Accepted Manuscript

Title: Organic Impurity Profiling of

3,4-Methylenedioxymethamphetamine (MDMA) Synthesised
from Catechol
Author: Erin Heather Ronald Shimmon Andrew M.
McDonagh
PII:
DOI:
Reference:

S0379-0738(14)00538-6
http://dx.doi.org/doi:10.1016/j.forsciint.2014.12.021
FSI 7854

To appear in:

FSI

Received date:
Revised date:
Accepted date:

23-6-2014
18-12-2014
19-12-2014

Please cite this article as: E. Heather, R. Shimmon, A.M. McDonagh,

Organic
Impurity
Profiling
of
3,4-Methylenedioxymethamphetamine
(MDMA) Synthesised from Catechol, Forensic Science International (2014),
http://dx.doi.org/10.1016/j.forsciint.2014.12.021
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Highlights
Safroleand3,4methylenedioxymethamphetamineweresynthesisedfromcatechol.
TheorganicimpurityprofileofMDMAsynthesisedfromcatecholhasbeenexamined.

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OrganicimpuritiesinMDMAmadefromcatecholindicatedsyntheticsafrolewasused.

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p

te

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Theimpuritiesindicatedwhichsyntheticrouteswereutilised.

Page 1 of 22

Organic Impurity Profiling of 3,4Methylenedioxymethamphetamine (MDMA)

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Synthesised from Catechol

Erin Heather, Ronald Shimmon and Andrew M. McDonagh*

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Centre for Forensic Science, University of Technology Sydney, Sydney NSW 2007 Australia

+61 2 95141035

Email:

andrew.mcdonagh@uts.edu.au

Postal Address:

University of Technology Sydney

PO Box 123

Broadway, NSW 2007

Australia

ABSTRACT

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Ph:

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*Corresponding author

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This work examines the organic impurity profile of 3,4-methylenedioxymethamphetamine

(MDMA) that has been synthesised from catechol (1,2-dihydroxybenzene), a common

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chemical reagent available in industrial quantities. The synthesis of MDMA from catechol
proceeded via the common MDMA precursor safrole. Methylenation of catechol yielded 1,3benzodioxole, 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.

Page 2 of 22

Keywords: Illicit drugs; 3,4-methylendioxymethamphetamine; MDMA; safrole; chemical

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synthesis; chemical profiling

Page 3 of 22

ABSTRACT
This work examines the organic impurity profile of 3,4-methylenedioxymethamphetamine
(MDMA) that has been synthesised from catechol (1,2-dihydroxybenzene), a common

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chemical reagent available in industrial quantities. The synthesis of MDMA from catechol

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proceeded via the common MDMA precursor safrole. Methylenation of catechol yielded 1,3benzodioxole, which was brominated and then reacted with magnesium allyl bromide to form

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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:

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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.

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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

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utilised.

Keywords: Illicit drugs; 3,4-methylendioxymethamphetamine; MDMA; safrole; chemical

synthesis; chemical profiling

Page 4 of 22

1. Introduction
The active ingredient in the drug colloquially referred to as ecstasy is the amphetamine-type

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stimulant 3,4-methylenedioxymethamphetamine (MDMA), Figure 1. First patented as

methylsafrylamin in 1912 as a precursor for blood-clotting agents [1, 2], the recreational

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use of MDMA gained popularity during the mid-1980s and it has since become a prevalent

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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

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against Illicit Traffic in Narcotic Drugs and Psychotropic Substances 1988.

HN

Figure 1: Chemical structure of MDMA

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There has been a significant amount of research into the organic impurity profiles of MDMA

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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.
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
5

Page 5 of 22

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,

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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

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impurity profiles that arise when these synthetic routes are utilised [8]. Organic impurities in

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MDMA can result from precursors, intermediates or reaction by-products [3] and their
identification can therefore provide valuable information about synthetic methods currently in

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use. Of course, adulterants are a further source of impurities however these will not be

O
O

HO

Br

HN

MDMA

Safrole

5Bromo1,3benzodioxole

d
vii

O
O

iv
v

te

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p

iii

1,3Benzodioxole

Catechol

ii

Route2

HO

addressed here.

vi
O

MDP2P

Route2

O
O

Isosafrole

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).

This paper presents the results of organic impurity profiling of MDMA synthesised from
catechol via the reaction pathways 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
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Page 6 of 22

(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.

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Importantly, numerous impurities arise from these methods that are not reported in the
significant amount of literature describing impurities in MDMA synthesised from

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commercially available safrole [3, 9-11].

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2. Materials and Methods

2.1 General Experimental

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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.

column

was

Zebron

ZB-5ms

5%

polysilarylene-95%

(5%-phenyl-95%-

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The

Samples were prepared using diethyl ether as solvent at a concentration of 5 10 mg/mL.

dimethylpolysiloxane) with a length of 30 m, diameter of 250 m and a film thickness of

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0.25 m. The front inlet was at a temperature of 250C and had a split injection, with a 1.0
L injection volume and a 50:1 split ratio. The transfer line was at a temperature of 280C.
Helium was used as a carrier gas at a rate of 1.2 mL/min. The temperature program had an
initial oven temperature of 50C for 2 mins, followed by a ramp of 10C/min until 290C
where it was held for 4 mins. 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 25C

Page 7 of 22

with the following acquisition parameters: 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.

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2.2 Chemicals

Catechol, diisobutylaluminium hydride (DIBAH, 1.5 M solution in cyclohexane), allyl

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bromide, magnesium, anhydrous tetrahydrofuran, p-benzoquinone, formic acid and

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nitromethane were purchased from Sigma-Aldrich. Diethyl ether, dichloromethane, methanol,

acetone, toluene, hydrogen peroxide (30%), ammonium chloride and sodium hydroxide were

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purchased from Chem-Supply. 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

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2.3 Synthesis

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from Cambridge Isotope Laboratories, Inc.

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 C. Dichloromethane (40 mL,
626 mL) was added drop wise to the solution, which was heated under reflux at 90 - 100 C
for four hours. 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 x 200 mL). The
diethyl ether extracts were washed with 3 x 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.

Page 8 of 22

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

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solution ensuring that the temperature remained below 25 C. The solution was heated to
approximately 35 C, and hydrogen peroxide (6.0 mL, 9.9 M, 59 mmol) was added drop

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wise, ensuring that the temperature did not exceed 50 C. The resulting solution was stirred at

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40 - 50 C for three hours and allowed to cool. The red organic layer was extracted with
diethyl ether (1 x 40 mL) and washed with 10 mL of aqueous 10% sodium bisulfite solution.

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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%). 1HNMR:

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

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mmol) and a 1.5 M solution of DIBAH in cyclohexane (0.10 mL, 150 mol) were stirred in

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20 mL of anhydrous THF. Additional 5-bromo-1,3-benzodioxole (2.60 mL, 21.5 mmol) was

added drop wise and the mixture was stirred for two hours. 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 hours and reaction quenched by the addition of 20 mL of water
and 20 mL of saturated ammonium chloride. The product was extracted into 3 x 80 mL of
diethyl ether and washed with 3 x 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%). 1HNMR: 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 mol), pbenzoquinone (0.85 g, 7.9 mmol), 5 mL of methanol and 0.5 mL of water. The resulting
9

Page 9 of 22

mixture was stirred for three hours and filtered. To the filtrate, 10 mL of 3.2 M hydrochloric
acid was added. The product was extracted with 3 x 20 mL of dichloromethane and washed
with 2 x 20 mL of a saturated sodium bicarbonate solution, 2 x 20 mL of 1.3 M sodium

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hydroxide and 2 x 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.

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Yield: 857 mg (78.0%). 1HNMR: Fig. S4. GC-MS: Fig. S11.

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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

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under reflux for three hours 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 x 40 mL of diethyl

ether and washed with 3 x 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%). 1HNMR: Fig. S5. GC-MS: Fig. S12.

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Synthesis of MDP2P (Route 2): A solution containing hydrogen peroxide (2.0 mL, 9.9 M, 20

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mmol) and formic acid (10 mL, 23.6 M, 240 mol) was stirred at room temperature for 30
minutes. Isosafrole (800 mg, 4.93 mmol) in 6 mL of acetone was added to the solution and
stirred at room temperature for 16 hours. 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 three hours and allowed to cool. The product was extracted with 3 x 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%).
1

HNMR: Fig. S6. GC-MS: Fig. S13.

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Page 10 of 22

Synthesis of MDMA: Aluminium foil (280 mg, 10.4 mmol), cut in approximate 1 cm x 1cm
squares, was added to a solution of mercuric chloride (80.0 mg, 295 mol) in 10 mL of
methanol. The mixture was heated under reflux until the aluminium foil turned a dark grey

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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

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performed using MDP2P synthesised by Route 1 and also with MDP2P synthesised by Route

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2]. The resulting mixture was heated under reflux for four hours and allowed to cool. An 8.8
M sodium hydroxide solution was added to the mixture until the majority of amalgam had

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dissolved. The mixture was filtered and the product extracted from the filtrate with toluene (3
x 20 mL). The solvent was removed with a rotary evaporator, producing a light brown oil.

Yield: 136 mg (62.7%). 1HNMR: Figs S7 S8. GC-MS: Figs 3 4.

3. Results and Discussion

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The synthetic methods described here were chosen such that they could be feasibly
performed in a moderately equipped clandestine laboratory. Elaborate product purification

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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 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.

11

Page 11 of 22

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

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and allyl bromide. The gas chromatogram of safrole synthesised from catechol is shown in

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Figure 2 and the eight impurities identified unambiguously are listed in Table 1.
50

0
6

10

12

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14

16

18

20

22

24

O
O
O

O
O

10

Br

Br

15

20

25

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30

Abundance(105)

35

40

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45

26

Time(min)

28

30

Figure 2: Gas chromatogram of safrole synthesised from catechol

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Page 12 of 22

Table 1: Organic impurities identified in safrole synthesised from catechol

No.

Impurity Structure

Impurity Name

m/z

1,3-benzodioxole

122/121, 63

5-bromo-1,3-benzodioxole

202/200, 121, 63

5-bromo-6-(2-propenyl)1,3-benzodioxole

242/240, 199, 131, 103, 77

O
O
O

Br
O

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1,3-benzodioxole dimer
O

5,5'-methylenebis-1,3benzodioxole

5,5'-bi-1,3-benzodioxole

244, 135, 122/121, 63

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cr

Br

ip
t

256, 135, 77

242, 126, 121/120, 63

5-allyl-6-(1,3-benzodioxol5-yl)-1,3-benzodioxole

282, 267, 237, 209, 165, 139

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p

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1,3-benzodioxole trimer

366, 244, 135, 122/121

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 dichloromethane. The formation of compound
5 involves methylenation across the aromatic rings of two 1,3-benzodioxole molecules.

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Page 13 of 22

Compound 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

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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

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decomposition could occur due to water contamination in the reactant set-up or result from an

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incomplete reaction at the time when the reaction mixture was quenched.
Br

MgBr

H 2O

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

Compound 6 is also a reaction by-product of the Grignard reaction, as shown in Scheme 2,

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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-

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product, 5,6-dibromo-1,3-benzodioxole, via the reaction schemes shown in Scheme 3.

O
O

2Br -

Mg

Br

Br

Br

2Mg
O
O

Br

Br
Br

O
O

Scheme 3: Synthesis of 5-bromo-6-(2-propenyl)-1,3-benzodioxole (3) and 5-allyl-6-(1,3benzodioxol-5-yl)-1,3-benzodioxole (7)

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Page 14 of 22

3.2 MDMA from Safrole

MDMA was synthesised by reductive amination of MDP2P. Two methods were used to

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synthesise MDP2P; Wacker oxidation of safrole (Route 1) and an isomerisation / peracid

oxidation / acid dehydration method (Route 2). The gas chromatograms of MDMA

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synthesised from catechol via Route 1 and Route 2 are shown in Figures 4 and 5 respectively.

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The organic impurities identified in MDMA, and the synthetic routes from which they arose,
are listed in Table 2.

an

18

HN

O
O

O
O

O
O

O
O

Br

Ac
ce
p

te

10

Abundance(105)

12

14

HN

16

10

12

14

16
18
Time(min)

20

22

24

26

28

30

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

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Page 15 of 22

10

12

14

16

20

22

24

26

O
O

18

an

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Br

OH

cr

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O
O

O
O

O
O

OH

10

15

Abundance(105)

HN

20

OH

25

28

Time(min)

30

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p

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Figure 4: Gas chromatogram of MDMA synthesised from catechol via Route 2

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Page 16 of 22

Table 2: Organic Impurities identified in MDMA synthesised from catechol via Route 1 and
Route 2
Impurity Structure

m/z

1,3-benzodioxole

122/121, 63

5-bromo-1,3-benzodioxole

202/200, 121,
63

O
O

244, 135,
122/121, 63

1 and 2

5,5'-methylenebis-1,3benzodioxole

256, 135, 77

1 and 2

242, 126,
121/120, 63

1 and 2

366, 244, 135,

122/121

cis and trans isosafrole

162, 131,
104/103, 77, 44

5-(1-methoxypropyl)-1,3benzodioxole

194, 165,
150/149, 135,
77

5-(1,3-dimethoxypropyl)1,3-benzodioxole

224, 192, 161,

135, 75

MDP2P dimethyl acetal

224, 193, 135,

89

1 and 2

5-(3,3-dimethoxypropyl)1,3-benzodioxole

224, 192, 161,

135, 75

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O
O

5,5'-bi-1,3-benzodioxole

1,3-benzodioxole trimer

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p

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10

11

O
O

12

1 and 2

1,3-benzodioxole dimer

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Br

cr

Synthetic
Route

Impurity Name

ip
t

No.

O
O

13

14

17

Page 17 of 22

HN

15

O
O

1-[6-(1,3-benzodioxol-5yl)-1,3-benzodioxol-5-yl]N-methyl-propan-2-amine

256, 58, 44

1,3-benzodioxole-5carboxylic acid

166, 150/149,
135, 121, 77

MDP2P methyl hemiacetal

196, 165,
150/149, 135,
121, 63

OH

O
O
OH

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17

18

1-(1,3-benzodioxol-5-yl)1-methoxy-propan-2-ol

OH

2,4-dimethyl-3,5-bis(3,4methylenedioxyphenyl)tetr
ahydrofuran

19
O

210, 165,
150/149, 135,
77

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cr

16

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t

O
O

340, 296, 281,

207, 44

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Compounds 1, 2, 4 - 6 and 8 found in MDMA synthesised via Route 1 were identified as

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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.

O
O

PdCl2

HN

O
O
O

CH3NO 2

Al(Hg)

O
O

Scheme 4: Synthesis of 1-[6-(1,3-benzodioxol-5-yl)-1,3-benzodioxol-5-yl]-N-methylpropan-2-amine (15)

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Page 18 of 22

Compounds 2, 4, 5 and 6 were also identified in MDMA synthesised via Route 2.

Compounds

1,

and

5-(1,3-benzodioxol-5-yl)-6-prop-1-enyl-1,3-benzodioxole

(isomerisation product of compound 7 identified in safrole) were found in isosafrole.

during the peracid oxidation and acid dehydration of isosafrole.

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However, these impurities were not detected in MDP2P and MDMA as they were removed

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With the exception of 1,3-benzodioxole (1), compounds 2, 4 - 6 and 8 and 15 have not been

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previously identified in sassafras oil or MDMA prepared from sassafras oil [11, 13].
Furthermore, they have not been identified in MDMA synthesised from commercially

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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

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safrole (as discussed below).

via both Route 1 and Route 2 unambiguously indicate the use of synthetic, catechol-derived

Compounds 4, 5 and 8 are characteristic of the methylenation of catechol; the detection of

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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,
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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 of both compounds 18 and 19, however, the

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t

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

cr

synthesised via the palladium catalysed isomerisation of safrole. Compound 16 was

us

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

an

a result of a reaction by-product, an intermediate or a precursor in a synthetic route. The

identification of isosafrole, or impurities stemming from isosafrole, in MDMA is therefore

[O]

OH

te

[O]

not indicative of a particular synthetic route.

Ac
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p

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

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 set up, variations in reaction
conditions or variations in the technique of different chemists performing the reaction.

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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

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t

laboratory. The synthesis involved the methylenation of catechol, the bromination of 1,3benzodixole and a Grignard reaction using 5-bromo-1,3-benzodioxole and allyl bromide.

cr

Eight organic impurities were identified in the synthetic safrole and, of these impurities, only

us

one (1,3-benzodioxole) has previously been identified in safrole obtained from natural
sassafras oil.

an

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

te

Route 1 and eleven organic impurities were identified in MDMA synthesised via Route 2.
The organic impurity profile of MDMA synthesised from catechol via both Route 1 and

Ac
ce
p

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.

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Page 21 of 22

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