4,6-Diamino­pyrimidine-2(1H)-thione hemihydrate: a three-dimensional hydrogen-bonded framework

In the title compound, C₄H₆N₄S·0.5H₂O, there are two independent pyrimidine­thione units, both of which lie across mirror planes in the space group Cmca. Hence, the H atoms bonded to the ring N atoms in each mol­ecule are disordered over two symmetry-related sites, each having an occupancy of 0.5. The water mol­ecule lies across a twofold rotation axis parallel to [010]. The mol­ecular components of (I) are linked by seven independent hydrogen bonds, of N-H...N, N-H...S, N-H...O and O-H...S types. A combination of disordered N-H...N hydrogen bonds and ordered N-H...S hydrogen bonds links the pyrimidine­thione units into a continuous tubular structure. The water mol­ecule acts as both a double donor of hydrogen bonds and a double acceptor, forming hydrogen bonds with components of four distinct pyrimidine­thione tubes, thus linking these tubes into a three-dimensional structure.

S1. Comment

Thiocytosine derivatives possess some powerful bioactivities, such as enzymatic reactivity, antitumour (Kawaguchi et al., 2000), antileukemic (Rostkowska et al., 1993) and antimicrobial (Semenov et al., 2011) activities. In addition, some thiocytosine derivatives have long been known to be constituents of DNA and RNA (Rink, 1974), and some seem to regulate nucleic acid structures by affecting base-pair formation (Inose et al., 1972). Correlational studies of thiocytosines are in progress, and as a part of this investigation we have determined the structure of 6-aminothiocytosine (4,6-diamino-2(1H)-pyrimidinethione) as its hemihydrate, the title compound, (I), and the result is reported here.

The asymmetric unit of (I) consists of two independent half molecules of the pyrimidinethione component and one half of a water molecule, giving an overall ratio of pyrimidinethione to water of 2:1. The presence of three independent molecular components permits considerable flexibility in the specification of the asymmetric unit, but it is possible to select a compact asymmetric unit (Fig. 1) in which the independent components are linked by multiple hydrogen bonds (Table 2). In the selected asymmetric unit, the pyrimidinethione units of types 1 and 2, containing atoms S12 and S22, respectively, lie across the mirror planes at x = 0 and x = 1/2, respectively, and the water molecule lies across the twofold rotation axis along (1/4, y, 3/4). At each pyimidinethione site, regardless of which molecular type is present, the C═S and C—H units lie in the mirror plane. In addition each such site contains, with equal probability, one or other of the two alternative orientations, (Ia) and (Ib) (see scheme), which can equally well be regarded as two tautomers, and which manifest themselves here as a twofold disorder of the H atom bonded to one of the symmetry-related ring N atoms. Hence, the H atoms bonded to atoms N11 and N21 have an occupancy of 0.5.

The corresponding bond distances in the two pyrinidinethione units are in general very similar (Table 1), although the C14—N14 bond is somewhat shorter than the corresponding C24—N24 bond. In addition, the amine group in the type 2 molecule is markedly pyramidal, with the sum of the interbond angles at atom N24 being 347.2°, while the amine group of the type 1 molecule is much more nearly planar, with the sum of the interbond angles at atom N14 being 358.4°. Associated with this difference in configuration is the fact that, while atom N24 acts as a hydrogen-bond acceptor, atom N14 does not (Table 2).

The protonated form of the neutral pyrimidinethione found in (I) occurs in the bis(methylsulfonyl)amide salt, (II) [Cambridge Structural Database (Allen, 2002) refcode LOSCOL; Wijaya et al. (2000)]. The cation in (II) has almost exact twofold symemtry with all H atoms fully ordered but, despite this, it lies in a general position in space group P2₁/n. There is thus an interesting, almost paradoxical, contrast between the behaviour of the neutral and cationic forms in (I) and (II), respectively: the neutral form lies across mirror planes so that the H atom bonded to a ring N atom must be disordered in the apparent superposition of two tautomers, whereas the molecular symmetry of the cation is not reflected in the crystallographic symmetry.

The crystal structure of (I) contains seven independent hydrogen bonds, spanning N—H···N, N—H···O, N—H···S and O—H···S types (Table 2), and the effect of these is amplified by the crystallographic symmetry exhibited by all three molecular components. Overall, the molecules are linked by the hydrogen bonds to form a complex three-dimensional framework, but the formation of this structure is readily analysed in terms of a number of simpler low-dimensional sub-structures (Ferguson et al., 1998a,b; Gregson et al., 2000).

Within the selected asymmetric unit, the two pyrimidinethione units are linked by both N—H···N and N—H···S hydrogen bonds (Table 2, Fig. 1). The N—H···N hydrogen bonds within the asymmetric unit both involve disordered H atoms having statistically a 0.5 occupancy at each site. However, the reference sites for atoms H11 and H21, both at (x, y, z), are separated by only 1.33 Å so that, for any given pair of adjacent pyrimidinethione units, both H-atom sites between a pair of ring N atoms cannot be concurrently occupied. Hence, if the H11 site at (x, y, z) is occupied, then both the symmetry-related H11 site at (-x, y, z) and the H21 site at (x, y, z) must be unoccupied, so that the H21 site at (1 - x, y, z) must be occupied, and so on. Whichever of the two alternative arrangements of atoms H11 and H21 is present, the resulting hydrogen bonds generate a C²₂(8) (Bernstein et al., 1995) chain running parallel to the [100] direction (Fig. 2). Eight such chains run through each unit cell, and while the directions of the hydrogen bonds within each chain must be fully correlated, there is no necessary correlation between adjacent chains. The linking of the pyrimidinethione units is augmented by the N—H···S hydrogen bonds, both of which involve full-occupancy H-atom sites.

In addition to the N—H···N hydrogen bonds involving disordered H atoms, there is also a fully ordered N—H···N hydrogen bond involving the amine groups, with pyramidal atom N24 acting as the acceptor (Table 2). The combination of the two types of N—H···N hydrogen bond, ordered and disordered, leads to the formation of an R₄⁴(16) motif linking four pyrimidinethione molecules, two of each type (Fig. 3).

The combination of the R₄⁴(16) rings and the C²₂(8) chains along [100], when propagated by the successive mirror planes, generates a complex tubular structure running along (x, 1/2, 1/2), in which the hydrogen bonds lie on the inner surface of the tube with a layer of H atoms on the outer surface (Fig. 4). Four of these tubular structures run through each unit cell, along (x, 0, 0), (x, 0, 1/2), (x, 1/2, 0) and (x, 1/2, 1/2). They are built from pyrimidinethione units only, but the water molecules link these one-dimensional substructures into a single three-dimensional framework.

The water molecule lies on a twofold rotation axis and acts as both a twofold donor of hydrogen bonds and a twofold acceptor. Thus, the reference water molecule with its O atom at (1/4, y, 3/4) acts as hydrogen-bond donor to the S12 atoms at (-x, 1/2 + y, 3/2 - z) and (1/2 + x, 1/2 + y, z) which lie, respectively, in the pyrimidinethione tubes along (x, 1, 1) and (x, 1, 1/2). The same water molecule accepts hydrogen bonds from atoms N24 at (x, y, z) and (1/2 - x, y, 3/2 - z), which form parts of the tubes along (x, 1/2, 1/2) and (x, 1/2, 1), respectively (Fig. 5). Similarly, the water molecule with its O atom at (1/4, -1/2 + y, 3/4) is directly linked via hydrogen bonds to the four tubes along (x, 0, 1/2), (x, 0, 1), (x, 1/2, 1/2) and (x, 1/2, 1) (Fig. 5) In this manner the water molecules act to link all the pyrimidinthione tubes into a single continuous structure

Compound (I) can be regarded as a hydrated co-crystal of the two tautomers (Ia) and (Ib). In this context, it is interesting to note the behaviour of the related oxo compound 2,6-diaminopyrimidin-4-one, where only tautomer (IIIa) was observed, to the exclusion of the alternative form, (IIIb), not only in solvent-free crystals but also in a number of solvates (Gerhardt et al., 2011). By contrast, in each of the two isostructural solvates of 2-amino-6-methyl-pyrimidin-4-one with either dimethylacetamide or N-methylpyrrolidin-2-one, the two tautomeric forms, (IVa) and (IVb), are present in equal numbers (Gerhardt et al., 2011).

Related literature

For related literature, see: Allen (2002); Bernstein et al. (1995); Ferguson et al. (1998a, 1998b); Gerhardt et al. (2011); Gregson et al. (2000); Inose et al. (1972); Kawaguchi et al. (2000); Rink (1974); Rostkowska et al. (1993); Semenov et al. (2011); Spek (2009); Wijaya et al. (2000).

S2. Experimental

A mixture of malononitrile (0.2 mol), thiourea (0.2 mol) and sodium ethoxide (0.2 mol) in absolute ethanol (100 ml) was heated under reflux for 1 h, after which a solid precipitate had formed. The solvent was removed under reduced pressure and the residue was dissolved in water (50 ml); this solution was acidified to pH 5 using concentrated aqueous hydrochloric acid and then cooled to ambient temperature. The resulting precipitate was collected by filtration, washed with water and dried to give a crystalline product, 6-aminothiocytosine (yield 75%). This was dissolved in an excess of a solution of sodium hydroxide in ethanol, to which was added carbon disulfide (5 ml), and the mixture was then left to stand overnight before being acidified with concentrated aqueous hydrochloric acid, giving a red–brown solid. Crystals of (I) suitable for single-crystal X-ray diffraction were obtained by slow cooling, in air, of a hot solution in ethanol.

S3. Refinement

The systematic absences permitted as possible space groups either Cmca (No. 64) or C2ca, an alternative setting of the standard setting Aba2 (No. 41). Structure solution was readily achieved in both Cmca and Aba2, but for the latter solution the ADDSYM routines in PLATON (Spek, 2009) reported the presence of crystallographic mirror symmetry. Accordingly, the centrosymmetric space group Cmca was adopted, and confirmed by the subsequent refinement. All H atoms were located in difference maps. The H atoms bonded to ring C or N atoms were then permitted to ride in geometrically idealized positions, with C—H = 0.93 Å and N—H = 0.86 Å, and with U_iso(H) = 1.2U_eq(carrier). The H atoms bonded to the amine N atoms were permitted to ride at the positions deduced from the difference maps, with U_iso(H) = 1.2U_eq(N), giving a range of N—H = 0.86–0.99 Å (Table 2). The coordinates of the H atom bonded to the water O atom were refined, with U_iso(H) = 1.5U_eq(O), subject to a restraint of O—H = 0.84 (1) Å.

Computing details

Data collection: SMART (Bruker, 1997); cell refinement: SMART (Bruker, 1997); data reduction: SAINT (Bruker, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures

	Fig. 1. The independent molecular components of (I), showing the atom-labelling scheme and the hydrogen bonds within the selected asymmetric unit (dashed lines). Displacement ellipsoids are drawn at the 30% probability level. Atoms marked `a' or `b' are at the symmetry positions (-x, y, z) and (-x + 1, y, z), respectively. The water molecule lies across the twofold rotation axis along (1/4, y, 3/4).
	Fig. 2. A stereoview of part of the crystal structure of (I), showing the formation of a hydrogen-bonded chain parallel to the [100] direction. For the sake of clarity, the water molecule and H atoms not involved in the motif shown have been omitted. For the effect of the H-atom disorder, see the Comment.
	Fig. 3. Part of the crystal structure of (I), showing the formation of an R4^4(16) motif built from N—H···N hydrogen bonds only. For the sake of clarity, the unit-cell outline, the water molecule and H atoms not involved in the motif shown have been omitted. For the effect of the H-atom disorder, see the Comment. Atoms marked with an asterisk (*) are at the symmetry position (x, -y + 1, -z + 1).
	Fig. 4. A stereoview of part of the crystal structure of (I), showing the formation of a hydrogen-bonded tubular structure along (x, 1/2, 1/2). For the sake of clarity, water molecules have been omitted.
	Fig. 5. A projection down [100] of part of the crystal structure of (I), showing both the arrangement of the pyrimidinethione tubes parallel to [100] and the linking, by the water molecules, of these tubes into a single three-dimensional framework structure.

4,6-Diaminopyrimidine-2(1H)-thione hemihydrate

Crystal data

C4H6N4S·0.5H2O	F(000) = 1264
Mr = 151.20	Dx = 1.559 Mg m^−3
Orthorhombic, Cmca	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -C 2bc 2	Cell parameters from 1701 reflections
a = 9.7274 (19) Å	θ = 2.0–28.5°
b = 13.259 (3) Å	µ = 0.42 mm^−1
c = 19.982 (4) Å	T = 293 K
V = 2577.2 (9) Å^3	Block, brown
Z = 16	0.30 × 0.20 × 0.20 mm

Data collection

Bruker APEXII CCD area-detector diffractometer	1570 independent reflections
Radiation source: fine-focus sealed tube	983 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.112
ϕ and ω scans	θmax = 27.5°, θmin = 2.8°
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	h = −12→12
Tmin = 0.884, Tmax = 0.921	k = −15→17
6772 measured reflections	l = −12→25

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.046	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.105	w = 1/[σ^2(Fo^2) + (0.0387P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.96	(Δ/σ)max = 0.001
1570 reflections	Δρmax = 0.26 e Å^−3
100 parameters	Δρmin = −0.25 e Å^−3
1 restraint	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^* = kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0025 (5)

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
N11	0.1197 (2)	0.43195 (13)	0.59257 (10)	0.0293 (5)
H11	0.1958	0.4463	0.6123	0.035*	0.50
C12	0.0000	0.4538 (2)	0.62198 (17)	0.0282 (8)
C14	0.1210 (3)	0.38681 (16)	0.53110 (12)	0.0295 (6)
C15	0.0000	0.3631 (2)	0.50014 (18)	0.0332 (9)
H15	0.0000	0.3314	0.4586	0.040*
S12	0.0000	0.51191 (7)	0.69803 (5)	0.0381 (3)
N14	0.2434 (2)	0.36958 (15)	0.50452 (12)	0.0420 (6)
H14A	0.3264	0.3745	0.5282	0.050*
H14B	0.2507	0.3391	0.4667	0.050*
N21	0.3805 (2)	0.53044 (13)	0.63819 (10)	0.0301 (5)
H21	0.3042	0.4986	0.6330	0.036*	0.50
C22	0.5000	0.4817 (2)	0.63050 (17)	0.0295 (8)
C24	0.3791 (3)	0.62980 (16)	0.65421 (12)	0.0293 (6)
C25	0.5000	0.6812 (2)	0.66219 (16)	0.0303 (8)
H25	0.5000	0.7495	0.6728	0.036*
S22	0.5000	0.35701 (6)	0.61298 (6)	0.0431 (3)
N24	0.2551 (2)	0.67278 (14)	0.65822 (11)	0.0399 (6)
H24A	0.1736	0.6303	0.6671	0.048*
H24B	0.2484	0.7339	0.6816	0.048*
O31	0.2500	0.85123 (19)	0.7500	0.0473 (8)
H31	0.185 (3)	0.8869 (19)	0.7454 (17)	0.071*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N11	0.0321 (12)	0.0278 (10)	0.0279 (12)	0.0016 (9)	−0.0007 (9)	−0.0032 (9)
C12	0.035 (2)	0.0220 (14)	0.027 (2)	0.000	0.000	0.0029 (14)
C14	0.0401 (16)	0.0209 (10)	0.0275 (15)	0.0053 (11)	0.0036 (12)	0.0013 (10)
C15	0.049 (2)	0.0254 (16)	0.025 (2)	0.000	0.000	−0.0071 (15)
S12	0.0371 (6)	0.0480 (5)	0.0291 (6)	0.000	0.000	−0.0111 (5)
N14	0.0440 (14)	0.0443 (12)	0.0377 (14)	0.0095 (11)	0.0076 (11)	−0.0096 (10)
N21	0.0320 (12)	0.0240 (9)	0.0342 (13)	−0.0003 (9)	−0.0013 (9)	−0.0018 (9)
C22	0.036 (2)	0.0257 (15)	0.027 (2)	0.000	0.000	0.0014 (15)
C24	0.0357 (15)	0.0257 (11)	0.0264 (14)	0.0034 (11)	−0.0037 (11)	0.0007 (10)
C25	0.041 (2)	0.0208 (14)	0.030 (2)	0.000	0.000	−0.0045 (14)
S22	0.0373 (6)	0.0224 (4)	0.0697 (8)	0.000	0.000	−0.0064 (4)
N24	0.0323 (13)	0.0303 (10)	0.0570 (16)	0.0054 (9)	0.0008 (10)	−0.0093 (10)
O31	0.0467 (19)	0.0354 (14)	0.060 (2)	0.000	−0.0031 (15)	0.000

Geometric parameters (Å, º)

N11—C12	1.336 (2)	N21—C24	1.356 (3)
N11—C14	1.366 (3)	N21—H21	0.8600
N11—H11	0.8600	C22—N21^ii	1.339 (2)
C12—N11^i	1.336 (2)	C22—S22	1.690 (3)
C12—S12	1.704 (4)	C24—N24	1.337 (3)
C14—N14	1.324 (3)	C24—C25	1.368 (3)
C14—C15	1.366 (3)	C25—C24^ii	1.368 (3)
C15—C14^i	1.366 (3)	C25—H25	0.9300
C15—H15	0.9300	N24—H24A	0.9880
N14—H14A	0.9383	N24—H24B	0.9372
N14—H14B	0.8597	O31—H31	0.79 (3)
N21—C22	1.339 (2)
C12—N11—C14	119.9 (2)	C22—N21—C24	120.3 (2)
C12—N11—H11	120.1	C22—N21—H21	119.9
C14—N11—H11	120.1	C24—N21—H21	119.9
N11^i—C12—N11	121.3 (3)	N21^ii—C22—N21	120.6 (3)
N11^i—C12—S12	119.35 (15)	N21^ii—C22—S22	119.71 (14)
N11—C12—S12	119.36 (15)	N21—C22—S22	119.71 (14)
N14—C14—C15	123.6 (2)	N24—C24—N21	115.9 (2)
N14—C14—N11	116.4 (2)	N24—C24—C25	123.8 (2)
C15—C14—N11	120.0 (3)	N21—C24—C25	120.2 (2)
C14—C15—C14^i	119.0 (3)	C24—C25—C24^ii	118.4 (3)
C14—C15—H15	120.5	C24—C25—H25	120.8
C14^i—C15—H15	120.5	C24^ii—C25—H25	120.8
C14—N14—H14A	124.0	C24—N24—H24A	119.4
C14—N14—H14B	120.5	C24—N24—H24B	117.4
H14A—N14—H14B	113.9	H24A—N24—H24B	110.4
C14—N11—C12—N11^i	0.3 (4)	C24—N21—C22—N21^ii	−0.3 (5)
C14—N11—C12—S12	−178.95 (18)	C24—N21—C22—S22	178.0 (2)
C12—N11—C14—N14	178.5 (2)	C22—N21—C24—N24	177.5 (3)
C12—N11—C14—C15	−0.7 (4)	C22—N21—C24—C25	0.4 (4)
N14—C14—C15—C14^i	−178.09 (18)	N24—C24—C25—C24^ii	−177.32 (17)
N11—C14—C15—C14^i	1.1 (5)	N21—C24—C25—C24^ii	−0.6 (5)

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

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N11—H11···N21	0.86	2.18	2.995 (3)	159
N21—H21···N11	0.86	2.16	2.995 (3)	165
N14—H14A···S22	0.94	2.40	3.310 (2)	162
N24—H24A···S12	0.99	2.39	3.368 (2)	171
N14—H14B···N24^iii	0.86	2.50	3.302 (2)	155
N24—H24B···O31	0.94	2.07	2.994 (3)	168
O31—H31···S12^iv	0.79 (3)	2.70 (3)	3.396 (2)	148 (3)

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