4-Amino-N-isopropyl­benzamidinium chloride ethanol solvate

The title compound, C₁₀H₁₆N·Cl⁻·C₂H₆O, is an important intermediate in the convergent synthesis of amidine-substituted polycyclic heterocycles, a class of compounds that shows significant anticancer activity. The molecule of (I) is not planar, having a dihedral angle of 25.00 (7)° between the aniline and amidine (–C—NH=C=NH₂) groups. The proton­ation of the amidine molecular fragment is accompanied by delocalized C—N bond distances of 1.320 (2) and 1.317 (2) Å. The cations and chloride anions are involved in a network of hydrogen bonds, resulting in the formation of infinite chains propagating along the b direction. The chains are further grouped within the ab plane, in such a way that the structure is segregated into layers dominated by hydro­phobic interactions involving N-isopropyl residues and layers dominated by N—H...Cl [N...Cl = 3.275 (2)–3.596 (2) Å], O—H...Cl [O...Cl = 3.229 (3) Å] and N—H...O [N...O = 2.965 (3) Å] hydrogen bonds.

S1. Comment

Amidine compounds have been widely investigated because of their biological activity. One of the first groups of amidine-substituted organic compounds included pentamidine and its analogs, which were prepared for screening against a rat model of Pneumocystis carinii pneumonia (PCP) (Tidwell et al., 1990; Patric et al., 1997). In addition to their activity against PCP, these compounds were also evaluated for DNA affinity, and showed modest anti-HIV-1 activity and selectivity in primary lymphocytes (Kumar et al., 1996). Amidine compounds show antiparasitic activity (Danan et al., 1997) and antifungal activity (Del Poeta, Schell, Dykstra, Jones, Tidwell, Czarny et al., 1998), as well as activity against a wide range of eucaryotic pathogens for Candida albicans and Cryptococus neoformans. Selected compounds were also found to be active against Aspergillus fumigantus, Fusarium solani and Candida species other than C. albicans (Del Poeta, Schell, Dykstra, Jones, Tidwell, Kumar et al., 1998).

We have synthesized and characterized a number of heterocyclic amidines and trisamidines of benzodithiophene, benzothienofuran, naphtho[2,1-b]furan and benzothiazole, which have potential as anticancer agents (Starčević et al., 2002, 2003; Hranjec et al., 2003; Ćaleta et al., 2003; Matković-Čalogović et al., 2003).

The molecule of (I) (Fig. 1) is not planar. The carboxamidinium moiety has a synperiplanar disposition with respect to the aniline group [C1—C6—C7—N2 = 25.8 (2)°]. This twist may serve to accommodate the formation of intermolecular hydrogen bonds. Deviation from coplanarity is observed, however, in other N-isopropylamidine derivatives, such as 6-(N-isopropyl)amidino-2-methylbenzothiazole and 2-amino-6-(N-isopropyl)amidinobenzothiazole, synthesized in the form of their hydrocloride salts (Ćaleta et al., 2003), in 2-amino-6-[N-(2-morpholine-4-yl-ethyl)]-1,3-benzothiazolecarboxamidinium chloride (Ćaleta et al., 2004) and in 1,3-benzothiazole-6-carboxamidinium chloride dihydrate (Matković-Čalogović et al., 2003).

The isopropyl substituent at atom N2 has an anticlinal disposition relative to atom N1 [C7—N2—C8—C9 = 143.84 (19)° and C7—N2—C8—C10 = −92.5 (2)°]. The bond distance values of C7—N1, 1.320 (2) Å, and C7—N2, 1.317 (2) Å, are equal to within 3σ, reflecting the protonation of the amidine group, while the N2—C8 bond [1.470 (2) Å] is σ in character. The N3—C3 and C6—C7 bond distances are shortened [1.365 (2) and 1.473 (2) Å, respectively] and exhibit partial π character, indicating some degree of π-electron delocalization through both the phenyl and the amidine moiety. Other bond distances are within expected values (Allen et al., 1987).

The cations and chloride ions are involved in a network of intermolecular hydrogen bonds, resulting in the formation of infinite chains propagating in the b direction (Fig. 2). The different moieties present are grouped into an AB pattern of layers parallel to the crystallographic ab plane, and composed alternately of amidinium cations and chloride ions. The layer formed principally by the N-isopropyl group of the cation and the ethyl residues of EtOH solvent molecules is characterized by hydrophobic interactions, while the layer containing the chloride ions is dominated by intermolecular hydrogen bonds. The chloride ion participates in N—H···Cl hydrogen-bond formation as a multiple proton acceptor, interacting with both the amine and amidine NH groups, [N···Cl range 3.275 (2)–3.597 (2) Å; Table 2]. The chloride ion is also involved in an O—H···Cl hydrogen bond with the ethanol O atom [O···Cl = 3.229 (3) Å]. The NH amidine group acts as a donor to the ethanol O atom, with an N···O distance of 2.966 (3) Å.

S2. Experimental

Compound (I) was prepared from 4-aminobenzonitrile by a modified Pinner reaction (Ferroni et al., 1995) (see scheme). A suspension of 4-aminobenzonitrile (9 g, 0.076 mmol) in absolute ethanol (130 ml) was cooled to 273 K and saturated with dry HCl gas. The suspension was stirred until IR spectra indicated the absence of the cyano peak (8 d). The imine ester hydrochloride intermediate was precipitated from the solution by addition of dry diethyl ether, filtered off, washed with dry ether and dried over KOH. Isopropyl amine (19.5 ml, 0.23 mmol) was added to the suspension of the crude imine ester hydrochloride in absolute ethanol (130 ml). The mixture was stirred at room temperature for 5 d. The crude product (9.35 g, yield 69%, m.p. 517–521 K) was filtered off, washed with acetone and recrystallized from ethanol. IR (KBr, cm⁻¹): 3480, 3300, 3080, 2950, 1650, 1590; ¹H NMR (300 MHz, DMSO-d₆): 8.98–9.03 (m, 2 H, H_amidine), 8.65 (s, 1 H, H_amidine), 7.48 (d, 2 H, H_arom., J = 8.72 Hz), 6.64 (d, 2 H, H_arom, J = 8.71 Hz), 6.17 (s, 2 H, H_amine), 4.02–4.04 (m, 1 H, HCH), 1.24 (d, 6 H, HCH₃, J = 6.46 Hz); ¹³C (300 MHz, DMSO-d₆): 161.1 (s), 153.9 (s), 129.9 (s, 2 C), 113.9 (s), 112.7.

S3. Refinement

Methyl atom C12 of the ethanol solvent molecule is disordered; the relative occupancies of the two positions, C12A (major component) and C12B, were refined to a final ratio of 73 (1):27 (1). The C12A—C11 [1.419 (5) Å] and C12B—C11 [1.472 (9) Å] bond distances were loosely restrained to a Csp³—Csp³ value (DFIX in SHELXL97; Sheldrick, 1997). H atoms bonded to C atoms were introduced at calculated positions and refined as riding [U_iso(H) = 1.2 or 1.5U_eq(C), and C—H = 0.93 (C_ar—H), 0.96 (C_methyl—H), 0.97 (C_methylene—H) and 0.98 Å (C_tertiary—H)]. The H atoms of the NH₂ group (N1) were also refined as riding [N—H = 0.86 Å and U_iso(H) = 1.2U_eq(N)]. The H atoms bonded to atoms N2, N3 and O1 were found in difference Fourier maps and refined freely.

Computing details

Data collection: CrysAlis (Oxford Diffraction, 2004); cell refinement: CrysAlis; data reduction: CrysAlis; program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON98 (Spek, 1998); software used to prepare material for publication: SHELXL97 (Sheldrick, 1997).

Figures

	Fig. 1. The structure of (I), with 50% probability displacement ellipsoids.
	Fig. 2. The crystal structure of (I). The non-H atoms are indicated as follows: C void, O black, N net and Cl slant. Hydrogen bonds are indicated by dashed lines. Only the major component, C12A, of the disordered EtOH methyl group is shown.

4-Amino-N-isopropylbenzamidinium chloride ethanol solvate

Crystal data

C10H16N3^+·Cl^−·C2H6O	Z = 2
Mr = 259.78	F(000) = 280
Triclinic, P1	Dx = 1.168 Mg m^−3
Hall symbol: -P 1	Melting point = 517–521 K
a = 8.7458 (15) Å	Mo Kα radiation, λ = 0.71073 Å
b = 9.2177 (14) Å	Cell parameters from 2250 reflections
c = 9.7938 (15) Å	θ = 6–20°
α = 96.339 (12)°	µ = 0.25 mm^−1
β = 105.022 (14)°	T = 296 K
γ = 100.649 (13)°	Prism, colourless
V = 738.9 (2) Å^3	0.48 × 0.19 × 0.18 mm

Data collection

Oxford Diffraction Xcalibur2 diffractometer with Sapphire 3 CCD detector	2461 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.022
Graphite monochromator	θmax = 27.0°, θmin = 4.4°
ϕ and ω scans	h = −11→11
9188 measured reflections	k = −11→11
3183 independent reflections	l = −12→12

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)] = 0.047	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.145	H atoms treated by a mixture of independent and constrained refinement
S = 1.11	w = 1/[σ^2(Fo^2) + (0.0883P)^2 + 0.0256P] where P = (Fo^2 + 2Fc^2)/3
3183 reflections	(Δ/σ)max < 0.001
184 parameters	Δρmax = 0.30 e Å^−3
2 restraints	Δρmin = −0.27 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.

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
Cl1	0.39400 (5)	0.78069 (5)	0.08104 (6)	0.0596 (2)
O1	0.2560 (2)	0.8158 (3)	0.3556 (3)	0.1024 (8)
H1O	0.272 (4)	0.786 (3)	0.290 (3)	0.078 (10)*
N1	−0.24967 (17)	0.02685 (16)	0.16455 (17)	0.0498 (4)
H1A	−0.3283	−0.0379	0.1752	0.060*
H1B	−0.2681	0.1061	0.1305	0.060*
N2	−0.06852 (19)	−0.11549 (16)	0.25277 (17)	0.0478 (4)
H2N	0.023 (3)	−0.113 (3)	0.285 (3)	0.069 (7)*
N3	0.4164 (2)	0.4300 (2)	0.1313 (2)	0.0626 (5)
H13N	0.406 (3)	0.522 (3)	0.125 (2)	0.069 (7)*
H23N	0.491 (3)	0.397 (2)	0.101 (2)	0.052 (5)*
C1	0.1721 (2)	0.07569 (18)	0.16374 (18)	0.0443 (4)
H1	0.1801	−0.0236	0.1626	0.053*
C2	0.2983 (2)	0.17866 (19)	0.14698 (19)	0.0469 (4)
H2	0.3906	0.1484	0.1357	0.056*
C3	0.2894 (2)	0.32857 (19)	0.14663 (18)	0.0464 (4)
C4	0.1493 (2)	0.3699 (2)	0.1640 (2)	0.0532 (5)
H4	0.1408	0.4690	0.1638	0.064*
C5	0.0233 (2)	0.26660 (19)	0.1814 (2)	0.0490 (4)
H5	−0.0693	0.2966	0.1925	0.059*
C6	0.03322 (19)	0.11669 (17)	0.18236 (16)	0.0407 (4)
C7	−0.1006 (2)	0.00468 (18)	0.20043 (17)	0.0415 (4)
C8	−0.1875 (2)	−0.2401 (2)	0.2734 (2)	0.0525 (5)
H8	−0.2931	−0.2449	0.2051	0.063*
C9	−0.1362 (3)	−0.3857 (2)	0.2419 (3)	0.0676 (6)
H9A	−0.1246	−0.3974	0.1468	0.101*
H9B	−0.2172	−0.4680	0.2492	0.101*
H9C	−0.0344	−0.3840	0.3099	0.101*
C10	−0.2031 (4)	−0.2119 (3)	0.4230 (3)	0.0982 (9)
H10A	−0.1001	−0.2057	0.4912	0.147*
H10B	−0.2823	−0.2925	0.4357	0.147*
H10C	−0.2369	−0.1195	0.4375	0.147*
C11	0.3546 (4)	0.7966 (4)	0.4878 (4)	0.1129 (11)
H11A	0.3166	0.8401	0.5641	0.135*	0.728 (14)
H11B	0.4647	0.8516	0.5009	0.135*	0.728 (14)
H11C	0.3896	0.8916	0.5526	0.135*	0.272 (14)
H11D	0.4508	0.7672	0.4731	0.135*	0.272 (14)
C12A	0.3576 (9)	0.6454 (5)	0.5014 (7)	0.115 (3)	0.728 (14)
H12D	0.4314	0.6420	0.5920	0.172*	0.728 (14)
H12E	0.3928	0.6004	0.4252	0.172*	0.728 (14)
H12F	0.2507	0.5916	0.4962	0.172*	0.728 (14)
C12B	0.2716 (19)	0.6835 (19)	0.5549 (15)	0.118 (6)	0.272 (14)
H12A	0.1903	0.7215	0.5883	0.177*	0.272 (14)
H12B	0.3492	0.6614	0.6345	0.177*	0.272 (14)
H12C	0.2211	0.5939	0.4859	0.177*	0.272 (14)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0469 (3)	0.0539 (3)	0.0862 (4)	0.0182 (2)	0.0204 (2)	0.0309 (2)
O1	0.0802 (12)	0.158 (2)	0.1109 (17)	0.0646 (13)	0.0459 (12)	0.0880 (16)
N1	0.0435 (8)	0.0449 (8)	0.0675 (10)	0.0140 (6)	0.0197 (7)	0.0200 (7)
N2	0.0380 (8)	0.0474 (8)	0.0598 (9)	0.0101 (6)	0.0113 (7)	0.0217 (7)
N3	0.0548 (10)	0.0492 (10)	0.0901 (13)	0.0079 (8)	0.0296 (9)	0.0231 (9)
C1	0.0472 (9)	0.0376 (8)	0.0505 (9)	0.0126 (7)	0.0141 (7)	0.0116 (7)
C2	0.0433 (9)	0.0466 (9)	0.0549 (10)	0.0149 (7)	0.0155 (7)	0.0138 (8)
C3	0.0480 (9)	0.0438 (9)	0.0466 (9)	0.0061 (7)	0.0133 (7)	0.0117 (7)
C4	0.0558 (11)	0.0361 (9)	0.0707 (12)	0.0117 (7)	0.0208 (9)	0.0127 (8)
C5	0.0496 (10)	0.0431 (9)	0.0615 (11)	0.0163 (7)	0.0222 (8)	0.0129 (8)
C6	0.0442 (9)	0.0376 (8)	0.0408 (8)	0.0093 (7)	0.0121 (7)	0.0089 (7)
C7	0.0439 (9)	0.0410 (8)	0.0417 (8)	0.0113 (7)	0.0137 (7)	0.0090 (7)
C8	0.0421 (9)	0.0479 (10)	0.0696 (12)	0.0073 (7)	0.0143 (8)	0.0265 (9)
C9	0.0640 (12)	0.0485 (11)	0.0881 (15)	0.0105 (9)	0.0172 (11)	0.0173 (10)
C10	0.133 (3)	0.0783 (17)	0.111 (2)	0.0178 (16)	0.082 (2)	0.0302 (15)
C11	0.094 (2)	0.118 (3)	0.122 (3)	0.0215 (18)	0.0116 (18)	0.048 (2)
C12A	0.123 (5)	0.089 (3)	0.103 (4)	0.005 (3)	−0.016 (3)	0.041 (3)
C12B	0.142 (13)	0.169 (14)	0.078 (8)	0.078 (11)	0.043 (8)	0.059 (8)

Geometric parameters (Å, º)

O1—C11	1.407 (4)	C8—C10	1.506 (3)
O1—H1O	0.73 (3)	C8—C9	1.517 (3)
N1—C7	1.320 (2)	C8—H8	0.9800
N1—H1A	0.8600	C9—H9A	0.9600
N1—H1B	0.8600	C9—H9B	0.9600
N2—C7	1.317 (2)	C9—H9C	0.9600
N2—C8	1.470 (2)	C10—H10A	0.9600
N2—H2N	0.77 (3)	C10—H10B	0.9600
N3—C3	1.365 (2)	C10—H10C	0.9600
N3—H13N	0.87 (3)	C11—C12A	1.419 (5)
N3—H23N	0.87 (2)	C11—C12B	1.472 (9)
C1—C2	1.374 (2)	C11—H11A	0.9700
C1—C6	1.386 (2)	C11—H11B	0.9700
C1—H1	0.9300	C11—H11C	0.9700
C2—C3	1.399 (2)	C11—H11D	0.9700
C2—H2	0.9300	C12A—H12D	0.9600
C3—C4	1.393 (3)	C12A—H12E	0.9600
C4—C5	1.377 (2)	C12A—H12F	0.9600
C4—H4	0.9300	C12B—H12A	0.9600
C5—C6	1.401 (2)	C12B—H12B	0.9600
C5—H5	0.9300	C12B—H12C	0.9600
C6—C7	1.473 (2)
C11—O1—H1O	119 (2)	C10—C8—H8	108.5
C7—N1—H1A	120.0	C9—C8—H8	108.5
C7—N1—H1B	120.0	C8—C9—H9A	109.5
H1A—N1—H1B	120.0	C8—C9—H9B	109.5
C7—N2—C8	126.21 (15)	H9A—C9—H9B	109.5
C7—N2—H2N	115.2 (18)	C8—C9—H9C	109.5
C8—N2—H2N	118.0 (18)	H9A—C9—H9C	109.5
C3—N3—H13N	118.6 (16)	H9B—C9—H9C	109.5
C3—N3—H23N	118.5 (13)	C8—C10—H10A	109.5
H13N—N3—H23N	120 (2)	C8—C10—H10B	109.5
C2—C1—C6	121.39 (15)	H10A—C10—H10B	109.5
C2—C1—H1	119.3	C8—C10—H10C	109.5
C6—C1—H1	119.3	H10A—C10—H10C	109.5
C1—C2—C3	120.72 (16)	H10B—C10—H10C	109.5
C1—C2—H2	119.6	O1—C11—C12A	114.5 (3)
C3—C2—H2	119.6	O1—C11—C12B	113.0 (6)
N3—C3—C4	121.87 (17)	O1—C11—H11A	108.6
N3—C3—C2	120.09 (17)	C12A—C11—H11A	108.6
C4—C3—C2	118.04 (15)	O1—C11—H11B	108.6
C5—C4—C3	121.14 (16)	C12A—C11—H11B	108.6
C5—C4—H4	119.4	H11A—C11—H11B	107.6
C3—C4—H4	119.4	O1—C11—H11C	109.0
C4—C5—C6	120.56 (16)	C12B—C11—H11C	109.0
C4—C5—H5	119.7	O1—C11—H11D	109.0
C6—C5—H5	119.7	C12B—C11—H11D	109.0
C1—C6—C5	118.14 (15)	C11—C12A—H12D	109.5
C1—C6—C7	120.58 (14)	C11—C12A—H12E	109.5
C5—C6—C7	121.27 (15)	C11—C12A—H12F	109.5
N2—C7—N1	121.42 (15)	C11—C12B—H12A	109.5
N2—C7—C6	119.07 (15)	C11—C12B—H12B	109.5
N1—C7—C6	119.51 (14)	H12A—C12B—H12B	109.5
N2—C8—C10	109.60 (17)	C11—C12B—H12C	109.5
N2—C8—C9	109.25 (16)	H12A—C12B—H12C	109.5
C10—C8—C9	112.46 (19)	H12B—C12B—H12C	109.5
N2—C8—H8	108.5
C6—C1—C2—C3	−0.7 (3)	C4—C5—C6—C7	−179.83 (16)
C1—C2—C3—N3	179.34 (17)	C8—N2—C7—N1	2.4 (3)
C1—C2—C3—C4	0.1 (3)	C8—N2—C7—C6	−177.88 (16)
N3—C3—C4—C5	−179.06 (18)	C1—C6—C7—N2	25.8 (2)
C2—C3—C4—C5	0.2 (3)	C5—C6—C7—N2	−155.16 (17)
C3—C4—C5—C6	0.2 (3)	C1—C6—C7—N1	−154.49 (16)
C2—C1—C6—C5	1.0 (2)	C5—C6—C7—N1	24.6 (2)
C2—C1—C6—C7	−179.89 (15)	C7—N2—C8—C10	−92.5 (2)
C4—C5—C6—C1	−0.8 (3)	C7—N2—C8—C9	143.84 (19)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1A···Cl1^i	0.86	2.56	3.344 (2)	153
N1—H1B···Cl1^ii	0.86	2.51	3.275 (2)	148
O1—H1O···Cl1	0.73 (3)	2.54 (3)	3.229 (3)	158 (3)
N2—H2N···O1^iii	0.78 (3)	2.22 (3)	2.965 (3)	162 (3)
N3—H13N···Cl1	0.88 (3)	2.49 (3)	3.356 (2)	172 (2)
N3—H23N···Cl1^iv	0.87 (3)	2.79 (2)	3.596 (2)	155 (2)
C1—H1···O1^iii	0.93	2.56	3.277 (3)	135
C8—H8···Cl1^i	0.98	2.76	3.708 (2)	164

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