INTRODUCTION
Derivatives of fluorophenoxyalkane acids show high biological activity. The salts, esters, amides, and other derivatives of these acids were applied widely in many areas of agriculture, with many as herbicides, fungicides, and regulators of the plant growth (Newman et al., Reference Newman, Fones and Renoll1947; Berhenke et al., Reference Berhenke, Begin, Williams and Beman1951; Melnikov, Reference Melnikov and Nowozyw1987). The chemical properties of these herbicides result from the aromatic radical (phenyl) and the presence of derivatives of the carboxyl group (Gruzdyev et al., Reference Gruzdyev, Zinchenko, Kalinin and Slovtsov1988).
The physiological activity of phenoxyacetic acid increases when a halogen such as fluorine or chlorine is introduced into the aromatic radical, and the position of the halogen is very important. For example, in the chlorophenoxyacetic acid series, 4-chlorophenoxyacetic acid has the highest physiological activity.
In the Department of Organic Chemistry at Maria Curie Sklodowska University (Lublin, Poland), investigations have been carried out for many years in order to search for new organic compounds of potential biological activity (Tarasiuk et al., Reference Tarasiuk, Podkościelny, Zimińska and Krawczyk2000; Tarasiuk, Reference Tarasiuk2007). Lately, it has concentrated on research related to the synthesis of N-fluorophenyl-pyridine-2-yl-amides and derivatives of 4-chloro-3,5-dimethylphenoxyacetic acid. Other groups of potential herbicides have been described (Olszewska et al., Reference Olszewska, Pikus and Tarasiuk2008; Olszewska et al., Reference Olszewska, Tarasiuk and Pikus2009).
The derivatives of 4-chloro-3,5-dimethylphenoxyacetamides have interesting pesticide activity. Highest pesticide activity will establish the derivatives of 2-(4-chloro-3,5-dimethylphenoxy)-N-[4-chloro-3-(trifluoromethyl)phenyl]acetamide and 1-benzyl-4-[(4-chloro-3,5-dimethylphenoxy) acetyl]piperazin.
SYNTHESIS
Materials
4-fluoroaniline (bp = 187 °C/767 mm Hg), 3-chloro-4-fluoroaniline (mp = 41–44 °C), 4-chloro-3-(trifluoromethyl) aniline (mp = 35–37 °C), 3-chloro-4-methylaniline (bp = 237–238 °C), 2,4,6-tribromoaniline (mp = 120–122 °C), 2-aminopyridine (mp = 58–60 °C), 4-methylpiperazine (bp= 138 °C), 1-benzylpiperazine (refractive index n20/D = 1.547), 4-chloro-3,5-dimethylphenol (mp = 114–116 °C), methyl bromoacetate (bp = 51–52 °C/15 mm Hg), thionyl chloride (bp = 79 °C), dimethyl sulfoxide (DMSO; bp = 189 °C), and phosphorus oxychloride (bp = 105 °C) were used. All reagents were supplied by Aldrich Chemical Company.
Synthesis of 4-chloro-3,5-dimethylphenoxyacetic acid
A mixture of the 4-chloro-3,5-dimethylphenol, methyl bromoacetate, potassium carbonate, and potassium iodide in dimethyl sulfoxide at solvent was stirred at 80 °C for 6 h.
Figure 1. Scheme of producing the 4-chloro-3,5-dimethylphenoxyacetic acid.
The DMSO was removed by evaporation in vacuum, and the solid was water added to the residue. The resulting solid was filtered and washed with 1N NaOH and water. The appropriate methyl 4-chloro-3,5-dimethylphenoxyacetate were hydrolysed for 2 h in a water ethanol solution of sodium hydroxide at 80 °C. Free acid were separated from the reaction mixture by adding a 10% water solution of hydrochloric acid. The product was purified by crystallisation from ethanol–water. Yield of acid was 89%; mp 150–151.5 °C; mp150–151 °C acc (Baker, Reference Baker and Neenan1972).
The course of reaction that produced the 4-chloro-3,5-dimethylphenoxyacetic acid is presented in a general scheme in Figure 1. The chloride of 4-chloro-3,5-dimethylphenoxyacetic acid was received in the reaction of the acids with an excess of thionyl chloride. N-Derivatives-2-(4-chloro-3,5-dimethylphenoxy)acetamides were synthesised in reaction of acid chloride with an excess of 2-aminopyridine or derivatives of piperazine in benzene, or 4-chloro-3,5-dimethylphenoxyacetic acid with fluoroanilines and phosphorus oxychloride in toluene.
Synthesis of the N-fluorophenyl-4-chloro-3,5-dimethylphenoxyacetamides—procedure I
In a round bottom three-necked flask of 250 cm3, equipped with a 0.025 mol of fluoroaniline, 100 cm3 of dry toluene, 0.02 mol of a 4-chloro-3,5-dimethylphenoxyacetic acid, and 2.3 g (0.015 mol) phosphorus oxychloride were placed. The mixture was heated at 110 °C for 5 h. The solution was then concentrated under diminished pressure while heating on the boiling water bath. After cooling to 5 °C, it was mixed with water. The crystals were carefully filtered. The raw compound was purified by crystallization from ethanol or benzene. The course of reaction, procedure I that produced the derivatives in question, is presented in a general scheme in Figure 2. This procedure was used to obtain samples 1–5.
Synthesis of the N-derivatives of 4-chloro-3,5-dimethylphenoxyacetamides—procedure II
In a round bottom three-necked flask of 250 cm3, equipped with a mechanical stirrer, a thermometer, (0.025 mol) of 2-aminopyridine or derivatives of piperazine, 50 cm3 of dry benzene, and 6.0 g (0.06 mol) pyridine were placed. While stirring the contents of the flask, a solution of 0.02 mol of 4-chloro-3,5-dimethylphenoxyacetic chloride was being added to 100 cm3 of dry benzene for 30 min, keeping in that period of time the temperature between 8 and 15 °C. While carrying out the reaction, colorless fine-crystal sediments of pyridine hydrochloride started to set out. After the whole amount of acid chloride was introduced into the reaction mixture, the whole of it was still stirred for 3 h at 30–35 °C. The sediments of pyridine hydrochloride were filtered and washed with dry warm benzene. Then, the solution was concentrated under diminished pressure while heating on the boiling water bath. After it was cooled down to 5 °C, the crystals were carefully filtered. The raw compound was purified by crystallization from toluene. Procedure II is presented in general scheme in Figure 3. This process was used to obtain samples 6–8.
The structure of investigated compounds is presented in a general scheme in Figure 4. The chemical structures of the synthesized samples were confirmed by elemental analysis, FTIR, and 1H-NMR. Characteristics of investigated samples are presented in Table I.
EXPERIMENTAL
Powder diffraction data were collected at room temperature in the 2θ range from 3 to 90° on a modified DRON-3.0 SEIFERT automated diffractometer by step scanning with a step equal 0.02° and a count time 6 s/step. Other experimental conditions were as follows: Cu target X-ray tube operated at 45 kV and 30 mA, 6° take-off angle, 1° divergence slit, 0.15 mm receiving slit, and scintillation counter with pulse
TABLE I. Chemical names, formulas, molecular masses, melting points, and solubility of derivatives for 4-chloro-3,5-dimethylphenoxyacetic acid.
Figure 2. Scheme of synthesis of derivatives of 4-chloro-3,5-dimethylphenoxyacetic acid (procedure I).
Figure 3. Scheme of synthesis of derivatives of 4-chloro-3,5-imethylphenoxyacetic acid (procedure II).
Figure 4. Structural formulas for N-derivatives of 4-chloro-3,5-dimethylphenoxyacetic acid.
Figure 5. X-ray powder diffraction patterns for samples: (1) 2-(4-chloro-3, 5-dimethylphenoxy)-N-(4-fluorophenyl)acetamide; (2) 2-(4-chloro-3, 5-dimethylphenoxy)-N-(3-chloro-4-fluorophenyl)acetamide; (3) 2-(4-chloro-3,5-dimethylphenoxy)-N-[4-chloro-3-(trifluoromethyl)phenyl]-acetamide; (4) 2-(4-chloro-3,5-dimethylphenoxy)-N-(3-chloro-4-methylophenyl)acetamide; (5) 2-(4-chloro-3,5-dimethylphenoxy)-N-(2,4,6-tribromophenyl)acetamide.
height analyzer. The diffractometer was calibrated by using a SRM 1976 standard. Throughout the XRD measurements, the ambient temperature was maintained at 20 ± 1 °C. The XRAYAN program (Marciniak and Diduszko, Reference Marciniak and Diduszko1994) was used for determining peak intensities and positions. The second derivative method used to determine peak observed positions, 2θobs.
RESULTS AND DISCUSSION
Figure 5 shows the experimental X-ray diffraction patterns for derivatives of chloro-3,5-dimethylphenoxyacetamide (samples 1–5). Figure 6 shows the patterns for the sample 2-(4-chloro-3,5-dimethylphenoxy)-N-pyridin-2-ylacetamide (sample 6), 1-[(4-chloro-3,5-dimethylphenoxy)-acetyl]-4-methylpiperazine (sample 7), and 1-benzyl-4-[(4-chloro-3,5-dimethyl-phenoxy)acetyl]piperazine (sample 8). In each diffraction pattern, all observed 2θ peak positions
Figure 6. X-ray powder diffraction patterns for samples: (6) 2-(4-chloro-3,5-dimethylphenoxy)-N-pyridin-2-ylacetamide; (7) 1-[(4-chloro-3,5-dimethylphenoxy)-acetyl]-4-methylpiperazine; (8) 1-benzyl-4-[(4-chloro-3, 5-dimethyl-phenoxy)acetyl]piperazine.
were used in the calculation. Pattern indexing was carried out using the personal computer version of the TREOR program (Werner et al., Reference Werner1985). The observed and calculated powder diffraction data for the eight compounds are given in Tables II–IX. Unit-cell data, values of M 30 (de Wolff, Reference de Wolff1968), and F 30 (Smith and Snyder, Reference Smith and Snyder1979) are presented in the Table X.
Powder patterns for four of the eight samples can be found in Powder Diffraction File: 1-[(4-chloro-3, 5-dimethylphenoxy)-acetyl]-4-methylpiperazine (PDF 00-60-1123), 2-(4-chloro-3,5-dimethylphenoxy)-N-pyridin-2-ylacetamide (PDF 00-60-1124), 1-benzyl-4-[(4-chloro-3, 5-dimethyl-phenoxy)acetyl]piperazine (PDF 00-60-1125), and 2-(4-chloro-3,5-dimethylphenoxy)-N-[4-chloro-3-(trifluoromethyl)phenyl]-acetamide (PDF 00-60-1135) (ICDD, Reference Kabekkodu2010).
As shown in Figures 5 and 6, all the samples of new pesticides are well crystallized. Seven out of the eight compounds crystallize in triclinic system, and only sample 4 (C17H17Cl2NO2) crystallizes in monoclinic system. For the samples 1–3 where we have different substituents (F, Cl, CF3, and Br), unit-cell volumes are similar. A little smaller volume for the sample 4 (Cl and CH3 as substituents) was obtained. The changes in type of substituent cause considerable structural changes revealing differences in intensity and position of diffraction peaks (see diffraction patterns in Figure 5) as well as in different unit cell parameters. This fact
TABLE II. Powder diffraction data for 2-(4-chloro-3,5-dimethylphenoxy)-N-(4-fluorophenyl)acetamide C16H15ClFNO2.
TABLE III. Powder diffraction data for 2-(4-chloro-3,5-dimethylphenoxy)-N-(3-chloro-4-fluorophenyl)acetamide C16H14Cl2FNO2.
TABLE IV. Powder diffraction data for 2-(4-chloro-3,5-dimethylphenoxy)-N-[4-chloro-3-(trifluoromethyl)phenyl]acetamide C17H14Cl2F3NO2.
TABLE V. Powder diffraction data for 2-(4-chloro-3,5-dimethylphenoxy)-N-(3-chloro-4-methylphenyl)acetamide C17H17Cl2NO2.
TABLE VI. Powder diffraction data for 2-(4-chloro-3,5-dimethylphenoxy)-N-(2,4,6-tribromophenyl)acetamide C16H13Br3Cl NO2.
TABLE VII. Powder diffraction data for 2-(4-chloro-3,5-dimethylphenoxy)-N-pyridin-2-ylacetamide C15H15Cl N2O2.
TABLE VIII. Powder diffraction data for 1-[(4-chloro-3,5-dimethylphenoxy)acetyl]-4-methylpiperazine C15H21Cl N2O2.
TABLE IX. Powder diffraction data for 1-benzyl-4-[(4-chloro-3,5-dimethylphenoxy)acetyl]-piperazine C21H25Cl N2O2.
confirms that diffraction analysis can be an effective instrument in identification of organic compounds.
The melting temperatures for investigated materials are presented in column 6 in Table I. For samples synthesised by procedure I, melting point is greater than for samples obtained by procedure II. In addition, samples 1–5 are not soluble in water.
In order to determine the correlation between biological activity and the crystal structure for the derivatives of 4-chloro-3,5-dimethylphenoxyacetamide (new compounds
TABLE X. Unit cell parameters for investigated samples.
belonging to a group of potential pesticides), research on more samples of this derivatives group will be needed in future.
ACKNOWLEDGMENT
We gratefully thank the International Centre for Diffraction Data for financial support of 5 samples (Grant No 97-01 S. Pikus 2007/2008, 2008/2009, No 04-08 E. Olszewska 2007/2008).
