2,4-Diamino-5-(1-naphthyl)-3,5-diaza-1-azoniaspiro[5.5]undeca-1,3-diene chloride

The title salt, C₁₈H₂₂N₅⁺·Cl⁻, is a member of a new series of lipophilic 4,6-di­amino spiro-s-triazines which are potent in­hib­itors of di­hydro­folate reductase. The protonated triazine ring deviates from planarity, whereas the cyclo­hexane ring adopts a chair conformation. A rather unusual hydrogen-bonding scheme exists in the crystal. There is a centrosymmetric arrangement involving two amino groups and two triazine ring N atoms, with graph-set R(8) and an N...N distance of 3.098 (3) Å, flanked by two additional R(8) systems, involving two amino groups, a triazine ring N atom and a Cl⁻ anion, with N...Cl distances in the range 3.179 (2)–3.278 (2) Å. Furthermore, the Cl⁻ anion, the protonated triazine ring N atom and an amino group form a hydrogen-bonding system with graph-set R(6).

S1. Comment

Dihydrofolate reductase (DHFR; EC 1.5.1.3 Please clarify this reference) is an enzyme which catalyzes the reduction of dihydrofolate to tetrahydrofolate using NADPH as coenzyme. It is of primary importance in biochemistry and medicinal chemistry, since tetrahydrofolate is a required cofactor in a number of biosynthetic processes involved in the synthesis of purines, pyrimidines and some amino acids (Blakley, 1995). An enormous number of molecules used for the selective inhibition of DHFR have been synthesized and used as antitumour (e.g. methotrexate) and antimicrobial (e.g. trimethoprim) drugs. s-Triazines are frequently tested in the area of non-classical antifolates, since it has been found that this class of compounds interferes with folic acid metabolism and has shown promise in cancer chemotherapy (Modest et al., 1952). Following Baker's extensive reports (Baker & Ashton, 1970, 1973), several 2,2-disubstituted s-triazines have been studied (Marlowe et al., 1995). However, for 2,2-spiro analogues of s-triazines, there is a complete lack of structure-activity studies in the literature to date. Therefore, two new series of lipophilic 4,6-diamino spiro s-triazines, bearing a tricyclic (general type I) or cyclic (general type II) substituent at position 2 of the triazines, have been synthesized and are currently being tested as possible DHFR inhibitors. The detailed and accurate geometries of these compounds are needed for modelling and crystallographic studies of enzyme(DHFR)-inhibitor complexes. The size of the attached cycloalkyl chain, as well as the volume and lipophilicity of the altered monocyclic spiro ring, seem to be good parameters to vary for a systematic study of the effectiveness of these compounds. The title hydrochloride salt, (III), belongs to general type II. \sch

In the crystal structure of (III), hydrochloric acid acts as a donor of an H atom, which protonates atom N4 at position 3 of the triazine ring. Protonation at this position is verified by difference Fourier maps. The cyclohexane ring attached to position 2 of the protonated triazine ring distorts the planarity of the latter, with maximum deviations of 0.24 Å for atom N4 and -0.26 Å for atom C5. The r.m.s. deviation from planarity of the atoms of the triazine ring is 0.17 Å, while the r.m.s. deviation from planarity of the naphthalene ring atoms is 0.02 Å. The cyclohexane ring adopts a chair conformation, and the plane of the naphthalene ring is almost perpendicular to that of the triazine ring.

A rather unusual hydrogen-bonding scheme exists in the crystal of (III) (Table 2, Fig. 2). Pairs of molecules related by a centre of symmetry are joined by two hydrogen bonds (Fig. 2, dashed lines), each formed by a donor amino group (N1) and an acceptor triazine ring N atom (N2). Thus, a central ring of eight atoms is formed. This ring is flanked by two additional eight-atom rings, each formed by two amino groups, one from each molecule (N1 and N3), the triazine ring atom N2 and the Cl^- anion, Cl1 (Fig. 2). The whole hydrogen-bonding pattern has a centre of symmetry, and can be described by graph-set analysis (Etter et al., 1990) as R₂²(8) and R₃²(8) for the inner and outer rings, respectively. Two other hydrogen bonds, involving the Cl^- anion Cl1 and atoms N4 and N3, which act as hydrogen-bond donors, create a ring of six atoms and can be described as graph set R₂¹(6).

S2. Experimental

A mixture of 1-(1-naphthyl)biguanide hydrochloride (2.64 g, 10 mmol), concentrated HCl (0.5 ml, 5 mmol), cyclohexanone (1.86 g, 20 mmol) and absolute ethanol (20 ml) was refluxed with stirring for about 10 h. The white crystalline precipitate was filtered and washed with ethanol (5 ml) (m.p. 508–509 K, yield 32%). Single crystals of (III) were obtained by slow evaporation of a water-methanol (Ratio?) solution.

S3. Refinement

The H atoms were treated as riding atoms, with C—H distances in the range 0.93–0.97 Å and N—H distances of 0.86 Å Is this added text OK?, and their isotropic displacement parameters were allowed to refine freely.

Computing details

Data collection: Please provide missing information; cell refinement: Please provide missing information; data reduction: Please provide missing information; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: Please provide missing information; software used to prepare material for publication: Please provide missing information.

Figures

	Fig. 1. A view of the molecule of (III). Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii.
	Fig. 2. A view of the hydrogen-bonding scheme in the crystal of (III) [symmetry code: (i) Please provide missing information].

2,4-Diamino-5-(1-naphthyl)-3,5-diaza-1-azoniaspiro[5.5]undeca-1,3-diene chloride

Crystal data

C18H22N5^+·Cl^−	F(000) = 1456
Mr = 343.86	Dx = 1.296 Mg m^−3
Monoclinic, I2/a	Melting point: 402 K
Hall symbol: -I 2ya	Cu Kα radiation, λ = 1.54180 Å
a = 24.862 (4) Å	Cell parameters from 16 reflections
b = 7.3778 (14) Å	θ = 11–20°
c = 19.633 (4) Å	µ = 1.98 mm^−1
β = 101.823 (6)°	T = 293 K
V = 3524.8 (11) Å^3	Prism, colourless
Z = 8	0.50 × 0.30 × 0.25 mm

Data collection

Syntex P21 diffractometer	2518 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.015
Graphite monochromator	θmax = 65.1°, θmin = 3.6°
θ/2θ scans	h = −29→28
Absorption correction: ψ scan (North et al., 1968)	k = 0→8
Tmin = 0.405, Tmax = 0.615	l = 0→23
3095 measured reflections	3 standard reflections every 97 reflections
2996 independent reflections	intensity decay: none

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)] = 0.052	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.155	H-atom parameters constrained
S = 1.03	w = 1/[σ^2(Fo^2) + (0.0784P)^2 + 5.797P] where P = (Fo^2 + 2Fc^2)/3
2996 reflections	(Δ/σ)max = 0.009
239 parameters	Δρmax = 0.55 e Å^−3
82 restraints	Δρmin = −0.32 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
C1	0.56136 (10)	0.2232 (4)	0.00190 (12)	0.0355 (6)
N1	0.55678 (10)	0.1314 (3)	0.05788 (11)	0.0447 (6)
H1A	0.5771	0.1588	0.0975	0.068 (11)*
H1B	0.5335	0.0441	0.0548	0.044 (8)*
N2	0.52821 (9)	0.1751 (3)	−0.05896 (10)	0.0360 (5)
C3	0.54354 (10)	0.2333 (3)	−0.11681 (13)	0.0343 (5)
N3	0.51588 (10)	0.1807 (3)	−0.17842 (11)	0.0462 (6)
H3A	0.4881	0.1094	−0.1813	0.056 (10)*
H3B	0.5256	0.2178	−0.2156	0.053 (9)*
N4	0.58752 (9)	0.3416 (3)	−0.11374 (10)	0.0369 (5)
H4	0.6074	0.3359	−0.1447	0.15 (2)*
C5	0.60021 (10)	0.4690 (4)	−0.05602 (12)	0.0362 (6)
N6	0.59798 (9)	0.3601 (3)	0.00714 (10)	0.0392 (5)
C7	0.62873 (11)	0.4215 (4)	0.07370 (14)	0.0436 (6)
C8	0.60993 (14)	0.5612 (4)	0.10914 (15)	0.0529 (7)
H8	0.5750	0.6079	0.0920	0.063 (10)*
C9	0.64139 (15)	0.6354 (5)	0.17002 (17)	0.0673 (9)
H9	0.6280	0.7304	0.1929	0.090 (14)*
C10	0.69313 (16)	0.5629 (5)	0.19520 (18)	0.0722 (10)
H10	0.7147	0.6111	0.2355	0.065 (10)*
C11	0.71399 (11)	0.4176 (4)	0.16133 (14)	0.0510 (7)
C12	0.68026 (12)	0.3433 (4)	0.10014 (14)	0.0505 (7)
C13	0.70035 (13)	0.1917 (4)	0.06703 (16)	0.0550 (8)
H13	0.6795	0.1390	0.0272	0.057 (10)*
C14	0.75161 (14)	0.1279 (6)	0.0966 (2)	0.0736 (10)
H14	0.7651	0.0288	0.0761	0.104 (17)*
C15	0.78433 (16)	0.2021 (7)	0.1551 (2)	0.0875 (13)
H15	0.8190	0.1546	0.1728	0.14 (2)*
C16	0.76559 (14)	0.3438 (6)	0.1865 (2)	0.0767 (11)
H16	0.7877	0.3936	0.2260	0.23 (4)*
C17	0.65773 (11)	0.5475 (4)	−0.05267 (14)	0.0424 (6)
H17A	0.6685	0.6176	−0.0103	0.059 (10)*
H17B	0.6838	0.4491	−0.0512	0.041 (8)*
C18	0.65981 (12)	0.6686 (4)	−0.11528 (16)	0.0500 (7)
H18A	0.6959	0.7238	−0.1092	0.051 (8)*
H18B	0.6542	0.5949	−0.1571	0.065 (10)*
C19	0.61629 (15)	0.8168 (4)	−0.12421 (19)	0.0599 (8)
H19A	0.6169	0.8847	−0.1663	0.073 (11)*
H19B	0.6245	0.8998	−0.0852	0.065 (11)*
C20	0.55942 (13)	0.7361 (4)	−0.12847 (17)	0.0533 (7)
H20A	0.5326	0.8330	−0.1321	0.065 (10)*
H20B	0.5499	0.6618	−0.1700	0.059 (10)*
C21	0.55736 (12)	0.6215 (4)	−0.06496 (15)	0.0439 (6)
H21A	0.5210	0.5693	−0.0696	0.055 (9)*
H21B	0.5642	0.6978	−0.0238	0.058 (9)*
Cl1	0.58605 (3)	0.39422 (11)	−0.27703 (3)	0.0488 (2)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0384 (13)	0.0408 (14)	0.0286 (12)	−0.0008 (11)	0.0094 (10)	−0.0001 (10)
N1	0.0499 (13)	0.0569 (14)	0.0269 (11)	−0.0140 (11)	0.0073 (9)	0.0037 (10)
N2	0.0401 (11)	0.0399 (12)	0.0275 (10)	−0.0054 (9)	0.0061 (8)	−0.0001 (9)
C3	0.0399 (13)	0.0327 (12)	0.0295 (12)	−0.0007 (10)	0.0053 (10)	0.0005 (10)
N3	0.0583 (14)	0.0513 (14)	0.0274 (11)	−0.0160 (12)	0.0053 (10)	0.0021 (10)
N4	0.0433 (12)	0.0407 (12)	0.0281 (10)	−0.0059 (10)	0.0107 (9)	−0.0025 (9)
C5	0.0412 (13)	0.0400 (14)	0.0275 (12)	−0.0070 (11)	0.0069 (10)	−0.0014 (10)
N6	0.0433 (12)	0.0471 (13)	0.0263 (10)	−0.0109 (10)	0.0054 (9)	0.0002 (9)
C7	0.0449 (14)	0.0502 (16)	0.0350 (13)	−0.0029 (12)	0.0063 (11)	−0.0005 (12)
C8	0.0652 (19)	0.0539 (17)	0.0418 (15)	0.0043 (15)	0.0161 (13)	−0.0074 (13)
C9	0.084 (2)	0.070 (2)	0.0453 (17)	−0.0040 (19)	0.0093 (16)	−0.0110 (16)
C10	0.084 (2)	0.082 (2)	0.0457 (18)	−0.020 (2)	0.0011 (17)	−0.0031 (17)
C11	0.0443 (15)	0.069 (2)	0.0369 (14)	−0.0139 (14)	0.0016 (12)	0.0106 (13)
C12	0.0445 (15)	0.0653 (19)	0.0421 (15)	−0.0043 (14)	0.0093 (12)	0.0155 (14)
C13	0.0553 (17)	0.0624 (19)	0.0508 (17)	0.0167 (15)	0.0188 (14)	0.0122 (15)
C14	0.062 (2)	0.093 (3)	0.070 (2)	0.0258 (19)	0.0233 (17)	0.031 (2)
C15	0.054 (2)	0.129 (4)	0.080 (3)	0.011 (2)	0.0142 (18)	0.050 (3)
C16	0.0477 (18)	0.113 (3)	0.068 (2)	−0.0075 (19)	0.0080 (16)	0.035 (2)
C17	0.0403 (14)	0.0472 (15)	0.0400 (14)	−0.0092 (12)	0.0090 (11)	−0.0006 (12)
C18	0.0523 (17)	0.0504 (17)	0.0510 (17)	−0.0133 (13)	0.0188 (13)	0.0006 (14)
C19	0.076 (2)	0.0434 (17)	0.066 (2)	−0.0032 (16)	0.0273 (17)	0.0081 (16)
C20	0.0618 (18)	0.0460 (16)	0.0539 (17)	0.0094 (15)	0.0159 (14)	0.0071 (14)
C21	0.0482 (16)	0.0424 (15)	0.0435 (15)	−0.0009 (12)	0.0153 (12)	−0.0036 (12)
Cl1	0.0519 (4)	0.0653 (5)	0.0288 (3)	0.0050 (3)	0.0072 (3)	0.0036 (3)

Geometric parameters (Å, º)

C1—N1	1.316 (3)	C11—C16	1.388 (4)
C1—N2	1.352 (3)	C11—C12	1.427 (4)
C1—N6	1.350 (3)	C12—C13	1.434 (4)
N2—C3	1.340 (3)	C13—C14	1.371 (4)
N3—C3	1.321 (3)	C13—H13	0.9300
N4—C3	1.346 (3)	C14—C15	1.378 (5)
N4—C5	1.456 (3)	C14—H14	0.9300
N6—C5	1.488 (3)	C15—C16	1.344 (5)
N6—C7	1.445 (3)	C15—H15	0.9300
C5—C17	1.532 (4)	C16—H16	0.9300
C5—C21	1.535 (4)	C17—C18	1.529 (4)
C7—C8	1.378 (4)	C17—H17A	0.9700
C7—C12	1.404 (4)	C17—H17B	0.9700
C8—C9	1.399 (4)	C18—C19	1.523 (5)
C9—C10	1.387 (4)	C18—H18A	0.9700
C10—C11	1.414 (4)	C18—H18B	0.9700
N1—H1A	0.8600	C19—C20	1.521 (5)
N1—H1B	0.8600	C19—H19A	0.9700
N3—H3A	0.8600	C19—H19B	0.9700
N3—H3B	0.8600	C20—C21	1.516 (4)
N4—H4	0.8600	C20—H20A	0.9700
C8—H8	0.9300	C20—H20B	0.9700
C9—H9	0.9300	C21—H21A	0.9700
C10—H10	0.9300	C21—H21B	0.9700
N1—C1—N2	117.5 (2)	C14—C13—C12	117.1 (3)
N1—C1—N6	119.6 (2)	C14—C13—H13	121.5
N2—C1—N6	122.9 (2)	C12—C13—H13	121.5
C1—N2—C3	115.9 (2)	C13—C14—C15	123.8 (4)
N2—C3—N3	119.8 (2)	C13—C14—H14	118.1
N2—C3—N4	121.5 (2)	C15—C14—H14	118.1
N3—C3—N4	118.7 (2)	C16—C15—C14	119.4 (4)
C3—N4—C5	117.6 (2)	C16—C15—H15	120.3
N4—C5—N6	105.1 (2)	C14—C15—H15	120.3
N4—C5—C17	109.2 (2)	C15—C16—C11	121.6 (4)
N6—C5—C17	111.2 (2)	C15—C16—H16	119.2
N4—C5—C21	110.5 (2)	C11—C16—H16	119.2
N6—C5—C21	110.3 (2)	C18—C17—C5	111.8 (2)
C17—C5—C21	110.3 (2)	C18—C17—H17A	109.3
C1—N6—C5	118.7 (2)	C5—C17—H17A	109.3
C1—N6—C7	121.8 (2)	C18—C17—H17B	109.3
C5—N6—C7	118.8 (2)	C5—C17—H17B	109.3
C8—C7—N6	121.3 (3)	H17A—C17—H17B	107.9
C12—C7—N6	118.6 (2)	C19—C18—C17	111.8 (2)
C8—C7—C12	119.9 (3)	C19—C18—H18A	109.3
C7—C8—C9	122.4 (3)	C17—C18—H18A	109.3
C10—C9—C8	118.0 (3)	C19—C18—H18B	109.3
C9—C10—C11	121.8 (3)	C17—C18—H18B	109.3
C1—N1—H1A	120.0	H18A—C18—H18B	107.9
C1—N1—H1B	120.0	C18—C19—C20	110.8 (3)
H1A—N1—H1B	120.0	C18—C19—H19A	109.5
C3—N3—H3A	120.0	C20—C19—H19A	109.5
C3—N3—H3B	120.0	C18—C19—H19B	109.5
H3A—N3—H3B	120.0	C20—C19—H19B	109.5
C3—N4—H4	121.2	H19A—C19—H19B	108.1
C5—N4—H4	121.2	C21—C20—C19	111.1 (3)
C7—C8—H8	118.8	C21—C20—H20A	109.4
C9—C8—H8	118.8	C19—C20—H20A	109.4
C10—C9—H9	121.0	C21—C20—H20B	109.4
C8—C9—H9	121.0	C19—C20—H20B	109.4
C9—C10—H10	119.1	H20A—C20—H20B	108.0
C11—C10—H10	119.1	C20—C21—C5	111.3 (2)
C16—C11—C10	122.1 (3)	C20—C21—H21A	109.4
C16—C11—C12	119.3 (3)	C5—C21—H21A	109.4
C10—C11—C12	118.6 (3)	C20—C21—H21B	109.4
C7—C12—C11	119.2 (3)	C5—C21—H21B	109.4
C7—C12—C13	122.0 (3)	H21A—C21—H21B	108.0
C11—C12—C13	118.9 (3)
N1—C1—N2—C3	−162.1 (2)	C9—C10—C11—C16	−179.6 (3)
N6—C1—N2—C3	18.3 (4)	C9—C10—C11—C12	−0.8 (5)
C1—N2—C3—N3	174.8 (2)	C8—C7—C12—C11	−3.9 (4)
C1—N2—C3—N4	−3.7 (4)	N6—C7—C12—C11	172.3 (3)
N3—C3—N4—C5	149.3 (2)	C8—C7—C12—C13	176.8 (3)
N2—C3—N4—C5	−32.1 (4)	N6—C7—C12—C13	−7.0 (4)
C3—N4—C5—N6	48.0 (3)	C16—C11—C12—C7	−178.2 (3)
C3—N4—C5—C17	167.4 (2)	C10—C11—C12—C7	2.9 (4)
C3—N4—C5—C21	−71.0 (3)	C16—C11—C12—C13	1.1 (4)
N1—C1—N6—C7	−6.3 (4)	C10—C11—C12—C13	−177.7 (3)
N2—C1—N6—C7	173.3 (2)	C7—C12—C13—C14	179.0 (3)
N1—C1—N6—C5	−176.5 (2)	C11—C12—C13—C14	−0.3 (4)
N2—C1—N6—C5	3.1 (4)	C12—C13—C14—C15	−0.7 (5)
N4—C5—N6—C1	−33.9 (3)	C13—C14—C15—C16	0.9 (6)
C17—C5—N6—C1	−152.0 (2)	C14—C15—C16—C11	−0.1 (6)
C21—C5—N6—C1	85.2 (3)	C10—C11—C16—C15	177.9 (4)
N4—C5—N6—C7	155.6 (2)	C12—C11—C16—C15	−0.9 (5)
C17—C5—N6—C7	37.5 (3)	N4—C5—C17—C18	67.6 (3)
C21—C5—N6—C7	−85.3 (3)	N6—C5—C17—C18	−176.7 (2)
C1—N6—C7—C8	−92.4 (4)	C21—C5—C17—C18	−54.0 (3)
C5—N6—C7—C8	77.8 (3)	C5—C17—C18—C19	54.0 (3)
C1—N6—C7—C12	91.4 (3)	C17—C18—C19—C20	−54.7 (4)
C5—N6—C7—C12	−98.4 (3)	C18—C19—C20—C21	56.6 (4)
C12—C7—C8—C9	2.8 (5)	C19—C20—C21—C5	−57.6 (3)
N6—C7—C8—C9	−173.3 (3)	N4—C5—C21—C20	−65.0 (3)
C7—C8—C9—C10	−0.6 (5)	N6—C5—C21—C20	179.2 (2)
C8—C9—C10—C11	−0.4 (6)	C17—C5—C21—C20	55.9 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1A···Cl1^i	0.86	2.46	3.179 (2)	142
N1—H1B···N2^ii	0.86	2.24	3.098 (3)	174
N3—H3A···Cl1^iii	0.86	2.44	3.278 (2)	164
N3—H3B···Cl1	0.86	2.48	3.264 (2)	152
N4—H4···Cl1	0.86	2.58	3.222 (2)	133

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