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Article history: Australia has seen an increase in the importation and use of drugs that are marketed and sold as ‘‘Legal
Received 28 July 2011 Highs’’. These compounds have largely tended to be various cathinone analogues, with 4-
Received in revised form 17 October 2011 methylmethcathinone the most prominent to date. In January 2009, unknown samples were submitted
Accepted 19 October 2011
for analysis along with a large seizure of 3-fluoromethcathinone as part of a police operation. The samples
Available online 15 November 2011
were analysed and determined to be 3,5-difluoromethcathinone and 3,5-dichloromethcathinone. These
compounds were synthesised and characterised. The GC–MS data of the samples and their N-acetyl
Keywords:
derivatives, NMR, vapour-phase and condensed-phase IR for these previously unreported compounds are
3,5-Difluoromethcathinone
presented. This analytical data will enable laboratories to confirm the presence of these compounds in
3,5-Dichloromethcathinone
3,5-Difluoro-isomethcathinone the absence of commercially available reference standards.
Designer drug ß 2011 Elsevier Ireland Ltd. All rights reserved.
Mass spectra
IR
0379-0738/$ – see front matter ß 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.forsciint.2011.10.042
140 S. Davis et al. / Forensic Science International 217 (2012) 139–145
derivative clauses in the legislation would classify these com- Derivatisation was achieved by adding an excess of acetic anhydride to a methanol
solution of the sample. The liquid was then agitated for several minutes to allow the
pounds as dangerous drugs in this jurisdiction [8].
reaction to reach completion, before being injected (0.2 mL) into the GCMS.
It is vital that a forensic laboratory be able to positively identify Electron Impact (EI) mass spectra were obtained using an Agilent 6890N gas
these compounds for the benefit of law enforcement, the judiciary and chromatograph fitted with a 5975 inert mass selective detector. The column was a
the community at large. The absence of reference standards and HP-5 capillary column (30 m 0.25 mm 0.25 mm) with helium as the carrier gas
reference library spectra means that a forensic chemist may not be able at a constant flow of 0.9 mL min1 and a split ratio of 25:1. The injector was heated
to 280 8C and the temperature program was 100 8C for 1 min, ramped at 30 8C/min
to identify these substances through routine analytical protocols. As is until reaching a temperature of 280 8C at which the temperature remained for
often seen with new designer drugs on the market, while reference 10 min. The mass spectra were collected after a 2.5 min solvent delay using a 40–
standards may eventually become available this usually does not meet 450 m/z scan range at 3.51 scans s1.
the time constraints prevalent in a busy forensic laboratory.
While a number of mono-substituted fluorinated cathinones 2.2. Vapour phase infrared analysis
and amphetamines have already been encountered on the market, The samples were prepared as described in Section 2.1, with an injection volume
so far there has not been the same observed number of chlorinated of 4 mL.
compounds. One compound that is readily available and analogous The vapour phase infrared spectra were collected using an Agilent 7890 gas
to cathinone is the anti-depressant bupropion 7 [9]. Several chromatograph equipped with an ASAP IRD II infrared detector. The carrier gas was
helium at a constant flow of 4.1 mL min1; the column was HP-5 capillary column
different analogues of bupropion have been synthesised and
(30 m 0.32 mm 0.25 mm). The injector was set at a pulsed split of 24 psi for
examined as indirect dopamine agonists for cocaine addiction [10]. 2 min with a split ratio of 1:1 and a temperature of 280 8C. The temperature
3,5-Difluoromethcathinone and 3,5-dichloromethcathinone program was 100 8C for 2 min, ramped at 20 8C/min until reaching a temperature of
have not previously been reported in the literature. Therefore 280 8C at which the temperature remained for 8 min. The temperature of the light
this laboratory has undertaken the syntheses of reference pipe and the flow cell in the detector were both 280 8C. The spectra were obtained
from 4000 to 550 cm1.
materials to compare against the samples (Schemes 1 and 2).
The synthesis and characterisation of these compounds will enable
2.3. Condensed phase infrared analysis
the forensic chemist to meet the analytical challenges successfully.
The analytical profiles are presented. The Fourier Transform Infrared Analysis was collected using a Thermo Nicolet
5700 FTIR with a Smart Orbit Diamond Attenuated Total Reflectance (ATR)
attachment. The infrared spectrum was obtained from 4000 to 400 cm1.
2. Materials and methods
A small quantity of each powder was extracted in methanol and 0.2 mL of each Samples were run in d6-DMSO. Spectra were acquired on a Varian 400 MHz Unity
extract was injected into the GCMS. INOVA spectrometer operating at 400 MHz (1H) and 100 MHz (13C).
Scheme 1. Formation of 3,5-difluoromethcathinone hydrochloride. a. Br2, CH2Cl2, RT, 30 min, 95%; b. CH3NH2, RT, 2 h, 27%.
Scheme 2. Formation of 3,5-dichloromethcathinone hydrochloride. a. EtMgBr, THF, RT, 18 h, 64%; b. Br2, CH2Cl2, RT, 18 h, 45%; c. CH3NH2, THF, RT, 1 h, 17%.
S. Davis et al. / Forensic Science International 217 (2012) 139–145 141
Fig. 2. Electron impact mass spectrum for (a) 3,5-difluoromethcathinone (b) suspected 3,5-difluoromethcathinone (c) N-acetyl-3,5-difluoromethcathinone (d) suspected N-
acetyl-3,5-difluoromethcathinone.
142 S. Davis et al. / Forensic Science International 217 (2012) 139–145
Fig. 5. EIMS for (a) compound tentatively identified as 3,5-difluoro-isomethcathinone (b) sample containing compound tentatively identified as 3,5-difluoro-
isomethcathinone and the N-acetyl derivatives (c) and (d), respectively.
1
As 3,5-difluoromethcathinone 5 was a minor component H (400 MHz, d6-DMSO, 298 K): d 7.77 (2H, m, H20 ,60 ), 7.71 (1H,
compared to the suspected undesired structural isomer 11 in tt, J = 8.4, 2.3 Hz, H40 ), 5.21 (1H, q, J = 7.2 Hz, H2), 2.58 (3H, s, N-
the sample submitted to the laboratory, the NMR was conducted Me), 1.43 (3H, d, J = 7.2 Hz, H3).
13
on the compound synthesised ‘in-house’. While the submitted C (100 MHz, d6-DMSO, 298 K): d194.5 (C1), 162.6 (d,
1
sample of 3,5-dichloromethcathinone 6 was sufficiently clean it J = 247 Hz, C30 ,50 ), 136.1 (t, 3J = 8 Hz, C10 ), 112.1 (d, 2J = 17 Hz
was found that both 5 and 6 were unstable in protic solvents. This C20 ,60 ), 110.1 (d, 2J = 15 Hz C40 ), 58.4 (C2), 30.6 (N-Me), 15.0 (C3).
resulted in the observation of extensive degradation products in
attempts to analyse the free bases using 1H and 13C NMR 4.2.2. 3,5-Dichloromethcathinone.HCl
spectroscopy. The methcathinone derivatives were therefore In the observed 1H and 13C NMR spectra the chemical shifts
analysed as their respective hydrochloride salts. were consistent with those observed in other methcathinone
derivatives [11,16]. The aromatic region of the 1H NMR exhibits
4.2.1. 3,5-Difluoromethcathinone.HCl two resonances, a doublet (d 8.03 ppm) and triplet (d 7.97 ppm),
In the observed 1H and 13C NMR spectra the chemical shifts with integral intensities of 2:1 respectively, sharing a mutual 4JHH
were closely related to those observed for the mono-fluorinated coupling of 1.9 Hz; confirming symmetrical meta-substitution in
analogue 2 [11]. The presence of fluorine in a molecule can result in the ring.
1
splitting of the peaks in the aromatic region due to spin–spin H (400 MHz, d6-DMSO, 298 K) d 8.03 (2H, d, J = 1.9 Hz, H20 ,60 ),
coupling with both the 1H and 13C NMR. The 13C spectrum of the 7.97 (1H, t, J = 1.9 Hz, H40 ), 5.26 (1H, q, J = 7.1 Hz, H2), 2.57 (3H, s,
compound was complicated by the second order multiplicity N-Me), 1.43 (3H, d, J = 7.1 Hz, H3).
observed in the 13C resonances in the aromatic region of the 13
C (100 MHz, d6-DMSO, 298 K) d 194.6 (C1), 136.1 (C10 ), 135.1
spectrum, due to the magnetic inequivalence of the two chemically (C30 , 50 ), 133.5 (C40 ), 127.3 (C20 , 60 ), 58.2 (C2), 30.5 (N-Me), 14.9
equivalent 19F substituents. (C3).
Fig. 6. EIMS for (a) 3,5-dichloromethcathinone (b) suspected 3,5-dichloromethcathinone (c) N-acetyl-3,5-dichloromethcathinone and (d) suspected N-acetyl-3,5-
dichloromethcathinone.
144 S. Davis et al. / Forensic Science International 217 (2012) 139–145
Fig. 7. ATR-FTIR spectra for (a) 3,5-difluoromethcathinone hydrochloride (b) suspected 3,5-difluoromethcathinone hydrochloride and the compound tentatively identified as
11 (c) 3,5-dichloromethcathinone hydrochloride and (d) suspected 3,5-dichloromethcathinone hydrochloride.
4.3. Infrared spectroscopy differences could be observed in the condensed phase infrared
spectra between the submitted and synthesised samples (Fig. 7).
Infrared analysis provides a rapid identification for organic The ability to separate the compounds via GCIRD, however,
compounds due to their unique infrared spectra [20]. Both enabled the vapour phase infrared spectra of these samples
condensed and vapour phase infrared spectra have been shown to be compared (Fig. 8). From this it can be demonstrated
to distinguish between the isomers of various methcathinone that the vapour phase infrared spectra between the two
analogues and it is also known to be an alternative to derivatisation compounds displays a high level of congruency. Both the
when this technique is unsuitable [12,16,21,22]. vapour phase (Fig. 8) and the condensed phase infrared spectra
As the submitted sample of the 3,5-difluoromethcathinone (Fig. 7) for 3,5-dichloromethcathinone shows they are in strong
contained an impurity suspected to be compound 11, clear agreement.
Fig. 8. Vapour phase infrared spectra for (a) 3,5-difluoromethcathinone, (b) suspected 3,5-difluoromethcathinone, (c) 3,5-dichloromethcathinone and (d) suspected 3,5-
dichloromethcathinone.
S. Davis et al. / Forensic Science International 217 (2012) 139–145 145
5. Conclusions [6] S.D. Brandt, S. Freeman, H.R. Sumnall, F. Measham, J. Cole, Analysis of NRG ‘legal
highs’ in the UK: identification and formation of novel cathinones, Drug Test Anal.
(2010), doi:10.1002/dta.204.
This study provides the synthesis and structural elucidation of [7] F. Westphal, T. Junge, B. Klein, G. Fritschi, U. Girreser, Spectroscopic characteriza-
the cathinone analogues 3,5-difluoromethcathinone 5 and 3,5- tion of 3,4-methylenedioxypyrrolidinobutyrophenone: a new designer drug with
a-pyrrolidinophenone structure, Forensic Sci. Int. (2011), doi:10.1016/j.forsciint.
dichloromethcathinone 6, which have not previously been 2011.01.016.
reported in the literature. As the ‘Legal High’ market evolves it [8] Queensland Drugs Misuse Act 1986, Reprinted as in force on 1 November 2010,
is likely that we will continue to see a greater number of variations http://legislation.govnet.qld.gov.au/LEGISLTN/CURRENT/D/DrugsMisuseA86.pdf.
[9] P.N. Friel, B.K. Logan, C.L. Fligner, Three fatal drug overdoses involving bupropion,
made to existing illicit drugs. It can be determined from the data J. Anal. Toxicol. 17 (1993) 436–438.
that the submitted samples were 3,5-difluoromethcathinone and [10] F.I. Carroll, B.E. Blough, P. Abraham, A.C. Mills, J.A. Hollerman, S.A. Wockenhauer,
3,5-dichloromethcathinone. We present the MS data for these A.M. Decker, A. Landavazo, K.T. McElroy, H.A. Navarro, M.B. Gatch, M.J. Forster,
Synthesis and biological evaluation of bupropion analogues as potential phar-
compounds and their N-acetyl derivatives. We have also provided
macotherapies for cocaine addiction, J. Med. Chem. 52 (2009) 6768–6781.
the 1H and 13C data, and both vapour and condensed phase IR [11] R.P. Archer, Fluoromethcathinone, a new substance of abuse, Forensic Sci. Int. 185
spectra. These analytical results will enable the rapid identification (2010) 10–20.
of these compounds if encountered by other forensic laboratories [12] F.I. Carroll, B. Blough, P. Abraham, PCT Int. Appl., WO2010121022, 2010.
[13] T. Awad, C.R. Clark, J. DeRuiter, Chromatographic and mass spectral studies on
or law enforcement agencies. We have also presented the tentative methoxymethcathinones related to 3,4-methylenedioxymethamphetamine, J.
identification of an isomeric by-product, which may act as a Chromatogr. Sci. 44 (2006) 155–161.
marker for similar halogenated cathinone analogues. [14] A. Camilleri, M.R. Johnston, M. Brennan, S. Davis, D.G.E. Caldicott, Chemical
analysis of four capsules containing the controlled substance analogues 4-
methylmethcathinone, 2-fluoromethamphetamine, a-phthalimidopropiophe-
Acknowledgments none and N-ethylcathinone, Forensic Sci. Int. 197 (2010) 59–66.
[15] T. Belal, T. Awad, J. DeRuiter, C.R. Clark, GC–MS studies on acylated derivatives of
3-methoxy-4-methyl and 4-methoxy-3-methyl-phenethylamines: regioisomers
The authors would like to acknowledge the support provided by related to 3,4-MDMA, Forensic Sci. Int. 178 (2008) 61–82.
the Clinical and Statewide Services (CASS) research committee and [16] T. Dal Cason, The characterisation of some 3,4-methylenedioxycathinone
(MDCATH) homologs, Forensic Sci. Int. 87 (1997) 9–53.
funding from the QHFSS Cabinet Research and Development Fund [17] P. Rosner, B. Quenow, U. Girreser, T. Junge, Isomeric fluoro-phenylalkylamines: a
for this study. new series of controlled-substance analogues (designer drugs), Forensic Sci. Int.
148 (2005) 143–156.
[18] S. Davies, M. Puchnarewicz, J. Button, P.I. Dargan, D.M. Wood, R. Archer, J. Ramsey,
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