- Preliminary communication
- Open Access
Synthesis and crystal structure of 1,4,10,13-tetraoxa-7,16-diazoniumcyclo-octadecane bis(4-chloro-2-methyl-phenoxyacetate)
© Adamovich et al 2011
Received: 15 February 2011
Accepted: 9 May 2011
Published: 9 May 2011
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.
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 .
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 , promoting to penetration of a matter through cellular membranes, represent a new class of biologically active compounds [4–9]. 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 [7–9].
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.
Crystal data and details of the structure solution and refinement
Crystal system, space group
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)°
Z, Calculated density
2, 1.328 g/cm-3
1.5 × 0.6 × 0.15 mm
Θ range for data collection
1.61 to 25.0°
Full-matrix least-squares on F2
Goodness-of-fit on F2
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
Selected bond lengths (Å), bond angles (°), and torsion angles (°)
Hydrogen bond geometry (Å, °)
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.
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 . The refinement was carried out using SHELXL-97 . 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  and ORTEP for Windows  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.
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.
The authors acknowledge O. P. Kolesnikova for screening of immunoactive properties of compound 1.
- Hiraoka M: Crown Compounds: Their Characterisistics and Applications. 1982, Amsterdam, Oxford, New York: Els. Scient. Publ. CompGoogle Scholar
- Bogatskii AV, Nazarov EI, Golovenko NYa: Biological aspects of activity of crown ethers, criptands and their analogs. J of the DI Mendeleev all-union Chem Soc. 1985, 30: 593-599.Google Scholar
- Voronkov MG, Albanov AI, Aksamentova TN, Adamovich SN, Chipanina NN, Mirskov RG, Kochina TA, Vrazhnov DV, Litvinov MYu: Tris(2-hydroxyethyl)ammonium Salts: 2,8,9-Trihydroprotatranes. Russ J Gen Chem. 2009, 79: 2339-2346. 10.1134/S1070363209110097.View ArticleGoogle Scholar
- Voronkov MG, Mirskova AN, Levkovskaja GG: Carcinostatic, Protective, and Adaptive Activities of Tris-(2-Hydroxyethyl)Ammonium Salts of Arylheteroacetic Acids. Dokl Biologica Sciences. 2002, 386: 404-406. 10.1023/A:1020797714298.View ArticleGoogle Scholar
- Kolesnikova OP, Kudaeva OT, Sukhenko TG, Limonov VL, Kozlov VA, Mirskova AN, Voronkov MG: Trekrezan as a Modulator of Hemato- and Immunopoieses. Dokl Biologica Sciences. 2003, 391: 306-308. 10.1023/A:1025186114079.View ArticleGoogle Scholar
- Mirskova AN, Levkovskaja GG, Mirskov RG, Voronkov MG: Hydroxyalkylammonium Salts of Organylsulfanyl(sulfonyl)acetic Acids - New Stimulators of Biological Processes. Russ J Org Chem. 2008, 44: 1478-1485. 10.1134/S1070428008100126.View ArticleGoogle Scholar
- Kolesnikova OP, Mirskova AN, Adamovich SN, Mirskov RG, Kudaeva OT, Voronkov MG: Alkanolammonium Salts of o-Cresoxy and p-Chlorocresoxyacetic Acids as Immunopoiesis Modulators and Cytostatics. Dokl Biologica Sciences. 2009, 425: 107-111. 10.1134/S0012496609020070.View ArticleGoogle Scholar
- Voronkov MG, Sofronov GA, Starchenko DA, Adamovich SN, Mirskova AN: Protective Properties of Chlorocresacine against Adverse Impact of Electromagnetic Radiation. Dokl Biologica Sciences. 2009, 428: 398-402. 10.1134/S0012496609050020.View ArticleGoogle Scholar
- Mirskova AN, Adamovich SN, Mirskov RG, Voronkov MG: Tris-(2-hydroxyethyl)ammonium 2-methyl- and 2-methyl-4-chlorophenoxyacetate serve as effective inhibitors of thrombocyte aggregation and antioxidants. Dokl Biologica Sciences (Engl. Transl.). 2010, 433: 244-246.View ArticleGoogle Scholar
- Smith G, Kennard CHL: 4-Chloro-2-methylphenoxyacetic acid (MCPA): C9H9ClO3. Cryst Struct Comm. 1981, 10: 295-299.Google Scholar
- Sheldrick GM: SHELXS-97: Program for the Solution of Crystal Structures. 1997, University of Göttingen, GermanyGoogle Scholar
- Sheldrick GM: SHELXL-97, Program for the Refinement of Crystal Structures. 1997, University of Göttingen, GermanyGoogle Scholar
- Farrugia LJ: ORTEP-3 for Windows - a version of ORTEP-III with a Graphical User Interface (GUI). J Appl Cryst. 1997, 30: 565-View ArticleGoogle Scholar
- Brandenburg K: DIAMOND, Version 3.1. 2005, Bonn: Crystal ImpactGoogle Scholar