Structural and theoretical studies of 4-chloro-2-methyl-6-oxo-3,6-dideuteropyrimidin-1-ium chloride (d6)

Butcher, R.J.; Purdy, A.P.; Fischer, S.A.; Gunlycke, D.

doi:10.1107/S205698902100270X

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ISSN: 2056-9890

Volume 77| Part 4| April 2021| Pages 390-395

https://doi.org/10.1107/S205698902100270X

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Structural and theoretical studies of 4-chloro-2-methyl-6-oxo-3,6-dideuteropyrimidin-1-ium chloride (d⁶)

Ray J. Butcher,^a ^* Andrew P. Purdy,^b Sean A. Fischer ^c and Daniel Gunlycke ^c

^aDepartment of Chemistry, Howard University, 525 College Street NW, Washington DC 20059, USA, ^bChemistry Division, Code 6100, Naval Research Laboratory, 4555 Overlook Av, SW, Washington DC 20375-5342, USA, and ^cChemistry Division, Code 6189, Naval Research Laboratory, 4555 Overlook Av, SW, Washington DC 20375-5342, USA
^*Correspondence e-mail: rbutcher99@yahoo.com

Edited by P. Roussel, ENSCL, France (Received 16 December 2020; accepted 11 March 2021; online 19 March 2021)

The title compound, C₅D₆ClN₂O⁺·Cl⁻, crystallizes in the orthorhombic space group, Pbcm, and consists of a 4-chloro-2-methyl-6-oxo-3,6-dihydropyrimidin-1-ium cation and a chloride anion where both moieties lie on a crystallographic mirror. The cation is disordered and was refined as two equivalent forms with occupancies of 0.750 (4)/0.250 (4), while the chloride anion is triply disordered with occupancies of 0.774 (12), 0.12 (2), and 0.11 (2). Unusually, the bond angles around the C=O unit range from 127.2 (6) to 115.2 (3)° and similar angles have been found in other structures containing a 6-oxo-3,6-dihydropyrimidin-1-ium cation, including the monclinic polymorph of the title compound, which crystallizes in the monoclinic space group P2₁/c [Kawai et al. (1973 ). Cryst. Struct. Comm. 2, 663–666]. The cations and anions pack into sheets in the ab plane linked by N—H⋯Cl hydrogen bonds as well as C—H⋯O and Cl⋯O interactions. In graph-set notation, these form R³₃(11) and R³₂(9) rings. Theoretical calculations seem to indicate that the reason for the unusual angles at the sp² C is the electrostatic interaction between the oxygen atom and the adjacent N—H hydrogen.

Keywords: crystal structure; pyrimidinium cation; distorted sp² C.

CCDC reference: 2069792

1. Chemical context

Heterocycles containing the pyrimidine moiety are of great interest because they constitute an important class of natural and non-natural products, many of which exhibit useful biological activities and clinical applications (Brown, 1984 ; Elderfield, 1957 ). Substituted purines and pyrimidines occur very widely in living organisms and were some of the first compounds studied by organic chemists (Bruice, 2007 ).

The presence of the pyrimidine base in thymine, cytosine, and uracil, which are the essential building blocks of nucleic acids DNA and RNA, is one possible reason for their widespread therapeutic applications. Pyrimidines represent one of the most active classes of compounds, possessing a wide spectrum of biological activities such as significant in vitro activity against unrelated DNA and RNA viruses including polio herpes viruses, and diuretic, antitumor, anti-HIV, and cardiovascular (Kappe, 1993 ) activity. In addition to this, various analogs of pyrimidines have been found to possess antibacterial (Sharma et al., 2004 ; Prakash et al., 2004 ; Botta et al., 1992 ; Cieplik et al., 2015 ), antifungal (Agarwal et al., 2000 ; Oliver et al., 2016 ), antileishmanial (Ram et al., 1992 ; Alptuzun et al., 2013 ), anti-inflammatory (Amir et al., 2007 ; Sondhi et al., 2008 ), analgesic (Vega et al., 1990 ; Gupta et al., 2011 ), antihypertensive (Hannah & Stevens, 2003 ; Rana et al., 2004 ; Alam et al., 2010 ), antipyretic (Smith & Kan, 1964 ; El-Sharkawy et al., 2018 ), antiviral (Balzarini & McGuigan, 2002 ; Nasr & Gineinah, 2002 ), antidiabetic (Lee et al., 2005 ; Reddy et al., 2019 ), antiallergic (Juby et al., 1979 ; Gupta et al., 1995 ), anticonvulsant (Gupta et al., 1994 ; Shaquiquzzaman et al., 2012 ), antioxidant (Krivonogov, et al., 2001 ; Abu-Hashem et al., 2010 , 2011 ), antihistaminic (Prasad & Rahaman, 2008 ; Rahaman et al., 2009 ), herbicidal (Nezu et al., 1996 ; Li et al., 2018 ), and anticancer activities (Abu-Hashem et al., 2010, 2011; Xie et al., 2009 ; Kaldrikyan et al., 2000 ; Mohamed et al., 2013 ) and many pyrimidine derivatives are reported to possess potential central nervous system (CNS) depressant properties (Rodrigues et al., 2005 ; Tani et al., 1979 ; Kimura et al., 1993 ) and also act as calcium channel blockers (Kumar et al., 2002 ; Ortner & Striessnig, 2016 ). Thus, in view of this extensive biochemical activity of pyrimidines and their derivatives, much effort has been expended on the structural study of both pyrimidines and their cations.

2. Structural commentary and database survey

The title compound, [C₅D₆ClN₂O]⁺Cl⁻, 1, crystallizes in the orthorhombic space group, Pbcm, unlike its polymorph, 2 (Kawai et al., 1973), which crystallizes in the monoclinic space group P2₁/c. It consists of a 4-chloro-2-methyl-6-oxo-3,6-dihydropyrimidin-1-ium cation and a chloride anion (Fig. 1). Since both moieties lie on a crystallographic mirror plane, the cation is strictly planar. The cation is disordered over two equivalent conformations (both of which lie on the mirror plane) with occupancies of 0.750 (4)/0.250 (4) while the chloride anion is triply disordered with occupancies of 0.774 (12), 0.12 (2), and 0.11 (2). The C—C, C—N, and C=O metrical parameters of the 6-oxo-3,6-dihydropyrimidin-1-ium skeleton for the two polymorphs are similar and both exhibit unusual bond angles for the ketonic moiety. The values for C3—C4—O1, N2—C4—O1, and N2—C4—C3 are 127.2 (6), 117.6 (6), and 115.2 (3)° for 1 and 126.1 (9), 118.2 (8), and 115.7 (8)° for 2.

Figure 1
Diagram showing the cation and anion and the atom-numbering scheme (only the major component of the disorder is shown) with atomic displacement parameters drawn at the 30% probability level. The N—H⋯Cl hydrogen bond is shown by a dashed line.

In view of the unusual values for these bond angles, a search was made of the Cambridge Structural Database [CSD version 5.41 (November 2019); Groom et al., 2016 ] for structures containing a 6-oxo-3,6-dihydropyrimidin-1-ium skeleton, which yielded 52 independent observations. A statistical analysis of the values for corresponding angles gave values of 126.7 (7), 118.8 (8), and 115.3 (10)°. An analysis of both lengths also revealed the similarity in all these derivatives. In all cases, the longest bond was C3—C4 which is 1.430 (7) Å in 1 and 1.430 (12) Å on average, while the second longest bond was N2—C4 at 1.402 (6) Å for 1 and 1.397 (10) Å on average. In fact, all the metrical parameters for the 6-oxo-3,6-dihydropyrimidin-1-ium skeleton are in agreement with average values. One reason to be considered for the unusual values for the C3—C4—O1, N2—C4—O1, and N2—C4—C3 angles is this difference in C3—C4 and C4—N2 distances, which would tilt the carbonyl moiety towards N2. However, there are examples where the lengths of these two distances are reversed [ACEYUD (Muthiah et al., 2004 ), EHAPOV (Tapmeyer & Prill, 2019 ), SUZFOJ (Suleiman Gwaram et al., 2010 )], but the same trend in angles prevails.

In light of these unusual bond angles for an sp² C atom, a theoretical analysis of the cation was undertaken. The geometries of the isolated cation, two neutral variants, and a tautomer of the cation were optimized using the PBE0 exchange-correlation functional (Adamo & Barone, 1999 ; Perdew et al., 1996 ) and aug-cc-pVTZ basis set (Dunning, 1989 ; Kendall et al., 1992 ; Woon & Dunning 1993 ; Davidson, 1996 ) via NWChem (Aprà et al., 2020 ). The geometry of the cation was also optimized as a scan was made of the nuclear charge of the hydrogen bound to N2.

Figs. 2–5 show the optimized geometries for the cation 1, two neutral structures, 3 and 4, which are tautomers of each other, and a tautomer of the cation, 5. When N2 is protonated, as in 1 (Fig. 2) and 4 (Fig. 4), the carbonyl moiety is tilted towards N2. When N2 is not protonated, as in 3 (Fig. 3) and 5 (Fig. 5), the carbonyl moiety assumes a normal orientation for an sp² C atom. This suggests an electrostatic interaction between oxygen and hydrogen may be responsible for the unusual angles. To explore this further, the geometry of 1 was optimized as the nuclear charge of the hydrogen bound to N2 was scanned from 0.7 to 1.3 e. As can be seen from the plot (Fig. 6), the two angles converge with decreasing nuclear charge on the hydrogen and diverge with increasing nuclear charge. This lends further support to the idea that the origin of the angle difference is an electrostatic interaction between the O1 and the hydrogen on N2.

Figure 2
Diagram showing the results of calculations for the cation, 1. Relevant angles are displayed.

Figure 3
Diagram showing the results of calculations for the neutral molecule, 3 (tautomer 1). Relevant angles are displayed.

Figure 4
Diagram showing the results of calculations for the neutral molecule, 4 (tautomer 2, with the N—H group adjacent to the C=O bond). Relevant angles are displayed.

Figure 5
Diagram showing the results of calculations for 5, a tautomer of the cation. Relevant angles are displayed.

Figure 6
Diagram showing a plot of the variation in the C—C—O and N—C—O angles around the sp² C atom as the nuclear charge of the hydrogen attached to the nitrogen is varied while keeping all other nuclear charges fixed at their normal values and keeping the number of electrons fixed.

3. Supramolecular features

In the crystal, the cations and anions pack into sheets in the ab plane linked by N—H⋯Cl hydrogen bonds, as well as Cl⋯O and weak C—H⋯O interactions (Table 1). In graph-set notation (Etter et al., 1990 ), these make R₃³(11) and R₂³(9) rings as seen in Fig. 7. Interestingly there are no N—H⋯O hydrogen bonds.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—D1A⋯Cl2ⁱ	0.88	2.23	3.103 (4)	175
N2—D2A⋯Cl2ⁱⁱ	0.88	2.24	3.119 (6)	178
C3—D3A⋯Cl2ⁱⁱⁱ	0.95	2.82	3.769 (7)	175
C5—D5B⋯Cl2ⁱ	0.95 (1)	2.96 (1)	3.798 (6)	148 (1)
C5—D5B⋯O1^iv	0.95 (1)	2.44 (1)	3.040 (8)	121 (1)
N1A—D1AA⋯Cl2Aⁱ	0.88	2.37	3.24 (3)	172
N2A—D2AA⋯Cl2Aⁱⁱⁱ	0.88	2.03	2.91 (4)	177
C3A—D3AA⋯Cl2Aⁱⁱ	0.95	2.94	3.88 (3)	171
C5A—D5C⋯O1A^v	0.95 (1)	2.36 (2)	2.985 (16)	123 (1)
C5A—D5D⋯O1A^vi	0.95 (1)	2.66 (1)	3.582 (9)	163 (1)
Symmetry codes: (i) $[x, -y+{\script{1\over 2}}, -z+1]$ ; (ii) ; (iii) ; (iv) $[-x+2, y+{\script{1\over 2}}, z]$ ; (v) $[-x+1, y+{\script{1\over 2}}, z]$ ; (vi) .

Figure 7
The packing viewed along the c axis showing how the cations and anions pack into sheets in the ab plane linked by N—H⋯Cl hydrogen bonds and Cl⋯O and weak C—H⋯O interactions, forming R₃³(11) and R₂³(9) rings.

4. Synthesis and crystallization

Inside a dry box, one side of an H-tube (with no filter between the sides) was charged with 250 mg triphosgene (Aldrich) and the other side was loaded with 20 mg tetramethylammonium chloride in 3 mL dry tetraglyme. Once attached to a vacuum line with Cajon flexible tubing, the components were mixed and the phosgene was collected in a vacuum trap. In one NMR tube, 0.36 mmol of phosgene were measured on the vacuum line, condensed into 0.75 mL of dry CD₃CN, and the tube was sealed as an NMR reference. In another tube, 0.36 mmol of phosgene was condensed onto 0.06 g (0.20 mmol) of silver oxalate in CD₃CN and the tube was sealed to attempt to prepare a CO₂ polymer. Upon warming, the ¹³C NMR of the reaction tube showed gaseous CO₂ and solvent only. After standing unobserved for three years, the reference tube was observed to be filled with crystals of the title compound, which is completely insoluble in acetonitrile, and the tube was opened in a drybox to keep the crystals dry. The ¹³C{¹H} NMR spectrum of the crystals in D₂O (DSS ref) is 167.07 (s), 164.11 (s), 161.28 (s), 113.05 (C3, t, ¹J_C–D = 27.5 Hz) , 22.35 (CD₃, septet, ¹J_C–D = 19.8 Hz) . The previous report (Yanagida et al., 1968 ) involved a reaction of phosgene, CH₃CN and HCl at 338 K. In contrast to a previous report for the structure of the monoclinic polymorph (Kawai et al., 1973), all crystals had the same habit and appearance and one suitable for X-ray diffraction studies was chosen for further study.

5. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. The cation is disordered and was refined as two equivalent forms with occupancies of 0.750 (4)/0.250 (4), while the chloride anion is triply disordered with occupancies of 0.774 (12), 0.12 (2), and 0.11 (2). The locations of all deuterium atoms for the major component except one attached to N1 were located in difference-Fourier maps and refined in idealized positions using a riding model with atomic displacement parameters of U_iso(D) = 1.2U_eq(C, N) [1.5U_eq(C) for CD₃], and C—D and N—D distances of 0.95 and 0.88 Å, respectively. The deuterium atoms for the methyl substituent were refined isotropically.

Table 2
Experimental details

Crystal data
Chemical formula	C₅D₆ClN₂O⁺·Cl⁻
M_r	187.05
Crystal system, space group	Orthorhombic, Pbcm
Temperature (K)	100
a, b, c (Å)	8.6030 (4), 13.1389 (6), 6.4812 (3)
V (Å³)	732.60 (6)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.81
Crystal size (mm)	0.25 × 0.18 × 0.06

Data collection
Diffractometer	Bruker APEXII CCD
Absorption correction	Multi-scan (SADABS; Sheldrick, 1996 )
T_min, T_max	0.635, 0.747
No. of measured, independent and observed [I > 2σ(I)] reflections	12377, 1802, 1558
R_int	0.041
(sin θ/λ)_max (Å⁻¹)	0.820

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.064, 0.152, 1.19
No. of reflections	1802
No. of parameters	137
No. of restraints	362
Δρ_max, Δρ_min (e Å⁻³)	0.68, −1.09
Computer programs: APEX2 (Bruker, 2005 ), SAINT (Bruker 2002 ), SHELXT (Sheldrick 2015a ), SHELXL2018/3 (Sheldrick, 2015b ), and SHELXTL (Sheldrick 2008 ).

Supporting information

CCDC reference: 2069792

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S205698902100270X/ru2073sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S205698902100270X/ru2073Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S205698902100270X/ru2073Isup3.cml

checkCIF report

Computing details top

Data collection: APEX2 (Bruker, 2005); cell refinement: SAINT (Bruker 2002); data reduction: SAINT (Bruker 2002); program(s) used to solve structure: SHELXT (Sheldrick 2015a); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015b); molecular graphics: SHELXTL (Sheldrick 2008); software used to prepare material for publication: SHELXTL (Sheldrick 2008).

4-Chloro-2-methyl-6-oxo-3,6-dihydropyrimidin-1-ium chloride top

Crystal data top

C₅D₆ClN₂O⁺·Cl⁻	D_x = 1.696 Mg m⁻³
M_r = 187.05	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, Pbcm	Cell parameters from 8906 reflections
a = 8.6030 (4) Å	θ = 2.8–35.6°
b = 13.1389 (6) Å	µ = 0.81 mm⁻¹
c = 6.4812 (3) Å	T = 100 K
V = 732.60 (6) Å³	Plate, pale yellow
Z = 4	0.25 × 0.18 × 0.06 mm
F(000) = 368

Data collection top

Bruker APEXII CCD diffractometer	1558 reflections with I > 2σ(I)
φ and ω scans	R_int = 0.041
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	θ_max = 35.6°, θ_min = 2.8°
T_min = 0.635, T_max = 0.747	h = −13→14
12377 measured reflections	k = −21→14
1802 independent reflections	l = −9→10

Refinement top

Refinement on F²	362 restraints
Least-squares matrix: full	Primary atom site location: structure-invariant direct methods
R[F² > 2σ(F²)] = 0.064	Secondary atom site location: difference Fourier map
wR(F²) = 0.152	w = 1/[σ²(F_o²) + (0.0253P)² + 2.2439P] where P = (F_o² + 2F_c²)/3
S = 1.19	(Δ/σ)_max = 0.001
1802 reflections	Δρ_max = 0.68 e Å⁻³
137 parameters	Δρ_min = −1.09 e Å⁻³

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	Occ. (<1)
Cl2	0.79527 (11)	0.10338 (6)	0.750000	0.0147 (2)	0.773 (4)
Cl2A	0.689 (3)	0.0986 (17)	0.750000	0.0189 (12)	0.09 (2)
Cl2B	0.714 (3)	0.1092 (13)	0.750000	0.0191 (11)	0.13 (2)
Cl1	0.46030 (12)	0.19112 (9)	0.250000	0.0235 (3)	0.747 (4)
O1	0.7595 (7)	−0.1423 (3)	0.250000	0.0247 (9)	0.747 (4)
N1	0.7600 (5)	0.1616 (3)	0.250000	0.0141 (6)	0.747 (4)
D1A	0.763535	0.228547	0.250000	0.017*	0.747 (4)
N2	0.8852 (7)	0.0087 (4)	0.250000	0.0152 (5)	0.747 (4)
D2A	0.973805	−0.024740	0.250000	0.018*	0.747 (4)
C1	0.8910 (6)	0.1091 (4)	0.250000	0.0143 (6)	0.747 (4)
C2	0.6181 (6)	0.1132 (4)	0.250000	0.0153 (6)	0.747 (4)
C3	0.6072 (8)	0.0099 (5)	0.250000	0.0185 (7)	0.747 (4)
D3A	0.508666	−0.022705	0.250000	0.022*	0.747 (4)
C4	0.7475 (9)	−0.0484 (3)	0.250000	0.0170 (6)	0.747 (4)
C5	1.0525 (9)	0.1617 (5)	0.250000	0.0233 (10)	0.747 (4)
D5A	1.0986 (14)	0.1441 (10)	0.1214 (19)	0.035*	0.747 (4)
D5B	1.0311 (14)	0.2329 (5)	0.250000	0.035*	0.747 (4)
Cl1A	1.0368 (7)	0.1850 (5)	0.250000	0.0364 (14)	0.253 (4)
O1A	0.734 (2)	−0.1471 (7)	0.250000	0.026 (2)	0.253 (4)
N1A	0.7367 (12)	0.1568 (8)	0.250000	0.0163 (11)	0.253 (4)
D1AA	0.733683	0.223774	0.250000	0.020*	0.253 (4)
N2A	0.6105 (17)	0.0044 (10)	0.250000	0.0179 (11)	0.253 (4)
D2AA	0.521578	−0.028785	0.250000	0.021*	0.253 (4)
C1A	0.6051 (12)	0.1048 (10)	0.250000	0.0168 (11)	0.253 (4)
C2A	0.8783 (12)	0.1079 (9)	0.250000	0.0164 (11)	0.253 (4)
C3A	0.8883 (18)	0.0046 (9)	0.250000	0.0168 (11)	0.253 (4)
D3AA	0.986561	−0.028400	0.250000	0.020*	0.253 (4)
C4A	0.748 (2)	−0.0533 (7)	0.250000	0.0177 (11)	0.253 (4)
C5A	0.4429 (14)	0.1574 (10)	0.250000	0.0233 (10)	0.253 (4)
D5C	0.464 (2)	0.2283 (10)	0.250000	0.035*	0.253 (4)
D5D	0.3968 (19)	0.1390 (15)	0.122 (2)	0.035*	0.253 (4)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl2	0.0144 (5)	0.0132 (3)	0.0164 (3)	0.0011 (3)	0.000	0.000
Cl2A	0.017 (3)	0.019 (2)	0.0204 (18)	−0.004 (2)	0.000	0.000
Cl2B	0.017 (2)	0.021 (2)	0.0193 (16)	−0.004 (2)	0.000	0.000
Cl1	0.0173 (4)	0.0233 (5)	0.0298 (5)	0.0084 (3)	0.000	0.000
O1	0.0121 (18)	0.0141 (12)	0.048 (2)	−0.0039 (10)	0.000	0.000
N1	0.0155 (12)	0.0117 (11)	0.0151 (11)	−0.0013 (9)	0.000	0.000
N2	0.0132 (11)	0.0139 (11)	0.0187 (12)	−0.0029 (9)	0.000	0.000
C1	0.0144 (12)	0.0139 (11)	0.0145 (12)	−0.0012 (10)	0.000	0.000
C2	0.0133 (12)	0.0160 (13)	0.0165 (12)	0.0030 (10)	0.000	0.000
C3	0.0161 (12)	0.0182 (13)	0.0212 (14)	0.0006 (11)	0.000	0.000
C4	0.0129 (12)	0.0158 (12)	0.0224 (13)	−0.0015 (10)	0.000	0.000
C5	0.0257 (17)	0.0149 (18)	0.029 (2)	0.0063 (13)	0.000	0.000
Cl1A	0.029 (2)	0.045 (3)	0.035 (2)	−0.005 (2)	0.000	0.000
O1A	0.018 (5)	0.017 (3)	0.044 (5)	0.001 (3)	0.000	0.000
N1A	0.018 (2)	0.014 (2)	0.016 (2)	0.0017 (18)	0.000	0.000
N2A	0.016 (2)	0.0172 (19)	0.021 (2)	0.0011 (18)	0.000	0.000
C1A	0.0154 (19)	0.017 (2)	0.018 (2)	0.0020 (18)	0.000	0.000
C2A	0.0168 (19)	0.0158 (19)	0.017 (2)	0.0003 (18)	0.000	0.000
C3A	0.015 (2)	0.0171 (19)	0.019 (2)	0.0007 (18)	0.000	0.000
C4A	0.014 (2)	0.0166 (19)	0.022 (2)	−0.0006 (18)	0.000	0.000
C5A	0.0257 (17)	0.0149 (18)	0.029 (2)	0.0063 (13)	0.000	0.000

Geometric parameters (Å, º) top

Cl1—C2	1.700 (5)	Cl1A—D5A	1.126 (8)
Cl1—D5Dⁱ	1.206 (11)	Cl1A—D5B	0.631 (10)
O1—C4	1.238 (4)	O1A—C4A	1.238 (5)
N1—C1	1.322 (6)	N1A—C1A	1.322 (7)
N1—C2	1.377 (6)	N1A—C2A	1.378 (7)
N1—D1A	0.8800	N1A—D1AA	0.8800
N2—C1	1.320 (6)	N2A—C1A	1.321 (8)
N2—C4	1.402 (6)	N2A—C4A	1.402 (8)
N2—D2A	0.8800	N2A—D2AA	0.8800
C1—C5	1.552 (9)	C1A—C5A	1.556 (10)
C2—C3	1.360 (7)	C2A—C3A	1.361 (8)
C3—C4	1.430 (7)	C3A—C4A	1.429 (9)
C3—D3A	0.9500	C3A—D3AA	0.9500
C5—D5A	0.952 (5)	C5A—D5C	0.950 (5)
C5—D5B	0.953 (5)	C5A—D5D	0.950 (5)
C5—D5Aⁱ	0.952 (5)	C5A—D5Dⁱ	0.950 (5)
Cl1A—C2A	1.698 (7)

C2—Cl1—D5Dⁱ	91.1 (7)	D5A—Cl1A—D5B	120.9 (9)
C1—N1—C2	121.0 (3)	D5A—Cl1A—D5Aⁱ	96 (2)
C1—N1—D1A	119.5	D5B—Cl1A—D5Aⁱ	120.9 (9)
C2—N1—D1A	119.5	C1A—N1A—C2A	121.1 (5)
C1—N2—C4	124.5 (4)	C1A—N1A—D1AA	119.5
C1—N2—D2A	117.7	C2A—N1A—D1AA	119.5
C4—N2—D2A	117.7	C1A—N2A—C4A	124.7 (8)
N2—C1—N1	119.3 (4)	C1A—N2A—D2AA	117.6
N2—C1—C5	118.7 (5)	C4A—N2A—D2AA	117.6
N1—C1—C5	122.1 (4)	N2A—C1A—N1A	119.1 (8)
C3—C2—N1	121.4 (4)	N2A—C1A—C5A	118.4 (8)
C3—C2—Cl1	123.1 (4)	N1A—C1A—C5A	122.5 (8)
N1—C2—Cl1	115.4 (3)	C3A—C2A—N1A	121.4 (8)
C2—C3—C4	118.5 (5)	C3A—C2A—Cl1A	123.0 (8)
C2—C3—D3A	120.8	N1A—C2A—Cl1A	115.6 (7)
C4—C3—D3A	120.8	C2A—C3A—C4A	118.5 (8)
O1—C4—N2	117.6 (6)	C2A—C3A—D3AA	120.7
O1—C4—C3	127.2 (6)	C4A—C3A—D3AA	120.7
N2—C4—C3	115.2 (3)	O1A—C4A—N2A	117.2 (10)
C1—C5—D5A	105.3 (8)	O1A—C4A—C3A	127.7 (10)
C1—C5—D5B	105.3 (8)	N2A—C4A—C3A	115.2 (5)
D5A—C5—D5B	108.7 (8)	C1A—C5A—D5C	105.2 (9)
C1—C5—D5Aⁱ	105.3 (8)	C1A—C5A—D5D	105.2 (9)
D5A—C5—D5Aⁱ	122 (2)	D5C—C5A—D5D	109.3 (8)
D5B—C5—D5Aⁱ	108.7 (8)	C1A—C5A—D5Dⁱ	105.2 (9)
C2A—Cl1A—D5A	95.4 (7)	D5C—C5A—D5Dⁱ	109.3 (8)
C2A—Cl1A—D5B	122.1 (14)	D5D—C5A—D5Dⁱ	121 (3)

C4—N2—C1—N1	0.0	C4A—N2A—C1A—N1A	0.0
C4—N2—C1—C5	180.0	C4A—N2A—C1A—C5A	180.0
C2—N1—C1—N2	0.0	C2A—N1A—C1A—N2A	0.0
C2—N1—C1—C5	180.0	C2A—N1A—C1A—C5A	180.0
C1—N1—C2—C3	0.0	C1A—N1A—C2A—C3A	0.0
C1—N1—C2—Cl1	180.0	C1A—N1A—C2A—Cl1A	180.0
N1—C2—C3—C4	0.0	N1A—C2A—C3A—C4A	0.0
Cl1—C2—C3—C4	180.0	Cl1A—C2A—C3A—C4A	180.0
C1—N2—C4—O1	180.0	C1A—N2A—C4A—O1A	180.0
C1—N2—C4—C3	0.0	C1A—N2A—C4A—C3A	0.0
C2—C3—C4—O1	180.0	C2A—C3A—C4A—O1A	180.0
C2—C3—C4—N2	0.0	C2A—C3A—C4A—N2A	0.0

Symmetry code: (i) x, y, −z+1/2.

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—D1A···Cl2ⁱⁱ	0.88	2.23	3.103 (4)	175
N2—D2A···Cl2ⁱⁱⁱ	0.88	2.24	3.119 (6)	178
C3—D3A···Cl2^iv	0.95	2.82	3.769 (7)	175
C5—D5B···Cl2ⁱⁱ	0.95 (1)	2.96 (1)	3.798 (6)	148 (1)
C5—D5B···O1^v	0.95 (1)	2.44 (1)	3.040 (8)	121 (1)
Cl1A—D5B···O1A^v	0.63 (1)	2.57 (2)	2.960 (16)	123 (1)
N1A—D1AA···Cl2Aⁱⁱ	0.88	2.37	3.24 (3)	172
N2A—D2AA···Cl2A^iv	0.88	2.03	2.91 (4)	177
C3A—D3AA···Cl2Aⁱⁱⁱ	0.95	2.94	3.88 (3)	171
C5A—D5C···O1A^vi	0.95 (1)	2.36 (2)	2.985 (16)	123 (1)
C5A—D5D···O1A^vii	0.95 (1)	2.66 (1)	3.582 (9)	163 (1)

Symmetry codes: (ii) x, −y+1/2, −z+1; (iii) −x+2, −y, −z+1; (iv) −x+1, −y, −z+1; (v) −x+2, y+1/2, z; (vi) −x+1, y+1/2, z; (vii) −x+1, −y, −z.

Funding information

RJB wishes to acknowledge the ONR Summer Faculty Research Program for funding in 2019 and 2020.

References

Abu-Hashem, A. A., El-Shehry, M. F. & Badria, F. A. (2010). Acta Pharm. 60, 311–323. CAS PubMed Google Scholar
Abu-Hashem, A. A., Youssef, M. M. & Hussein, H. A. R. (2011). Jnl Chin. Chem. Soc. 58, 41–48. CAS Google Scholar
Adamo, C. & Barone, V. (1999). J. Chem. Phys. 110, 6158–6170. Web of Science CrossRef CAS Google Scholar
Agarwal, N., Raghuwanshi, S. K., Upadhyay, D. N., Shukla, P. K. & Ram, V. J. (2000). Bioorg. Med. Chem. Lett. 10, 703–706. Web of Science CrossRef PubMed CAS Google Scholar
Alam, O., Khan, S. A., Siddiqui, N., Ahsan, W., Verma, S. P. & Gilani, S. J. (2010). Eur. J. Med. Chem. 45, 5113–5119. CrossRef CAS PubMed Google Scholar
Alptuzun, V., Cakiroglu, G., Limoncu, E. M., Erac, B., Hosgor-Limoncu, M. & Erciyas, E. (2013). J. Enzyme Inhib. Med. Chem. 28, 960–967. CrossRef CAS PubMed Google Scholar
Amir, M., Javed, S. A. & Kumar, H. (2007). Indian J. Pharm. Sci. 69, 337–343. CrossRef CAS Google Scholar
Aprà, E., Bylaska, E. J., de Jong, W. A., Govind, N., Kowalski, K., Straatsma, T. P., Valiev, M., van Dam, H. J. J., Alexeev, Y., Anchell, J., Anisimov, V., Aquino, F. W., Atta-Fynn, R., Autschbach, J., Bauman, N. P., Becca, J. C., Bernholdt, D. E., Bhaskaran-Nair, K., Bogatko, S., Borowski, P., Boschen, J., Brabec, J., Bruner, A., Cauët, E., Chen, Y., Chuev, G. N., Cramer, C. J., Daily, J., Deegan, M. J. O., Dunning, T. H. Jr, Dupuis, M., Dyall, K. G., Fann, G. I., Fischer, S. A., Fonari, A., Früchtl, H., Gagliardi, L., Garza, J., Gawande, N., Ghosh, S., Glaesemann, K., Götz, A. W., Hammond, J., Helms, V., Hermes, E. D., Hirao, K., Hirata, S., Jacquelin, M., Jensen, L., Johnson, B. G., Jónsson, H., Kendall, R. A., Klemm, M., Kobayashi, R., Konkov, V., Krishnamoorthy, S., Krishnan, M., Lin, Z., Lins, R. D., Littlefield, R. J., Logsdail, A. J., Lopata, K., Ma, W., Marenich, A. V., Martin del Campo, J., Mejia-Rodriguez, D., Moore, J. E., Mullin, J. M., Nakajima, T., Nascimento, D. R., Nichols, J. A., Nichols, P. J., Nieplocha, J., Otero-de-la-Roza, A., Palmer, B., Panyala, A., Pirojsirikul, T., Peng, B., Peverati, R., Pittner, J., Pollack, L., Richard, R. M., Sadayappan, P., Schatz, G. C., Shelton, W. A., Silverstein, D. W., Smith, D. M. A., Soares, T. A., Song, D., Swart, M., Taylor, H. L., Thomas, G. S., Tipparaju, V., Truhlar, D. G., Tsemekhman, K., Van Voorhis, T., Vázquez-Mayagoitia, , Verma, P., Villa, O., Vishnu, A., Vogiatzis, K. D., Wang, D., Weare, J. H., Williamson, M. J., Windus, T. L., Woliński, K., Wong, A. T., Wu, Q., Yang, C., Yu, Q., Zacharias, M., Zhang, Z., Zhao, Y. & Harrison, R. J. (2020). J. Chem. Phys. 152, 184102. Google Scholar
Balzarini, J. & McGuigan, C. (2002). J. Antimicrob. Chemother. 50, 5–9. CrossRef PubMed CAS Google Scholar
Botta, M., Artico, M., Massa, S., Gambacorta, A., Marongiu, M., Pani, A. & La Colla, P. (1992). Eur. J. Med. Chem. 27, 251–257. CrossRef CAS Google Scholar
Brown, D. J. (1984). Comprehensive Heterocyclic Chemistry, Vol. 14, edited by A. R. Katritzky and C. W. Rees. Oxford: Pergamon Press. Google Scholar
Bruice, P. Y. (2007). Essential Organic Chemistry, 3rd ed. Singapore: Pearson Education. Google Scholar
Bruker (2002). SAINT. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Bruker (2005). APEX2.Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Cieplik, J., Stolarczyk, M., Pluta, J., Gubrynowicz, O., Bryndal, I., Lis, T. & Mikulewicz, M. (2015). Acta Pol. Pharm. 72, 53–64. Web of Science PubMed Google Scholar
Davidson, E. R. (1996). Chem. Phys. Lett. 260, 514–518. CrossRef CAS Google Scholar
Dunning, T. H. Jr (1989). J. Chem. Phys. 90, 1007–1023. CrossRef CAS Web of Science Google Scholar
Elderfield, R. C. (1957). Heterocyclic Compounds, vol. 6. New York: John Wiley & Sons. Google Scholar
El-Sharkawy, K. A., AlBratty, M. M. & Alhazmi, H. A. (2018). Braz. J. Pharm. Sci. 54, e00153. Google Scholar
Etter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256–262. CrossRef ICSD CAS Web of Science IUCr Journals Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
Gupta, A. K., Sanjay, K. H. P., Singh, A., Sharma, G. & Mishra, K. C. (1994). Indian J. Pharmacol. 26, 227–228. CAS Google Scholar
Gupta, J. K., Sharma, P. K., Dudhe, R., Mondal, S. C., Chaudhary, A. & Verma, P. K. (2011). Acta Pol. Pharm. 68, 785–793. CAS PubMed Google Scholar
Gupta, P. P., Srimal, R. C., Avasthi, K., Garg, N., Chandra, T. & Bhakuni, D. S. (1995). Indian J. Exp. Biol. 33, 38–40. CAS PubMed Google Scholar
Hannah, D. R. & Stevens, M. F. G. (2003). J. Chem. Res. pp. 398–401. CrossRef Google Scholar
Juby, P. F., Hudyma, T. W., Brown, M., Essery, J. M. & Partyka, R. A. (1979). J. Med. Chem. 22, 263–269. CrossRef CAS PubMed Google Scholar
Kaldrikyan, M. A., Grigoryan, L. A., Geboyan, V. A., Arsenyan, F. G., Stepanyan, G. M. & Garibdzhanyan, B. T. (2000). Pharm. Chem. J. 34, 521–524. CrossRef CAS Google Scholar
Kappe, C. O. (1993). Tetrahedron, 49, 6937–6963. CrossRef CAS Google Scholar
Kawai, T., Yasuoka, N., Kasai, N. & Kakudo, M. (1973). Cryst. Struct. Comm. 2, 663–666. CAS Google Scholar
Kendall, R. A., Dunning, T. H. Jr & Harrison, R. J. (1992). J. Chem. Phys. 96, 6796–6806. CrossRef CAS Web of Science Google Scholar
Kimura, T., Teraoka, S., Kuze, J., Watanabe, K., Kondo, S., Ho, I. K. & Yamamoto, I. (1993). Nucleic Acids Symp. Ser. pp. 51–52. Google Scholar
Krivonogov, V. P., Myshkin, V. A., Sivkova, G. A., Greben'kova, N. A., Srubillin, D. V., Kozlova, G. G., Abdrakhmanov, I. B., Mannapova, R. T., Spirikhin, L. V. & Tolstikov, G. A. (2001). Pharm. Chem. J. 35, 411–413. CrossRef CAS Google Scholar
Kumar, B., Kaur, B., Kaur, J., Parmar, A., Anand, R. D. & Kumar, H. (2002). Indian Journal of Chemistry B, 41, 1526–1530. Google Scholar
Lee, H. W., Kim, B. Y., Ahn, J. B., Kang, S. K., Lee, J. H., Shin, J. S., Ahn, S. K., Lee, S. J. & Yoon, S. S. (2005). Eur. J. Med. Chem. 40, 862–874. CrossRef PubMed CAS Google Scholar
Li, K.-J., Qu, R.-Y., Liu, Y.-C., Yang, J.-F., Devendar, P., Chen, Q., Niu, C.-W., Xi, Z. & Yang, G.-F. (2018). J. Agric. Food Chem. 66, 3773–3782. CrossRef CAS PubMed Google Scholar
Mohamed, A. M., El-Sayed, W. A., Alsharari, M. A., Al-Qalawi, H. R. M. & Germoush, M. O. (2013). Arch. Pharm. Res. 36, 1055–1065. Web of Science CrossRef CAS PubMed Google Scholar
Muthiah, P. T., Hemamalini, M., Bocelli, G. & Cantoni, A. (2004). Acta Cryst. E60, o2038–o2040. Web of Science CSD CrossRef IUCr Journals Google Scholar
Nasr, M. N. & Gineinah, M. M. (2002). Arch. Pharm. Pharm. Med. Chem. 335, 289–295. Web of Science CrossRef CAS Google Scholar
Nezu, Y., Miyazaki, M., Sugiyama, K. & Kajiwara, I. (1996). Pestic. Sci. 47, 103–113. CrossRef CAS Google Scholar
Oliver, J. D., Sibley, G. E. M., Beckmann, N., Dobb, K. S., Slater, M. J., McEntee, L., du Pré, S., Livermore, J., Bromley, M. J., Wiederhold, N. P., Hope, W. W., Anthony, J., Kennedy, A. J., Law, D. & Birch, M. (2016). PNAS 113, 12809–12814. CrossRef CAS PubMed Google Scholar
Ortner, N. J. & Striessnig, J. (2016). Channels, 10, 7–13. CrossRef PubMed Google Scholar
Perdew, J. P., Burke, K. & Ernzerhof, M. (1996). Phys. Rev. Lett. 77, 3865–3868. CrossRef PubMed CAS Web of Science Google Scholar
Prakash, O., Bhardwaj, V., Kumar, R., Tyagi, P. & Aneja, K. R. (2004). Eur. J. Med. Chem. 39, 1073–1077. CrossRef PubMed CAS Google Scholar
Prasad, Y. R. & Rahaman, S. A. (2008). Int. J. Chem. Sci. 6, 2038–2044. CAS Google Scholar
Rahaman, S. A., Rajendra Pasad, Y., Kumar, P. & Kumar, B. (2009). Saudi Pharm. J. 17, 255–258. CrossRef PubMed Google Scholar
Ram, V. J., Haque, N. & Guru, P. Y. (1992). Eur. J. Med. Chem. 27, 851–855. CrossRef CAS Google Scholar
Rana, K., Kaur, B. & Kumar, B. (2004). Indian J. Chem. B, 43, 1553–1557. Google Scholar
Reddy, B. N., Ruddarraju, R. R., Kiran, G., Pathak, M. & Reddy, A. R. N. (2019). Chemistry Select, 4, 10072–10078. CAS Google Scholar
Rodrigues, A. L., Rosa, J. M., Gadotti, V. M., Goulart, E. C., Santos, M. M., Silva, A. V., Sehnem, B., Rosa, L. S., Gonçalves, R. M., Corrêa, R. & Santos, A. R. (2005). Pharmacol. Biochem. Behav. 82, 156–162. CrossRef PubMed CAS Google Scholar
Shaquiquzzaman, M., Khan, S. A., Amir, M. & Alam, M. M. (2012). Saudi Pharm. J. 20, 149–154. CrossRef PubMed Google Scholar
Sharma, P., Rane, N. & Gurram, V. K. (2004). Bioorg. Med. Chem. Lett. 14, 4185–4190. Web of Science CrossRef PubMed CAS Google Scholar
Sheldrick, G. M. (1996). SADABS. University of Göttingen, Germany. Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Smith, P. A. S. & Kan, R. O. (1964). J. Org. Chem. 29, 2261–2265. CrossRef CAS Web of Science Google Scholar
Sondhi, S. M., Jain, S., Dwivedi, A. D., Shukla, R. & Raghubir, R. (2008). Indian J. Chem. B, 47, 136–143. Google Scholar
Suleiman Gwaram, N., Khaledi, H. & Mohd Ali, H. (2010). Acta Cryst. E66, o2294. Web of Science CSD CrossRef IUCr Journals Google Scholar
Tani, J., Yamada, Y., Oine, T., Ochiai, T., Ishida, R. & Inoue, I. (1979). J. Med. Chem. 22, 95–99. CrossRef CAS PubMed Web of Science Google Scholar
Tapmeyer, L. & Prill, D. (2019). IUCrData, 4, x190689. Google Scholar
Vega, S., Alonso, J., Diaz, J. A. & Junquera, F. (1990). J. Heterocycl. Chem. 27, 269–273. CrossRef CAS Web of Science Google Scholar
Woon, D. E. & Dunning, T. H. Jr (1993). J. Chem. Phys. 98, 1358–1371. CrossRef CAS Web of Science Google Scholar
Xie, F., Zhao, H., Zhao, L., Lou, L. & Hu, Y. (2009). Bioorg. Med. Chem. Lett. 19, 275–278. Web of Science CrossRef PubMed CAS Google Scholar
Yanagida, S., Ohoka, M., Okahara, M. & Komori, S. (1968). Tetrahedron Lett. 9, 2351–2353. CrossRef Google Scholar

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