A pseudo-quadruple hydrogen-bonding motif consisting of six N—H...O hydrogen bonds in trimethoprim formate

The title compound, trimethoprim (TMP) formate [systematic name: 2,4-di­amino-5-(3,4,5-tri­methoxy­benzyl)­pyrimidin-1-ium formate], C₁₄H₁₉N₄O₃⁺·CHO₂⁻, reveals a pseudo-quadruple hydrogen-bonding motif consisting of six N—H...O hydrogen bonds involving two unpaired TMP cations and two formate anions which are symmetrically disposed. The hydrogen-bonding motif is strikingly comparable with that observed in other TMP salts where the amino­pyrimidine moieties of the TMP cations are centrosymmetrically paired. These conserved hydrogen-bonding motifs may serve as robust synthons in crystal engineering and design. The characteristic pseudo-quadruple hydrogen-bonding motif and other intermolecular hydrogen bonds operating in the crystal form a two-dimensional supramolecular sheet structure.

S1. Comment

Trimethoprim (TMP) is a well known antifolate drug, which selectively inhibits the bacterial species of enzyme dihydrofolate reductase (DHFR) (Hitching et al., 1988; Feeney, 2000). The drug in its N1-protonated form inhibits DHFR. In order to study the conformation and hydrogen-bonding patterns of the TMP molecule in various crystalline environments, we have investigated the crystal structures of trimethoprim salicylate monohydrate (Murugesan & Muthiah, 1996), trimethoprim nitrate (Murugesan & Muthiah, 1997), trimethoprim hydrogen maleate (Prabakaran et al., 2001), trimethoprim hydrogen glutarate (Robert et al., 2001), trimethoprim sulfate trihydrate (Muthiah et al., 2001), trimethoprim perchlorate (Muthiah et al., 2002) and trimethoprim salicylate methanol solvate (Panneerselvam et al., 2002). The crystal structures of TMP (Koetzle & Williams, 1976) and some of its salts, such as trimethoprim monobenzoate (Giuseppetti et al., 1984), trimethoprim monobenzoate-benzoic acid 1:1 complex (Bettinetti et al., 1985), trimethoprim acetate (Bryan et al., 1987), trimethoprim sulfametrole (Giuseppetti et al., 1994), and trimethoprim sulfadimidine 1:1 (Bettinetti & Sardone, 1997) and 1:2 (Sardone et al., 1997) complexes, have also been reported in the literature. Here, we present the crystal structure of TMP formate, (I), and explore the hydrogen-bonding patterns in aminopyrimidine-carboxylate interactions. \sch

The entry for (I) in the Cambridge Structural Database (CSD; Allen & Kennard, 1993), refcode TMPFOR (Reference?), contains no atom coordinates. The structure of the molecule of (I) with the atom-labelling scheme is shown in Fig. 1. The TMP cation is protonated at N1, as is evident from the increase in the ring angle at N1 from 115.46 (5)° in neutral trimethoprim to 119.6 (2)° in (I). The conformation of the TMP cation is best described by two torsion angles, C4—C5—C7—C1' -70.2 (2)° and C5—C7—C1'-C2' 159.1 (2)°. The pyrimidine ring makes a dihedral angle of 82.3 (1)° with the phenyl ring, which is in agreement with the range of 70.0 (1)–96.0 (1)° reported for the related TMP salts mentioned above.

The carboxylate group of the formate anion forms two nearly parallel hydrogen bonds of the N—H···O type, with the 2-amino group and the protonated N1 atom of the TMP cation, which is reminiscent of the carboxylate interaction with the TMP cation observed in the DHFR-TMP complex (Kuyper, 1990). Similar specific double hydrogen bonds have been noted in almost all the structures of TMP-carboxylate complexes which we have previously studied.

The aminopyrimidine moieties of the TMP cations are not paired, as routinely expected, but their 2-amino groups are connected by hydrogen bonds through two symmetry-related formate anions, which combines with the specific double hydrogen bonds to form a pseudo-quadruple hydrogen-bonding motif consisting of six intermolecular N—H···O hydrogen bonds (Fig. 2). This pseudo-quadruple hydrogen-bonding motif can be represented in the form of three fused rings of R₂²(8), R₄²(8) and R₂²(8), in order, using graph-set notation (Etter, 1990; Bernstein et al., 1995) (Scheme and Fig. 2).

This motif appears to be potentially recurrent, as we have recently found the same hydrogen-bonding pattern involving unpaired TMP cations in the structure of trimethoprim hydrogen glutarate (Robert et al., 2001). However, all other TMP salts generally possess paired aminopyrimidine moieties of TMP cations and consequently have a subtly different pseudo-quadruple hydrogen-bonding motif, with R₃²(8), R₂²(8) and R₃²(8) rings (Scheme).

In the case of paired TMP cation-carboxylate interactions, it is interesting to note that the 2-amino and 4-amino groups of the diaminopyrimidine moieties of the TMP cations are bridged by an O atom of a carboxylate group (Prabakaran et al., 2001), a methoxy group of TMP itself (Murugesan & Muthiah, 1997; Muthiah et al., 2002), a methanol molecule (Panneerselvam et al., 2002) or a water molecule (Muthiah et al., 2001). Hence, the motif observed in all these TMP salts involving paired aminopyrimidine moieties can be effectively referred to as an O-mediated synthon. These conserved hydrogen-bonding motifs, shown also in (I), may serve as robust synthons in crystal engineering and design (Desiraju, 2001).

In the present structure, the 4-amino group of the TMP cation also forms intermolecular hydrogen bonds with the carboxylate moiety of the formate anion, as well as with the methoxy group of a neighbouring TMP cation. The characteristic pseudo-quadruple hydrogen-bonding motif and other intermolecular hydrogen bonds operating in the crystal form a two-dimensional supramolecular sheet structure (Fig. 2).

S2. Experimental

Trimethoprim (obtained as a gift from Shilpa Antibiotics Ltd.) and formic acid, in a 1:1 ratio, were dissolved in warm water and crystallized from the mother liquor.

S3. Refinement

All H atoms were treated as riding, with C—H distances of 0.93–0.97 Å and N—H distances of 0.86 Å, except for atom H1 attached to N1, whose coordinates were refined, giving N—H = 0.94 (3) Å.

Computing details

Data collection: MolEN (Fair, 1990); cell refinement: MolEN; data reduction: MolEN; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1976) and PLATON (Spek, 1997); software used to prepare material for publication: PLATON.

Figures

	Fig. 1. A view of the molecular structure of (I) with the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radii.
	Fig. 2. The two-dimensional supramolecular sheet structure of (I) formed by TMP and formate ions. The pseudo-quadruple hydrogen-bonding motifs consisting of three fused rings are depicted. Atoms labelled with an asterisk (*), hash (#) or dollar sign (add) are at the symmetry positions (1 - x, y, 1/2 - z), (x, 1 - y, z + 1/2) and (-x, 1 - y, 1 - z), respectively.

2,4-Diamino-5-(3,4,5-trimethoxybenzyl)pyrimidin-1-ium formate

Crystal data

C14H19N4O3^+·CHO2^−	F(000) = 1424
Mr = 336.35	Dx = 1.303 Mg m^−3
Monoclinic, C2/c	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: -C 2yc	Cell parameters from 40 reflections
a = 17.555 (2) Å	θ = 5–25°
b = 11.708 (2) Å	µ = 0.83 mm^−1
c = 16.696 (8) Å	T = 293 K
β = 92.43 (3)°	Block, colourless
V = 3428.5 (18) Å^3	0.30 × 0.22 × 0.19 mm
Z = 8

Data collection

Enraf-Nonius CAD-4 diffractometer	Rint = 0.047
Radiation source: fine-focus sealed tube	θmax = 70.0°, θmin = 4.5°
Graphite monochromator	h = −11→21
ω/2θ scans	k = −11→14
6169 measured reflections	l = −20→19
3081 independent reflections	3 standard reflections every 60 min
2824 reflections with I > 2σ(I)	intensity decay: none

Refinement

Refinement on F^2	0 restraints
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.061	w = 1/[σ^2(Fo^2) + (0.0986P)^2 + 1.3308P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.166	(Δ/σ)max < 0.001
S = 1.07	Δρmax = 0.26 e Å^−3
3081 reflections	Δρmin = −0.33 e Å^−3
246 parameters

Special details

Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All e.s.d.'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

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

	x	y	z	Uiso*/Ueq
O3	−0.12086 (7)	0.58365 (12)	0.44332 (7)	0.0482 (4)
O4	−0.11255 (7)	0.35929 (13)	0.44208 (8)	0.0543 (4)
O5	0.00357 (8)	0.24956 (13)	0.37233 (9)	0.0601 (5)
N1	0.29722 (8)	0.48960 (15)	0.22406 (8)	0.0431 (5)
N2	0.40878 (8)	0.41869 (16)	0.28007 (9)	0.0500 (5)
N3	0.31832 (7)	0.48487 (13)	0.36420 (7)	0.0382 (4)
N4	0.22844 (8)	0.54865 (16)	0.44641 (8)	0.0457 (5)
C1'	0.06250 (8)	0.54860 (15)	0.34716 (9)	0.0361 (4)
C2	0.34125 (9)	0.46510 (15)	0.29028 (9)	0.0374 (4)
C2'	0.00142 (8)	0.60297 (15)	0.38133 (9)	0.0367 (5)
C3'	−0.05770 (8)	0.53876 (16)	0.40999 (8)	0.0367 (5)
C4	0.24918 (9)	0.53104 (14)	0.37228 (9)	0.0355 (4)
C4'	−0.05579 (9)	0.41987 (16)	0.40637 (9)	0.0397 (5)
C5	0.20024 (8)	0.56276 (15)	0.30421 (9)	0.0369 (5)
C5'	0.00555 (9)	0.36595 (16)	0.37245 (9)	0.0420 (5)
C6	0.22798 (9)	0.53874 (17)	0.23199 (9)	0.0420 (5)
C6'	0.06418 (9)	0.43043 (16)	0.34207 (10)	0.0409 (5)
C7	0.12509 (8)	0.62126 (16)	0.31300 (10)	0.0420 (5)
C8	−0.12533 (12)	0.7039 (2)	0.45097 (14)	0.0619 (7)
C9	−0.15994 (12)	0.2913 (2)	0.38984 (14)	0.0618 (7)
C10	0.06460 (14)	0.1904 (2)	0.33740 (16)	0.0687 (8)
O6	0.45571 (7)	0.39261 (14)	0.11789 (7)	0.0528 (4)
O7	0.34024 (7)	0.44652 (18)	0.07607 (7)	0.0662 (6)
C11	0.40669 (10)	0.4148 (2)	0.06544 (10)	0.0517 (6)
H1	0.3149 (14)	0.475 (2)	0.1726 (17)	0.061 (6)*
H2'	0.00030	0.68220	0.38490	0.038 (5)*
H2A	0.43780	0.40130	0.32100	0.068 (7)*
H2B	0.42370	0.40590	0.23250	0.042 (5)*
H4A	0.25880	0.53070	0.48620	0.064 (7)*
H4B	0.18460	0.57810	0.45480	0.065 (7)*
H6	0.19860	0.55650	0.18600	0.066 (7)*
H6'	0.10460	0.39430	0.31830	0.054 (6)*
H7A	0.10730	0.64890	0.26070	0.055 (6)*
H7B	0.13320	0.68730	0.34740	0.053 (6)*
H8A	−0.08210	0.73110	0.48270	0.059 (6)*
H8B	−0.17140	0.72390	0.47670	0.061 (6)*
H8C	−0.12550	0.73830	0.39880	0.090 (9)*
H9A	−0.16920	0.33090	0.34000	0.106 (11)*
H9B	−0.20750	0.27700	0.41430	0.093 (9)*
H9C	−0.13500	0.21990	0.38000	0.078 (8)*
H10A	0.06900	0.21520	0.28300	0.084 (9)*
H10B	0.05480	0.10980	0.33830	0.100 (10)*
H10C	0.11130	0.20640	0.36730	0.064 (7)*
H11	0.4240 (14)	0.411 (3)	0.0078 (18)	0.078 (8)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O3	0.0422 (6)	0.0594 (8)	0.0439 (7)	0.0009 (5)	0.0134 (5)	−0.0056 (5)
O4	0.0552 (7)	0.0618 (9)	0.0471 (7)	−0.0190 (6)	0.0166 (6)	−0.0058 (6)
O5	0.0641 (8)	0.0450 (8)	0.0723 (9)	−0.0009 (6)	0.0141 (7)	−0.0005 (6)
N1	0.0370 (7)	0.0725 (10)	0.0198 (6)	0.0015 (6)	0.0016 (5)	−0.0008 (6)
N2	0.0391 (7)	0.0811 (12)	0.0299 (7)	0.0094 (7)	0.0026 (5)	−0.0007 (6)
N3	0.0348 (6)	0.0582 (9)	0.0214 (6)	−0.0024 (6)	0.0002 (5)	0.0016 (5)
N4	0.0368 (7)	0.0787 (10)	0.0220 (7)	−0.0022 (7)	0.0044 (5)	−0.0028 (6)
C1'	0.0324 (7)	0.0520 (9)	0.0236 (7)	−0.0004 (6)	−0.0021 (5)	0.0027 (6)
C2	0.0340 (7)	0.0532 (9)	0.0250 (7)	−0.0040 (6)	0.0014 (6)	0.0003 (6)
C2'	0.0372 (8)	0.0458 (9)	0.0268 (7)	0.0003 (6)	−0.0010 (6)	0.0001 (6)
C3'	0.0345 (8)	0.0534 (10)	0.0221 (7)	0.0004 (6)	−0.0015 (6)	−0.0015 (6)
C4	0.0359 (7)	0.0487 (9)	0.0220 (7)	−0.0086 (6)	0.0027 (5)	0.0008 (5)
C4'	0.0393 (8)	0.0528 (10)	0.0270 (7)	−0.0078 (7)	0.0019 (6)	−0.0010 (6)
C5	0.0315 (7)	0.0501 (9)	0.0290 (8)	−0.0048 (6)	0.0011 (6)	0.0025 (6)
C5'	0.0447 (9)	0.0475 (10)	0.0336 (8)	−0.0013 (7)	−0.0009 (6)	−0.0019 (6)
C6	0.0371 (8)	0.0652 (11)	0.0234 (8)	−0.0013 (7)	−0.0032 (6)	0.0039 (6)
C6'	0.0362 (8)	0.0517 (10)	0.0351 (8)	0.0034 (7)	0.0035 (6)	−0.0020 (6)
C7	0.0367 (8)	0.0509 (9)	0.0386 (9)	0.0011 (7)	0.0043 (6)	0.0077 (7)
C8	0.0562 (11)	0.0638 (13)	0.0670 (13)	0.0093 (9)	0.0163 (9)	−0.0120 (10)
C9	0.0564 (11)	0.0615 (12)	0.0675 (13)	−0.0187 (9)	0.0039 (9)	−0.0021 (10)
C10	0.0780 (15)	0.0507 (12)	0.0781 (16)	0.0112 (10)	0.0125 (12)	−0.0060 (10)
O6	0.0467 (7)	0.0738 (9)	0.0374 (6)	0.0041 (6)	−0.0033 (5)	−0.0077 (6)
O7	0.0459 (7)	0.1292 (15)	0.0233 (6)	0.0087 (8)	−0.0012 (5)	−0.0071 (7)
C11	0.0469 (9)	0.0797 (13)	0.0285 (8)	−0.0018 (9)	0.0021 (7)	−0.0102 (8)

Geometric parameters (Å, º)

O3—C3'	1.367 (2)	C2'—C3'	1.383 (2)
O3—C8	1.416 (3)	C3'—C4'	1.394 (3)
O4—C4'	1.379 (2)	C4—C5	1.444 (2)
O4—C9	1.423 (3)	C4'—C5'	1.389 (2)
O5—C5'	1.363 (3)	C5—C6	1.349 (2)
O5—C10	1.422 (3)	C5—C7	1.499 (2)
O6—C11	1.229 (2)	C5'—C6'	1.390 (2)
O7—C11	1.244 (2)	C2'—H2'	0.9298
N1—C2	1.353 (2)	C6—H6	0.9302
N1—C6	1.356 (2)	C6'—H6'	0.9294
N2—C2	1.322 (2)	C7—H7A	0.9704
N3—C2	1.335 (2)	C7—H7B	0.9701
N3—C4	1.341 (2)	C8—H8B	0.9607
N4—C4	1.321 (2)	C8—H8A	0.9612
N1—H1	0.94 (3)	C8—H8C	0.9595
N2—H2B	0.8599	C9—H9B	0.9596
N2—H2A	0.8593	C9—H9C	0.9610
N4—H4A	0.8600	C9—H9A	0.9604
N4—H4B	0.8602	C10—H10C	0.9601
C1'—C7	1.520 (2)	C10—H10A	0.9598
C1'—C6'	1.387 (3)	C10—H10B	0.9595
C1'—C2'	1.390 (2)	C11—H11	1.02 (3)
C3'—O3—C8	117.91 (15)	N1—C6—C5	122.32 (15)
C4'—O4—C9	115.92 (15)	C1'—C6'—C5'	120.12 (15)
C5'—O5—C10	117.91 (16)	C1'—C7—C5	115.74 (15)
C2—N1—C6	119.58 (14)	C1'—C2'—H2'	120.13
C2—N3—C4	118.22 (13)	C3'—C2'—H2'	120.12
C2—N1—H1	120.6 (15)	N1—C6—H6	118.82
C6—N1—H1	119.8 (15)	C5—C6—H6	118.86
C2—N2—H2A	119.97	C1'—C6'—H6'	119.93
H2A—N2—H2B	119.98	C5'—C6'—H6'	119.96
C2—N2—H2B	120.05	C1'—C7—H7A	108.31
H4A—N4—H4B	120.11	C1'—C7—H7B	108.32
C4—N4—H4A	119.95	C5—C7—H7A	108.38
C4—N4—H4B	119.94	C5—C7—H7B	108.33
C6'—C1'—C7	121.20 (14)	H7A—C7—H7B	107.49
C2'—C1'—C6'	120.06 (15)	O3—C8—H8A	109.49
C2'—C1'—C7	118.70 (16)	O3—C8—H8B	109.49
N1—C2—N3	122.33 (15)	O3—C8—H8C	109.48
N2—C2—N3	119.87 (15)	H8A—C8—H8B	109.44
N1—C2—N2	117.80 (15)	H8A—C8—H8C	109.47
C1'—C2'—C3'	119.75 (16)	H8B—C8—H8C	109.47
O3—C3'—C4'	115.04 (14)	O4—C9—H9A	109.52
C2'—C3'—C4'	120.53 (15)	O4—C9—H9B	109.47
O3—C3'—C2'	124.43 (17)	O4—C9—H9C	109.43
N3—C4—N4	116.35 (14)	H9A—C9—H9B	109.55
N3—C4—C5	122.38 (14)	H9A—C9—H9C	109.48
N4—C4—C5	121.26 (15)	H9B—C9—H9C	109.38
O4—C4'—C3'	118.41 (15)	O5—C10—H10A	109.46
O4—C4'—C5'	121.95 (17)	O5—C10—H10B	109.51
C3'—C4'—C5'	119.47 (15)	O5—C10—H10C	109.48
C4—C5—C6	115.13 (14)	H10A—C10—H10B	109.51
C6—C5—C7	122.36 (15)	H10A—C10—H10C	109.38
C4—C5—C7	122.49 (14)	H10B—C10—H10C	109.48
O5—C5'—C6'	124.18 (16)	O6—C11—O7	126.43 (16)
C4'—C5'—C6'	120.05 (17)	O6—C11—H11	115.7 (15)
O5—C5'—C4'	115.76 (15)	O7—C11—H11	117.7 (15)
C8—O3—C3'—C2'	−1.7 (2)	C1'—C2'—C3'—C4'	1.3 (2)
C8—O3—C3'—C4'	178.18 (15)	O3—C3'—C4'—C5'	179.08 (14)
C9—O4—C4'—C3'	117.30 (18)	O3—C3'—C4'—O4	−5.6 (2)
C9—O4—C4'—C5'	−67.5 (2)	C2'—C3'—C4'—C5'	−1.0 (2)
C10—O5—C5'—C4'	179.25 (18)	C2'—C3'—C4'—O4	174.29 (14)
C10—O5—C5'—C6'	−1.4 (3)	N3—C4—C5—C6	2.3 (2)
C6—N1—C2—N3	1.8 (3)	N4—C4—C5—C7	2.5 (3)
C6—N1—C2—N2	−179.09 (18)	N3—C4—C5—C7	−175.97 (16)
C2—N1—C6—C5	−1.2 (3)	N4—C4—C5—C6	−179.23 (18)
C4—N3—C2—N1	−0.2 (3)	C3'—C4'—C5'—O5	179.07 (14)
C4—N3—C2—N2	−179.37 (17)	O4—C4'—C5'—C6'	−175.52 (15)
C2—N3—C4—N4	179.62 (15)	O4—C4'—C5'—O5	3.9 (2)
C2—N3—C4—C5	−1.8 (2)	C3'—C4'—C5'—C6'	−0.3 (2)
C2'—C1'—C6'—C5'	−1.2 (2)	C4—C5—C6—N1	−0.7 (3)
C7—C1'—C2'—C3'	177.48 (14)	C7—C5—C6—N1	177.53 (17)
C6'—C1'—C2'—C3'	−0.2 (2)	C4—C5—C7—C1'	−70.2 (2)
C6'—C1'—C7—C5	−23.3 (2)	C6—C5—C7—C1'	111.63 (19)
C7—C1'—C6'—C5'	−178.81 (15)	O5—C5'—C6'—C1'	−177.89 (15)
C2'—C1'—C7—C5	159.11 (14)	C4'—C5'—C6'—C1'	1.5 (2)
C1'—C2'—C3'—O3	−178.83 (14)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O7	0.94 (3)	1.72 (3)	2.662 (2)	176 (2)
N2—H2A···O6^i	0.86	2.09	2.883 (2)	152
N2—H2B···O6	0.86	2.02	2.880 (2)	174
N4—H4A···O7^ii	0.86	2.05	2.860 (2)	158
N4—H4B···O4^iii	0.86	2.30	3.015 (2)	141
C2′—H2′···O6^iv	0.93	2.58	3.474 (3)	161
C6—H6···O3^v	0.93	2.53	3.452 (3)	174
C9—H9C···O5	0.96	2.47	2.938 (3)	110

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