Coca­ethyl­ene, the in vivo product of cocaine and ethanol, is a narcotic more potent than its precursors

Maia, A.F. da S.; Martins, F.T.; Silva Neto, L. da; Alves, R.B.; De Fátima, Â.

doi:10.1107/S2053229617012852

Cocaethylene, the in vivo product of cocaine and ethanol, is a narcotic more potent than its precursors

A. F. da S. Maia, F. T. Martins, L. da Silva Neto, R. B. Alves and Â. De Fátima

The molecular conformation and supramolecular architecture of cocaethylene [systematic name: ethyl (1R,2R,3S,5S)-3-benzoyloxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate], C₁₈H₂₃NO₄, have been determined for the first time. Cocaethylene is a narcotic produced in vivo when cocaine and ethanol are administered concomitantly. The intra- and intermolecular features of cocaethylene and its less potent narcotic precursor cocaine are very similar. The only molecular difference is in the conformation of the methyl group of the ethoxycarbonyl group. Similar to cocaine, the carboxylate atoms and the α-C atom are coplanar in cocaethylene, but the methyl C atom of the ethyl group is bent by ca 90° away from this plane in the narcotic reported here. The main supramolecular motif is a one-dimensional chain stabilized by weak C—H

O contacts.

Keywords: crystal structure; cocaethylene; cocaine; narcotic; conformation; transesterification; benzoylecgonine ester.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229617012852/cu3117sup1.cif Contains datablocks global, I
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229617012852/cu3117Isup2.hkl Contains datablock I
	Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229617012852/cu3117Isup3.cml Supplementary material

CCDC reference: 1573265

Computing details top

Data collection: APEX2 (Bruker, 2003); cell refinement: SAINT (Bruker, 2003); data reduction: SAINT (Bruker, 2003); program(s) used to solve structure: SIR92 (Altomare et al., 1993); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997), Mercury (Macrae et al., 2006); software used to prepare material for publication: WinGX publication routines (Farrugia, 1999).

ethyl (1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate top

Crystal data top

C₁₈H₂₃NO₄	F(000) = 340
M_r = 317.37	D_x = 1.248 Mg m⁻³
Monoclinic, P2₁	Cu Kα radiation, λ = 1.54178 Å
a = 8.4533 (2) Å	Cell parameters from 2631 reflections
b = 10.2380 (3) Å	θ = 6.0–66.1°
c = 10.2552 (2) Å	µ = 0.72 mm⁻¹
β = 107.881 (1)°	T = 296 K
V = 844.66 (4) Å³	Needle, colourless
Z = 2	0.35 × 0.15 × 0.10 mm

Data collection top

Bruker APEXII CCD area-detector diffractometer	2026 reflections with I > 2σ(I)
CCD scans	R_int = 0.024
Absorption correction: multi-scan (SADABS; Krause et al., 2015)	θ_max = 66.5°, θ_min = 6.0°
T_min = 0.725, T_max = 0.931	h = −9→9
3969 measured reflections	k = −9→12
2133 independent reflections	l = −12→11

Refinement top

Refinement on F²	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F² > 2σ(F²)] = 0.036	w = 1/[σ²(F_o²) + (0.0631P)² + 0.0701P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.101	(Δ/σ)_max < 0.001
S = 1.03	Δρ_max = 0.15 e Å⁻³
2133 reflections	Δρ_min = −0.17 e Å⁻³
208 parameters	Absolute structure: Flack x parameter determined using 568 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013).
1 restraint	Absolute structure parameter: −0.03 (14)

Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O4	0.5751 (2)	0.4990 (2)	−0.13426 (17)	0.0664 (6)
O1	0.65669 (18)	0.5018 (2)	0.27718 (16)	0.0563 (5)
O3	0.6899 (2)	0.6327 (3)	0.0426 (2)	0.0703 (6)
N1	0.2831 (2)	0.6666 (2)	−0.0355 (2)	0.0519 (5)
C17	0.5764 (6)	0.6617 (5)	−0.2996 (4)	0.1061 (14)
H17A	0.642	0.6992	−0.3516	0.159*
H17B	0.4754	0.627	−0.3609	0.159*
H17C	0.5503	0.7277	−0.243	0.159*
C16	0.6698 (4)	0.5572 (5)	−0.2134 (3)	0.0863 (12)
H16A	0.6977	0.4911	−0.2705	0.104*
H16B	0.7727	0.592	−0.1524	0.104*
C15	0.5920 (3)	0.5498 (3)	−0.0097 (2)	0.0500 (6)
C2	0.4677 (3)	0.4846 (3)	0.0482 (2)	0.0467 (5)
H2	0.4796	0.3896	0.0436	0.056*
C3	0.4847 (3)	0.5233 (3)	0.1952 (2)	0.0487 (6)
H3	0.4143	0.4648	0.2291	0.058*
C8	0.6854 (3)	0.4519 (3)	0.4018 (2)	0.0523 (6)
C9	0.8662 (3)	0.4243 (3)	0.4680 (2)	0.0507 (6)
C14	0.9159 (4)	0.3499 (3)	0.5864 (3)	0.0677 (8)
H14	0.837	0.3186	0.625	0.081*
C13	1.0819 (5)	0.3221 (4)	0.6474 (3)	0.0780 (9)
H13	1.1148	0.271	0.7261	0.094*
C12	1.1978 (4)	0.3697 (4)	0.5917 (3)	0.0831 (11)
H12	1.3097	0.3517	0.6337	0.1*
C10	0.9846 (3)	0.4709 (3)	0.4126 (3)	0.0626 (7)
H10	0.9527	0.5209	0.333	0.075*
C11	1.1512 (4)	0.4433 (5)	0.4756 (3)	0.0825 (10)
H11	1.2312	0.4751	0.4386	0.099*
C4	0.4298 (3)	0.6621 (3)	0.2072 (2)	0.0552 (6)
H4A	0.5113	0.7227	0.1932	0.066*
H4B	0.4207	0.6766	0.2981	0.066*
C5	0.2607 (3)	0.6856 (3)	0.0992 (3)	0.0561 (6)
H5	0.2202	0.7739	0.1075	0.067*
C18	0.1473 (4)	0.7238 (4)	−0.1467 (3)	0.0772 (10)
H18A	0.1483	0.817	−0.1365	0.116*
H18B	0.1618	0.7019	−0.2333	0.116*
H18C	0.0429	0.6899	−0.1428	0.116*
C1	0.2916 (3)	0.5243 (3)	−0.0423 (2)	0.0511 (6)
H1	0.2727	0.4956	−0.1371	0.061*
C7	0.1534 (3)	0.4726 (3)	0.0128 (3)	0.0659 (8)
H7A	0.0516	0.4574	−0.0613	0.079*
H7B	0.187	0.392	0.0634	0.079*
C6	0.1309 (3)	0.5823 (4)	0.1068 (3)	0.0694 (8)
H6A	0.152	0.551	0.1999	0.083*
H6B	0.0193	0.6179	0.0746	0.083*
O2	0.5794 (3)	0.4319 (3)	0.45504 (19)	0.0812 (8)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O4	0.0741 (11)	0.0762 (15)	0.0519 (9)	0.0089 (11)	0.0238 (9)	−0.0017 (10)
O1	0.0401 (8)	0.0775 (13)	0.0467 (8)	0.0054 (8)	0.0066 (6)	0.0137 (9)
O3	0.0495 (9)	0.0973 (18)	0.0612 (11)	−0.0194 (10)	0.0129 (8)	−0.0028 (10)
N1	0.0381 (9)	0.0570 (13)	0.0533 (11)	0.0001 (9)	0.0031 (8)	0.0101 (10)
C17	0.148 (4)	0.081 (3)	0.091 (3)	−0.004 (3)	0.039 (3)	0.010 (2)
C16	0.0776 (19)	0.127 (4)	0.0625 (17)	0.017 (2)	0.0336 (15)	0.0166 (19)
C15	0.0386 (11)	0.0581 (16)	0.0491 (12)	0.0082 (11)	0.0076 (10)	0.0042 (11)
C2	0.0445 (11)	0.0451 (13)	0.0475 (11)	0.0018 (9)	0.0095 (9)	−0.0012 (10)
C3	0.0360 (10)	0.0625 (16)	0.0431 (11)	−0.0004 (10)	0.0057 (9)	0.0045 (11)
C8	0.0524 (13)	0.0618 (16)	0.0396 (11)	−0.0022 (12)	0.0097 (10)	0.0005 (11)
C9	0.0560 (13)	0.0515 (15)	0.0371 (10)	0.0033 (11)	0.0034 (10)	−0.0004 (10)
C14	0.0776 (18)	0.070 (2)	0.0447 (13)	0.0009 (15)	0.0035 (13)	0.0063 (13)
C13	0.092 (2)	0.070 (2)	0.0501 (14)	0.0138 (19)	−0.0109 (15)	0.0072 (14)
C12	0.0645 (17)	0.093 (3)	0.0682 (19)	0.0173 (18)	−0.0145 (15)	0.0024 (19)
C10	0.0512 (13)	0.080 (2)	0.0485 (12)	0.0065 (13)	0.0028 (10)	0.0136 (13)
C11	0.0534 (15)	0.112 (3)	0.0719 (18)	0.0078 (18)	0.0046 (13)	0.0153 (19)
C4	0.0485 (12)	0.0642 (17)	0.0500 (12)	0.0018 (12)	0.0110 (10)	−0.0096 (12)
C5	0.0456 (12)	0.0595 (17)	0.0614 (14)	0.0089 (11)	0.0139 (11)	−0.0031 (12)
C18	0.0526 (15)	0.093 (3)	0.0732 (19)	0.0075 (16)	0.0009 (13)	0.0305 (18)
C1	0.0406 (11)	0.0598 (16)	0.0477 (12)	−0.0054 (10)	0.0058 (9)	−0.0045 (11)
C7	0.0422 (12)	0.070 (2)	0.0772 (16)	−0.0127 (12)	0.0063 (11)	0.0089 (15)
C6	0.0391 (12)	0.101 (2)	0.0691 (16)	0.0041 (14)	0.0180 (12)	0.0147 (16)
O2	0.0612 (11)	0.129 (2)	0.0524 (10)	−0.0048 (13)	0.0163 (9)	0.0109 (12)

Geometric parameters (Å, º) top

O4—C15	1.346 (3)	C14—C13	1.379 (4)
O4—C16	1.434 (4)	C14—H14	0.93
O1—C8	1.328 (3)	C13—C12	1.367 (6)
O1—C3	1.456 (3)	C13—H13	0.93
O3—C15	1.192 (3)	C12—C11	1.361 (5)
N1—C1	1.462 (4)	C12—H12	0.93
N1—C5	1.463 (3)	C10—C11	1.387 (4)
N1—C18	1.468 (3)	C10—H10	0.93
C17—C16	1.456 (7)	C11—H11	0.93
C17—H17A	0.96	C4—C5	1.535 (3)
C17—H17B	0.96	C4—H4A	0.97
C17—H17C	0.96	C4—H4B	0.97
C16—H16A	0.97	C5—C6	1.543 (4)
C16—H16B	0.97	C5—H5	0.98
C15—C2	1.511 (3)	C18—H18A	0.96
C2—C3	1.522 (3)	C18—H18B	0.96
C2—C1	1.548 (3)	C18—H18C	0.96
C2—H2	0.98	C1—C7	1.539 (4)
C3—C4	1.512 (4)	C1—H1	0.98
C3—H3	0.98	C7—C6	1.529 (5)
C8—O2	1.202 (3)	C7—H7A	0.97
C8—C9	1.497 (3)	C7—H7B	0.97
C9—C10	1.379 (4)	C6—H6A	0.97
C9—C14	1.385 (4)	C6—H6B	0.97

C15—O4—C16	117.5 (3)	C11—C12—H12	119.6
C8—O1—C3	117.99 (17)	C13—C12—H12	119.6
C1—N1—C5	101.5 (2)	C9—C10—C11	119.9 (3)
C1—N1—C18	113.5 (2)	C9—C10—H10	120
C5—N1—C18	112.5 (2)	C11—C10—H10	120
C16—C17—H17A	109.5	C12—C11—C10	120.0 (3)
C16—C17—H17B	109.5	C12—C11—H11	120
H17A—C17—H17B	109.5	C10—C11—H11	120
C16—C17—H17C	109.5	C3—C4—C5	109.2 (2)
H17A—C17—H17C	109.5	C3—C4—H4A	109.8
H17B—C17—H17C	109.5	C5—C4—H4A	109.8
O4—C16—C17	110.9 (3)	C3—C4—H4B	109.8
O4—C16—H16A	109.5	C5—C4—H4B	109.8
C17—C16—H16A	109.5	H4A—C4—H4B	108.3
O4—C16—H16B	109.5	N1—C5—C4	107.42 (19)
C17—C16—H16B	109.5	N1—C5—C6	104.9 (2)
H16A—C16—H16B	108.1	C4—C5—C6	112.0 (2)
O3—C15—O4	124.0 (2)	N1—C5—H5	110.8
O3—C15—C2	127.5 (2)	C4—C5—H5	110.8
O4—C15—C2	108.6 (2)	C6—C5—H5	110.8
C15—C2—C3	114.1 (2)	N1—C18—H18A	109.5
C15—C2—C1	107.80 (19)	N1—C18—H18B	109.5
C3—C2—C1	107.85 (18)	H18A—C18—H18B	109.5
C15—C2—H2	109	N1—C18—H18C	109.5
C3—C2—H2	109	H18A—C18—H18C	109.5
C1—C2—H2	109	H18B—C18—H18C	109.5
O1—C3—C4	111.83 (19)	N1—C1—C7	105.7 (2)
O1—C3—C2	107.86 (18)	N1—C1—C2	106.57 (19)
C4—C3—C2	112.8 (2)	C7—C1—C2	112.9 (2)
O1—C3—H3	108.1	N1—C1—H1	110.5
C4—C3—H3	108.1	C7—C1—H1	110.5
C2—C3—H3	108.1	C2—C1—H1	110.5
O2—C8—O1	124.2 (2)	C6—C7—C1	103.6 (2)
O2—C8—C9	124.2 (2)	C6—C7—H7A	111
O1—C8—C9	111.65 (19)	C1—C7—H7A	111
C10—C9—C14	119.3 (2)	C6—C7—H7B	111
C10—C9—C8	121.1 (2)	C1—C7—H7B	111
C14—C9—C8	119.6 (2)	H7A—C7—H7B	109
C13—C14—C9	120.2 (3)	C7—C6—C5	104.1 (2)
C13—C14—H14	119.9	C7—C6—H6A	110.9
C9—C14—H14	119.9	C5—C6—H6A	110.9
C12—C13—C14	119.8 (3)	C7—C6—H6B	110.9
C12—C13—H13	120.1	C5—C6—H6B	110.9
C14—C13—H13	120.1	H6A—C6—H6B	109
C11—C12—C13	120.8 (3)

C15—O4—C16—C17	−90.5 (4)	C8—C9—C10—C11	−179.6 (3)
C16—O4—C15—O3	−6.1 (4)	C13—C12—C11—C10	0.1 (6)
C16—O4—C15—C2	173.6 (2)	C9—C10—C11—C12	0.3 (6)
O3—C15—C2—C3	−6.0 (4)	O1—C3—C4—C5	169.50 (19)
O4—C15—C2—C3	174.3 (2)	C2—C3—C4—C5	47.7 (3)
O3—C15—C2—C1	113.7 (3)	C1—N1—C5—C4	75.8 (3)
O4—C15—C2—C1	−66.0 (3)	C18—N1—C5—C4	−162.6 (3)
C8—O1—C3—C4	95.5 (3)	C1—N1—C5—C6	−43.6 (2)
C8—O1—C3—C2	−139.9 (2)	C18—N1—C5—C6	78.1 (3)
C15—C2—C3—O1	−53.0 (3)	C3—C4—C5—N1	−61.3 (3)
C1—C2—C3—O1	−172.69 (19)	C3—C4—C5—C6	53.3 (3)
C15—C2—C3—C4	71.1 (2)	C5—N1—C1—C7	43.2 (2)
C1—C2—C3—C4	−48.7 (3)	C18—N1—C1—C7	−77.8 (3)
C3—O1—C8—O2	−5.6 (4)	C5—N1—C1—C2	−77.1 (2)
C3—O1—C8—C9	174.8 (2)	C18—N1—C1—C2	161.9 (2)
O2—C8—C9—C10	−168.0 (3)	C15—C2—C1—N1	−59.9 (2)
O1—C8—C9—C10	11.6 (4)	C3—C2—C1—N1	63.8 (2)
O2—C8—C9—C14	12.5 (4)	C15—C2—C1—C7	−175.5 (2)
O1—C8—C9—C14	−167.9 (3)	C3—C2—C1—C7	−51.8 (3)
C10—C9—C14—C13	−0.5 (5)	N1—C1—C7—C6	−25.7 (3)
C8—C9—C14—C13	179.0 (3)	C2—C1—C7—C6	90.4 (3)
C9—C14—C13—C12	1.0 (5)	C1—C7—C6—C5	−1.1 (3)
C14—C13—C12—C11	−0.8 (6)	N1—C5—C6—C7	27.4 (3)
C14—C9—C10—C11	−0.1 (5)	C4—C5—C6—C7	−88.8 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C6—H6B···O3ⁱ	0.97	2.71	3.618 (3)	157

Symmetry code: (i) x−1, y, z.

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Coca­ethyl­ene, the in vivo product of cocaine and ethanol, is a narcotic more potent than its precursors

Supporting information

Cocaethylene, the in vivo product of cocaine and ethanol, is a narcotic more potent than its precursors