4,4′-Dichloro-2,2′-[(3aR,7aR/3aS,7aS)-2,3,3a,4,5,6,7,7a-octa­hydro-1H-1,3-benzimidazole-1,3-di­yl)bis­(methyl­ene)]diphenol

Mol­ecules of the the title compound, C₂₁H₂₄Cl₂N₂O₂, are located on a twofold rotation axis, which passes through the C atom linking the two N atoms. Two intra­molecular O—H...N hydrogen bonds were observed. In the crystal, non-classical inter­molecular C—H...O hydrogen bonds link the mol­ecules into chains along the a axis. The crystal studied was a racemic twin.

Key indicators

• Single-crystal X-ray study
• T = 120 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.022
• wR factor = 0.068
• Data-to-parameter ratio = 12.3

checkCIF/PLATON results

No syntax errors found



Alert level C
STRVA01_ALERT_4_C           Flack test results are ambiguous.
           From the CIF: _refine_ls_abs_structure_Flack    0.320
           From the CIF: _refine_ls_abs_structure_Flack_su    0.010
THETM01_ALERT_3_C  The value of sine(theta_max)/wavelength is less than 0.590
            Calculated sin(theta_max)/wavelength =    0.5752
PLAT023_ALERT_3_C Resolution (too) Low [sin(theta)/Lambda < 0.6]..      62.49 Deg.
PLAT033_ALERT_4_C Flack x Parameter Value Deviates from Zero .....       0.32

Alert level G
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           62.49
           From the CIF: _reflns_number_total               1566
           Count of symmetry unique reflns          952
           Completeness (_total/calc)            164.50%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured       614
           Fraction of Friedel pairs measured     0.645
           Are heavy atom types Z>Si present        yes
PLAT791_ALERT_4_G Note: The Model has Chirality at C9     (Verify)          R

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   4 ALERT level C = Check and explain
   2 ALERT level G = General alerts; check

   0 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   0 ALERT type 2 Indicator that the structure model may be wrong or deficient
   2 ALERT type 3 Indicator that the structure quality may be low
   4 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. Comment

It is interesting to notice that two types of non-classical intermolecular hydrogen bonds of C—H···O and C—H···Cl were found according to crystallographic data. The molecular structure and atom-numbering scheme for (I) are shown in Fig. 1. Its X-ray structure confirms the presence of intramolecular hydrogen bonds between the phenolic hydroxyl groups and nitrogen atoms [N—H, 1.83 (2) Å), whereas the N···O distances [2.652 (2) Å,] is significantly shorter than the corresponding N···O bond in related structures [2.70 (1) Å]. Furthermore the observed C—O bond length [1.354 (2) Å] is considerably shortened in relation to related structures [1.364 (2) Å] (Rivera et al., 2010) and [1.365 (2) Å] (Rivera et al., 2009). This additional H-bonding does not influence the H—O distance, which shows (as a result of unrestrained refinement) a typical separation of 0.91 (2) Å. Thus, these results indicate an increase in hydrogen-bonding strength due to the presence of chlorine atom. In fact, the presence of the chlorine atom favours the formation of weak intermolecular C—H···O interactions between neighboring molecules, which link them into 1-D extended chains along the a axis and help to stabilize the chain.

The chains are linked along the c direction by C—H···Cl interactions [2.902 (2) Å]. This interaction involves contacts between an apparently electron deficient aromatic C6—H6 and the chlorine atom from a second molecule. The phenyl group in both molecules lies in an orientation which favours hydrogen bond formation.

In the title compound, C₂₁H₂₄Cl₂N₂O₂,the asymmetric unit contains one-half of the molecule, which is related to the other half by a twofold rotation axis [symmetry code: - x, y, -z] passing through C1 (Figure 1). Unlike the related structures Rivera et al. (2010, 2009), the title compound crystallizes in a different crystal system and it has a chiral space group. The compound is a racemic twin and the absolute structure was determined on the basis of that of the starting amine whose stereochemistry is: trans-(rac)-1,2-cyclohexanediamine and the chiral centers were not affected when reacted.

Related literature

For related structures, see: Rivera et al. (2009, 2010). For uses of di-Mannich bases, see: Mitra et al. (2006); Elias et al. (1997). For the antimalarial activity of di-Mannich bases, see: Shanks & Edstein (2005).

S2. Experimental

Preparation of title compound (I)

A solution of (2R,7R,11S,16S)-1,8,10,17-tetraazapentacyclo[8.8.1.18,17.0^2,7.0^11,16] icosane (276 mg, 1.00 mmol) in dioxane (3 ml) and water (4 ml), prepared beforehand following previously described procedures, was added dropwise in a dioxane solution (3 ml) containing two equivalents of p-chlorophenol (257 mg, 2.00 mmol) in a two-necked round-bottomed flask. The mixture was refluxed for about 6 h until precipitation of a colourless solid. The resulting solid was collected by filtration, washed with cool methanol and dried under vacuum (yield 30%, m.p. = 490–492 K). Next, the racemic product (100 mg, 0.246 mmol) was dissolved in 5 ml of a 4:1 mixture of chloroform: methanol. Single crystals of title compound (I) suitable for X-ray analysis were grown by slow evaporation of the solvent at room temperature over a period of about 2 weeks in a preferential crystallization (yield 46%). 1H NMR (CDCl₃, 400 MHz): δ 1.29 (4H, m), 1.85 (2H, m), 2.04 (2H, m), 2.34 (2H, m), 3.42 (2H, d, J = 14.0 Hz, ArCH₂N), 3.51 (2H, s, NCH₂N), 4.14 (2H, d, J = 14.0 Hz, ArCH₂N), 6.74 (2H, d, J = 8.8 Hz), 6.92 (2H, s), 7.10 (2H, d, J = 8.8 Hz).

S3. Refinement

All hydrogen atoms were discernible in difference Fourier maps and could be refined to reasonable geometry. According to common practice H atoms attached to C atoms were nevertheless kept in ideal positions during the refinement. The coordinates of the hydroxyl H atom were refined. The isotropic atomic displacement parameters of all hydrogen atoms were set to 1.2*U_eq of the parent atom.

Computing details

Data collection: CrysAlis CCD (Oxford Diffraction, 2009); cell refinement: CrysAlis RED (Oxford Diffraction, 2009); data reduction: CrysAlis RED (Oxford Diffraction, 2009); program(s) used to solve structure: SIR2002 (Burla et al., 2003); program(s) used to refine structure: JANA2006 (Petříček et al., 2006); molecular graphics: DIAMOND (Brandenburg & Putz, 2005); software used to prepare material for publication: JANA2006 (Petříček et al., 2006).

Figures

	Fig. 1. Molecule of the title compound with atom-labeling scheme. Displacement elipsoids are drawn at 50% probability level.
	Fig. 2. Hydrogen bonding of the molecules of the title compound in a direction.

4,4'-Dichloro-2,2'-[(3aR,7aR/3aS,7aS)- 2,3,3a,4,5,6,7,7a-octahydro-1H-1,3-benzimidazole-1,3- diyl)bis(methylene)]diphenol

Crystal data

C21H24Cl2N2O2	F(000) = 428
Mr = 407.3	Dx = 1.378 Mg m^−3
Orthorhombic, P21212	Cu Kα radiation, λ = 1.54184 Å
Hall symbol: P 2 2ab	Cell parameters from 10371 reflections
a = 5.9529 (2) Å	θ = 4.8–62.4°
b = 18.3846 (5) Å	µ = 3.11 mm^−1
c = 8.9704 (3) Å	T = 120 K
V = 981.74 (5) Å^3	Irregular shape, colorless
Z = 2	0.36 × 0.21 × 0.12 mm

Data collection

Oxford Diffraction Xcalibur diffractometer with an Atlas (Gemini ultra Cu) detector	1566 independent reflections
Radiation source: X-ray tube	1517 reflections with I > 3σ(I)
Mirror monochromator	Rint = 0.027
Detector resolution: 10.3784 pixels mm^-1	θmax = 62.5°, θmin = 4.8°
Rotation method data acquisition using ω scans	h = −6→6
Absorption correction: analytical [CrysAlis PRO (Oxford Diffraction, 2009), based on expressions derived by Clark & Reid (1995)]	k = −21→20
Tmin = 0.518, Tmax = 0.773	l = −10→10
12720 measured reflections

Refinement

Refinement on F^2	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.022	Weighting scheme based on measured s.u.'s w = 1/[σ^2(I) + 0.0016I^2]
wR(F^2) = 0.068	(Δ/σ)max = 0.010
S = 1.50	Δρmax = 0.11 e Å^−3
1566 reflections	Δρmin = −0.11 e Å^−3
127 parameters	Absolute structure: Flack (1983), 615 Friedel pairs
0 restraints	Absolute structure parameter: 0.32 (1)
45 constraints

Special details

Experimental. CrysAlisPro, Oxford Diffraction Ltd., Version 1.171.33.51 (release 27-10-2009 CrysAlis171 .NET) Analytical numeric absorption correction using a multifaceted crystal model based on expressions derived by Clark & Reid (1995)

Physical Measurements

The melting point was determined with an Electrothermal apparatus, and it has not been corrected. IR spectrum was recorded as KBr pellets at 292 K on a Perkin-Elmer Paragon FT-IR instrument. NMR spectra were performed in CDCl₃ at room temperature on a Bruker AMX 400 Advance spectrometer.

Refinement. The refinement was carried out against all reflections. The conventional R-factor is always based on F. The goodness of fit as well as the weighted R-factor are based on F and F² for refinement carried out on F and F², respectively. The threshold expression is used only for calculating R-factors etc. and it is not relevant to the choice of reflections for refinement.

The program used for refinement, Jana2006, uses the weighting scheme based on the experimental expectations, see _refine_ls_weighting_details, that does not force S to be one. Therefore the values of S are usually larger than the ones from the SHELX program.

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

	x	y	z	Uiso*/Ueq
Cl1	0.56453 (8)	0.22892 (2)	0.85004 (4)	0.03657 (14)
O1	0.99889 (19)	0.41865 (6)	0.41066 (13)	0.0278 (3)
N1	0.59603 (9)	0.44360 (5)	0.29542 (10)	0.0191 (4)
C1	0.5	0.5	0.39535 (12)	0.0190 (6)
C2	0.5511 (3)	0.36844 (7)	0.34499 (16)	0.0207 (4)
C3	0.6738 (3)	0.34996 (7)	0.48640 (16)	0.0188 (4)
C4	0.8923 (2)	0.37633 (8)	0.51184 (18)	0.0208 (4)
C5	1.0043 (3)	0.35815 (8)	0.64297 (17)	0.0260 (5)
C6	0.9061 (3)	0.31220 (8)	0.74665 (18)	0.0266 (5)
C7	0.6930 (3)	0.28560 (8)	0.71952 (17)	0.0244 (5)
C8	0.5774 (3)	0.30421 (7)	0.59086 (16)	0.0204 (4)
C9	0.5027 (2)	0.45884 (7)	0.14700 (16)	0.0214 (4)
C10	0.6300 (3)	0.43023 (9)	0.01323 (18)	0.0313 (5)
C11	0.5134 (3)	0.45859 (9)	−0.12729 (18)	0.0387 (6)
H1a	0.382262	0.478981	0.454451	0.0228*
H2a	0.392563	0.362122	0.359869	0.0249*
H2b	0.594229	0.335034	0.267886	0.0249*
H5	1.151137	0.37767	0.661739	0.0312*
H6	0.984963	0.299065	0.836016	0.0319*
H8	0.429374	0.285198	0.574125	0.0245*
H9	0.361614	0.434259	0.134648	0.0257*
H10a	0.626351	0.378021	0.013612	0.0375*
H10b	0.781744	0.447839	0.016012	0.0375*
H11a	0.368381	0.436182	−0.136609	0.0464*
H11b	0.597131	0.443924	−0.213654	0.0464*
H1o	0.893 (3)	0.4356 (10)	0.347 (2)	0.0334*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0514 (3)	0.0328 (2)	0.0254 (2)	−0.00039 (19)	0.00732 (18)	0.00639 (15)
O1	0.0191 (5)	0.0233 (5)	0.0410 (6)	−0.0026 (4)	0.0007 (5)	0.0049 (5)
N1	0.0231 (6)	0.0132 (6)	0.0208 (6)	0.0018 (5)	0.0003 (5)	0.0012 (5)
C1	0.0188 (10)	0.0153 (9)	0.0231 (10)	−0.0004 (8)	0	0
C2	0.0217 (7)	0.0140 (6)	0.0264 (8)	−0.0016 (6)	−0.0020 (7)	−0.0004 (6)
C3	0.0200 (7)	0.0116 (6)	0.0249 (8)	0.0028 (6)	−0.0009 (6)	−0.0019 (6)
C4	0.0173 (7)	0.0150 (6)	0.0300 (9)	0.0027 (5)	0.0017 (6)	−0.0035 (6)
C5	0.0200 (8)	0.0239 (7)	0.0341 (9)	0.0039 (6)	−0.0053 (7)	−0.0055 (7)
C6	0.0314 (9)	0.0230 (7)	0.0253 (8)	0.0095 (7)	−0.0050 (7)	−0.0058 (6)
C7	0.0339 (9)	0.0179 (7)	0.0213 (8)	0.0045 (7)	0.0050 (7)	−0.0005 (6)
C8	0.0204 (7)	0.0142 (6)	0.0267 (7)	0.0010 (6)	0.0021 (6)	−0.0023 (6)
C9	0.0246 (8)	0.0177 (8)	0.0218 (7)	0.0029 (5)	−0.0014 (6)	−0.0014 (6)
C10	0.0446 (10)	0.0239 (8)	0.0253 (9)	0.0088 (7)	0.0027 (8)	−0.0020 (7)
C11	0.0611 (13)	0.0322 (10)	0.0229 (8)	0.0134 (8)	−0.0012 (9)	−0.0039 (7)

Geometric parameters (Å, º)

Cl1—C7	1.7441 (16)	C5—H5	0.96
O1—C4	1.3535 (19)	C6—C7	1.381 (2)
O1—H1o	0.91 (2)	C6—H6	0.96
N1—C1	1.4850 (11)	C7—C8	1.386 (2)
N1—C2	1.4761 (16)	C8—H8	0.96
N1—C9	1.4697 (17)	C9—C9^i	1.5138 (19)
C1—H1a	0.96	C9—C10	1.514 (2)
C1—H1a^i	0.96	C9—H9	0.96
C2—C3	1.503 (2)	C10—C11	1.531 (2)
C2—H2a	0.96	C10—H10a	0.96
C2—H2b	0.96	C10—H10b	0.96
C3—C4	1.406 (2)	C11—C11^i	1.531 (2)
C3—C8	1.384 (2)	C11—H11a	0.96
C4—C5	1.393 (2)	C11—H11b	0.96
C5—C6	1.386 (2)
C4—O1—H1o	106.9 (12)	C5—C6—H6	120.4925
C1—N1—C2	113.70 (8)	C7—C6—H6	120.4933
C1—N1—C9	105.56 (8)	Cl1—C7—C6	119.74 (12)
C2—N1—C9	112.50 (9)	Cl1—C7—C8	119.24 (12)
N1—C1—N1^i	105.74 (8)	C6—C7—C8	121.01 (14)
N1—C1—H1a	109.4709	C3—C8—C7	120.52 (14)
N1—C1—H1a^i	109.4712	C3—C8—H8	119.7416
N1^i—C1—H1a	109.4713	C7—C8—H8	119.7416
N1^i—C1—H1a^i	109.4709	N1—C9—C9^i	101.45 (10)
H1a—C1—H1a^i	112.9619	N1—C9—C10	117.56 (12)
N1—C2—C3	112.19 (11)	N1—C9—H9	110.2149
N1—C2—H2a	109.4717	C9^i—C9—C10	110.98 (12)
N1—C2—H2b	109.4705	C9^i—C9—H9	116.8873
C3—C2—H2a	109.4714	C10—C9—H9	100.538
C3—C2—H2b	109.4717	C9—C10—C11	107.90 (14)
H2a—C2—H2b	106.6084	C9—C10—H10a	109.4715
C2—C3—C4	120.58 (13)	C9—C10—H10b	109.4705
C2—C3—C8	120.48 (13)	C11—C10—H10a	109.4721
C4—C3—C8	118.88 (14)	C11—C10—H10b	109.4708
O1—C4—C3	121.52 (14)	H10a—C10—H10b	110.9991
O1—C4—C5	118.68 (13)	C10—C11—C11^i	112.71 (13)
C3—C4—C5	119.80 (14)	C10—C11—H11a	109.4707
C4—C5—C6	120.75 (14)	C10—C11—H11b	109.4709
C4—C5—H5	119.6278	C11^i—C11—H11a	109.472
C6—C5—H5	119.6266	C11^i—C11—H11b	109.4712
C5—C6—C7	119.01 (15)	H11a—C11—H11b	106.0299

Symmetry code: (i) −x+1, −y+1, z.

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C1—H1a···O1^ii	0.95	2.56	3.3398 (11)	137.58
O1—H1o···N1	0.91 (2)	1.83 (2)	2.6515 (13)	149.3 (18)

Symmetry code: (ii) x−1, y, z.