Isotopic changes during the synthesis of amphetamines

Article abstract of DOI:10.1039/b207775b

Observed variations in the δ¹³C and δ¹⁵N content of amphetamines are shown to be attributable to kinetic isotope effects during synthesis; chemical degradation and isotopic characterisation provides a means to identify the synthetic origins of illicit MDMA and other amphetamines.

Full text of DOI:10.1039/b207775b

Isotopic changes during the synthesis of amphetamines
James F. Carter,*a Emma L. Titterton,b Helen Grantc and Richard Sleemanb
a Organic and Biological Section, School of Chemistry, University of Bristol, Cantock’s Close, Bristol, UK
BS8 1TS. E-mail: jim.carter@bristol.ac.uk; Fax: +44 117 9298611; Tel: +44 117 9546967
b Mass Spec Analytical Limited, Building 20F, Golf Course Lane, PO Box 77, Bristol, UK BS99 7AR
c
Centre for Ecology and Hydrology, Merlewood Research Station, Grange-over-Sands, Cumbria, UK LA11
6JU
Received (in Cambridge, UK) 8th August 2002, Accepted 20th September 2002
First published as an Advance Article on the web 8th October 2002
Observed variations in the d13C and d15N content of
amphetamines are shown to be attributable to kinetic isotope
effects during synthesis; chemical degradation and isotopic
characterisation provides a means to identify the synthetic
origins of illicit MDMA and other amphetamines.
Using this model the theoretical d13C value for the syn-
thesised methamphetamine is 229.4‰ ± 0.39. The measured
d13C values of the methamphetamine (Table 1) are consistent
with this value indicating no observable KIE with respect to
carbon for the reductive amination process.
Table 1 d13C isotopic values of synthesised amphetamines
A number of researchers have proposed that variations in the
stable isotopic composition of controlled substances may
provide a means of linking drugs to a common source of supply
or manufacture. Variation in the d13C content of natural
products e.g. cocaine1 may be attributed to climatic conditions
during biosynthesis and provides an indicator of geographical
origin. It has also been demonstrated that variations in the
isotopic content of synthetic controlled substances, specifically
3,4-methylenedioxymethylamphetamine (MDMA), can be used
to classify ‘ecstasy’ tablets as members of specific batches.2,3
Variations in the isotopic content of synthetic materials are
broadly attributed to variations in precursor materials or to
kinetic isotope effects (KIE) during synthesis. The preparation
of MDMA, and its N-substituted homologues, typically begins
with natural materials4 such as safrole, isosafrole and piperonal
which are readily and cheaply available. These compounds are
used to prepare 3,4-methylenedioxyphenylacetone which is
then converted to the corresponding amine via reductive
amination.4 This study attempts to identify sources of d13C and
d15N variations observed in illicit amphetamines by studying
the preparation of methamphetamine. Conversely, samples of
illicit MDMA were reverted to the corresponding ketone to
assess potential isotopic effects during synthesis.
All solvents were supplied by Rathbone (Walkerburn, UK)
and other reagents by Sigma-Aldrich (Poole, UK) unless
specified. Methamphetamine was prepared from phenylacetone
(Fluka, supplied by Sigma-Aldrich) by reaction with methyl-
amine (2.0 M solution in tetrahydrofuran) and sodium cyano-
borohydride according to the standard method described by
Taylor Noggle et al.5 The reaction was performed in duplicate
and then repeated, in duplicate, with a second batch of
methylamine solution yielding four lots of methamphetamine.
The reaction is shown in Scheme 1.
Residual
phenylacetone
d13C ‰ vs.
Methylamine
d13C ‰ vs.
VPDBa
Phenylacetone
d13C ‰ vs.
VPDBa
Methamphetamine
d13C ‰ vs. VPDBa VPDBa
230.76 ± 0.12 229.25 ± 0.37
230.76 ± 0.12 229.25 ± 0.37
229.01 ± 0.02
229.34 ± 0.57
226.02 ± 0.18
223.47 ± 0.26
a Vienna PeeDee Belemnite.
Fig. 1 shows the GC-irmMS chromatogram for the synthetic
methamphetamine (peak 2) in which approximately 5% of the
reactant ketone (peak 1) is still present. The three peaks at the
beginning and end of the chromatogram correspond to reference
CO2 pulses. Although no isotopic fractionation was observed in
the product methamphetamine the residual ketone is sig-
nificantly enriched in 13C with respect to the starting material
(Table 1). This reflects a concentration of 13C ketone as the 12
C
ketone is preferentially consumed in the reaction. Since the
reaction of the carbonyl group will only be affected by the
adjoining carbon atoms formation of methamphetamine with
13C present in the aromatic ring will not be affected. Hence, a
small KIE appears in this reaction but a depletion in 13C of the
product methamphetamine may be masked because methyl-
amine is in excess and has a similar d13C value to the parent
ketone.
Scheme 1 Synthesis of methamphetamine.
Fig. 1 GC-irmMS chromatogram of synthesised methamphetamine (ion
current m/z 44).
The products of the reactions were tested for purity by GC/
Table 2 shows the d15N values for the methylamine and
synthesised methamphetamine. The two batches of methyl-
amine were isotopically distinct by ca 1.4‰ which may affect
the d15N content of the product. The isotopic differences
between the methylamine and product methamphetamine,
however, range from +9.2 to 20.3‰ and since methylamine is
the only source of nitrogen in the product, methamphetamine,
these differences are clearly due to KIEs more than the reagents.
The differences are remarkable since the reactions for each
batch of methylamine were performed simultaneously with
1
MS and H NMR and then analysed for d13C content by GC-
irmMS as previously described.3 d13C analysis of the reactant
methylamine and d15N analysis of both methylamine and
methamphetamine was performed by EA-irmMS.†
The simple mass balance equation (1) (Ca = d13C of
methamphetamine, Ck = d13C of phenylacetone, Cm = d13C of
methylamine) defines the isotopic value of the product molecule
in terms of the reactants.6
(1)
Ca = (9Ck + Cm)/10
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Table 2 d15N isotopic values of synthesised amphetamines
Table 3 13C isotopic values MDMA oxidation products
Methylamine
d15N ‰ vs. air
Methamphetamine
d15N ‰ vs. air
MDMA d13C ‰ vs.
VPDBa
Ketone d13C ‰ vs.
VPDBa
Aldehyde d13C ‰ vs.
VPDBa
21.54 ± 0.16
21.54 ± 0.16
+0.90 ± 0.63
+0.90 ± 0.63
+7.73 ± 0.05
+4.20 ± 0.51
+7.24 ± 0.11
+0.56 ± 0.06
228.01 ± 0.71
227.87 ± 0.19
229.80 ± 0.08
230.42 ± 0.23
226.95 ± 0.24
226.51 ± 0.27
226.85 ± 1.05
225.03 ± 0.23
227.28 ± 0.08
226.14 ± 0.32
226.56 ± 1.15
222.11 ± 0.23
a Vienna PeeDee Belemnite.
similar conditions and identical reagents and apparatus. The
relative reaction rates of 14N and 15N methylamine must,
therefore, be highly dependent upon changes in reaction
conditions such as the rate of reagent addition and resulting
reaction temperature.
Four samples of MDMA which had been isolated and
purified from illicit ecstasy tablets during an earlier study were
oxidized to the corresponding ketone and aldehyde (piperonal).
A small quantity of each extract (ca. 10 mg) was reacted with
potassium permanganate and copper sulfate (100 mg each) in
dichloromethane (2 mL) for 48 hrs for complete oxidation
(Scheme 2).
approximately 10% of the reaction products a large KIE during
their formation may be expected.7 Comparison of the relative
d13C values for the ketone and aldehyde reveals that for three of
the samples these values are not significantly different. For the
fourth sample the aldehyde is approximately 3‰ enriched in
13C with respect to the ketone. It is believed that this difference
reflects the effect of the terminal methyl group having been
added during manufacture. It is possible, therefore, to speculate
that the fourth sample has been synthesised from piperonal as
opposed to safrole or isosafrole.
In conclusion, this study has shown that the large variations
in d15N and smaller variations in d13C content of illicit
amphetamines results, at least in part, from the reductive
amination stage of synthesis. Isotopic content appears charac-
teristic of a specific synthesis and these findings, therefore,
validate the use of stable isotope content as a ‘fingerprint’ for
illicit amphetamines. In addition, the use of chemical degrada-
tion to investigate isotopic substitution at specific sites within a
molecule offers the potential to identify synthetic precursors.
The authors would like to thank Hugh Grundy and Eve
Mason of Avon and Somerset Constabulary Scientific In-
vestigation for providing ecstasy tablets, Dr. Andy Stott of
NERC 15N SIF (Merlewood) for d15N analyses and Prof. Tim
Gallagher for sound chemical advice.
Scheme 2 Oxidation of MDMA.
The GC-irmMS chromatogram of the reaction products is
shown in Fig. 2. The major oxidation products are 3,4-methyl-
enedioxyphenylacetone (peak 4), piperonal (peak 3) and the
corresponding imine (peak 5).
Notes and references
The d13C values of the MDMA, ketone and aldehyde are
presented in Table 3. There is a large isotopic difference
between the amphetamine and its oxidation products, ranging
from 1.2 to 5.4‰. Since the ketone and aldehyde each represent
† Samples were micro-pipetted into 6 mm 3 4 mm tin capsules containing
Chromosorb and combusted at 1000 °C using an automated Carlo Erba
NA1500 elemental analyser coupled to a Dennis Leigh Technology isotope
ratio mass spectrometer. NOx were reduced to N2 with copper at 600 °C. A
working standard was analysed during each analytical run. Samples were
analysed in triplicate. All d15N and d13C results are expressed relative to the
international standards air and VPDB respectively.
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408, 311–312.
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Forensic Sci. Int., 1995, 71, 225–231.
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4 T. A. DalCason, J. Forensic Sci., 1990, 35, 675–697.
5 F. Taylor Noggle, J. DeRuiter, S. T. Coker and C. Randall Clark, J. Assoc.
Off. Anal. Chem., 1987, 6, 981–986.
6 D. M. Jones, J. F. Carter, G. Eglinton, E. J. Jumeau and C. S. Fenwick,
Biol. Mass Spectrom., 1991, 20, 641–646.
Fig. 2 GC-irmMS chromatogram of oxidized MDMA (ion current m/z
44).
7 L. Melander and W. H. Saunders, Reaction rates of isotopic molecules,
Wiley, New York, 1980.
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