Analysis of amphetamine-type substances and piperazine analogues using desorption electrospray ionisation mass spectrometry

Article abstract of DOI:10.1002/rcm.6832

RATIONALE: Although amphetamine-type substances (ATS) have been investigated extensively in recent years, scarce data is available on screening tests for piperazine analogues. The need for a universal technique capable of detecting an extensive range of drug compounds becomes increasingly important with the continued emergence of novel drug analogues. METHODS: Desorption electrospray ionisation mass spectrometry (DESI-MS) is a technique that allows examination of compounds in drug materials directly from ambient surfaces. In this study, DESI-MS was utilised in the analysis of ATS including amphetamine (AP), methylamphetamine (MA), 3,4-methylenedioxymethylamphetamine (MDMA), N,N-dimethylamphetamine (DMA), 4-methoxyamphetamine (PMA) and 4-methoxymethylamphetamine (PMMA), and piperazine analogues including 1-benzylpiperazine (BZP), 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP), 1-(3-chlorophenyl)piperazine (mCPP) and 1-(4-methoxyphenyl)piperazine (MeOPP). Semi-porous polytetrafluoroethylene (PTFE or Teflon) sheets welled with a 3 mm hole punch were used to contain the 2 μL liquid sample (spot size 7 mm ²). RESULTS: The limits of detection (LODs) of these compounds using DESI-MS were determined to be in the range 0.02-2.80 μg/mm². The intra-day and inter-day precision of the technique were <25% and <33%, respectively. DESI-MS was successful in determining the compound of interest and reaction by-products and impurities in the samples tested (such as 1,4-dibenzylpiperazine in BZP samples) with the exception of those present in trace amounts. The effects of common adulterants on the detectability of MA were evaluated. The addition of magnesium stearate to MA significantly enhanced the signal response. CONCLUSIONS: This work has demonstrated the applicability of DESI-MS in the screening and profiling of MDMA, PMMA, BZP, TFMPP, mCPP, MeOPP as well as other complex mixtures. Copyright

Full text of DOI:10.1002/rcm.6832

Research Article
Received: 9 November 2013
Revised: 8 January 2014
Accepted: 9 January 2014
Published online in Wiley Online Library
Rapid Commun. Mass Spectrom. 2014, 28, 731–740
(wileyonlinelibrary.com) DOI: 10.1002/rcm.6832
Analysis of amphetamine-type substances and piperazine
analogues using desorption electrospray ionisation mass
spectrometry
Natasha Stojanovska1, Tamsin Kelly2, Mark Tahtouh3, Alison Beavis1 and Shanlin Fu1
*
1Centre for Forensic Science, University of Technology, Sydney (UTS), PO Box 123, Broadway, NSW 2007, Australia
2National Centre for Forensic Studies, Faculty of Education, Science, Technology and Mathematics (ESTeM), University of
Canberra, ACT 2601, Australia
3Australian Federal Police, 110 Goulburn St, Sydney, NSW 2000, Australia
RATIONALE: Although amphetamine-type substances (ATS) have been investigated extensively in recent years, scarce data
is available on screening tests for piperazine analogues. The need for a universal technique capable of detecting an extensive
range of drug compounds becomes increasingly important with the continued emergence of novel drug analogues.
METHODS: Desorption electrospray ionisation mass spectrometry (DESI-MS) is a technique that allows examination
of compounds in drug materials directly from ambient surfaces. In this study, DESI-MS was utilised in the analysis
of ATS including amphetamine (AP), methylamphetamine (MA), 3,4-methylenedioxymethylamphetamine (MDMA),
N,N-dimethylamphetamine (DMA), 4-methoxyamphetamine (PMA) and 4-methoxymethylamphetamine (PMMA), and
piperazine analogues including 1-benzylpiperazine (BZP), 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP), 1-(3-
chlorophenyl)piperazine (mCPP) and 1-(4-methoxyphenyl)piperazine (MeOPP). Semi-porous polytetrafluoroethylene
(PTFE or Teflon) sheets welled with a 3 mm hole punch were used to contain the 2 μL liquid sample (spot size 7 mm2).
RESULTS: The limits of detection (LODs) of these compounds using DESI-MS were determined to be in the range
0.02–2.80 μg/mm2. The intra-day and inter-day precision of the technique were <25% and <33%, respectively. DESI-MS
was successful in determining the compound of interest and reaction by-products and impurities in the samples tested
(such as 1,4-dibenzylpiperazine in BZP samples) with the exception of those present in trace amounts. The effects of
common adulterants on the detectability of MA were evaluated. The addition of magnesium stearate to MA significantly
enhanced the signal response.
CONCLUSIONS: This work has demonstrated the applicability of DESI-MS in the screening and profiling of MDMA,
PMMA, BZP, TFMPP, mCPP, MeOPP as well as other complex mixtures. Copyright © 2014 John Wiley & Sons, Ltd.
The recreational use of illicit drugs has been apparent for many
years. The amphetamine-type substances (ATS) are particularly
popular drugs of abuse.[1,2] According to the United Nations
Office on Drugs and Crime (UNODC), ATS are still firmly
established on the global illicit drug market.[1] In Australia,
ATS are the second most commonly used illicit drugs, after
cannabis. In East and South-East Asia, as well as in the Middle
East, consumption of ATS, particularly methylamphetamine
(MA), is increasing.[3] Piperazine drugs are another group of
compounds of high prevalence. 1-Benzylpiperazine (BZP) and
related active ingredients of some recently encountered ’party
piperazines became known as drugs of abuse in the UK in early
2008. Fatal cases where BZP has been detected have been
reported and typically involve other drugs; however, toxicity
involving BZP alone has also been reported.[5] Piperazine
analogues may be trafficked easily since current screening
techniques lack the selectivity and specificity required for their
detection. Although ATS have been investigated extensively in
recent years, scarce data is available on the screening test of
piperazine analogues. The need for a universal technique
capable of detecting an extensive range of drug compounds
has become increasingly important with the continued
emergence of novel drug analogues.
pills’,
such
as
1-[3-(trifluoromethyl)phenyl]piperazine
(TFMPP), 1-(4-methoxyphenyl)piperazine (MeOPP), 1-(3-
chlorophenyl)piperazine (mCPP) and 1-(3-fluorophenyl)
piperazine (FPP), are used extensively as recreational drugs
globally despite their prohibition in several countries.[4] These
Traditional colour tests with specific reagents are still
predominately used as a first step for screening of suspected
seizures.[6] Other techniques include Fourier transform infrared
(FTIR) spectroscopy, Raman spectroscopy, ion mobility mass
spectrometry, and ultraviolet (UV)-visible absorption
spectroscopy.[7] Raman and FTIR spectroscopy and ion mobi-
lity mass spectrometry have the ability to provide high-
throughput analysis without the need for prior sample
preparation. These techniques provide useful, however
somewhat limited, information on the chemical composition
* Correspondence to: S. Fu, Centre for Forensic Science,
University of Technology, Sydney (UTS), PO Box 123,
Broadway, NSW 2007, Australia.
E-mail: shanlin.fu@uts.edu.au
Rapid Commun. Mass Spectrom. 2014, 28, 731–740
Copyright © 2014 John Wiley & Sons, Ltd.

N. Stojanovska et al.
of drug materials in a non-destructive fashion as they are best
suited for the analysis of uncut or pure samples.[7–9] In the past,
by-product/impurity profiling of synthetic drugs has mainly
utilised gas chromatography (GC), with a range of detectors
including flame ionisation and mass spectrometers.[10] For gas
chromatography/mass spectrometry (GC/MS), large spectral
libraries have been developed, making the method suitable
for the analysis of unknown samples. Alternative methods such
as liquid chromatography (LC), coupled to an ultraviolet-diode
array detector (UV-DAD) or MS, have also been applied.[9,11–15]
Desorption electrospray ionisation mass spectrometry (DESI-
MS) is an atmospheric pressure ionisation (API) technique that
has gained popularity as a fast screening technique in many
applications including illicit drugs, explosives, chemical
warfare agents, inks/documents, fingermarks, gunshot resi-
dues, and drugs in urine and plasma.[8,14,16–23] DESI allows
MS to be used for the on-line high-throughput monitoring of
drug samples in the ambient environment, without prior
sample preparation.[8] The electrohydrodynamically nebulised
solution is directed onto a surface bearing the sample. Analytes
present on the sample exterior are ionised and transported
from the ambient pressure conditions into a standard
atmospheric pressure interface for mass analysis. The
interface of DESI with the MS detector allows for the
identification of charged species, providing molecular mass
MA, USA) at a flow rate of 0.21 mL/h. The DESI operating
parameters were optimised as follows: operating at room
temperature (22°C); incident angle, 55°; tip-to-surface distance,
3 mm; tip-to-sample distance, 5 mm; sniffer angle-to-surface,
15°; and desorption time, 1 min/sample spot. The MS operating
parameters were as follows: positive electrospray ionisation
with spray high voltage on the capillary tip, 4 kV; nitrogen
gas pressure, 100 psi; fragmentor voltage, 175 V. Experiments
in full scan mode were operated in the range of m/z 50–500.
Tandem mass spectrometry (MS/MS) experiments were
conducted in the targeted product ion scan mode with a
collision energy of 20 eV and the protonated molecule of an
analyte as the precursor ion. Samples were dissolved in
methanol at varying concentrations and 2 μL of liquid was
deposited onto the PTFE sample stage. Analyte identity was
supported by MS/MS experiments. Samples were dissolved
in methanol (10 mg/mL) unless otherwise specified. Data
analysis was conducted using Agilent MassHunter Works-
tation Software (Qualitative Analysis, version B.03.01).
GC/MS was performed on a 7890A gas chromatograph
coupled to a 5975C electron ionisation (EI) quadrupole mass
spectrometer (Agilent Technologies). The column used was an
Agilent HP-5MS (30 m × 0.25 mm i.d. × 0.25 μm). GC/MS was
conducted in full scan mode (m/z 50–500). The GC conditions
were optimised as follows: injector temperature, 250°C; oven
temperature program, 100°C (hold 1 min), 30°C/min to 300°C
(hold 3 min). The samples were dissolved in methanol
(1 mg/mL). Injection was performed in splitless mode and
the injection volume was 2 μL. The fragment ion peaks reported
are at greater than 10% abundance relative to the base peak.
1H and 13C nuclear magnetic resonance (NMR) spectra were
recorded on a DRX NMR spectrometer (Bruker, Billerica, MA,
USA) operating at 300.13 MHz and 75.48 MHz, respectively,
or on a 500/54 Premium Shielded NMR spectrometer with
7510-AS (Agilent Technologies), operating at 500 MHz and
125 MHz, respectively. Spectra were calibrated using residual
protic solvent, which included methanol and chloroform.
1H NMR was conducted using 16 scans and 13C NMR was
conducted using 512 scans. Infrared spectra were recorded
using a Nicolet Magna IR-760 spectrometer (Thermo Nicolet,
Madison, WI, USA) with the sample incorporated into KBr
and spectra collected in transmittance mode (resolution
4 cm–1, 16 scans).
and structural information, and thus offers
a rapid
qualitative screening tool for drug analysis.[24–26]
In this study, the DESI-MS method was applied to the
screening of ATS such as amphetamine (AP), methylamphe-
tamine (MA), 3,4-methylenedioxymethylamphetamine (MDMA),
N,N-dimethylamphetamine (DMA), 4-methoxyamphetamine
(PMA) and 4-methoxymethylamphetamine (PMMA), and fur-
ther expanded to demonstrate its applicability to piperazine
analogues such as BZP, TFMPP, mCPP and MeOPP. The
DESI-MS method also aimed to identify any reaction by-
products, impurities or adulterants that may be present, discri-
minating them from other batches and aiding in rapid chemical
profiling of samples.
EXPERIMENTAL
Semi-porous polytetrafluoroethylene (PTFE or Teflon) sheets,
acquired from the Plastix Centre (Arncliffe, NSW, Australia),
were cut to the desired size. These plates were welled with a
3 mm hole punch to contain the 2 μL liquid sample (spot size
7 mm2). AP, MA, MDMA, DMA and PMA standards were
obtained from the National Measurement Institute (NMI,
North Ryde, NSW, Australia). A seized MDMA tablet was
obtained from the Australian Federal Police (AFP, Sydney,
NSW, Australia). MDMA base and PMMA base were
synthesised via reductive amination of piperonal and anethole,
respectively.[27] Methanol (HPLC grade), formic acid (analytical
reagent grade) and potassium bromide (KBr) were purchased
from Sigma Aldrich (Castle Hill, NSW, Australia).
1-Benzylpiperazine was synthesised in four separate
batches (BZP 1–BZP 4, Fig. 1). The first three batches followed
a common synthetic pathway as described by Cymerman and
Young.[28] In the synthesis of BZP 1, 0.025 mole of piperazine
hexahydrate, 0.025 mole of piperazine dihydrochloride
monohydrate and 0.025 mole of benzyl chloride were used.
A commercially available DESI interface was purchased from
Prosolia™, Inc. (Indianapolis, IN, USA). This DESI source was
coupled to a 6500 Series accurate mass quadrupole time-of-
flight (QTOF) mass spectrometer (Agilent Technologies, Forest
Hill, VIC, Australia). The desorption solvent was a mixture of
methanol/water 1:1 (v/v) with 1% formic acid and was
delivered by a syringe pump (Harvard Apparatus, Holliston,
Figure 1. Structures of synthesised piperazine analogues.
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Copyright © 2014 John Wiley & Sons, Ltd.
Rapid Commun. Mass Spectrom. 2014, 28, 731–740

DESI-MS for analysis of amphetamines and piperazines
Figure 2. Effect of different adulterants on the detection of methylam-
phetamine, 1:1 of methylamphetamine to adulterant, n = 4.
Crude BZP 1.base yielded 4.34 g (98 %) with melting point
130.12 (h), 130.55 (j), 131.54 (k), 132.54 (i), 134.04 (g), 145.68 (e).
IR νmax (cm-1): 3087 (NH stretching), 3063 (CH aromatic
stretching), 2922 and 2873 (CH aliphatic stretching), 1605 (NH
bending), 1524 and 1496 (C=C aromatic), 1433 (CH bending),
1323 (CN), 1299 and 1134 (C-F stretching). TFMPP.HCl: EI:
m/z 230 (M+, 26 %), 188 (100), 172 (15), 145 (17), 56 (15). TFMPP
2-TFMPP 4 provided comparable characteristic data.
mCPP 1 was synthesised via the method reported for
TFMPP 4, where the starting material 3-(trifluoromethyl)
aniline was replaced with 6.35 g of 3-chloroaniline. mCPP 1
yielded 2.30 g (92%) of the HCl salt with melting point
214–217°C (literature value 210–214°C[32]). mCPP 1.base:
1H NMR (500 MHz, CDCl3): δppm 1.22 (1H, s, Hd), 2.98
(4H, s, Hc), 3.13 (4H, s, Hb), 6.76 - 7.18 (4H, Ar, Hf-j).
13C NMR (125 MHz, CDCl3): δppm 45.49 (c), 49.50 (b), 113.84
(k), 115.63 (h) 119.20 (j), 129.20 (i), 134.67 (g), 152.51 (e). IR νmax
(cm-1): 3100 (NH stretching), 3050 (CH aromatic stretching),
2909 (CH aliphatic stretching), 1595 (NH bending), 1568 and
253°C (literature value 253°C[29]). No attempts were made to
purify the synthesised samples since it was beneficial to
chemically profile any potential by-products or impurities
present. In the synthesis of BZP 2, 0.017 mole of benzyl chloride
was used. Crude BZP 2.HCl yielded 2.74 g (92%) with melting
point 245°C. In the synthesis of BZP 3, 0.039 mole of benzyl
chloride and 0.013 mole of piperazine were used. Crude BZP
3.HCl yielded 2.08 g (91%) with melting point 230°C. BZP 4
was synthesised via the published method by Baltzly et al.[29]
Crude BZP 4.HCl yielded 0.81 g (58%) with melting point
260°C.
1
BZP 1.base: H NMR (300 MHz, CDCl3): δppm 1.52 (1H, s,
Hd), 2.31 - 2.51 (4H, broad t, Hc), 2.85 (4H, t, J = 4.8 Hz, Hb),
3.49 (2H, s, He), 7.26 (5H, Ar, Hg-i). 13C NMR (75 MHz, CDCl3):
δppm 46.12 (c), 54.54 (b), 63.68 (e), 126.94 (i), 128.13 (h), 129.17
(g), 138.10 (f). IR νmax (cm-1): 3241 (NH stretching), 3128 (CH
aromatic stretching), 2993 and 2759 (CH aliphatic stretching),
1631 (NH bending), 1557 and 1443 (C=C aromatic), 1421 (CH
bending), 1063 (CN). BZP 1.HCl: EI: m/z 176 (M+, 16 %), 134
(60), 91 (100), 85 (10), 65 (14), 56 (23). BZP 2 – BZP 4 provided
comparable characteristic data.
Table 1. Limits of detection (LODs) of amphetamine-type
substances and piperazine analogues (n = 3)
TFMPP was synthesised in four batches (TFMPP 1–TFMPP 4).
The first three batches followed a common synthetic pathway
as described by Cymerman and Young.[28] In the synthesis of
TFMPP 1, 0.020 mole of piperazine hexahydrate and 0.010 mole
of 3-chlorobenzotrifluoride were heated under reflux at 135°C.
TFMPP 1.base yielded 1.12 g (49%). In the synthesis of TFMPP
2, the temperature was increased from 135°C to 140°C. TFMPP
2.base yielded 1.27 g (55%). In the synthesis of TFMPP 3, the
reaction temperature was kept at 135°C; however, the reaction
time was increased from 36 to 72 h. TFMPP 3.base yielded
1.11 g (48%).
LODb
Samplea
(μg/mm2)
MA
AP
0.02
0.02
0.02
0.24
0.26
0.44
2.00
2.30
2.80
DMA
PMA
TFMPP
MeOPP
BZP
mCPP
MDMA
TFMPP 4 was synthesised via the method reported by Liu
and Robichaud.[30] Bis(2-chloroethyl)amine (50 mmol) and
3-(trifluoromethyl)aniline (50 mmol) were used in the reaction
to form the product TFMPP, yielding 3.80 g (42%) in base form
and 2.00 g (95%) in HCl salt form with melting point 238°C
(literature value 240°C[31]).
aMA = methylamphetamine, AP= amphetamine, DMA= N,
N-dimethylamphetamine, PMA= 4-methoxyamphetamine,
TFMPP = 1-[3-(trifluoromethyl)phenyl]piperazine, MeOPP
= 1-(4-methoxyphenyl)piperazine, BZP = 1-benzylpiperazine,
mCPP = 1-(3-chlorophenyl)piperazine, MDMA = 3,4-methyl-
enedioxymethylamphetamine.
TFMPP 1.base: 1H NMR (500 MHz, CDCl3): δppm 1.58 (1H, s,
Hd), 2.86 (4H, s, Hc), 3.48 (4H, s, Hb), 7.27 - 7.62 (4H, Ar, Hf-j). 13
C
bApplication of 2 μL sample on a sample well size 7 mm2.
NMR (125 MHz, CDCl3): δppm 46.87 (c), 50.69 (b), 109.97 (f),
Rapid Commun. Mass Spectrom. 2014, 28, 731–740
Copyright © 2014 John Wiley & Sons, Ltd.
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N. Stojanovska et al.
1487 (C=C aromatic), 1399 (CH bending), 1256 (CN), 750
(Cl). mCPP 1.HCl: EI: m/z 196 (M+, 30 %), 154 (100), 138
(13), 111 (12), 56 (17).
Adulteration was used as a means to establish the robustness
and specificity of the technique. The compounds used to
adulterate MA were magnesium stearate, paracetamol
(acetaminophen), caffeine and dimethyl sulfone, as these are
some of the most prevalent adulterants in ATS preparations.
MeOPP 1 was synthesised via the method reported for
TFMPP 4, where the starting material 3-(trifluoromethyl)
aniline was replaced with 6.15 g of 4-anisidine. MeOPP 1
yielded 2.20 g (89%) of the HCl salt with melting point
1
220°C (literature value 261–262°C[33]). MeOPP.base: H NMR
RESULTS AND DISCUSSION
(500 MHz, CDCl3): δppm 1.67 (1H, s, Hd), 3.04 (4H, s, Hc),
3.48 (4H, s, Hb), 3.77 (3H, s Hk), 6.84 – 6.92 (4H, Ar, Hf-J).
13C NMR (125 MHz, CDCl3): δppm 48.13 (c), 52.72 (b), 57.54
(k), 116.41 (f, j), 120.20 (g, i), 148.17 (e), 155.87 (h). IR νmax
(cm-1): 3379 (NH stretching), 3000 (CH aromatic stretching),
2936 (CH aliphatic stretching), 1646 (NH bending), 1601 and
1515(C=C aromatic), 1467 (CH bending), 1027 (CN), 1250
(CO). MeOPP.HCl: EI: m/z 192 (M+, 62 %), 150 (100), 135 (25),
120 (28), 56 (21).
The effect of common adulterants on the detectability of MA
was evaluated. It was found that the addition of magnesium
stearate to a MA sample significantly enhanced the signal
response of the protonated molecule [M+H]+ (p <0.05)
(Fig. 2). This was thought to be due to the hydrophobic
properties of magnesium stearate itself aiding in the
initial wetting of the surface and subsequent splashing
of the secondary droplets carrying the more hydrophilic
Figure 3. Structures of protonated molecules and the possible product ions for
amphetamine-type substances and piperazine analogues (see Table 2 for corresponding ions).
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Rapid Commun. Mass Spectrom. 2014, 28, 731–740

DESI-MS for analysis of amphetamines and piperazines
components, i.e. the MA ions. On the contrary, parace-
tamol, caffeine and dimethyl sulfone did not result in
significant enhancement effects.
(MDP-2-POH), 3,4-methylenedioxydimethylamphetamine
(MDDMA), and 3,4-methylenedioxyphenyl-2-propanone
(MDP-2-P). Using DESI-MS, MDMA was detected as the
protonated molecule at m/z 194. The impurities MDP-2-POH
and MDDMA were detected with [M+H]+ ions at m/z 181 and
208 (in trace amounts), respectively. The presence of MDMA and
the by-products/impurities was supported by their MS/MS
spectra (Fig. 3 and Table 2). The third impurity MDP-2-P remained
undetected due to its low concentration. The identification of
these compounds supports the route of manufacture utilised,
i.e. reductive amination of MDP-2-P to MDMA.
The synthesised MDMA base was analysed using DESI-MS
and was found to contain MDMA, present as the protonated
molecule at m/z 194. One major by-product of reaction with its
[M+H]+ ion at m/z 179 was determined to be MDP-2-P.
Piperonylnitrile was also identified in the MDMA sample with
its [M+H]+ ion at m/z 148. The presence of this by-product
indicates that MDMA was synthesised via MDP-2-P using
piperonal as the main starting material, consistent with the
method utilised.[35] The DESI-MS analysis of MDMA base,
conducted in under 1 min, including the identification of
impurities, demonstrates the rapid nature of this technique and
the ability to give an indication of synthetic methods utilised.
The limits of detection (LODs) of the ATS and piperazine
analogues were determined based on the amount of
background noise present (average signal response from the
solvent blank plus 3 standard deviations[34]). The absolute
amount of sample spotted onto the plate varied depending
on the concentrations tested (2 μL spot). The final LOD
concentrations (μg/mm2) are presented in Table 1 as a
concentration relative to the spot size being sampled. The
intra-day and inter-day precision (n = 3 and n = 15, i.e. n = 3
on 5 consecutive days, respectively) of the technique were
found to be <25% and <33% relative standard deviation
(RSD), respectively, suggesting that limited quantitative
information is obtainable using the DESI-MS technique
(accuracy within 10%).
Amphetamine-type substances (ATS)
Prior to DESI-MS analysis, the seized MDMA tablet was analysed
by the NMI and found to contain 25.7% MDMA as the HCl salt
and three impurities: 3,4-methylenedioxyphenyl-2-propanol
Figure 3. Continued
Rapid Commun. Mass Spectrom. 2014, 28, 731–740
Copyright © 2014 John Wiley & Sons, Ltd.
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N. Stojanovska et al.
Table 2. Mass accuracy of MS/MS ions in positive ion mode with collision energy of 20 eV
Ion
Predicted mass
Measured
mass (m/z)
Mass
difference (ppm)
Compounda
Chemical formula
structureb
(m/z)
MDMA
C11H16NO2 ([M+H]+)
C10H11O2
(1)
194.1181
163.0759
135.0446
105.0340
181.0865
163.0759
135.0446
119.0497
91.0548
208.1338
163.0759
135.0446
121.0290
105.0340
179.0708
149.0603
135.0446
121.0290
107.0497
91.0548
194.1186
163.0771
135.0458
105.0348
181.0871
163.0760
135.0437
119.0508
91.0546
208.1329
163.0767
135.0433
121.0282
105.0348
179.0712
149.0588
135.0449
121.0288
107.0491
91.0540
2.6
7.4
(2)
C8H7O2
(3)
8.9
C7H5O
(4)
7.6
MDP-2-POH
MDDMA
C10H13O3 ([M+H]+)
C10H11O2
(5)
3.3
(2)
0.6
C8H7O2
(3)
À6.7
C8H7O
(6)
9.2
C7H7
(7)
1.2
C12H18NO2 ([M+H]+)
C10H11O2
(8)
À4.3
(2)
4.9
C8H7O2
(3)
À9.6
À6.6
7.6
C7H5O2
(9)
C7H5O
(4)
MDP-2-P
C10H11O3 ([M+H]+)
C9H9O2
(10)
(11)
(3)
2.2
À10
C8H7O2
2.2
C7H5O2
(9)
(12)
(7)
(13)
(9)
(14)
(15)
(16)
(17)
(18)
(7)
À1.7
À5.6
À8.8
3.4
C7H7O
C7H7
piperonylnitrile
PMMA
C8H6NO2 ([M+H]+)
C7H5O2
148.0399
121.0290
93.0340
148.0394
121.0284
93.0340
À5.0
C6H5O
0.0
C4H4N
66.0344
66.0341
À4.5
À2.8
9.4
C11H18NO ([M+H]+)
C10H13O
180.1388
149.0966
121.0653
91.0548
180.1383
149.0980
121.0662
91.0539
C8H9O
7.4
C7H7
À9.9
BZP
C11H17N2 ([M+H]+)
C9H12N
(20)
(21)
(22)
(23)
(19)
(20)
(21)
(22)
(23)
(24)
(20)
(23)
(25)
(20)
(23)
(26)
(23)
(27)
(28)
(29)
(30)
(31)
(32)
(33)
(34, 35)
(36)
(37)
(34, 35)
(36)
(38)
(39)
(40)
177.1392
134.0970
120.0813
91.0548
267.1861
177.1392
134.0970
120.0813
91.0548
235.1447
177.1392
91.0548
249.1603
177.1392
91.0548
177.1396
134.0973
120.0819
91.0542
267.1858
177.1383
134.0975
120.0818
91.0551
235.1436
177.1384
91.0549
249.1597
177.1394
91.0539
2.3
2.2
C8H N
5.0
10
C7H
À6.6
À1.1
À5.1
3.7
7
DBZP
C18H23N2 ([M+H]+)
C11H17N2
C9H12N
C8H10N
4.2
3.3
C7H
7
MBCP
EBCP
C13H19N2O2 ([M+H]+)
C11H17N2
À4.7
À4.5
1.1
C7H7
C14H21N2O2 ([M+H]+)
C11H17N2
À2.4
1.1
C7H7
À9.9
3.1
benzyl chloride
TFMPP
C7H8Cl ([M+H]+)
C7H7
127.0315
91.0548
127.0319
91.0542
À6.6
C11H14F3N2 ([M+H]+)
C9H9F3N
231.1109
188.0687
174.0531
111.0046
163.0371
143.0308
123.0246
93.0141
231.1111
188.0670
174.0532
111.0053
163.0378
143.0317
123.0248
93.0136
0.9
À9.0
0.6
C8H7F3N
C6HF2
6.3
TFMP
C7H6F3O ([M+H]+)
C7H5F2O
4.3
6.3
C7H4FO
1.6
C6H2F
À5.4
À8.2
À2.5
9.7
C6H
73.0078
73.0072
3-(trifluoromethyl)-aniline
C7H7NF3 ([M+H]+)
C6H2F
162.0531
93.0141
162.0527
93.0150
C6H
73.0078
73.0081
4.1
piperazine
C4H11N2 ([M+H]+)
C4H8N
87.0922
87.0923
1.1
70.0657
70.0657
0.0
C3H6N
56.0500
56.0503
5.4
(Continues)
wileyonlinelibrary.com/journal/rcm
Copyright © 2014 John Wiley & Sons, Ltd.
Rapid Commun. Mass Spectrom. 2014, 28, 731–740

DESI-MS for analysis of amphetamines and piperazines
Table 2. (Continued)
Ion
Predicted mass
Measured
mass (m/z)
Mass
difference (ppm)
Compounda
Chemical formula
structureb
(m/z)
mCPP
C10H14ClN2 ([M+H]+)
C8H9ClN
(41)
(42)
(43)
(44)
(45)
(46)
(47)
(48)
(49)
(50)
(44)
(51)
(52)
(53)
197.0846
154.0424
140.0267
118.0657
128.0267
111.0002
92.0500
193.1341
176.1075
150.0919
118.0657
124.0762
109.0528
93.0340
197.0847
154.0429
140.0262
118.0650
128.0270
110.9998
92.0491
193.1340
176.1084
150.0926
118.0660
124.0759
109.0532
93.0337
0.5
3.2
À3.6
À5.9
2.3
À3.6
À9.8
À0.5
5.1
C7H7ClN
C8H8N
3-chloroaniline
MeOPP
C6H7NCl ([M+H]+)
C6H4Cl
C6H6N
C11H17N2O ([M+H]+)
C11H14NO
C9H12NO
4.7
2.5
C8H8N
4-anisidine
C7H10NO ([M+H]+)
C6H7NO
À2.4
3.7
C6H5O
À3.2
aMDMA = 3,4-methylenedioxymethylamphetamine, MDP-2-POH=3,4-methylenedioxyphenyl-2-propanol, MDDMA=3,4-methy-
lenedioxydimethylamphetamine, MDP-2-P = 3,4-methylenedioxyphenyl-2-propanone, PMMA = 4-methoxymethylamphetamine,
BZP = 1-benzylpiperazine, DBZP = 1,4-dibenzylpiperazine, MBCP = methyl 1-benzyl-4-carboxypiperazine, EBCP = ethyl 1-benzyl-4-
carboxypiperazine, TFMPP = 1-[3-(trifluoromethyl)phenyl]piperazine, TFMP = 3-trifluoromethylphenol, mCPP = 1-(3-
chlorophenyl)piperazine, MeOPP = 1-(4-methoxyphenyl)piperazine.
bNumber corresponds to the structure of the ions in Fig. 3.
The synthesised PMMA base was also analysed using DESI-
MS. PMMA was detected as the protonated molecule at m/z 180
and supported by MS/MS spectra. A possible by-product with
its [M+H]+ ion at m/z 149 could correspond to anethole.
However, due to its presence in trace amounts, MS/MS spectra
could not be obtained and the presence of this by-product could
not be confirmed. In the synthesis, peracid oxidation was
utilised in the conversion of anethole, originating from star
anise (the starting material used in this synthesis), into the
BZP 4 was synthesised via a different reaction pathway. The
product BZP was detected with its [M+H]+ ion at m/z 177 and
further supported by MS/MS. In addition, four other com-
pounds were detected. DBZP (trace amounts) and benzyl
chloride were detected with protonated molecules at m/z 267
and 127, respectively. The intermediate was detected as a
protonated molecule at m/z 249 and further supported by
MS/MS as being ethyl 1-benzyl-4-carboxypiperazine (EBCP).
Another by-product with its [M+H]+ ion at m/z 235 was
suggested to be methyl 1-benzyl-4-carboxypiperazine (MBCP),
with this assignment being supported by its MS/MS spectra. It
was hypothesised that this by-product originated from the
transesterification reaction between the intermediate EBCP
and the methanol solvent during the reflux process used in
the production of BZP.[37]
intermediate
4-methoxyphenyl-2-propanone
(PMP-2-P),
followed by its conversion into the end product PMMA (via
Leuckart route). 4-Methoxyphenyl-2-propanone (PMP-2-P)
was not detected using DESI-MS; therefore, it is difficult to
ascertain the exact method of synthesis based on DESI-MS
spectra alone. However, the presence of anethole is a good
indicator of the method employed.[36]
TFMPP was synthesised in four batches all yielding
different impurities of synthesis. TFMPP exhibited a peak at
m/z 231 representing the protonated molecule in all four
samples, supported by MS/MS spectra. TFMPP 1 did not
exhibit any impurities/by-products specific to the synthetic
route of manufacture. The impurity 3-trifluoromethylphenol
(TFMP) was detected as the protonated molecule at m/z 163
in TFMPP 2. This impurity was thought to be present in the
starting material, 3-chlorobenzotrifluoride, and was carried
through to the product. TFMPP 3 contained the impurity
piperazine with its [M+H]+ ion at m/z 87. Piperazine was
present as unreacted starting material in the synthesis of
TFMPP 3. The DESI-MS spectra of TFMPP 4 identified trace
amounts of the impurity 3-(trifluoromethyl)aniline (starting
material) as the protonated molecule at m/z 162. The presence
of these impurities was supported by MS/MS spectra.
DESI-MS was successful in identifying the compound mCPP
having its [M+H]+ ion at m/z 197. In addition, an impurity was
detected in trace amounts that corresponded to unreacted
3-chloroaniline (starting material) with a protonated molecule
Piperazine analogues
The analysis of BZP 1 indicated the presence of the protonated
BZP at m/z 177. The peak at m/z 267 corresponded to protonated
DBZP. The MS/MS spectra of these [M+H]+ ions exhibited
characteristic fragmentation patterns corresponding to BZP 1
and DBZP, respectively. A by-product present was further
confirmed as being 1,4-dibenzylpiperazine (DBZP) via GC/
MS and NMR analysis (data not shown).
BZP 2 and BZP 3 were synthesised in order to alter the
amount of by-product present to mimic the possible variation
observed in a clandestine setting. BZP 2 contained the
smallest amount of DBZP and BZP 3 contained the largest
amount of DBZP relative to BZP. However, the DESI-MS
spectra did not reflect this due to possible matrix effects
causing suppression of the DBZP ion, thus making it difficult
to distinguish the three samples based on the amount of by-
product present.
Rapid Commun. Mass Spectrom. 2014, 28, 731–740
Copyright © 2014 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/rcm

N. Stojanovska et al.
at m/z 128. A distinguishing feature in the spectra of mCPP was
the presence of chlorine isotope (35Cl, 37Cl) peaks, i.e. the
protonated molecule exhibited a 35Cl isotope peak at m/z 197
and also a 37Cl isotope peak at m/z 199, in a 3:1 ratio. DESI-
MS analysis identified the presence of MeOPP at m/z 193 as
the protonated molecule. In addition, the impurity 4-anisidine
having its [M+H]+ ion at m/z 124, present as unreacted starting
material, was detected.
Table 3. Summary of compounds detected using DESI-MS
Molecular
weight
(Da)
DESI-
MSb
Sample
Compounda
MDMA
MDP-2-POH
MDDMA
MDP-2-P
MDMA
MDMA
tablet
193
180
207
178
193
178
147
221
179
148
164
176
266
176
267
234
248
126
230
230
162
179
230
86
Y
Y
The collision-induced dissociation spectra of the [M+H]+
ions of the ATS and the piperazine analogues indicated
some common fragmentation pathways. The presence of
the product ion at m/z 91 (i.e. C7H7) was consistent in the
MS/MS spectra of a number of compounds in this study
including MA, PMA, AP, DMA, MDP-2-POH, MDP-2-P,
PMMA, BZP, DBZP, MBCP, EBCP and benzyl chloride. Other
common product ions observed included [M+H–NH3]+
(for primary amines), [M+H–H2O]+, [M+H–CO2]+, [M+H–
CH2O]+ (for methoxy-substituted compounds), [M+H–CH3OH]+,
[M+H–HF]+ and [M+H–HCl]+.
In most samples, the by-products/impurities were
detectable using DESI-MS (Table 3). The identification of by-
products and impurities present in these samples is highly
indicative of the starting materials used and also the synthetic
route of manufacture, thus aiding in future detection and
profiling using DESI-MS. In the analysis of the seized MDMA
tablet, DESI-MS successfully identified MDMA, MDP-2-POH,
and MDDMA in the sample; however, MDP-2-P remained
undetected. MDMA, MDP-2-P and piperonylnitrile were
detected in the MDMA base. PMMA and anethole were
detected in the PMMA base; however, PMP-2-P remained
undetected. Bis(2-chloroethyl)amine and the starting material
3-chlorobenzotrifluoride remained undetected in MeOPP 1
and the TFMPP 2 base, respectively.
With analysis times under 1 min, and the ability to identify
adulterants, impurities and by-products concurrently, the rapid
nature of this technique is demonstrated. In addition, a large
amount of information is gained from the analysis of one sample
that can be used to determine the synthetic route of manufacture
or batch variations. Typical analysis times using GC/MS are of
the order of 30 min/sample which is significantly longer than
the time taken using the DESI-MS technique.
Confirming the presence of compounds detected using
DESI-MS is an important task in drug analysis. Using the
DESI-QTOF-MS method we were able to obtain accurate
mass data on each compound. This enabled a mass accuracy
determination based on exact masses of protonated molecules
and their product ions (Fig. 3 and Table 2). The measured
masses for all the ions detected were within 10 ppm of the
predicted masses.
Y
N
MDMA
base
Y
MDP-2-P
piperonylnitrile
N-FormylMDMA
PMMA
Y
Y
N
PMMA
BZP
1– BZP 3 DBZP
BZP 4
Y
anethole
Y trace
PMP-2-P
X
BZP
Y
Y
BZP
Y
DBZP
Y trace
MBCP
Y
Y
EBCP
benzyl chloride
Y trace
TFMPP 1 TFMPP
TFMPP 2 TFMPP
TFMP
Y
Y
Y
3-chlorobenzotrifluoride
TFMPP 3 TFMPP
piperazine
TFMPP 4 TFMPP
3-(trifluoromethyl)aniline
mCPP
3-chloroaniline
MeOPP 2 MeOPP
bis(2-chloroethyl)amine
4-anisidine
N
Y
Y
230
161
196
127
192
141
123
Y
Y trace
Y
mCPP 3
Y trace
Y
N
Y trace
aMDMA = 3,4-methylenedioxymethylamphetamine, MDP-
2-POH=3,4-methylenedioxyphenyl-2-propanol, MDDMA=
3,4-methylenedioxydimethylamphetamine, MDP-2-P = 3,4-
methylenedioxyphenyl-2-propanone, PMMA = 4-methoxyme
-thylamphetamine, BZP = 1-benzylpiperazine, DBZP = 1,4-
dibenzylpiperazine, MBCP = methyl 1-benzyl-4-carboxypi-
perazine,EBCP = ethyl1-benzyl-4-carboxypiperazine,TFMPP =
1-[3-(trifluoromethyl)phenyl]piperazine, TFMP= 3-trifluoro-
methylphenol, mCPP=1-(3-chlorophenyl)pipe-razine, MeOPP =
1-(4-methoxyphenyl)piperazine.
bY = detected, N = not detected.
When a compound is detected using DESI-MS, MS/MS
experiments should be performed in order to prevent as many
false-positive results as possible. Some compounds possess
the same chemical formula and thus the same molecular mass;
therefore, identification based on molecular mass alone can be
unreliable. However, encountering two compounds with the
exact molecular mass is an unlikely event. Nonetheless, by
using MS/MS experiments, characteristic fragmentation
patterns are obtained for each compound that can then be
compared with known product ion spectra in a library. As
an example, the Agilent Personal Compound Database and
Library (PCDL) software provides the user with a match score
based on the similarities between the acquired spectrum and
the library spectrum. A lower match score suggests that there
is a lesser likelihood of a match and this should also be
considered when reporting compound identification. In the
context of drug detection, there is usually ample sample
available from seizures for analysis. This suggests that when
drug screening is performed using DESI-MS,
a more
concentrated sample (>10 mg/mL) should be used in an
attempt to minimise the number of false-negative results
obtained due to the relatively high LODs determined for some
of the analytes using DESI-MS (Table 1).
The simultaneous detection of multiple compounds in a
mixture commonly results in ion suppression or enhancement
(matrix effects) suggesting that compounds present in trace
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Rapid Commun. Mass Spectrom. 2014, 28, 731–740

DESI-MS for analysis of amphetamines and piperazines
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amounts may not always be detectable. Therefore, caution
should be taken when interpreting the results and confir-
matory analysis techniques should be employed in order to
confirm the identification of compounds.
The advantages of using the DESI-MS technique for the fast
screening test of drug compounds include factors such as
minimal sample preparation, fast analysis times, and most
importantly the ability to analyse multiple compounds in a
single sample, i.e. impurities, by-products, intermediates
and any adulterants that may be present as well as the novel
drug compounds. With the large variability of novel
substances entering the market every week, the DESI-MS
technique becomes increasingly important for the rapid
analysis of novel substances. Fast screening methods are
encouraged and are very useful for the pre-selection of
samples for further detailed analysis. This suggests that an
ambient ionisation technique such as DESI-MS may assist
greatly in future screening tests and chemical analysis of a
vast array of compounds, in turn providing essential
information for profiling and drug intelligence purposes with
very rapid turnaround times. With the future potential of
coupling DESI to a field portable mass spectrometer (or
miniature QTOF mass spectrometer), in-depth analysis of
common ATS and piperazine analogues as well as other
novel drug analogues at the scene may become a reality.
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CONCLUSIONS
DESI-MS was successful in detecting the compounds of interest
and any reaction by-products/impurities in the samples tested,
with the exception of some compounds present in trace
amounts, in less than 1 min. The LODs of these compounds
were determined to be in the range 0.02–2.80 μg/mm2. The
intra-day and inter-day precision of the technique were found
to be <25% and <33%, respectively. DESI-MS has been
demonstrated as a screening technique capable of analysing
common ATS and drug analogues such as BZP, TFMPP, mCPP
and MeOPP. The application of DESI-MS to the rapid detection
and analysis of common ATS and piperazine analogues,
presented in this work, may see fast chemical profiling of
samples aiding in future drug detection, profiling and
intelligence work.
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Acknowledgements
We acknowledge the AFP for funding and for the samples
that were provided for this project. We also acknowledge
the AFP for providing the Prosolia™ DESI source for its use
at the University of Technology, Sydney.
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