Summary A clean method for the rapid and solventless preparation of herbicides based on 2,4-dichlorophenoxyacetic acid (2,4-D esters) is reported. Micro-particulate inorganic materials such as silica, clays and zeolites are able to act as supports for the 2,4-D esterification reactions under mild conditions in the absence of organic solvents. The synthesis takes place with elevated yield and the conversion rate of the process is strongly enhanced when the reaction is microwave-assisted.Not only can well-defined supports be used, but soil can also be used for this synthesis, except when iron oxides are present which lead to extensive oxi - dation under microwave irradiation. The 2,4-D ester remains adsorbed on the solid support as a bioactive product. Therefore the resulting powder is a partially formulated compound that can be directly applied in the field avoiding the use of solvents and with minimal hazardous and pollutant effects.Introduction 2,4-Dichlorophenoxy acetic acid (2,4-D) esters are extensively used around the globe as effective hormonal herbicides with high selectivity receiving wide application to e . g . cereals, grazing land and sugar cane plantations.1 These herbicides are also used in domestic gardening in Western Europe and in the USA.Unfortunately, as is well known, the manufacture and use of pesticides often results in environmental damage. Besides, more than 40 years of experience in the continuous and increasing use of such herbicides shows that their usage provokes only minor changes in the soil when they are employed with caution.There is thus the opportunity to study strategies to mitigate their harmful environmental impact in their use and preparation. New approaches to 2,4-D ester preparation and use have been developed with the aim to make these herbicides more ecologically acceptable. Thus, bioactive polymers based on 2,4-D and cross-linked acrylamide gels have been recently prepared in order to obtain controlled-release formulations enhancing the efficacy of the herbicide and reducing any environmental problems.2 The conventional esterification of 2,4-D and related compounds following standard methods consists in the treatment of these acids with the corresponding alcohol, the mixture being refluxed in benzene for long periods of time (in general more Synthesis of 2,4-D ester herbicides New routes using inorganic solid supports Laura Lami,b Blanca Casal,a Luis Cuadra,c Jesús Merino,a Amauri Alvarezb and Eduardo Ruiz-Hitzky*a a Instituto de Ciencia de Materiales de Madrid, CSIC, Cantoblanco, E-28049 Madrid, Spain.E-mail: eduardo@icmm.csic.es b Instituto Cubano de Investigaciones de los Derivados de la Caña de Azúcar, ICIDCA Cuba c Centro de Ciencias Medioambientales, CSIC, c/ Serrano 115 dpdo., E-28006 Madrid, Spain Received 29th March 1999 than 10 hours) in the presence of an acid catalyst (e.g.H2SO4) and using the 2,4-D in excess with respect to the alcohol.3 It is necessary to control the amount of alcohol present in the reaction media as the esterification progresses. Thus, a progressive addition of alcohol is needed, the reaction yield being critically determined by the quantity of water produced in the reaction.Alternative procedures for 2,4-D esters synthesis are based either on (i) direct reaction of the 2,4-D in the acid chloride form with the appropriate alcohol,4 or (ii) use of polymer-supported reagents involving the preparation of intermediate Amberlist 2,4- dichlorophenoxy acetate resins.5 Although this last method appears a laborious procedure, it produces under mild experimental conditions (2–9 h at room temperature), different 2,4-D esters in high yield (85–97%).However, all these routes involve the use of large quantities of chemicals and generate a significant volume of waste. This paper reports the synthesis of 2-4-D esters using microparticulate inorganic solids such as silica, clays and zeolites as reaction media, without organic solvents, i.e. in so-called dry media conditions,6–10 either by conventional heating or using microwaves.8,11,15 In the last case, the esters of 2,4-D are obtained in high yield in short reaction times (Scheme 1).In addition, the resulting product can be directly applied to the field because they are semi-formulated compounds which could find application in controlled release processes.Green Chemistry August 1999 199 C G The use of microwaves on a solid support has led to many very useful synthetic methods. Rapid reaction times and high conversions and selectivities are some of the benefits of this approach (see e.g. R. S. Varma, Green Chemistry, 1999, 1, 43.This paper deals with the preparation of a herbicide, and the authors have shown that the solid support can actually be a soil. This could allow the possibility of a preparative method for a soil–pesticide composite which could be applied to the land with fewer handling difficulties than traditional methods. DJM Green ContextScheme 1 Results and discussion The preparation of the 2,4-D ester in dry media conditions consisted of heating the 2,4-D and the alcohol in almost equi-molecular quantities (1+1 molar ratio) with both co-adsorbed on an inorganic powder.Heating can be either conventional (100–150 °C, 2–6 h) or, better, by microwave (MW) irradiation (150–350 W, 3–10 min). The 2,4-D esterification yield, using different alcohols, in experiments carried out on silica under microwave irradiation (3–5 min) always occurs with high conversion rates (Table 1).Table 1 2,4-D esterifications on silica gel using MW irradiation Reaction Yield of Alcohol:acid Alcohol time/min ester (%) 1.5:1 ethyl 3 98 1.5:1 isopropyl 3 99 1.5:1 n-octyl 3 98 1.5:1 isooctyl 3 99 1:1 ethyl 5 98a 1:1 isopropyl 5 95a 1:1 n-octyl 5 96a 1:1 isooctyl 5 97a 1:1 isopropyl 5 96b a 50% of full power MW irradiation.b 75% of full power MW irradiation. Cl Cl O CH2 C O OH + ROH Cl Cl O CH2 C O OR + H2O 2,4-D ester (yield>90%) 2,4-D acid heat Solid support Fig. 1 shows, as an example, the IR spectra of the reaction products after MW heating of the 2,4-D and isooctanol mixture co-adsorbed on a silica support. The intense band around 1725 cm21 is clearly observed and is assigned to the n(CNO) stretching vibrations of the ester functional group, whereas the 342 cm21 band associated to the 2,4-D acid is absent, confirming that the esterification reaction is almost quantitative. Typical n(O–H) bands of possible residual alcohol or acid reagents is overlapped by the broad intense n(O–H) absorption band of silanol groups of the silica support (3300–3700 cm21).The bands observed in the 1500–1650 and 750–1000 cm21 regions correspond to the characteristic vibrations of the 1,2,4-substituted aromatic ring, and the stretching vibrations corresponding to the C–H groups, appears in the 2800–3100 cm21 region. The organic reaction products are easily extracted by an organic solvent such as methanol or acetone, and analysed by GC-MS and GC-FTIR.The mass spectra (MS) of the resulting products show typical fragmentation of the 2,4-D esters. As an example, the MS of the reaction product with isooctanol shows the main fragments corresponding to the 2,4-D isooctyl ester at (m/z): 332 [M+], 220 [M+ 2isooctyl (2,4-D acid)], 164 [M+2acetate (2,4-dichlorophenol)], 145, 111 and 71 [2,4-dichlorophenol fragmentation]. High conversion rates (>90%) were also observed when other solids were used as the support, (Table 2).In particular, silicates of relatively high So specific surface area (So > 100 m2 g21) (zeolites, sepiolite and saponite), and therefore solids with high adsorptive capacity, were particularly efficient reaction supports.By contrast, the kaolinite aluminosilicate of low specific surface area So = 8.5 m2 g21, gives much lower reaction yield (<50%) than the other silicates used, in experiments carried out under similar experimental conditions (Table 2). The water content of the supports must also be considered in order to explain the effectiveness of the microwave activation. In fact, the kaolinite is practically water-free because only its external surface contains physically adsorbed water molecules (<1% w/w).In contrast, zeolites and saponites are tecto- and layeredsilicates respectively, containing water molecules (5–10% w/w) that belong to the hydration shell of the exchangeable cations which are located either on the external surfaces and/or in the intracrystalline region of these silicates.Sepiolite is a hydrated magnesium silicate of large specific surface area (>300 m2 g21) containing about 15% (w/w) water. As is well known, the MW action in heating materials is directly related to their dielectric polarisation capacity and, therefore, with the presence of associ- 200 Green Chemistry August 1999 Fig. 1 Infrared spectra of the 2,4-D isooctyl ester synthesised on silica gel (5 min of MW irradiation).ated water molecules with the solids.Thus, the action of the alternating electromagnetic field on the water molecules produces rotational energy which is transferred to the surrounding environment, activating the supported reactions.15 The temperatures reached by the solids supports after 2–5 min of MW irradiation are in the 150–180 °C range, using sample amounts and MW powers as employed in this work.The use of metal oxides, such as alumina and iron(iii) oxides, produces a strong decrease in the reaction yield (<5% for the 2,4- D isooctyl ester synthesis) (Table 3). Alumina has been largely used as an efficient support for dry media synthesis.1 6 Nevertheless, in this case it is probable that the carboxylic acid remains chemisorbed on the alumina surface preventing further reaction between the CO2H and the OH group of the alcohol.Such explanation implies the existence of symmetric bi-anchored carboxylate anions (Fig. 2), as reported elsewhere.17 The incorporation of an additional amount of water to those systems increases the conversion rate. In this way, the addition of 5% (w/w) of water to the alcohol increases the ester yield from 5 to about 15% (Table 3).In agreement with other authors17 this behaviour is probably due to the enhancement of reactivity produced by the presence of water on the alumina surface inducing the capture of protons. Besides this effect, the role of the MW–water interactions increasing the heating of the system should be considered although it is necessary to take into account the fact that the presence of water could disfavour the esterification reaction (Scheme 1).At present, it is difficult to ascertain a balance between these factors. When the experiments were carried out using a-Fe2O3 as support, the reaction yield drops practically to zero due to the oxidative degradation of the adsorbed organic compounds (Table 3).As occurs in general for MW-assisted organic phases,9,10,13 the activation by MW irradiation compared to conventional heating (oven) is always more efficient in producing strong acceleration of reactions. In the case of 2,4-D esterification, some representa - tive results are shown in Table 4, showing the potential interest in the use of such a procedure as a promising clean method.The potential advantages of using clay minerals are well known because the herbicide interacting with such micro-particulate solids could be slowly released resulting in a sustainable activity. Large amounts of clay minerals are used as pesticide carriers (around 200 000 tons per year both in the USA and in Western Europe). This means that 2,4-D supported esters can be directly used as obtained in the procedure involving the use of natural silicates operating in dry media conditions.In this way we have carried out bioassays consisting in the application of such compounds as aqueous dispersions containing the same amount of the herbicide as in conventional formulations, revealing good activity towards young plants of the Amaranthaceae family (Amaranthus albus).Such bioactivity assayed in the greenhouse (30 °C at daylight and 5 °C at night), corresponds to herbicide amounts that could be extrapolated to around 600 g a.i. ha21, i.e. almost the same quantity that is currently used in field application. The observed pre-emergent activity in soils afforded by the silicate/2,4-D isooctyl ester is also a novelty because the activity of 2,4-D esters has been always described to have a post-emergent character.It is also noteworthy, that in place of the more or less pure silicates described above, it is possible to use soil to prepare the 2,4- D esters. Thus, we have selected two agricultural soils (calcium Luvisol from Toledo, Spain, and ortic ferralsol from Havana, Cuba).Both were finely sieved and used under the same conditions as the silicates (Table 5). Thermal treatment in the same Green Chemistry August 1999 201 Table 2 2,4-D isooctanol esterification using silicates as supports in dry media microwave-assisted synthesis Alcohol: acid molar ratio (support : reagents Irradiation Yield of Inorganic support w/w, %) Power (%) time/min ester (%) Na–Y zeolite 1:1 (50) 50 10 90 Na–Y zeolite 1.5:1 (55) 50 5 92 Zeolite (natural)a 1:1 (33) 50 5 93 Zeolite (natural)b 1:1 (50) 50 5 97 Kaolinite 1:1 (50) 75 5 47 Saponite 1.5:1 (55) 100 10 100 Sepiolite 1.5:1 (55) 50 10 97 Sepiolite 1:1 (50) 50 15 93 Sepiolite (Pangel) 1:1 (50) 50 7 100 a From San Ignacio.b From La Pita. Table 3 2,4-D isooctanol esterification using Al2O3 and a-Fe2O3 metal oxides as supports in dry media microwave-assisted synthesis Alcohol+acid molar ratio Inorganic (support+reagents Irradiation Yield of support w/w %) Power (%) time/min ester (%) Al2O3 1+1 (50) 100 10 <5 Al2O3 a 1+1 (50) 75 5 14 a-Fe2O3 1+1 (50) 50 2 0 a-Fe2O3 1+1 (50) 50 5 0 a-Fe2O3 1+1 (50) 50 10 0 a Experiments carried out adding 5% (w/w) of water with respect to the alcohol.Fig. 2 Schematic representation of carboxylate anions adsorbed onto alumina. way as pure silicates in a conventional oven gives the supported esters which also exhibit good activity in the corresponding bioassays. The only negative result detected was with ferralsols when the activation of the esterification reaction was carried out using MW irradiation. In this case, the iron content (identified by X-ray diffraction as a-Fe2O3) of the soil used as reaction support induces organic decomposition which can be explained in terms of oxidation enhancement imposed by the electromagnetic field interacting with the strongly paramagnetic iron oxide particles.The addition of small amounts of a-Fe2O3 (i.e. 5% w/w) to the Toledo soil, or to a selected clay mineral, also reduces the reaction yield (Table 5) corroborating the role of such oxide.Finally, Fig. 3 resumes the steps needed in the use of soil minerals to obtain semi-formulated 2,4-D ester compounds. We have reported here a profitable approach to a selected herbicide which could be extended to other pesticide formulations. It should also be noted that this approach could lead to a lower dosage based on the slow release of the bio-active agents associated with the inorganic materials that have been used as supports in the preparation. Experimental Reagents 2,4-Dichlorophenoxyacetic acid (2,4-D) as well as ethyl, isopropyl, n-octyl and isooctyl alcohol (i.e. 2-ethylhexanol) were purchased from Fluka (reactive quality) and were used without further purification.Mineral substrates and metal oxides Sepiolite This mineral is a hydrated magnesium silicate, Si12O30Mg8(OH,F)4(H2O)4x· 8H2O, which is structurally formed by the alternation of blocks and tunnels along the c-axis.18 Sepiolite from Yunclillos (Toledo, Spain) (<200 mesh), purchased from TOLSA S.A., with 99% pure mineral, was used. The specific surface area (N2, B.E.T.) is 340 m2 g21 and the cationic exchange capacity is close to 0.15 meq g21.Micronised sepiolite purchased from TOLSA S.A. with the trade name of Pangel was also used as a reaction support. Other characteristics of sepiolite and Pangel are described in ref. 19. Saponite This clay mineral belongs to the layered 2+1 charged silicates, with its octahedral sites mainly occupied by magnesium ions and the electrical charge located in the tetrahedral layers (Si/Al substitutions).The mineral used here, also purchased from TOLSA S.A., is from Vicálvaro (Madrid, Spain) deposits, that contains about 15% of sepiolite. The hydrated exchangeable cations located in the interlayer space are mainly Mg2+ and Ca2+. Other characteristics are described elsewhere.20 Kaolin From Asturias (Spain), with a high content in pure kaolinite mineral (>90%).The chemical composition (%) of this 1+1 layer aluminosilicate is: SiO2 = 48.68; Al2O3 = 38.40; Fe2O3 = 0.15; CaO = 0.012; MgO = 0.049; TiO2 = 1.05; K2O = 1.08; Na2O = 0.011. Specific surface area (BET, N2): 8.5 m2 g21. Quartz content: <5%. Zeolites Synthetic (Y-zeolite) in its Na+ form, was purchased from Union Carbide.Chemical composition (%): SiO2 = 67.9; Al2O3 = 20.6; Na2O = 8.49. Two natural zeolites: from San Ignacio (zeolite-1) and from La Pita (zeolite-2), Cuba, were also used, and consisted of a mixture of minerals: zeolite-1 (heulandite-clinoptilolite 56%; mordenite 30%; quartz and montmorillonite <5%) and zeolite-2 (heulandite-clinoptilolite 26%; mordenite 10%; montmorillonite 22%; calcite 5,4%).Oxides S i l i c a+silica gel 60 (Merck), for column chromatography (220–440 mesh). Alumina (Fluka) for chromatography, type 507 C neutral (100–125 mesh). Iron oxide identified as hematite (a-Fe2O3). Soils The raw mineral fraction (<200 mesh) of the two soils used was (i) from Toledo (Spain), a calcium luvisol containing 67.5% of sand, 20.1% of slime, 12.4% of clays, and (ii) from Havana (Cuba), an ortic ferralsol containing 18.9% of sand, 22.0% of slime and a 59.1% fraction of clays and iron oxide which is mainly a-Fe2O3 hematite representing about 38% of this fraction.Synthesis of 2,4-D esters The standard procedure consists in the preparation, as the first step, of a homogeneous mixture of the reagents, i.e. 2,4-D and the 202 Green Chemistry August 1999 Table 4 Comparison between conventional thermal treatment and microwave-assisted synthesis of 2,4-D esters on inorganic solid supports (dry media conditions) MW Inorganic Alcohol+acid ratio Conventional irradiation Time of Yield of support (support+reagent, %) heating (T/°C) (power) (%) treatment ester (%) Silica gel 1+1 (50) — 100 3 min 97 Silica gel 1.5+1 (50) — 100 5 min 93 Silica gel 1.5+1 (50) 150 — 4 h 94 Silica gel 1+1 (50) 100 — 6 h 90 Zeolitea 1+1 (50) — 50 5 min 97 Zeolitea 1+1 (50) 100 — 4 h 93 a Natural zeolite (from San Ignacio, Cuba).alcohol (in general isooctanol was used, i.e. 2-ethylhexanol), with the inorganic solid as support (support/reagent: 50% w/w; typical experiments involve the use of 1 g of solid support).This operation could also be carried out with the assistance of an organic solvent common for both the acid and the alcohol which after impregnation is completely removed in a rotary evaporator. The reaction mixture is heated over variable periods of time (2–6 h) in an oven (100–150 °C). Alternatively, the heating could be carried out by MW irradiation (150–350 W, 3–10 min). The resulting products that remain impregnated on the solid support are extracted with a solvent (methanol, acetone, etc.), filtered over microporous alumina and analysed by GC-MS and FTIR.The yields (%) are deduced from the amount of unreacted material remaining adsorbed on the inorganic support. Apparatus The experiments using MW irradiation (2450 MHz) were carried out in a domestic Moulinex FM 460 oven.Characterisation of the extracted phases (2,4-D esters) was carried out by GC-MS using a Hewlett Packard 5890 series II spectrometer coupled to a selective mass detector series 5971 equipped with a capillary column (25 m length and 0.20 mm internal diameter), with a stationary phase thickness (methylsilicone) of 0.33 mm. FTIR Nicolet 20SXC spectrophotometer was used (Nujol dispersion or KBr pellets).Acknowledgements We gratefully acknowledge Professor R. González-Ponce for bioassays facilities, Dr P. Aranda for revising the manuscript and ICIDCA (Cuba), CSIC and CICYT (Spain) for financial support. We are also indebted to the Spanish Ministry of Foreign Office (Programa Fondo de Expertos, AECI) for the facilities given to develop this work. References 1 (a) Pesticide Manual.Basic Information on the Chemicals used as Active Components of Pesticides, ed. H. Martin and C. R. Worthing, British Crop Protection Council, Nottingham, 1977, 5th edn.; (b) C. Barbera, Pesticidas Agrícolas, Omega S. A., Barcelona, 1989, 4th edn. 2 E. R. Kenawy, React. Funct. Polym., 1998, 36, 31. 3 M. S. Newman, W. Fones and M. Renoll, J.Am. Chem. Soc., 1947, 69, 718. 4 C. R. Wagner, C. L. Hamner and H. M. Shell, J. Am. Chem. Soc., 1953, 75, 4861. 5 M. M. Shalunkhe, M. T. Thorat, R. B. Mane and P. P. Wadgaonkar, Eur. Polym. 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Green Chemistry August 1999 203 Table 5 Esterification of 2,4-D with isooctyl alcohol using soil as reaction support (1+1 alcohol+2,4-D acid molar ratio and 50% w/w soil+reagents) Yield (2,4-D Soil Heating method isooctyl ester) (%) Luvisol (Toledo) Conventional heating, 125 °C, 2 h 98 Luvisol (Toledo) MW irradiation, 7 min 97 Ferralsol (Havana) Conventional heating, 125 °C, 2 h 95 Ferralsol (Havana) MW irradiation 5–10 min <5 Luvisol + 5% Fe2O3 MW irradiation 2–10 min <50 Fig. 3 Methodology proposed for 2,4-D ester synthesis using soil as reaction support.11 A. Ben Alloum, B. Labiad and D. Villemin, J. Chem. Soc., Chem. Commun., 1989, 386. 1 2 G. Bram, A. Loupy, M. Majdoub, E. Gutiérrez and E. Ruiz-Hitzky, Tetrahedron, 1990, 46, 5167. 13 M. P Mingos and D. R Baghurst, Chem. Soc. Rev., 1991, 2 0, 1. 1 4 R. Alajarín, J. J. Vaquero, J. L. García Navío and J. Alvarez-Builla, Synlett, 1992, 297. 1 5 Microwave Enhanced Chemistry. Fundamentals, Sample Preparation and Applications, ed. H. M. Kingston and S. J. Haswell, American Chemical Society, Washington, 1997. 16 G. H. Posner, Angew. Chem., Int. Ed. Engl., 1978, 17, 487. 17 H. Ogawa, T. Chihara and K. Taya, J. Am. Chem. Soc., 1989, 107, 1365. 18 K. Brauner and A. Preisinger, Miner. Petr. Mitt., 1956, 6, 120. 1 9 A. Alvarez, J. Santaren, R. Perez Castell, B. Casal, E. Ruiz-Hitzky, P. Levitz and J. J. Fripiat, Proc. Int. Clay Conference, Denver 1985, ed. L. G. Schultz, H. Van Olphen and F. A. Mumpton, The Clay Minerals Society, Bloomington, 1987, pp. 370. 20 (a) B. Casal, J. Merino, E. Ruiz-Hitzky, E. Gutiérrez and A. Alvarez, Clay Miner., 1997, 32, 39; (b) S. Moreno, R. Sun Kuo and G. Poncelet, J. Catal., 1996, 162, 198. Paper 9/02531F 204 Green Chemistry August 1999