The structure of a confiscated street drug: 6-Monoacetyl morphine hydrochloride trihydrate - C19H22NO4Cl·3H2O European Journal of Chemistry 12 (1) (2021) 52-55 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2021 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.12.1.52-55.2077 European Journal of Chemistry View Journal Online View Article Online The structure of a confiscated street drug: 6-Monoacetyl morphine hydrochloride trihydrate - C19H22NO4Cl·3H2O Matthew R. Wood 1, Ivan Bernal 1,2 and Roger A. Lalancette 1,* 1 Carl A. Olson Memorial Laboratories, Department of Chemistry, Rutgers University, 73 Warren St., Newark, NJ, 07102 USA matthewr.wood@gmail.com (M.R.W.), bernalibg@gmail.com (I.B.), roger.lalancette@gmail.com (R.A.L.) 2 Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, 2050 Johannesburg ZA South Africa * Corresponding author at: Carl A. Olson Memorial Laboratories, Department of Chemistry, Rutgers University, 73 Warren St., Newark, NJ, 07102 USA. e-mail: roger.lalancette@gmail.com (R.A. Lalancette). 10.5155/eurjchem.12.1.52-55.2077 Received: 22 January 2021 Received in revised form: 10 February 2021 Accepted: 18 February 2021 Published online: 31 March 2021 Printed: 31 March 2021 Since street drugs are frequently and rapidly modified, in order to circumvent the current laws that make them illicit, it is necessary to fully identify them by single crystal X-ray diffraction; subsequently, ideal powder patterns are computed for rapid identification of additional confiscations, which are mostly available in powder form. Monoacetyl morphine is found in samples of heroin as a by-product of incomplete synthesis, or from degradation of diacetyl morphine caused by heat, humidity, or pH changes. It is formed by the hydrolysis of the acetyl function on the benzene moiety of the morphine ring, thereby inserting an OH moiety at that site. This compound, 6-monoacetyl morphine, is the primary and active metabolite of heroin, rapidly hydrolyzed in the user’s blood. Herein, we describe the structure of 6-monoacetyl morphine, IUPAC name: [(4R,4aR,7S,7aR,12bS)-9-hydroxy-3- methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl] acetate (A), as the trihydrated hydrochloride, whose structure has not been described previously. Our crystals belong in space group P212121 with cell parameters of a = 6.9367(2), b = 13.0374(3), c = 21.9856(6) Å, V = 1988.30 (9) Å3; its composition is C19H22NO4Cl·3H2O, and Z = 4.0. A full sphere of data was collected at 100 K using CuKα radiation (λ = 1.54178 Å), yielding 3594 unique reflections measured and a final R-factor = 4.1%, with a Flack parameter = 0.05(1). Heroin Morphine Pi-pi bonds Water clusters Hydrogen bonds Water amphoterism Cite this: Eur. J. Chem. 2021, 12(1), 52-55 Journal website: www.eurjchem.com 1. Introduction In the past, we have determined [1-3] the structure of confiscated street drugs in order to add them to the list of illicit substances examined by law-enforcing agencies. The current species is a tri-hydrated, 6-mono-acetylated derivative of morphine that has not previously been characterized. This compound is important in forensic toxicology casework as 6- monoacetyl morphine is the primary and active metabolite of heroin, which is rapidly hydrolyzed in the user’s blood [4,5]. It constitutes an interesting crystalline example of hydrogen bonding by water since, in this lattice, water acts as both an acid and as a base, confirming its amphoteric nature and its ability to form highly crystalline, useful crystallographic specimens by its ambidextrous ability to link suitable substrates through strong hydrogen bonds. Finally, in the published record, there is only one example [6,7] of a hydrated acetylated form of morphine, which is a di-acetyl mono-hydrated species appea- ring in CSD [7] as FAZDAM, determined at 296 K, crystallizing in the tetragonal space group P412121, Z = 8.0. There also is the structure of a closely-related derivative of morphine, 6α- acetoxy-4, 5α-epoxy-3-methoxy-17-methylmorphin-7-ene, that has been determined at two different temperatures [8,9]. They are listed in the CSD as DATCEH (90 K) [7,8] and DATCEH01 (RT) [7,9]. 2. Experimental 2.1. Preparation of the crystalline sample A specimen of 6-monoacetyl morphine was obtained from a law enforcement seizure of suspected heroin (diacetyl morphine). A few milligrams of a specimen assumed to be heroin were dissolved on a glass slide in H2O and diluted (~1 M) HCl was added. Upon evaporation, crystals of 6- acetylmorphine hydrochloride trihydrate (A) formed, as documented below. 2.2. Single crystal X-ray diffraction collection A suitable crystal of compound A was mounted on a Bruker- AXS SMART APEX II CCD diffractometer at 100(1) K in a Cryoloop using Paratone-N oil. The cell dimensions and inten- sities were measured with CuKα radiation (λ = 1.54178 Å). Data processing, Lorentz-polarization, and face-indexed numerical absorption corrections were performed using SAINT, APEX, and ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.12.1.52-55.2077 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.12.1.52-55.2077 mailto:matthewr.wood@gmail.com mailto:bernalibg@gmail.com mailto:roger.lalancette@gmail.com mailto:roger.lalancette@gmail.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.12.1.52-55.2077&domain=pdf&date_stamp=2021-03-31 Wood et al. / European Journal of Chemistry 12 (1) (2021) 52-55 53 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.1.52-55.2077 Table 1. Crystal data and structure refinement for compound A. Empirical formula C19H22NO4, Cl, 3H2O Formula weight 417.87 Temperature (K) 100(2) Crystal system Orthorhombic Space group P212121 a (Å) 6.9367(2) b (Å) 13.0374(3) c (Å) 21.9856(6) α (°) 90 β (°) 90 γ (°) 90 Volume (Å3) 1988.30(9) Z 4 ρcalc (g/cm3) 1.396 μ (mm-1) 2.066 F(000) 888.0 Crystal size/mm3) 0.209 × 0.121 × 0.101 Radiation CuKα (λ = 1.54178) 2Θ range for data collection (°) 8.042 to 138.232 Index ranges -8 ≤ h ≤ 8, -15 ≤ k ≤ 15, -26 ≤ l ≤ 26 Reflections collected 18382 Independent reflections 3594 [Rint = 0.0517, Rsigma = 0.0456] Data/restraints/parameters 3594/7/271 No. of observed [I>2σ(I)] reflections 3181 Tmin, Tmax 0.710, 0.849 Absorption correction Numerical (sin θ/λ)max (Å−1) 0.606 Goodness-of-fit on F2 1.037 Final R indexes [I≥2σ (I)] R1 = 0.0414, wR2 = 0.0984 Final R indexes [all data] R1 = 0.0489, wR2 = 0.1026 Largest diff. peak/hole / (e Å-3) 0.50/-0.44 Flack parameter 0.05(1) CCDC number 2054880 Computer programs Bruker (2008) SAINT, APEX, SADABS, Sheldrick (2015) SHELXL [11,12], Putz & Brandenburg (2019) DIAMOND [13]. Table 2. Bond Lengths for compound A. Atom Atom Length (Å) Atom Atom Length (Å) O1 C13 1.375(4) C6 C5 1.546(5) O1 C1 1.467(4) C5 C10 1.528(5) O3 C18 1.345(5) C11 C12 1.384(5) O3 C9 1.450(4) C11 C16 1.397(5) O4 C14 1.366(4) C11 C10 1.500(5) N1 C17 1.491(5) C12 C2 1.498(5) N1 C4 1.500(5) C2 C3 1.532(5) N1 C5 1.523(5) C2 C1 1.543(5) O2 C18 1.211(5) C15 C16 1.380(5) C13 C12 1.376(5) C3 C4 1.520(5) C13 C14 1.392(5) C7 C8 1.324(5) C14 C15 1.396(5) C1 C9 1.542(5) C6 C7 1.503(5) C18 C19 1.486(6) C6 C2 1.544(5) C9 C8 1.508(5) Figure 1. N1 is the protonated site, whose proton links the individual 6-monoacetyl-morphine cations via chlorides and waters. O1 and O4 are hydrogen-bonded in a bidentate form to water O5, which is acting as both an acid and a base; also, O6 and O7 act as both hydrogen donors and acceptors. SADABS computer programs [10-12] and those data are given in Table 1. The structure was solved by direct methods and refined by full-matrix least-squares methods on F2, using the SHELXTL V6.14 program package, Table 1 [13,14]. All non- hydrogen atoms were refined anisotropically. All H atoms were found in electron-density difference maps and allowed to ride on their respective C, N, or O atoms with thermal displacement parameters fixed at 1.2Ueq(C), 1.2Ueq(N), and 1.5Ueq(O). The numbers in parentheses are the errors in the least significant digit. 54 Wood et al. / European Journal of Chemistry 12 (1) (2021) 52-55 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.1.52-55.2077 Table 3. Bond Angles for compound A. Atom Atom Atom Angle (°) Atom Atom Atom Angle (°) C13 O1 C1 107.3(3) C12 C2 C3 112.0(3) C18 O3 C9 116.3(3) C12 C2 C1 100.8(3) C17 N1 C4 110.9(3) C3 C2 C1 110.6(3) C17 N1 C5 113.8(3) C12 C2 C6 106.6(3) C4 N1 C5 113.0(3) C3 C2 C6 109.1(3) O1 C13 C12 111.9(3) C1 C2 C6 117.4(3) O1 C13 C14 127.2(3) C16 C15 C14 122.9(3) C12 C13 C14 120.8(3) C4 C3 C2 112.3(3) O4 C14 C13 125.4(3) C8 C7 C6 120.1(3) O4 C14 C15 118.8(3) O1 C1 C9 111.3(3) C13 C14 C15 115.8(3) O1 C1 C2 105.5(3) C7 C6 C2 110.3(3) C9 C1 C2 112.7(3) C7 C6 C5 113.9(3) C11 C10 C5 114.2(3) C2 C6 C5 107.0(3) C15 C16 C11 120.8(3) N1 C5 C10 112.2(3) N1 C4 C3 111.1(3) N1 C5 C6 106.6(3) O2 C18 O3 122.6(4) C10 C5 C6 115.1(3) O2 C18 C19 125.6(4) C12 C11 C16 115.8(3) O3 C18 C19 111.7(4) C12 C11 C10 118.9(3) O3 C9 C8 106.0(3) C16 C11 C10 124.9(3) O3 C9 C1 111.7(3) C13 C12 C11 123.4(3) C8 C9 C1 115.1(3) C13 C12 C2 109.6(3) C7 C8 C9 121.7(3) C11 C12 C2 126.7(3) Table 4. Hydrogen bonding in structure A. D–H···A d(D–H) (Å) d(H···A) (Å) ∠ D–H···A (°) d(D···A) (Å) O4-H4···O5 0.840 1.774 168.54 2.603(4) O6-H22···Cl1 i 0.837 2.355 163.89 3.1672(16) O6-H23···Cl1 0.849 2.254 163.44 3.0773(17) N1-H3···Cl1 0.880 2.217 168(3) 3.083(3) O5-H20···O7 ii 0.840 1.927(15) 165(6) 2.747(4) O5-H21···O1 0.840 2.504 110(4) 2.902(4) O5-H21···O2 iii 0.840 2.20(3) 145(4) 2.925(5) O7-H24···Cl1 iv 0.840 2.31(2) 160(5) 3.115(3) O7-H25···O6 0.840 1.931 162(5) 2.743(4) i = x-1/2, -y+1/2, -z+1; ii = x, y+1, z; iii = x+1/2, -y+1/2, -z+1; iv = x-1, y, z. Figure 2. Fused pentagonal clusters in the form of pleated sheets extend in the a-direction while acting as linkages to hydrogen-bonded acetyl morphinium cations. Also note that the phenyl rings of the drug are oriented in a way to form pi-pi bonds, separated by an a-translation (ca. 6.94 Å), which is substantial and adds to the coherence of the lattice. Figures were drawn using the graphics program DIAMOND [15]. The crystallographic data have been deposited in the Cambridge Crystallographic Data Center; the deposition number is 2054880 and is given in Table 1. 3. Results and discussion In the crystalline state, the mono-acetylated morphinium cations are hydrogen-bonded to one another through three water molecules and the chloride counter-anion in an infinite fashion as shown in Figure 1. Bond lengths and angles are given in Tables 2 and 3. In Table 4, we list some of the strongest hydrogen bonds present in the lattice to quantify the above assertions. 3.1. Packing of the acetyl morphine cations and water- chloride-cluster anions An interesting observation, suggested by a referee, upon observation of Figure 1, is that the entire lattice may be a massively hydrogen-bonded ensemble. Indeed, such is the case and the result is displayed in Figure 2. Wood et al. / European Journal of Chemistry 12 (1) (2021) 52-55 55 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.1.52-55.2077 Figure 3. Powder pattern of compound A generated from single crystal data. 4. Conclusions Above, we describe a new form of monoacetylated morphine in order to totally document its composition and structure in crystalline form, as obtained in a drug seizure and prepared for X-ray diffraction as described above. Its powder diffraction can readily be computed by the coordinates available in the CIF document previously deposited, Figure 3 (CCDC 2054880 [7]). Morphine has been modified by a variety of substitution methods, some of which are very useful acetylated forms [6,16,17], these are available in the CSD database [7]. Acknowledgements We acknowledge interesting conversations on this topic with colleagues at our respective institutions and to the National Science Foundation for NSF-CRIF Grant No. 0443538 for part of the purchase of the X-ray diffractometer. We are pleased to acknowledge the contribution of a referee who pointed out to us the attractive feature of the water-chloride clusters in these crystals. It is refreshing to have such positive and useful observations. Supporting information CCDC-2054880 contains the supplementary crystallo- graphic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/, or by e- mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. Funding We acknowledge the National Science Foundation for NSF- CRIF Grant No. 0443538 for part of the purchase of the X-ray diffractometer. Disclosure statement Conflict of interest: The authors have declared that no competing interests exist. Author contributions: Matthew R. Wood, Ivan Bernal and Roger Lalancette wrote the manuscript. Competing interests: The authors have declared that no competing interests exist. Ethical approval: All ethical guidelines have been adhered. ORCID Matthew R. Wood https://orcid.org/0000-0001-9579-5317 Ivan Bernal https://orcid.org/0000-0002-8168-5907 Roger Lalancette https://orcid.org/0000-0002-3470-532X References [1]. Wood, M. R.; Lalancette, R. A.; Bernal, I. Acta Crystallogr. C 2015, 71 (1), 32–38. [2]. Wood, M. R.; Bernal, I.; Lalancette, R. A. Acta Crystallogr. C 2016, 72 (1), 48–51. [3]. Wood, M. R.; Bernal, I.; Lalancette, R. A. Struct. Chem. 2017, 28 (5), 1369–1376. [4]. Andersen, J. M.; Ripel, A.; Boix, F.; Normann, P. T.; Morland, J. J. Pharmacol. Exp. Ther. 2009, 331 (1), 153–161. [5]. Boix, F.; Andersen, J. M.; Morland, J. Addiction Biology 2011, 18 (1), 1– 7. [6]. 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Brandenburg GbR, Kreuzherrenstr. 102, 53227 Bonn, Germany [16]. Canfield, D.; Barrick, J.; Giessen, B. C. Acta Crystallogr. B 1979, 35 (11), 2806–2809. [17]. Deschamps, J. R.; George, C.; Flippen-Anderson, J. L. Acta Crystallogr. C 1996, 52 (3), 698–700. Copyright © 2021 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. 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Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). https://www.ccdc.cam.ac.uk/structures/ mailto:data_request@ccdc.cam.ac.uk https://orcid.org/0000-0001-9579-5317 https://orcid.org/0000-0002-8168-5907 https://orcid.org/0000-0002-3470-532X http://www.ccdc.cam.ac.uk/ http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Preparation of the crystalline sample 2.2. Single crystal X-ray diffraction collection 3. Results and discussion 3.1. Packing of the acetyl morphine cations and water-chloride-cluster anions 4. Conclusions Acknowledgements Supporting information Funding Disclosure statement ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField20: PrintField21: PrintField22: PrintField23: