(MDMA) Synthesised from Catechol

Forensic Science International 248 (2015) 140–147

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Forensic Science International

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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: This work examines the organic impurity proﬁle of 3,4-methylenedioxymethamphetamine (MDMA)

Received 23 June 2014

that has been synthesised from catechol (1,2-dihydroxybenzene), a common chemical reagent available

Received in revised form 18 December 2014

in industrial quantities. The synthesis of MDMA from catechol proceeded via the common MDMA

Accepted 19 December 2014

precursor safrole. Methylenation of catechol yielded 1,3-benzodioxole, which was brominated and then

Available online 31 December 2014

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

Keywords:

two synthetic methods: Wacker oxidation (Route 1) and an isomerisation/peracid oxidation/acid

Illicit drugs

dehydration method (Route 2). MDMA was then synthesised by reductive amination of MDP2P. Thirteen

3,4-Methylendioxymethamphetamine

MDMA organic impurities were identiﬁed in MDMA synthesised via Route 1 and eleven organic impurities were

Safrole identiﬁed in MDMA synthesised via Route 2.

Chemical synthesis Overall, organic impurities in MDMA prepared from catechol indicated that synthetic safrole was

Chemical proﬁling used in the synthesis. The impurities also indicated which of the two synthetic routes was utilised.

1. Introduction Catechol (Scheme 1) is a common chemical reagent that is

synthesised on an industrial scale with applications in the

The active ingredient in the drug colloquially referred to as synthesis of fragrances, pesticides, drugs and dyes [4]. Diversion

‘ecstasy’ is the amphetamine-type stimulant 3,4-methylenediox- of catechol into illicit activities is therefore highly feasible. Safrole,

ymethamphetamine (MDMA), Fig. 1. First patented as ‘methylsa- a common starting material for MDMA production, is a natural

frylamin’ in 1912 as a precursor for blood-clotting agents [1,2], the product obtained from sassafras oil and is also used for the

recreational use of MDMA gained popularity during the mid-1980s industrial production of fragrances, ﬂavours and some insecticides

and it has since become a prevalent drug of choice [1,3]. MDMA is [5]. The synthesis of safrole from synthetic precursors, including

an illicit substance in many jurisdictions around the world and is catechol, has been investigated as a means to reduce the reliance

under international control through its inclusion to the United upon variable natural sources [5,6]. Thus, with such precedent as

Nations Convention against Illicit Trafﬁc in Narcotic Drugs and well as available literature, it is unsurprising that this route has

Psychotropic Substances 1988. been reported for the synthesis of MDMA in literature readily

There has been a signiﬁcant amount of research into the organic available to the clandestine laboratory operator [7].

impurity proﬁles of MDMA synthesised from the most common The techniques and procedures for the synthesis of MDMA from

precursors: 3,4-methylenedioxyphenyl-2-propanone (MDP2P), uncontrolled precursors, including catechol, are described in detail

safrole, isosafrole and piperonal [3]. These precursors, however, in numerous freely available documents on the internet [7]. There is,

are controlled or regulated substances in many jurisdictions. The however, only limited information available regarding the organic

use of uncontrolled precursors therefore offers clandestine impurity proﬁles that arise when these synthetic routes are utilised

laboratory operators a strategy to reduce the risk associated with [8]. Organic impurities in MDMA can result from precursors,

detection. 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.

* Corresponding author at: University of Technology Sydney, P.O. Box 123,

This paper presents the results of organic impurity proﬁling of

Broadway, NSW 2007, Australia. Tel.: +61 2 95141035.

E-mail address: [email protected] (A.M. McDonagh). MDMA synthesised from catechol via the reaction pathways

http://dx.doi.org/10.1016/j.forsciint.2014.12.021

E. Heather et al. / Forensic Science International 248 (2015) 140–147 141

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.

2.2. Chemicals

Fig. 1. Chemical structure of MDMA.

Catechol, diisobutylaluminium hydride (DIBAH, 1.5 M solution

shown in Scheme 1. As the organic impurity proﬁle is dependent in cyclohexane), allyl bromide, magnesium, anhydrous tetrahy-

on synthetic route, the synthesis of MDP2P from safrole was drofuran, p-benzoquinone, formic acid and nitromethane were

performed via the two most common methods used in clandestine purchased from Sigma–Aldrich. Diethyl ether, dichloromethane,

laboratories – Wacker oxidation of safrole (Route 1) and the methanol, acetone, toluene, hydrogen peroxide (30%), ammonium

isomerisation of safrole and peracid oxidation and acid dehydra- chloride and sodium hydroxide were purchased from Chem-

tion of isosafrole (Route 2) [3,9,10]. We show that the organic Supply. Dimethyl sulfoxide, mercuric chloride and hydrobromic

impurity proﬁle of MDMA synthesised from catechol can indicate if acid (46–49%) were obtained from UNILAB. Glacial acetic acid,

synthetic safrole (from catechol) was used. Importantly, numerous hydrochloric acid (36%) and sodium bicarbonate were purchased

impurities arise from these methods that are not reported in the from Labscan. Sulphuric acid was purchased from BDH Chemicals.

signiﬁcant amount of literature describing impurities in MDMA Anhydrous sodium sulphate was purchased from AJAX Finechem.

synthesised from commercially available safrole [3,9–11]. Sodium bisulﬁte was obtained from the Mallinckrodt Chemical

Works. Chloroform-D was purchased from Cambridge Isotope

2. Materials and methods Laboratories, Inc.

2.1. General experimental 2.3. Synthesis

Each reaction was performed at minimum in duplicate. Gas Synthesis of 1,3-benzodioxole: Catechol (20.0 g, 182 mmol) and

chromatography–mass spectrometry (GC–MS) analysis was per- an aqueous solution of sodium hydroxide (30 mL, 19.4 M,

formed using an Agilent 6890 Series Gas Chromatographic System 582 mmol) were dissolved in 200 mL of dimethyl sulfoxide. The

coupled to an Agilent 5973 Network Mass Selective Detector. resultant green solution was heated to 90–100 8C. Dichloro-

Samples were prepared using diethyl ether as solvent at a methane (40 mL, 626 mL) was added drop wise to the solution,

concentration of 5–10 mg/mL. The column was a Zebron ZB-5ms which was heated under reﬂux at 90–100 8C for 4 h. The mixture

5% polysilarylene-95% (5%-phenyl-95%-dimethylpolysiloxane) was allowed to cool and 200 mL of water was added. The mixture

with a length of 30 m, diameter of 250 mm and a ﬁlm thickness was decanted and the product was extracted with diethyl ether

of 0.25 mm. The front inlet was at a temperature of 250 8C and had (3 200 mL). The diethyl ether extracts were washed with 3

a split injection, with a 1.0 mL injection volume and a 50:1 split 200 mL of water, dried over anhydrous sodium sulphate and

ratio. The transfer line was at a temperature of 280 8C. Helium was decanted. Solvent was removed with a rotary evaporator,

used as a carrier gas at a rate of 1.2 mL/min. The temperature producing a light brown oil. Yield: 14.8 g (66.7%). H NMR: Fig.

programme had an initial oven temperature of 50 8C for 2 min, S1. GC–MS: Fig. S9.

followed by a ramp of 10 8C/min until 290 8C where it was held for Synthesis of 5-bromo-1,3-benzodioxole: 1,3-Benzodioxole

4 min. The scan parameters enabled collection of a mass range of (6.00 mL, 52.2 mmol) was dissolved in a mixture of glacial acetic

45–450 amu with an abundance threshold of 100. The data were acid (2.6 mL, 45 mmol), 16 mL of methanol, and 2 mL of water.

analysed using MSD Chem Station software. Proton nuclear Hydrobromic acid (6.0 mL, 8.9 M, 53 mmol) was then added

magnetic resonance ( H NMR) spectroscopy was performed using dropwise to the solution ensuring that the temperature remained

an Agilent Technologies 500 MHz NMR instrument. Samples were below 25 8C. The solution was heated to approximately 35 8C, and

dissolved in deuterated chloroform (CDCl3) and the solvent hydrogen peroxide (6.0 mL, 9.9 M, 59 mmol) was added drop wise,

residual chemical shift of 7.26 ppm was used as an internal ensuring that the temperature did not exceed 50 8C. The resulting

standard to calibrate the spectra. The H NMR spectra were solution was stirred at 40–50 8C for 3 h and allowed to cool. The red

collected at 25 8C with the following acquisition parameters: organic layer was extracted with diethyl ether (1 40 mL) and

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).

142 E. Heather et al. / Forensic Science International 248 (2015) 140–147

washed with 10 mL of aqueous 10% sodium bisulﬁte solution. The Synthesis of MDP2P (Route 2): A solution containing hydrogen

ether extracts were dried over anhydrous sodium sulphate, peroxide (2.0 mL, 9.9 M, 20 mmol) and formic acid (10 mL, 23.6 M,

decanted and the solvent removed with a rotary evaporator, 240 mol) was stirred at room temperature for 30 min. Isosafrole

producing an orange oil. Yield: 8.95 g (85.2%). H NMR: Fig. S2. GC– (800 mg, 4.93 mmol) in 6 mL of acetone was added to the solution

MS: Fig. S10. and stirred at room temperature for 16 h. The volatile components

Synthesis of safrole: The following Grignard reaction was of the resulting solution were removed in vacuo, leaving a red

conducted using dry glassware under nitrogen. Magnesium residue. The residue was redissolved in 10 mL of methanol and

(0.60 g, 25 mmol), 5-bromo-1,3-benzodioxole (0.40 mL, 3.3 mmol) 10 mL of 2.8 M sulphuric acid was added. The resulting solution

and a 1.5 M solution of DIBAH in cyclohexane (0.10 mL, 150 mmol) was heated under reﬂux for 3 h and allowed to cool. The product

were stirred in 20 mL of anhydrous THF. Additional 5-bromo-1,3- was extracted with 3 40 mL of diethyl ether and washed with

benzodioxole (2.60 mL, 21.5 mmol) was added drop wise and the 40 mL of water and 40 mL of saturated sodium bicarbonate

mixture was stirred for 2 h. The solution was removed via syringe solution. The ether extracts were dried over anhydrous sodium

and added dropwise to allyl bromide (4.0 mL, 46 mmol) contained sulphate, decanted and the solvent removed with a rotary

in an ice bath. The solution was stirred for 24 h and reaction evaporator, producing a brown oil. Yield: 538 mg (61.2%). H

quenched by the addition of 20 mL of water and 20 mL of saturated NMR: Fig. S6. GC–MS: Fig. S13.

ammonium chloride. The product was extracted into 3 80 mL of Synthesis of MDMA: Aluminium foil (280 mg, 10.4 mmol), cut in

diethyl ether and washed with 3 100 mL of water. The ether approximate 1 cm 1 cm squares, was added to a solution of

extracts were dried over anhydrous sodium sulphate, decanted, mercuric chloride (80.0 mg, 295 mmol) in 10 mL of methanol. The

and the solvent removed with a rotary evaporator, producing a mixture was heated under reﬂux until the aluminium foil turned a

brown oil. Yield: 3.30 g (82.1%). H NMR: Fig. S3. GC–MS: Fig. 2. dark grey and bubbles formed on the surface. Then, a solution of

Synthesis of MDP2P (Route 1): Safrole (1.00 g, 6.17 mmol) was MDP2P (200 mg, 1.12 mmol) and nitromethane (0.20 mL,

dissolved in 1 mL of methanol and added dropwise to a mixture of 3.7 mmol) in 5 mL of methanol was added [note: this procedure

palladium (II) chloride (12 mg, 68 mmol), p-benzoquinone (0.85 g, was performed using MDP2P synthesised by Route 1 and also with

7.9 mmol), 5 mL of methanol and 0.5 mL of water. The resulting MDP2P synthesised by Route 2]. The resulting mixture was heated

mixture was stirred for 3 h and filtered. To the filtrate, 10 mL of under reflux for 4 h and allowed to cool. An 8.8 M sodium

3.2 M hydrochloric acid was added. The product was extracted hydroxide solution was added to the mixture until the majority of

with 3 20 mL of dichloromethane and washed with 2 20 mL of a amalgam had dissolved. The mixture was ﬁltered and the product

saturated sodium bicarbonate solution, 2 20 mL of 1.3 M sodium extracted from the ﬁltrate with toluene (3 20 mL). The solvent

hydroxide and 2 20 mL of brine. The organic extracts were dried was removed with a rotary evaporator, producing a light brown oil.

over anhydrous sodium sulphate, decanted and the solvent Yield: 136 mg (62.7%). H NMR: Figs. S7–S8. GC–MS: Figs. 3–4.

removed with a rotary evaporator, producing a brown oil. Yield:

857 mg (78.0%). H NMR: Fig. S4. GC–MS: Fig. S11. 3. Results and discussion

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 The synthetic methods described here were chosen such that

(10 mL, 30 mmol). The resulting solution was heated under reﬂux they could be feasibly performed in a moderately equipped

for 3 h and allowed to cool. To the solution, 10 mL of a 1.6 M clandestine laboratory. Elaborate product puriﬁcation techniques

hydrochloric acid solution was added. The product was extracted were not used so as to mimic the procedures that may be expected

with 3 40 mL of diethyl ether and washed with 3 40 mL of in relatively unsophisticated clandestine laboratories. As such,

water. The organic extracts were dried over anhydrous sodium there were some variations in the concentration of organic

sulphate, decanted, and the solvent removed with a rotary impurities that were detected across series of repeat synthesises.

evaporator, producing a brown oil. Yield: 1.19 g (85.0%). H The products from each step in the reaction pathway were

NMR: Fig. S5. GC–MS: Fig. S12. analysed using GC–MS and H NMR spectroscopy. Organic

) 30 5

Abundance (×10 15

4 6 8 10 12 14 16 18 20 22 24 26 28 30

Time (min)

Fig. 2. Gas chromatogram of safrole synthesised from catechol.

E. Heather et al. / Forensic Science International 248 (2015) 140–147 143

12 ) 5 10

6 Abundance (×10

4 6 8 10 12 14 16 18 20 22 24 26 28 30

Time (min)

Fig. 3. Gas chromatogram of MDMA synthesised from catechol via Route 1.

impurities were identiﬁed based on the fragmentation pattern of methane. The formation of compound 5 involves methylenation

their mass spectrum. The identiﬁcation of these organic impurities across the aromatic rings of two 1,3-benzodioxole molecules.

was also conﬁrmed by H NMR spectroscopy when impurities were Compounds 1 and 2 are intermediates in the synthesis of safrole

of a sufﬁcient concentration to produce distinct NMR signals. from catechol. Their presence indicates that the reactions ii–iii

(Scheme 1) did not proceed to completion. Compound 1, however,

3.1. Safrole from catechol is also a reaction by-product in the Grignard reaction (Step 3,

Scheme 1) whereby the Grignard reagent, formed through the

Safrole was synthesised from catechol in three steps: the reaction of 5-bromo-1,3-benzodioxole and magnesium, reacts

methylenation of catechol, the bromination of 1,3-benzodioxole with water to form 1,3-benzodioxole (1), as shown in Scheme 2.

and a Grignard reaction using 5-bromo-1,3-benzodioxole and allyl This decomposition could occur due to water contamination in the

bromide. The gas chromatogram of safrole synthesised from reactant setup or result from an incomplete reaction at the time

catechol is shown in Fig. 2 and the eight impurities identiﬁed when the reaction mixture was quenched.

unambiguously are listed in Table 1. Compound 6 is also a reaction by-product of the Grignard

Compounds 4, 5, and 8 arose during the methylenation of reaction, as shown in Scheme 2, arising from the reaction of the

catechol (Step 1, Scheme 1). Compound 4 was formed through the Grignard reagent with 5-bromo-1,3-benzodioxole [12]. Com-

cyclisation of two catechoxide dianions with dichloromethane pounds 3 and 7 are synthesised by Grignard reactions of the

while compound 8 was synthesised via a similar reaction involving bromination reaction by-product, 5,6-dibromo-1,3-benzodioxole,

the cyclisation of three catechoxide dianions with dichloro- via the reaction schemes shown in Scheme 3.

15 ) 5

10 Abundance (×10

4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (min)

Fig. 4. Gas chromatogram of MDMA synthesised from catechol via Route 2.

144 E. Heather et al. / Forensic Science International 248 (2015) 140–147

Table 1

Organic impurities identiﬁed in safrole synthesised from catechol.

No. Impurity structure 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 5,5 -Methylenebis-1,3-benzodioxole 256, 135, 77

6 5,5 -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

H2O

Scheme 2. Synthesis of 1,3-benzodioxole (1) and 5,5 -bi-1,3-benzodioxole (6).

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).

E. Heather et al. / Forensic Science International 248 (2015) 140–147 145

Table 2

Organic impurities identiﬁed in MDMA synthesised from catechol via Route 1 and Route 2.

No. Impurity structure 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 5,5 -Methylenebis-1,3-benzodioxole 256, 135, 77 1 and 2

6 5,5 -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]-N- 256, 58, 44 1

methyl-propan-2-amine

16 1,3-Benzodioxole-5-carboxylic acid 166, 150/149, 135, 121, 77 2

146 E. Heather et al. / Forensic Science International 248 (2015) 140–147

Table 2 (Continued )

No. Impurity structure 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) 340, 296, 281, 207, 44 2

tetrahydrofuran

3.2. MDMA from safrole available MDP2P, safrole, isosafrole and piperonal [3]. The

identiﬁcation of compounds 2–6, 8 and 15 therefore indicates

MDMA was synthesised by reductive amination of MDP2P. Two the use of safrole, synthesised from catechol, as a precursor to

methods were used to synthesise MDP2P; Wacker oxidation of MDMA. Thus, elements of the organic impurity proﬁle of MDMA

safrole (Route 1) and an isomerisation/peracid oxidation/acid synthesised from catechol via both Route 1 and Route 2

dehydration method (Route 2). The gas chromatograms of MDMA unambiguously indicate the use of synthetic, catechol-derived

synthesised from catechol via Route 1 and Route 2 are shown in Fig. 3 safrole (as discussed below).

and Fig. 4, respectively. The organic impurities identiﬁed in MDMA, Compounds 4, 5 and 8 are characteristic of the methylenation of

and the synthetic routes from which they arose, are listed in Table 2. catechol; the detection of any of these impurities therefore

Compounds 1, 2, 4–6 and 8 found in MDMA synthesised via indicates that catechol was the precursor utilised. The presence of

Route 1 were identiﬁed as impurities in safrole (Table 1) and have compound 2 is indicative of the bromination reaction used in the

been carried over, unchanged, in subsequent reactions. Compound second step of the synthetic pathway. The Grignard reaction, used

15 arose from compound 7 (identiﬁed in safrole) via an analogue in the ﬁnal step of the synthesis of safrole, can be inferred by the

route to MDMA, as shown in Scheme 4. presence of compounds 6 and/or 15, which are characteristic

Compounds 2, 4, 5 and 6 were also identiﬁed in MDMA impurities formed when the Grignard reagent is prepared from

synthesised via Route 2. Compounds 1, 8 and 5-(1,3-benzodioxol- 5-bromo-1,3-benzodioxole (2).

5-yl)-6-prop-1-enyl-1,3-benzodioxole (isomerisation product of The synthesis of MDP2P from safrole via Route 1 or Route 2 can

compound 7 identiﬁed in safrole) were found in isosafrole. also be differentiated based upon the organic impurity proﬁle of

However, these impurities were not detected in MDP2P and MDMA. Compounds 11, 12 and 14 are characteristic impurities for

MDMA as they were removed during the peracid oxidation and the Wacker oxidation of safrole when methanol is used as a solvent

acid dehydration of isosafrole. [10] and, therefore, their identiﬁcation in MDMA is indicative of

With the exception of 1,3-benzodioxole (1), compounds 2, 4–6 synthesis via Route 1. Similarly, compounds 18 and 19 are

and 8 and 15 have not been previously identiﬁed in sassafras oil or characteristic for the peracid oxidation and acid dehydration of

MDMA prepared from sassafras oil [11,13]. Furthermore, they have isosafrole [9] and their identiﬁcation in MDMA is indicative

not been identiﬁed in MDMA synthesised from commercially of synthesis via Route 2. There are two diasteroisomers identiﬁed PdCl 2 CH3NO2

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] [O]

Scheme 5. Synthesis of 1,3-benzodioxole-5-carboxylic acid (16).

E. Heather et al. / Forensic Science International 248 (2015) 140–147 147

of both compounds 18 and 19, however, the stereoconﬁguration of The organic impurity proﬁle of MDMA synthesised from

these cannot be determined without isolation of the impurity. catechol via both Route 1 and Route 2 indicated that synthetic,

Isosafrole (10) is also a reaction by-product of the Wacker catechol-derived safrole was used. The organic impurities identi-

oxidation of safrole that was synthesised via the palladium- ﬁed also indicated which of the two synthetic routes was utilised.

catalysed isomerisation of safrole. Compound 16 was synthesised We conclude, therefore, that the organic impurities identiﬁed in

through the oxidation of isosafrole, as shown in Scheme 5, during MDMA indicated the precursor and the reaction pathway used to

the peracid oxidation and acid dehydration of isosafrole. Isosafrole synthesise MDMA from catechol.

can be detected in MDMA samples as a result of a reaction by-

product, an intermediate or a precursor in a synthetic route. The Appendix A. Supplementary data

identiﬁcation of isosafrole, or impurities stemming from isosafrole,

in MDMA is therefore not indicative of a particular synthetic route. Supplementary data associated with this article can be found, in the

Compounds 13 and 17 are by-products of the reductive amination

online version, at http://dx.doi.org/10.1016/j.forsciint.2014.12.021.

of MDP2P, synthesised through the reaction of MDP2P with the

reaction solvent, methanol [8]. The MDMA synthesised via Route 2

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