1-(3-Chloro­phenyl)-4-(3-chloro­propyl)­piperazinium chloride

The title compound, C₁₃H₁₉Cl₂N₂⁺·Cl^-, exhibits stereochemical features that are deemed necessary for 5-HT₁ subtype serotonin receptor interaction. A distance of 5.69 (1) Å is observed between the protonated nitro­gen and the centroid of the phenyl ring. The piperazine ring adopts a chair conformation and the protonated nitro­gen is involved in hydrogen bonding to the chloride counter-ion. The chloro­phenyl moiety is disordered, with the major conformer adopting a trans, trans geometry while the minor conformer is trans, gauche.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.004 Å
• R factor = 0.047
• wR factor = 0.130
• Data-to-parameter ratio = 17.1

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry

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S1. Comment

The stereochemical requirements of the 5-HT₁ (5-hydroxytryptamine₁) subtype serotonin receptors dictate that drugs exhibit several common features. General characteristics which persist are (a) a protonated or protonable aminic nitrogen separated by a short chain of 3–4 atoms from an aromatic ring, as a conformational constraint at least two atoms of the chain should be embedded in a ring, (b) a nitrogen to aromatic ring centroid distance of 5–6 Å and, to a lesser extent, (c) the presence of long bulky chain substituents on the aminic nitrogen (Dalpiaz et al., 1996, Chilmonczyk et al., 1995). The three-dimensional structure of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride, (I), was determined in order to compare its conformation to other compounds of this type.

The piperazine ring in (I) adopts a chair conformation, with N1 and N2 out-of-plane deviations of 0.68 and 0.64 Å, respectively. The ring is protonated at N2 and it is this nitrogen that is involved in hydrogen bonding to Cl1 [3.048 (2) Å, 171°]. A distance of 5.69 Å is observed between N2 and the centroid of the phenyl ring in (I). This is consistent with known 5-HT₁ receptor ligands such as 1-[3-(3,4-methylenedioxyphenoxy)propyl]-4-phenylpiperazinium chloride (5.68 Å; Okamoto et al., 1993), eltoprazine (5.65 Å; Verdonk et al., 1992) and 1-(2-methoxyphenyl)-4-[4-(2-(phthalimido)butyl]piperazinium bromide (5.66 Å; Dalpiaz et al., 1996).

The chloropropyl moiety in (I) is disordered over two principal conformations. The major conformer is fully extended with a trans, trans geometry about C11—C12 and C12—C13 (torsion angles of −178.7 (4)° and −172.3 (4)°, respectively). The minor conformer is folded with a trans, gauche geometry about C11'-C12' and C12—C13' (torsion angles of −175 (1)° and 67 (2)°, respectively.

S2. Experimental

Crystals of (I) were obtained as colorless irregular blocks from slow evaporation of alcoholic solutions maintained at room temperature.

S3. Refinement

The position of H1 was located directly from the difference map at an N—H distance of 1.09 Å, then adjusted to a more acceptable distance of 0.87 Å and held at this distance in subsequent refinements. The remaining hydrogen atoms were calculated based on geometric criteria and treated with a riding model. All H-atom isotropic temperature factors were defined as 1.2U_eq of the adjacent atom. The chloropropyl moiety shows disorder over two principal conformations. Refinement of the anisotropic displacement parameters, although still exhibiting signs of unresolved disorder, proceeded the most agreeably when occupancies where held at 70:30.

Computing details

Data collection: P3/P4-PC (Siemens, 1989); cell refinement: P3/P4-PC; data reduction: XDISK (Siemens, 1989); program(s) used to solve structure: SHELXTL (Bruker, 2000); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Figures

Fig. 1. : Structure of (I), showing 50% probability displacement ellipsoids and atomic numbering scheme. The minor conformer of the disordered chloropropyl group is drawn with open bonds. For clarity, all H atoms with the exception of the one involved in hydrogen bonding have been omitted.

1-(3-chlorophenyl)-4-(3-chloropropyl)piperazinium chloride

Crystal data

C13H19Cl2N2^+·Cl^−	F(000) = 648
Mr = 309.65	Dx = 1.376 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 10.856 (2) Å	Cell parameters from 40 reflections
b = 9.815 (2) Å	θ = 5.0–15.0°
c = 14.052 (3) Å	µ = 0.60 mm^−1
β = 93.07 (3)°	T = 293 K
V = 1495.1 (5) Å^3	Irregular block, colorless
Z = 4	0.55 × 0.55 × 0.50 mm

Data collection

Siemens P3 diffractometer	Rint = 0.026
Radiation source: normal-focus sealed tube	θmax = 27.6°, θmin = 1.9°
Graphite monochromator	h = 0→14
θ–2θ scans	k = 0→12
3573 measured reflections	l = −18→18
3403 independent reflections	3 standard reflections every 300 reflections
2409 reflections with I > 2σ(I)	intensity decay: 4.1%

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) = 0.130	H atoms treated by a mixture of independent and constrained refinement
S = 1.02	w = 1/[σ^2(Fo^2) + (0.0526P)^2 + 0.7734P] where P = (Fo^2 + 2Fc^2)/3
3403 reflections	(Δ/σ)max = 0.001
199 parameters	Δρmax = 0.36 e Å^−3
0 restraints	Δρmin = −0.36 e Å^−3

Special details

Experimental. A decay correction was applied (correction: min. 0.959, max. 1.001) to the reflections based on 3 standard reflections monitored every 300 reflections.

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)
Cl1	0.04192 (7)	0.25754 (8)	0.61546 (4)	0.0736 (2)
Cl2	0.70204 (7)	0.09023 (8)	0.24925 (6)	0.0836 (3)
N1	0.26821 (17)	0.10839 (19)	0.36999 (13)	0.0517 (4)
N2	0.04802 (18)	0.2633 (2)	0.39891 (12)	0.0586 (5)
H1	0.0422	0.2710	0.4602	0.070*
C1	0.3796 (2)	0.0350 (2)	0.36797 (14)	0.0489 (5)
C2	0.3946 (3)	−0.0947 (3)	0.40601 (17)	0.0630 (6)
H2	0.3312	−0.1345	0.4382	0.076*
C3	0.5035 (3)	−0.1652 (3)	0.39620 (19)	0.0751 (8)
H3	0.5114	−0.2525	0.4215	0.090*
C4	0.6002 (3)	−0.1105 (3)	0.35039 (19)	0.0698 (7)
H4	0.6733	−0.1583	0.3448	0.084*
C5	0.5843 (2)	0.0182 (3)	0.31305 (16)	0.0567 (6)
C6	0.4773 (2)	0.0911 (2)	0.32073 (16)	0.0521 (5)
H6	0.4700	0.1778	0.2944	0.062*
C7	0.1610 (2)	0.0434 (3)	0.40808 (18)	0.0625 (6)
H7A	0.1679	0.0458	0.4772	0.075*
H7B	0.1570	−0.0512	0.3881	0.075*
C8	0.0448 (2)	0.1169 (3)	0.37255 (17)	0.0664 (7)
H8A	0.0354	0.1086	0.3038	0.080*
H8B	−0.0261	0.0742	0.3994	0.080*
C9	0.1614 (2)	0.3265 (3)	0.36517 (16)	0.0566 (6)
H9A	0.1668	0.4200	0.3874	0.068*
H9B	0.1571	0.3280	0.2960	0.068*
C10	0.2750 (2)	0.2505 (2)	0.40018 (16)	0.0530 (5)
H10A	0.3473	0.2929	0.3752	0.064*
H10B	0.2831	0.2549	0.4692	0.064*
C11	−0.0585 (4)	0.3549 (5)	0.3575 (3)	0.0491 (8)	0.70
H11A	−0.0315	0.4492	0.3579	0.059*	0.70
H11B	−0.0789	0.3290	0.2920	0.059*	0.70
C12	−0.1726 (3)	0.3421 (4)	0.4149 (2)	0.0511 (7)	0.70
H12A	−0.2007	0.2483	0.4155	0.061*	0.70
H12B	−0.1547	0.3713	0.4801	0.061*	0.70
C13	−0.2685 (7)	0.4314 (7)	0.3672 (5)	0.0635 (15)	0.70
H13A	−0.2926	0.3946	0.3049	0.076*	0.70
H13B	−0.2347	0.5217	0.3584	0.076*	0.70
Cl3	−0.40196 (12)	0.44283 (14)	0.43778 (10)	0.0860 (4)	0.70
C11'	−0.0790 (9)	0.2831 (12)	0.3656 (6)	0.055 (2)	0.30
H11C	−0.0896	0.2710	0.2971	0.066*	0.30
H11D	−0.1337	0.2215	0.3969	0.066*	0.30
C12'	−0.0995 (10)	0.4220 (11)	0.3924 (9)	0.074 (3)	0.30
H12C	−0.0448	0.4799	0.3580	0.089*	0.30
H12D	−0.0774	0.4319	0.4598	0.089*	0.30
C13'	−0.241 (2)	0.476 (2)	0.3720 (19)	0.115 (9)	0.30
H13C	−0.2438	0.5731	0.3836	0.138*	0.30
H13D	−0.2655	0.4606	0.3054	0.138*	0.30
Cl3'	−0.3396 (4)	0.4024 (5)	0.4364 (4)	0.1398 (19)	0.30

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0873 (5)	0.1010 (5)	0.0322 (3)	−0.0103 (4)	0.0026 (3)	0.0012 (3)
Cl2	0.0641 (4)	0.0819 (5)	0.1068 (6)	0.0054 (4)	0.0221 (4)	−0.0163 (4)
N1	0.0527 (10)	0.0504 (10)	0.0520 (10)	−0.0050 (8)	0.0039 (8)	0.0025 (8)
N2	0.0544 (11)	0.0920 (15)	0.0296 (8)	0.0036 (10)	0.0057 (7)	−0.0025 (9)
C1	0.0605 (13)	0.0477 (12)	0.0377 (10)	−0.0019 (10)	−0.0050 (9)	−0.0044 (9)
C2	0.0849 (18)	0.0535 (14)	0.0504 (12)	−0.0006 (13)	0.0018 (12)	0.0067 (11)
C3	0.108 (2)	0.0542 (15)	0.0626 (15)	0.0175 (15)	−0.0045 (15)	0.0069 (12)
C4	0.0801 (18)	0.0679 (17)	0.0602 (15)	0.0236 (14)	−0.0078 (13)	−0.0086 (13)
C5	0.0602 (14)	0.0580 (14)	0.0514 (12)	0.0040 (11)	−0.0032 (10)	−0.0126 (11)
C6	0.0575 (13)	0.0467 (12)	0.0515 (12)	0.0031 (10)	−0.0024 (10)	−0.0022 (10)
C7	0.0683 (15)	0.0650 (15)	0.0547 (13)	−0.0154 (12)	0.0077 (11)	0.0041 (11)
C8	0.0534 (13)	0.099 (2)	0.0473 (12)	−0.0151 (13)	0.0062 (10)	−0.0004 (13)
C9	0.0612 (14)	0.0650 (15)	0.0444 (11)	0.0053 (12)	0.0103 (10)	0.0036 (10)
C10	0.0537 (13)	0.0537 (13)	0.0515 (12)	−0.0025 (10)	0.0028 (10)	−0.0011 (10)
C11	0.057 (2)	0.048 (2)	0.0421 (17)	0.006 (2)	0.0070 (15)	0.0105 (19)
C12	0.0518 (18)	0.061 (2)	0.0404 (15)	0.0048 (16)	0.0059 (13)	0.0024 (14)
C13	0.070 (3)	0.060 (4)	0.060 (3)	0.020 (3)	0.006 (2)	−0.001 (2)
Cl3	0.0629 (7)	0.0840 (8)	0.1131 (9)	0.0126 (6)	0.0225 (7)	0.0095 (7)
C11'	0.062 (5)	0.063 (6)	0.039 (4)	−0.009 (5)	0.001 (3)	0.002 (4)
C12'	0.060 (6)	0.077 (7)	0.085 (7)	0.014 (5)	−0.011 (5)	0.008 (6)
C13'	0.128 (15)	0.099 (14)	0.112 (13)	−0.010 (11)	−0.047 (10)	0.039 (11)
Cl3'	0.116 (3)	0.134 (3)	0.178 (4)	0.039 (3)	0.078 (3)	0.050 (3)

Geometric parameters (Å, º)

Cl2—C5	1.749 (3)	C9—C10	1.502 (3)
N1—C1	1.409 (3)	C9—H9A	0.9700
N1—C7	1.454 (3)	C9—H9B	0.9700
N1—C10	1.458 (3)	C10—H10A	0.9700
N2—C11'	1.446 (10)	C10—H10B	0.9700
N2—C9	1.479 (3)	C11—C12	1.519 (5)
N2—C8	1.484 (4)	C11—H11A	0.9700
N2—C11	1.553 (5)	C11—H11B	0.9700
N2—H1	0.8700	C12—C13	1.493 (8)
C1—C2	1.387 (3)	C12—H12A	0.9700
C1—C6	1.394 (3)	C12—H12B	0.9700
C2—C3	1.382 (4)	C13—Cl3	1.802 (6)
C2—H2	0.9300	C13—H13A	0.9700
C3—C4	1.370 (4)	C13—H13B	0.9700
C3—H3	0.9300	C11'—C12'	1.434 (14)
C4—C5	1.375 (4)	C11'—H11C	0.9700
C4—H4	0.9300	C11'—H11D	0.9700
C5—C6	1.374 (3)	C12'—C13'	1.64 (3)
C6—H6	0.9300	C12'—H12C	0.9700
C7—C8	1.514 (4)	C12'—H12D	0.9700
C7—H7A	0.9700	C13'—Cl3'	1.61 (2)
C7—H7B	0.9700	C13'—H13C	0.9700
C8—H8A	0.9700	C13'—H13D	0.9700
C8—H8B	0.9700
C1—N1—C7	119.22 (19)	N2—C9—H9B	109.3
C1—N1—C10	117.67 (18)	C10—C9—H9B	109.3
C7—N1—C10	109.95 (19)	H9A—C9—H9B	107.9
C11'—N2—C9	129.5 (5)	N1—C10—C9	110.62 (19)
C11'—N2—C8	92.3 (5)	N1—C10—H10A	109.5
C9—N2—C8	109.58 (18)	C9—C10—H10A	109.5
C11'—N2—C11	28.7 (4)	N1—C10—H10B	109.5
C9—N2—C11	104.6 (2)	C9—C10—H10B	109.5
C8—N2—C11	117.4 (2)	H10A—C10—H10B	108.1
C11'—N2—H1	101.0	C12—C11—N2	111.4 (3)
C9—N2—H1	112.7	C12—C11—H11A	109.3
C8—N2—H1	109.2	N2—C11—H11A	109.3
C11—N2—H1	103.2	C12—C11—H11B	109.3
C2—C1—C6	118.0 (2)	N2—C11—H11B	109.3
C2—C1—N1	123.0 (2)	H11A—C11—H11B	108.0
C6—C1—N1	118.9 (2)	C13—C12—C11	106.4 (4)
C3—C2—C1	120.2 (3)	C13—C12—H12A	110.5
C3—C2—H2	119.9	C11—C12—H12A	110.5
C1—C2—H2	119.9	C13—C12—H12B	110.5
C4—C3—C2	122.1 (3)	C11—C12—H12B	110.5
C4—C3—H3	118.9	H12A—C12—H12B	108.6
C2—C3—H3	118.9	C12—C13—Cl3	110.6 (5)
C3—C4—C5	117.1 (3)	C12—C13—H13A	109.5
C3—C4—H4	121.4	Cl3—C13—H13A	109.5
C5—C4—H4	121.4	C12—C13—H13B	109.5
C6—C5—C4	122.5 (3)	Cl3—C13—H13B	109.5
C6—C5—Cl2	118.3 (2)	H13A—C13—H13B	108.1
C4—C5—Cl2	119.2 (2)	C12'—C11'—N2	101.6 (8)
C5—C6—C1	120.0 (2)	C12'—C11'—H11C	111.4
C5—C6—H6	120.0	N2—C11'—H11C	111.4
C1—C6—H6	120.0	C12'—C11'—H11D	111.4
N1—C7—C8	109.8 (2)	N2—C11'—H11D	111.4
N1—C7—H7A	109.7	H11C—C11'—H11D	109.3
C8—C7—H7A	109.7	C11'—C12'—C13'	114.7 (11)
N1—C7—H7B	109.7	C11'—C12'—H12C	108.6
C8—C7—H7B	109.7	C13'—C12'—H12C	108.6
H7A—C7—H7B	108.2	C11'—C12'—H12D	108.6
N2—C8—C7	111.8 (2)	C13'—C12'—H12D	108.6
N2—C8—H8A	109.3	H12C—C12'—H12D	107.6
C7—C8—H8A	109.3	Cl3'—C13'—C12'	113.8 (15)
N2—C8—H8B	109.3	Cl3'—C13'—H13C	108.8
C7—C8—H8B	109.3	C12'—C13'—H13C	108.8
H8A—C8—H8B	107.9	Cl3'—C13'—H13D	108.8
N2—C9—C10	111.7 (2)	C12'—C13'—H13D	108.8
N2—C9—H9A	109.3	H13C—C13'—H13D	107.7
C10—C9—H9A	109.3
C7—N1—C1—C2	−3.9 (3)	C11—N2—C8—C7	173.3 (2)
C10—N1—C1—C2	133.3 (2)	N1—C7—C8—N2	−57.7 (3)
C7—N1—C1—C6	172.0 (2)	C11'—N2—C9—C10	−164.3 (6)
C10—N1—C1—C6	−50.7 (3)	C8—N2—C9—C10	−53.9 (2)
C6—C1—C2—C3	−0.4 (3)	C11—N2—C9—C10	179.4 (2)
N1—C1—C2—C3	175.7 (2)	C1—N1—C10—C9	159.12 (18)
C1—C2—C3—C4	0.8 (4)	C7—N1—C10—C9	−59.9 (2)
C2—C3—C4—C5	−0.7 (4)	N2—C9—C10—N1	57.4 (2)
C3—C4—C5—C6	0.3 (4)	C11'—N2—C11—C12	50.0 (8)
C3—C4—C5—Cl2	−177.2 (2)	C9—N2—C11—C12	−157.0 (3)
C4—C5—C6—C1	0.1 (3)	C8—N2—C11—C12	81.3 (4)
Cl2—C5—C6—C1	177.63 (16)	N2—C11—C12—C13	−178.7 (4)
C2—C1—C6—C5	−0.1 (3)	C11—C12—C13—Cl3	−172.3 (4)
N1—C1—C6—C5	−176.3 (2)	C9—N2—C11'—C12'	−66.7 (8)
C1—N1—C7—C8	−160.1 (2)	C8—N2—C11'—C12'	175.4 (7)
C10—N1—C7—C8	59.6 (2)	C11—N2—C11'—C12'	−32.1 (8)
C11'—N2—C8—C7	−172.2 (4)	N2—C11'—C12'—C13'	−175.4 (12)
C9—N2—C8—C7	54.2 (2)	C11'—C12'—C13'—Cl3'	66.7 (19)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N2—H1···Cl1	0.87	2.19	3.048 (2)	171