Forensic Science International 234 (2014) e10e13

Contents lists available at ScienceDirect

Forensic Science International

journal homepage: www.elsevier.com/locate/forsciint

Case Report

An unusual presentation of a customs importation seizure containing

amphetamine, possibly synthesized by the APAANP2PLeuckart
route
John D. Power a,b,*, Michael G. Barry b, Kenneth R. Scott b, Pierce V. Kavanagh b
a
b

Forensic Science Laboratory, Garda HQ, Dublin 8, Ireland

Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, St. Jamess Hospital, Dublin 8, Ireland

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 19 April 2013
Received in revised form 20 September 2013
Accepted 5 October 2013
Available online 14 October 2013

During the analysis of an Irish customs seizure (14 packages each containing approximately one
kilogram of a white wet paste) were analysed for the suspected presence of controlled drugs. The
samples were found to contain amphetamine and also characteristic by-products including benzyl
cyanide, phenylacetone (P2P), methyl-phenyl-pyrimidines, N-formylamphetamine, naphthalene
derivatives and amphetamine dimers. The analytical results corresponded with the impurity prole
observed and recently reported for the synthesis of 4-methylamphetamine from 4-methylphenylacetoacetonitrile [1]. The synthesis of amphetamine from alpha-phenylacetoacetonitrile (APAAN) was
performed (via an acid hydrolysis and subsequent Leuckart reaction) and the impurity prole of the
product obtained was compared to those observed in the customs seizure. Observations are made
regarding the route specicity of these by-products.
2013 Elsevier Ireland Ltd. All rights reserved.

Keywords:
APAAN
Amphetamine
Amphetamine dimers
P2P
Benzyl cyanide
Pryimidines
Naphthalenes
Formylamphetamine
Synthetic route and route specic
impurities in amphetamine synthesis

1. Introduction
Amphetamine and its related compounds are controlled
substances and there have been many studies looking at the
synthetic routes for their manufacture [24]. There are numerous
synthetic approaches to the synthesis of amphetamine type
compounds and the exchange of recipes amongst clandestine
chemists is prolic. In Ireland, a typical content of amphetamine in
street samples has been reported to be between 1% and 10% [5].
In the Irish Republic, the Forensic Science Laboratory (FSL)
receives all samples seized by An Garda Sochana (the Irish
National Police Force) and Irish Customs Ofcers for examination
under the Misuse of Drugs legislation. A customs seizure (an
importation case) was presented to the FSL and analysis conrmed

* Corresponding author at: Department of Pharmacology and Therapeutics,

School of Medicine, Trinity Centre for Health Sciences, St. Jamess Hospital, Dublin 8,
Ireland. Tel.: +353 16662948.
E-mail addresses: jdpower@fsl.gov.ie, jddpower@gmail.com (J.D. Power).
0379-0738/$ see front matter 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.forsciint.2013.10.003

the presence of amphetamine. The seizure consisted of fourteen

packages each containing approximately one kilogram of a white
wet paste-like material wrapped in assorted layers of plastic and
outer foil packaging (see Fig. 1). In the second from innermost layer
of packaging there was a yellow liquid that had apparently seeped
from the white paste. Amongst the outer layers of plastic packaging
and in the foil packaging there was a mixture of brown granules
(coffee) and blue/white granules (detergent). These substances
may have been added to disguise the smell of the amphetamine
containing paste in an effort to avoid canine detection. The white
paste was found to contain amphetamine and a mixture of various
compounds, including phenylacetone (P2P), benzyl cyanide
(phenylacetonitrile), pyrimidines, N-formylamphetamine, amphetamine dimers and naphthalene derivatives. The yellow liquid
was found to contain greater concentrations of these by-products.
The analytical results for the yellow liquid and the white paste
corresponded with a by-product prole recently observed and
reported for the Leuckart synthesis of 4-methylamphetamine from
4-methylphenylacetone made from 4-methylphenylacetoacetonitrile [1]. Consequently, it was proposed that the amphetamine in

J.D. Power et al. / Forensic Science International 234 (2014) e10e13

e11

Fig. 1. Montage of photographs of a package containing amphetamine.

this importation case might have been synthesized from by

hydrolysis of alpha-phenylacetoacetonitrile (APAAN) to P2P
followed by a Leuckart reaction.
In Europe, the major synthetic route for most amphetamine
syntheses is the Leuckart reaction of phenylacetone (P2P, BMK,
benzyl methyl ketone, phenylacetone) [68]. In this route,
condensation of formamide with P2P at elevated temperatures
results in the formation of an intermediate N-formylamphetamine
and its subsequent hydrolysis yields amphetamine and also
numerous by-products. Many investigations have sought to
identify route specic impurities for the distinct synthetic routes
to amphetamine or substituted amphetamine production, i.e.
unique by-products [917,7,1821]. To circumvent international
control measures, P2P has been made from various preprecursors, most typically from APAAN, which may be synthesized
from benzyl cyanide, benzaldehyde, or phenylacetic acid, [10].
Recent reports have highlighted the increase in the seizures of
APAAN in Europe and also that some European criminal groups
have imported and/or synthesized APAAN [8,11]. APAAN is not
currently listed as a controlled substance under international
precursor regulations or as a controlled drug under Irish national
legislation.
To investigate the proposal that the amphetamine in this
importation seizure may have been produced from APAAN, a
laboratory synthesis was performed and the by-product prole of
the resulting amphetamine was found to be very similar to that of
the customs sample.
2. Materials and methods
2.1. Reagents and standards
All reagents and dry solvents used in the syntheses were obtained from Sigma
Aldrich Ltd. (Arklow, Ireland).
2.2. Synthesis of P2P from APAAN and its further conversion to amphetamine
2.2.1. APAAN to P2P
APAAN, alpha-phenylacetoacetonitrile (5 g) was added to water (30 ml) and
concentrated sulfuric acid (30 ml) was added drop-wise, keeping the temperature
below 10 8C. The mixture was then heated (oil bath, 150 8C) with vigorous stirring
for 4 h and allowed to cool to room temperature. This was then partitioned between
dichloromethane and water, the organic layer collected, washed with saturated

aqueous sodium bicarbonate, dried (anhydrous magnesium sulfate) and evaporated

to dryness to give a light brown oil (3.2 g).
2.2.2. Amphetamine, Leuckart synthesis
A portion of the oil (0.75 g), formamide (240 mg) and formic acid (140 mg) was
heated at 150 8C for 4 h. The mixture was allowed to cool to room temperature,
concentrated hydrochloric acid (4 ml) was added and the mixture was reuxed for
2 h. This was then allowed to cool to room temperature, diluted with water, made
basic (sodium hydroxide), extracted with dichloromethane, the organic layer
collected, dried (anhydrous magnesium sulfate) and evaporated under water
aspirator vacuum at 30 8C to give a brown oil (770 mg).
2.3. Sample analysis
2.3.1. GCMS
Samples were prepared by dissolving approximately 1 mg of each in 1 ml
methanol and analysed on an Agilent 6890N GC coupled to 5975 Mass Selective
Detector. A HP-ULTRA 1 column (12 m  0.2 mm  0.33 mm) was used with helium
carrier gas at a constant ow of 1 ml/min and a split ratio of 50:1. The injector was
set at 250 8C and the transfer line at 280 8C. The initial oven temperature was 60 8C,
held for 2 min then ramped at 258 C/min to 295 8C with a hold time of 3 min. The
mass spectra were collected after a 1.5 min solvent delay time. The ionization
energy was set at 70 eV and the mass range was m/z 40450.

3. Results and discussion

In the examination of the fourteen packages seized by Irish
Customs, it was noted that no typical adulterants or diluents were
found to be present; this suggests that the seized material came
directly from the illicit production site or that no post synthesis
adulteration of the product had taking place prior to the attempted
importation into Ireland. The white paste and the yellow liquid
from the customs importation seizure were each found to contain
amphetamine and a mixture of various compounds, including P2P,
benzyl cyanide, 4-methyl-5-phenylpyrimidine, 4-benzylpyrimidine, N-acetylamphetamine, N-formylamphetamine, di-(b-phenylisopropyl)amine isomers, 1-benzyl-3-methylnaphthalene and
1,3-dimethyl-2-phenyl-naphthalene. The white paste was similar
in prole to the components found in the yellow liquid but the byproducts were less abundant (see Fig. 2a and b). The yellow liquid
was found to contain 8% amphetamine (calculated as freebase)
while the wet white paste was found to contain 24% amphetamine
(calculated as freebase). Some of the paste was allowed to air dry

e12

J.D. Power et al. / Forensic Science International 234 (2014) e10e13

Fig. 2. (a) The chromatogram of the white paste material. (b) The chromatogram of
the yellow liquid, adjacent to the paste material. (c) The chromatogram of the
synthesis of APAAN to P2P. (d) The chromatogram of the synthesis of P2P to
amphetamine.

and the resulting powder (which now had a slight yellow colour)
was found to contain 60% amphetamine (calculated as freebase).
The counter ion was identied as sulfate.
The samples from this seizure contained synthesis by-products
(pyrimidines, dimers and naphthalenes) which were previously
reported and thought to be route specic for two different
synthesis routes to the production of amphetamine and methamphetamine, namely the Leuckart reaction of P2P to yield
amphetamine (or methamphetamine) and the Nagai synthesis, a
non-metal reduction of ephedrine using hydriodic acid/red
phosphorus to produce methamphetamine [68].
It has been reported that 1-benzyl-3-methylnaphthalene and
1,3-dimethyl-2-phenyl-naphthalene are considered route specic
for the ephedrine/hydriodic acid/red phosphorus route to methamphetamine. It is known that a by-product of the Nagai synthesis
of methamphetamine from ephedrine is 1,2 dimethyl-3-phenylaziridine, which may undergo hydrolysis to yield P2P. This P2P
could react with strong acids to yield naphthalenes [14,16]. 4Methyl-5-phenylpyrimidine, 4 benzylpyrimidine and di-(b-phenylisopropyl)amine have all been considered route specic for
amphetamine synthesis via the Leuckart reaction [6,16,20,21].
Doubt has been cast on the route specic nature of the 4-methyl-5phenylpyrimidine and 4-benzylpyrimidine for the Leuckart
synthesis as these compounds have also been detected in reductive
amination routes [9]. The presence of the di-(b-phenylisopropyl)amine isomers (dimers) have been linked to the Leuckart
synthesis of amphetamine type compounds [17,20,21].
Our laboratory Leuckart synthesis starting with P2P, made from
APAAN, yielded amphetamine that had the same characteristic
component by-products present as in the customs importation
seizure. The presence of naphthalenes suggests that P2P was
exposed to a strong acid, one plausible explanation is that they
were produced by the acidic hydrolysis of APAAN. The relative
abundances of the by-products were different which is unsurprising as it has previously been reported that the exact conditions of
the synthesis can greatly affect yields [7,17]. The conversion of
APAAN to P2P (see Fig. 2c) clearly shows the presence of 1-benzyl3-methylnaphthalene and 1,3-dimethyl-2-phenyl-naphthalene. In
the APAAN synthesis to P2P, it was the crude product (i.e. without
any distillation of the P2P) that was used in the Leuckart
Amphetamine synthesis. This reaction yielded amphetamine and
also 4-methyl-5-phenylpyrimidine, 4-benzylpyrimidine, N-formylamphetamine and di-(b-phenylisopropyl)amine dimers (see
Fig. 2d). If distillation of the P2P made from the APAAN had been
performed a considerably purer P2P would have resulted (the
naphthalenes are relatively non-volatile), thus leading to the
potential absence of naphthalenes found in the nal Leuckart
amphetamine product. This suggests that a crude P2P was used
in the synthesis of the amphetamine in the customs seizure and it
may indicate that the illicit producers simplied the clandestine
manufacturing process by removal of the distillation step.
The synthesis route from APAAN via acid hydrolysis to P2P and
its subsequent Leuckart reaction to yield amphetamine has shown
that both naphthalenes and expected Leuckart by-products are
obtained. Thus, the detection of naphthalenes in amphetamine
may no longer be considered route specic to an ephedrine based
route.
In a subsequent acidic extraction of the customs seizure the
presence of benzyl cyanide was noted (chromatogram not shown).
This was a surprising nd in a number of respects. The acid
hydrolysis of APAAN in our laboratory yielded P2P and the two
naphthalenes, along with other by-products, but no APAAN or
benzyl cyanide remained. It would be expected that benzyl cyanide
would be hydrolysed to phenylacetic acid in the presence of a
strong acid. It is possible that the APAAN used in the illicit
manufacture of the amphetamine was grossly contaminated with

J.D. Power et al. / Forensic Science International 234 (2014) e10e13

benzyl cyanide which was not fully hydrolysed. It is also possible

that the P2P may have been contaminated with benzyl cyanide
following the hydrolysis.
4. Conclusion
A customs importation case was found to contain amphetamine. Some of the impurities found along with the amphetamine
were previously reported to be route specic for both amphetamine synthesized via the Leuckart synthesis route utilizing P2P
and also for methamphetamine synthesized via the Nagai
synthesis utilizing ephedrine. Both P2P and ephedrine are known
precursors to many amphetamine type stimulants and both are
under international control. It has been demonstrated that the acid
hydrolysis of APAAN yields naphthalenes. The Leuckart conversion
of P2P from the APAAN to amphetamine yields the majority of the
other components found in the importation seizure. This APAAN
P2PLeuckart impurity prole, and specically the formation of
the naphthalenes, has implications for the determination of the
synthetic route from seized samples of amphetamine type
stimulants. The presence of naphthalenes in amphetamine
seizures is indicative of a process where P2P was exposed to
strong acid and one reasonable explanation is the synthesis of P2P
by the acidic hydrolysis of APAAN.
Acknowledgements
The authors wish to acknowledge Mr. Eoin Conway for
Photographic assistance and all Colleagues at the Forensic Science
Laboratory and at the Department of Pharmacology and Therapeutics, Trinity College Dublin, Ireland.
References
[1] J.D. Power, K. Clarke, S.D. McDermott, P. McGlynn, M. Barry, C. White, J. OBrien, P.
Kavanagh, The identication of 4-methylamphetamine and its synthesis byproducts in forensic samples, Forensic Sci. Int. 228 (10 May (13)) (2013)
115131.
[2] The recommended methods for the identication and analysis of amphetamine,
methamphetamine and their ring-substituted analogues in seized materials.
United Nations Ofce on Drugs and Crime 2006 ST/NAR/34 ISBN 92-1-148208-9.
[3] ,D.R.
, ISBN:
Christian,
0-8493-1227-2.
Forensic Investigation of Clandestine Laboratories, CRC Press, 2004

e13

[4] E. Lock, Development of a Harmonized Method for the Proling of Amphetamine.

Volume 31 of Serie Criminalistique, Universite de Lausanne, Faculte de droit, Ecole
des sciences criminelles, Institut de police scientique, 2005 ISBN 2940098352,
9782940098354.
[5] Personal communication, Amphetamine purity levels in Ireland.
[6] K. Paul Kirkbride, A. David Ward, N.F. Jenkins, G. Klass, J.C. Coumbaros, Synthesis
of 4-methyl-5-arylpyrimidines and 4-arylpyrimidines: route specic markers for
the Leuckardt preparation of amphetamine, 4-methoxyamphetamine, and 4methylthioamphetamine, Forensic Sci. Int. 115 (1 January (12)) (2001) 5367.
[7] V. Kunalan, W.J. Kerr, N. Nic Daeid, Investigation of the reaction impurities
associated with methamphetamine synthesized using the Nagai method, Anal.
Chem. 84 (2012) 57445752.
[8] Amphetamine: A European Union Perspective in the Global Context,
2011
www.emcdda.europa.eu/publications/joint-publications/amphetamine.
[9] N. Stojanovska, S. Fu, M. Tahtouh, T. Kelly, A. Beavis, K.P. Kirkbride, A review of
impurity proling and synthetic route of manufacture of methylamphetamine,
3,4-methylenedioxymethylamphetamine, amphetamine, dimethylamphetamine
and p-methoxyamphetamine, Forensic Sci. Int. (Online) 224 (1) (2013) 826.
http://dx.doi.org/10.1016/j.forsciint.2012.10.040.
[10] W. Krawczyk, T. Kunda, I. Perkowska, D. Dudek, Impurity proling/comparative
analyses of samples of 1-phenyl-2-propanone, Bull. Narc. 57 (12) (2005) 3362.
[11] Annual report on the state of the drugs problem in Europe, 2012 www.emcdda.europa.eu/publications/annual-report/2012.
[12] Problem amphetamine and methamphetamine use in Europe, 2010 www.emcdda.europa.eu/publications/selected -issues/problem-amphetamine.
[13] K.L. Windhal, M.J. McTigue, J.R. Pearson, S.J. Pratt, J.E. Rowe, E.M. Sear, Investigation of the impurities found in methamphetamine synthesized from pseudoephedrine by reduction with hydriodic acid and red phosphorus, Forensic Sci. Int.
76 (1995) 97114.
[14] Y. Qi, I. Evans, A. McCluskey, New impurity proles of recent Australian imported
ice: methamphetamine impurity proling and the identication of (pseudo)ephedrine and Leukart specic marker compounds, Forensic Sci. Int. 169 (2007)
173180.
[15] H. Inoue, Y.T. Iwata, K. Kuwayama, Characterization and proling of methamphetamine seizures, J. Health Sci. 54 (6) (2008) 615622.
[16] T.S. Cantrell, B. John, L. Johnson, A.C. Alien, A study of impurities found in
methamphetamine synthesized from ephedrine, Forensic Sci. Int. 39 (1988)
3953.
[17] V. Kunalan, N.N. Nic Daeid, W.J. Kerr, H.A.S. Buchanan, A.R. McPherson, Characterization of route specic impurities found in methamphetamine synthesized by
the Leuckart and reductive amination methods, Anal. Chem. 81 (17) (2009) 7342
7348.
[18] V. Ottaviano, C. Furnari, F. Rosati, Identication of di-(B-phenypisopropyl)amine
as the main ingredient in illicit amphetamine tablets, Ann. Ist. Super. Sanita 38 (3)
(2002) 331335.
[19] S.M. Cloonan, J.J. Keating, D. Corrigan, J.E. OBrien, P.V. Kavanagh, Synthesis and
invitro toxicity of 4-MTA, its characteristic clandestine synthesis byproducts and
related sulfur substituted alkylthioamphetamines, Bioorg. Med. Chem. 18 (2010)
40094031.
[20] A.M. Van Der Ark, M.A. Verweij, A. Sinnema, Weakly basic impurities in illicit
amphetamine, J. Forensic Sci. 23 (October (4)) (1978) 693700.
[21] H. Huizer, et al., Di-(B-phenylisopropyl)amine in illicit amphetamine, J. Forensic
Sci. 30 (April (2)) (1985) 427438.