Intermolecular N–H...O hydrogen-bonding inter­actions in 5-fluoro­cytosinium salicyl­ate

The title compound, C₄H₅FN₃O⁺·C₇H₅O₃⁻, exists as a hydrogen-bonded heterodimer of 5-fluoro­cytosinium and salicyl­ate ions which are connected through a pair of nearly parallel specific N—H...O hydrogen bonds. The heterodimer self-assembles via intermolecular N—H...O hydrogen bonds to form linear, as well as helical, hydrogen-bonded supramolecular chains that are interwoven into a three-dimensional network structure.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.003 Å
• R factor = 0.034
• wR factor = 0.103
• Data-to-parameter ratio = 11.2

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S1. Comment

The potential importance of hydrogen bonding in the structure and function of biomolecules has been well established (Jeffrey & Saenger, 1991). Particularly, N—H···O hydrogen bonds are most predominant in determining the formation of secondary structure elements in proteins, base-pairing in nucleic acids and their biomolecular interactions. Model studies on complexes between nucleic acid bases and amino acids reveal some elementary stereochemical patterns, including N—H···O-type interactions, which are helpful for understanding the protein–nucleic acid recognition. Cytosine (C) base has been the subject of several investigations aiming to study the relative stabilities of tautomeric forms (Kobayashi, 1998), hydration effects and hydrogen bonding (Sivanesan et al., 2000). The structures of nucleotide complexes, especially cytosine along with amino acids, were extensively studied (Ohki et al., 1974, 1975, 1976; Takenaka et al., 1980). As we have been interested in hydrogen bonding patterns involving aminopyrimidine–carboxylate interactions, we have recently determined the crystal structures of cytosinium hydrogen maleate (Balasubramanian et al., 1996), trimethoprim salicylate monohydrate (Murugesan & Muthiah, 1996), trimethoprim formate (Umadevi & Muthiah, 1994) and trimethoprim maleate (Prabakaran et al., 2001). For the present work, we have chosen salicylic acid to interact with 5-fluorocytosine. Salicylic acid, a well known analgesic, and its complexes with a few drug molecules such as antipyrine (Singh & Vijayan, 1974) and sulfadimidine (Patel et al., 1988) were already reported in the literature. We present herein the crystal structure of 5-fluorocytosinium salicylate, (I), which exhibits an extensive network of intermolecular N—H···O hydrogen bonds.

A view of the molecular structure with the atom-labelling scheme is shown in Fig. 1. The 5-fluorocytosine molecule is protonated at N3 leading to widening of the corresponding internal angle from 120.8 (5) to 124.6 (1)° compared with neutral 5-fluorocytosine (Louis et al., 1982). There is an intramolecular N—H···F hydrogen bond between the N4-amino group and the F atom of the 5-flurocytosinium cation, and the hydrogen-bonding parameters (Table 2) agree with those values (2.41 Å and 96°) noted for 5-flurocytosine monohydrate (Louis et al., 1982). There is also an intramolecular O—H···O hydrogen bond involving the phenolic OH and carboxylate groups, which is commonly observed in salicylic moiety. The pyrimidine ring of 5-fluorocytosinium cation makes a dihedral angle of 65.7 (1)° with the phenyl ring of the salicylate anion in the asymmetric unit of (I).

In the crystal, the carboxylate group of the salicylate anion makes a pair of nearly parallel specific hydrogen bonds of the type N—H···O through the N3 and N4 atoms of the 5-fluorocytosinium cation, forming a hydrogen-bonded heterodimer of the 5-fluorocytosinium and salicylate ions. Each hydrogen-bonded heterodimer forms an eight-membered ring with a graph-set motif of R²₂(8) (Etter, 1990; Bernstein et al., 1995). The least-squares planes passing through the carboxylate group of the salicylate anion and the pyrimidine ring of the 5-fluorocytosinium cation at (1/2 - x, y - 1/2, 3/2 - z) involved in the specific hydrogen-bond interaction make an angle of 9.4 (2)°. The neighbouring 5-fluorocytosinium cations in the heterodimers interact through N4—H···O2 hydrogen bonds to form a linear hydrogen-bonded supramolecular chain (Fig. 2). This type of cytosine–cytosine interaction through N4—H···O2 hydrogen bond was previously proposed for a single stranded poly(C) nucleotide based on an NMR study (Broido & Kearns, 1982). It is interesting to note that 5-fluorocytosinium cations are neither paired nor stacked as usually expected, but self-assemble into infinite chains by intermolecular N—H···O hydrogen bonds. Such a self-assembly via intermolecular N—H···O and N—H···N hydrogen bonds have been recently reported for enaminonic (Bertolasi et al., 1998) and pyrazole (Bertolasi et al., 1999) derivatives, respectively. The hydrogen-bonded heterodimers themselves also form a helical chain with a pitch length equivalent to b through intermolecular N1—H···O3 hydrogen bonds involving aminopyrimidine–carboxylate interactions (Fig. 3). Since the acceptor atom O3 links the helical chain and simultaneously participates in the specific hydrogen bond, it acts as a bifurcated acceptor. Thus, the hydrogen-bonding patterns observed in (I) are elegantly characterized by supramolecular linear and helical chains built up of heterodimers of 5-fluorocytosinium and salicylate ions. Indeed, these chains are interwoven into a three-dimensional hydrogen-bonding network to form an intricate structure (Fig. 4).

S2. Experimental

Hot aqueous solutions of 5-fluorocytosine and salicylic acid (received from Hoffmann La Roche, Basel and Loba Chemie Pvt. Ltd., respectively) were mixed in a 1:1 molar ratio. Crystals of (I) were grown from the solution by slow evaporation at room temperature.

S3. Refinement

H atoms attached to C atoms were treated as riding, with an average value of 0.93 Å. All other H atoms were located from difference Fourier maps and refined isotropically. The H1 and H3 atoms attached to N1 and N3 were drifting and so their coordinates were fixed during the final refinements.

Computing details

Data collection: MolEN (Fair, 1990); cell refinement: MolEN; data reduction: MolEN; program(s) used to solve structure: SHELXL97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 1997) and RPluto (Cambridge Structural Database, 2000); software used to prepare material for publication: PLATON (Spek, 1997).

Figures

	Fig. 1. ORTEP diagram (PLATON; Spek, 1997) of (I) with the atom-labeling scheme. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 2. Hydrogen-bonded heterodimers of 5-fluorocytosinium and salicylate ions self-assemble into a linear chain through N4—H···O2' interactions (similarly coloured hydrogen bonds are crystallographically equivalent) (Cambridge Structural Database, 2000).
	Fig. 3. Hydrogen-bonded heterodimers of 5-fluorocytosinium and salicylate ions self-assemble into a helical chain through N1—H···O3' interactions (similarly coloured hydrogen bonds are crystallographically equivalent) (Cambridge Structural Database, 2000).
	Fig. 4. Crystal-packing diagram along the (001) plane illustrating the interweaving of linear and helical hydrogen-bonded chains leading to an intricate three-dimensional structure (PLATON; Spek, 1997).

(I)

Crystal data

C4H5FN3O^+·C7H5O3^−	F(000) = 552
Mr = 267.22	Dx = 1.574 Mg m^−3
Monoclinic, P21/n	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: -P 2yn	Cell parameters from 25 reflections
a = 13.509 (5) Å	θ = 2.0–25.0°
b = 10.519 (3) Å	µ = 1.15 mm^−1
c = 8.099 (2) Å	T = 293 K
β = 101.540 (15)°	Needle, colorless
V = 1127.6 (6) Å^3	0.26 × 0.23 × 0.17 mm
Z = 4

Data collection

Enraf Nonius CAD-4 diffractometer	Rint = 0.010
Radiation source: fine-focus sealed tube	θmax = 70.0°
Graphite monochromator	h = −16→14
ω–2θ scans	k = −11→12
2289 measured reflections	l = −2→9
2141 independent reflections	3 standard reflections every 60 min
1631 reflections with I > 2σ(I)	intensity decay: none

Refinement

Refinement on F^2	H atoms treated by a mixture of independent and constrained refinement
Least-squares matrix: full	w = 1/[σ^2(Fo^2) + (0.1407P)^2] where P = (Fo^2 + 2Fc^2)/3
R[F^2 > 2σ(F^2)] = 0.034	(Δ/σ)max < 0.001
wR(F^2) = 0.103	Δρmax = 0.19 e Å^−3
S = 1.02	Δρmin = −0.16 e Å^−3
2141 reflections	Extinction correction: SHELXL97, FC^*=KFC[1+0.001XFC^2Λ^3/SIN(2Θ)]^-1/4
192 parameters	Extinction coefficient: 0.0066 (7)
0 restraints

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	0.07135 (7)	0.47759 (10)	0.79894 (14)	0.0411 (3)
O4	−0.08899 (8)	0.51316 (11)	0.6807 (2)	0.0505 (4)
O5	−0.22903 (9)	0.36377 (15)	0.7271 (2)	0.0630 (5)
C7	−0.15615 (12)	0.2994 (2)	0.8345 (2)	0.0442 (5)
C8	−0.1844 (2)	0.1901 (2)	0.9123 (3)	0.0573 (7)
C9	−0.1133 (2)	0.1213 (2)	1.0227 (3)	0.0602 (7)
C10	−0.0134 (2)	0.1602 (2)	1.0603 (2)	0.0544 (6)
C11	0.01514 (13)	0.2674 (2)	0.9830 (2)	0.0440 (5)
C12	−0.05457 (11)	0.33791 (14)	0.8671 (2)	0.0374 (5)
C13	−0.02160 (11)	0.45017 (14)	0.7781 (2)	0.0363 (4)
F1	0.48059 (7)	0.43555 (9)	1.14158 (12)	0.0489 (3)
O2	0.20854 (8)	0.16762 (11)	0.7089 (2)	0.0478 (4)
N1	0.24711 (9)	0.34496 (13)	0.8719 (2)	0.0413 (4)
N3	0.37067 (8)	0.19523 (11)	0.8498 (2)	0.0337 (4)
N4	0.53687 (9)	0.22223 (14)	0.9866 (2)	0.0397 (4)
C2	0.27041 (11)	0.23208 (14)	0.8042 (2)	0.0368 (4)
C4	0.44313 (10)	0.26105 (13)	0.9563 (2)	0.0327 (4)
C5	0.41056 (11)	0.37238 (14)	1.0295 (2)	0.0360 (4)
C6	0.31536 (12)	0.41294 (15)	0.9853 (2)	0.0403 (5)
H5	−0.196 (2)	0.435 (3)	0.689 (3)	0.102 (9)*
H8	−0.2514 (2)	0.1638 (2)	0.8894 (3)	0.074 (7)*
H9	−0.1327 (2)	0.0482 (2)	1.0724 (3)	0.067 (6)*
H10	0.0341 (2)	0.1145 (2)	1.1366 (2)	0.068 (6)*
H11	0.08225 (13)	0.2935 (2)	1.0086 (2)	0.051 (5)*
H1	0.17910	0.38000	0.84010	0.084 (7)*
H3	0.39020	0.12000	0.80020	0.051 (5)*
H4A	0.5533 (15)	0.146 (2)	0.931 (3)	0.065 (6)*
H4B	0.5839 (15)	0.2663 (18)	1.059 (2)	0.053 (5)*
H6	0.29551 (12)	0.48731 (15)	1.0317 (2)	0.059 (6)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O3	0.0285 (5)	0.0346 (6)	0.0583 (7)	0.0010 (4)	0.0041 (5)	0.0022 (5)
O4	0.0320 (6)	0.0436 (7)	0.0718 (8)	0.0019 (5)	0.0009 (5)	0.0129 (6)
O5	0.0337 (6)	0.0620 (9)	0.0902 (11)	−0.0051 (6)	0.0047 (6)	0.0059 (8)
C7	0.0392 (8)	0.0407 (9)	0.0549 (10)	−0.0022 (7)	0.0149 (7)	−0.0097 (8)
C8	0.0559 (11)	0.0513 (11)	0.0715 (12)	−0.0156 (9)	0.0292 (10)	−0.0126 (9)
C9	0.0834 (14)	0.0419 (10)	0.0651 (12)	−0.0037 (10)	0.0386 (11)	0.0017 (9)
C10	0.0693 (12)	0.0465 (10)	0.0515 (10)	0.0066 (9)	0.0219 (9)	0.0050 (8)
C11	0.0464 (9)	0.0414 (9)	0.0455 (9)	0.0048 (7)	0.0126 (7)	−0.0004 (7)
C12	0.0375 (8)	0.0319 (8)	0.0443 (8)	0.0006 (6)	0.0115 (6)	−0.0062 (7)
C13	0.0299 (7)	0.0318 (8)	0.0455 (8)	0.0024 (6)	0.0037 (6)	−0.0048 (6)
F1	0.0470 (5)	0.0464 (6)	0.0488 (5)	−0.0073 (4)	−0.0010 (4)	−0.0094 (4)
O2	0.0286 (5)	0.0458 (7)	0.0619 (7)	−0.0014 (5)	−0.0081 (5)	−0.0024 (6)
N1	0.0289 (6)	0.0370 (7)	0.0555 (8)	0.0057 (5)	0.0026 (6)	0.0045 (6)
N3	0.0250 (6)	0.0309 (6)	0.0420 (7)	0.0017 (5)	−0.0008 (5)	0.0000 (5)
N4	0.0260 (6)	0.0410 (8)	0.0476 (8)	0.0007 (5)	−0.0032 (5)	−0.0039 (6)
C2	0.0259 (7)	0.0372 (8)	0.0446 (8)	0.0009 (6)	0.0005 (6)	0.0067 (7)
C4	0.0280 (7)	0.0320 (7)	0.0359 (7)	−0.0017 (5)	0.0012 (5)	0.0052 (6)
C5	0.0355 (7)	0.0335 (8)	0.0369 (8)	−0.0042 (6)	0.0020 (6)	0.0008 (6)
C6	0.0413 (8)	0.0317 (8)	0.0486 (9)	0.0027 (6)	0.0106 (7)	0.0021 (7)

Geometric parameters (Å, º)

F1—C5	1.348 (2)	C7—C12	1.404 (2)
O3—C13	1.266 (2)	C7—C8	1.400 (3)
O4—C13	1.266 (2)	C8—C9	1.379 (3)
O5—C7	1.357 (2)	C9—C10	1.385 (4)
O5—H5	0.95 (3)	C10—C11	1.382 (3)
O2—C2	1.223 (2)	C11—C12	1.402 (2)
N1—C6	1.366 (2)	C12—C13	1.497 (2)
N1—C2	1.371 (2)	C8—H8	0.929 (4)
N3—C2	1.386 (2)	C9—H9	0.930 (3)
N3—C4	1.358 (2)	C10—H10	0.931 (3)
N4—C4	1.306 (2)	C11—H11	0.930 (3)
N1—H1	0.9755	C4—C5	1.422 (2)
N3—H3	0.9485	C5—C6	1.334 (2)
N4—H4B	0.902 (18)	C6—H6	0.930 (2)
N4—H4A	0.97 (2)
C7—O5—H5	105.8 (16)	O3—C13—C12	119.88 (14)
C2—N1—C6	122.98 (13)	C9—C8—H8	119.8 (3)
C2—N3—C4	124.65 (13)	C7—C8—H8	119.8 (3)
C6—N1—H1	116.94	C10—C9—H9	119.7 (3)
C2—N1—H1	120.08	C8—C9—H9	119.6 (3)
C2—N3—H3	117.41	C9—C10—H10	120.4 (3)
C4—N3—H3	117.92	C11—C10—H10	120.3 (3)
H4A—N4—H4B	122.1 (18)	C12—C11—H11	119.2 (2)
C4—N4—H4A	118.4 (13)	C10—C11—H11	119.2 (2)
C4—N4—H4B	119.5 (13)	N1—C2—N3	115.22 (13)
O5—C7—C8	118.03 (17)	O2—C2—N1	123.37 (14)
O5—C7—C12	122.20 (17)	O2—C2—N3	121.41 (14)
C8—C7—C12	119.76 (18)	N3—C4—N4	120.57 (13)
C7—C8—C9	120.4 (2)	N3—C4—C5	116.17 (13)
C8—C9—C10	120.6 (2)	N4—C4—C5	123.26 (14)
C9—C10—C11	119.32 (19)	F1—C5—C4	116.93 (13)
C10—C11—C12	121.63 (18)	F1—C5—C6	122.14 (14)
C11—C12—C13	121.01 (14)	C4—C5—C6	120.91 (14)
C7—C12—C11	118.27 (15)	N1—C6—C5	119.85 (15)
C7—C12—C13	120.71 (14)	N1—C6—H6	120.10 (19)
O4—C13—C12	117.82 (14)	C5—C6—H6	120.05 (19)
O3—C13—O4	122.28 (14)
C2—N1—C6—C5	2.7 (2)	C8—C9—C10—C11	−1.5 (3)
C6—N1—C2—O2	176.36 (16)	C9—C10—C11—C12	−0.1 (3)
C6—N1—C2—N3	−4.3 (2)	C10—C11—C12—C7	2.0 (3)
C2—N3—C4—N4	−176.95 (15)	C10—C11—C12—C13	−177.01 (16)
C4—N3—C2—N1	1.5 (2)	C7—C12—C13—O3	−174.45 (15)
C4—N3—C2—O2	−179.18 (16)	C7—C12—C13—O4	4.1 (2)
C2—N3—C4—C5	2.7 (2)	C11—C12—C13—O3	4.6 (2)
C8—C7—C12—C13	176.56 (17)	C11—C12—C13—O4	−176.89 (16)
O5—C7—C8—C9	−179.9 (2)	N3—C4—C5—F1	176.98 (13)
O5—C7—C12—C13	−2.5 (3)	N4—C4—C5—C6	175.19 (16)
C8—C7—C12—C11	−2.5 (3)	N3—C4—C5—C6	−4.5 (2)
O5—C7—C12—C11	178.48 (16)	N4—C4—C5—F1	−3.4 (2)
C12—C7—C8—C9	1.0 (3)	C4—C5—C6—N1	1.9 (2)
C7—C8—C9—C10	1.0 (3)	F1—C5—C6—N1	−179.58 (14)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O3	0.98	1.76	2.7151 (19)	166
N3—H3···O3^i	0.95	1.82	2.7719 (19)	179
N4—H4A···O4^i	0.97 (2)	1.78 (2)	2.748 (2)	175 (2)
N4—H4B···F1	0.902 (18)	2.437 (19)	2.751 (2)	100.7 (15)
N4—H4B···O2^ii	0.902 (18)	1.994 (19)	2.880 (2)	167.0 (18)
O5—H5···O4	0.95 (3)	1.68 (3)	2.544 (2)	149 (3)

Symmetry codes: (i) −x+1/2, y−1/2, −z+3/2; (ii) x+1/2, −y+1/2, z+1/2.