Crystal structure of the α-racemate of methohexital

N—H⋯O=C bonded mol­ecules of the title compound are linked into a inversion dimer with an (8) motif.

Abstract

Mol­ecules of the title compound, C₁₄H₁₈N₂O₃ [systematic name: 5-allyl-5-(hex-3-yn-2-yl)-1-methylpyrimidine-2,4,6(1H,3H,5H)-trione in the (R_bS_h)/(S_bR_h) racemic form], are connected by mutual N—H⋯O=C hydrogen bonds in which the carbonyl group at the 2-position of the pyrimidine­trione ring is employed. These inter­actions result in an inversion dimer which displays a central R ₂ ²(8) ring motif. This dimer is topologically distinct from that of the previously reported (S_bR_h) form, which is, however, also based on an R ₂ ²(8) motif. The methyl group at the 1-position of the pyrimidine­trione ring in the title structure is disordered over two sets of sites in a 0.57 (2):0.43 (2) ratio.

Chemical context  

The title compound is a barbiturate derivative, the Na salt of which (trade name Brevimytal, Eli Lilly) is a widely used short-acting anaesthetic with a rapid onset of action. The mol­ecule contains two asymmetric centres and can exist as two diastereomeric enanti­omer pairs. Its stereoisomerism is known to affect the anaesthetic activity and possible side effects of the drug (Gibson et al., 1959 ▸). The crystal structure of the (S_bR_h) form of methohexital was previously reported by Brunner et al. (2003 ▸), who also established that the commercial product (α-racemate) consists of the (R_bS_h) and (S_bR_h) isomers.

Structural commentary  

This study confirmed the presence of the (R_bS_h)/(S_bR_h) racemate. The mol­ecule (Fig. 1 ▸) displays an approximately planar pyrimidine­trione unit in which the oxygen atoms of the C2 and C4 carbonyl groups lie at distances of −0.160 (2) and 0.156 (2) Å from the mean plane of the six-membered ring (r.m.s. deviation = 0.046 Å). The conformation of the two 5-substituents of the ring is characterized by three parameters, the torsion angles C5—C7—C8—C9 of −103.3 (2) and C10—C5—C7—C8 of −171.51 (13)° and the pseudo-torsion angle C5—C10⋯C13–C14 of 23.2 (2)°.

Figure 1.

The mol­ecular structure of the title compound with displacement ellipsoids drawn at the 50% probability level; hydrogen atoms are drawn as spheres of arbitrary size.

The previously reported (S_bR_h) form contains two independent mol­ecules (denoted A and B), which differ from the mol­ecule of the title structure in the conformation adopted by the terminal groups of both 5-substituents (Fig. 2 ▸). Specifically, in mol­ecule A, the torsion angle analogous to C5—C7—C8—C9 in the present α-racemate is 125.3°, and the pseudo-torsion angles analogous to C5—C10⋯C13—C14 of the title structure are −15.4° (A) and −26.3° (B).

Figure 2.

Overlay of the mol­ecule of the α-racemate (denoted X) with the two independent mol­ecules (A, B) of the previously reported (S_bR_h) form, generated by least-squares fits of their 1-methyl-2,4,6-pyrimidine­trione units (ten non-H atomic positions).

Supra­molecular features  

Two mol­ecules are linked to one another by two mutual anti­parallel N—H⋯O=C bonds so that an inversion dimer is formed (Table 1 ▸, Fig. 3 ▸), which displays a central (8) ring motif (Etter et al., 1990 ▸; Bernstein et al., 1995 ▸). This inter­action involves the carbonyl group at the 2-position of the ring. The (8) ring motif is also present in the (S_bR_h) form (Brunner et al., 2003 ▸) where it connects the two crystallographically independent mol­ecules. However, in this case the dimer is based on two topologically distinct N—H⋯O=C inter­actions which involve the carbonyl groups at the 4-position of the ring of mol­ecule A and at the 2-position of mol­ecule B.

Table 1. Hydrogen-bond geometry (, ).

DHA	DH	HA	D A	DHA
N3H3O2i	0.85(2)	2.03(2)	2.8826(17)	173.2(17)

Symmetry code: (i) .

Figure 3.

The N—H⋯O=C hydrogen-bonded inversion dimer displaying a central (8) ring. These inter­actions (dotted lines) involve the carbonyl group at the 2-position of the six-membered ring. O and H atoms engaged in hydrogen bonding are drawn as spheres.

Database survey  

The Cambridge Structural Database (Groom & Allen, 2014 ▸; Version 3.35) contains 11 unique entries for derivatives of barbituric acid which are analogous to the title compound and substituted at the 1-position, but not at the 3-position of the six-membered ring. A common characteristic of these compounds is the presence of one hydrogen-bond donor group (NH) and three potential acceptor groups, viz. the carbonyl groups at the ring positions 2, 4 and 6. Thus, three topologically distinct hydrogen-bonding acceptor inter­actions are possible. Additionally, there is a competition between possible dimer and catemer motifs, which is similar to the competition between hydrogen-bonded dimer and catemer motifs between carboxyl groups (Beyer & Price; 2000 ▸) or carboxamide groups (Arlin et al., 2010 ▸, 2011 ▸).

Closer inspection of the geometric possibilities (Fig. 4 ▸) shows that dimer formation is feasible for N—H⋯O=C2 and N—H⋯O=C4 connections only, whereas N—H⋯O=C6 should be the preferred connection mode for chain formation. Indeed, five crystal structures containing N—H⋯O=C6 chain motifs are known and their CSD refcodes are DMCYBA01 (Nichol & Clegg, 2005 ▸), DULMED (Gelbrich et al., 2010 ▸), MDEBAR (Wunderlich, 1973 ▸), MIBABA (Wilhelm & Fischer, 1976 ▸), OBIPUM (Gelbrich & Griesser, 2009 ▸). So far, the crystal structure with refcode VEMQUB (Savechenkov et al., 2012 ▸) is the only example in the set where another chain type, viz. N—H⋯O=C2, is present.

Figure 4.

The three fundamental connection modes for the formation of N—H⋯O=C bonds in 1-substituted derivatives of barbituric acid arising from the involvement of different carbonyl groups, and the corresponding numbers of observed dimer and catemer isomers. The (S_bR_h) form of methohexithal contains a dimer with mixed N—H⋯O=C2/N—H⋯O=C4 connectivity and was therefore not included.

Apart from the title structure, two analogues with refcodes CXALBA (Dideberg et al., 1975 ▸) and DULMAZ (Gelbrich et al., 2010 ▸) also form N—H⋯O=C2 bonded dimers. The alternative N—H⋯O=C4 dimer was observed in the two structures with refcodes ALLBTC (Pyżalska et al., 1980 ▸) and MEPBAB01 (Lewis et al., 2005 ▸). The (S_bR_h) form of methohexital provides the only case of a dimer based on a mixed N—H⋯O=C2/N—H⋯O=C4 connectivity.

Synthesis and crystallization  

The crystals investigated in this study were obtained at room temperature, by slow evaporation from an aqueous solution of the α-racemate of methohexital (Lilly Research Centre Ltd., Windlesham, England).

Refinement  

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. H atoms were identified in difference maps. The H atoms of the C14 methyl group and disordered C1 methyl group [occupancy ratio 0.57 (2):0.43 (2)] were idealized and included as rigid groups allowed to rotate but not tip (C—H = 0.96 Å) and refined with U _iso set to 1.5U _eq(C) of the parent carbon atom. H atoms bonded to secondary CH₂ (C—H = 0.97 Å), tertiary CH (C—H = 0.98 Å) carbon and aromatic CH carbon atoms (C—H = 0.93 Å) were positioned geometrically and refined with U _iso set to 1.2U _eq(C) of the parent carbon atom. The NH hydrogen atom was refined with a restrained distance [N—H = 0.86 (2) Å] and its U _iso parameter was freely refined.

Table 2. Experimental details.

Crystal data
Chemical formula	C14H18N2O3
M r	262.30
Crystal system, space group	Triclinic, P
Temperature (K)	293
a, b, c ()	7.7502(6), 7.9792(5), 12.6881(10)
, , ()	93.713(6), 96.226(6), 113.314(7)
V (3)	711.32(10)
Z	2
Radiation type	Mo K
(mm1)	0.09
Crystal size (mm)	0.35 0.20 0.20
Data collection
Diffractometer	Agilent Xcalibur (Ruby, Gemini ultra)
Absorption correction	Multi-scan (CrysAlis PRO; Agilent, 2012 ▸)
T min, T max	0.883, 1.000
No. of measured, independent and observed [I > 2(I)] reflections	6896, 3363, 2462
R int	0.022
(sin /)max (1)	0.690
Refinement
R[F 2 > 2(F 2)], wR(F 2), S	0.049, 0.135, 1.05
No. of reflections	3363
No. of parameters	180
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
max, min (e 3)	0.22, 0.20

Computer programs: CrysAlis PRO (Agilent, 2012 ▸), SHELXS97 (Sheldrick, 2008 ▸), SHELXL2014/6 (Sheldrick, 2015 ▸), XP in SHELXTL (Sheldrick, 2008 ▸), Mercury (Macrae et al., 2006 ▸) and publCIF (Westrip, 2010 ▸).

Supplementary Material

CCDC reference: 1044166

Additional supporting information: crystallographic information; 3D view; checkCIF report

supplementary crystallographic information

Crystal data

C14H18N2O3	Z = 2
Mr = 262.30	F(000) = 280
Triclinic, P1	Dx = 1.225 Mg m−3
a = 7.7502 (6) Å	Mo Kα radiation, λ = 0.71073 Å
b = 7.9792 (5) Å	Cell parameters from 1814 reflections
c = 12.6881 (10) Å	θ = 4.4–28.8°
α = 93.713 (6)°	µ = 0.09 mm−1
β = 96.226 (6)°	T = 293 K
γ = 113.314 (7)°	Prism, colourless
V = 711.32 (10) Å3	0.35 × 0.20 × 0.20 mm

Data collection

Agilent Xcalibur (Ruby, Gemini ultra) diffractometer	3363 independent reflections
Radiation source: Enhance (Mo) X-ray Source	2462 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.022
Detector resolution: 10.3575 pixels mm-1	θmax = 29.4°, θmin = 2.8°
ω scans	h = −9→10
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2012)	k = −11→9
Tmin = 0.883, Tmax = 1.000	l = −16→15
6896 measured reflections

Refinement

Refinement on F2	0 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.049	H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.135	w = 1/[σ2(Fo2) + (0.0572P)2 + 0.1234P] where P = (Fo2 + 2Fc2)/3
S = 1.05	(Δ/σ)max < 0.001
3363 reflections	Δρmax = 0.22 e Å−3
180 parameters	Δρmin = −0.19 e Å−3

Special details

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

Refinement. The C1 methyl group is disordered over two positions.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
N1	−0.00769 (16)	−0.12155 (16)	0.75511 (9)	0.0382 (3)
N3	0.15035 (17)	0.08665 (17)	0.63981 (10)	0.0412 (3)
H3	0.145 (2)	0.115 (2)	0.5763 (16)	0.055 (5)*
O2	−0.12784 (15)	−0.15309 (16)	0.58085 (9)	0.0582 (4)
O4	0.42793 (15)	0.32706 (15)	0.69135 (9)	0.0546 (3)
O6	0.12730 (17)	−0.09825 (17)	0.92461 (9)	0.0589 (3)
C1	−0.1759 (2)	−0.2810 (2)	0.77286 (14)	0.0550 (4)
H1A	−0.1624	−0.3036	0.8461	0.082*	0.43 (2)
H1B	−0.2871	−0.2566	0.7570	0.082*	0.43 (2)
H1C	−0.1881	−0.3870	0.7272	0.082*	0.43 (2)
H1D	−0.2627	−0.3279	0.7074	0.082*	0.57 (2)
H1E	−0.1380	−0.3749	0.7965	0.082*	0.57 (2)
H1F	−0.2370	−0.2445	0.8263	0.082*	0.57 (2)
C2	−0.0015 (2)	−0.06791 (19)	0.65385 (11)	0.0393 (3)
C4	0.30668 (19)	0.18923 (19)	0.71322 (11)	0.0376 (3)
C5	0.32002 (19)	0.11774 (19)	0.82021 (11)	0.0368 (3)
C6	0.1393 (2)	−0.04093 (19)	0.83867 (11)	0.0383 (3)
C7	0.3687 (2)	0.2764 (2)	0.90965 (12)	0.0460 (4)
H7A	0.3993	0.2375	0.9775	0.055*
H7B	0.4802	0.3803	0.8970	0.055*
C8	0.2092 (2)	0.3359 (2)	0.91640 (13)	0.0527 (4)
H8	0.1068	0.2623	0.9479	0.063*
C9	0.2045 (3)	0.4828 (3)	0.88144 (18)	0.0759 (6)
H9A	0.3047	0.5594	0.8496	0.091*
H9B	0.1010	0.5118	0.8882	0.091*
C10	0.4766 (2)	0.0383 (2)	0.82568 (12)	0.0463 (4)
H10	0.4680	−0.0253	0.8897	0.057 (5)*
C11	0.4322 (2)	−0.1006 (2)	0.73331 (14)	0.0510 (4)
C12	0.3973 (3)	−0.2041 (3)	0.65519 (17)	0.0620 (5)
C13	0.3521 (4)	−0.3299 (3)	0.55608 (19)	0.0882 (7)
H13A	0.4699	−0.3204	0.5319	0.106*
H13B	0.2858	−0.4551	0.5716	0.106*
C14	0.2356 (5)	−0.2930 (4)	0.4700 (2)	0.1143 (10)
H14A	0.2091	−0.3809	0.4086	0.171*
H14B	0.3027	−0.1714	0.4518	0.171*
H14C	0.1185	−0.3025	0.4931	0.171*
C15	0.6801 (2)	0.1819 (3)	0.83485 (16)	0.0640 (5)
H15A	0.7656	0.1217	0.8353	0.096*
H15B	0.7106	0.2628	0.8999	0.096*
H15C	0.6922	0.2517	0.7751	0.096*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
N1	0.0343 (6)	0.0402 (6)	0.0336 (6)	0.0085 (5)	0.0022 (5)	0.0091 (5)
N3	0.0409 (7)	0.0458 (7)	0.0270 (6)	0.0083 (5)	−0.0027 (5)	0.0108 (5)
O2	0.0463 (6)	0.0661 (7)	0.0372 (6)	−0.0001 (5)	−0.0087 (5)	0.0094 (5)
O4	0.0494 (6)	0.0501 (6)	0.0469 (7)	0.0019 (5)	0.0011 (5)	0.0168 (5)
O6	0.0592 (7)	0.0696 (8)	0.0345 (6)	0.0109 (6)	0.0028 (5)	0.0210 (5)
C1	0.0428 (8)	0.0541 (9)	0.0541 (10)	0.0037 (7)	0.0054 (7)	0.0182 (8)
C2	0.0366 (7)	0.0430 (8)	0.0328 (8)	0.0117 (6)	−0.0010 (6)	0.0069 (6)
C4	0.0357 (7)	0.0389 (7)	0.0326 (7)	0.0100 (6)	0.0014 (6)	0.0072 (6)
C5	0.0351 (7)	0.0424 (7)	0.0276 (7)	0.0115 (6)	−0.0017 (5)	0.0054 (5)
C6	0.0396 (7)	0.0429 (8)	0.0302 (7)	0.0143 (6)	0.0026 (6)	0.0081 (6)
C7	0.0433 (8)	0.0508 (9)	0.0329 (8)	0.0110 (7)	−0.0046 (6)	−0.0011 (6)
C8	0.0504 (9)	0.0550 (10)	0.0433 (9)	0.0138 (8)	0.0031 (7)	−0.0034 (7)
C9	0.0711 (13)	0.0635 (12)	0.0904 (16)	0.0273 (10)	0.0032 (11)	0.0041 (11)
C10	0.0434 (8)	0.0571 (9)	0.0387 (8)	0.0215 (7)	−0.0007 (6)	0.0112 (7)
C11	0.0491 (9)	0.0562 (10)	0.0533 (10)	0.0268 (8)	0.0064 (8)	0.0122 (8)
C12	0.0633 (11)	0.0639 (11)	0.0663 (12)	0.0352 (9)	0.0044 (9)	0.0051 (9)
C13	0.1023 (18)	0.0897 (16)	0.0816 (16)	0.0565 (14)	−0.0012 (14)	−0.0187 (13)
C14	0.146 (3)	0.130 (2)	0.0667 (16)	0.064 (2)	0.0027 (17)	−0.0222 (15)
C15	0.0396 (9)	0.0777 (12)	0.0671 (12)	0.0194 (9)	−0.0034 (8)	0.0029 (10)

Geometric parameters (Å, º)

N1—C2	1.3800 (18)	C7—H7A	0.9700
N1—C6	1.3804 (17)	C7—H7B	0.9700
N1—C1	1.4687 (18)	C8—C9	1.292 (3)
N3—C2	1.3648 (18)	C8—H8	0.9300
N3—C4	1.3701 (17)	C9—H9A	0.9300
N3—H3	0.85 (2)	C9—H9B	0.9300
O2—C2	1.2140 (16)	C10—C11	1.471 (2)
O4—C4	1.2032 (17)	C10—C15	1.526 (2)
O6—C6	1.2083 (17)	C10—H10	0.9800
C1—H1A	0.9600	C11—C12	1.182 (2)
C1—H1B	0.9600	C12—C13	1.474 (3)
C1—H1C	0.9600	C13—C14	1.460 (3)
C1—H1D	0.9600	C13—H13A	0.9700
C1—H1E	0.9600	C13—H13B	0.9700
C1—H1F	0.9600	C14—H14A	0.9600
C4—C5	1.5151 (18)	C14—H14B	0.9600
C5—C6	1.5248 (19)	C14—H14C	0.9600
C5—C7	1.541 (2)	C15—H15A	0.9600
C5—C10	1.574 (2)	C15—H15B	0.9600
C7—C8	1.498 (2)	C15—H15C	0.9600
C2—N1—C6	123.81 (12)	O6—C6—C5	120.29 (12)
C2—N1—C1	117.84 (12)	N1—C6—C5	119.14 (12)
C6—N1—C1	118.24 (12)	C8—C7—C5	112.61 (12)
C2—N3—C4	127.42 (12)	C8—C7—H7A	109.1
C2—N3—H3	113.2 (12)	C5—C7—H7A	109.1
C4—N3—H3	119.3 (12)	C8—C7—H7B	109.1
N1—C1—H1A	109.5	C5—C7—H7B	109.1
N1—C1—H1B	109.5	H7A—C7—H7B	107.8
H1A—C1—H1B	109.5	C9—C8—C7	124.36 (18)
N1—C1—H1C	109.5	C9—C8—H8	117.8
H1A—C1—H1C	109.5	C7—C8—H8	117.8
H1B—C1—H1C	109.5	C8—C9—H9A	120.0
N1—C1—H1D	109.5	C8—C9—H9B	120.0
H1A—C1—H1D	141.1	H9A—C9—H9B	120.0
H1B—C1—H1D	56.3	C11—C10—C15	110.95 (15)
H1C—C1—H1D	56.3	C11—C10—C5	109.25 (12)
N1—C1—H1E	109.5	C15—C10—C5	114.96 (14)
H1A—C1—H1E	56.3	C11—C10—H10	107.1
H1B—C1—H1E	141.1	C15—C10—H10	107.1
H1C—C1—H1E	56.3	C5—C10—H10	107.1
H1D—C1—H1E	109.5	C12—C11—C10	176.00 (18)
N1—C1—H1F	109.5	C11—C12—C13	178.4 (2)
H1A—C1—H1F	56.3	C14—C13—C12	113.7 (2)
H1B—C1—H1F	56.3	C14—C13—H13A	108.8
H1C—C1—H1F	141.1	C12—C13—H13A	108.8
H1D—C1—H1F	109.5	C14—C13—H13B	108.8
H1E—C1—H1F	109.5	C12—C13—H13B	108.8
O2—C2—N3	121.50 (13)	H13A—C13—H13B	107.7
O2—C2—N1	121.22 (13)	C13—C14—H14A	109.5
N3—C2—N1	117.27 (12)	C13—C14—H14B	109.5
O4—C4—N3	120.57 (12)	H14A—C14—H14B	109.5
O4—C4—C5	122.59 (12)	C13—C14—H14C	109.5
N3—C4—C5	116.82 (12)	H14A—C14—H14C	109.5
C4—C5—C6	114.41 (11)	H14B—C14—H14C	109.5
C4—C5—C7	108.82 (12)	C10—C15—H15A	109.5
C6—C5—C7	108.29 (12)	C10—C15—H15B	109.5
C4—C5—C10	108.59 (12)	H15A—C15—H15B	109.5
C6—C5—C10	105.19 (11)	C10—C15—H15C	109.5
C7—C5—C10	111.55 (11)	H15A—C15—H15C	109.5
O6—C6—N1	120.54 (13)	H15B—C15—H15C	109.5
C10—C5—C7—C8	−171.51 (13)	C5—C7—C8—C9	−103.3 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N3—H3···O2i	0.85 (2)	2.03 (2)	2.8826 (17)	173.2 (17)

Symmetry code: (i) −x, −y, −z+1.