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

  • Sergey N Adamovich1,

    Affiliated with

    • Anna N Mirskova1,

      Affiliated with

      • Rudolf G Mirskov1 and

        Affiliated with

        • Uwe Schilde2Email author

          Affiliated with

          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.

          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).
          http://static-content.springer.com/image/art%3A10.1186%2F1752-153X-5-23/MediaObjects/13065_2011_284_Fig1_HTML.jpg
          Figure 1

          Synthesis of the title compound1.

          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 F 2

          Data/restraints/parameters

          2738/0/288

          Goodness-of-fit on F 2

          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

          http://static-content.springer.com/image/art%3A10.1186%2F1752-153X-5-23/MediaObjects/13065_2011_284_Fig2_HTML.jpg
          Figure 2

          ORTEP plot of1, drawn at a 50% probability level, with atom labeling. Symmetry operation: i2-x, 2-y, 2-z.

          http://static-content.springer.com/image/art%3A10.1186%2F1752-153X-5-23/MediaObjects/13065_2011_284_Fig3_HTML.jpg
          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)
          University of Potsdam, Institute of Chemistry

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          Copyright

          © Adamovich et al; licensee Chemistry Central Ltd. 2011

          This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.