1-(2-Chloro­phenyl)-N-methyl-N-(1-methyl­propyl)iso­quinoline-3-carbox­amide

The quinoline fragment of the title compound, C₂₁H₂₁ClN₂O (PK11195), is planar; the dihedral angle between this plane and the chloro­phenyl plane is 78.6 (1)°. In the crystal structure, there are two disordered alternative mol­ecules that have different relative stereochemistry of the disordered parts.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.005 Å
• Disorder in main residue
• R factor = 0.069
• wR factor = 0.164
• Data-to-parameter ratio = 12.3

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry


 Alert Level C:



PLAT_301  Alert C Main Residue Disorder ........................      19.00 Perc.


 0 Alert Level A = Potentially serious problem

 0 Alert Level B = Potential problem

 1 Alert Level C = Please check

---

S1. Comment

The title compound, PK11195 [(I) in Scheme below], is the first specific non-benzodiazepine ligand which was found to bind the peripheral benzodiazepine receptors with nanomolar affinity (Dubroeucq et al., 1984; LeFur, Perrier et al., 1983; LeFur, Guilloux et al., 1983), and is commonly used as the radioligand for these receptors. Structural, conformational and electronic requirements for recognition and binding processes were widely studied (for example, Cappelli et al. 1997, and references therein).

Here, we report the results of X-ray crystallographic studies of PK11195. Unfortunately, the crystal structure is highly disordered: the methylpropyl substituent was found in two different positions (hereinafter denoted as A and B, Fig. 1) with site-occupation factors of 0.62 (1) and 0.38 (1) for the A and B fragments, respectively. Moreover, the Cl substituent in the chlorophenyl fragment was also found in two positions (2' and 6'), with site-occupation factors of 0.94 (1) and 0.06 (1), respectively.

Both disordered methylpropyl fragments define different relative stereochemistry of the chiral C33 atom. Attempts to refine the structure in a chiral space group P2₁ gave no significant improvement; the structure could be solved with two different molecules in the asymmetric part of the unit cell, but the refinement was unstable and, what is more important, both independent molecules also showed significant disorder.

Fig. 2 shows a perspective view of the molecule A. The quinoline moiety and the phenyl ring are planar, the maximum deviations from their least-squares planes are 0.019 (3) Å for the former and 0.012 (3) Å for the latter. The dihedral angle between these planes is 78.63 (12)°, close to the value of 74.6° found by molecular mechanics for the receptor-bound molecule (Fiorini et al., 1994). The amide plane C3/C31/O31/N31 makes a dihedral angle of 58.40 (12)° with the quinoline plane.

The crystal packing is mainly determined by van der Waals forces and very weak C—H···Cl and C—H···O interactions.

S2. Experimental

Colourless crystals were grown from an acetone solution by slow evaporation.

S3. Refinement

The sum of the site-occupancy factors for the disordered fragments was constrained to unity. The Cl atom of less occupancy was refined isotropically. Constraints were applied to the geometry (bond lengths and angles), as well as to the anisotropic displacement parameters of the less occupied fragments.

Computing details

Data collection: CAD-4 Software(Enraf-Nonius, 1989); cell refinement: CAD-4 Software; data reduction: ENPROC (Rettig, 1978); program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: Stereochemical Workstation Operation Manual (Siemens, 1989).

Figures

	Fig. 1. Comparison of the disordered fragments (Siemens, 1989). H atoms have been omitted for clarity.
	Fig. 2. A perspective view of the molecule with the atom-numbering scheme (Siemens, 1989). Displacement ellipsoids are drawn at the 33% probability level and H atoms are depicted as spheres of arbitrary radii. Only the molecule of higher occupancy is shown.

1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)isoquinoline-3-carboxamide

Crystal data

C21H21ClN2O	F(000) = 744
Mr = 352.85	Dx = 1.240 Mg m^−3
Monoclinic, P21/c	Cu Kα radiation, λ = 1.54178 Å
a = 10.365 (2) Å	Cell parameters from 25 reflections
b = 15.529 (4) Å	θ = 11–23°
c = 11.767 (3) Å	µ = 1.86 mm^−1
β = 93.33 (2)°	T = 293 K
V = 1890.8 (8) Å^3	Block, colourless
Z = 4	0.15 × 0.1 × 0.1 mm

Data collection

CAD4-F four-circle diffractometer	Rint = 0.074
Radiation source: fine-focus sealed tube	θmax = 67.5°, θmin = 4.3°
Ni-filter monochromator	h = 0→12
ω/2θ scans	k = −14→18
7214 measured reflections	l = −12→14
3385 independent reflections	2 standard reflections every 33 min
2278 reflections with I > 2σ(I)	intensity decay: 5%

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)] = 0.069	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.164	H-atom parameters constrained
S = 1.29	w = 1/[σ^2(Fo^2) + (0.005P)^2 + 0.5P] where P = (Fo^2 + 2Fc^2)/3
3385 reflections	(Δ/σ)max = 0.003
276 parameters	Δρmax = 0.64 e Å^−3
19 restraints	Δρmin = −0.51 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	Occ. (<1)
C1	0.9486 (3)	0.23215 (18)	0.4205 (2)	0.0469 (7)
C1'	0.8930 (3)	0.1463 (2)	0.4479 (3)	0.0564 (8)
C2'	0.8570 (3)	0.0891 (2)	0.3638 (3)	0.0612 (9)
H2B	0.8634	0.1049	0.2882	0.073*	0.064 (2)
Cl2A	0.86755 (12)	0.11831 (7)	0.22397 (8)	0.0801 (4)	0.936 (2)
C3'	0.8107 (4)	0.0073 (2)	0.3891 (4)	0.0853 (13)
H3'	0.7860	−0.0311	0.3312	0.102*
C4'	0.8025 (4)	−0.0151 (3)	0.5000 (5)	0.0910 (13)
H4'	0.7745	−0.0701	0.5176	0.109*
C5'	0.8338 (5)	0.0403 (3)	0.5851 (4)	0.1032 (15)
H5'	0.8251	0.0229	0.6599	0.124*
C6'	0.8797 (3)	0.1243 (3)	0.5641 (4)	0.0957 (15)
H6A	0.9000	0.1630	0.6228	0.115*	0.936 (2)
Cl6B	0.9168 (13)	0.1953 (7)	0.6710 (9)	0.122*	0.064 (2)
N2	1.0708 (2)	0.23158 (15)	0.3962 (2)	0.0501 (6)
C3	1.1277 (3)	0.30875 (19)	0.3754 (2)	0.0453 (7)
C4	1.0654 (3)	0.38537 (19)	0.3793 (2)	0.0472 (7)
H4	1.1094	0.4363	0.3662	0.057*
C4a	0.9335 (3)	0.38763 (18)	0.4033 (2)	0.0446 (7)
C5	0.8620 (3)	0.46484 (19)	0.4094 (3)	0.0540 (8)
H5	0.9021	0.5173	0.3973	0.065*
C6	0.7356 (3)	0.4631 (2)	0.4329 (3)	0.0605 (8)
H6	0.6895	0.5142	0.4370	0.073*
C7	0.6741 (3)	0.3842 (2)	0.4510 (3)	0.0620 (9)
H7	0.5869	0.3834	0.4654	0.074*
C8	0.7401 (3)	0.3093 (2)	0.4478 (3)	0.0540 (8)
H8	0.6980	0.2576	0.4608	0.065*
C8a	0.8725 (3)	0.30848 (18)	0.4247 (2)	0.0441 (7)
C31	1.2704 (3)	0.3049 (2)	0.3562 (3)	0.0496 (7)
O31	1.3445 (2)	0.34467 (16)	0.4223 (2)	0.0708 (7)
N31	1.3089 (2)	0.2586 (2)	0.2697 (3)	0.0685 (9)
C32A	1.2164 (11)	0.2327 (9)	0.1757 (11)	0.076 (4)	0.624 (9)
H32A	1.2606	0.1997	0.1210	0.092*	0.624 (9)
H32B	1.1795	0.2832	0.1397	0.092*	0.624 (9)
H32C	1.1490	0.1985	0.2054	0.092*	0.624 (9)
C33A	1.4472 (7)	0.2607 (6)	0.2448 (8)	0.063 (2)	0.624 (9)
H33A	1.4951	0.2772	0.3156	0.076*	0.624 (9)
C34A	1.4848 (16)	0.3240 (7)	0.1547 (15)	0.102 (4)	0.624 (9)
H34A	1.4576	0.3808	0.1748	0.123*	0.624 (9)
H34B	1.4438	0.3081	0.0825	0.123*	0.624 (9)
H34C	1.5769	0.3233	0.1497	0.123*	0.624 (9)
C35A	1.4883 (8)	0.1691 (5)	0.2180 (7)	0.081 (2)	0.624 (9)
H35A	1.5805	0.1687	0.2080	0.097*	0.624 (9)
H35B	1.4450	0.1516	0.1463	0.097*	0.624 (9)
C36A	1.459 (2)	0.1030 (7)	0.3091 (16)	0.124 (5)	0.624 (9)
H36A	1.4868	0.0470	0.2862	0.149*	0.624 (9)
H36B	1.3672	0.1018	0.3185	0.149*	0.624 (9)
H36C	1.5032	0.1185	0.3799	0.149*	0.624 (9)
C32B	1.2261 (17)	0.1992 (14)	0.199 (2)	0.085 (8)	0.376 (9)
H32D	1.2764	0.1734	0.1416	0.102*	0.376 (9)
H32E	1.1556	0.2309	0.1624	0.102*	0.376 (9)
H32F	1.1929	0.1550	0.2459	0.102*	0.376 (9)
C33B	1.4506 (11)	0.2290 (9)	0.2770 (13)	0.064 (4)	0.376 (9)
H33B	1.4941	0.2577	0.3429	0.077*	0.376 (9)
C34B	1.472 (2)	0.1334 (11)	0.291 (3)	0.124 (10)	0.376 (9)
H34D	1.4351	0.1145	0.3601	0.149*	0.376 (9)
H34E	1.5628	0.1214	0.2955	0.149*	0.376 (9)
H34F	1.4309	0.1036	0.2275	0.149*	0.376 (9)
C35B	1.5071 (12)	0.2652 (10)	0.1705 (12)	0.097 (5)	0.376 (9)
H35C	1.5985	0.2514	0.1728	0.117*	0.376 (9)
H35D	1.4663	0.2364	0.1046	0.117*	0.376 (9)
C36B	1.492 (4)	0.3609 (13)	0.154 (3)	0.155 (13)	0.376 (9)
H36D	1.5289	0.3778	0.0850	0.186*	0.376 (9)
H36E	1.5350	0.3904	0.2174	0.186*	0.376 (9)
H36F	1.4016	0.3754	0.1506	0.186*	0.376 (9)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0415 (16)	0.0483 (16)	0.0516 (18)	−0.0031 (13)	0.0072 (13)	−0.0017 (13)
C1'	0.0427 (17)	0.0470 (17)	0.080 (2)	−0.0012 (14)	0.0105 (15)	0.0035 (16)
C2'	0.057 (2)	0.0512 (18)	0.077 (2)	−0.0019 (16)	0.0192 (17)	0.0016 (16)
Cl2A	0.1093 (9)	0.0711 (6)	0.0606 (6)	−0.0157 (6)	0.0105 (5)	−0.0101 (5)
C3'	0.096 (3)	0.050 (2)	0.113 (3)	−0.005 (2)	0.031 (3)	−0.011 (2)
C4'	0.096 (3)	0.070 (3)	0.109 (4)	−0.013 (2)	0.025 (3)	0.020 (3)
C5'	0.113 (4)	0.099 (3)	0.100 (4)	−0.021 (3)	0.019 (3)	0.035 (3)
C6'	0.073 (3)	0.101 (3)	0.116 (3)	−0.005 (2)	0.031 (2)	0.062 (3)
N2	0.0417 (14)	0.0480 (14)	0.0615 (16)	−0.0001 (11)	0.0105 (11)	0.0022 (11)
C3	0.0371 (15)	0.0526 (17)	0.0466 (16)	−0.0034 (13)	0.0065 (12)	−0.0034 (13)
C4	0.0403 (16)	0.0483 (16)	0.0537 (17)	−0.0071 (13)	0.0088 (13)	−0.0043 (13)
C4a	0.0406 (15)	0.0469 (15)	0.0464 (16)	−0.0017 (13)	0.0046 (12)	−0.0035 (12)
C5	0.0530 (19)	0.0434 (16)	0.066 (2)	0.0018 (14)	0.0049 (15)	−0.0053 (14)
C6	0.0509 (19)	0.059 (2)	0.071 (2)	0.0109 (16)	0.0046 (16)	−0.0082 (16)
C7	0.0392 (16)	0.077 (2)	0.070 (2)	0.0054 (17)	0.0081 (14)	−0.0095 (18)
C8	0.0418 (17)	0.0591 (19)	0.062 (2)	−0.0070 (15)	0.0073 (14)	−0.0054 (15)
C8a	0.0383 (15)	0.0485 (16)	0.0455 (16)	−0.0003 (13)	0.0031 (12)	−0.0017 (12)
C31	0.0369 (16)	0.0550 (18)	0.0573 (19)	−0.0054 (14)	0.0074 (13)	−0.0029 (14)
O31	0.0451 (13)	0.0879 (17)	0.0802 (16)	−0.0133 (12)	0.0093 (11)	−0.0301 (13)
N31	0.0360 (14)	0.101 (2)	0.0692 (19)	−0.0028 (14)	0.0094 (13)	−0.0330 (16)
C32A	0.046 (4)	0.120 (9)	0.062 (6)	−0.005 (5)	−0.006 (3)	−0.036 (7)
C33A	0.038 (4)	0.087 (6)	0.065 (5)	−0.001 (4)	0.012 (3)	−0.011 (4)
C34A	0.083 (7)	0.095 (8)	0.134 (10)	−0.006 (7)	0.056 (7)	0.027 (8)
C35A	0.054 (4)	0.094 (6)	0.095 (6)	0.013 (4)	0.012 (4)	−0.020 (4)
C36A	0.146 (11)	0.083 (8)	0.143 (11)	0.031 (8)	0.002 (9)	0.003 (8)
C32B	0.042 (7)	0.142 (19)	0.072 (10)	0.007 (9)	0.020 (7)	−0.023 (11)
C33B	0.038 (6)	0.073 (8)	0.082 (10)	0.000 (5)	0.011 (6)	−0.018 (6)
C34B	0.070 (11)	0.074 (11)	0.23 (3)	0.015 (10)	−0.009 (16)	−0.018 (12)
C35B	0.054 (7)	0.157 (15)	0.083 (9)	−0.025 (9)	0.018 (6)	−0.027 (9)
C36B	0.14 (2)	0.19 (2)	0.134 (18)	0.02 (2)	0.023 (15)	0.087 (19)

Geometric parameters (Å, º)

C1—N2	1.315 (4)	C6—C7	1.403 (5)
C1—C8a	1.426 (4)	C7—C8	1.351 (4)
C1—C1'	1.495 (4)	C8—C8a	1.414 (4)
C1'—C2'	1.366 (5)	C3—C31	1.510 (4)
C1'—C6'	1.423 (5)	C31—O31	1.228 (3)
C2'—C3'	1.395 (5)	C31—N31	1.327 (4)
C2'—Cl2A	1.717 (4)	N31—C32A	1.476 (8)
C3'—C4'	1.358 (6)	N31—C33A	1.479 (7)
C4'—C5'	1.345 (6)	N31—C32B	1.48 (1)
C5'—C6'	1.416 (5)	N31—C33B	1.54 (1)
C6'—Cl6B	1.70 (1)	C33A—C34A	1.51 (1)
N2—C3	1.364 (3)	C33A—C35A	1.52 (1)
C3—C4	1.356 (4)	C35A—C36A	1.53 (1)
C4—C4a	1.412 (4)	C33B—C34B	1.51 (2)
C4a—C8a	1.412 (4)	C33B—C35B	1.52 (1)
C4a—C5	1.414 (4)	C35B—C36B	1.51 (2)
C5—C6	1.355 (4)
N2—C1—C8a	123.7 (3)	C8—C7—C6	120.8 (3)
N2—C1—C1'	115.4 (3)	C7—C8—C8a	120.7 (3)
C8a—C1—C1'	120.9 (2)	C4a—C8a—C8	118.5 (3)
C2'—C1'—C6'	120.2 (3)	C4a—C8a—C1	117.6 (2)
C2'—C1'—C1	121.1 (3)	C8—C8a—C1	124.0 (3)
C6'—C1'—C1	118.7 (3)	O31—C31—N31	123.6 (3)
C1'—C2'—C3'	121.4 (4)	O31—C31—C3	117.8 (3)
C1'—C2'—Cl2A	119.5 (3)	N31—C31—C3	118.5 (3)
C3'—C2'—Cl2A	119.1 (3)	C31—N31—C32A	120.7 (6)
C4'—C3'—C2'	118.6 (4)	C31—N31—C33A	118.6 (5)
C5'—C4'—C3'	121.7 (4)	C32A—N31—C33A	116.9 (7)
C4'—C5'—C6'	121.9 (4)	C31—N31—C32B	125.4 (9)
C5'—C6'—C1'	116.1 (4)	C33A—N31—C32B	116 (1)
C5'—C6'—Cl6B	122.2 (6)	C31—N31—C33B	116.6 (7)
C1'—C6'—Cl6B	121.7 (5)	C32A—N31—C33B	123 (1)
C1—N2—C3	117.7 (2)	C32B—N31—C33B	111.4 (9)
C4—C3—N2	123.6 (3)	N31—C33A—C34A	116.4 (8)
C4—C3—C31	120.9 (3)	N31—C33A—C35A	107.8 (6)
N2—C3—C31	115.4 (3)	C34A—C33A—C35A	112.0 (8)
C3—C4—C4a	119.8 (3)	C33A—C35A—C36A	114.3 (8)
C4—C4a—C8a	117.6 (3)	C34B—C33B—C35B	113 (1)
C4—C4a—C5	123.2 (3)	C34B—C33B—N31	116 (1)
C8a—C4a—C5	119.2 (3)	C35B—C33B—N31	104.8 (8)
C6—C5—C4a	120.6 (3)	C36B—C35B—C33B	115 (1)
C5—C6—C7	120.1 (3)
N2—C1—C1'—C2'	−78.3 (4)	C5—C6—C7—C8	1.4 (5)
C8a—C1—C1'—C2'	103.5 (4)	C6—C7—C8—C8a	−0.7 (5)
N2—C1—C1'—C6'	100.9 (3)	C4—C4a—C8a—C8	−179.4 (3)
C8a—C1—C1'—C6'	−77.3 (4)	C5—C4a—C8a—C8	2.2 (4)
C6'—C1'—C2'—C3'	−2.2 (5)	C4—C4a—C8a—C1	0.0 (4)
C1—C1'—C2'—C3'	177.0 (3)	C5—C4a—C8a—C1	−178.5 (3)
C6'—C1'—C2'—Cl2A	177.4 (3)	C7—C8—C8a—C4a	−1.0 (5)
C1—C1'—C2'—Cl2A	−3.5 (4)	C7—C8—C8a—C1	179.6 (3)
C1'—C2'—C3'—C4'	−0.3 (6)	N2—C1—C8a—C4a	−1.1 (4)
Cl2A—C2'—C3'—C4'	−179.9 (3)	C1'—C1—C8a—C4a	176.9 (3)
C2'—C3'—C4'—C5'	2.1 (7)	N2—C1—C8a—C8	178.2 (3)
C3'—C4'—C5'—C6'	−1.4 (8)	C1'—C1—C8a—C8	−3.8 (5)
C4'—C5'—C6'—C1'	−1.1 (6)	O31—C31—N31—C32A	−162.7 (8)
C4'—C5'—C6'—Cl6B	178.8 (6)	C3—C31—N31—C32A	17.6 (8)
C2'—C1'—C6'—C5'	2.8 (5)	O31—C31—N31—C33A	−5.5 (6)
C1—C1'—C6'—C5'	−176.4 (3)	C3—C31—N31—C33A	174.9 (4)
C2'—C1'—C6'—Cl6B	−177.1 (5)	O31—C31—N31—C32B	170 (1)
C1—C1'—C6'—Cl6B	3.7 (4)	C3—C31—N31—C32B	−9 (1)
C8A—C1—N2—C3	0.9 (4)	O31—C31—N31—C33B	21.2 (7)
C1'—C1—N2—C3	−177.2 (3)	C3—C31—N31—C33B	−158.4 (5)
C1—N2—C3—C4	0.4 (4)	C31—N31—C33A—C34A	−95 (1)
C1—N2—C3—C31	175.8 (3)	C32A—N31—C33A—C34A	63 (1)
C4—C3—C31—O31	56.3 (4)	C31—N31—C33A—C35A	137.7 (6)
N2—C3—C31—O31	−119.2 (3)	C32A—N31—C33A—C35A	−64 (1)
C4—C3—C31—N31	−124.0 (3)	N31—C33A—C35A—C36A	−54 (1)
N2—C3—C31—N31	60.5 (4)	C34A—C33A—C35A—C36A	177 (1)
N2—C3—C4—C4a	−1.5 (4)	C31—N31—C33B—C34B	112 (2)
C31—C3—C4—C4a	−176.7 (3)	C32B—N31—C33B—C34B	−41 (2)
C3—C4—C4a—C8a	1.3 (4)	C31—N31—C33B—C35B	−122.6 (9)
C3—C4—C4a—C5	179.6 (3)	C32B—N31—C33B—C35B	84 (1)
C4—C4a—C5—C6	−179.9 (3)	C34B—C33B—C35B—C36B	−178 (2)
C8a—C4a—C5—C6	−1.6 (4)	N31—C33B—C35B—C36B	55 (2)
C4a—C5—C6—C7	−0.2 (5)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C4—H4···Cl2A^i	0.93	3.03	3.891 (3)	154
C5—H5···Cl2A^i	0.93	3.25	4.064 (3)	147
C6—H6···O31^ii	0.93	2.78	3.560 (4)	142
C7—H7···O31^iii	0.93	2.60	3.468 (4)	155

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