Carter Jim (Orcid ID: 0000-0002-2171-8631)

Stable isotope characterisation of MDP2P and MDA

prepared from piperonal
Justin Cormick a, James F. Carter * b, Timothy Currie b, Carney Matheson a, Sarah L.
Cresswell a
a
School of Environment and Science, Griffith University, Nathan QLD 4111 Australia
b
Queensland Health Forensic and Scientific Services, Coopers Plains, QLD 4108 Australia
* Corresponding author: jim.carter@health.qld.gov.au,

ABSTRACT

RATIONALE
Stable isotopic ratios can provide information for illicit drug profiling. The research presented
here investigated the variations in stable isotopic ratios of hydrogen (δ2H), carbon (δ13C),
nitrogen (δ15N) and oxygen (δ18O) during the synthesis of MDP2P (3,4-methylenedioxyphenyl-
2-propanone) and MDA (3,4-methylenedioxamphetamine) prepared via the ‘nitrostyrene’
route.
METHOD
Samples of MDA and MDP2P were synthesised from two isotopically characterised starting
materials, piperonal and nitroethane. The isotopic composition of the nitrostyrene intermediate
(3,4-methylenedioxyphenyl-2-nitropropene, MDP2NP) and products MDP2P and MDA were
also measured by isotope ratio mass spectrometry (IRMS).
RESULTS

A significantly negative change occurred to δ2H values during the production of MDP2NP,
MDP2P and MDA, indicating a mechanism that favours inclusion or retention of 1H over 2H.
This suggests that the δ2H compositions of MDA/MDP2P prepared from piperonal will not
provide information on the synthetic history. Minimal changes were observed in δ13C
composition during the synthesis of MDP2NP, MDP2P and MDA, and minimal δ15N
compositional changes occurred in MDP2NP and MDA. Progressing from piperonal to
MDP2NP a minimal change occurred to δ18O composition. A variable change to δ18O was
observed from MDP2NP with one sample becoming more positive in δ18O composition and
two samples becoming more negative Progressing from MDP2NP to MDA a significant
negative change occurred to δ18O composition.

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CONCLUSIONS

The changes to stable isotopic ratios observed during the preparation of MDA and MDP2P
from piperonal may prove useful when attempting to compare batch-to-batch variations
between seizures and provide information with tactical intelligence applications.

KEY WORDS
 Isotope ratio mass spectrometry (IRMS)
 Piperonal
 3,4-methylenedioxyphenyl-2-propanone (MDP2P)
 3,4-methylenedioxyamphetamine (MDA)
 3,4-methylenedioxymethylamphetamine (MDMA)
1 INTRODUCTION
The production and trafficking of amphetamine type stimulants (ATS) creates serious problems
for law enforcement worldwide.1 Two common ATS are 3,4-methylenedioxyamphetamine
(MDA) and 3,4-methylenedioxymethylamphetamine (MDMA) (included in Figure 1). Illicit
drug profiling can provide information to law enforcement as they attempt to monitor and
control the illicit drug trade. Illicit drug profiling involves chemical or physical analysis of
drugs and organic impurity profiling by gas chromatography/mass spectrometry (GC/MS) is
one common method of chemical analysis.2
Isotope ratio mass spectrometry (IRMS) has been used as an additional method of analysis that
can provide important information for illicit drug profiling, particularly when used in
combination with other techniques (such as impurity profiling). Previous research into the
IRMS analysis of MDA/MDMA suggests minimal information can be obtained about the
synthetic history of samples.3-7 IRMS data has, however, been used to compare batch-to-batch
variations and provide information for law enforcement.
One example demonstrated how a connection was established between two seizures when no
discernible differences could be found in δ13C and δ15N compositions.8 In another example,
variations in δ15N composition throughout a large seizure suggested multiple batches had been
prepared.9 This information can provide tactical intelligence information for law enforcement,
which aims to establish links between seizures, samples and suspects.10
The following research investigates the changes to δ2H, δ13C, δ15N and δ18O composition
during the ‘nitrostyrene’ route (outline in Figure 1) to MDA and MDMA. This pathway sees
piperonal and nitroethane (in the presence of N-butylamine) produce the nitrostryene
intermediate 3,4-methylenedioxyphenyl-2-nitropropene (MDP2NP) from which MDA or 3,4-
methylenedioxyphenyl-2-propanone (MDP2P) can be produced. MDMA can then be produced
from MDP2P. Any changes seen in stable isotope ratios during this pathway can be utilised
when attempting to explain batch-to-batch variations and provide tactical intelligence
information for seized samples. Research has previously been conducted on changes to stable
isotope ratios during the synthesis of MDA and MDMA however, the research presented here
further contributes to the knowledge base by investigating pathways and elements which had
not previously been investigated.
Synthetic pathways previously investigated by IRMS include from helional to MDA,11 helional
to MDMA7 and MDP2P to MDMA.4-6 While minimal change was observed in δ13C

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composition, changes occurred in δ2H, δ15N and δ18O values. Billault et al.3 investigated δ13C
and δ15N changes during the synthesis of MDMA from piperonal, isosafrole and safrole via
several pathways including via MDP2P (prepared from safrole or isosafrole) by reductive
amination, the Leuckart reaction, and a tosylate derivative. A pathway from piperonal was
investigated that converted MDP2NP to MDA, which then proceeded to MDMA via the N-
formyl intermediate. No stable isotope ratio data were, however, provided for intermediates,
only starting materials (piperonal, isosafrole and safrole), nitrogen sources and the MDMA
end-product3. Previous research has shown additional fractionation can occur to δ2H and δ15N
compositions during the hydrogen chloride (HCl) salt precipitation of MDA and MDMA.7
Collins et al.12 investigated the nitrostyrene pathway for benzaldehyde to amphetamine (the
non 3,4-methylenedioxy ATS equivalent) and found minimal change to δ13C. When prepared
from industrial benzaldehyde (with a considerably positive δ2H value), δ2H values decreased
significantly in the nitrostyrene intermediate (phenyl-2-nitropropene, P2NP) and amphetamine.
No δ15N or δ18O data were presented.
2 EXPERIMENTAL
2.1 Materials
The one piperonal sample included in this study had been retained during the investigation of
a clandestine laboratory in Queensland, Australia. MDP2NP #2 had previously been prepared
in-house at Queensland Health Forensic & Scientific Services (QHFSS). Additional chemicals
and reagents were purchased from chemical supply companies as follows: diethyl ether,
isopropanol (IPA), anhydrous tetrahydrofuran (THF) lithium aluminium hydride (LiAlH4),
sodium chloride (NaCl) and sodium sulfate (Na2SO4) from Sigma-Aldrich (St Louis MO,
USA); dichloromethane (DCM), ethanol, iron powder and phosphorous pentoxide
(SICAPENT with indicator) from Merck (Damstadt, Germany); nitroethane from BDH Ltd
(Poole, England); N-butylamine from Ajax Chemicals Ltd (Sydney NSW Australia); HCl
(32%) from Univar (Ajax Finechem Ptd Ltd, Taren Point NSW Australia); iron (III) chloride
from Chem-Supply Pty. Ltd. (Gillman SA, Australia). For IRMS analysis tin and silver
capsules were purchased from IVA Analysentechnik (Meerbush, Germany) and activated
Chromosorb G HP 80/100 mesh from Applied Science Laboratories Inc. (CA, USA).
2.2 Synthesis
The following methods were modified from Billault et al.3 and Collins et al.12
Piperonal to MDP2NP: To N-butylamine (0.249 g) in 10 mL ethanol was added piperonal
(10.0199 g, 0.066741 mol) and nitroethane (5.357 g) under N2. The reaction was heated at
reflux for 24 hours. After cooling the resulting precipitate was collected with vacuum filtration,
washed with cold ethanol, and dried in a vacuum desiccator over phosphorous pentoxide to
give yellow crystals (5.5462 g, 0.0268 mol, 40.1 % yield) given the ID MDP2NP #1.
MDP2NP to MDP2P: MDP2NP #1 (1.9754, 0.009535 mol) and iron powder (3.9148 g) were
added to iron (III) chloride (0.1842 g) in 10 mL H2O, heated to 80 °C and HCl (2 mL) was
added dropwise. The reaction was cooled and 10 mL NaOH (5 M) was added. The organic
layer was extracted into diethyl ether (3 x 30 mL), washed with saturated NaCl solution and
dried over sodium sulfate. The solvent was removed by rotary evaporation and the residue dried
in a vacuum desiccator over phosphorous pentoxide to give a brown oil (1.1019 g, 0.006184
mol, 64.9% yield). The reaction was repeated twice more to give three samples of MDP2P.
MDP2NP to MDA: MDP2NP #2 (1.1307 g, 0.005458 mol) in 10 mL THF was slowly added
to LiAlH4 (0.9492 g) in 20 mL THF then heated to reflux for 1 hr. Once cooled, 2 mL IPA was

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added dropwise followed by 2 mL NaOH (1M) and 3 mL H2O. The solution was filtered under
vacuum and washed with 100 mL DCM. The filtrate was collected, and solvent removed by
rotary evaporation to give a brown oil to which was added 50 mL H2O, pH was adjusted to 1
with HCl (32%) and washed with DCM (3 x 50 mL). The pH was adjusted to 9 with NaOH (2
M), extracted into DCM (3 x 50 mL) and dried over sodium sulfate. The solvent was removed
by rotary evaporation to give a brown oil (0.7900 g, 0.004408 mol, 81.8% yield). The reaction
was repeated twice more to give three samples of MDA.
2.3 Gas chromatography / flame ionisation detector (GC/FID)
The purities of samples were determined by GC/FID and data acquired with Chromeleon 7.2
software. A Trace 1310 GC was equipped with a RSH autosampler (Thermo Scientific, Milan,
Italy) and FID with a TG-5MS column (30 m x 0.25 mm, 0.25 μm film) (Thermo Scientific,
USA), 280 °C inlet temperature, 10: split and flow of 1 mL/min. The initial 80 °C temperature
(held for 2 min) was increased to 280 °C at 15 °C / min and held for 2 min (total run time 20
min).
2.4 Stable isotope analysis
Stable isotope ratios were determined with a Delta VPLUS IRMS (ThermoScientific, Bremen,
Germany) with a ConFlo IV interface and ISODAT 3 software. Prior to stable isotope analysis,
samples were crimped into tin (for δ13C or δ15N analysis) or silver (δ2H or δ18O analysis)
capsules. Activated Chromosorb was added to capsules before addition of volatile oils (MDP2P
and MDA). Chromosorb was selected from various absorbents as it was determined to not give
a significant blank for δ2H, δ13C, δ15N or δ18O.
δ13C and δ15N analysis, were performed with a Flash 2000 elemental analyser
(ThermoScientific) with a 950 °C combustion temperature and 100 mL/min helium flow.
Reactor packaging contained chromium (II) oxide, electrolytic copper and silvered cobalt
(II/III) oxide (IVA). A magnesium perchlorate water trap was located between the reactor and
GC column (at 100 °C). An additional Carbosorb (IVA) CO2 trap was used for δ15N analysis.
δ2H and δ18O analyses were performed with a HTC/EA elemental analyser (Thermo Scientific).
Samples were loaded into a zero-blank autosampler (Costech Analytical Technologies Inc.
Valencia, CA, USA) and analysis was performed at 1400 °C with a 90 mL/min helium flow
via bottom-feed adaptor. An alumina reactor tube was used for δ2H analysis (developed by
Meikle et al.13), or a reactor packed with glassy carbon for δ18O analysis.
δ13C results were reported on the VPDB scale by reference to IAEA-CH-7 (International
Atomic Energy Agency (IAEA), Vienna, Austria), NBS-19 and LSVEC materials. δ15N was
reported on the NAIR scale by reference to USGS25, USGS26 (United States Geological Survey
(USGS), Reston, VA, USA), IAEA-601 and IAEA-N2. δ2H and δ18O were reported on the
VSMOW scale by reference to GISP, VSMOW and UC04 (USGS). IAEA-601 and well
characterised phenacetin14 (Aldrich, MO, USA) were used for QC purposes. Overall
measurement uncertainties (with a coverage factor of two) were calculated as ±2.0‰ for δ2H,
and ±0.2‰ for δ13C, δ15N and δ18O.
3 RESULTS AND DISCUSSION
Table 1 summarises the IRMS results for the three samples of MDP2P produced from
MDP2NP #1 (synthesised from piperonal and nitroethane). From MDP2NP #2 (previously
prepared in-house) three samples of MDA were prepared and IRMS results are included in
Table 2. Quality control data can be found in the supplementary material.

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From a previous survey of MDA/MDMA precursors15 the piperonal sample included in this
study had a considerably more positive δ2H value compared to other traditional precursors. If
this value carried through to the production of MDA/MDMA, δ2H composition could be useful
when attempting to identify piperonal as the source of seized MDA/MDMA. However, as
outlined in Figure 2 (a), during the synthesis of MDP2NP and MDP2P from piperonal the δ2H
value became progressively more negative. The δ2H value also decreased progressing from
MDP2NP to MDA. The MDP2P and MDA samples prepared in this study had δ2H values
consistent with those previously reported for MDA/MDMA (as outlined by Cormick et al.15),
suggesting MDP2P and MDA prepared from piperonal will not have a characteristic δ2H
composition, and that δ2H cannot be used to identify piperonal as the source of MDA/MDMA.
Minimal data are available for δ2H values of MDA/MDMA precursors, and other than the
previous survey15 no previous δ2H data have been reported for piperonal. As such it is difficult
to elaborate further on the potential use of δ2H to identify precursors of MDA or MDMA.
Additional δ2H changes are expected during the synthesis of MDMA from MDP2P4-7 and
during the HCl salt precipitation of MDA and MDMA.7An interesting pattern emerged in δ2H
composition when the results presented here were compared to those of Collins et al.12 for the
synthesis of amphetamine from benzaldehyde (Figure 3). Essentially, the more positive the
δ2H value of the precursor the greater the negative shift in δ2H value during the preparation of
P2NP and MDP2NP, through to amphetamine, MDP2P and MDA. Minimal δ2H change was
observed for amphetamine prepared from natural benzaldehyde with a starting δ2H value of
approximately –125‰. A significant negative decrease was observed in MDP2NP and MDA
prepared from piperonal (with a more positive δ2H value than the natural benzaldehyde of
+99‰) and from MDA prepared from MDP2NP (+73‰). Synthetic benzaldehyde was found
with a much more positive δ2H (+552‰) and amphetamine prepared from it was found with
the greatest decrease in δ2H composition.
As outlined in Figure 2 (b) and (c), minimal changes to δ13C and δ15N values were observed
during the synthesis of MDP2NP, MDA and MDP2P (the latter does not contain nitrogen).
This is consistent with the δ13C values results reported by Collins et al.12 for the equivalent
amphetamine reaction and minimal δ13C change was expected when MDMA is prepared from
MDP2P7.
According to the reaction mechanism,16, 17 as outlined below (see also Figure 4), the nitrogen
atom in the final MDA molecule is contributed to by the nitroethane nitrogen source. These
results suggest that δ15N values may be useful when attempting to compare MDA to the
nitroethane from which it was prepared. However, this nitrogen atom is lost when MDP2P is
prepared from MDP2NP, and a new nitrogen source is then required when MDMA is
synthesised from MDP2P. Previous research3-7 has shown some δ15N composition changes can
occur from nitrogen source to MDMA. Additional changes may occur to δ15N compositions
during the HCl salt precipitation of MDA and MDMA7.
Proceeding from piperonal to MDP2NP minimal change occurred to δ18O composition (Figure
2 (d)). Significantly more negative δ18O values were observed continuing from MDP2NP to
MDA (between –6.17 to –7.20‰). Some δ18O compositional change was expected at this step,
as two oxygen atoms are lost when MDA is prepared from MDP2NP. A slight change was
observed in MDP2P prepared from MDP2NP (between –0.81 and +1.40‰). An additional
change in δ18O composition can be expected if MDMA is prepared from MDP2P, as observed
during reductive amination.5-7
During the Henry reaction, piperonal and nitroethane react, under basic conditions, to give a β-
nitro alcohol intermediate, the mechanism for which has been outlined by Sasai16 and is
summarised in Figure 4. Dehydration of the β-nitro alcohol then produces MDP2NP.

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According to this mechanism the oxygen atom present in piperonal is lost during this
dehydration, and the two additional oxygen atoms present in MDP2NP are contributed by
nitroethane. This oxygen is ultimately lost when MDA or MDMA (via MDP2P) is produced.
As oxygen atoms are gained and lost during the production of MDA/MDMA from piperonal
and nitroethane, it is difficult to compare δ18O values between precursors and end-products,
δ18O values may, however, be useful when attempting to identify batch-to-batch variations.
The nitroalkene (MDP2NP) can be easily reduced to a nitroalkane, which undergoes additional
reduction to give MDA. While the mechanisms involved in the reduction of nitro compounds
to amines are not fully understood, it would appear that the nitrogen present in MDP2NP (and
contributed to by nitroethane) is indeed the nitrogen present in the final MDA molecule17. As
outlined in Figure 2 (c), minimal variation was observed in δ15N values changing between
MDP2NP and MDA, supporting this mechanism.
4 CONCLUSIONS
The results presented here can be of use when identifying batch-to-batch variations between
seizures of MDA or MDMA with tactical intelligence applications. During the production of
MDP2NP from piperonal, and MDP2P/MDA from MDP2NP a significantly negative change
occurred in δ2H composition. Although piperonal has been found with considerably positive
δ2H compositions, these values are not carried through to MDP2P or MDA. Additional changes
to δ2H are expected when MDMA is prepared from MDP2P. Minimal δ13C and δ15N
compositional changes occurred to MDP2NP, MDA and MDP2P; the latter does not contain
nitrogen, and an additional nitrogen source is included during the preparation of MDMA from
MDP2P. Changes can occur to δ15N composition during this step and the δ15N results moving
from piperonal to MDA are consistent with the proposed mechanism. From piperonal to
MDP2NP minimal change occurred to δ18O composition, and a slight change occurred from
MDP2NP to MDP2P. Additional δ18O compositional change is expected during the synthesis
of MDMA from MDP2P. A negative shift occurred to δ18O composition moving from
MDP2NP to MDA and the δ18O results support the proposed mechanism. Additional changes
to δ2H and δ15N compositions are expected if the HCl salt forms of MDA or MDMA are
produced.
ACKNOWLEDGMENTS
Griffith University, School of Environment and Science, Queensland Health Forensic and
Scientific Services (QH-FSS) (research project RSS19-015) and the Australian Government
Research Training Programme Scholarship are acknowledged.

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TABLE 1
Yield, purity (by GC/FID) and IRMS results for MDP2NP #1 and MDP2P #1 to 3 prepared
from piperonal and nitroethane. Isotopic compositions are expressed as per mil (‰)
sample yield (%) purity (%) δ2HVSMOW δ13CVPDB δ15NAIR δ18OVSMOW
piperonal 99.7 +99.4 –27.77 +17.93
nitroethane –2.21
MDP2NP #1 40.1 98.3 +41.7 –26.41 –2.35 +17.89
MDP2P #1 64.9 96.5 –28.7 –26.54 +17.44
MDP2P #2 55.1 98.1 –29.0 –26.65 +16.49
MDP2P #3 37.8 90.8 –28.2 –26.42 +18.70

TABLE 2
Purity (by GC/FID) and IRMS results for MDA #1 to #3 prepared from MDP2NP #2.
Isotopic compositions are expressed as per mil (‰)
sample yield (%) purity (%) δ2HVSMOW δ13CVPDB δ15NAIR δ18OVSMOW
MDP2NP #2 99.7 +73.5 –30.44 +0.31 +20.36
MDA #1 76.4 98.3 –37.9 –30.47 –1.17 +13.16
MDA #2 73.5 96.2 –40.6 –30.39 –0.29 +14.05
MDA #3 80.8 96.2 –39.3 –30.39 –0.60 +14.19

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Figure 1. The ‘nitrostyrene’ route shows MDA and MDMA prepared from piperonal via
MPD2NP and MDP2P

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Figure 2. Stable isotope ratios for MDP2P prepared from piperonal and nitroethane via
MDP2NP (orange), and MDA prepared from MDP2NP (red), error bars shown at 95%
confidence level

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Figure 3. δ2H results for MDP2P (red) and MDA (orange) prepared from MDP2NP and
piperonal prepared for this study (with error bars shown at 95% confidence level) compared
to amphetamine prepared from natural (green) and industrial (blue) benzaldehyde, provided
by Collins et al.12 (no error data available)

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Figure 4. During the Henry reaction an aldehyde and nitroalkane form a β-nitro-alcohol
which can dehydrate to give a nitroalkene. The nitroalkene can be reduced to an amine

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