organic compounds
4-[(2-Chloroethyl)amino]quinolinium chloride monohydrate
aInstituto de Tecnologia em Farmacos, Fundação Oswaldo Cruz (FIOCRUZ), FarManguinhos, Rua Sizenando Nabuco, 100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil, bDepartment of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia, cCentro de Desenvolvimento Tecnológico em Saúde (CDTS), Fundação Oswaldo Cruz (FIOCRUZ), Casa Amarela, Campus de Manguinhos, Av. Brasil 4365, 21040-900 Rio de Janeiro, RJ, Brazil, and dCHEMSOL, 1 Harcourt Road, Aberdeen AB15 5NY, Scotland
*Correspondence e-mail: edward.tiekink@gmail.com
In the title salt hydrate, C11H12ClN2+·Cl−·H2O, the quinolinium core is essentially planar (r.m.s. deviation = 0.027 Å) with the chloroethyl side chain being almost orthogonal to the core [C—N—C—C torsion angle = −80.0 (3)°]. In the crystal packing, the water molecule bridges three species, forming donor interactions to two chloride anions and accepting a hydrogen bond from the quinolinium H atom. The chloride anion accepts a hydrogen bond from the amine N atom with the result that a two-dimensional supramolecular array is formed in the ac plane. A C—H⋯Cl interaction also occurs.
Related literature
For background to malaria, see: Snow et al. (1999); Breman (2001); World Health Organization (1999). For background information on the pharmacological activity of quinoline derivatives, see: Elslager et al. (1969); Font et al. (1997); Kaminsky & Meltzer (1968); Musiol et al. (2006); Nakamura et al. (1999); Palmer et al. (1993); Ridley (2002); Sloboda et al. (1991); Tanenbaum & Tuffanelli (1980); Warshakoon et al. (2006). For recent studies on quinoline-based anti-malarials, see: Andrade et al. (2007); Cunico et al. (2006); da Silva et al. (2003); de Souza et al. (2005). For a related crystallographic study on a neutral species related to the title compound, see: Kaiser et al. (2009). For the synthesis, see: Elderfield et al. (1946).
Experimental
Crystal data
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Data collection: COLLECT (Hooft, 1998); cell DENZO (Otwinowski & Minor, 1997) and COLLECT; data reduction: DENZO and COLLECT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg, 2006); software used to prepare material for publication: publCIF (Westrip, 2009).
Supporting information
10.1107/S160053680904834X/hg2592sup1.cif
contains datablocks global, I. DOI:Structure factors: contains datablock I. DOI: 10.1107/S160053680904834X/hg2592Isup2.hkl
A mixture of 7-chloro-N-(2-hydroxyethyl)quinolin-4-amine) (Kaiser et al., 2009) (0.5 g, 2.2 mmol), thionyl chloride (33 ml, 45 mmol) and DMF (0.3 ml, 0.22 mol) was stirred under nitrogen at room temperature for 24 h. The resulting mixture was treated with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield solid (I); yield: 94%.The compound was recrystallized from ethanol, m. pt.: 402–403 K. The melting point of the free base was reported to be 427 K (Elderfield et al., 1946).
The C-bound H atoms were geometrically placed (C–H = 0.95–0.99 Å) and refined as riding with Uiso(H) = 1.2Ueq(C). The N-bound H atoms were located from a difference map and included in their idealized positions with N–H = 0.88 Å, and with Uiso(H) = 1.2Ueq(N). The water-H atoms were located from a difference map and refined with O–H = 0.840±0.001 Å and H···H = 1.39±0.01 Å, and with Uiso(H) = 1.5Ueq(O).
Data collection: COLLECT (Hooft, 1998); cell
DENZO (Otwinowski & Minor, 1997) and COLLECT (Hooft, 1998); data reduction: DENZO (Otwinowski & Minor, 1997) and COLLECT (Hooft, 1998); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg, 2006); software used to prepare material for publication: publCIF (Westrip, 2009).C11H12ClN2+·Cl−·H2O | F(000) = 544 |
Mr = 261.14 | Dx = 1.424 Mg m−3 |
Orthorhombic, Pna21 | Mo Kα radiation, λ = 0.71070 Å |
Hall symbol: P 2c -2n | Cell parameters from 1650 reflections |
a = 18.7513 (7) Å | θ = 2.9–27.5° |
b = 14.1030 (5) Å | µ = 0.51 mm−1 |
c = 4.606 (1) Å | T = 120 K |
V = 1218.1 (3) Å3 | Needle, colourless |
Z = 4 | 0.46 × 0.03 × 0.03 mm |
Bruker–Nonius 95mm CCD camera on κ-goniostat diffractometer | 2681 independent reflections |
Radiation source: Bruker-Nonius FR591 rotating anode | 2390 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.049 |
Detector resolution: 9.091 pixels mm-1 | θmax = 27.5°, θmin = 3.1° |
ϕ & ω scans | h = −19→24 |
Absorption correction: multi-scan (SADABS; Sheldrick, 2003) | k = −18→18 |
Tmin = 0.816, Tmax = 1 | l = −5→5 |
11264 measured reflections |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.032 | H-atom parameters constrained |
wR(F2) = 0.065 | w = 1/[σ2(Fo2) + (0.0173P)2 + 0.5206P] where P = (Fo2 + 2Fc2)/3 |
S = 1.06 | (Δ/σ)max = 0.001 |
2681 reflections | Δρmax = 0.22 e Å−3 |
151 parameters | Δρmin = −0.21 e Å−3 |
4 restraints | Absolute structure: Flack (1983), 1123 Friedel pairs |
Primary atom site location: structure-invariant direct methods | Absolute structure parameter: 0.03 (6) |
C11H12ClN2+·Cl−·H2O | V = 1218.1 (3) Å3 |
Mr = 261.14 | Z = 4 |
Orthorhombic, Pna21 | Mo Kα radiation |
a = 18.7513 (7) Å | µ = 0.51 mm−1 |
b = 14.1030 (5) Å | T = 120 K |
c = 4.606 (1) Å | 0.46 × 0.03 × 0.03 mm |
Bruker–Nonius 95mm CCD camera on κ-goniostat diffractometer | 2681 independent reflections |
Absorption correction: multi-scan (SADABS; Sheldrick, 2003) | 2390 reflections with I > 2σ(I) |
Tmin = 0.816, Tmax = 1 | Rint = 0.049 |
11264 measured reflections |
R[F2 > 2σ(F2)] = 0.032 | H-atom parameters constrained |
wR(F2) = 0.065 | Δρmax = 0.22 e Å−3 |
S = 1.06 | Δρmin = −0.21 e Å−3 |
2681 reflections | Absolute structure: Flack (1983), 1123 Friedel pairs |
151 parameters | Absolute structure parameter: 0.03 (6) |
4 restraints |
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. |
x | y | z | Uiso*/Ueq | ||
Cl1 | 0.13741 (3) | 0.81412 (4) | 0.18205 (16) | 0.02165 (12) | |
Cl2 | 0.21007 (3) | 0.53250 (3) | 0.01935 (15) | 0.02136 (12) | |
O1 | 0.10851 (8) | 0.59720 (11) | 0.5181 (4) | 0.0271 (4) | |
H1W | 0.1283 | 0.5858 | 0.6780 | 0.041* | |
H2W | 0.1365 | 0.5852 | 0.3805 | 0.041* | |
N1 | 0.48246 (10) | 0.82732 (12) | 0.3467 (4) | 0.0188 (4) | |
H1 | 0.5241 | 0.8470 | 0.4104 | 0.023* | |
N2 | 0.29024 (9) | 0.73519 (11) | 0.0155 (4) | 0.0163 (3) | |
H2 | 0.2742 | 0.6796 | 0.0728 | 0.020* | |
C1 | 0.44596 (12) | 0.88075 (15) | 0.1575 (5) | 0.0203 (5) | |
H1A | 0.4657 | 0.9397 | 0.0982 | 0.024* | |
C2 | 0.38179 (12) | 0.85382 (14) | 0.0472 (5) | 0.0184 (4) | |
H2A | 0.3572 | 0.8943 | −0.0839 | 0.022* | |
C3 | 0.35148 (11) | 0.76568 (14) | 0.1268 (4) | 0.0158 (5) | |
C4 | 0.39002 (11) | 0.70904 (15) | 0.3390 (5) | 0.0152 (4) | |
C5 | 0.36387 (12) | 0.62250 (15) | 0.4527 (4) | 0.0179 (5) | |
H5 | 0.3194 | 0.5985 | 0.3873 | 0.021* | |
C6 | 0.40215 (12) | 0.57290 (15) | 0.6566 (5) | 0.0208 (5) | |
H6 | 0.3837 | 0.5153 | 0.7328 | 0.025* | |
C7 | 0.46856 (13) | 0.60686 (16) | 0.7533 (5) | 0.0230 (5) | |
H7 | 0.4951 | 0.5715 | 0.8917 | 0.028* | |
C8 | 0.49518 (11) | 0.69039 (15) | 0.6493 (5) | 0.0192 (5) | |
H8 | 0.5399 | 0.7133 | 0.7159 | 0.023* | |
C9 | 0.45584 (11) | 0.74244 (15) | 0.4426 (4) | 0.0158 (5) | |
C10 | 0.24785 (13) | 0.78772 (16) | −0.1954 (5) | 0.0181 (5) | |
H10A | 0.2162 | 0.7429 | −0.2993 | 0.022* | |
H10B | 0.2802 | 0.8167 | −0.3402 | 0.022* | |
C11 | 0.20268 (11) | 0.86510 (15) | −0.0584 (4) | 0.0177 (5) | |
H11A | 0.1783 | 0.9017 | −0.2125 | 0.021* | |
H11B | 0.2337 | 0.9091 | 0.0515 | 0.021* |
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl1 | 0.0166 (3) | 0.0257 (3) | 0.0227 (3) | −0.0021 (2) | 0.0006 (2) | 0.0039 (3) |
Cl2 | 0.0218 (3) | 0.0193 (2) | 0.0230 (3) | −0.0009 (2) | −0.0043 (2) | 0.0008 (3) |
O1 | 0.0220 (9) | 0.0335 (9) | 0.0258 (8) | 0.0085 (7) | 0.0002 (8) | 0.0060 (9) |
N1 | 0.0138 (10) | 0.0193 (10) | 0.0234 (10) | −0.0035 (8) | −0.0001 (8) | −0.0019 (8) |
N2 | 0.0164 (9) | 0.0140 (8) | 0.0186 (8) | 0.0010 (7) | −0.0025 (8) | 0.0033 (9) |
C1 | 0.0211 (11) | 0.0162 (10) | 0.0235 (11) | −0.0012 (9) | 0.0026 (10) | 0.0002 (10) |
C2 | 0.0187 (11) | 0.0169 (10) | 0.0196 (11) | 0.0036 (9) | 0.0018 (10) | 0.0010 (10) |
C3 | 0.0136 (11) | 0.0169 (10) | 0.0168 (12) | 0.0041 (8) | 0.0021 (8) | −0.0028 (8) |
C4 | 0.0135 (11) | 0.0158 (10) | 0.0163 (11) | 0.0040 (8) | 0.0009 (8) | −0.0036 (8) |
C5 | 0.0172 (12) | 0.0158 (10) | 0.0206 (12) | −0.0003 (9) | −0.0029 (8) | −0.0015 (9) |
C6 | 0.0235 (12) | 0.0156 (10) | 0.0235 (11) | 0.0031 (9) | −0.0009 (11) | 0.0002 (10) |
C7 | 0.0237 (13) | 0.0235 (12) | 0.0217 (13) | 0.0108 (10) | −0.0031 (9) | −0.0017 (9) |
C8 | 0.0139 (11) | 0.0241 (11) | 0.0196 (12) | 0.0031 (9) | −0.0012 (10) | −0.0062 (9) |
C9 | 0.0160 (11) | 0.0162 (10) | 0.0151 (11) | 0.0020 (9) | 0.0022 (8) | −0.0032 (8) |
C10 | 0.0175 (12) | 0.0193 (11) | 0.0175 (11) | 0.0016 (9) | −0.0032 (9) | 0.0011 (8) |
C11 | 0.0155 (12) | 0.0186 (11) | 0.0192 (12) | −0.0011 (9) | 0.0009 (8) | 0.0029 (8) |
Cl1—C11 | 1.800 (2) | C4—C5 | 1.416 (3) |
O1—H1W | 0.8400 | C5—C6 | 1.374 (3) |
O1—H2W | 0.8401 | C5—H5 | 0.9500 |
N1—C1 | 1.340 (3) | C6—C7 | 1.407 (3) |
N1—C9 | 1.370 (3) | C6—H6 | 0.9500 |
N1—H1 | 0.8800 | C7—C8 | 1.366 (3) |
N2—C3 | 1.329 (3) | C7—H7 | 0.9500 |
N2—C10 | 1.457 (3) | C8—C9 | 1.411 (3) |
N2—H2 | 0.8800 | C8—H8 | 0.9500 |
C1—C2 | 1.360 (3) | C10—C11 | 1.519 (3) |
C1—H1A | 0.9500 | C10—H10A | 0.9900 |
C2—C3 | 1.415 (3) | C10—H10B | 0.9900 |
C2—H2A | 0.9500 | C11—H11A | 0.9900 |
C3—C4 | 1.454 (3) | C11—H11B | 0.9900 |
C4—C9 | 1.405 (3) | ||
H1W—O1—H2W | 110.3 | C5—C6—H6 | 119.8 |
C1—N1—C9 | 121.00 (19) | C7—C6—H6 | 119.8 |
C1—N1—H1 | 119.5 | C8—C7—C6 | 120.4 (2) |
C9—N1—H1 | 119.5 | C8—C7—H7 | 119.8 |
C3—N2—C10 | 124.33 (17) | C6—C7—H7 | 119.8 |
C3—N2—H2 | 117.8 | C7—C8—C9 | 119.6 (2) |
C10—N2—H2 | 117.8 | C7—C8—H8 | 120.2 |
N1—C1—C2 | 122.5 (2) | C9—C8—H8 | 120.2 |
N1—C1—H1A | 118.7 | N1—C9—C4 | 120.24 (19) |
C2—C1—H1A | 118.7 | N1—C9—C8 | 118.81 (19) |
C1—C2—C3 | 120.2 (2) | C4—C9—C8 | 120.95 (19) |
C1—C2—H2A | 119.9 | N2—C10—C11 | 113.12 (18) |
C3—C2—H2A | 119.9 | N2—C10—H10A | 109.0 |
N2—C3—C2 | 122.08 (19) | C11—C10—H10A | 109.0 |
N2—C3—C4 | 120.73 (18) | N2—C10—H10B | 109.0 |
C2—C3—C4 | 117.2 (2) | C11—C10—H10B | 109.0 |
C9—C4—C5 | 117.89 (19) | H10A—C10—H10B | 107.8 |
C9—C4—C3 | 118.74 (19) | C10—C11—Cl1 | 110.35 (15) |
C5—C4—C3 | 123.36 (19) | C10—C11—H11A | 109.6 |
C6—C5—C4 | 120.7 (2) | Cl1—C11—H11A | 109.6 |
C6—C5—H5 | 119.6 | C10—C11—H11B | 109.6 |
C4—C5—H5 | 119.6 | Cl1—C11—H11B | 109.6 |
C5—C6—C7 | 120.4 (2) | H11A—C11—H11B | 108.1 |
C9—N1—C1—C2 | −1.0 (3) | C5—C6—C7—C8 | 1.2 (3) |
N1—C1—C2—C3 | −1.1 (4) | C6—C7—C8—C9 | −0.4 (3) |
C10—N2—C3—C2 | −0.3 (3) | C1—N1—C9—C4 | 1.2 (3) |
C10—N2—C3—C4 | 179.32 (19) | C1—N1—C9—C8 | −177.8 (2) |
C1—C2—C3—N2 | −177.4 (2) | C5—C4—C9—N1 | −177.87 (18) |
C1—C2—C3—C4 | 2.9 (3) | C3—C4—C9—N1 | 0.7 (3) |
N2—C3—C4—C9 | 177.64 (19) | C5—C4—C9—C8 | 1.2 (3) |
C2—C3—C4—C9 | −2.7 (3) | C3—C4—C9—C8 | 179.73 (18) |
N2—C3—C4—C5 | −3.9 (3) | C7—C8—C9—N1 | 178.23 (19) |
C2—C3—C4—C5 | 175.8 (2) | C7—C8—C9—C4 | −0.8 (3) |
C9—C4—C5—C6 | −0.4 (3) | C3—N2—C10—C11 | −80.0 (3) |
C3—C4—C5—C6 | −178.9 (2) | N2—C10—C11—Cl1 | −63.9 (2) |
C4—C5—C6—C7 | −0.8 (3) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O1i | 0.88 | 1.84 | 2.710 (2) | 172 |
N2—H2···Cl2 | 0.88 | 2.41 | 3.2298 (18) | 155 |
O1—H1w···Cl2ii | 0.84 | 2.32 | 3.1288 (19) | 161 |
O1—H2w···Cl2 | 0.84 | 2.29 | 3.1204 (19) | 173 |
C5—H5···Cl2 | 0.95 | 2.82 | 3.730 (2) | 161 |
Symmetry codes: (i) x+1/2, −y+3/2, z; (ii) x, y, z+1. |
Experimental details
Crystal data | |
Chemical formula | C11H12ClN2+·Cl−·H2O |
Mr | 261.14 |
Crystal system, space group | Orthorhombic, Pna21 |
Temperature (K) | 120 |
a, b, c (Å) | 18.7513 (7), 14.1030 (5), 4.606 (1) |
V (Å3) | 1218.1 (3) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.51 |
Crystal size (mm) | 0.46 × 0.03 × 0.03 |
Data collection | |
Diffractometer | Bruker–Nonius 95mm CCD camera on κ-goniostat diffractometer |
Absorption correction | Multi-scan (SADABS; Sheldrick, 2003) |
Tmin, Tmax | 0.816, 1 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 11264, 2681, 2390 |
Rint | 0.049 |
(sin θ/λ)max (Å−1) | 0.650 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.032, 0.065, 1.06 |
No. of reflections | 2681 |
No. of parameters | 151 |
No. of restraints | 4 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.22, −0.21 |
Absolute structure | Flack (1983), 1123 Friedel pairs |
Absolute structure parameter | 0.03 (6) |
Computer programs: , DENZO (Otwinowski & Minor, 1997) and COLLECT (Hooft, 1998), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), DIAMOND (Brandenburg, 2006), publCIF (Westrip, 2009).
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O1i | 0.88 | 1.84 | 2.710 (2) | 172 |
N2—H2···Cl2 | 0.88 | 2.41 | 3.2298 (18) | 155 |
O1—H1w···Cl2ii | 0.84 | 2.32 | 3.1288 (19) | 161 |
O1—H2w···Cl2 | 0.84 | 2.29 | 3.1204 (19) | 173 |
C5—H5···Cl2 | 0.95 | 2.82 | 3.730 (2) | 161 |
Symmetry codes: (i) x+1/2, −y+3/2, z; (ii) x, y, z+1. |
Footnotes
‡Additional correspondence author,e-mail: j.wardell@abdn.ac.uk.
Acknowledgements
The use of the EPSRC X-ray crystallographic service at the University of Southampton, England and the valuable assistance of the staff there is gratefully acknowledged. JLW acknowledges support from CAPES (Brazil).
References
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The majority of drugs used against malaria, such as chloroquine (Tanenbaum & Tuffanelli, 1980), mefloquine (Palmer et al., 1993), primaquine (Elslager et al., 1969) and amodiaquine (Ridley, 2002) possess a quinoline ring which has been the mainstay of malaria chemotherapy for much of the past 40 years (Font et al., 1997; Kaminsky & Meltzer, 1968; Musiol et al., 2006; Nakamura et al., 1999; Sloboda et al., 1991; Warshakoon et al., 2006). However, their effectiveness has been seriously eroded in recent years, mainly as a result of the development of parasite resistance (Ridley, 2002). Malaria remains one of the most important diseases of humans with over half of the world population at risk of infection. It affects mainly those living in tropical and subtropical areas with an incidence of 500 million cases per year globally (Snow et al., 1999; Breman, 2001; World Health Organization, 1999). As part of our studies (de Souza et al., 2005; Andrade et al., 2007; da Silva et al., 2003; Cunico et al., 2006) of drugs for neglected diseases, various quinoline derivatives with potential antimalarial activities have been investigated. It was during this study that the the title salt hydrate, (I), was characterized.
The quinolinium core in (I), Fig. 1, is essentially planar with a RMS deviation of the 10 atoms comprising the framework being 0.027 Å, with a maximum deviation exhibited by the C3 atom [0.031 (2) Å]. The amine side-chain deviates significantly from this plane starting with the N2 atom which lies 0.082 (2) Å above the plane. Further along the side-chain, the C11 and Cl1 atoms are almost orthogonal to the quinolinium core as seen in the magnitude of the C3/N2/C10/C11 torsion angle of -80.0 (3) °. The N—H group is orientated towards the aromatic ring. These conformational features are as found in the neutral parent compound (Kaiser et al. (2009). The most significant difference between the geometric parameters in the neutral and protonated forms is found in the angles subtended at the N1 atom, i.e. this has widened considerably in (I), 121.00 (19) Å, compared with 115.3 (2) ° in the neutral form, consistent with protonation in the former.
As expected from the composition of (I), there are significant hydrogen bonding interactions operating in the crystal structure, Table 1. The quinolinium nitrogen atom forms a donor interaction to the water molecule which in turn forms two donor interactions to the Cl2 anion. The Cl2 anion accepts a hydrogen bond from the amine-H with the result that a 2-D supramolecular array is formed in the ac plane, Fig. 2. Additional stability to the array is provided by C–H···Cl interactions involving the Cl1 atom, Table 1. Layers stack along the b axis to consolidate the crystal structure.