Recently, a new class of psychoactive substances, synthetic cathinones, has emerged on the drug-use market. Each year the European Union (EU) warning system operated by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) notifies the appearance of new synthetic cathinone derivatives. Those compounds are the second biggest (after synthetic cannabinoids) group of new psychoactive substances monitored by the EMCDDA. According to the last report, the group of monitored synthetic cathinones consists of 130 substances. Synthetic cathinones are related to the parent cathinone, one of the psychoactive substances naturally present in khat (Catha edulis
). Cathinone derivatives can be also considered as the β
-keto analogues of amphetamine [1
Cathinone derivatives can easily pass through the brain–blood barrier and because of structural similarities with phenethylamine, they display psychoactive properties. The most important mechanism of action of cathinones is inhibiting of protein-transporting monoamines (dopamine, noradrenaline and serotonin) of the synaptic gap. The sympathomimetic syndrome dominates in a clinical picture [2
].4-CDC / 4-cdc crystals / 4-cdc crystals Buy
Due to the properties of synthetic cathinones, attempts have been made to use them in medicine. In the first half of the twentieth century, they were used to treat parkinsonism, depression and obesity, but because of the danger they brought, the efforts to use them for medical purposes were abandoned. Synthetic cathinones gained interest in the illegal drug market after 2000, when they began to be used as “legal highs”. Since then, further cathinones were synthesized and marketed, posing a real threat to public health [4
Cathinones cause a number of side effects associated with the cardiovascular system (increased heart rate, arrhythmias, increased blood pressure, myocardial ischemia with ECG changes and chest pain, myocarditis and sudden cardiac death), the coagulation system (disseminated vascular coagulation syndrome and decrease in platelet count), the nervous system (sleep disturbances, headache, vision disorder, mydriasis, paresthesia, convulsions and hyperthermia), and the gastrointestinal tract (nausea, vomiting and abdominal pain). These compounds also cause mental disorders and metabolic disorders (including metabolic acidosis, dehydration, electrolyte disorders and nitrogen body retention). The most commonly reported adverse reactions for cathinones are cardiovascular, nervous, and psychiatric disorders (including acute psychoses).4-CDC / 4-cdc crystals / 4-cdc crystals Buy
To the best of the authors’ knowledge, the first synthesis of a synthetic cathinone was described in 1928 by Hyde et al. [6
]. Cathinone derivatives occurring on the drug market leads to compounds that can be divided into four groups:
a) cathinones modified on C-α (alkylation is the most popular);
b) N-alkylated cathinones—one or two alkyl group attached to the nitrogen atom, it is also possible to incorporate the nitrogen atom into the pyrrolidine ring;
c) cathinones containing a modified aromatic ring, e.g., an alkyl or halogen substituent, as well as additional 3,4-methylenedioxy group that can be attached to the phenyl ring; and
d) compounds with two or more of the above-mentioned modifications [7
The popularity of synthetic cathinones results in numerous publications devoted to their analysis using various research methods among which LC-MS remains the most popular [8
]. Successful attempts are also being made regarding identification of specific enantiomers of synthetic cathinones by various spectroscopic methods [17
]. X-ray diffraction methods are also widely applied for NPS analyses. Both powder diffraction and single-crystal X-ray crystallography provide valuable information on the structure of these compounds and help in their identification [14
]. Therefore, enlarging the database of the crystal structures of synthetic cathinones can significantly facilitate the analysis of material evidence to law enforcement authorities.
Herein we report the results of the analysis of four cathinones: 4-CDC / 4-cdc crystals / 4-cdc crystals Buy, tBuONE, 4F-PHP and 3-MEC (1
, ), carried out using various instrumental methods. The analyzed samples were products seized by the police during the apartment search. To the best of the authors’ knowledge, all presented crystal structures for 1
are published for the first time. Chromatographic analyses of Compounds 1
(GC-MS) and NMR data for 1
were reported before [20
]. They are convergent with our results. 4F-PHP was also studied in a toxicokinetic context [26
Figure 1. Structures of 1-(4-chlorophenyl)-2-(dimethylamino)propan-1-one hydrochloride (1), 1-(1,3-benzodioxol-5-yl)-2-(tert-butylamino)propan-1-one hydrochloride (2), 1-(4-fluorophenyl)-2-(pyrrolidin-1-yl)hexan-1-one hydrobromide (3) and 2-(ethylamino)-1-(3-methylphenyl)propan-1-one hydrochloride (4).
2. Materials and Methods
4-CDC / 4-cdc crystals / 4-cdc crystals Buy . Chemicals and reagents used in analyses were acetonitrile, methanol, water (Chem Solve LC–MS, Witko, Łódź, Poland), ammonium formate (Fluka, Seelze, Germany), formic acid (Sigma-Aldrich, Darmstadt, Germany) and DMSO-d6 (Sigma-Aldrich, Darmstadt, Germany).
Analyzed compounds have been seized by the police during the search of an apartment. Secured evidence () in the form of a white crystalline powder was packed in sachets of two different sizes: one of them contained 1 g, the other 0.5 g. Performed analyzes showed that each of the evidence contained only one of the psychoactive substances described in this paper.
Figure 2. Material evidence seized by the police. From left to right: 1-(4-chlorophenyl)-2-(dimethylamino)propan-1-one hydrochloride (1), 1-(1,3-benzodioxol-5-yl)-2-(tert-butylamino)propan-1-one hydrochloride (2), 1-(4-fluorophenyl)-2-(pyrrolidin-1-yl)hexan-1-one hydrobromide (3) and 2-(ethylamino)-1-(3-methylphenyl)propan-1-one hydrochloride (4).
2.3. X-ray Crystallography
4-CDC / 4-cdc crystals / 4-cdc crystals Buy . X-ray quality crystals were taken directly from crude sample (sachet content). Single-crystal data collection was performed on a KUMA diffractometer (Rigaku Americas Holding Company, Inc. The Woodlands, Texas, TX, USA) with a Saphire CCD detector, equipped with an Oxford Cryosystems open-flow nitrogen cryostat, using ω-scan and graphite-monochromated Mo Kα
= 0.71073 Å) radiation at 100 K. Cell refinement, data reduction, analysis and absorption correction were carried out with CRYSALISPro
] software. The structures were solved by direct methods with SHELXS [21
], and refined with full-matrix least-squares techniques on F2
with SHELXL [28
]. All hydrogen atoms were calculated in idealized geometry riding on their parent atoms. The molecular structure plots were prepared using Diamond [29
]. Full details can be found in the CIF files CCDC 1945259–1945262.
2.4. NMR Spectra
NMR spectra were recorded in DMSO-d6 at room temperature on a Bruker 500 MHz Avance II spectrometer (Billerica, Massachusetts, MA, USA) (1H frequency 500.13 MHz, 13C 125.7 MHz). Spectra were referenced to the residual solvent signals (2.50 and 39.5 ppm). 2D experiments (COSY, HSQC, HMBC) were performed by means of standard Bruker software, recorded with 2048 data points in the t2 domain and up to 1024 points in the t1 domain, with a 0.5–1 s recovery delay.
2.5. LC-MS/MS Analysis For 4-CDC / 4-cdc crystals / 4-cdc crystals Buy
A total of 100 mg of the sample was dissolved in 5 mL of methanol and diluted 1000-fold with MeOH. A total of 10 μL of diluted solution was transferred to a 150 μL insert containing 80 μL of MeOH and 10 μL of IS (4-MMC-d3, c = 1 μg/mL), mixed on a vortex and analyzed with UHPLC-QQQ-MS/MS.
Analyses were performed using an ultra-high-performance liquid chromatograph (Nexera X2, Shimadzu, Kyoto, Japan). The separation was done using a Kinetex XB-C18 2.6 μm 2.1 mm × 150 mm column (Phenomenex, Torrance, California, CA, USA) with the thermostat set at 40 °C. The mobile phase consisted of a mixture of 10 mM ammonium formate and 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). The gradient elution was carried out at a constant flow of 0.4 mL/min. The gradient applied was as follows: 0 min, 5% B; 12 min, 98% B; 14 min, 98% B; and 15 min, 5% B. A return to the initial gradient compositions (95% A and 5% B) was performed at 5 min.
Detection of the investigated compounds was achieved using a triple-quadrupole mass spectrometer (LCMS-8050, Shimadzu, Kyoto, Japan). The spectrometer was equipped with an ESI source; determination of the investigated substances was carried out in the Scan mode with positive ionization, and mass range of 50–1000 m/z. The following MS parameters were fixed: nebulizing gas flow, 3 L/min; heating gas flow, 10 L/min; interface temperature, 250 °C; DL temperature, 200 °C; heat block temperature, 350 °C; and drying gas flow, 10 L/min.
2.6. GC-MS Analysis For 4-CDC / 4-cdc crystals / 4-cdc crystals Buy
A 100 mg sample was dissolved in 5 mL of methanol and analyzed with GC-MC. Gas chromatography–mass spectrometry (GC-MS) analyses were performed using a gas chromatograph coupled with a triple quadrupole mass spectrometer (GC-MS-TQ8040; Shimadzu, Kyoto, Japan). The injector was maintained at 250 °C. Sample injection (2 μL) was in the direct mode. Separation of sample components was conducted using the ZB-5MSi column (30 m length, 0.25 mm inner diameter and 0.25 µm film thickness; Phenomenex, Torrance, California, CA, USA). Helium was used as a carrier gas at the flow rate of 2 mL min−1. The mass detector was set to positive electron ionization (EI) mode and the electron beam energy was 70 eV. The mass detector was operating in a full scan mode in the 50–650 amu range.