiling
1. Introduction The active ingredient in the drug colloquially referred to as ‘ecstasy’ is the amphetamine-type stimulant 3,4-methylenedioxymethamphetamine (MDMA), Fig. 1. First patented as ‘methylsafrylamin’ in 1912 as a precursor for blood-clotting agents [1,2], the recreational use of MDMA gained popularity during the mid-1980s and it has since become a prevalent drug of choice [1,3]. MDMA is an illicit substance in many jurisdictions around the world and is under international control through its inclusion to the United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances 1988. There has been a significant amount of research into the organic impurity profiles of MDMA synthesised from the most common precursors: 3,4-methylenedioxyphenyl-2-propanone (MDP2P), safrole, isosafrole and piperonal [3]. These precursors, however, are controlled or regulated substances in many jurisdictions. The use of uncontrolled precursors therefore offers clandestine laboratory operators a strategy to reduce the risk associated with detection.
* Corresponding author at: University of Technology Sydney, P.O. Box 123, Broadway, NSW 2007, Australia. Tel.: +61 2 95141035. E-mail address: [email protected] (A.M. McDonagh). http://dx.doi.org/10.1016/j.forsciint.2014.12.021 0379-0738/ß 2015 Elsevier Ireland Ltd. All rights reserved.
Catechol (Scheme 1) is a common chemical reagent that is synthesised on an industrial scale with applications in the synthesis of fragrances, pesticides, drugs and dyes [4]. Diversion of catechol into illicit activities is therefore highly feasible. Safrole, a common starting material for MDMA production, is a natural product obtained from sassafras oil and is also used for the industrial production of fragrances, flavours and some insecticides [5]. The synthesis of safrole from synthetic precursors, including catechol, has been investigated as a means to reduce the reliance upon variable natural sources [5,6]. Thus, with such precedent as well as available literature, it is unsurprising that this route has been reported for the synthesis of MDMA in literature readily available to the clandestine laboratory operator [7]. The techniques and procedures for the synthesis of MDMA from uncontrolled precursors, including catechol, are described in detail in numerous freely available documents on the internet [7]. There is, however, only limited information available regarding the organic impurity profiles that arise when these synthetic routes are utilised [8]. Organic impurities in MDMA can result from precursors, intermediates or reaction by-products [3] and their identification can therefore provide valuable information about synthetic methods currently in use. Of course, adulterants are a further source of impurities however these will not be addressed here. This paper presents the results of organic impurity profiling of MDMA synthesised from catechol via the reaction pathways
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16 acquisitions, 8012.8 Hz spectral width, 4.089 s acquisition time, 1.0 s relaxation delay and 60.0 degree pulse. Spectra are available in the supplementary data files. Fig. 1. Chemical structure of MDMA.
2.2. Chemicals
2. Materials and methods
Catechol, diisobutylaluminium hydride (DIBAH, 1.5 M solution in cyclohexane), allyl bromide, magnesium, anhydrous tetrahydrofuran, p-benzoquinone, formic acid and nitromethane were purchased from Sigma–Aldrich. Diethyl ether, dichloromethane, methanol, acetone, toluene, hydrogen peroxide (30%), ammonium chloride and sodium hydroxide were purchased from ChemSupply. Dimethyl sulfoxide, mercuric chloride and hydrobromic acid (46–49%) were obtained from UNILAB. Glacial acetic acid, hydrochloric acid (36%) and sodium bicarbonate were purchased from Labscan. Sulphuric acid was purchased from BDH Chemicals. Anhydrous sodium sulphate was purchased from AJAX Finechem. Sodium bisulfite was obtained from the Mallinckrodt Chemical Works. Chloroform-D was purchased from Cambridge Isotope Laboratories, Inc.
2.1. General experimental
2.3. Synthesis
Each reaction was performed at minimum in duplicate. Gas chromatography–mass spectrometry (GC–MS) analysis was performed using an Agilent 6890 Series Gas Chromatographic System coupled to an Agilent 5973 Network Mass Selective Detector. Samples were prepared using diethyl ether as solvent at a concentration of 5–10 mg/mL. The column was a Zebron ZB-5ms 5% polysilarylene-95% (5%-phenyl-95%-dimethylpolysiloxane) with a length of 30 m, diameter of 250 mm and a film thickness of 0.25 mm. The front inlet was at a temperature of 250 8C and had a split injection, with a 1.0 mL injection volume and a 50:1 split ratio. The transfer line was at a temperature of 280 8C. Helium was used as a carrier gas at a rate of 1.2 mL/min. The temperature programme had an initial oven temperature of 50 8C for 2 min, followed by a ramp of 10 8C/min until 290 8C where it was held for 4 min. The scan parameters enabled collection of a mass range of 45–450 amu with an abundance threshold of 100. The data were analysed using MSD Chem Station software. Proton nuclear magnetic resonance (1H NMR) spectroscopy was performed using an Agilent Technologies 500 MHz NMR instrument. Samples were dissolved in deuterated chloroform (CDCl3) and the solvent residual chemical shift of 7.26 ppm was used as an internal standard to calibrate the spectra. The 1H NMR spectra were collected at 25 8C with the following acquisition parameters:
Synthesis of 1,3-benzodioxole: Catechol (20.0 g, 182 mmol) and an aqueous solution of sodium hydroxide (30 mL, 19.4 M, 582 mmol) were dissolved in 200 mL of dimethyl sulfoxide. The resultant green solution was heated to 90–100 8C. Dichloromethane (40 mL, 626 mL) was added drop wise to the solution, which was heated under reflux at 90–100 8C for 4 h. The mixture was allowed to cool and 200 mL of water was added. The mixture was decanted and the product was extracted with diethyl ether (3 200 mL). The diethyl ether extracts were washed with 3 200 mL of water, dried over anhydrous sodium sulphate and decanted. Solvent was removed with a rotary evaporator, producing a light brown oil. Yield: 14.8 g (66.7%). 1H NMR: Fig. S1. GC–MS: Fig. S9. Synthesis of 5-bromo-1,3-benzodioxole: 1,3-Benzodioxole (6.00 mL, 52.2 mmol) was dissolved in a mixture of glacial acetic acid (2.6 mL, 45 mmol), 16 mL of methanol, and 2 mL of water. Hydrobromic acid (6.0 mL, 8.9 M, 53 mmol) was then added dropwise to the solution ensuring that the temperature remained below 25 8C. The solution was heated to approximately 35 8C, and hydrogen peroxide (6.0 mL, 9.9 M, 59 mmol) was added drop wise, ensuring that the temperature did not exceed 50 8C. The resulting solution was stirred at 40–50 8C for 3 h and allowed to cool. The red organic layer was extracted with diethyl ether (1 40 mL) and
shown in Scheme 1. As the organic impurity profile is dependent on synthetic route, the synthesis of MDP2P from safrole was performed via the two most common methods used in clandestine laboratories – Wacker oxidation of safrole (Route 1) and the isomerisation of safrole and peracid oxidation and acid dehydration of isosafrole (Route 2) [3,9,10]. We show that the organic impurity profile of MDMA synthesised from catechol can indicate if synthetic safrole (from catechol) was used. Importantly, numerous impurities arise from these methods that are not reported in the significant amount of literature describing impurities in MDMA synthesised from commercially available safrole [3,9–11].
Scheme 1. Synthesis of MDMA from catechol. (i) CH2Cl2, NaOH. (ii) HBr, H2O2, CH3COOH. (iii) 1: Mg, DIBAH; 2: allyl bromide. (iv) p-benzoquinone, PdCl2. (v) KOH. (vi) 1: H2O2, HCOOH; 2: H2SO4. vii CH3NO2, Al(Hg).
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Synthesis of MDP2P (Route 2): A solution containing hydrogen peroxide (2.0 mL, 9.9 M, 20 mmol) and formic acid (10 mL, 23.6 M, 240 mol) was stirred at room temperature for 30 min. Isosafrole (800 mg, 4.93 mmol) in 6 mL of acetone was added to the solution and stirred at room temperature for 16 h. The volatile components of the resulting solution were removed in vacuo, leaving a red residue. The residue was redissolved in 10 mL of methanol and 10 mL of 2.8 M sulphuric acid was added. The resulting solution was heated under reflux for 3 h and allowed to cool. The product was extracted with 3 40 mL of diethyl ether and washed with 40 mL of water and 40 mL of saturated sodium bicarbonate solution. The ether extracts were dried over anhydrous sodium sulphate, decanted and the solvent removed with a rotary evaporator, producing a brown oil. Yield: 538 mg (61.2%). 1H NMR: Fig. S6. GC–MS: Fig. S13. Synthesis of MDMA: Aluminium foil (280 mg, 10.4 mmol), cut in approximate 1 cm 1 cm squares, was added to a solution of mercuric chloride (80.0 mg, 295 mmol) in 10 mL of methanol. The mixture was heated under reflux until the aluminium foil turned a dark grey and bubbles formed on the surface. Then, a solution of MDP2P (200 mg, 1.12 mmol) and nitromethane (0.20 mL, 3.7 mmol) in 5 mL of methanol was added [note: this procedure was performed using MDP2P synthesised by Route 1 and also with MDP2P synthesised by Route 2]. The resulting mixture was heated under reflux for 4 h and allowed to cool. An 8.8 M sodium hydroxide solution was added to the mixture until the majority of amalgam had dissolved. The mixture was filtered and the product extracted from the filtrate with toluene (3 20 mL). The solvent was removed with a rotary evaporator, producing a light brown oil. Yield: 136 mg (62.7%). 1H NMR: Figs. S7–S8. GC–MS: Figs. 3–4.
washed with 10 mL of aqueous 10% sodium bisulfite solution. The ether extracts were dried over anhydrous sodium sulphate, decanted and the solvent removed with a rotary evaporator, producing an orange oil. Yield: 8.95 g (85.2%). 1H NMR: Fig. S2. GC– MS: Fig. S10. Synthesis of safrole: The following Grignard reaction was conducted using dry glassware under nitrogen. Magnesium (0.60 g, 25 mmol), 5-bromo-1,3-benzodioxole (0.40 mL, 3.3 mmol) and a 1.5 M solution of DIBAH in cyclohexane (0.10 mL, 150 mmol) were stirred in 20 mL of anhydrous THF. Additional 5-bromo-1,3benzodioxole (2.60 mL, 21.5 mmol) was added drop wise and the mixture was stirred for 2 h. The solution was removed via syringe and added dropwise to allyl bromide (4.0 mL, 46 mmol) contained in an ice bath. The solution was stirred for 24 h and reaction quenched by the addition of 20 mL of water and 20 mL of saturated ammonium chloride. The product was extracted into 3 80 mL of diethyl ether and washed with 3 100 mL of water. The ether extracts were dried over anhydrous sodium sulphate, decanted, and the solvent removed with a rotary evaporator, producing a brown oil. Yield: 3.30 g (82.1%). 1H NMR: Fig. S3. GC–MS: Fig. 2. Synthesis of MDP2P (Route 1): Safrole (1.00 g, 6.17 mmol) was dissolved in 1 mL of methanol and added dropwise to a mixture of palladium (II) chloride (12 mg, 68 mmol), p-benzoquinone (0.85 g, 7.9 mmol), 5 mL of methanol and 0.5 mL of water. The resulting mixture was stirred for 3 h and filtered. To the filtrate, 10 mL of 3.2 M hydrochloric acid was added. The product was extracted with 3 20 mL of dichloromethane and washed with 2 20 mL of a saturated sodium bicarbonate solution, 2 20 mL of 1.3 M sodium hydroxide and 2 20 mL of brine. The organic extracts were dried over anhydrous sodium sulphate, decanted and the solvent removed with a rotary evaporator, producing a brown oil. Yield: 857 mg (78.0%). 1H NMR: Fig. S4. GC–MS: Fig. S11. Synthesis of isosafrole (Route 2): Safrole (1.40 g, 8.63 mmol) was dissolved in a 3 M solution of potassium hydroxide in 1-butanol (10 mL, 30 mmol). The resulting solution was heated under reflux for 3 h and allowed to cool. To the solution, 10 mL of a 1.6 M hydrochloric acid solution was added. The product was extracted with 3 40 mL of diethyl ether and washed with 3 40 mL of water. The organic extracts were dried over anhydrous sodium sulphate, decanted, and the solvent removed with a rotary evaporator, producing a brown oil. Yield: 1.19 g (85.0%). 1H NMR: Fig. S5. GC–MS: Fig. S12.
3. Results and discussion The synthetic methods described here were chosen such that they could be feasibly performed in a moderately equipped clandestine laboratory. Elaborate product purification techniques were not used so as to mimic the procedures that may be expected in relatively unsophisticated clandestine laboratories. As such, there were some variations in the concentration of organic impurities that were detected across series of repeat synthesises. The products from each step in the reaction pathway were analysed using GC–MS and 1H NMR spectroscopy. Organic
50 45 40
Abundance (×105)
35 30 25
20 15 10 5 0 4
6
8
10
12
14
16
18
20
22
24
Time (min) Fig. 2. Gas chromatogram of safrole synthesised from catechol.
26
28
30
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18 16 14
Abundance (×105)
12 10
8 6 4 2 0
4
6
8
10
12
14
16 18 Time (min)
20
22
24
26
28
30
Fig. 3. Gas chromatogram of MDMA synthesised from catechol via Route 1.
impurities were identified based on the fragmentation pattern of their mass spectrum. The identification of these organic impurities was also confirmed by 1H NMR spectroscopy when impurities were of a sufficient concentration to produce distinct NMR signals. 3.1. Safrole from catechol Safrole was synthesised from catechol in three steps: the methylenation of catechol, the bromination of 1,3-benzodioxole and a Grignard reaction using 5-bromo-1,3-benzodioxole and allyl bromide. The gas chromatogram of safrole synthesised from catechol is shown in Fig. 2 and the eight impurities identified unambiguously are listed in Table 1. Compounds 4, 5, and 8 arose during the methylenation of catechol (Step 1, Scheme 1). Compound 4 was formed through the cyclisation of two catechoxide dianions with dichloromethane while compound 8 was synthesised via a similar reaction involving the cyclisation of three catechoxide dianions with dichloro-
methane. The formation of compound 5 involves methylenation across the aromatic rings of two 1,3-benzodioxole molecules. Compounds 1 and 2 are intermediates in the synthesis of safrole from catechol. Their presence indicates that the reactions ii–iii (Scheme 1) did not proceed to completion. Compound 1, however, is also a reaction by-product in the Grignard reaction (Step 3, Scheme 1) whereby the Grignard reagent, formed through the reaction of 5-bromo-1,3-benzodioxole and magnesium, reacts with water to form 1,3-benzodioxole (1), as shown in Scheme 2. This decomposition could occur due to water contamination in the reactant setup or result from an incomplete reaction at the time when the reaction mixture was quenched. Compound 6 is also a reaction by-product of the Grignard reaction, as shown in Scheme 2, arising from the reaction of the Grignard reagent with 5-bromo-1,3-benzodioxole [12]. Compounds 3 and 7 are synthesised by Grignard reactions of the bromination reaction by-product, 5,6-dibromo-1,3-benzodioxole, via the reaction schemes shown in Scheme 3.
25
Abundance (×105)
20
15
10
5
0 4
6
8
10
12
14
16
18
20
22
24
26
Time (min) Fig. 4. Gas chromatogram of MDMA synthesised from catechol via Route 2.
28
30
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Table 1 Organic impurities identified in safrole synthesised from catechol. Impurity name
m/z
1
1,3-Benzodioxole
122/121, 63
2
5-Bromo-1,3-benzodioxole
202/200, 121, 63
3
5-Bromo-6-(2-propenyl)-1,3-benzodioxole
242/240, 199, 131, 103, 77
4
1,3-Benzodioxole dimer
244, 135, 122/121, 63
5
5,50 -Methylenebis-1,3-benzodioxole
256, 135, 77
6
5,50 -Bi-1,3-benzodioxole
242, 126, 121/120, 63
7
5-Allyl-6-(1,3-benzodioxol-5-yl)-1,3-benzodioxole
282, 267, 237, 209, 165, 139
8
1,3-Benzodioxole trimer
366, 244, 135, 122/121
No.
Impurity structure
H2O
Scheme 2. Synthesis of 1,3-benzodioxole (1) and 5,50 -bi-1,3-benzodioxole (6).
Mg
2Br 2Mg
Scheme 3. Synthesis of 5-bromo-6-(2-propenyl)-1,3-benzodioxole (3) and 5-allyl-6-(1,3-benzodioxol-5-yl)-1,3-benzodioxole (7).
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Table 2 Organic impurities identified in MDMA synthesised from catechol via Route 1 and Route 2. Impurity name
m/z
Synthetic route
1
1,3-Benzodioxole
122/121, 63
1
2
5-Bromo-1,3-benzodioxole
202/200, 121, 63
1 and 2
4
1,3-Benzodioxole dimer
244, 135, 122/121, 63
1 and 2
5
5,50 -Methylenebis-1,3-benzodioxole
256, 135, 77
1 and 2
6
5,50 -Bi-1,3-benzodioxole
242, 126, 121/120, 63
1 and 2
8
1,3-Benzodioxole trimer
366, 244, 135, 122/121
1
10
cis and trans isosafrole
162, 131, 104/103, 77, 44
1
11
5-(1-Methoxypropyl)-1,3-benzodioxole
194, 165, 150/149, 135, 77
1
12
5-(1,3-Dimethoxypropyl)-1,3-benzodioxole
224, 192, 161, 135, 75
1
13
MDP2P dimethyl acetal
224, 193, 135, 89
1 and 2
14
5-(3,3-Dimethoxypropyl)-1,3-benzodioxole
224, 192, 161, 135, 75
1
15
1-[6-(1,3-Benzodioxol-5-yl)-1,3-benzodioxol-5-yl]-Nmethyl-propan-2-amine
256, 58, 44
1
16
1,3-Benzodioxole-5-carboxylic acid
166, 150/149, 135, 121, 77
2
No.
Impurity structure
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146 Table 2 (Continued )
Impurity name
m/z
Synthetic route
17
MDP2P methyl hemiacetal
196, 165, 150/149, 135, 121, 63
2
18
1-(1,3-Benzodioxol-5-yl)-1-methoxy-propan-2-ol
210, 165, 150/149, 135, 77
2
19
2,4-Dimethyl-3,5-bis(3,4-methylenedioxyphenyl) tetrahydrofuran
340, 296, 281, 207, 44
2
No.
Impurity structure
3.2. MDMA from safrole MDMA was synthesised by reductive amination of MDP2P. Two methods were used to synthesise MDP2P; Wacker oxidation of safrole (Route 1) and an isomerisation/peracid oxidation/acid dehydration method (Route 2). The gas chromatograms of MDMA synthesised from catechol via Route 1 and Route 2 are shown in Fig. 3 and Fig. 4, respectively. The organic impurities identified in MDMA, and the synthetic routes from which they arose, are listed in Table 2. Compounds 1, 2, 4–6 and 8 found in MDMA synthesised via Route 1 were identified as impurities in safrole (Table 1) and have been carried over, unchanged, in subsequent reactions. Compound 15 arose from compound 7 (identified in safrole) via an analogue route to MDMA, as shown in Scheme 4. Compounds 2, 4, 5 and 6 were also identified in MDMA synthesised via Route 2. Compounds 1, 8 and 5-(1,3-benzodioxol5-yl)-6-prop-1-enyl-1,3-benzodioxole (isomerisation product of compound 7 identified in safrole) were found in isosafrole. However, these impurities were not detected in MDP2P and MDMA as they were removed during the peracid oxidation and acid dehydration of isosafrole. With the exception of 1,3-benzodioxole (1), compounds 2, 4–6 and 8 and 15 have not been previously identified in sassafras oil or MDMA prepared from sassafras oil [11,13]. Furthermore, they have not been identified in MDMA synthesised from commercially
available MDP2P, safrole, isosafrole and piperonal [3]. The identification of compounds 2–6, 8 and 15 therefore indicates the use of safrole, synthesised from catechol, as a precursor to MDMA. Thus, elements of the organic impurity profile of MDMA synthesised from catechol via both Route 1 and Route 2 unambiguously indicate the use of synthetic, catechol-derived safrole (as discussed below). Compounds 4, 5 and 8 are characteristic of the methylenation of catechol; the detection of any of these impurities therefore indicates that catechol was the precursor utilised. The presence of compound 2 is indicative of the bromination reaction used in the second step of the synthetic pathway. The Grignard reaction, used in the final step of the synthesis of safrole, can be inferred by the presence of compounds 6 and/or 15, which are characteristic impurities formed when the Grignard reagent is prepared from 5-bromo-1,3-benzodioxole (2). The synthesis of MDP2P from safrole via Route 1 or Route 2 can also be differentiated based upon the organic impurity profile of MDMA. Compounds 11, 12 and 14 are characteristic impurities for the Wacker oxidation of safrole when methanol is used as a solvent [10] and, therefore, their identification in MDMA is indicative of synthesis via Route 1. Similarly, compounds 18 and 19 are characteristic for the peracid oxidation and acid dehydration of isosafrole [9] and their identification in MDMA is indicative of synthesis via Route 2. There are two diasteroisomers identified
PdCl2
CH3NO 2 Al(Hg)
Scheme 4. Synthesis of 1-[6-(1,3-benzodioxol-5-yl)-1,3-benzodioxol-5-yl]-N-methyl-propan-2-amine (15).
[O]
Scheme 5. Synthesis of 1,3-benzodioxole-5-carboxylic acid (16).
[O]
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of both compounds 18 and 19, however, the stereoconfiguration of these cannot be determined without isolation of the impurity. Isosafrole (10) is also a reaction by-product of the Wacker oxidation of safrole that was synthesised via the palladiumcatalysed isomerisation of safrole. Compound 16 was synthesised through the oxidation of isosafrole, as shown in Scheme 5, during the peracid oxidation and acid dehydration of isosafrole. Isosafrole can be detected in MDMA samples as a result of a reaction byproduct, an intermediate or a precursor in a synthetic route. The identification of isosafrole, or impurities stemming from isosafrole, in MDMA is therefore not indicative of a particular synthetic route. Compounds 13 and 17 are by-products of the reductive amination of MDP2P, synthesised through the reaction of MDP2P with the reaction solvent, methanol [8]. The MDMA synthesised via Route 2 contains both of these impurities, whereas the MDMA synthesised via Route 1 contains only impurity 13 in a significantly lower concentration. This demonstrates that there can be large variation in the organic impurity profiles of reaction products when synthesised in a clandestine laboratory environment. In such an environment, these variations could be introduced due to an imperfect reaction setup, variations in reaction conditions or variations in the technique of different chemists performing the reaction. 4. Conclusions Safrole was synthesised from catechol, a common industrial chemical, via a three-step synthetic pathway that could be feasibly performed in a moderately equipped clandestine laboratory. The synthesis involved the methylenation of catechol, the bromination of 1,3-benzodixole and a Grignard reaction using 5-bromo-1,3benzodioxole and allyl bromide. Eight organic impurities were identified in the synthetic safrole and, of these impurities, only one (1,3-benzodioxole) has previously been identified in safrole obtained from natural sassafras oil. The synthesis of MDP2P from safrole was performed via two common synthetic methods: Wacker oxidation (Route 1) and an isomerisation/peracid oxidation/acid dehydration method (Route 2). MDMA was then synthesised by reductive amination of MDP2P in both of these synthetic routes. Thirteen organic impurities were identified in MDMA synthesised via Route 1 and eleven organic impurities were identified in MDMA synthesised via Route 2.
147
The organic impurity profile of MDMA synthesised from catechol via both Route 1 and Route 2 indicated that synthetic, catechol-derived safrole was used. The organic impurities identified also indicated which of the two synthetic routes was utilised. We conclude, therefore, that the organic impurities identified in MDMA indicated the precursor and the reaction pathway used to synthesise MDMA from catechol. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.forsciint.2014.12.021. References ¨ xler, S. Bernschneider-Reif, The origin of MDMA (ecstasy) [1] R.W. Freudenmann, F. O revisited: the true story reconstructed from the original documents, Addiction 101 (2006) 1241–1245. [2] R.J.H. Waddell-Smith, A review of recent advances in impurity profiling of illicit MDMA samples, J. Forensic Sci. 52 (2007) 1297–1304. [3] N. Stojanovska, et al., A review of impurity profiling and synthetic route of manufacture of methylamphetamine, 3,4-methylenedioxymethylamphetamine, amphetamine, dimethylamphetamine and p-methoxyamphetamine, Forensic Sci. Int. 224 (2013) 8–26. [4] H. Fiege, et al., Phenol derivatives, in: Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH Verlag GmbH & Co. KGaA, 2000. [5] J. Coppen, Flavours and Fragrances of Plant Origin, 1995 Available from: http:// www.fao.org/docrep/v5350e/v5350e00.HTM. [6] B. Lin, X. Yang, Research on the Synthesis for Safrole, vol. 30, Guangdong Huagong, 2003, pp. 6–7. [7] Rhodium Drug Chemistry Archive, 2004 Available from: http://www.erowid.org/ archive/rhodium/chemistry/index.html or http://www.drugs-forum.com/ chemistry/chemistry/index.html. [8] R. Gallagher, R. Shimmon, A.M. McDonagh, Synthesis and impurity profiling of MDMA prepared from commonly available starting materials, Forensic Sci. Int. 223 (2012) 306–313. [9] M. Cox, et al., Chemical markers from the peracid oxidation of isosafrole, Forensic Sci. Int. 179 (2008) 44–53. [10] M. Cox, G. Klass, Synthesis by-products from the Wacker oxidation of safrole in methanol using r-benzoquinone and palladium chloride, Forensic Sci. Int. 164 (2006) 138–147. [11] P. Gimeno, et al., A study of impurities in intermediates and 3,4-methylenedioxymethamphetamine (MDMA) samples produced via reductive amination routes, Forensic Sci. Int. 155 (2005) 141–157. [12] J.F. Garst, M.P. Soriaga, Grignard reagent formation, Coord. Chem. Rev. 248 (2004) 623–652. [13] M. Scha¨ffer, et al., Forensic profiling of sassafras oils based on comprehensive twodimensional gas chromatography, Forensic Sci. Int. 229 (2013) 108–115.