Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270109000237/gd3265sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270109000237/gd3265Isup2.hkl |
CCDC reference: 724208
Equimolar quantities of racemic malic acid and trimethoprim were dissolved in water. The solution was stirred well and set aside to crystallize. Colourless crystals of (I), suitable for X-ray diffraction analysis, were obtained from the resulting solution after a week of slow evaporation.
The acid component is disordered about a crystallographic center of inversion. Atoms H16A and H16B on atom C16 could not be geometrically constrained for riding-model refinement. This is because one of the C—H directions coincides with the C16—O6 direction (O6 is disordered over two sites). Hence the displacement parameters of these two H atoms were fixed as 1.2Ueq of the carrier C atom taken from the previous refinement. H atoms attached to N atoms were located in difference maps and then refined isotropically. All other H atoms were treated as riding atoms with O—H distances of 0.82 and C—H distances of 0.93–0.97 Å, and with Uiso(H) = kUeq(carrier) (k = 1.2 or 1.5). The distances of atoms H16A and H16B from C16 and the distance of atom H6 from O6 were restrained.
Data collection: APEX2 (Bruker–Nonius, 2004); cell refinement: APEX2 and SAINT (Bruker–Nonius, 2004); data reduction: SAINT and XPREP (Bruker–Nonius, 2004); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997) and Mercury (Macrae et al., 2006); software used to prepare material for publication: PLATON (Spek, 2003).
2C14H19N4O3+·C4H4O52− | F(000) = 756 |
Mr = 714.74 | Dx = 1.343 Mg m−3 |
Monoclinic, P21/c | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: -P 2ybc | Cell parameters from 7891 reflections |
a = 12.9850 (3) Å | θ = 2.5–32.1° |
b = 9.3038 (2) Å | µ = 0.10 mm−1 |
c = 15.6815 (3) Å | T = 293 K |
β = 111.065 (1)° | Plate, colourless |
V = 1767.88 (7) Å3 | 0.30 × 0.20 × 0.20 mm |
Z = 2 |
Bruker Kappa APEXII CCD diffractometer | 3108 independent reflections |
Radiation source: fine-focus sealed tube | 2763 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.020 |
ω and ϕ scans | θmax = 25.0°, θmin = 1.7° |
Absorption correction: multi-scan (SADABS; Bruker, 1999) | h = −15→15 |
Tmin = 0.970, Tmax = 0.980 | k = −11→8 |
16178 measured reflections | l = −18→18 |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.045 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.115 | w = 1/[σ2(Fo2) + (0.0299P)2 + 1.0993P] where P = (Fo2 + 2Fc2)/3 |
S = 1.18 | (Δ/σ)max < 0.001 |
3108 reflections | Δρmax = 0.33 e Å−3 |
265 parameters | Δρmin = −0.18 e Å−3 |
3 restraints | Extinction correction: SHELXL97 (Sheldrick, 2008), FC*=KFC[1+0.001XFC2Λ3/SIN(2Θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.0071 (10) |
2C14H19N4O3+·C4H4O52− | V = 1767.88 (7) Å3 |
Mr = 714.74 | Z = 2 |
Monoclinic, P21/c | Mo Kα radiation |
a = 12.9850 (3) Å | µ = 0.10 mm−1 |
b = 9.3038 (2) Å | T = 293 K |
c = 15.6815 (3) Å | 0.30 × 0.20 × 0.20 mm |
β = 111.065 (1)° |
Bruker Kappa APEXII CCD diffractometer | 3108 independent reflections |
Absorption correction: multi-scan (SADABS; Bruker, 1999) | 2763 reflections with I > 2σ(I) |
Tmin = 0.970, Tmax = 0.980 | Rint = 0.020 |
16178 measured reflections |
R[F2 > 2σ(F2)] = 0.045 | 3 restraints |
wR(F2) = 0.115 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.18 | Δρmax = 0.33 e Å−3 |
3108 reflections | Δρmin = −0.18 e Å−3 |
265 parameters |
Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All su's are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles |
Refinement. Refinement on F2 for ALL reflections except those flagged by the user for potential systematic errors. Weighted R-factors wR and all goodnesses of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The observed criterion of F2 > σ(F2) is used only for calculating -R-factor-obs etc. 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. |
x | y | z | Uiso*/Ueq | Occ. (<1) | |
O1 | −0.15807 (14) | 1.2462 (2) | 0.41545 (14) | 0.0743 (8) | |
O2 | −0.21086 (12) | 0.9778 (2) | 0.35824 (11) | 0.0624 (6) | |
O3 | −0.06160 (14) | 0.7989 (2) | 0.33500 (13) | 0.0658 (7) | |
N1 | 0.48206 (17) | 0.8276 (2) | 0.30313 (14) | 0.0504 (7) | |
N2 | 0.34759 (16) | 0.9180 (2) | 0.52878 (12) | 0.0469 (7) | |
N3 | 0.41602 (14) | 0.87465 (19) | 0.41741 (11) | 0.0407 (5) | |
N4 | 0.37301 (15) | 1.0254 (2) | 0.28944 (12) | 0.0430 (6) | |
C1 | 0.42365 (16) | 0.9091 (2) | 0.33764 (13) | 0.0382 (6) | |
C2 | 0.31133 (17) | 1.1114 (2) | 0.32213 (15) | 0.0439 (7) | |
C3 | 0.29895 (16) | 1.0840 (2) | 0.40228 (14) | 0.0402 (6) | |
C4 | 0.35477 (15) | 0.9590 (2) | 0.45018 (13) | 0.0384 (6) | |
C5 | 0.22698 (17) | 1.1764 (2) | 0.43654 (15) | 0.0461 (7) | |
C6 | 0.11054 (16) | 1.1202 (2) | 0.41540 (13) | 0.0400 (6) | |
C7 | 0.08111 (17) | 0.9818 (2) | 0.38468 (14) | 0.0437 (7) | |
C8 | −0.02617 (18) | 0.9337 (3) | 0.36540 (14) | 0.0462 (7) | |
C9 | −0.10467 (17) | 1.0260 (3) | 0.37653 (14) | 0.0488 (7) | |
C10 | −0.07485 (17) | 1.1639 (3) | 0.40692 (15) | 0.0492 (7) | |
C11 | 0.03258 (18) | 1.2117 (3) | 0.42697 (15) | 0.0476 (7) | |
C12 | −0.1451 (3) | 1.3945 (4) | 0.4203 (3) | 0.0910 (14) | |
C13 | −0.2836 (2) | 1.0146 (4) | 0.26882 (19) | 0.0768 (10) | |
C14 | 0.0157 (3) | 0.7033 (3) | 0.3216 (2) | 0.0760 (11) | |
O4 | 0.44619 (16) | 0.65344 (18) | 0.61581 (11) | 0.0596 (6) | |
O5 | 0.40311 (14) | 0.42714 (17) | 0.62939 (11) | 0.0552 (6) | |
O6 | 0.3701 (4) | 0.5719 (5) | 0.4280 (2) | 0.0606 (11) | 0.500 |
C15 | 0.42935 (17) | 0.5278 (2) | 0.58784 (13) | 0.0426 (7) | |
C16 | 0.44079 (18) | 0.4920 (3) | 0.49666 (14) | 0.0462 (7) | |
H1A | 0.4751 (19) | 0.840 (3) | 0.2441 (18) | 0.057 (7)* | |
H1B | 0.518 (2) | 0.752 (3) | 0.3338 (17) | 0.058 (7)* | |
H2 | 0.27670 | 1.19130 | 0.28830 | 0.0530* | |
H2A | 0.383 (2) | 0.837 (3) | 0.5547 (18) | 0.060 (8)* | |
H2B | 0.301 (2) | 0.965 (3) | 0.5499 (16) | 0.055 (7)* | |
H4 | 0.379 (2) | 1.040 (3) | 0.2361 (18) | 0.060 (7)* | |
H5A | 0.22240 | 1.27140 | 0.41000 | 0.0550* | |
H5B | 0.26220 | 1.18640 | 0.50220 | 0.0550* | |
H7 | 0.13350 | 0.92030 | 0.37680 | 0.0520* | |
H11 | 0.05210 | 1.30490 | 0.44810 | 0.0570* | |
H12A | −0.08690 | 1.41980 | 0.47640 | 0.1360* | |
H12B | −0.21270 | 1.43880 | 0.41830 | 0.1360* | |
H12C | −0.12670 | 1.42740 | 0.36950 | 0.1360* | |
H13A | −0.29260 | 1.11710 | 0.26420 | 0.1150* | |
H13B | −0.35400 | 0.97000 | 0.25710 | 0.1150* | |
H13C | −0.25330 | 0.98160 | 0.22480 | 0.1150* | |
H14A | 0.04000 | 0.74040 | 0.27490 | 0.1140* | |
H14B | −0.01820 | 0.61110 | 0.30320 | 0.1140* | |
H14C | 0.07790 | 0.69340 | 0.37760 | 0.1140* | |
H6 | 0.39360 | 0.65430 | 0.43120 | 0.0550* | 0.500 |
H16A | 0.4118 (18) | 0.4019 (11) | 0.4752 (15) | 0.0550* | |
H16B | 0.394 (5) | 0.553 (2) | 0.452 (3) | 0.0550* | 0.500 |
U11 | U22 | U33 | U12 | U13 | U23 | |
O1 | 0.0495 (10) | 0.0830 (14) | 0.1055 (15) | 0.0107 (9) | 0.0461 (10) | −0.0052 (11) |
O2 | 0.0360 (8) | 0.0949 (14) | 0.0589 (10) | −0.0087 (8) | 0.0201 (7) | 0.0076 (9) |
O3 | 0.0604 (11) | 0.0655 (11) | 0.0753 (12) | −0.0180 (9) | 0.0290 (9) | −0.0147 (9) |
N1 | 0.0622 (12) | 0.0566 (12) | 0.0431 (11) | 0.0125 (10) | 0.0318 (10) | 0.0056 (9) |
N2 | 0.0465 (11) | 0.0626 (13) | 0.0399 (10) | 0.0061 (10) | 0.0255 (9) | 0.0046 (9) |
N3 | 0.0398 (9) | 0.0508 (10) | 0.0366 (9) | 0.0038 (8) | 0.0198 (7) | 0.0034 (8) |
N4 | 0.0482 (10) | 0.0488 (11) | 0.0405 (9) | 0.0014 (8) | 0.0263 (8) | 0.0060 (8) |
C1 | 0.0363 (10) | 0.0455 (11) | 0.0365 (10) | −0.0040 (9) | 0.0177 (8) | −0.0011 (9) |
C2 | 0.0419 (11) | 0.0441 (12) | 0.0507 (12) | 0.0008 (9) | 0.0228 (10) | 0.0053 (10) |
C3 | 0.0340 (10) | 0.0451 (12) | 0.0461 (11) | −0.0052 (9) | 0.0200 (9) | −0.0029 (9) |
C4 | 0.0321 (10) | 0.0498 (12) | 0.0369 (10) | −0.0052 (9) | 0.0166 (8) | −0.0020 (9) |
C5 | 0.0414 (11) | 0.0486 (12) | 0.0544 (13) | −0.0032 (10) | 0.0246 (10) | −0.0063 (10) |
C6 | 0.0368 (10) | 0.0508 (12) | 0.0365 (10) | 0.0012 (9) | 0.0180 (9) | 0.0017 (9) |
C7 | 0.0396 (11) | 0.0522 (13) | 0.0429 (11) | 0.0021 (10) | 0.0192 (9) | −0.0011 (10) |
C8 | 0.0450 (12) | 0.0557 (14) | 0.0400 (11) | −0.0086 (10) | 0.0178 (9) | −0.0011 (10) |
C9 | 0.0368 (11) | 0.0708 (16) | 0.0426 (11) | −0.0038 (11) | 0.0189 (9) | 0.0055 (11) |
C10 | 0.0388 (11) | 0.0666 (15) | 0.0491 (12) | 0.0069 (11) | 0.0242 (10) | 0.0041 (11) |
C11 | 0.0462 (12) | 0.0515 (13) | 0.0526 (12) | 0.0009 (10) | 0.0268 (10) | −0.0029 (10) |
C12 | 0.0671 (19) | 0.083 (2) | 0.132 (3) | 0.0266 (17) | 0.047 (2) | 0.001 (2) |
C13 | 0.0496 (15) | 0.103 (2) | 0.0670 (17) | −0.0117 (15) | 0.0080 (13) | 0.0024 (16) |
C14 | 0.087 (2) | 0.0653 (18) | 0.0759 (18) | −0.0148 (16) | 0.0295 (16) | −0.0236 (15) |
O4 | 0.0944 (13) | 0.0522 (10) | 0.0437 (9) | 0.0079 (9) | 0.0387 (9) | 0.0023 (7) |
O5 | 0.0735 (11) | 0.0547 (10) | 0.0557 (9) | 0.0074 (8) | 0.0453 (9) | 0.0043 (8) |
O6 | 0.057 (2) | 0.081 (2) | 0.0383 (19) | 0.0021 (18) | 0.0105 (15) | 0.0021 (17) |
C15 | 0.0426 (11) | 0.0548 (14) | 0.0360 (10) | 0.0087 (10) | 0.0211 (9) | 0.0022 (10) |
C16 | 0.0454 (13) | 0.0636 (15) | 0.0327 (10) | −0.0027 (11) | 0.0179 (9) | −0.0034 (10) |
O1—C10 | 1.370 (3) | C5—C6 | 1.520 (3) |
O1—C12 | 1.389 (4) | C6—C7 | 1.380 (3) |
O2—C9 | 1.379 (3) | C6—C11 | 1.384 (3) |
O2—C13 | 1.423 (3) | C7—C8 | 1.389 (3) |
O3—C8 | 1.362 (3) | C8—C9 | 1.391 (4) |
O3—C14 | 1.412 (4) | C9—C10 | 1.375 (4) |
O4—C15 | 1.240 (3) | C10—C11 | 1.388 (3) |
O5—C15 | 1.256 (3) | C2—H2 | 0.9300 |
O6—C16 | 1.358 (5) | C5—H5A | 0.9700 |
O6—H6 | 0.8200 | C5—H5B | 0.9700 |
N1—C1 | 1.318 (3) | C7—H7 | 0.9300 |
N2—C4 | 1.325 (3) | C11—H11 | 0.9300 |
N3—C4 | 1.344 (3) | C12—H12A | 0.9600 |
N3—C1 | 1.329 (3) | C12—H12C | 0.9600 |
N4—C2 | 1.356 (3) | C12—H12B | 0.9600 |
N4—C1 | 1.348 (3) | C13—H13C | 0.9600 |
N1—H1B | 0.89 (3) | C13—H13A | 0.9600 |
N1—H1A | 0.91 (3) | C13—H13B | 0.9600 |
N2—H2A | 0.90 (3) | C14—H14A | 0.9600 |
N2—H2B | 0.90 (3) | C14—H14C | 0.9600 |
N4—H4 | 0.88 (3) | C14—H14B | 0.9600 |
C2—C3 | 1.348 (3) | C15—C16 | 1.527 (3) |
C3—C5 | 1.504 (3) | C16—C16i | 1.511 (3) |
C3—C4 | 1.432 (3) | C16—H16A | 0.931 (14) |
O1···O2 | 2.659 (3) | C13···H2Bii | 2.94 (2) |
O1···C13 | 3.145 (4) | C14···H7 | 2.4900 |
O2···O3 | 2.677 (3) | C15···H4iii | 2.71 (3) |
O2···N2ii | 3.081 (3) | C15···H13Bx | 3.1000 |
O2···O1 | 2.659 (3) | C15···H1Aiii | 2.61 (3) |
O3···C13 | 3.356 (4) | C15···H2A | 2.95 (3) |
O3···O2 | 2.677 (3) | C15···H1Bi | 2.86 (3) |
O4···O6 | 2.852 (3) | C15···H6i | 2.9600 |
O4···N1iii | 2.810 (3) | C15···H12Bii | 2.8000 |
O4···N2 | 2.882 (3) | H1A···H4 | 2.22 (4) |
O5···N1i | 2.798 (3) | H1A···H13Bvii | 2.4700 |
O5···N4iii | 2.712 (2) | H1A···O5v | 2.76 (3) |
O6···C13iv | 2.929 (4) | H1A···C15v | 2.61 (3) |
O6···O4 | 2.852 (3) | H1A···O4v | 1.91 (3) |
O6···N3 | 2.896 (5) | H1B···O5i | 1.93 (3) |
O1···H2Bii | 2.89 (3) | H1B···C15i | 2.86 (3) |
O1···H13A | 2.6700 | H2···H5A | 2.3800 |
O2···H2Bii | 2.22 (3) | H2A···O4 | 1.99 (3) |
O4···H16Ai | 2.76 (2) | H2A···C15 | 2.95 (3) |
O4···H6 | 2.7300 | H2B···C5 | 2.59 (3) |
O4···H2A | 1.99 (3) | H2B···C6 | 2.98 (3) |
O4···H1Aiii | 1.91 (3) | H2B···C7 | 3.09 (3) |
O5···H12Bii | 2.6300 | H2B···H5B | 2.1900 |
O5···H4iii | 1.84 (3) | H2B···O1ii | 2.89 (3) |
O5···H1Aiii | 2.76 (3) | H2B···O2ii | 2.22 (3) |
O5···H1Bi | 1.93 (3) | H2B···C13ii | 2.94 (2) |
O6···H13Aiv | 2.8400 | H4···C15v | 2.71 (3) |
O6···H13Civ | 2.4800 | H4···O5v | 1.84 (3) |
N1···O5i | 2.798 (3) | H4···H1A | 2.22 (4) |
N1···O4v | 2.810 (3) | H5A···H2 | 2.3800 |
N2···C7 | 3.437 (3) | H5A···H11 | 2.5100 |
N2···O4 | 2.882 (3) | H5B···H2B | 2.1900 |
N2···O2ii | 3.081 (3) | H5B···N2 | 2.7000 |
N2···C1vi | 3.365 (3) | H6···C15i | 2.9600 |
N3···C4vi | 3.335 (3) | H6···H16Ai | 2.4800 |
N3···O6 | 2.896 (5) | H6···C4 | 2.9100 |
N4···O5v | 2.712 (2) | H6···O4 | 2.7300 |
N1···H13Bvii | 2.8100 | H6···N3 | 2.0900 |
N2···H7 | 2.9400 | H6···C1 | 2.8900 |
N2···H5B | 2.7000 | H7···C4 | 2.7100 |
N3···H6 | 2.0900 | H7···N2 | 2.9400 |
C1···N2vi | 3.365 (3) | H7···C3 | 2.5500 |
C4···N3vi | 3.335 (3) | H7···C14 | 2.4900 |
C4···C7 | 3.332 (3) | H7···H14A | 2.3300 |
C6···C9ii | 3.561 (3) | H7···H14C | 2.2300 |
C6···C14viii | 3.566 (3) | H11···C12 | 2.5800 |
C7···C4 | 3.332 (3) | H11···H5A | 2.5100 |
C7···N2 | 3.437 (3) | H11···H12A | 2.2700 |
C7···C10ii | 3.566 (3) | H11···H12C | 2.4800 |
C8···C11ii | 3.554 (3) | H12A···C11 | 2.7600 |
C8···C10ii | 3.453 (3) | H12A···H11 | 2.2700 |
C9···C6ii | 3.561 (3) | H12A···H12Axi | 2.5800 |
C10···C7ii | 3.566 (3) | H12A···H14Cii | 2.4800 |
C10···C8ii | 3.453 (3) | H12B···O5ii | 2.6300 |
C11···C8ii | 3.554 (3) | H12B···C15ii | 2.8000 |
C13···O3 | 3.356 (4) | H12C···C11 | 2.7900 |
C13···O6viii | 2.929 (4) | H12C···H11 | 2.4800 |
C13···O1 | 3.145 (4) | H13A···O1 | 2.6700 |
C14···C6iv | 3.566 (3) | H13A···C10 | 2.9400 |
C1···H6 | 2.8900 | H13A···O6viii | 2.8400 |
C3···H7 | 2.5500 | H13B···N1xii | 2.8100 |
C4···H7 | 2.7100 | H13B···H1Axii | 2.4700 |
C4···H6 | 2.9100 | H13B···C15xiii | 3.1000 |
C5···H2B | 2.59 (3) | H13C···C8 | 3.0100 |
C5···H16Aix | 3.08 (2) | H13C···O6viii | 2.4800 |
C6···H2B | 2.98 (3) | H14A···C7 | 2.7600 |
C7···H14A | 2.7600 | H14A···H7 | 2.3300 |
C7···H14Bviii | 3.0100 | H14A···C11iv | 2.9700 |
C7···H2B | 3.09 (3) | H14B···C7iv | 3.0100 |
C7···H14C | 2.6900 | H14C···C7 | 2.6900 |
C8···H13C | 3.0100 | H14C···H7 | 2.2300 |
C10···H13A | 2.9400 | H14C···C12ii | 3.0800 |
C11···H12C | 2.7900 | H14C···H12Aii | 2.4800 |
C11···H14Aviii | 2.9700 | H16A···C5xiv | 3.08 (2) |
C11···H12A | 2.7600 | H16A···O4i | 2.76 (2) |
C12···H14Cii | 3.0800 | H16A···H6i | 2.4800 |
C12···H11 | 2.5800 | ||
C10—O1—C12 | 118.5 (3) | N4—C2—H2 | 119.00 |
C9—O2—C13 | 112.76 (19) | C3—C2—H2 | 119.00 |
C8—O3—C14 | 117.6 (2) | C3—C5—H5A | 109.00 |
C16—O6—H6 | 109.00 | C3—C5—H5B | 109.00 |
C1—N3—C4 | 118.27 (17) | H5A—C5—H5B | 108.00 |
C1—N4—C2 | 119.80 (18) | C6—C5—H5B | 109.00 |
C1—N1—H1B | 120.2 (17) | C6—C5—H5A | 109.00 |
C1—N1—H1A | 119.1 (17) | C6—C7—H7 | 120.00 |
H1A—N1—H1B | 120 (2) | C8—C7—H7 | 120.00 |
H2A—N2—H2B | 123 (2) | C6—C11—H11 | 120.00 |
C4—N2—H2B | 118.9 (16) | C10—C11—H11 | 120.00 |
C4—N2—H2A | 117.8 (17) | O1—C12—H12A | 109.00 |
C1—N4—H4 | 117.8 (18) | O1—C12—H12B | 109.00 |
C2—N4—H4 | 122.4 (18) | H12B—C12—H12C | 109.00 |
N3—C1—N4 | 122.34 (19) | O1—C12—H12C | 109.00 |
N1—C1—N3 | 119.75 (18) | H12A—C12—H12B | 110.00 |
N1—C1—N4 | 117.91 (19) | H12A—C12—H12C | 109.00 |
N4—C2—C3 | 121.71 (19) | O2—C13—H13A | 109.00 |
C4—C3—C5 | 122.63 (18) | O2—C13—H13B | 110.00 |
C2—C3—C5 | 121.52 (18) | O2—C13—H13C | 109.00 |
C2—C3—C4 | 115.81 (19) | H13B—C13—H13C | 109.00 |
N2—C4—N3 | 115.89 (18) | H13A—C13—H13B | 109.00 |
N3—C4—C3 | 122.08 (18) | H13A—C13—H13C | 109.00 |
N2—C4—C3 | 122.01 (19) | O3—C14—H14B | 110.00 |
C3—C5—C6 | 115.00 (16) | H14A—C14—H14C | 109.00 |
C5—C6—C7 | 121.76 (19) | O3—C14—H14C | 109.00 |
C5—C6—C11 | 118.50 (18) | H14A—C14—H14B | 109.00 |
C7—C6—C11 | 119.7 (2) | O3—C14—H14A | 109.00 |
C6—C7—C8 | 120.5 (2) | H14B—C14—H14C | 109.00 |
C7—C8—C9 | 119.8 (2) | O5—C15—C16 | 117.33 (18) |
O3—C8—C7 | 124.0 (2) | O4—C15—O5 | 124.5 (2) |
O3—C8—C9 | 116.2 (2) | O4—C15—C16 | 118.2 (2) |
O2—C9—C10 | 120.8 (2) | O6—C16—C15 | 111.0 (3) |
C8—C9—C10 | 119.5 (2) | O6—C16—C16i | 112.5 (3) |
O2—C9—C8 | 119.8 (2) | C15—C16—C16i | 110.66 (18) |
O1—C10—C9 | 114.9 (2) | O6—C16—H16A | 97.8 (13) |
O1—C10—C11 | 124.2 (2) | C15—C16—H16A | 111.9 (14) |
C9—C10—C11 | 120.8 (2) | C16i—C16—H16A | 112.5 (15) |
C6—C11—C10 | 119.8 (2) | ||
C12—O1—C10—C9 | −162.1 (3) | C11—C6—C7—C8 | −0.1 (3) |
C12—O1—C10—C11 | 18.1 (4) | C7—C6—C11—C10 | −0.5 (3) |
C13—O2—C9—C10 | 84.5 (3) | C5—C6—C7—C8 | −179.62 (19) |
C13—O2—C9—C8 | −96.4 (3) | C6—C7—C8—C9 | 0.5 (3) |
C14—O3—C8—C9 | 179.0 (2) | C6—C7—C8—O3 | −179.9 (2) |
C14—O3—C8—C7 | −0.6 (3) | O3—C8—C9—O2 | 1.0 (3) |
C1—N3—C4—N2 | 178.38 (19) | O3—C8—C9—C10 | −179.9 (2) |
C4—N3—C1—N1 | −179.2 (2) | C7—C8—C9—C10 | −0.3 (3) |
C4—N3—C1—N4 | 0.5 (3) | C7—C8—C9—O2 | −179.37 (19) |
C1—N3—C4—C3 | −0.5 (3) | O2—C9—C10—O1 | −1.0 (3) |
C2—N4—C1—N3 | −0.3 (3) | C8—C9—C10—C11 | −0.3 (3) |
C2—N4—C1—N1 | 179.4 (2) | O2—C9—C10—C11 | 178.8 (2) |
C1—N4—C2—C3 | 0.0 (3) | C8—C9—C10—O1 | 179.9 (2) |
N4—C2—C3—C4 | 0.0 (3) | O1—C10—C11—C6 | −179.5 (2) |
N4—C2—C3—C5 | −177.6 (2) | C9—C10—C11—C6 | 0.7 (3) |
C4—C3—C5—C6 | −81.2 (2) | O4—C15—C16—O6 | −59.2 (4) |
C5—C3—C4—N3 | 177.82 (19) | O4—C15—C16—C16i | 66.4 (3) |
C2—C3—C5—C6 | 96.2 (2) | O5—C15—C16—O6 | 120.7 (3) |
C2—C3—C4—N2 | −178.5 (2) | O5—C15—C16—C16i | −113.8 (3) |
C2—C3—C4—N3 | 0.3 (3) | O6—C16—C16i—O6i | 180.0 (3) |
C5—C3—C4—N2 | −1.0 (3) | O6—C16—C16i—C15i | −55.3 (3) |
C3—C5—C6—C7 | 13.0 (3) | C15—C16—C16i—O6i | 55.3 (3) |
C3—C5—C6—C11 | −166.57 (19) | C15—C16—C16i—C15i | −180.0 (2) |
C5—C6—C11—C10 | 179.1 (2) |
Symmetry codes: (i) −x+1, −y+1, −z+1; (ii) −x, −y+2, −z+1; (iii) x, −y+3/2, z+1/2; (iv) −x, y−1/2, −z+1/2; (v) x, −y+3/2, z−1/2; (vi) −x+1, −y+2, −z+1; (vii) x+1, y, z; (viii) −x, y+1/2, −z+1/2; (ix) x, y+1, z; (x) x+1, −y+3/2, z+1/2; (xi) −x, −y+3, −z+1; (xii) x−1, y, z; (xiii) x−1, −y+3/2, z−1/2; (xiv) x, y−1, z. |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1A···O4v | 0.91 (3) | 1.91 (3) | 2.810 (3) | 173 (3) |
N1—H1B···O5i | 0.89 (3) | 1.93 (3) | 2.798 (3) | 165 (2) |
N2—H2A···O4 | 0.90 (3) | 1.99 (3) | 2.882 (3) | 173 (3) |
N2—H2B···O2ii | 0.90 (3) | 2.22 (3) | 3.081 (3) | 159 (2) |
N4—H4···O5v | 0.88 (3) | 1.84 (3) | 2.712 (2) | 176 (3) |
O6—H6···N3 | 0.8200 | 2.0900 | 2.896 (5) | 166.00 |
C13—H13C···O6viii | 0.96 | 2.48 | 2.929 (4) | 109 |
C14—H14A···Cg2iv | 0.96 | 2.97 | 3.546 (3) | 119 |
Symmetry codes: (i) −x+1, −y+1, −z+1; (ii) −x, −y+2, −z+1; (iv) −x, y−1/2, −z+1/2; (v) x, −y+3/2, z−1/2; (viii) −x, y+1/2, −z+1/2. |
Experimental details
Crystal data | |
Chemical formula | 2C14H19N4O3+·C4H4O52− |
Mr | 714.74 |
Crystal system, space group | Monoclinic, P21/c |
Temperature (K) | 293 |
a, b, c (Å) | 12.9850 (3), 9.3038 (2), 15.6815 (3) |
β (°) | 111.065 (1) |
V (Å3) | 1767.88 (7) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.10 |
Crystal size (mm) | 0.30 × 0.20 × 0.20 |
Data collection | |
Diffractometer | Bruker Kappa APEXII CCD diffractometer |
Absorption correction | Multi-scan (SADABS; Bruker, 1999) |
Tmin, Tmax | 0.970, 0.980 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 16178, 3108, 2763 |
Rint | 0.020 |
(sin θ/λ)max (Å−1) | 0.595 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.045, 0.115, 1.18 |
No. of reflections | 3108 |
No. of parameters | 265 |
No. of restraints | 3 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.33, −0.18 |
Computer programs: APEX2 (Bruker–Nonius, 2004), APEX2 and SAINT (Bruker–Nonius, 2004), SAINT and XPREP (Bruker–Nonius, 2004), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), ORTEP-3 for Windows (Farrugia, 1997) and Mercury (Macrae et al., 2006), PLATON (Spek, 2003).
C10—O1—C12 | 118.5 (3) | O3—C8—C9 | 116.2 (2) |
C9—O2—C13 | 112.76 (19) | O2—C9—C10 | 120.8 (2) |
C8—O3—C14 | 117.6 (2) | O2—C9—C8 | 119.8 (2) |
C1—N4—C2 | 119.80 (18) | O1—C10—C9 | 114.9 (2) |
O3—C8—C7 | 124.0 (2) | O1—C10—C11 | 124.2 (2) |
C12—O1—C10—C11 | 18.1 (4) | C14—O3—C8—C7 | −0.6 (3) |
C13—O2—C9—C8 | −96.4 (3) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1A···O4i | 0.91 (3) | 1.91 (3) | 2.810 (3) | 173 (3) |
N1—H1B···O5ii | 0.89 (3) | 1.93 (3) | 2.798 (3) | 165 (2) |
N2—H2A···O4 | 0.90 (3) | 1.99 (3) | 2.882 (3) | 173 (3) |
N2—H2B···O2iii | 0.90 (3) | 2.22 (3) | 3.081 (3) | 159 (2) |
N4—H4···O5i | 0.88 (3) | 1.84 (3) | 2.712 (2) | 176 (3) |
O6—H6···N3 | 0.8200 | 2.0900 | 2.896 (5) | 166.00 |
C13—H13C···O6iv | 0.9600 | 2.4800 | 2.929 (4) | 109.00 |
C14—H14A···Cg2v | 0.9600 | 2.9700 | 3.546 (3) | 119.00 |
Symmetry codes: (i) x, −y+3/2, z−1/2; (ii) −x+1, −y+1, −z+1; (iii) −x, −y+2, −z+1; (iv) −x, y+1/2, −z+1/2; (v) −x, y−1/2, −z+1/2. |
Trimethoprim (TMP) is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections. It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitor. Dihydrofolate reductase (DHFR) is an essential cellular enzyme involved in several biosynthetic processes as well as the target for antifolate drugs such as TMP. Antifolate drugs complexed with DHFR from various sources have been widely studied (Feeney, 2000). TMP has greater affinity towards bacterial DHFR than towards human DHFR. More than a dozen structures of TMP salts have been recorded in the Cambridge Structural Database (Version 5.29; Allen, 2002).
The role of malic acid (2-hydroxy-1,4-butanedioic acid) in supramolecular chemistry has not been widely studied although it is one of the simplest chiral dicarboxylic acids. Studies on the salts formed with primary amines and diamines using L-malic acid (Aakeröy & Nieuwenhuyzen, 1994, 1996) and racemic malic acid (Kaniskas, 1985; Farrell et al., 2002) have been reported. The crystal structures of racemic malic acid adducted with aniline (Perpétuo & Janczak, 2003), melamine (Janczak & Perpétuo, 2003) and piperazine (Wang et al., 2005) have been studied for their aggregation modes and hydrogen-bonding interactions.
The crystal structures of TMP salts formed with racemic compounds have not yet been explored. An earlier report reveals that when both the components of a system are achiral, the adducts generally crystallize in centrosymmetric space groups. This may be due to the occurrence of inversion centres in molecular crystals (Brock & Dunitz, 1994). Even if one component is a racemic mixture of the two enantiomers of a chiral building block, similar considerations apply (Burchell et al., 2000, 2001). The complex of TMP with DL-malic acid, which crystallizes in the centrosymmetric space group P21/c, has been studied in order to investigate the conformations of the components, which is very important in determining the DHFR selectivity and biological functions. The robustness and reliability of the self-complimentary DL-malic acid have also been used for crystal engineering (Pang et al., 1997; Aakeröy et al., 2000). The present study on the salt, (I), of TMP with racemic malic acid is the first to report the synthesis and structure with a view to understanding the conformations and hydrogen-bonding interactions.
The asymmetric unit of (I) (Fig. 1) contains two TMP cations and a malate dianion disordered across a centre of inversion such that half of the sites accommodate molecules of D-configuration and the other half accommodate molecules of L-configuration. If a molecule of D-malic acid occupies any particular site then atom O6 is present and O6$ is absent [the dollar ($) symbol indicates the symmetry operation (- x + 1, -y + 1, -z + 1)]; occupation by L-malic acid means that atom O6$ is present and O6 is absent. This is similar to the 1:1 adduct formed between 1, 2-bis (4'-pyridyl)-ethene and racemic-malic acid (Farrell et al., 2002).
The TMP cations are protonated at atom N4, as confirmed by the increase in the internal angle C1—N4—C2 to 119.80 (18)° from 115.46° found in neutral TMP (Koetzle & Williams, 1976). The bond lengths and angles of the TMP cation are comparable to those of previously reported TMP cations. The C—O—C angles at the methoxy groups differ significantly. This difference has also been observed in the crystal structure of neutral trimethoprim and can be attributed to the close approaches involving the atoms of the three methoxy groups (Koetzle & Williams, 1976). The O atoms of the methoxy groups of the crystal structure of (I) lie in the plane of the benzene ring, as reported previously (Yu et al., 2005).
The conformation adopted by the trimethoprim molecule in this structure is described by the two torsion angles C4—C3—C5—C6 and C3—C5—C6—C11. These torsion angles are -81.2 (2) and -166.57 (19)°, respectively, which are comparable with the earlier reported values (Hemamalini et al., 2003). TMP conformation plays an important role in DHFR selectivity (Hitching et al., 1988). The conformation adopted by the methoxy groups C—C—O—C in the trimethoprim molecule is similar to that in the related structure reported by Trilleras et al. (2005). Consistent with these different conformations, the pairs of exocyclic C—C—O angles at C8 and C10 differ widely, while the angles at C9 differ slightly (Table 1). These are typical of the angles found in planar methoxyarenes. An all-trans conformation is observed for the carbon skeleton of the malate anion [C15—C16—C16'—C15' (ψ) = -180.0°; van der Sluis & Kroon, 1985, 1989]. The pyrimidine ring makes a dihedral angle of 78.08 (7)° with the phenyl ring of the TMP cation, which is found to be within the range reported previously (Giuseppetti et al., 1984; Muthiah et al., 2001; Raj, Muthiah et al., 2003; Raj, Sethuraman et al., 2003).
In (I), the carboxylate group of the malate anion forms two nearly parallel N—H···O hydrogen bonds with the amine group and the protonated N4 atom of the TMP cation. This is reminiscent of the carboxylate interaction with the TMP cation in the DHFR–TMP complex (Kuyper, 1990). Similar specific double hydrogen bonds have been formed in almost all the structures of TMP–carboxylate complexes previously reported. This hydrogen-bonded motif formed as a result of the pair of N—H···O hydrogen bonds can be represented by the graph-set notation R22(8) (Etter, 1990; Bernstein et al., 1995). It is one of the 24 recurrent hydrogen-bonded cyclic bimolecular motifs observed in organic crystal structures (Allen et al., 1998). This motif is a well known supramolecular synthon in aminopyrimidine–carboxylate salts (Stanley et al., 2005). It self-organizes in different ways to give different types of hydrogen-bonding patterns (Raj, Stanley et al., 2003). An intermolecular hydrogen bond between the hydroxy group of the anion (O6) and the ring nitrogen (N3) of the cation is observed. The geometries of the hydrogen-bonding interactions of (I) are given in Table 2. The amine groups of each TMP cation form intermolecular hydrogen bonds with the neighbouring carboxylate group of the malate dianion as well as with the methoxy group of the neighbouring TMP cations. Part of the crystal structure of (I), showing the formation of an R22(8) hydrogen-bonded motif is shown in Fig 3. The parallel phenyl rings at (x, y, z) and (-x, 2 - y, 1 - z), which lie in different frameworks, are linked by aromatic π–π stacking interactions. They have an interplanar spacing of 3.427 Å and a centroid separation of 3.56 Å [are s.u. values available?]. The presence of this aromatic π–π interaction along with the C—H···π(arene) interaction (Table 2) is illustrated in Fig. 4. These observed interactions together form an extensive three-dimensional hydrogen-bonded framework.