Open Access

Synthesis and crystal structure of 1,4,10,13-tetraoxa-7,16-diazoniumcyclo-octadecane bis(4-chloro-2-methyl-phenoxyacetate)

  • Sergey N Adamovich1,
  • Anna N Mirskova1,
  • Rudolf G Mirskov1 and
  • Uwe Schilde2Email author
Chemistry Central Journal20115:23

DOI: 10.1186/1752-153X-5-23

Received: 15 February 2011

Accepted: 9 May 2011

Published: 9 May 2011

Abstract

The title compound was prepared by the reaction of 1,4,10,13-tetraoxa-7,16-diazacyclo-octadecane with 4-chloro-2-methyl-phenoxyacetic acid in a ratio of 1:2. The structure has been proved by the data of elemental analysis, IR spectroscopy, NMR (1H, 13C) technique and by X-ray diffraction analysis. Intermolecular hydrogen bonds between the azonium protons and oxygen atoms of the carboxylate groups were found. Immunoactive properties of the title compound have been screened. The compound has the ability to suppress spontaneous and Con A-stimulated cell proliferation in vitro and therefore can be considered as immunodepressant.

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Findings

Over many years the complexes of crown ethers (CE) with protonic acids and their metal salts attract the attention of scientific community due to both their peculiar molecular and stereoelectronic structure as well as the possibility of practical application [1, 2]. The CE complexes enhance physiological activity of several chemical compounds. This fact is likely related to the ability of the complexes formed to overpass cellular and hematoorganic barriers. In particular, specific complex-forming properties of CE allow them to be used for the drug design [2].

Recently, we have shown that tris-(2-hydroxyethyl)ammonium salts of organylheteroacetic acids [RYCH2COO] -·[NH(CH2CH2OH)]3+, (R = Ar, Het; Y = O, S, SO2), the cation of which has compact tricyclic atrane (2,8,9-trihydro-prototranic) structure [3], promoting to penetration of a matter through cellular membranes, represent a new class of biologically active compounds [49]. For example, tris(2-hydroxyethyl)ammonium salt of 4-chloro-2-methyl-phenoxyacetic acid exhibits adaptogenic, immunomodulating and antitumor properties. Besides, it effectively increases the resistance of animals to microwave electromagnetic radiation [79].

To search for new immunoactive congeners of this series, we have synthesized 1,4,10,13-tetraoxa-7,16-diazoniumcyclo-octadecane bis(4-chloro-2-methyl-phenoxyacetate) 1 and studied its immunoactive properties. Compound 1 was prepared in a yield of up to 98% by the reaction of 1,4,10,13-tetraoxa-7,16-diazacyclo-octadecane (1,10-diaza-18-crown-6 ether) with 4-chloro-2-methyl-phenoxyacetic acid in a ratio of 1:2 (Figure 1).
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Figure 1

Synthesis of the title compound 1.

Compound 1 forms colorless crystals with m.p. 128°C. The structure of 1 has been proved by the data of elemental analysis, IR spectroscopy and NMR (1H, 13C) technique. The IR spectra of 1 show broad vibration bands of ν(NH2+) in the region 2800-2200 cm-1. The stretching vibration bands of the O-C-O fragments of starting CE are high-field shifted from 1120, 1100 and 1067 to 1150-1090 cm-1. In the IR spectrum, the bands of symmetric and asymmetric stretching vibrations of the carboxylate-ion are observed at 1580-1350 cm-1.

The structure of compound 1 was established by crystal structure analysis. Crystal and experimental data are summarized in Table 1. The molecular structure with the atom labeling scheme is given in Figure 2. The packing diagram is shown in Figure 3. Selected bond lengths (Å), bond angles (°) as well as torsion angles (°) are listed in Table 2.
Table 1

Crystal data and details of the structure solution and refinement

Emirical formula

C15H22ClNO5

Formula weight

331.79

Temperature

210(2) K

Wavelength

0.71073 Å

Crystal system, space group

Triclinic, P

Unit cell dimensions

a = 7.5342(6) Å α = 97.624(7)°

b = 9.1935(8) Å β = 93.340(6)°

c = 12.8532(10) Å γ = 108.945(6)°

Volume

829.73(12) Å3

Z, Calculated density

2, 1.328 g/cm-3

Absorption coefficient

0.252 mm-1

F(000)

352

Crystal size

1.5 × 0.6 × 0.15 mm

Θ range for data collection

1.61 to 25.0°

Reflections collected/unique

5361/2738

Refinement method

Full-matrix least-squares on F2

Data/restraints/parameters

2738/0/288

Goodness-of-fit on F2

1.001

R indices [I > 2σ(I); 2280]

R1 = 0.0423, wR2 = 0.1110

R indices (all data)

R1 = 0.0495, wR2 = 0.1147

Largest diff. Peak and hole

0.413 and -0.319 eÅ-3

https://static-content.springer.com/image/art%3A10.1186%2F1752-153X-5-23/MediaObjects/13065_2011_Article_284_Fig2_HTML.jpg
Figure 2

ORTEP plot of 1, drawn at a 50% probability level, with atom labeling. Symmetry operation: i2-x, 2-y, 2-z.

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Figure 3

Packing diagram, showing a ribbon structure along b. Symmetry operation: ii2-x, 1-y, 2-z.

Table 2

Selected bond lengths (Å), bond angles (°), and torsion angles (°)

C1-O1

1.369(2)

C4-Cl1

1.744(2)

C2-C9

1.502(2)

C7-O1

1.423(2)

C7-C8

1.523(2)

C8-O2

1.237(2)

C8-O3

1.249(2)

C10-O4

1.420(2)

C11-O4

1.419(2)

C12-O5

1.425(2)

C13-O5

1.405(2)

C14-N1

1.490(2)

C15-N1

1.500(2)

  

O1-C1-C6

124.33(15)

O1-C1-C2

115.40(13)

O1-C7-C8

115.00(14)

O2-C8-O3

126.33(16)

O2-C8-C7

119.17(14)

O3-C8-O7

114.48(15)

O4-C10-C15i

109.71(13)

O4-C11-C12

108.92(15)

O5-C12-C11

108.47(15)

O5-C13-C14

107.27(14)

N1-C14-C13

110.33(14)

N1-C15-C10i

113.09(14)

C14-N1-C15

115.90(13)

C1-O1-C7

117.34(12)

C11-O4-C1

112.78(13)

C13-O5-C12

111.91(13)

O1-C1-C2-C3

-178.46(15)

O1-C1-C2-C9

-1.0(3)

C2-C3-C4-Cl1

-177.68(14)

O1-C7-C8-O2

-15.4(2)

O1-C7-C8-O3

166.31(14)

O4-C11-C12-O5

67.19(19)

O5-C13-C14-N1

-173.03(15)

C13-C14-N1-C15

-179.80(15)

C10i-C15-N1-C14

-72.10(19)

C6-C1-O1-C7

5.5(2)

C2-C1-O1-C7

-174.16(16)

C8-C7-O1-C1

-79.74(19)

C12-C11-O4-C10

-167.40(15)

C15i-C10-O4-C11

167.28(14)

C14-C13-O5-C12

-175.94(15)

C11-C12-O5-C13

179.36(16)

Symmetry code: i2-x, 2-y, 2-z

The asymmetric unit of 1 contains a half of the diprotonated 1,10-diazatetraoxa-18-crown-6 moiety and 4-chloro-2-methylphenoxyacetate as anion. The crown ether is centrosymmetric and the second half of the cation is generated by inversion. 4-Chloro-2-methylphenoxyacetic acid is known as herbicide. In this molecule, the benzene ring and the oxoacetic acid side-chain are almost coplanar (CSD-Code CMPHAA) [10]. In contrast to this, in 1 the acetate moiety is torsioned around O1-C7 forming a torsion angle of -79.7(2)°, whereas a torsion angle of only -8.0(1)° was found in the reference compound. Additionally, the distorsion of the exo-C1 ring angles is more pronounced 1: 115.4(1), 124.3(2)°; CMPHAA: 115.8(12), 122.0(13)°). The molecular packing is characterized by hydrogen bonds forming a ribbon-like structure along the crystallographic b axis. The geometry of the hydrogen bonds are given in Table 3.
Table 3

Hydrogen bond geometry (Å, °)

D-H...A

D-H

H...A

D...A

D-H...A

N1-H1...O2ii

0.89(2)

1.83(2)

2.698(2)

165(2)

N1-H2...O3

0.93(2)

1.81(2)

2.708(2)

161(2)

Symmetry code: ii2-x, 1-y, 2-z

Immunoactive properties of 1 have been screened. For example, the ability to impact on spontaneous and mitogen-stimulated (Con A, Sigma, 2 mkg/ml) proliferation of splenocytes in mice in vitro (antiproliferative properties) have been studied. It has been found that compound 1 exerts a distinct influence on spontaneous and mitogen-stimulated proliferation of splenocytes. The ability to suppress spontaneous (up to 72%) and Con A-stimulated (up to 99%) cell proliferation of spleen in vitro in the dosage of 3-300 mkg/ml allows compound 1 to be considered as immunodepressant.

Experimental

IR spectra were recorded on a Varian 3100 FT- IR75 spectrophotometer. NMR spectra (ppm) were measured on a DPX 400 instrument (400,13 MHz for 1H and 101,62 MHz for 13C) in D2O or methanol D4 at 25°C. Reflections were collected using a STOE Imaging Plate Diffraction System (IPDS-II) at 210 K. The structure was solved by direct methods as implemented in the program SHELXS-97 [11]. The refinement was carried out using SHELXL-97 [12]. All the non-hydrogen atoms were refined anisotropically. The hydrogen atoms were located from the difference Fourier map and refined isotropically. For the visualisation of the structure the graphic programs DIAMOND [13] and ORTEP for Windows [14] were used. CIF data: Additional file 1. CCDC reference number: 812142.

Compound 1 was synthesized in the following manner. To a solution of 4-Cl-2-CH3-C6H3OCH2COOH (4.01 g, 0.02 mol) in MeOH (10 ml), was added dropwise a methanol (10 ml) solution of (CE) (2.62 g, 0.01 mol). The mixture was stirred at 25°C for 12 h. The solvent was distilled in vacuum. The solid residue was repeatedly washed with ether and dried in vacuum to afford colorless powder (6.50 g, 98% yield), soluble in water and alcohol. Crystals suitable for X-ray diffraction were obtained by recrystallyzation of 1 from methanol (20°C). 1H NMR (D2O): 7.11-6.68 (m, 6H, C6H3O); 4.37 (s, 4H, CH2COO); 3.63-3.56 (m, 16H, OCH2, OCH2CH2O); 3.15 (t, 8H, NCH2); 2.13 (s, 6H, C6H3-CH3). 13C NMR (D2O): 176.80 (C=O); 156.04 (C6H4O); 140.87-111.56 (C6H3); 69.42 (OCH2); 66.99 (CH2COO); 65.29 (OCH2CH2O); 47.31 (NCH2); 15.53 (C6H3-CH3). Anal. Calcd. for C30H44Cl2O10N2: C, 54.24; H, 6.63; Cl, 10.68; N, 4.22; Found: C, 54.54; H, 6.60; Cl, 10.68; N, 4.02.

Conclusions

1,4,10,13-Tetraoxa-7,16-diazoniumcyclo-octadecane bis(4-chloro-2-methyl-phenoxyacetate) 1 has been synthesized by the reaction of 1,10-diaza-18-crown-6 ether with 4-chloro-2-methyl-phenoxyacetic acid in a ratio of 1:2 (yield 98%). The structure of 1 has been proved by the data of elemental analysis, IR spectroscopy, NMR (1H, 13C) technique and X-ray diffraction analysis. X-ray diffraction analysis has shown that the crown ether cation is centrosymmetric. The packing is characterized by a ribbon-like structure stabilized by hydrogen bonds. The title compound is a representative of a novel class of physiologically active compounds possessing immunodepressant properties. The investigation of physiological activity of 1 will be conducted in a new future.

Declarations

Acknowledgements

The authors acknowledge O. P. Kolesnikova for screening of immunoactive properties of compound 1.

Authors’ Affiliations

(1)
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences
(2)
Institute of Chemistry, University of Potsdam

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Copyright

© Adamovich et al 2011