Linköping Studies in Science and Technology Thesis No. 1766 Synthesis and spectroscopic characterization of emerging synthetic cannabinoids and cathinones Andreas Carlsson Department of Physics, Chemistry and Biology Linköping University, Sweden Linköping 2016 © Copyright Andreas Carlsson 2016, unless otherwise noted Paper I © 2015 John Wiley & Sons Ltd, reprinted with permission. Pictures © NFC Photo Cover: Layout and illustrations made by Andreas Carlsson and Maria Åsén. Backside picture is taken by NFC Photo. Andreas Carlsson Synthesis and spectroscopic characterization of emerging synthetic cannabinoids and cathinones ISBN: 978-91-7685-625-3 ISSN: 0280-7971 Linköping Studies in Science and Technology, Thesis No. 1766 Printed in Sweden by LiU-Tryck, 2016 ”Ett problem är bara möjligheter i arbetskläder” - Mulle Meck I 4N6 II Abstract The application of different analytical techniques is fundamental in forensic drug analysis. In the wake of the occurrence of large numbers of new psychoactive substances possessing similar chemical structures as already known ones, focus has been placed on applied criteria for their univocal identification. These criteria vary, obviously, depending on the applied technique and analytical approach. However, when two or more substances are proven to have similar analytical properties, these criteria no longer apply, which imply that complementary techniques have to be used in their differentiation. This work describes the synthesis of some structural analogues to synthetic cannabinoids and cathinones based on the evolving patterns in the illicit drug market. Six synthetic cannabinoids and six synthetic cathinones were synthesized, that, at the time for this study, were not as yet found in drug seizures. Further, a selection of their spectroscopic data is compared to those of already existing analogues; mainly isomers and homologues. The applied techniques were mass spectrometry (MS), Fourier transformed infrared (FTIR, gas phase) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy. In total, 59 different compounds were analyzed with the selected techniques. The results from comparison of spectroscopic data showed that isomeric substances may in some cases be difficult to unambiguously identify based only on their GC-MS EI spectra. On the other hand, GC-FTIR demonstrated more distinguishable spectra. The spectra for the homologous compounds showed however, that the GC-FTIR technique was less successful compared to GC-MS. Also a pronounced fragmentation pattern for some of the cathinones was found. In conclusion, this thesis highlights the importance of using complementary techniques for the univocal identification of synthetic cannabinoids and cathinones. By increasing the number of analogues investigated, the more may be learnt about the capabilities of different techniques for structural differentiations, and thereby providing important identification criteria leading to trustworthy forensic evidence. III IV Table of Contents Abstract............................................................................................................................. III Table of Contents................................................................................................................V List of Papers ....................................................................................................................VII Preface .............................................................................................................................. IX 1 General Introduction ................................................................................................... 1 1.1 The Crime Scene..................................................................................................................1 1.2 Narcotics..............................................................................................................................1 1.3 The Drug Situation in Sweden .............................................................................................2 1.4 Classification Process...........................................................................................................4 2 New Psychoactive Substances...................................................................................... 7 2.1 Definitions ...........................................................................................................................7 2.2 Different Types and Classes of NPS .....................................................................................7 2.3 Legislation and Rate of Change ...........................................................................................8 3 Synthetic Cannabinoids.............................................................................................. 15 3.1 Cannabis Sativa and the Cannabinoids .............................................................................15 3.2 The Evolution of Synthetic Cannabinoids..........................................................................15 4 Synthetic Cathinones ................................................................................................. 19 4.1 Catha edulis and Cathinone...............................................................................................19 4.2 The Evolution of Cathinone Analogues .............................................................................20 5 Methodology............................................................................................................. 23 5.1 GC-MS................................................................................................................................23 5.2 GC-FTIR ..............................................................................................................................24 5.3 LC-HRMS ............................................................................................................................24 5.4 NMR...................................................................................................................................25 6 Narcotic Investigations and Structural Elucidations..................................................... 27 6.1 Screening Concepts ...........................................................................................................27 6.2 General Approach and Standard Operating Procedure ....................................................27 6.3 Criteria for Unambiguous Identification............................................................................28 6.4 The Need for Reference Compounds ................................................................................30 6.5 Structural Elucidation of Unknowns..................................................................................30 7 Aim ........................................................................................................................... 31 V 8 Synthetic Strategies................................................................................................... 33 8.1 Selection of Synthetic Cannabinoids (Paper I)...................................................................33 8.2 Selection of Synthetic Cathinones (Paper II) .....................................................................34 8.3 Synthetic Aspects...............................................................................................................34 8.4 Synthesized and Studied Compounds ...............................................................................37 9 NPS Analogue Differentiation .................................................................................... 39 9.1 Spectral Comparison of Homologous Compounds............................................................39 9.2 Spectral Comparison of Isomeric Compounds ..................................................................44 9.3 Other Findings ...................................................................................................................47 10 Conclusions............................................................................................................ 51 11 Future Perspectives................................................................................................ 53 12 Acknowledgements................................................................................................ 55 13 References............................................................................................................. 57 VI List of Papers This thesis is based on the following papers which are appended. PAPER I Andreas Carlsson, Sandra Lindberg, Xiongyu Wu, Simon Dunne, Martin Josefsson, Crister Åstot and Johan Dahlén Prediction of designer drugs: synthesis and spectroscopic analysis of synthetic cannabinoid analogues of 1H-indol-3-yl(2,2,3,3- tetramethylcyclopropyl)methanone and 1Hindol- 3-yl(adamantan-1-yl)methanone Drug Testing and Analysis, 2016, 8, 1015-1029 PAPER II Andreas Carlsson, Veronica Sandgren, Stefan Svensson, Peter Konradsson, Simon Dunne, Martin Josefsson and Johan Dahlén Prediction of designer drugs: synthesis and spectroscopic analysis of synthetic cathinone analogues that may appear on the Swedish drug market In manuscript VII VIII Preface The recent increase of many new substances on the illicit drug market has been challenging for forensic laboratories and placed focus on the importance of the capability of different analytical techniques to identify and differentiate between