Accepted Manuscript

Title: Identification and derivatization of selected cathinones

by spectroscopic studies

Author: Jacek E. Nycz Tadeusz Pazdziorek Grzegorz Malecki

Marcin Szala

PII: S0379-0738(16)30301-2
DOI: http://dx.doi.org/doi:10.1016/j.forsciint.2016.06.034
Reference: FSI 8527

To appear in: FSI

Received date: 31-3-2016

Revised date: 21-6-2016
Accepted date: 27-6-2016

Please cite this article as: J.E. Nycz, T. Pazdziorek, G. Malecki, M. Szala, Identification
and derivatization of selected cathinones by spectroscopic studies, Forensic Science
International (2016), http://dx.doi.org/10.1016/j.forsciint.2016.06.034

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 Identification and derivatization of selected cathinones by spectroscopic studies

Jacek E. Nycz,a* Tadeusz Pazdziorek,b Grzegorz Maleckia and Marcin Szalaa

a
Institute of Chemistry, University of Silesia, ul. Szkolna 9; PL-40007 Katowice, Poland.
b
Department of Chemistry, Forensic Laboratory, The Regional Headquarters Katowice,

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Poland.

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*
Corresponding author; E-mail: jacek.nycz@us.edu.pl

Page 1 of 37
 Identification and derivatization of selected cathinones by spectroscopic studies

ABSTRACT

In this study we identified three novel hydrochloride salts of cathinones 2-(pyrrolidin-1-yl)-1-

t
(5,6,7,8-tetrahydronaphthalen-2-yl)pentan-1-one (1a) (TH-PVP), 2-(methylamino)-1-(2-

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methylphenyl)-1-propanone (1b) (2-MMC) and 1-(4-chlorophenyl)-2-(methylamino)propan-

cr
1-one (1c) (4-CMC). Their properties have been examined through combinations of GC-MS,

IR, NMR, electronic absorption spectroscopy and single crystal X-ray diffraction method.

us
NMR solution spectra showed readily diagnostic H-1 and C-13 signals from methyl, N

methyl and carbonyl groups. Additionally the use of thionation and amination reactions for

an
identification of selected cathinones was presented.
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1. Introduction
d

The classical cathinones are a series of bioisostere compounds containing -

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aminopropiophenone moiety. They are the derivatives of cathinone, a natural amphetamine-

like alkaloid, which is the major pharmacologically active constituent extracted from fresh
p

leaves and stems of Catha edulis Forsk, Celastraceae (Khat) [1]. The first described synthesis
ce

of cathinones was published in 1928 [2]. Independent to J.F. Hyde et al. in 1929 Saem de

Burnaga Sanchez reported the synthesis of mephedrone as an example of cathinone [3]. Until
Ac

now over 97 individual substances were reported to United Nations Office on Drugs Crime

(UNODC) up to July 2015 [4]. The cathinones are expected to act as a central nervous system

stimulants by promoting the release of monoamine neurotransmitters such as catecholamines

and likely inhibiting their reuptake [5]. Their pharmacological profiles were closely resemble

to that of amphetamine's acting on central nervous system and subsequent sympathomimetic

effects. Frequently cathinones with chiral atom centre show differing potencies for every

Page 2 of 37
enantiomeric form [5]. The postulated metabolic phase I pathways of cathinones are through

the N-dealkylation in particular demethylations, followed by the O-methylation and reduction

of the keto moiety to alcohols, and the oxidation of the tolyl moiety to the corresponding

alcohols or carboxylic acids [6, 7]. Until now there is only the Zimmerman test suitable for

t
identification of synthetic cathinones, which provides a clear and unambiguous response for

ip
both the hydrochloride and hydrobromide salts in most cases.

cr
Recently we have already presented five novel cathinones and their hydrochloride salts. They

were characterized by FTIR, UV-Vis, multinuclear NMR spectroscopy and four by single

us
crystal X-ray diffraction method [8]. The current work focused on characteristic reactions for

the identification of keto fragment in cathinone constitution and three novel representatives of

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the compounds in their hydrochloride salt form through the combination of IR, NMR, GC-
M
MS, electronic absorption spectroscopy and single crystal X-ray diffraction method.
d

2. Experimental
te

2.1 Apparatus

NMR spectra were obtained with Bruker Avance 400 operating at 400.13 MHz (1H) and
p

100.5 MHz (13C) at 21oC; chemical shifts referenced to ext. TMS (1H, 13
C); coupling
ce

constants are given in Hz. The 1H and 13C NMR calculations were performed with the ACD

Labs NMR Predictor v.7 program. For GC-MS a Gas Chromatograph Agilent Technologies
Ac

7890A with MS 5975 EI/CI MSD with autosampler 7693 with capillary column Agilent HP-

5MS (30 m x 0.25 mm x 0.25 m) was used. FTIR spectra were recorded on a Perkin Elmer

spectrophotometer in the spectral range 4000450 cm-1 with the samples in the form of KBr

pellets. Electronic spectra were measured on a spectrophotometer Lab. Alliance UVVis 8500

in the range 500180 nm in CH2Cl2 solution. Melting points were determined on MPA100

OptiMelt melting point apparatus and uncorrected.

Page 3 of 37
2.2 Materials

All experiments were carried out in an atmosphere of argon. The analyzed hydrochloride salts

of 1a, 1b and 1c were confiscated in 2015 by the police in the Upper Silesia region of South

t
Poland and delivered to our laboratory for spectroscopic examination. Lawessons reagent

ip
(LR), tetraphosphorusdecasulfide (P4S10) and aminoguanidine bicarbonate were purchased

cr
from SigmaAldrich, and were used without further purification.

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2.3 Synthesis of thiocathinones

To a suspension of LR (0.505 g, 1.25 mmol) or P4S10 (0.556 g, 1.25 mmol) in pyridine (20

an
mL) appropriate hydrochloride salts of 1a, 1b or 1c (1.25 mmol) was added in one portion.
M
The reaction mixture was stirred under reflux overnight. Then the reaction mixture was

allowed to cool down to room temperature, and ethanol (100 mL) was added. After the
d

solvents were evaporated a sample of the reaction mixture was taken for NMR analysis and

the 13C NMR and 31P{1H} NMR spectra were recorded.

p te

2.4 Amination reactions

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Aminoguanidine bicarbonate (0.38 g, 2.8 mmol) was partially dissolved in a mixture of

methanol (15 mL) and water (15 mL). Subsequently, K2CO3 (0.39 g, 2.8 mmol) was added,
Ac

and the reagents were heated under reflux for an hour, then hydrochloride salt of 1a (0.90 g,

2.8 mmol) in a solution of methanol (5 mL) was added. After the addition, the reaction

mixture was stirred under reflux overnight, followed by filtration. After the solvents were

evaporated a sample of the reaction mixture was taken and the GC-MS spectra were recorded.

2.5 Test reactions

Page 4 of 37
All colour tests were interpreted: immediately (0 min), after 5 min, 15 min, 30 min, 60 min

and 20 hours.

2.5.1 Thionation

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To the solution of hydrochloride salts of 1a, 1b or 1c (10 mg) in pyridine (5 mL) LR (10 mg)

ip
was added. The reaction mixture was vigorously stirred at 100C under argon. Resulting

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colours were presented on the Figure 4.

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2.6 Identification of drug samples

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2.6.1 Sample preparation for the purpose of liquid and gas chromatography

The water solution of hydrochloride salts of 1a, 1b or 1c was alkalified by K2CO3. Reagents
M
were shaken for a few minutes. The mixture was poured into CH2Cl2. The organic phase was

separated and dried by MgSO4. After the solvent was evaporated, the residue was analyzed by
d

gas chromatography:
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2-(Pyrrolidin-1-yl)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)pentan-1-one (TH-PVP; 1a);

GC-MS: tr = 8.94 min.; (EI) (M-H)+ = 284, 159 (benzoyl part 3%).
p

2-(Methylamino)-1-o-tolylpropan-1-one (2-MMC; 1b); GC-MS: tr = 4.99 min.; (EI)

ce

(M+H)+ = 178 (0.1%), 119 (benzoyl part 6%).

1-(4-Chlorophenyl)-2-(methylamino)propan-1-one (4-CMC; 1c); GC-MS: tr = 5.58 min.,

Ac

(EI) (M+H)+ = 198 (0.5%), 139 (benzoyl part 13%).

2.6.2 Spectroscopic characterization and physical data

1a x HCl; mpdec = 197.5C; 1H NMR (DMSOd6; 400.2 MHz) = 0.80 (t, J = 7.2 Hz, 3H,

CH3), 1.11 (m, 1H, CH2), 1.26 (m, 1H, CH2), 1.77 (m, 4H, CH2), 1.95 (m, 6H, CH2), 2.82 (m,

4H, CH2), 3.03 (m, 1H, CH2), 3.27 (m, 1H, CH2), 3.46 (m, 1H, CH2), 3.63 (m, 1H, CH2), 5.43

Page 5 of 37
(m, 1H, CH), 7.29 (d, J = 7.7 Hz, 1H, aromatic), 7.79 (m, 2H, aromatic), 10.56 (bs, 1H, NH);
13
C{1H} NMR(DMSOd6; 100.6 MHz) = 13.4, 17.3, 21.9, 22.0, 22.6, 28.4, 28.8, 31.6, 51.7,

53.2, 66.6, 125.6, 129.2, 129.5, 132.0, 137.6, 144.8, 195.9; UV-Vis (methanol; [nm]): 202,

222, 267; IR (KBr): 3324 (NH), 2957, 2938 (PhH), 2871, 2839 (CH3), 1671 (s C=O),

t
1604 (scissor. NH2), 1570 (C=C), 1448 (PhH), 1255, 1230 (C-N), 771, 755 (wag. NH2);

ip
CCDC 1416393.

cr
1b x HCl; mpdec. = 150.8C; 1H NMR (DMSOd6; 400.2MHz) = 1.35 (d, J = 7.2 Hz, 3H,

us
CH3), 2.42 (s, 3H, CH3), 2.60 (s, 3H, CH3), 5.07 (q, J = 7.2 Hz, 1H, CH), 7.38 (m, 2H,

aromatic), 7.53 (d, J = 7.4 Hz, 1H, aromatic), 7.91 (d, J = 7.7 Hz, 1H, aromatic), 9.58 (s, 2H,

an
NH2); 13C{1H} NMR (DMSOd6; 100.6MHz) = 14.4, 20.6, 30.5, 59.6, 126.2, 129.2, 132.0,

132.7, 133.6, 138.6, 199.2; UV-Vis (methanol; [nm]): 205, 215, 257; IR (KBr): 3372
M
(NH), 2984, 2959 (PhH), 2889, 2738 (CH3), 1697 (s C=O), 1601 (scissor. NH2), 1584

(C=C), 1456 (PhH), 1302, 1247 (C-N), 754, 728 (wag. NH2); CCDC 1422008.
d

1c x HCl; mpdec. = 210.9C; 1H NMR (DMSOd6; 400.2 MHz) = 1.45 (d, J = 7.2 Hz, 3H,
te

CH3), 2.58 (s, 3H, NCH3), 5.18 (q, J = 7.1 Hz, 1H, CH), 7.68 (d, J = 8.6 Hz, 1H, aromatic),
p

13
8.06 (d, J = 8.7 Hz, 1H, aromatic), 9.32 (s, 1H, NH), 9.77 (s, 1H, NH); C{1H}
ce

NMR(DMSOd6; 100.6MHz) = 15.2, 30.6, 58.2, 129.3, 130.7, 131.7, 139.6, 195.4; UV-Vis

(methanol; [nm]): 207, 247, 291; IR (KBr): 3443, 3366 (NH), 3062, 3036 (PhH), 2744
Ac

(CH3), 1682, 1679 (s C=O), 1623 (scissor. NH2), 1589 (C=C), 1454 (PhH), 1345, 1295

(C-N), 778, 741 (wag. NH2); CCDC 1434968.

2.7 Crystallization

The colorless crystals suitable for X-ray analysis were obtained from hot water solution of the

hydrochloride salts of 1a, 1b and 1c.

Page 6 of 37
3. Results and discussion

Every day on the market new psychoactive substances are emerging. The preliminary

identification of cathinones and their analogues presents a growing challenge. V. Gambaro et

al. indentified non classical thiothinone, 2-(methylamino)-1-(2-thienyl)-1-propanone, also

t
known as MTPA, where the phenyl group is replaced with a thiophene ring [9]. Thiothinone

ip
is a bioisostere of methcathinone. Bioisosteres appear on the market complicated the routine

cr
identification. The further complication and danger are the ambiguity and chemical

complexity of the substances. A. Klein has identified black cocaine as a chemical

us
composition of a forensically relevant black powder composed of cocaine, copper, iron,

thiocyanate, and graphite [10]. We could expect that similarly the metal cations to cathinone

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base might modify their essential properties so that improved solubility or hampered
M
detection.
d

3.1 GC-MS studies

te

For the identification of confiscated cathinones, non-target screening, a capillary GC coupled

with electron impact ionisation mass spectrometer (GC-EIMS) is widely used (Figure 1) [11-
p

13].
ce

((Figure 1_1a))

((Figure 1_1b))
Ac

((Figure 1_1c))

Figure 1. Chromatograms of the confiscated cathinones 1a, 1b and 1c.

However, frequently no molecular ion is detectable on the obtained mass spectrum using this

method. Even if the target compound to be identified was registered in a database, it is

difficult to accurately distinguish it from phenethylamine-based compounds which had mass-

Page 7 of 37
spectrum patterns highly similar to those of the cathinone-based compounds. The cathinones 1

during ionization underwent -fragmentation leading to a benzoyl part giving m/z = 159 (for

1a), 119 (for 1b) and 139 (for 1c) fragmentation ions (Figure 2).

((Figure 2_1a))

t
((Figure 2_1b))

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((Figure 2_1c))

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Figure 2. Mass spectra of the confiscated cathinones 1.

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3.2 NMR studies

The 1H NMR solution spectra of examined hydrochloride salts of cathinones 1 showed

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distinctive H-1 signals from aromatic protons and CH or CH3 groups. For C-13 NMR
M
spectroscopy the largest difference is visible by comparing aromatic signals because of their

structural and chemical differences. The chemical shifts of experimental and calculated
d

carbonyl group are almost the same, ca. 194 ppm and they are similar to our earlier work
te

results [8]. An only experimental chemical shift in 1b was moved significantly to downfield

(larger ). The deshielding effect (downfield shift) can be explained in the frame of electron
p

density.
ce

13
Table 1. The experimental (Ex.) and calculated (Cal.) C chemical shifts of hydrochloride

salts of cathinone 1 in DMSO-d6.

Ac

((Table 1))

3.3 Color reaction studies

In these studies we focused on the characteristic reactions of carbonyl group, which is the

most distinguish part of cathinone in comparison with amphetamine-based compounds. Color

test remains an important tool for the preliminary test of suspected illicit drug samples since

they are inexpensive and readily available without any use of analytical equipment. However,

Page 8 of 37
the color reaction used for the detection of a given controlled substance is not specific, which

might be interfered by other materials to form similar colors. Furthermore, in certain cases no

reaction was observed even though a controlled drug may be presented. Frequently the

mechanism of color reaction is unknown. Therefore, further experiments were required to find

t
potentially useful reagents as future color tests for cathinone type of compounds.

ip
The analyzed hydrochloride salts of 1a, 1b and 1c were confiscated in 2015 by the police in

cr
the Upper Silesia region of South Poland as a white powder and/or crystals (Fig. 3).

((Figure 3))

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Figure 3. The forms of confiscated hydrochloride salts of 1a, 1b and 1c.

3.3.1 Synthesis of thiocathinones

an
M
In literature there were many reported thionating agents such as sulfur dihydride,

tetraphosphorusdecasulfide (P4S10), Davy, Heimgartner or Lawessons reagents (LR) which

d

could convert carbonyls into thiocarbonyl compounds [14-17]. However this type of
te

transformation only found limited applications for the synthesis of simple thioketones because

they were relatively unstable at room temperature [18]. The selected reagents for the current
p

thionations reactions were P4S10 and LR due to their low cost of the starting materials and the
ce

simplicity of the synthesis (Scheme 1 and Fig.4).

((Scheme 1))
Ac

Scheme 1. Thionation of hydrochloride salts of 1. Reagents and conditions: (i) P4S10, Py

reflux, (ii) LR, Py reflux.

((Figure 4))

Figure 4. The reaction mixtures from thionation reactions of LR and confiscated

hydrochloride salts of 1a (A), 1b (B) and 1c (C).

Page 9 of 37
The 1H NMR, 13
C NMR and 31
P{1H} NMR analysis showed complicated reaction mixture.

From the theoretical point of view it was only expected the presence of one or two signals

from carbonyl group or thiocarbonyl, as a result of simple and expected transformation

13
process of >C=O group into >C=S. However, on each C NMR spectrum from all reaction

t
mixtures, in the range of 190-210 ppm more than five signals corresponding to carbonyl or

ip
thiocarbonyl group were identified. These results could be interpreted based on the additional

cr
reaction of cathinones through their nitrogen centre with the phosphorus atom of P4S10, or LR

(Scheme 1). Cathinones, as N-nucleophiles should react faster with P4S10, or LR than that

us
through the simple thionation transformation of carbonyl group. This reactivity was evidenced

by the complicated 31P{1H} NMR spectra with four intense signals 93.9, 90.9, 83.5 and 81.4

an
ppm, which were characteristic for compounds with N-P(=S)S2 fragments [19]. Aydemir et
M
al. reported similar type of reactivity leading to N-phosphorylated products [20].
d

3.3.2 Elimination reaction, induced by a nucleophilic addition of aminoguanidine to the

te

carbonyl group of 1a

Other reagents of choice are primary amines such as guanidine and aminoguanidine. Carbonyl
p

groups as electrophiles are subject to be attacked by nucleophiles, and participate in many

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nucleophilic addition and condensation reactions. Due to its huge potential there were many

papers describing this type of conversion. In most cases products were Schiff bases. However,
Ac

there were a few reports showing the ring closure reaction including our attempts [21].

((Scheme 2))

Scheme 2. Elimination reaction, induced by a nucleophilic addition of aminoguanidine to the

carbonyl group of 1a. Reagents and conditions: (i) aminoguanidine, MeOH, K2CO3, reflux.

((Figure 5))

Figure 5. Chromatogram of the reaction mixture from the reaction of 1a and aminoguanidine.

Page 10 of 37
 ((Figure 6_E))

((Figure 6_Z))

Figure 6. Mass spectra of the products from the reaction of 1a and aminoguanidine; tr = 9.814

min, (EI) (M-H)+ = 268 (top), tr = 9.845 min, (EI) (M-H)+ = 268 (bottom).

t
ip
In this paper, we reported the transformation of carbonyl group of selected cathinones by

cr
aminoguanidine to their dehydrated derivatives. Similarly to the Schiff base synthesis the

ketone fragment was heated in a solution of primary amines such as aminoguanidine. The

us
analysis of GC chromatogram showed two additional signals with similar mass-spectrum

patterns, and the same m/z (Figure 5). This result was interpreted by the reaction of primary

an
amines to the carbonyl group of cathinone to form labile Schiff base, followed an elimination
M
process which converted it into a vinyl group, giving two E/Z (cis-trans) isomers namely (E)-

1-(1-(5,6,7,8-tetrahydronaphthalen-2-yl)pent-1-en-2-yl)pyrrolidine and (Z)-1-(1-(5,6,7,8-

d

tetrahydronaphthalen-2-yl)pent-1-en-2-yl)pyrrolidine, in a 1:2.8 ratio (Figure 5 and 6). Both

conformers were characterized as m/z = 268 [M-H]+ pseudo-molecular ions and a m/z = 198
te

fragmentation ions. It is very probable that the elimination process of pyrrolidine was easier
p

for Z conformer because of the trans position of both hydrogen and pyrrolidine group
ce

(Scheme 3 and Figure 6).

((Scheme 3))
Ac

Scheme 3. Illustration of the process of removing pyrrolidine and Et part from products of

amination reaction of 1a.

3.4 Crystal structure determination and refinement

The crystals of the hydrochloride salts of 1a, 1b and 1c were mounted in turn on a Gemini A

Ultra automatic diffractometer equipped with a CCD detector for data collection. X-ray

Page 11 of 37
intensity data were collected with graphite monochromated MoK radiations at room

temperature with scan mode. Lorentz, polarization and empirical absorption correction

using spherical harmonics implemented in SCALE3 ABSPACK scaling algorithm were

applied [22]. The structures were solved by the direct method and subsequently completed by

t
the difference Fourier recycling. All the non-hydrogen atoms were refined anisotropically

ip
using full-matrix, least-squares technique. All the hydrogen atoms were found from difference

cr
Fourier synthesis after four cycles of anisotropic refinement, and refined as riding on the

adjacent carbon atom with individual isotropic temperature factor equal to 1.2 times the value

us
of equivalent temperature factor of the parent atom. The Olex2 [23] and SHELXS, SHELXL

an
[24] programs were used for all the calculations. Details of crystal data and refinement are

gathered in Table 2 and selected bond lengths in Table 3. Presented data correspond well with
M
our earlier works and literature data [8, 25]. The molecular structures of the hydrochloride

salts of 1a, 1b and 1c compounds are shown on the Figure 7.

d
te

Table 2. Crystal data and structure refinement details of hydrochloride salts of 1a, 1b and 1c.

((Table 2))
p

((Figure 7_1a))
ce

((Figure 7_1b))

((Figure 7_1c))
Ac

Figure 7. ORTEP drawings of hydrochloride salts of 1a, 1b and 1c.

Table 3. Selected bond lengths for hydrochloride salts of 1a, 1b and 1c ().

((Table 3))

In the structure of the hydrochloride salt of 1c compound the intramolecular hydrogen bonds

create the dimers of D11 (2) type (ClHO/HN) and moreover the crystal structure is stabilized

Page 12 of 37
by stacking interaction between parallel phenyl rings as one can see from the data collected in

tables 4 and 5.

Table 4. Hydrogen bonds for hydrochloride salts of 1b and 1c ( and o).

t
((Table 4))

ip
Symmetry transformations used to generate equivalent atoms: #1 -1-x,1-y,-z; #2 -1+x,y,z

cr
Table 5. -stacking interactions in molecular structures of hydrochloride salt of 1c.

((Table 5))

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4. Conclusion

In the present study, we reported the spectroscopic characterization through the combinations

an
of GC-MS, IR, NMR, electronic absorption spectroscopy and single crystal X-ray diffraction

method for three novel crystalline hydrochloride salts of cathinones. The chemical
M
characteristics of cathinones was shown through their thionation reactions and dehydration

induced by a nucleophilic addition of aminoguanidine to the carbonyl group. The examination

d

of the crystal structure and the chemical reactivity especially with primary amines of the title
te

compounds will lead to a better understanding of cathinones. Furthermore, the presented idea
p

to derivatization of carbonyl group can be used in future to identify and separate new
ce

cathinone derivatives.
Ac

Page 13 of 37
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t
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ce

[15] C. Trebaul, J. Teste, Bull. Soc. Chim. Fr. Composs htrocycliques soufrs. VII.

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Ac

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[18] T.J. Curphey, Thionation with the reagent combination of phosphorus pentasulfide and

hexamethyldisiloxane, J. Org. Chem. 67 (2002) 64616473.

[19] W. Feng, X.-Y. Teo, W. Novera, P. M. Ramanujulu, D. Liang, D. Huang, P. K. Moore,

L.-W. Deng, B. W. Dymock, Discovery of new H2S releasing phosphordithioates and 2,3-

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dihydro-2-phenyl-2-sulfanylenebenzo[d][1,3,2]oxazaphospholes with improved

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antiproliferative activity, J. Med. Chem. 58 (2015) 64566480.

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[20] C. Aydemir, M. Karakus, I. Kara, A. . Kiraz, N. Kolsuz, Synthesis and theoretical

studies on new amidodithiophosphonates, J. Mol. Struct. 1111 (2016) 6168.

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[21] J.E. Nycz, G.J. Malecki, One-step aldehyde group transformation by using guanidine and

aminoguanidine: synthetic, structural and computational studies, J. Mol. Struct. 1064 (2014)

4449.
an
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[22] CrysAlis RED, Oxford Diffraction Ltd., Version 1.171.37.35g

[23] O.V. Dolomanov, L.J. Bourhis, R.J. Gildea, J.A.K. Howard, H. Puschmann, OLEX2: a
d

complete structure solution, refinement and analysis program, J. Appl. Cryst. 42 (2009) 339
te

341.

[24] G.M. Sheldrick, A short history of SHELX, Acta Cryst. A64 (2008) 112122.
p

[25] D. Trzybiski, P. Niedziakowski, T. Ossowski, A. Trynda, A. Sikorski, Single-crystal

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X-ray diffraction analysis of designer drugs: Hydrochlorides of metaphedrone and

pentedrone, Forensic Sci. Int. 232 (2013) e28e32.

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 13
Table 1. The experimental (Ex.) and calculated (Cal.) C chemical shifts of hydrochloride

salts of cathinone 1 in DMSO-d6.

1 x HCl Alkyl Aryl C=O

1a Ex. 13.4, 17.3, 21.9, 22.0, 22.63, 28.4, 28.8, 125.6, 129.2, 129.5, 132.0, 195.9
31.6, 51.7, 53.2, 66.6 137.6, 144.8

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Cal. 13.3, 18.0, 22.9, 23.1, 23.4, 25.5, 30.6, 123.3, 126.1, 127.3, 129.7, 193.6
30.8, 52.3, 67.6 140.0, 146.0

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1b Ex. 14.4, 20.6, 30.5, 59.6 126.2, 129.2, 132.0, 132.7, 199.2
133.6, 138.6

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Cal. 7.2, 19.9, 30.6, 42.4 128.3, 128.6, 129.5, 130.7, 193.8
131.3, 136.6
1c Ex. 15.2, 30.6, 58.2 129.3, 130.7, 131.7, 139.6 195.4

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Cal. 7.0, 30.8, 41.9 127.1, 130.0, 130.4, 140.3 193.2

Table 2. Crystal data and structure refinement details of hydrochloride salts of 1a, 1b and 1c.
M
1a x HCl 1b x HCl 1c x HCl
Empirical formula C19H28NO, Cl C11H16NO, Cl C10H13ClNO, H2O, Cl
Formula weight 321.87 213.70 252.13
d

Temperature [K] 295(2) 295(2) 295(2)

Wavelength [] 0.71073 (MoK) 0.71073 (Mo K) 0.71073 (Mo K)
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Crystal system monoclinic orthorhombic monoclinic

Space group P21/c Pbca P21/n
Unit cell dimensions
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a[] 13.9294(17) 13.2859(6) 6.1057(3)

b[] 11.9238(12) 7.2153(4) 6.1057(3)
c[] 11.4610(12) 23.8804(14) 6.1057(3)
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90 90 90
111.405(14) 90 90.146(5)
90 90 90
Volume [3] 1772.3(4) 2289.2(2) 1209.54(11)
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Z 4 8 4
Calculated density[Mg/m3] 1.206 1.240 1.385
Absorption coefficient[mm1] 0.218 0.303 0.518
F(000) 696 912 528
Crystal dimensions[mm] 0.18x0.12x0.03 0.22x0.17x0.07 0.24x0.14x0.04
range for data collection [] 3.417 to 25.040 3.413 to 25.242 3.346 to 25.242
Index ranges -14h16; -11k11; -13l11 -14h18; -7k9; -32l22 -8h8; -8k10; -33l31
Reflections collected 7325 8594 10879
Independent reflections 3129[R(int) = 0.0451] 2824[R(int) = 0.0358] 3025[R(int) = 0.0357]
Data / restraints / parameters 3129/ 0 /200 2824/ 0 /130 3025/ 0/ 142
Goodness-of-fit on F2 1.055 1.034 1.028
Final R indices [I>2(I)] R1=0.0640; wR2=0.1753 R1=0.0420; wR2=0.1001 R1=0.0389; wR2=0.0837
R indices (all data) R1=0.0973; wR2=0.1955 R1=0.0619; wR2=0.1124 R1=0.0587; wR2=0.0938
Largest diff. Peak and hole 0.540/0.242 0.258/ -0.206 0.259// -0.288
CCDC number 1416393 1422008 1434968

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Table 3. Selected bond lengths for hydrochloride salts of 1a, 1b and 1c ().

1a 1b 1c
C=O 1.212(4) 1.213(2) 1.216(2)
N(1)-C(H) 1.492(4) 1.487(2) 1.491(2)
N(1)-C(H2) 1.508(5) 1.484(2) 1.486(2)

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N(1)-C(H2) 1.496(4) - -

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Caryl-C=O 1.477(5) 1.492(2) 1.480(2)
O=C-C 1.534(4) 1.525(2) 1.525(2)

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C-C(alkyl) 1.548(5) 1.518(2) 1.518(2)

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Table 4. Hydrogen bonds for hydrochloride salts of 1b and 1c ( and o).

D-H...A d(DH) d(H...A) d(D...A) <(DHA)

M
1b
N(1)H(1A)O(1) 0.89 2.30 2.6054(16) 99.8
1c
d

N(1)H(1A)Cl(2) #1 0.89 2.24 3.0873(13) 158.9

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N(1)H(1B)O(2) #2 0.89 1.99 2.8123(18) 153.5

Symmetry transformations used to generate equivalent atoms: #1 -1-x,1-y,-z; #2 -1+x,y,z
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Table 5. -stacking interactions in molecular structures of hydrochloride salt of 1c.

angle [o] distance [] shift distance []

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1c centroid: #Cg1: (C1-C6)

#Cg1:#Cg1 [-1-x,1-y,-z] 0.000 3.841 1.791

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Highlights

Three HCl salts of cathinones have been characterized by X-ray crystallography

Three HCl salts of cathinones have been identified by GC-MS, IR, NMR and UV-Vis

The use of thionation reactions for identification of selected cathinones

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Graphical Abstract (Adobe Photoshop Version: 12.0)

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Figure 1_1a (Adobe Photoshop Version: 12.0)

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Figure 1_1b (Adobe Photoshop Version: 12.0)

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Figure 1_1c (Adobe Photoshop Version: 12.0)

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Figure 2_1a (Adobe Photoshop Version: 12.0)

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Figure 2_1b (Adobe Photoshop Version: 12.0)

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Figure 2_1c (Adobe Photoshop Version: 12.0)

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Figure 3 (Adobe Photoshop Version: 12.0)

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Figure 4 (Adobe Photoshop Version: 12.0)

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Figure 5_GC (Adobe Photoshop Version: 12.0)

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Figure 6_EA (Adobe Photoshop Version: 12.0)

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Figure 6 MS_ZA Adobe Photoshop Version: 12.0)

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Figure 7_1a (Olex 2)

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Figure 7_1b (Olex 2)

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Figure 7_1c (Olex 2)

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Scheme 1 (ChemDraw)

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Scheme 2 (ChemDraw)

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Scheme 3 (ChemDraw)

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