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The crystal structure of the cocrystal salt form of the anti­malarial drug pyrimethamine with 2,4-di­hydroxy­benzoic acid in methanol [systematic name: 2,4-di­amino-5-(4-chloro­phen­yl)-6-ethyl­pyrimidin-1-ium 2,4-di­hydroxy­benzoate methanol monosolvate, C12H14ClN4+·C7H5O4·CH3OH] has been studied using X-ray diffraction data collected at room temperature. The crystal structure was refined using the classical Independent Atom Model (IAM) and the Multipolar Atom Model by transferring electron-density parameters from the ELMAM2 database. The Cl atom was refined anharmonically. The results of both refinement methods have been compared. The inter­molecular inter­actions have been characterized on the basis of Hirshfeld surface analysis and topological analysis using Bader's theory of Atoms in Mol­ecules. The results show that the mol­ecular assembly is built primarily on the basis of charge transfer between 2,4-di­hydroxy­benzoic acid and pyrimethamine, which results in strong inter­molecular hydrogen bonds. This fact is further validated by the calculation of the electrostatic potential based on transferred electron-density parameters.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229617017788/ly3057sup1.cif
Contains datablock I

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229617017788/ly3057Isup2.hkl
Contains datablock I

pdf

Portable Document Format (PDF) file https://doi.org/10.1107/S2053229617017788/ly3057sup3.pdf
Tables of refinement details and topological properties, as well as some additional figures

CCDC reference: 1810824

Computing details top

Data collection: APEX2 (Bruker, 2014); cell refinement: APEX2 (Bruker, 2014); data reduction: SAINT (Bruker, 2014); program(s) used to solve structure: SIR92 (Altomare et al., 1993); program(s) used to refine structure: MoPro (Jelsch et al., 2005); molecular graphics: Mercury (Macrae et al., 2008) and MoProViewer (Guillot, 2011); software used to prepare material for publication: publCIF (Westrip, 2010).

2,4-Diamino-5-(4-chlorophenyl)-6-ethylpyrimidin-1-ium 2,4-dihydroxybenzoate methanol monosolvate top
Crystal data top
C12H14ClN4+·C7H5O4·CH4OZ = 2
Mr = 434.86F(000) = 456
Triclinic, P1Dx = 1.373 Mg m3
Hall symbol: -P 1Mo Kα radiation, λ = 0.71073 Å
a = 9.0137 (4) ÅCell parameters from 845 reflections
b = 10.6080 (6) Åθ = 1.7–28.4°
c = 11.8132 (6) ŵ = 0.22 mm1
α = 84.941 (3)°T = 296 K
β = 85.798 (2)°Rod like, colorless
γ = 69.408 (2)°0.42 × 0.32 × 0.28 mm
V = 1052.18 (9) Å3
Data collection top
Bruker Kappa APEXII CCD detector
diffractometer
5192 independent reflections
Radiation source: fine-focus sealed tube3920 reflections with > 2.0σ(I)
Graphite monochromatorRint = 0.026
ω and φ scanθmax = 28.4°, θmin = 1.7°
Absorption correction: multi-scan
(SADABS; Krause et al., 2015)
h = 012
Tmin = 0.913, Tmax = 0.941k = 1214
18806 measured reflectionsl = 1515
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.032Hydrogen site location: difference Fourier map
wR(F2) = 0.061H-atom parameters constrained
S = 1.02 w = 1/[σ2(Fo2) + (0.01P)2 + 0.2P]
where P = (Fo2 + 2Fc2)/3
5182 reflections(Δ/σ)max = 0.001
271 parametersΔρmax = 0.18 e Å3
0 restraintsΔρmin = 0.33 e Å3
Special details top

Refinement. Refinement of F2 against reflections. The threshold expression of F2 > 2sigma(F2) is used for calculating R-factors(gt) and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
CL10.33917 (5)0.65702 (4)0.66837 (3)0.06917 (6)
N10.49573 (12)0.76445 (10)0.01870 (8)0.04435 (12)
N20.30231 (11)0.97539 (9)0.01302 (7)0.03601 (11)
H2A0.234721.073880.022620.05240
N30.58108 (14)0.60521 (11)0.12608 (9)0.05699 (14)
H3A0.662020.549710.066450.05975
H3B0.585250.575820.212890.05739
N40.42086 (12)0.92775 (10)0.16533 (8)0.04617 (12)
C10.36847 (13)0.77349 (11)0.29333 (9)0.03487 (12)
C20.41118 (15)0.84220 (13)0.37355 (10)0.04276 (15)
H20.451500.925130.345280.06197
C30.40338 (15)0.80602 (14)0.48885 (10)0.04662 (16)
H30.435130.860930.550430.07108
C40.35427 (15)0.69867 (13)0.52432 (9)0.04350 (14)
C50.31429 (16)0.62668 (13)0.44737 (11)0.04883 (16)
H50.278620.541460.476590.06249
C60.32080 (15)0.66498 (13)0.33185 (10)0.04378 (15)
H60.288570.609150.271300.05634
C70.37513 (13)0.81587 (11)0.17042 (9)0.03530 (12)
C80.48437 (14)0.72848 (12)0.09141 (9)0.04050 (13)
C90.40732 (13)0.88723 (11)0.05628 (9)0.03643 (12)
C100.28437 (13)0.94036 (11)0.12575 (9)0.03415 (12)
C110.15735 (14)1.04593 (12)0.18997 (9)0.04290 (14)
H11A0.174581.142750.172180.05727
H11B0.168031.019380.281190.05922
C120.00847 (16)1.06057 (16)0.15766 (12)0.06105 (18)
H12A0.025030.964660.172630.06199
H12B0.022061.093250.068880.06026
H12C0.095361.134350.207840.06519
H4A0.356801.025370.195740.05493
H4B0.501710.863650.216490.05922
O10.12156 (11)0.77498 (9)0.06705 (7)0.05233 (11)
O20.24389 (10)0.80607 (8)0.23764 (7)0.05055 (10)
O30.13368 (11)0.57317 (9)0.03745 (7)0.06016 (12)
H3C0.040250.657410.021470.05307
O40.29860 (10)0.23892 (8)0.33503 (7)0.04685 (10)
H4C0.268580.214480.413390.06035
C130.13934 (14)0.73606 (12)0.17024 (9)0.03873 (13)
C140.02874 (13)0.60170 (11)0.21147 (9)0.03473 (12)
C150.10360 (14)0.52848 (12)0.14411 (9)0.03901 (13)
C160.21195 (14)0.40712 (12)0.18746 (9)0.04283 (14)
H160.314660.352000.135650.05911
C170.18823 (13)0.35672 (11)0.29675 (9)0.03611 (13)
C180.05498 (15)0.42560 (12)0.36399 (9)0.04299 (14)
H180.034740.384970.448700.06575
C190.05053 (14)0.54690 (12)0.32008 (9)0.04207 (14)
H190.153580.600140.372440.06595
O50.23042 (12)0.14695 (9)0.54390 (7)0.05488 (12)
H5A0.239760.172470.621580.06964
C200.0976 (2)0.10696 (18)0.54816 (14)0.0736 (2)
H20A0.058900.110980.463380.07710
H20B0.003370.174350.598490.08158
H20C0.127580.005430.585870.08161
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
CL10.0932 (3)0.0603 (2)0.03487 (16)0.0082 (2)0.01056 (16)0.00861 (14)
N10.0481 (6)0.0342 (6)0.0314 (5)0.0075 (4)0.0044 (4)0.0014 (4)
N20.0370 (5)0.0307 (5)0.0297 (4)0.0011 (4)0.0014 (4)0.0009 (4)
H2A0.055600.042340.041760.003400.001830.00241
N30.0660 (7)0.0374 (6)0.0390 (5)0.0139 (5)0.0059 (5)0.0057 (4)
H3A0.054380.052530.048130.007320.012290.00228
H3B0.058930.053560.040180.000940.003750.00771
N40.0491 (6)0.0400 (6)0.0312 (5)0.0044 (5)0.0041 (4)0.0045 (4)
C10.0374 (6)0.0333 (6)0.0285 (5)0.0062 (5)0.0013 (4)0.0004 (4)
C20.0534 (7)0.0451 (7)0.0324 (6)0.0210 (6)0.0047 (5)0.0027 (5)
H20.078400.054120.046160.015360.007420.00600
C30.0562 (7)0.0504 (8)0.0312 (6)0.0162 (6)0.0061 (5)0.0015 (5)
H30.100980.064670.041510.020430.011430.00017
C40.0465 (7)0.0407 (7)0.0313 (5)0.0028 (5)0.0032 (5)0.0047 (5)
C50.0594 (8)0.0401 (7)0.0434 (7)0.0164 (6)0.0085 (6)0.0032 (5)
H50.077060.056930.043580.014600.006340.00439
C60.0539 (7)0.0395 (7)0.0382 (6)0.0172 (6)0.0018 (5)0.0033 (5)
H60.066380.052290.040070.009010.003750.00329
C70.0378 (6)0.0319 (6)0.0269 (5)0.0012 (5)0.0002 (4)0.0008 (4)
C80.0443 (6)0.0314 (6)0.0306 (5)0.0042 (5)0.0017 (5)0.0015 (5)
C90.0363 (6)0.0332 (6)0.0286 (5)0.0010 (5)0.0018 (4)0.0011 (4)
C100.0345 (6)0.0317 (6)0.0294 (5)0.0028 (5)0.0017 (4)0.0031 (4)
C110.0450 (7)0.0380 (7)0.0340 (6)0.0014 (5)0.0008 (5)0.0088 (5)
H11A0.061800.044690.054610.005640.001900.00216
H11B0.066280.058620.036190.001950.000420.00199
C120.0416 (7)0.0708 (10)0.0595 (8)0.0063 (7)0.0111 (6)0.0125 (7)
H12A0.062730.044210.067140.005540.000150.00121
H12B0.060240.067410.041710.009050.001450.00011
H12C0.058730.058850.060560.003190.009810.02275
H4A0.059110.045290.043380.000480.000000.00565
H4B0.061540.052090.042830.003070.011950.00021
O10.0615 (6)0.0385 (5)0.0341 (4)0.0076 (4)0.0032 (4)0.0078 (4)
O20.0504 (5)0.0400 (5)0.0379 (4)0.0107 (4)0.0045 (4)0.0030 (4)
O30.0653 (6)0.0496 (6)0.0363 (4)0.0104 (4)0.0145 (4)0.0085 (4)
H3C0.055850.039920.046350.002790.001780.00135
O40.0480 (5)0.0365 (5)0.0383 (4)0.0065 (4)0.0024 (4)0.0017 (3)
H4C0.063850.054470.046250.004570.004590.00971
C130.0413 (6)0.0313 (6)0.0321 (6)0.0005 (5)0.0004 (5)0.0018 (5)
C140.0357 (6)0.0289 (6)0.0300 (5)0.0000 (5)0.0004 (4)0.0002 (4)
C150.0428 (6)0.0334 (6)0.0286 (5)0.0007 (5)0.0031 (5)0.0007 (4)
C160.0431 (6)0.0351 (7)0.0324 (5)0.0065 (5)0.0055 (5)0.0005 (5)
H160.060830.047420.047180.005390.009980.00075
C170.0386 (6)0.0293 (6)0.0304 (5)0.0008 (5)0.0017 (4)0.0024 (4)
C180.0478 (7)0.0337 (7)0.0311 (5)0.0035 (5)0.0050 (5)0.0038 (5)
H180.068560.062200.048230.006290.010850.01155
C190.0427 (6)0.0344 (7)0.0330 (6)0.0039 (5)0.0064 (5)0.0024 (5)
H190.058160.059550.058400.001090.018080.00201
O50.0646 (6)0.0529 (6)0.0401 (5)0.0137 (5)0.0020 (4)0.0013 (4)
H5A0.079590.070250.048090.016430.001580.00955
C200.0670 (10)0.0770 (12)0.0685 (10)0.0169 (9)0.0055 (8)0.0022 (8)
H20A0.078610.082480.061560.022340.009100.02163
H20B0.072320.077570.080070.013290.014240.00383
H20C0.082350.070220.080530.019710.009900.03309
Geometric parameters (Å, º) top
CL1—C41.7278 (11)C11—H11B1.0920
N1—C91.3222 (14)C11—H11A1.0920
N1—C81.3298 (14)C12—H12A1.0770
N2—C91.3563 (13)C12—H12B1.0770
N2—C101.3642 (13)C12—H12C1.0770
N2—H2A1.0734 (2)O1—C131.2693 (13)
N3—C81.3393 (14)O2—C131.2553 (13)
N3—H3A1.0348O3—C151.3493 (13)
N3—H3B1.0447O3—H3C1.0037
N4—C91.3324 (13)O4—C171.3594 (13)
N4—H4B1.0090O4—H4C0.9837
N4—H4A1.0388C13—C141.4872 (15)
C1—C71.4849 (14)C14—C151.4063 (15)
C1—C61.3942 (17)C14—C191.3908 (15)
C1—C21.3964 (16)C15—C161.3950 (15)
C2—C31.3858 (16)C16—C171.3844 (15)
C2—H21.0830C16—H161.0830
C3—C41.3826 (18)C17—C181.3974 (15)
C3—H31.0830C18—C191.3867 (16)
C4—C51.3797 (18)C18—H181.0830
C5—C61.3921 (16)C19—H191.0830
C5—H51.0830O5—C201.3999 (19)
C6—H61.0830O5—H5A0.9968
C7—C81.4408 (15)C20—H20A1.0770
C7—C101.3682 (15)C20—H20B1.0770
C10—C111.5037 (15)C20—H20C1.0770
C11—C121.5211 (19)
C9—N1—C8118.58 (9)C8—C7—C1121.14 (8)
C9—N2—C10120.79 (8)C10—C7—C1122.91 (9)
C9—N2—H2A118.480C12—C11—H11B109.046
C10—N2—H2A120.725C12—C11—H11A109.070
C8—N3—H3A117.422H11B—C11—H11A107.966
C8—N3—H3B119.300H12A—C12—H12B109.384
H3A—N3—H3B122.458H12A—C12—H12C109.809
C9—N4—H4B118.256H12B—C12—H12C109.280
C9—N4—H4A121.090C15—O3—H3C104.751
H4B—N4—H4A120.468C17—O4—H4C109.567
C7—C1—C6121.54 (9)C15—C14—C19117.97 (9)
C7—C1—C2120.15 (9)C17—C16—C15120.06 (9)
C6—C1—C2118.30 (10)C17—C16—H16119.847
C3—C2—H2119.271C19—C18—H18120.763
C4—C3—C2119.02 (10)C20—O5—H5A107.051
C4—C3—H3120.363H20A—C20—H20B109.262
C5—C4—C3121.37 (11)H20A—C20—H20C109.353
C6—C5—H5120.580H20B—C20—H20C109.601
C8—C7—C10115.89 (9)
CL1—C4—C5—C6177.37 (3)C6—C1—C7—C10117.9 (2)
CL1—C4—C5—H52.77H6—C6—C1—C70.51
CL1—C4—C3—C2178.13 (2)C7—C8—N1—C92.57 (15)
CL1—C4—C3—H31.82C7—C10—N2—C91.22 (15)
N1—C9—N2—C100.34 (14)C7—C10—C11—C12107.1 (2)
N1—C9—N2—H2A179.53C7—C10—C11—H11B14.09
N1—C9—N4—H4B1.80C7—C10—C11—H11A131.94
N1—C9—N4—H4A176.85C8—C7—C10—C11176.97 (16)
N1—C8—N3—H3A3.86C9—N2—C10—C11176.82 (13)
N1—C8—N3—H3B173.75C10—C11—C12—H12A57.40
N1—C8—C7—C101.05 (15)C10—C11—C12—H12B62.36
N1—C8—C7—C1178.52 (5)C10—C11—C12—H12C177.90
N2—C9—N1—C82.21 (15)H11A—C11—C12—H12A178.31
N2—C9—N4—H4B177.80H11A—C11—C12—H12B58.55
N2—C9—N4—H4A2.75H11A—C11—C12—H12C61.18
N2—C10—C7—C80.85 (15)H11B—C11—C12—H12A64.01
N2—C10—C7—C1176.57 (11)H11B—C11—C12—H12B176.24
N2—C10—C11—C1270.81 (19)H11B—C11—C12—H12C56.50
N2—C10—C11—H11B167.99O1—C13—C14—C158.49 (15)
N2—C10—C11—H11A50.14O1—C13—C14—C19173.81 (15)
H2A—N2—C9—N40.07O2—C13—C14—C15170.86 (15)
H2A—N2—C10—C7177.95O2—C13—C14—C196.84 (16)
H2A—N2—C10—C114.01O3—C15—C14—C132.75 (14)
N3—C8—N1—C9177.31 (19)O3—C15—C14—C19179.50 (16)
N3—C8—C7—C10178.82 (18)O3—C15—C16—C17179.43 (16)
N3—C8—C7—C11.35 (15)O3—C15—C16—H160.71
H3A—N3—C8—C7176.02H3C—O3—C15—C144.73
H3B—N3—C8—C76.13H3C—O3—C15—C16177.00
N4—C9—N2—C10179.25 (16)O4—C17—C16—C15179.22 (16)
N4—C9—N1—C8177.4 (2)O4—C17—C16—H160.91
C1—C7—C10—C115.62 (14)O4—C17—C18—C19178.47 (18)
C1—C6—C5—C40.67 (17)O4—C17—C18—H181.47
C1—C6—C5—H5179.20H4C—O4—C17—C16179.64
C1—C2—C3—C40.85 (17)H4C—O4—C17—C180.45
C1—C2—C3—H3179.09C13—C14—C15—C16175.47 (14)
C2—C1—C7—C8114.9 (2)C13—C14—C19—C18176.24 (13)
C2—C1—C7—C1062.38 (19)C13—C14—C19—H194.06
C2—C1—C6—C50.63 (18)C14—C15—C16—C171.13 (16)
C2—C1—C6—H6179.19C14—C15—C16—H16179.01
C2—C3—C4—C50.50 (18)C14—C19—C18—C170.40 (16)
H2—C2—C1—C71.30C14—C19—C18—H18179.65
H2—C2—C1—C6178.41C15—C14—C19—C181.53 (16)
H2—C2—C3—C4178.96C15—C14—C19—H19178.17
H2—C2—C3—H31.09C15—C16—C17—C180.87 (16)
C3—C4—C5—C61.25 (18)C16—C17—C18—C191.62 (16)
C3—C4—C5—H5178.62C16—C17—C18—H18178.43
C3—C2—C1—C7178.89 (7)C16—C15—C14—C192.29 (16)
C3—C2—C1—C61.40 (18)H16—C16—C17—C18179.00
H3—C3—C4—C5179.55C17—C18—C19—H19179.90
C4—C5—C6—H6179.51H18—C18—C19—H190.05
C5—C6—C1—C7179.67 (3)H5A—O5—C20—H20A160.85
H5—C5—C6—H60.62H5A—O5—C20—H20B41.16
C6—C1—C7—C864.80 (19)H5A—O5—C20—H20C78.99
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N3—H3B···C11.05 (2)2.51 (2)2.9011 (18)101 (1)
N3—H3B···C61.05 (2)2.59 (2)3.193 (2)115 (1)
C11—H11B···C11.09 (10)2.60 (2)3.0522 (19)104 (2)
C11—H11B···C21.09 (10)2.57 (4)3.321 (2)125 (3)
O3—H3C···O11.00 (2)1.64 (2)2.5591 (16)149 (2)
O3—H3C···C131.00 (2)2.30 (2)2.9024 (17)117 (1)
O4—H4C···O50.97 (2)1.72 (2)2.6820 (16)170 (1)
O4—H4C···C200.97 (2)2.61 (2)3.474 (2)149 (2)
O5—H5A···O2i1.00 (3)1.70 (3)2.6904 (16)169 (1)
N2—H2A···O1ii1.07 (2)1.64 (2)2.7046 (15)175 (1)
N2—H2A···C13ii1.07 (2)2.50 (2)3.5152 (17)158 (1)
C12—H12B···O1ii1.08 (9)2.60 (5)3.409 (2)131 (4)
N4—H4A···O2ii1.04 (2)1.77 (2)2.8023 (16)176 (3)
N4—H4A···C13ii1.04 (2)2.63 (2)3.5757 (19)152 (9)
N3—H3A···O3iii1.03 (2)2.20 (2)3.2278 (17)170 (3)
N4—H4B···O4iii1.03 (2)2.22 (2)3.2051 (16)167 (6)
C16—H16···N1iii1.08 (5)2.20 (6)3.2736 (18)174 (1)
N3—H3B···CL1iv1.05 (2)2.62 (2)3.4364 (14)133 (1)
Symmetry codes: (i) x, y+1, z+1; (ii) x, y+2, z; (iii) x+1, y+1, z; (iv) x+1, y+1, z+1.
Refinement details top
Refinement IAM_SHELX
R[F2 > 2σ(F2)], wR(F2), S0.042, 0.125, 1.06
No. of reflections5182
No. of parameters282
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å-3)0.35, -0.44
Refinement IAM_MoPro
R[F2 > 2σ(F2)], wR(F2), S0.043, 0.085, 1.38
No. of reflections5182
No. of parameters281
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å-3)0.26, -0.25
Refinement ELMAM2_MoPro
R[F2 > 2σ(F2)], wR(F2), S0.032, 0.061, 1.02
No. of reflections5182
No. of parameters271
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å-3)0.18, -0.33
Topological properties at the critical points of O···H, C···H and H···H intermolecular interactions in the crystal packing of compound (2) for the ELMAM2 model.
d12, d1cp and d2cp are the distances (Å) between the two atoms, between the first atom and the CP, and between the CP and the second atom. ρCP is the total electron density (e Å-3) at the CP and \nabla2ρCP, its Laplacian (e Å-5). λ1, λ2 and λ3 are the eigenvalues (e Å-5) of the Hessian matrix ∂2ρ/∂xixj·ε = λ1/λ2 - 1 is the ellipticity. GCP is the bond kinetic energy and VCP is the bond potential energy (kJ mol -1 Bohr-1)
top
Interacting atomsd12 (Å)d1CP (Å)d2CP (Å)ρCP (e Å-3)\nabla2ρCP (e Å-5)λ1 (e Å-5)λ2 (e Å-5)λ3 (e Å-5)εGCPVCP
Cl1···H3Bi2.62251.69660.93450.06650.7-0.23-0.181.110.294116.07-13.16
Cl1···H12Cii2.92311.81761.10650.04670.43-0.15-0.150.730.02439.66-7.67
N1···H16iii2.19671.37350.82330.12761.36-0.62-0.592.570.057634.76-32.56
H2A···O1iv1.63290.53241.10060.37322.47-2.66-2.657.780.0025105.39-143.45
H3A···O3iii2.20440.841.3650.09830.88-0.49-0.471.850.041322.54-21.09
H3···O4i2.67351.14991.5430.03630.63-0.11-0.070.810.473212.63-8.18
H12B···O1iv2.60391.09541.50880.04140.66-0.12-0.10.890.224713.58-9.11
H4A···O2iv1.76520.59411.1710.2562.22-1.62-1.615.440.00672.53-84.68
H4B···O4iii2.2150.8481.36780.09680.9-0.47-0.461.830.01822.65-20.91
O2···H5Av1.70321.12860.57580.3271.23-2.3-2.275.810.016670.96-108.31
H3C···O1'1.64210.53561.11020.36422.25-2.63-2.327.20.133798.96-136.64
Symmetry codes: (i) -x+1, -y+1, -z+1; (ii) -x, -y+2, -z+1; (iii) -x+1, -y+1, -z; (iv) -x, -y+2, -z; (v) -x, -y+1, -z+1.

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