Gas chromatography/mass spectrometry analysis of the six-ring regioisomeric dimethoxybenzyl-N-methylpiperazines (DMBMPs)

Article abstract of DOI:10.1002/rcm.6716

rationale Piperazine-based designer drugs represent a novel class of substances found in illicit drug samples in the US and abroad. The clandestine production of these substances often makes use of piperazine as a key commercially available precursor substance. The commercial availability of 1-methylpiperazine suggests additional designer modification based on this additional precursor material. MethodsThis study focuses on the electron ionization mass spectrometric (EI-MS) fragmentation of the dimethoxybenzyl-N- methylpiperazines as potential designer modifications of the general benzylpiperazine drug skeleton and explores the gas chromatography (GC)/MS properties of all six of these regioisomeric substances. Results Fragmentation of the bond between the benzylic carbon and the adjacent piperazine nitrogen provides the base peak in all six spectra. The internal fragmentation within the piperazine ring produces a number of unique ions in the mass spectra of these dimethoxybenzyl-N-methylpiperazines. The migration of methyl groups from nitrogen and oxygen were confirmed by deuterium-labeling experiments. ConclusionsThe six regioisomeric dimethoxybenzyl-N-methylpiperazines yield equivalent fragment ions and deuterium labeling confirmed the elemental composition of the characteristic fragments in their mass spectra. Mixtures of the dimethoxybenzyl-N-methylpiperazines were successfully resolved via capillary gas chromatography using a relatively polar stationary phase and temperature-programming conditions. Copyright 2013 John Wiley & Sons, Ltd. Copyright

Full text of DOI:10.1002/rcm.6716

Research Article
Received: 12 July 2013
Revised: 20 August 2013
Accepted: 21 August 2013
Published online in Wiley Online Library
Rapid Commun. Mass Spectrom. 2013, 27, 2551–2558
(wileyonlinelibrary.com) DOI: 10.1002/rcm.6716
Gas chromatography/mass spectrometry analysis of the six-ring
regioisomeric dimethoxybenzyl-N-methylpiperazines (DMBMPs)
Karim M. Abdel-Hay1,2, Jack DeRuiter1 and C. Randall Clark1
*
1Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA
2Dept. of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt
RATIONALE: Piperazine-based designer drugs represent a novel class of substances found in illicit drug samples in the
US and abroad. The clandestine production of these substances often makes use of piperazine as a key commercially
available precursor substance. The commercial availability of 1-methylpiperazine suggests additional designer
modification based on this additional precursor material.
METHODS: This study focuses on the electron ionization mass spectrometric (EI-MS) fragmentation of the
dimethoxybenzyl-N-methylpiperazines as potential designer modifications of the general benzylpiperazine drug
skeleton and explores the gas chromatography (GC)/MS properties of all six of these regioisomeric substances.
RESULTS: Fragmentation of the bond between the benzylic carbon and the adjacent piperazine nitrogen provides the
base peak in all six spectra. The internal fragmentation within the piperazine ring produces a number of unique ions
in the mass spectra of these dimethoxybenzyl-N-methylpiperazines. The migration of methyl groups from nitrogen
and oxygen were confirmed by deuterium-labeling experiments.
CONCLUSIONS: The six regioisomeric dimethoxybenzyl-N-methylpiperazines yield equivalent fragment ions and
deuterium labeling confirmed the elemental composition of the characteristic fragments in their mass spectra. Mixtures
of the dimethoxybenzyl-N-methylpiperazines were successfully resolved via capillary gas chromatography using a
relatively polar stationary phase and temperature-programming conditions. Copyright © 2013 John Wiley & Sons, Ltd.
A
number of synthetic piperazine compounds have
drugs of abuse including amphetamine,[8] MDMA,[9] bath
salts[10] and other clandestine drug series,[11] where legislative
control has stimulated the development of numerous designer
drug derivatives.
Structural modifications of drugs of abuse are well
known for the phenethylamines or amphetamine-derived
designer drugs. The most common variations are the
introduction of a methylenedioxy or dimethoxy moiety
into the aromatic ring of amphetamine leading to 3,4-methylene-
dioxyamphetamine (MDA) or 2,5-dimethoxyamphetamine
(2,5-DMA), respectively. Structural modifications similar
to those found in the phenethylamines have already been
encountered in the piperazine compounds. Recently, 1-(3,4-
appeared in illicit drug samples in the US and abroad in
recent years and these compounds represent a novel class
of designer drugs. The most common piperazines
encountered in clandestine drug samples to date include
benzylpiperazine (BZP), m-chlorophenylpiperazine (mCPP)
and 1-(3-trifluoromethylphenyl)piperazine (TFMPP) and
these compounds appear to be obtained from commercial
sources.[1] These drugs are often found in combination and
the most common product combination appears to be BZP
with TFMPP,[2] sometimes mixed with other illicit drugs
such as amphetamine, cocaine, ketamine and MDMA.[3,4] BZP
produces stimulant effects similar to d-amphetamine although
only one-tenth as potent. The phenylpiperazines such as
TFMPP appear to produce their effects by interacting with
serotonergic receptors, and their affinity and selectivity for
these receptors are dependent on the nature and position of
the aromatic substituents.[5–7] Both BZP and TFMPP were
placed in Schedule 1 of the United States Controlled Substance
Act in 2002, and have been controlled in other countries as well.
With this heightened control it is anticipated that clandestine
chemists will continue to explore the development of designer
derivatives to obtain novel psychoactive piperazines that are
not specifically controlled by existing regulation. This
phenomenon has been observed in the phenethylamine-type
methylenedioxybenzyl)piperazine (3,4-MDBP)
–
the
methylenedioxy analogue of N-benzylpiperazine (BZP) –
has been reported in clandestine samples. This compound has
been described as producing psychoactive effects similar to
those of 3,4-methylenedioxymethamphetamine (MDMA).[5–7]
Furthermore,
a
clandestine sample of 4-bromo-2,5-
dimethoxybenzylpiperazine (a dimethoxybenzylpiperazine
derivative) was seized in Germany in 2006.[12] It is likely that
additional designer derivatives in this series will appear, and
probably include methoxy and dimethoxy ring substituted
analogues since this substitution pattern has yielded
enhanced psychoactive substances in other drug classes.
Additionally, the starting materials for the clandestine
synthesis of such designer analogues are readily available
and include dimethoxybenzaldehydes, piperazine and
1-methylpiperazine. This could result in the production of a
number of novel regioisomeric drugs of abuse (Fig. 1).
* Correspondence to: C. R. Clark, Department of Pharmacal
Sciences, Harrison School of Pharmacy, Auburn University,
Auburn, AL 36849, USA.
E-mail: clarkcr@auburn.edu
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Copyright © 2013 John Wiley & Sons, Ltd.

K. M. Abdel-Hay, J. DeRuiter and C. R. Clark
of 9°C/min, held at 180°C for 2.0 min then ramped to 200°C
at a rate of 10°C/min and held at 200°C for 5.0 min.
Gas chromatography/mass spectrometry (GC/MS) is the
most widely used technique in the analysis of controlled
substances in forensic laboratories. However, the identification
of psychoactive drugs in a number of structural categories by
this method is complicated by the possibility of regioisomeric
substances.[8–11] Many regioisomeric and isobaric substances
yield essentially identical mass spectral fragments in addition
to equivalent molecular weights. Previous studies[13,14] have
shown that chemical derivatization methods (primarily
acylation) can be applied to solve these analytical challenges
for primary and secondary amines. However, in some cases,
derivatization does not yield any additional characteristic mass
spectral fragments.[15] Thus, identification of structurally
related substances such as regioisomers remains a challenge
to forensic analyses that depend heavily on mass spectrometry
for confirmation level data. The commercial availability of
many regioisomeric forms of the synthetic precursor chemicals
makes differentiation of potential regioisomeric forms of
designer substances a critical issue in forensic drug chemistry.
This study focuses on the EI-MS fragmentation of the
dimethoxybenzyl-N-methylpiperazines as potential designer
modifications of the general BZP drug skeleton and explores
the GC/MS properties of these regioisomeric substances. All
six precursor dimethoxybenzaldehydes are commercially
available as well as N-methylpiperazine. The structures for
the six regioisomeric dimethoxybenzyl-N-methylpiperazines
in this study are shown in Fig. 1.
The GC/time-of-flight (TOF) analysis was carried out at the
Mass Spectrometry Center, Auburn University. The analysis
utilized a 6890N gas chromatograph with a 7683B auto injector
purchased (Agilent Technologies, Santa Clara, CA, USA)
coupled to a Waters GCT Premier benchtop orthogonal
acceleration time-of-flight (oa-TOF) mass spectrometer.
Chromatographic separation was carried out using a DB5-MS
capillary column (30 m × 0.25 mm i.d., coated with a stationary
phase film thickness of 0.50 μm; J&W Scientific). The
temperature program consisted of an initial temperature of 70°
C for 1 min, ramped up to 250°C at a rate of 15°C/min followed
by a hold at 250°C for 7 min. The identification was confirmed
by elemental composition analysis using accurate mass
measurement with an internal calibrant (lockmass 118.9919
m/z, heptacosafluorotributylamine, Sigma) with an acceptable
error of less than 5 ppm and by isotope modeling comparing
the experimental and theoretical isotope distribution.
Drugs and reagents
The general procedure for the synthesis of these six
regioisomeric dimethoxybenzyl-N-methylpiperazines begins
with the appropriate aldehyde, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and
3,5-dimethoxybenzaldehyde, as starting materials. All six of
these precursor aldehydes were obtained from Aldrich
Chemical Co. (Milwaukee, WI, USA). The desired regioisomeric
dimethoxybenzyl-N-methylpiperazines were synthesized by
stirring a solution of the appropriate aldehyde in methanol
with N-methylpiperazine and sodium cyanoborohydride.
Isolation of the basic fraction gave the dimethoxybenzyl-N-
methylpiperazines, which were converted into the corresponding
hydrochloride salts using gaseous HCl. All laboratory reagents
and chemicals were obtained from Aldrich Chemical Co.
(Milwaukee, WI, USA) or Fisher Scientific (Atlanta, GA, USA).
EXPERIMENTAL
Instrumentation
GC/MS analysis was performed using a model 7890A gas
chromatograph and a model 7683B auto injector coupled with
a
5975C VL mass-selective detector (all from Agilent
Technologies, Santa Clara, CA, USA). The mass spectral scan rate
was 2.86 scans/s. The GC instrument was operated in splitless
mode with a helium (grade 5) flow rate of 0.7 mL/min and
the column head pressure was 10 psi. The mass spectrometer
was operated in the EI mode using an ionization voltage of
70 eV and a source temperature of 230°C. The GC injector
was maintained at 250°C and the transfer line at 280°C.
GC/MS chromatographic separations were carried out on
a column (30 m × 0.25 mm i.d.) coated with 0.5 μm 100%
trifluoropropyl methyl polysiloxane (Rtx-200; Restek
Corporation, Bellefonte, PA, USA). The separations were
performed using a temperature program consisting of an
initial hold at 100°C for 1.0 min, ramped up to 180°C at a rate
RESULTS AND DISCUSSION
The structures for the six regioisomeric dimethoxybenzyl-N-
methylpiperazines are shown in Fig. 1. All six of the
corresponding dimethoxybenzaldehyde presursors, as well
as N-methylpiperazine, are commercially available materials
and a one-step reductive amination process yields the desired
compounds for this study. The selectivity of the reagent
sodium cyanoborohydride allows for the reduction of the
imine intermediate formed between the aldehyde and the
Figure 1. Structures for the dimethoxybenzyl-N-methylpiperazines studied.
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GC/MS study of the six-ring regioisomeric DMBMPs
Figure 2. Mass spectra for the six regioisomeric dimethoxybenzyl-N-methylpiperazines.
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K. M. Abdel-Hay, J. DeRuiter and C. R. Clark
Figure 2. (Continued)
secondary nitrogen of N-methylpiperazine to yield the desired
dimethoxybenzyl-N-methylpiperazines. This reduction occurs
without the potential competitive reduction of the precursor
aldehyde to the corresponding alcohol.
ring and is almost universal in all N-1-monosubstituted
piperazines (N-4 substituent is hydrogen). This m/z 56 ion
yielded a mass shift of +6 Da when d8-piperazine was used
to label all the four carbons of the piperazine ring.[16] Thus,
the m/z 56 ion was confirmed to contain six hydrogen atoms
and three of the carbons from the original piperazine
portion of these molecules; this confirmation was based
on studies in the dimethoxybenzylpiperazines (N-4 = H).
The formation of the m/z 56 ion in the previous series
of dimethoxybenzylpiperazine (N-4 = H) regioisomers
involved an initial migration of the hydrogen on nitrogen
at N-4 to the tertiary N-1 nitrogen followed by a radical site
alpha cleavage initiated by the N-4 nitrogen to break the
carbon–carbon bond of the piperazine ring. The last step in
the formation of the m/z 56 ion is the heterolytic breaking
of the N-1 to carbon bond to yield the C3H6N+ cation.
The equivalent mechanistic pathway is illustrated for the
N-4 = CH3 compounds in this study in Fig. 4.
Mass spectrometry is the primary method for confirming
the identity of drugs in forensic samples. Figure 2 shows the
EI mass spectra of the six regioisomeric dimethoxybenzyl-N-
methylpiperazines (compounds 1–6) in this study. All six
regioisomers show molecular ions at m/z 250 and these ions
are of significant relative intensity. Major fragment ions of
equivalent mass occur in the spectra for these six
compounds with only the relative intensity of the individual
ions as the major spectral variation. Fragmentation of
the bond between the benzylic carbon and the adjacent
piperazine nitrogen provides the base peak in all six spectra.
The dimethoxybenzyl cation at m/z 151 is the base peak for
compounds 2, 3, 4, and 5 while the dimethoxybenzyl radical
cation (m/z 152) resulting from a hydrogen migration
rearrangement pathway is the base peak for compound 6.
Fragmentation of the same bond between the benzylic
carbon and the adjacent piperazine nitrogen with charge
retention on the N-methylpiperazine group yields the cation
at m/z 99, the base peak for compound 1. The structures for
the base peaks and other characteristic fragment ions in the
mass spectra for these regioisomeric dimethoxybenzyl-N-
methylpiperazines are shown in Fig. 3.
The formation of the C3H6N+ m/z 56 ion for the N-4 = CH3
series of regioisomers involves methyl group migration from
N-4 to N-1 of the piperazine ring. The N-4 = CD3 labeled form
of 2,3-dimethoxybenzyl-N-methylpiperazine was prepared
by reacting the monosubstituted dimethoxybenzylpiperazine
(N-4 = H) with CD3I. The mass spectrum for this labeled
compound is presented in Fig. 5(A) and shows that the
m/z 56 species did not undergo a mass shift as a result
of the N-CD3 group. Thus, the N-4 methyl group is not
a part of the m/z 56 ion and indicates that the methyl
group migration is consistent with the N-H migration in
the monosubstituted series.[16] The use of piperazine-D8
in the monosubstituted series produced a mass shift of +6 Da
The internal fragmentation within the piperazine ring
produces a number of unique ions in the mass spectra of these
dimethoxybenzyl-N-methylpiperazines. The low-mass ion of
highest relative abundance in these spectra is the m/z 56
cation. This ion is a characteristic fragment for the piperazine
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GC/MS study of the six-ring regioisomeric DMBMPs
Figure 3. Mass spectral fragmentation for the six regioisomeric dimethoxybenzyl-N-
methylpiperazines (*2,3-isomer only).
Figure 4. Mechanism for the formation of the m/z 56 cation in the six regioisomeric
dimethoxybenzyl-N-methylpiperazines.
for the ion in question yielding the C3D6N+ cation at m/z 62.
dimethoxybenzylpiperazines[16] showed that the methyl group
lost to form the m/z 136 species is from the methoxy group at
the 3-position of the aromatic ring. The resonance-stabilizing
effects of the 2-methoxy group favor the loss of the methyl
group from the 3-position. A possible mechanistic pathway
for the formation of the m/z 136 ion has been described.[16]
The mass spectrum in Fig. 6 provides support that the
fragmentation pathway for these N-methylpiperazines in
this study is equivalent to the previously reported
monosubstituted dimethoxybenzylpiperazines.[16] The mass
spectrum in Fig. 6 is for the deuterium-labeled benzylic
carbon of 2,3-dimethoxybenzyl-N-methylpiperazine and
the results show a mass shift of +1 Da at m/z 137. These
data indicate that the benzylic carbon remains a part of
the ion in question and leaves only the methyl group from
one of the two methoxy ring substituents as the source for
the elimination fragmentation. Thus, the formation of
the m/z 136 radical cation in this N-methylpiperazine
series is the same process as the previously reported[16]
2,3-dimethoxybenzylpiperazine series. The deuterium labeling
of the benzylic carbon followed the previously described
synthetic method using sodium cyanoborodeuteride (NaBD3CN)
as the reducing reagent.
The mass spectrum for 2,3-dimethoxybenzylpiperazine-D8 is
shown in Fig. 5(B). When the N-4-methyl (CH3) group is added
to the 2,3-dimethoxybenzylpiperazine-D8, the resulting mass
spectrum (Fig. 5(C)) continues to show a mass shift of +6 Da
for the C3D6N+ cation at m/z 62. The mass spectrum for the
2,3-dimethoxybenzyl-N-CD3-piperazine-D8 in Fig. 5(D) also
shows the +6 Da mass shift for this ion further confirming the
structure for this characteristic fragment. The mass shifts for
the molecular ions in Figs. 5(A)–5(D) provide validation of the
structures of the labeled species. Furthermore, the fragment
ions for the individual piperazine species at m/z 102, 93, 107
and 110 in Figs. 5(A)–5(D) respectively confirm the position of
the deuterium labels in the model compounds.
The mass spectrum for the 2,3-dimethoxybenzyl-N-
methylpiperazine regioisomer in Fig. 2 as well as all the
deuterium-labeled derivatives of this compound in Fig. 5 show
a unique fragment at m/z 136. This ion does not undergo any
deuterium-initiated mass shifts; thus, this fragment does not
come from the piperazine portion of the molecule. Exact mass
analysis shows this ion to be C8H8O2, a radical cation species.
This ion essentially represents the molecular equivalent of a
methyl group loss from the m/z 151 cation to form a peak of
intensity approximately equal to the base peak for the
2,3-dimethoxybenzyl regioisomer. Previous carbon-13- and
deuterium-labeling studies in the monosubstituted (N-4 = H)
The spectra for these six regioisomeric dimethoxybenzyl-N-
methylpiperazines in Fig. 2 show two major high-mass
fragment ions at m/z 179 and 192 of variable relative
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K. M. Abdel-Hay, J. DeRuiter and C. R. Clark
A
B
C
D
Figure 5. Mass spectra for deuterium-labeled 2,3-dimethoxybenzyl-N-
methylpiperazines.
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GC/MS study of the six-ring regioisomeric DMBMPs
Figure 6. Mass spectrum the benzylic carbon deuterium-labeled 2,3-dimethoxy-
benzyl-N-methylpiperazines.
Figure 7. Gas chromatographic separation of the six regioisomeric
dimethoxybenzyl-N-methylpiperazines.
abundance. A comparison of the fully deuterium-labeled 2,3-
and elutes last in this group of compounds. The two
compounds with maximum crowding substituted in a 1,2,3-
manner on the aromatic ring show the 2,3-dimethoxy
substitution pattern to elute first followed by the 2,6-dimethoxy
isomer eluting second. The relative position of the methoxy
groups appears to determine the elution order in the three
compounds having two groups substituted in a 1,2-pattern.
Within this group of three compounds the first to elute is the
1,4-relationship for the two methoxy groups in compound 3.
This is followed by the 1,3-pattern for compound 2 and lastly
the 1,2-pattern for compound 5.
dimethoxybenzyl-N-CD3-piperazine-D8 in Fig. 5(D) with the
spectrum for the equivalent unlabeled isomer in Fig. 2
supports the proposed structures for the m/z 179 and 192
fragments in Fig. 3. Furthermore, the spectrum in Fig. 5(D)
for the D11 derivative supports the proposed structures for
the minor high-mass ions at m/z 206 and 221 observed in
many of the spectra in Fig. 2.
Gas chromatography
In previous studies on the chromatographic properties of
the monosubstituted piperazines (N4 = H), these secondary
amines showed severe chromatographic tailing on a number
of stationary phases. This issue was overcome by acylation
of the secondary amine nitrogen with perfluoroacyl groups
such as the pentafluoropropionyl group and others.
Adequate peak shape and resolution were obtained for these
tertiary amines (compounds 1–6) in this study.
Gas chromatographic separation of the dimethoxybenzyl-N-
methylpiperazines was accomplished using an Rtx-200
(100% trifluoropropyl methyl polysiloxane) stationary phase
in a capillary column (30 m × 0.25 mm) of 0.5-μm film
thickness. Several temperature programs were evaluated
and the most efficient program (see Experimental section)
was used to generate the representative chromatogram
shown in Fig. 7. This chromatogram shows the separation
of the six dimethoxybenzyl-N-methylpiperazine regioisomers
and the elution order appears related to the degree of
substituent crowding on the aromatic ring. Compounds 1 and
4 elute first and these two isomers contain substituents
arranged in a 1,2,3-pattern on the aromatic ring. Three isomers
(compounds 2, 3 and 5) have two groups substituted 1,2 with
one isolated substituent. The 1,3,5-trisubstituted pattern in
compound 6 provides minimum intramolecular crowding
CONCLUSIONS
The six regioisomeric dimethoxybenzyl-N-methylpiperazines
yield the same fragment ions in their mass spectra. Deuterium
labeling was successful in confirming the elemental
composition of the characteristic fragments in the mass spectra
Rapid Commun. Mass Spectrom. 2013, 27, 2551–2558
Copyright © 2013 John Wiley & Sons, Ltd.
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K. M. Abdel-Hay, J. DeRuiter and C. R. Clark
[6] H. Tsutsumi, M. Katagi, A. Miki, N. Shima, T. Kamata,
M. Nishikawa, K. Nakajima, H. Tsuchihashi. Development
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[7] R. Haroz, M. I. Greenberg. New drugs of abuse in North
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[8] H. M. Maher, T. Awad, J. DeRuiter, C. R. Clark. GC–MS and
GC-IRD studies on brominated dimethoxyamphetamines
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of all the dimethoxybenzyl-N-methylpiperazines. Methyl-
group migration from the N-4 position allows for the
formation of the major low-mass fragment at m/z 56 in
these spectra. Mixtures of the dimethoxybenzyl-N-
methylpiperazines were successfully resolved via capillary
gas chromatography using a relatively polar stationary
phase and temperature-programming conditions. The
elution order appears related to the degree of substituent
crowding on the aromatic ring with the most crowded 1,2,3-
substitution patterns eluting first and the highest retention for
the compound with minimum intramolecular crowding (the
1,3,5-trisubstitution pattern).
[9] K. M. Hegadoren, G. B. Baker, M. Bourin. 3,4-Methylenedioxy
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Acknowledgement
[10] Y. F. Hamad Abiedalla, K. Abdel-Hay, J. DeRuiter, C. R. Clark.
Synthesis and GC-MS analysis of a series of homologs and
regioisomers of 3,4-methylenedioxypyrovalerone (MDPV).
Forensic Sci. Int. 2012, 223, 189.
[11] P. Jankovics, A. Váradi, L. Tölgyesi, S. Lohner. Detection
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[12] F. Westphal, T. Junge, U. Girreser, S. Stobbe, S. B. Péres.
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[13] T. Awad, J. DeRuiter, C. R. Clark. GC-MS analysis of
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This project was supported by Award No. 2011-DN-BX-K530,
awarded by the National Institute of Justice, Office of Justice
Programs, U.S. Department of Justice. The opinions, findings,
and conclusions or recommendations expressed in this
publication are those of the author(s) and do not necessarily
reflect those of the Department of Justice.
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