2-Amino-4-chloro-6-[N-methyl-N-(4-methyl­phen­yl)amino]pyrimidine: formation versus fragmentation of hydrogen-bonded chains of edge-fused R₂²(8) rings in 4,6-disubstituted 2-amino­pyrimidines

Mol­ecules of the title compound, C₁₂H₁₃ClN₄, are linked by two independent N-H...N hydrogen bonds into a chain of edge-fused R₂²(8) rings. The significance of this study lies in its attempt to rationalize the patterns of supra­molecular aggregation in the title compound and in a range of analogous 4,6-disubstituted 2-amino­pyrimidines.

S1. Comment

In recent years we have reported the molecular and supramolecular structures of a number of 4,6-disubstituted-2-aminopyrimidines (Low et al., 2002; Bowes et al., 2003; Glidewell et al., 2003; Melguizo et al., 2003; Quesada et al., 2002, 2004), which have proven to exhibit a very wide range of supramolecular aggregation patterns. We report here the structure of the title compound, (I), and we attempt a simple rationalization of some of the structural themes observed in earlier determinations. For the preparation of (I), which is intended for eventual use as an intermediate in the synthesis of a variety of fused heterocyclic derivatives, a solvent-free fusion method was used for the selective monosubstitution by N-methyl-4-toluidine of the 6-chloro substituent in the precursor compound 2-amino-4,6-dichloropyrimidine.

The molecules of (I) are linked into sheets by a combination of two independent N—H···N hydrogen bonds and one C—H···π(pyrimidine) hydrogen bond (Table 1). The amino atom N2 in the molecule at (x, y, z) acts as a hydrogen-bond donor, respectively, to the ring atoms N1 and N3 in the molecules at (-x + 1, y - 1/2, -z + 3/2) and (-x + 1, y +1/2, -z +3/2), so that molecules related by the 2₁ screw axis along (1/2, y, 3/4) are linked into a C(4)C(4)[R₂²(8)] chain of rings (Bernstein et al., 1995) (Fig. 2). In addition, the aryl atoms C63 in the molecules at (x, y, z) and (-x + 1, y + 1/2, -z + 3/2) act as hydrogen-bond donors, respectively, to the pyrimidine rings of the molecules at (-x, -y + 1, -z + 1) and (x + 1, -y + 3/2, z + 1/2), which are themselves components of the chains of rings along (-1/2, -y, 1/4) and (3/2, -y, 5/4), respectively. Hence the C—H···π(pyrimidine) hydrogen bond links the chains of rings parallel to [010] into a sheet parallel to (102).

The formation of edge-fused chains of R₂²(8) as found in compound (I) occurs in a number of other simple 2-aminopyrimidines, but the disruption of such a chain formation appears to be readily accomplished, resulting either from steric factors arising from bulky substituents or from the presence of an alternative hydrogen-bond acceptor which can compete effectively with the pyrimidine ring N atoms. Chains of edge-fused R₂²(8) rings that are topologically identical to that in (I) are found both in the symmetrically disubstituted aminopyrimidines (II) and (III) (Low et al., 2002) and in the unsymmetrically substituted compounds (IV) (Glidewell et al., 2003) and (V) (Melguizo et al., 2003), although the different space groups and Z' values mean that different symmetry operations relate the molecules within the chains.

However, in the structures of the related compounds (VI)–(IX), it is possible to discern only small fragments of a chain of edge-fused rings built from N—H···N hydrogen bonds. Thus, in compound (VI), whose constitution is similar to that of compound (III), the N—H···N hydrogen bonds generate only a centrosymmetric R₂²(8) dimer, i.e. a two-molecule fragment of the chain found in compounds (I)–(V), and only one of the N—H bonds in (VI) is active in hydrogen-bond formation, although the dimers are further linked by a single C—H···π(pyrimidine) interaction (Quesada et al., 2004). Compound (VII) crystallizes with Z' = 2 in P2₁/c, and three independent N—H···N hydrogen bonds form an aggregate containing three edge-fused R₂²(8) rings, i.e. a four-molecule fragment of the chain, with again one of the N—H bonds playing no role in the hydrogen bonding (Bowes et al., 2003). The morpholino analogue of (VII), compound (VIII), crystallizes in two polymorphic forms, both in P2₁/c, with Z' = 1 and 2 (Bowes et al., 2003). In each polymorph, paired N—H···N hydrogen bonds generate a two-component R₂²(8) fragment, and these are linked by N—H···O hydrogen bonds to form sheets of R₂²(8) and R⁶₆(40) rings in the Z' = 1 form, and chains of alternating R₂²(8) and R⁴₄(18) rings in the Z' = 2 form. Hence all of the N—H bonds are active in hydrogen-bond formation here. Entirely analogous behaviour is exhibited by compound (IX), which is closely related to compound (II); paired N—H···N hydrogen bonds form an R₂²(8) dimer, again a two-molecule component of the chain found in (I)–(V), and N—H···O hydrogen bonds link these dimers into a chain of alternating R₂²(8) and R⁴₄(16) rings (Quesada et al., 2002)

The disruption of the chain formation in compounds (VIII) and (IX) can be interpreted straightforwardly in terms of the effective competition by the more electronegative O atoms as hydrogen-bond acceptors, leading to the replacement of some of the N—H···N hydrogen bonds by N—H···O hydrogen bonds. A more subtle question arises from the structural differences between compounds (II) and (IX), where precisely the same sets of potential hydrogen-bond acceptors are present, arranged with the same relative dispositions; the original report on the structure of (IX), where the molecule has no internal symmetry in the crystal (Quesada et al., 2002), emphasized the interplay between the conformations adopted by the benzyl substituents and the hydrogen-bond formation as a significant determinant of the overall crystal structure. The short-fragment formation by compound (VI) is readily understood in terms of steric factors, but a significant anomaly is apparent in the structure of compound (VII), where any steric factors might have been expected to be significantly less than those in compound (V). However, compound (VII) is, in fact, isomorphous and almost isostructural with the Z' = 2 polymorph of compound (VIII) (Bowes et al., 2003), and it is entirely possible that a Z' = 1 polymorph of (VII) having a different overall aggregation pattern could also exist.

Related literature

For related literature, see: Bernstein et al. (1995); Bowes et al. (2003); Glidewell et al. (2003); Low et al. (2002); Melguizo et al. (2003); Quesada et al. (2002, 2004).

S2. Experimental

A mixture of 2-amino-4,6-dichloropyrimidine (1.037 mmol) and N-methyl-4-toluidine (1.815 mmol) was placed in a test tube and heated at 473–483 K in an oil bath for 35 min. The reaction mixture was cooled to ambient temperature, and the resulting solid was washed with an excess of a saturated aqueous solution of sodium hydrogencarbonate. The crude product was collected by filtration, washed successively with water and diethyl ether, and then dried in an oven at 333 K to give the title compound. Crystals suitable for single-crystal X-ray diffraction were obtained by slow evaporation of a solution in dimethylsulfoxide (yield 92%, m.p. 473–475 K). HRMS: found 248.0822; C₁₂H₁₃³⁵ClN₄ requires: 248.0829.

S3. Refinement

The space group P2₁/c was uniquely assigned from the systematic absences. All H atoms were located in difference maps and then treated as riding atoms with C—H distances of 0.95 Å (arene and pyrimidine) or 0.98 Å (CH₃) and N—H distances of 0.88 Å, and with U_iso(H) = kU_eq(carrier), where k = 1.5 for the methyl groups and k = 1.2 for all other H atoms.

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: OSCAIL (McArdle, 2003) and SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and PRPKAPPA (Ferguson, 1999).

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 chain of edge-fused rings parallel to the [010] direction.

2-Amino-4-chloro-6-[N-methyl-N-(4-methylphenyl)amino]pyrimidine

Crystal data

C12H13ClN4	F(000) = 520
Mr = 248.71	Dx = 1.396 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 2720 reflections
a = 9.8184 (5) Å	θ = 3.1–27.5°
b = 7.8683 (7) Å	µ = 0.31 mm^−1
c = 15.5719 (16) Å	T = 120 K
β = 100.309 (7)°	Block, colourless
V = 1183.57 (17) Å^3	0.41 × 0.25 × 0.22 mm
Z = 4

Data collection

Bruker–Nonius KappaCCD diffractometer	2720 independent reflections
Radiation source: Bruker–Nonius FR591 rotating anode	1933 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.058
Detector resolution: 9.091 pixels mm^-1	θmax = 27.5°, θmin = 3.1°
ϕ and ω scans	h = −12→12
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	k = −10→10
Tmin = 0.885, Tmax = 0.936	l = −20→20
29284 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)] = 0.048	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.128	H-atom parameters constrained
S = 1.10	w = 1/[σ^2(Fo^2) + (0.0499P)^2 + 1.245P] where P = (Fo^2 + 2Fc^2)/3
2720 reflections	(Δ/σ)max = 0.001
156 parameters	Δρmax = 0.44 e Å^−3
0 restraints	Δρmin = −0.30 e Å^−3

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

	x	y	z	Uiso*/Ueq
Cl4	0.42043 (6)	0.18477 (7)	0.49308 (4)	0.02783 (18)
N1	0.36047 (19)	0.6356 (2)	0.65346 (12)	0.0211 (4)
N2	0.5017 (2)	0.5031 (3)	0.76763 (13)	0.0317 (5)
N3	0.45815 (19)	0.3576 (2)	0.63768 (12)	0.0228 (4)
N6	0.20445 (19)	0.7550 (2)	0.54132 (12)	0.0223 (4)
C2	0.4385 (2)	0.4998 (3)	0.68330 (15)	0.0222 (5)
C4	0.3943 (2)	0.3631 (3)	0.55480 (15)	0.0209 (5)
C5	0.3121 (2)	0.4897 (3)	0.51529 (14)	0.0198 (5)
C6	0.2934 (2)	0.6275 (3)	0.57035 (14)	0.0194 (5)
C61	0.1298 (2)	0.7584 (3)	0.45309 (14)	0.0209 (5)
C62	−0.0067 (2)	0.7045 (3)	0.43561 (15)	0.0231 (5)
C63	−0.0827 (2)	0.7184 (3)	0.35200 (15)	0.0248 (5)
C64	−0.0251 (2)	0.7869 (3)	0.28407 (15)	0.0248 (5)
C65	0.1137 (2)	0.8356 (3)	0.30266 (16)	0.0267 (5)
C66	0.1908 (2)	0.8221 (3)	0.38572 (16)	0.0260 (5)
C67	0.1798 (3)	0.8975 (3)	0.59714 (15)	0.0266 (5)
C68	−0.1113 (3)	0.8110 (4)	0.19497 (16)	0.0338 (6)
H2A	0.4962	0.5969	0.7976	0.038*
H2B	0.5501	0.4144	0.7899	0.038*
H5	0.2703	0.4859	0.4554	0.024*
H62	−0.0482	0.6580	0.4810	0.028*
H63	−0.1761	0.6804	0.3407	0.030*
H65	0.1562	0.8790	0.2570	0.032*
H66	0.2852	0.8563	0.3968	0.031*
H67A	0.1991	0.8616	0.6584	0.040*
H67B	0.0831	0.9339	0.5816	0.040*
H67C	0.2408	0.9923	0.5887	0.040*
H68A	−0.0666	0.8941	0.1622	0.051*
H68B	−0.2034	0.8523	0.2008	0.051*
H68C	−0.1203	0.7023	0.1638	0.051*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl4	0.0314 (3)	0.0216 (3)	0.0295 (3)	0.0038 (2)	0.0029 (2)	−0.0046 (2)
N1	0.0218 (10)	0.0229 (10)	0.0170 (9)	0.0019 (8)	−0.0005 (8)	0.0003 (8)
N2	0.0401 (12)	0.0266 (11)	0.0233 (11)	0.0077 (9)	−0.0082 (9)	−0.0016 (9)
N3	0.0231 (10)	0.0236 (10)	0.0201 (10)	0.0021 (8)	−0.0002 (8)	0.0019 (8)
N6	0.0258 (10)	0.0193 (9)	0.0196 (10)	0.0054 (8)	−0.0018 (8)	−0.0012 (8)
C2	0.0207 (11)	0.0228 (12)	0.0219 (12)	0.0002 (9)	0.0003 (9)	0.0005 (9)
C4	0.0199 (11)	0.0206 (11)	0.0224 (12)	−0.0024 (9)	0.0049 (9)	−0.0011 (9)
C5	0.0186 (11)	0.0223 (11)	0.0176 (11)	−0.0003 (9)	0.0003 (8)	0.0002 (9)
C6	0.0180 (10)	0.0204 (11)	0.0196 (11)	−0.0013 (9)	0.0028 (9)	0.0015 (9)
C61	0.0246 (11)	0.0165 (11)	0.0198 (11)	0.0033 (9)	−0.0005 (9)	−0.0011 (9)
C62	0.0244 (11)	0.0214 (12)	0.0236 (12)	0.0003 (9)	0.0042 (9)	0.0013 (9)
C63	0.0224 (12)	0.0237 (13)	0.0267 (13)	0.0008 (9)	−0.0002 (10)	−0.0034 (10)
C64	0.0301 (12)	0.0205 (12)	0.0222 (12)	0.0027 (10)	0.0007 (10)	−0.0012 (9)
C65	0.0304 (13)	0.0272 (13)	0.0229 (12)	−0.0019 (10)	0.0053 (10)	0.0023 (10)
C66	0.0239 (12)	0.0246 (12)	0.0286 (13)	−0.0019 (10)	0.0023 (10)	0.0008 (10)
C67	0.0288 (13)	0.0239 (12)	0.0257 (13)	0.0055 (10)	0.0010 (10)	−0.0032 (10)
C68	0.0396 (15)	0.0342 (14)	0.0237 (13)	0.0010 (12)	−0.0049 (11)	0.0024 (11)

Geometric parameters (Å, º)

Cl4—C4	1.745 (2)	C62—C63	1.384 (3)
N1—C6	1.345 (3)	C62—H62	0.95
N1—C2	1.348 (3)	C63—C64	1.394 (3)
N2—C2	1.348 (3)	C63—H63	0.95
N2—H2A	0.88	C64—C65	1.395 (3)
N2—H2B	0.88	C64—C68	1.503 (3)
N3—C4	1.331 (3)	C65—C66	1.381 (3)
N3—C2	1.358 (3)	C65—H65	0.95
N6—C6	1.353 (3)	C66—H66	0.95
N6—C61	1.437 (3)	C67—H67A	0.98
N6—C67	1.465 (3)	C67—H67B	0.98
C4—C5	1.358 (3)	C67—H67C	0.98
C5—C6	1.415 (3)	C68—H68A	0.98
C5—H5	0.95	C68—H68B	0.98
C61—C62	1.386 (3)	C68—H68C	0.98
C61—C66	1.391 (3)
C6—N1—C2	116.4 (2)	C61—C62—H62	120.0
C2—N2—H2A	118.1	C62—C63—C64	121.4 (2)
C2—N2—H2B	119.4	C62—C63—H63	119.3
H2A—N2—H2B	122.4	C64—C63—H63	119.3
C4—N3—C2	113.24 (19)	C63—C64—C65	117.6 (2)
C6—N6—C61	121.43 (19)	C63—C64—C68	120.7 (2)
C6—N6—C67	122.28 (19)	C65—C64—C68	121.7 (2)
C61—N6—C67	116.29 (18)	C66—C65—C64	121.7 (2)
N1—C2—N2	117.0 (2)	C66—C65—H65	119.2
N1—C2—N3	126.7 (2)	C64—C65—H65	119.2
N2—C2—N3	116.2 (2)	C65—C66—C61	119.7 (2)
N3—C4—C5	127.0 (2)	C65—C66—H66	120.1
N3—C4—Cl4	114.71 (17)	C61—C66—H66	120.1
C5—C4—Cl4	118.30 (18)	N6—C67—H67A	109.5
C4—C5—C6	114.8 (2)	N6—C67—H67B	109.5
C4—C5—H5	122.6	H67A—C67—H67B	109.5
C6—C5—H5	122.6	N6—C67—H67C	109.5
N1—C6—N6	117.5 (2)	H67A—C67—H67C	109.5
N1—C6—C5	121.7 (2)	H67B—C67—H67C	109.5
N6—C6—C5	120.8 (2)	C64—C68—H68A	109.5
C62—C61—C66	119.6 (2)	C64—C68—H68B	109.5
C62—C61—N6	119.5 (2)	H68A—C68—H68B	109.5
C66—C61—N6	120.9 (2)	C64—C68—H68C	109.5
C63—C62—C61	120.0 (2)	H68A—C68—H68C	109.5
C63—C62—H62	120.0	H68B—C68—H68C	109.5
C6—N1—C2—N2	−177.3 (2)	C4—C5—C6—N6	−174.2 (2)
C6—N1—C2—N3	1.2 (3)	C6—N6—C61—C62	99.8 (3)
C4—N3—C2—N1	2.1 (3)	C67—N6—C61—C62	−80.9 (3)
C4—N3—C2—N2	−179.4 (2)	C6—N6—C61—C66	−83.1 (3)
C2—N3—C4—C5	−2.3 (3)	C67—N6—C61—C66	96.2 (3)
C2—N3—C4—Cl4	178.48 (16)	C66—C61—C62—C63	−1.7 (3)
N3—C4—C5—C6	−0.7 (3)	N6—C61—C62—C63	175.4 (2)
Cl4—C4—C5—C6	178.46 (16)	C61—C62—C63—C64	−0.4 (3)
C2—N1—C6—N6	174.1 (2)	C62—C63—C64—C65	2.2 (3)
C2—N1—C6—C5	−4.6 (3)	C62—C63—C64—C68	−176.2 (2)
C61—N6—C6—N1	179.02 (19)	C63—C64—C65—C66	−2.1 (4)
C67—N6—C6—N1	−0.3 (3)	C68—C64—C65—C66	176.3 (2)
C61—N6—C6—C5	−2.3 (3)	C64—C65—C66—C61	0.1 (4)
C67—N6—C6—C5	178.4 (2)	C62—C61—C66—C65	1.8 (4)
C4—C5—C6—N1	4.4 (3)	N6—C61—C66—C65	−175.3 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2A···N3^i	0.88	2.29	3.147 (3)	163
N2—H2B···N1^ii	0.88	2.47	3.333 (3)	168
C63—H63···Cg^iii	0.95	2.68	3.517 (2)	147

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