4,6-Diamino-2-morpholino-5-nitro­so­pyrimidine: a polarized mol­ecular structure within hydrogen-bonded sheets

In the title compound, C₈H₁₂N₆O₂, the mol­ecular dimensions provide evidence for significant polarization of the electronic structure. There is an intra­molecular N—H...N hydrogen bond, and the mol­ecules are linked into complex sheets by a combination of two-centre hydrogen bonds, one each of the N—H...N and N—H...O types, and a three-centre N—H...(N,O) hydrogen bond.

S1. Comment

As part of a study of synthetic routes to 2-substituted 6-amino-5-nitrosopyrimidines for use as intermediates for the introduction of a wide variety of substituents at the 2- position in fused pyrimidine derivatives, we have recently reported the use of the methoxy group (Melguizo et al., 2002) and the methylsulfanyl group (Orozco et al., 2008) as leaving groups at position 2 in order to introduce a variety of amino groups into pyrimidin-4(3H)-one systems. We have already incorporated a morpholino moiety at C2 by reaction of 6-amino-2-methylsulfanyl-5-nitrosopyrimidine with morpholine (Orozco et al., 2008); and accordingly we have used similar conditions in order to prepare 4,6-diamino-2-morpholino-5-nitrosopyrimidine from 4,6-diamino-2-methylsulfanyl-5-nitrosopyrimidine. Thus, we compare here the molecular and supramolecular structure of the symmetrically substituted 4,6-diamino-2-morpholino-5-nitrosopyrimidine, (I) (Fig. 1), with the symmetrically substituted 2-amino-4,6-dimorpholino-5-nitrosopyrimidine, (II) (see the scheme), whose structural properties were reported several years ago as part of a wider study of 4,6-disubstituted 2-aminopyrimidines and 2-amino-5-nitrosopyrimidines (Quesada et al., 2002, 2004).

The morpholino ring in compound (I) adopts a chair conformation with the bond N21—C2 (Fig. 1) occupying an equatorial site. Despite the presence of four substituents on the pyrimidine ring, three of them at adjacent sites, the pyrimidine ring is effectively planar: the maximum deviation of any ring atom from the mean plane of the ring atoms is that of atom N3, 0.012 (3) Å. This planarity may be contrasted with the boat conformation adopted by the pyrimidine ring in compound (II), where the ring atoms C2 and C5 represent the stem and stern of the boat, such that the amino and nitroso substituents are markedly displaced to one side of the ring, while the two morpholino substituents are displaced to the opposite side (Quesada et al., 2004).

Within the molecule of (I), the bond distances (Table 1) provide evidence for considerable polarization of the electronic structure, which resembles that in (II) despite the different substituents on the pyrimidine rings in (I) and (II). Thus, for example, the C—N distances in (I) for the atom sequence N21—C2—N1—C6—N6 all lie within a fairly narrow range; however, the shortest distance in this sequence is found for the formal single bond C6—N6, while the longest distance corresponds to the formally aromatic bond C2—N1. In addition, the similarity between the distances C4—N3 (formally an aromatic bond) and C4—N4 (formally a single bond) is striking. The distances C5—N5 and N5—O5 in the nitroso group are rather similar, differing by less than 0.06 Å, whereas in simple unperturbed C-nitroso compounds, where no polarization of the structure can occur, the N—O distance is generally less than 1.25 Å (Davis et al., 1965; Bauer & Andreassen, 1972; Talberg, 1977; Schlemper et al., 1986), while the difference between the C—N and N—O distances is usually greater than 0.20 Å (Talberg, 1977; Schlemper et al., 1986). In summary, these observations point to the occurrence of significant contributions to the overall electronic structure from the polarized forms (Ia) and (Ib), as well as from the classical aromatic form (I) (see the scheme).

The molecules of compound (I) contain an intramolecular N—H···O hydrogen bond (Table 2), forming an S(6) motif (Bernstein et al., 1995), and this feature in substituted 5-nitroso-6-aminopyrimidines lends the molecules an overall shape similar to that in substituted purines (Quesada et al., 2002; Melguizo et al., 2003) which, in turn, may underlie the biological activity of this type of substituted pyrimidine (Chae et al., 1995). The molecules are linked into sheets of considerable complexity by a combination of two independent two-centre hydrogen bonds and one three-centre N—H···(N,O) hydrogen bond which is asymmetric but planar (Table 2). Because of the polarization of the electronic structure in (I), it is likely that all of the hydrogen bonds apart from the one having a morpholino O atom as the acceptor can be regarded as charge-assisted hydrogen bonds (Gilli et al., 1994); it is thus surprising that the shorter component of the three-centre hydrogen bond involves the N atom of the nitroso substituent as the acceptor rather than the O atom. The asymmetry of this three-centre system may, in fact, be largely a consequence of the overall intermolecular packing rather than of any local intermolecular energies.

The formation of the hydrogen-bonded sheet in compound (I) is readily analysed in terms of the centrosymmetric R²₂(8) dimer unit generated by the N—H···N hydrogen bond, with the reference dimer unit centred at (0, 1/2, 1/2) (Fig. 2). The action of the two-centre N—H···O hydrogen bond is to link this reference dimer directly to four further such dimer units, those centred at (-1, 0, 0), (-1, 1, 0), (1, 0, 1) and (1, 1, 1), respectively, while the action of the three-centre hydrogen bond links the reference dimer centred at (0, 1/2, 1/2) directly to the dimer units centred at (2, 1/2, 1.5) and (-2, 1/2, -0.5) (Fig. 2).

The combination of all these hydrogen bonds, when propagated by the space-group symmetry operations, generates a hydrogen-bonded sheet parallel to (102) in which rings of S(6), R²₁(3), R²₂(8), R²₂(10) and R⁴₅(22) types can be identified (Fig. 2). The only direction-specific interaction between adjacent sheets is a C—H···N contact involving a C—H bond of low acidity, arising from the morpholino substituent, which is expected to be only very weakly attractive and thus probably of only marginal structural significance.

By contrast with the sheet formation in compound (I), where both N and O atoms are utilized as hydrogen-bond acceptors, in compound (II) there are only two intermolecular hydrogen bonds, both of N—H···O type with each involving an O atom from a different morpholino substituent as the hydrogen-bond acceptor. These two hydrogen bonds generate a very simple and elegant sheet in the form of a (4,4) net (Batten & Robson, 1998) built from a single type of R⁴₄(32) ring (Quesada et al., 2004).

Related literature

For related literature, see: Batten & Robson (1998); Bauer & Andreassen (1972); Bernstein et al. (1995); Chae et al. (1995); Davis et al. (1965); Gilli et al. (1994); Melguizo et al. (2002, 2003); Orozco et al. (2008); Quesada et al. (2002, 2004); Schlemper et al. (1986); Talberg (1977).

S2. Experimental

Morpholine (100 mmol) was added dropwise with magnetic stirring to a hot suspension of 4,6-diamino-2-methylsulfanyl-5-nitrosopyrimidine (10 mmol) in methanol (40 cm³) during[for] 9 h. The reaction proceeded with a change of colour from blue to violet and liberation of methanethiol. The reaction mixture was cooled to ambient temperature and the solvent was then removed under reduced pressure; the resulting solid product was washed with water and then crystallized from dimethylsulfoxide to give red–violet crystals suitable for single-crystal X-ray diffraction. Yield 98%, m.p. 512–513 K (decomp); MS (EI) m/z 224 [M⁺], 207, 139, 137.

S3. Refinement

All H atoms were located in difference maps, and then treated as riding atoms in geometrically idealized positions, with distances C—H 0.99 Å and N—H 0.88 Å, and with U_iso(H) = 1.2U_eq(carrier).

Computing details

Data collection: COLLECT (Hooft, 1999); cell refinement: DIRAX/LSQ (Duisenberg et al., 2000); data reduction: EVALCCD (Duisenberg et al., 2003); program(s) used to solve structure: SIR2004 (Burla et al., 2005); 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 molecular structure of compound (I) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 2. A stereoview of part of the crystal structure of compound (I) showing the formation of a hydrogen-bonded sheet parallel to (102) built from four types of hydrogen bond and containing five types of ring. For the sake of clarity, the H atoms bonded to C atoms have been omitted.

4,6-Diamino-2-morpholino-5-nitrosopyrimidine

Crystal data

C8H12N6O2	F(000) = 472
Mr = 224.24	Dx = 1.545 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 1902 reflections
a = 6.3340 (7) Å	θ = 3.4–26.1°
b = 19.247 (3) Å	µ = 0.12 mm^−1
c = 8.4472 (12) Å	T = 120 K
β = 110.562 (13)°	Block, red-violet
V = 964.2 (2) Å^3	0.47 × 0.26 × 0.24 mm
Z = 4

Data collection

Bruker–Nonius KappaCCD diffractometer	1902 independent reflections
Radiation source: Bruker–Nonius FR591 rotating anode	1151 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.077
Detector resolution: 9.091 pixels mm^-1	θmax = 26.1°, θmin = 3.4°
ϕ and ω scans	h = −7→7
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	k = −23→23
Tmin = 0.955, Tmax = 0.973	l = −10→10
13807 measured reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.059	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.174	H-atom parameters constrained
S = 1.12	w = 1/[σ^2(Fo^2) + (0.0762P)^2 + 0.7491P] where P = (Fo^2 + 2Fc^2)/3
1902 reflections	(Δ/σ)max = 0.001
145 parameters	Δρmax = 0.44 e Å^−3
0 restraints	Δρmin = −0.34 e Å^−3

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

	x	y	z	Uiso*/Ueq
N1	0.2606 (4)	0.56455 (12)	0.5428 (3)	0.0240 (6)
C2	0.4025 (5)	0.61254 (15)	0.5196 (4)	0.0224 (7)
N3	0.6260 (4)	0.61796 (13)	0.6027 (3)	0.0246 (6)
C4	0.7193 (5)	0.57345 (15)	0.7261 (4)	0.0235 (7)
C5	0.5896 (5)	0.52000 (15)	0.7663 (3)	0.0210 (7)
C6	0.3531 (5)	0.51857 (15)	0.6657 (4)	0.0232 (7)
N4	0.9360 (4)	0.58099 (13)	0.8138 (3)	0.0281 (6)
H4A	1.0126	0.6148	0.7890	0.034*
H4B	1.0039	0.5522	0.8971	0.034*
N5	0.6995 (4)	0.47617 (13)	0.8906 (3)	0.0267 (6)
O5	0.5911 (3)	0.42688 (11)	0.9292 (3)	0.0323 (6)
N6	0.2250 (4)	0.47077 (13)	0.6953 (3)	0.0273 (6)
H6A	0.0803	0.4693	0.6346	0.033*
H6B	0.2836	0.4401	0.7761	0.033*
N21	0.3119 (4)	0.66174 (13)	0.4029 (3)	0.0262 (6)
C22	0.4502 (5)	0.70794 (16)	0.3446 (4)	0.0289 (7)
H22A	0.4455	0.6930	0.2312	0.035*
H22B	0.6086	0.7054	0.4228	0.035*
C23	0.3685 (5)	0.78086 (16)	0.3357 (4)	0.0298 (8)
H23A	0.3895	0.7975	0.4511	0.036*
H23B	0.4589	0.8109	0.2887	0.036*
O24	0.1358 (3)	0.78600 (11)	0.2323 (3)	0.0293 (6)
C25	0.0053 (5)	0.74386 (17)	0.3003 (4)	0.0305 (8)
H25A	−0.1558	0.7483	0.2287	0.037*
H25B	0.0228	0.7609	0.4148	0.037*
C26	0.0712 (5)	0.66843 (16)	0.3111 (4)	0.0297 (8)
H26A	−0.0134	0.6420	0.3700	0.036*
H26B	0.0333	0.6490	0.1959	0.036*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0253 (13)	0.0208 (14)	0.0229 (13)	−0.0001 (11)	0.0048 (10)	0.0007 (11)
C2	0.0251 (15)	0.0202 (16)	0.0201 (14)	0.0006 (12)	0.0058 (12)	−0.0026 (12)
N3	0.0236 (13)	0.0251 (14)	0.0232 (13)	0.0005 (11)	0.0061 (10)	0.0009 (11)
C4	0.0257 (16)	0.0222 (17)	0.0223 (15)	0.0030 (12)	0.0080 (13)	−0.0009 (13)
C5	0.0246 (15)	0.0174 (15)	0.0197 (15)	0.0033 (12)	0.0064 (12)	0.0004 (12)
C6	0.0267 (15)	0.0182 (16)	0.0235 (15)	0.0011 (12)	0.0073 (12)	−0.0021 (13)
N4	0.0208 (13)	0.0258 (15)	0.0330 (15)	−0.0001 (10)	0.0036 (11)	0.0056 (12)
N5	0.0287 (14)	0.0218 (14)	0.0280 (14)	−0.0008 (11)	0.0079 (11)	0.0020 (11)
O5	0.0332 (12)	0.0262 (12)	0.0331 (13)	−0.0028 (10)	0.0061 (10)	0.0075 (10)
N6	0.0254 (13)	0.0255 (15)	0.0266 (14)	0.0010 (11)	0.0036 (11)	0.0050 (11)
N21	0.0217 (13)	0.0242 (14)	0.0290 (14)	−0.0020 (10)	0.0042 (11)	0.0051 (11)
C22	0.0281 (17)	0.0316 (19)	0.0250 (16)	−0.0009 (13)	0.0067 (13)	0.0039 (14)
C23	0.0301 (17)	0.0305 (19)	0.0266 (16)	−0.0035 (14)	0.0073 (13)	0.0031 (14)
O24	0.0284 (12)	0.0274 (12)	0.0312 (12)	0.0010 (9)	0.0094 (10)	0.0055 (10)
C25	0.0276 (16)	0.0321 (19)	0.0276 (17)	−0.0012 (14)	0.0043 (14)	0.0061 (14)
C26	0.0247 (16)	0.0294 (18)	0.0285 (17)	−0.0011 (13)	0.0012 (13)	0.0064 (14)

Geometric parameters (Å, º)

N1—C2	1.350 (4)	N21—C22	1.450 (4)
C2—N3	1.345 (3)	N21—C26	1.453 (4)
N3—C4	1.318 (4)	C22—C23	1.488 (4)
C4—C5	1.430 (4)	C22—H22A	0.9900
C5—C6	1.439 (4)	C22—H22B	0.9900
C6—N1	1.333 (4)	C23—O24	1.429 (3)
C2—N21	1.342 (4)	C23—H23A	0.9900
C4—N4	1.319 (4)	C23—H23B	0.9900
C5—N5	1.336 (4)	O24—C25	1.416 (4)
N5—O5	1.278 (3)	C25—C26	1.505 (4)
C6—N6	1.308 (4)	C25—H25A	0.9900
N4—H4A	0.8800	C25—H25B	0.9900
N4—H4B	0.8800	C26—H26A	0.9900
N6—H6A	0.8800	C26—H26B	0.9900
N6—H6B	0.8800
C6—N1—C2	115.7 (2)	N21—C22—H22A	109.5
N21—C2—N3	115.4 (3)	C23—C22—H22A	109.5
N21—C2—N1	117.1 (2)	N21—C22—H22B	109.5
N3—C2—N1	127.5 (3)	C23—C22—H22B	109.5
C4—N3—C2	117.4 (3)	H22A—C22—H22B	108.1
N3—C4—N4	117.5 (3)	O24—C23—C22	111.2 (2)
N3—C4—C5	121.3 (3)	O24—C23—H23A	109.4
N4—C4—C5	121.2 (3)	C22—C23—H23A	109.4
N5—C5—C4	117.1 (3)	O24—C23—H23B	109.4
N5—C5—C6	126.8 (3)	C22—C23—H23B	109.4
C4—C5—C6	116.1 (3)	H23A—C23—H23B	108.0
N6—C6—N1	118.9 (3)	C25—O24—C23	109.7 (2)
N6—C6—C5	119.2 (3)	O24—C25—C26	112.9 (3)
N1—C6—C5	121.9 (3)	O24—C25—H25A	109.0
C4—N4—H4A	120.0	C26—C25—H25A	109.0
C4—N4—H4B	120.0	O24—C25—H25B	109.0
H4A—N4—H4B	120.0	C26—C25—H25B	109.0
O5—N5—C5	119.4 (2)	H25A—C25—H25B	107.8
C6—N6—H6A	120.0	N21—C26—C25	109.6 (2)
C6—N6—H6B	120.0	N21—C26—H26A	109.8
H6A—N6—H6B	120.0	C25—C26—H26A	109.8
C2—N21—C22	121.9 (2)	N21—C26—H26B	109.8
C2—N21—C26	123.5 (2)	C25—C26—H26B	109.8
C22—N21—C26	114.2 (2)	H26A—C26—H26B	108.2
N21—C22—C23	110.8 (3)
C6—N1—C2—N21	−176.5 (3)	C4—C5—C6—N1	−0.2 (4)
C6—N1—C2—N3	2.1 (4)	C4—C5—N5—O5	−178.9 (2)
N21—C2—N3—C4	175.6 (3)	C6—C5—N5—O5	0.0 (4)
N1—C2—N3—C4	−3.0 (4)	N3—C2—N21—C22	12.9 (4)
C2—N3—C4—N4	−176.4 (3)	N1—C2—N21—C22	−168.3 (3)
C2—N3—C4—C5	2.1 (4)	N3—C2—N21—C26	−174.2 (3)
N3—C4—C5—N5	178.4 (3)	N1—C2—N21—C26	4.5 (4)
N4—C4—C5—N5	−3.2 (4)	C2—N21—C22—C23	−135.5 (3)
N3—C4—C5—C6	−0.7 (4)	C26—N21—C22—C23	51.0 (3)
N4—C4—C5—C6	177.8 (3)	N21—C22—C23—O24	−55.4 (3)
C2—N1—C6—N6	179.8 (3)	C22—C23—O24—C25	59.9 (3)
C2—N1—C6—C5	−0.4 (4)	C23—O24—C25—C26	−59.6 (3)
N5—C5—C6—N6	0.7 (4)	C2—N21—C26—C25	137.4 (3)
C4—C5—C6—N6	179.7 (3)	C22—N21—C26—C25	−49.2 (3)
N5—C5—C6—N1	−179.2 (3)	O24—C25—C26—N21	53.6 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N4—H4A···O24^i	0.88	2.18	3.040 (3)	166
N4—H4B···O5^ii	0.88	2.50	3.023 (3)	119
N4—H4B···N5^ii	0.88	2.16	2.954 (4)	149
N6—H6A···N1^iii	0.88	2.25	3.102 (4)	163
N6—H6B···O5	0.88	1.94	2.603 (3)	131
C23—H23B···N3^iv	0.99	2.58	3.547 (4)	167

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