Weak inter­molecular inter­actions in 11-chloro-2,3,4,5-tetra­hydro-1H-cyclo­hepta­[b]quinoline

The title compound, C₁₄H₁₄ClN, is a chloro analogue of tacrine, an acetyl­cholinesterase inhibitor. The compound comprises a seven-membered alicyclic ring whose CH donor groups are engaged in extensive inter­molecular inter­actions. The important feature of this crystal structure is that, regardless of the presence of two typical hydrogen-bonding acceptors, viz. chlorine and nitro­gen, the corresponding C-H...Cl and C-H...N inter­actions take no significant role in crystal stabilization. The mol­ecules form dimers through [pi]-[pi] inter­actions with an inter­planar distance between inter­acting pyridine rings of 3.576 (1) Å. Within the dimers, the mol­ecules are additionally inter­connected by four C-H...[pi] inter­actions. The dimers arrange into regular columns via further inter­molecular C-H...[pi] inter­actions.

S1. Comment

Tacrine, (I), is the first reversible inhibitor of acetylcholinesterase (AChE, EC 3.1.1.7) approved by the US Federal Drug Administration for palliative treatment of Alzheimer's disease. Harel et al. (1993) have determined the TcAChE crystal structure (from Torpedo californica) complexed with (I) (Protein Data Bank code 1acj). Tacrine forms stacking interactions with Trp 84 and Phe 330 aromatic rings inside of the AChE active site gorge. Protonated aromatic N atoms form hydrogen bonds with carbonyl O atoms of His 440 (a part of the AChE catalytic triad), while amino N atoms form hydrogen bonds with conserved water molecules. However, the determined AChE–tacrine crystal structure does not reveal the nature of the cycloalkyl group's influence on the anticholinesterase activity. Severe hepatotoxicity has reduced the therapeutic use of (I), but the search for tacrine analogs with improved properties is of persistent interest (Munoz-Torrero & Camps, 2006).

In the past decade, approximately 100 homo- and heterodimeric tacrine analogs, (III) (n = 5–7 and m = 6–8), have been synthesized. These compounds are diverse in respect to the linker length, the substituents on the tetrahydroacridine nucleus and the size of the alicyclic ring. 4-Aminopyridine and 4-aminoquinoline, (IV), have very weak anticholinesterase activity, indicating the importance of the cycloalkyl ring for the inhibition potency (Kaul, 1962). The same is true for the homodimeric AChE inhibitors. 4-Aminoquinoline dimers are considerably weaker AChE inhibitors than tacrine homodimers (Han et al., 1999). Furthermore, a decrease in the size of the alicyclic ring to five-membered causes a 100-fold decrease in the AChE inhibition abilities, while their increase to seven-membered produces a negligible decrease (Hu et al., 2002). Different 9-chloro analogs of tacrine serve as synthones for the synthesis of dual homo- and heterodimeric tacrine derivatives. Having this in mind, we report here the molecular structure of the title compound, (II).

Compound (II) (Fig. 1) consists of a 4-chloroquinoline system and a cycloheptyl ring, which is fused to the aromatic moiety. As expected, the quinoline system is highly planar, having an r.m.s. deviation of fitted atoms of 0.016 Å. The Cl atom lies 0.067 (1) Å out of the quinoline plane, while atoms C6 and C10 of the fused cycloheptyl ring are coplanar within 0.083 (2) Å. The seven-membered ring adopts a quite regular chair conformation, where the C6—C5A—C10A—C10 torsion angle and the C6—C7···C9—C10 angle are 2.2 (2) and -1.6 (2)° respectively. The bond distances within the molecule (Table 1) are in good agreement with those reported for the two derivatives that contain an additional phenyl ring fused to the cycloheptyl ring, namely 10-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline, (V), and 10-methyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]-quinoline. (VI) (Ray et al., 1998).

Despite the presence of the typical hydrogen-bonding acceptors nitrogen and chlorine, the crystal structure of (II) lacks the expected intermolecular C—H···N and C—H···Cl hydrogen bonding. On the other hand, the crystal structure is characterized by a number of weak C—H···π interactions (Desiraju & Steiner, 1999), which involve all of the axial H atoms of the cycloheptyl fragment and the quinoline moiety as a π system (Table 2).

The cycloheptyl donors C6 and C10, which are the most coplanar with the quinoline system, are involved in the C—H···π interactions with the shortest H···Perp distances (Table 2). Two pairs of these interactions connect the centrosymmetrically related molecules into a dimer. The formation of dimers is also favored by π stacking interactions occurring between the pyridine rings of the molecular pair. Owing to inversion symmetry, the stacked pyridine rings have opposite orientations, with a Cg1···Cg1ⁱⁱ distance of 3.837 (1) Å and a slippage of 1.391 Å [Cg1 refers to the centroid of the pyridine ring; symmetry codes: (ii) -x + 1, -y, -z]. The pyridine rings are arranged in such a way that atom C10A is positioned above the center of the neighboring ring (Fig. 2). The interplanar separation between the rings is 3.576 (1) Å, while the shortest distance found between the atoms, C5A···C11ⁱⁱ [please check added symmetry code], is 3.567 (2) Å.

The additional C—H···π interactions (Table 2) formed from each side of the dimer engage the rest of the cycloheptyl C—H donors, connecting the dimers into a column extending along the b axis (Fig. 2). Although rather weak, the C—H···π interactions between the dimers imply simultaneous engagement of six CH donor groups and their clear directionality toward the two neighboring quinoline systems. The perpendicular distances of all interacting H atoms to quinoline planes are below 3.05 Å. The dimers within a column are strictly parallel; however, the size and chair-like conformation of the cycloheptyl ring increase the separation between the dimers in the b direction, preventing the potential π–π stacking between their aromatic parts. In this case, the interplanar distance between the quinoline rings is 5.035 (1) Å. The columns of dimers are further related through very weak, cyclic, C4—H4···N5ⁱⁱⁱ and C8—H8b···Cl1^iv interactions, forming a two-dimensional structure parallel to the ab plane [C4—H4 = 0.93 Å, H4···N5ⁱⁱⁱ = 2.89 Å, C4···N5ⁱⁱⁱ = 3.661 (4) Å, C4—H4···N5ⁱⁱⁱ = 141° and C9—H9B = 0.97 Å, H9B···Cl1^iv = 3.31 Å, C8···Cl1^iv = 4.027 (4) Å, C9—H9b···Cl1^iv = 132°; symmetry codes: (iii) -x + 2, -y + 1, -z; (v) -x, -y, -z; Fig. 3]. These are the shortest intermolecular interactions concerning the N5 and Cl1 acceptors.

The crystal arrangements in (V) and (VI), and also in 6,9-dichloro-1,2,3,4-tetrahydroacridine (Elsinghorst et al., 2007), which is the cyclohexyl analogue of (II), display a similar method of dimer formation. In each of these structures, the centrosymmetrically related molecules are associated by weak C—H···π interactions, where the cycloalkyl rings provide the donors and the quinoline cores serve as the acceptors. In addition to C—H···π interactions the dimers are stabilized by π–π stacking involving only the pyridine fragments of the molecules. The interplanar distances between the parallel quinoline systems in these structures range from 3.55 to 3.70 Å.

According to previous reports, weak C—H···π and π–π interactions play a dominant role in crystal structure of 11-chloro-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinoline (reference?) as well as in similar crystal structures (references?).

Related literature

For related literature, see: Desiraju & Steiner (1999); Elsinghorst et al. (2007); Han et al. (1999); Harel et al. (1993); Hu et al. (2002); Kaul (1962); Munoz-Torrero & Camps (2006); Ray et al. (1998).

S2. Experimental

All chemicals used were of analytical grade. To a mixture of anthranilic acid (2.4 g, 17.5 mmol) and cycloheptanone (2.1 ml, 17.5 mmol) in an ice-bath was carefully added phosphorous oxychloride (POCl₃, 17.5 ml). The mixture was refluxed for 2 h and then cooled to room temperature. Surplus POCl₃ was removed under reduced pressure and the resulting slurry was subsequently poured into an ice and solid K₂CO₃ mixture with vigorous stirring. The separated solid was taken up in ethyl acetate; the solution was evaporated and the crude residue was recrystallized from acetone to afford 3.20 g (39.42%) of (II) as yellow crystals. The single crystals that were submitted for single-crystal X-ray analysis were obtained after recrystalization from acetone (m.p. 367–369 K). Analysis found for C₁₄H₁₄ClN: C 72.06, H 6.17, N 6.04% (also give expected values?). ¹H NMR: δ 1.67–1.95 (m, 6H); 3.17, 3.20, 3.22, 3.25 (m, 4H); 7.50, 7.53, 7.56 (triplet-like peaks, 1H); 7.62, 7.65, 7.69 (triplet-like peaks, 1H); 7.96, 8.00 (doublet-like peaks, 1H); 8.13, 8.17 (doublet-like peaks, 1H). ¹³C NMR: δ 26.78, 27.367, 30.26, 31.74, 40.148, 76.38, 77.00, 77.64, 124.45, 125.40, 126.62, 128.80, 129.07, 133.84, 139.63, 146.42, 164.76.

S3. Refinement

All H atoms were found in a difference Fourier map, but they were placed at geometrically calculated positions and refined using a riding model. C—H distances were fixed to 0.97 and 0.93 Å for Csp³ and Csp² atoms, respectively. The U_iso values of all H atoms were set to 1.2U_eq of the parent atom.

Computing details

Data collection: CAD-4 Software (Enraf–Nonius, 1989); cell refinement: CAD-4 Software (Enraf–Nonius, 1989); data reduction: XCAD4 (Harms & Wocadlo, 1995); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 1997); software used to prepare material for publication: WinGX (Farrugia, 1999) and PLATON (Spek, 2003).

Figures

	Fig. 1. A view of the molecule of (II), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 40% probability level.
	Fig. 2. Segment of a column of molecules generated by C—H···π and π–π interactions. [Ideally the atom labels should include symmetry codes in accordance with those given in the text.]
	Fig. 3. Columns of molecules connected by weak C4—H4···N5^iii and C9—H9B···Cl1^iv interactions, viewed approximately along the c axis. The interactions within the columns (presented in Fig. 2) have been omitted for clarity. [Ideally the atom labels should include symmetry codes in accordance with those given in the text.]

11-chloro-2,3,4,5-tetrahydro-1H-cyclohepta[b]quinoline

Crystal data

C14H14ClN	Z = 2
Mr = 231.71	F(000) = 244
Triclinic, P1	Dx = 1.306 Mg m^−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 8.213 (2) Å	Cell parameters from 25 reflections
b = 8.727 (2) Å	θ = 11.5–15.2°
c = 9.042 (3) Å	µ = 0.29 mm^−1
α = 90.50 (2)°	T = 293 K
β = 95.32 (3)°	Prism, yellow
γ = 113.86 (3)°	0.56 × 0.44 × 0.42 mm
V = 589.4 (3) Å^3

Data collection

Enraf–Nonius CAD-4 diffractometer	Rint = 0.011
Radiation source: fine-focus sealed tube	θmax = 26.0°, θmin = 2.3°
Graphite monochromator	h = 0→10
ω/2θ scans	k = −10→9
2548 measured reflections	l = −11→11
2309 independent reflections	3 standard reflections every 60 min
2003 reflections with I > 2σ(I)	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)] = 0.037	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.107	H-atom parameters constrained
S = 1.08	w = 1/[σ^2(Fo^2) + (0.0537P)^2 + 0.133P] where P = (Fo^2 + 2Fc^2)/3
2309 reflections	(Δ/σ)max < 0.001
145 parameters	Δρmax = 0.19 e Å^−3
0 restraints	Δρmin = −0.20 e Å^−3

Special details

Experimental. Melting point was obtained on Buchi apparatus in open capillary tube and is uncorrected. NMR spectra were recorded on Varian Gemini 200 (200/50 MHz) spectrometer in CDCl3, using tetramethylsilane (TMS) as internal standard.

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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	0.6756 (2)	0.2078 (2)	0.37705 (18)	0.0508 (4)
H1	0.5854	0.1643	0.4395	0.061*
C2	0.8504 (3)	0.2616 (2)	0.43426 (19)	0.0591 (4)
H2	0.8782	0.2527	0.5350	0.071*
C3	0.9886 (2)	0.3302 (2)	0.3424 (2)	0.0601 (4)
H3	1.1074	0.3681	0.3828	0.072*
C4	0.9495 (2)	0.3415 (2)	0.19432 (19)	0.0531 (4)
H4	1.0420	0.3877	0.1344	0.064*
C4A	0.76991 (19)	0.28386 (18)	0.13073 (16)	0.0407 (3)
C5A	0.5718 (2)	0.24434 (17)	−0.07907 (16)	0.0415 (3)
C6	0.5489 (2)	0.2602 (2)	−0.24480 (17)	0.0533 (4)
H6A	0.4697	0.1514	−0.2908	0.064*
H6B	0.6642	0.2917	−0.2826	0.064*
C7	0.4727 (3)	0.3889 (2)	−0.2919 (2)	0.0645 (5)
H7A	0.5307	0.4882	−0.2256	0.077*
H7B	0.5033	0.4217	−0.3913	0.077*
C8	0.2719 (3)	0.3287 (2)	−0.2915 (2)	0.0664 (5)
H8B	0.2139	0.2314	−0.3602	0.080*
H8A	0.2370	0.4161	−0.3287	0.080*
C9	0.2027 (3)	0.2822 (2)	−0.1411 (2)	0.0629 (5)
H9B	0.0753	0.2552	−0.1510	0.075*
H9A	0.2609	0.3790	−0.0721	0.075*
C10	0.2338 (2)	0.1327 (2)	−0.0748 (2)	0.0582 (4)
H10B	0.1470	0.0817	−0.0047	0.070*
H10A	0.2128	0.0493	−0.1542	0.070*
C10A	0.41920 (19)	0.17982 (17)	0.00316 (17)	0.0425 (3)
C11	0.4537 (2)	0.16740 (18)	0.15295 (17)	0.0425 (3)
C11A	0.6304 (2)	0.21762 (17)	0.22388 (16)	0.0398 (3)
Cl1	0.27868 (6)	0.09149 (6)	0.26571 (5)	0.06761 (19)
N5	0.73866 (16)	0.29468 (15)	−0.01926 (14)	0.0437 (3)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0615 (10)	0.0509 (9)	0.0416 (8)	0.0232 (8)	0.0118 (7)	0.0098 (7)
C2	0.0713 (11)	0.0645 (11)	0.0413 (9)	0.0292 (9)	−0.0028 (8)	0.0058 (8)
C3	0.0520 (10)	0.0675 (11)	0.0575 (10)	0.0235 (9)	−0.0065 (8)	0.0015 (8)
C4	0.0433 (8)	0.0588 (10)	0.0548 (9)	0.0177 (7)	0.0070 (7)	0.0075 (7)
C4A	0.0432 (8)	0.0376 (7)	0.0428 (8)	0.0173 (6)	0.0077 (6)	0.0068 (6)
C5A	0.0493 (8)	0.0341 (7)	0.0418 (8)	0.0176 (6)	0.0047 (6)	0.0057 (6)
C6	0.0658 (10)	0.0544 (9)	0.0411 (8)	0.0262 (8)	0.0042 (7)	0.0042 (7)
C7	0.0870 (13)	0.0565 (10)	0.0489 (10)	0.0297 (10)	−0.0022 (9)	0.0138 (8)
C8	0.0837 (13)	0.0572 (10)	0.0618 (11)	0.0381 (10)	−0.0205 (10)	−0.0007 (8)
C9	0.0568 (10)	0.0638 (11)	0.0726 (12)	0.0328 (9)	−0.0101 (9)	−0.0014 (9)
C10	0.0458 (9)	0.0519 (9)	0.0687 (11)	0.0132 (7)	−0.0033 (8)	0.0087 (8)
C10A	0.0430 (8)	0.0339 (7)	0.0499 (8)	0.0152 (6)	0.0034 (6)	0.0064 (6)
C11	0.0424 (8)	0.0363 (7)	0.0507 (8)	0.0159 (6)	0.0139 (6)	0.0106 (6)
C11A	0.0475 (8)	0.0338 (7)	0.0407 (7)	0.0184 (6)	0.0087 (6)	0.0071 (5)
Cl1	0.0522 (3)	0.0795 (3)	0.0717 (3)	0.0225 (2)	0.0281 (2)	0.0234 (2)
N5	0.0456 (7)	0.0440 (7)	0.0417 (7)	0.0175 (6)	0.0092 (5)	0.0090 (5)

Geometric parameters (Å, º)

C1—C2	1.364 (2)	C7—H7A	0.9700
C1—C11A	1.413 (2)	C7—H7B	0.9700
C1—H1	0.9300	C8—C9	1.518 (3)
C2—C3	1.405 (3)	C8—H8B	0.9700
C2—H2	0.9300	C8—H8A	0.9700
C3—C4	1.361 (2)	C9—C10	1.543 (2)
C3—H3	0.9300	C9—H9B	0.9700
C4—C4A	1.413 (2)	C9—H9A	0.9700
C4—H4	0.9300	C10—C10A	1.508 (2)
C4A—N5	1.3680 (19)	C10—H10B	0.9700
C4A—C11A	1.417 (2)	C10—H10A	0.9700
C5A—N5	1.3169 (19)	C10A—C11	1.372 (2)
C5A—C10A	1.432 (2)	C11—C11A	1.420 (2)
C5A—C6	1.508 (2)	C11—Cl1	1.7485 (15)
C6—C7	1.537 (2)	C8—H8A	0.9700
C6—H6A	0.9700	C7—H7A	0.9700
C6—H6B	0.9700	C7—H7B	0.9700
C7—C8	1.515 (3)
C2—C1—C11A	120.61 (15)	H7A—C7—H7B	107.5
C2—C1—H1	119.7	C7—C8—C9	115.18 (15)
C11A—C1—H1	119.7	C7—C8—H8B	108.5
C1—C2—C3	120.58 (15)	C9—C8—H8B	108.5
C1—C2—H2	119.7	C7—C8—H8A	108.5
C3—C2—H2	119.7	C9—C8—H8A	108.5
C4—C3—C2	120.24 (16)	H8B—C8—H8A	107.5
C4—C3—H3	119.9	C8—C9—C10	114.14 (16)
C2—C3—H3	119.9	C8—C9—H9B	108.7
C3—C4—C4A	120.70 (15)	C10—C9—H9B	108.7
C3—C4—H4	119.7	C8—C9—H9A	108.7
C4A—C4—H4	119.7	C10—C9—H9A	108.7
N5—C4A—C4	118.09 (13)	H9B—C9—H9A	107.6
N5—C4A—C11A	122.82 (13)	C10A—C10—C9	113.83 (14)
C4—C4A—C11A	119.09 (14)	C10A—C10—H10B	108.8
N5—C5A—C10A	124.20 (13)	C9—C10—H10B	108.8
N5—C5A—C6	115.23 (14)	C10A—C10—H10A	108.8
C10A—C5A—C6	120.57 (14)	C9—C10—H10A	108.8
C5A—C6—C7	114.31 (14)	H10B—C10—H10A	107.7
C5A—C6—H6A	108.7	C11—C10A—C5A	116.21 (13)
C7—C6—H6A	108.7	C11—C10A—C10	123.68 (14)
C5A—C6—H6B	108.7	C5A—C10A—C10	120.10 (14)
C7—C6—H6B	108.7	C10A—C11—C11A	122.32 (13)
H6A—C6—H6B	107.6	C10A—C11—Cl1	120.60 (12)
C8—C7—C6	115.12 (15)	C11A—C11—Cl1	117.07 (11)
C8—C7—H7A	108.5	C1—C11A—C4A	118.76 (14)
C6—C7—H7A	108.5	C1—C11A—C11	125.36 (14)
C8—C7—H7B	108.5	C4A—C11A—C11	115.88 (13)
C6—C7—H7B	108.5	C5A—N5—C4A	118.53 (13)