INTERNATIONAL JOURNAL OF CHEMICAL

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Volume 6 2008 Article A78

Microwave Irradiated Acetylation ofp-Anisidine: A Step towards Green

Chemistry

Mousumi Chakraborty∗ Vaishali Umrigar†

Parimal A. Parikh‡

∗S.V. National Institute of Technology, mch@ched.svnit.ac.in†S.V. National Institute of Technology, vaishali svnit@yahoo.co.in‡S.V. National Institute of Technology, pap@ched.svnit.ac.in

ISSN 1542-6580Copyright c©2008 The Berkeley Electronic Press. All rights reserved.

Microwave Irradiated Acetylation of p-Anisidine: AStep towards Green Chemistry∗

Mousumi Chakraborty, Vaishali Umrigar, and Parimal A. Parikh

Abstract

The present study aims at assessing the effect of microwave irradiation againstthermal heat on the production of N-acetyl-p-anisidine by acetylation of p-anisidine.The acetylation of p-anisidine under microwave irradiation produces N-acetyl-p-anisidine in shorter reaction times, which offers a benefit to the laboratories aswell as industries. It also eliminates the use of excess solvent. Effects of oper-ating parameters such as reaction time, feed composition, and microwave energyand reaction temperature on selectivity to the desired product have been investi-gated. The results indicate as high as a 98% conversion of N-acetyl-p-anisidinecan be achieved within 12-15 minutes using acetic acid. The use of acetic acid asan acetylating agent against conventionally used acetic anhydride eliminates thehandling of explosive acetic anhydride and also the energy intensive distillationstep for separation of acetic acid. Organic solvent like acetic anhydride are notonly hazardous to the environment, they are also expensive and flammable.

KEYWORDS: microwave reactor, green chemistry, acetylation, kinetic study

∗The authors thank Prof. K.R. Desai, Department of Chemistry, V.N. South Gujarat University,Surat for allowing the use of the microwave reactor.

Introduction Development of cleaner technology is a major emphasis in green chemistry. Use of large excess of solvents required providing a medium for chemical reaction causes ecological and economic concerns (Verma, R.S. and Namboodiri, V.V. 2001). One of the most accepted and a reported advancement in recent years is the use of microwave (MW) assisted chemistry. The effects usually observed with microwave activation in organic reaction are: decreasing reaction times, increased product yields, cleaner reaction with easier work-up and reduced effluent load (Braibante et al. 2003, Raston et al. 2004). The MW dielectric heating effect uses the ability of some liquids and solids to transform electromagnetic energy into heat and thereby drive chemical reactions (Kidwai, M. 2001). Most of articles on MW assisted organic synthesis are available in published literature. Various examples of organic synthesis using microwave radiation, e.g., Heck reaction, Sonogashira reaction, Stille, Negishi and Kunada reaction, Buchwald-Hartwig reactions, Ullmann condensation reaction, transition metal-catalyzed carbonylation reactions etc. were cited (Kappe, C.O. 2004). Umrigar et al. (2007) also studied sulphonation of 2-Naphthol. They found that Schaeffer’s acid can be produced from sulfonation of 2-Naphthol with high values of conversion (87%) and selectivity (90%) at 90 ºC and 200 W power in much less time, 4-5 minutes as compared to conventional process. They observed all benefits of MW process include more precise and controlled volumetric heating, faster heating rates, lower energy consumption and improved quality and properties of the processed materials. Functional group protection strategies are central to target molecule synthesis. The protection of alcohols, phenols and amines as their acetates is one of the most fundamental, useful and widely used transformations in organic synthesis. Although numerous methods are available for the preparation of acetates, an acetic anhydride–pyridine mixture is commonly used. The acylation reactions are generally carried out in batch reactors over corrosive conventional Friedel–Crafts catalysts, such as AlCl3, FeCl3, or other Lewis acid metal chlorides. Because of the formation of very stable complexes between the metal chloride and the arylketone, arylamine, more than stoichiometric amounts of catalysts and a final hydrolysis step of the 1:1 molar adduct are required (Koningsveld et al. 1987) . Therefore, such a process leads to the production of huge quantities of acidic by-products to be neutralised, treated, and properly discharged. As in the last two decades many zeolitic catalysts have been tested under various conditions and with different acylating agents. Most of the works were carried out on alkylarenes or alkoxyarenes such as benzene, toluene, xylene, anisole, veratrole, and methoxynaphthalene (Fromentin et al. 2000, Spagnol et al. 1996, Corma et al. 1989, Guignard et al. 2002). Smith et al. (2003) found that the

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acetylation of aryl ethers using acetic anhydride in the presence of zeolites catalyst under modest conditions in a solvent-free system gave the corresponding para-acetylated products in high yields. Guidotti et al. (2005) carried out acetylation of aromatic substrates in a batch reactor at 373K over H-BEA zeolite and observed that the H-BEA zeolite is a viable alternative to Friedel-Crafts catalyst. They carried out acylation with acetic anhydride of six aromatic substrates in a batch reactor at 373 K over H-BEA zeolite (Si/Al = 15) with nitrobenzene as a solvent. Heravi et al. (2006a) found a trace amount of Fe(ClO4)3 (ferric perchlorate) is effective as Lewis acid catalyst for acetylation of alcohols and phenols with acetic acid at room temperature. They also used a trace amount of heteropoly acid as catalyst for acetylation of alcohols and phenols with acetic anhydride at room temperature (Heravi et al. 2006b). However many of these methods are associated with one or two drawbacks, such as harsh reaction conditions, long reaction times, unsatisfactory yields and disturbance to other functional groups. Deactivated and sterically hindered phenols have been acetylated with acetic anhydride under microwave irradiation and using iodine as catalyst in an eco-friendly process. The reaction was carried out under solvent-free conditions and the acetates were obtained in nearly quantitative yields with dramatic reduction of reaction time compared to standard oil-bath heating (Deka et al. 2001). Gupta et al. (2002) studied the acetylation of hydroxyl, thiol and amino groups in solvent free conditions under microwave irradiation using acetic anhydride-pyridine over basic alumina. They found acetic anhydride when adsorbed over silica gel, is found to act as a good acetylating agent for amines. Acetic acid has been used for acetylation of seven aromatic amines and two phenols under microwave exposure. The time taken for these reactions ranges from 18-25 min with reasonability good yields (65-77%) (Jain et al.2007). Under microwave irradiation steroidal enones were efficiently and selectively converted to the corresponding enol acetates using acetic anhydride and a catalytic amount of toluene-p-sulfonic acid (Marwah et al. 2003). Indium (III) chloride catalyzed microwave assisted acetylation of different carbohydrates is an efficient synthesis of per-O-acetyl derivatives and provides good yields of the product (Das et al. 2005). Gronnow et al.(2005) found that solid acids can offer truly catalytic acetylations of relatively complex substrates albeit in lower yields than their traditional alternatives such as aluminium chloride. Microwave heating enables lower by-product formation and more importantly reaction times in the order of minutes as opposed to hours required by conventional means. In view of this, Microwave Irradiation (MWI) of p-anisidine for the synthesis of N-acetyl-p-anisidine has been investigated .Cheaper acetylating reagent, acetic acid has been used to carry out acetylation. In conventional batch process employing acetic anhydride in 50% excess (by volume) this reaction takes

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about 3-4 hours at 126 ºC affording a maximum conversion of about 98%. Use of acetic anhydride entails safety issues as well as energy intensive distillation step for separation of acetic acid formed during the reaction. MWI methodology eliminates the use of excess solvent during the course of reaction. Optimal use of materials and energy and safer operation were the driving forces behind the present work. Effects of various operating parameters (e.g., reaction time, feed composition, microwave energy and reaction temperature) in p-anisidine acetylation with acetic acid using MWI on product yields were studied. Kinetic study of the reaction also had been attempted. Experimental Procedure Materials p-anisidine, glacial acetic acid and sulfuric acid, each having a purity of 0.98 mass fractions were obtained from Merck, India. Sodium nitrate, potassium bromide and hydrogen chloride required for analysis of amine group using Nitrite Value method were also obtained from Merck, India with a quoted purity of 0.99, 0.98 and 0.25, respectively Apparatus and Procedure Batch reactions were carried out in a thermo-stated microwave assisted glass reactor (Questern Technology, Canada) equipped with a magnetic stirrer. Frequency of the microwave was 2450 MHz. The oven has power levels in five-stages and eight stage stirring facility. Thermocouple was provided for measuring reaction-mixture temperature and specially designed glass flask with reflux condenser. The oven has a blower on the backside for the purposes of venting as well as cooling the glass reactor after completion of reaction. For each run, p-anisidine powder (40gm) and acetic acid (8.4 ml) and a sulfuric acid (0.4ml) (as a catalyst) (totalling 40 to 60 ml volume) were mixed to prepare homogeneous slurry by maintaining the room temperature while addition of drop by drop sulfuric acid into the acetic acid and p-anisidine powder with continuous stirring. The oven can accommodate a glass reactor with a maximum capacity of 250ml. Reactions were carried out at different temperatures and powers. Samples of about 5 ml were withdrawn from the reactor at different intervals of time and analyzed. Purity of product mixture was measured with Thin Layer Chromatography (TLC) (0.25 mm thickness) silica gel G coated Al plates (Merck) and the spots were visualized by exposing the dry plates in iodine vapor using methanol: toluene (1:9 vol/vol, upper layer) as a solvent. Concentration of

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reactant in the product mixture was measured following Nitrite Value method (Kirk-Othmer Encyclopedia of Chemical Technology, 1978). Results and Discussion Reaction Mechanism Reaction shown in scheme 1 takes place during p-anisidine acetylation under microwave irradiation using acetic acid and a catalytic amount of sulfuric acid.

Scheme 1.Reactions occurring during p-anisidine acetylation Effect of Feed Composition In conventional batch process at least 50% excess acetic acid is employed for acetylation of p-anisidine. To reduce effluent load of excess reagent, attempt had been made to carry out acetylation reaction with 1:1 mole ratio of p-anisidine and acetic acid (p-A: A) in presence of small amount of catalyst sulfuric acid (0.1 molar ratio). As shown in (fig.1), acetylation assisted by MWI afforded 86% conversion of p-anisidine along with 100% selectivity within 10 minutes of reaction time with 1:1 molar ratio even at 200 W power supplies. Conversion is maximum (98%) with 1:1 molar ratio at 400 W power supply. Acetic acid concentration lower than 1 mol per mol of p-anisidine did not produce homogeneous feed slurry mixture and conversion decreased with increasing molar ratio. So it was found that 1:1 molar ratio of p-anisidine and acetic acid was sufficient to get maximum conversion in microwave assisted reaction. Backward reaction would dominate with higher mole ratio and result lower conversion.

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Fig.1.Effect of feed composition on MWI p-A acetylation at 126 ºC and with different power supply Effect of Power on Conversion Reactions were carried out at constant reaction temperature of 126 ºC and fixed molar ratio of p-anisidine:acetic acid:sulfuric acid (p-A:A: S = 1:1:0.1) at different values of power, namely, 200 W, 300 W and 400 W. When the reaction started, the temperature was around the room temperature. It was observed during the experimentation that reaction at 200 W took 8 minutes for reaching reaction temperature of 126 ºC. While at 400 W; the reaction attained the desired temperature within 60 seconds. This indicates that approach to equilibrium was faster in case of higher rate of power supply. 90% and 98% conversions were observed at 300 W and 400 W after 8 and 5 minutes of reaction time whereas for 200 W power supply maxima was shifted to 12 minutes of reaction time, as depicted in fig.2. Compared to conventional process, microwave-assisted method

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under identical conditions of reaction temperature and lower molar ratio yields higher conversion.

Fig.2.Effect of Power supply on % Conversion on MWI p-A acetylation at 126ºC and with feed composition 1:1:0.1 molar ratio Effect of Temperature on Conversion At constant value of power supply and molar ratio at 400 W and p-A: A: S of 1:1:0.1, reaction temperature was varied from 117 to 126ºC. This acetylation reaction is endothermic in nature, so the rate of conversion was expected to increase as the temperature rises. But it has been observed (fig.3) that with increase of reaction temperature from 117 ºC to 126 º C, conversions slightly increases.Observation demonstrates clearly the effect of microwave irradiation is

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Fig.3 Effect of Temperature on % Conversion on MWI p-A acetylation at 400 W power supply and with feed composition 1:1:0.1 molar ratio

Scheme 2. Reaction-mechanism occurring during p-anisidine acetylation not purely thermal. These specific microwave effects might originate in the rate determining step of the mechanism (nucleophilic attack of the amine nitrogen

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lone pair on carbonyl moiety) since it leads to a development of charges in the transition state thus inducing an important exaltation in dipole-dipole interactions (Scheme2).In this circumstance, an increased stabilization of the dipolar transition state results under MW irradiation when compared with its less polar ground state and the activation energy is consequently reduced (Vishnoi, N.K. 1996). Reaction Kinetics First order reaction follows the equation given below (Levenspeil, O. 2001)

ktCC

XA

AA ==−−

0

ln)1ln( -----------(1)

A plot of ln(1-XA) or ln(CA/CA0) vs t gives a straight line. It shows that the acetylation reaction follows 1st order reaction kinetics (fig.4).

Fig.4 Plot of –ln (1-Xa) Vs. time (min) for MWI of p-A acetylation at 400 W power supply and with feed composition 1:1:0.1 molar ratio The values of rate constants at different temperatures and powers were calculated from the slope of curve and shown in Table I. It is found that rate

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constant for the acetylation of p-A increases with the increase in both, temperature and power as acetylation reaction is endothermic (ΔHr = 18.8-19.9 kJ/mol). Table: I Reaction rate constant (k1) at different temperatures and power supplies with feed composition p-A: A: S =1:1:0.1

Fig.5 Effect of power consumption on activation energy and reaction rate constant on MWI p-A acetylation at 126 ºC

Variation of the rate constant with temperature can be presented by Arrhenius equation. RTEekk /

0−= ------------(2)

Temperature, ºC k1, gmol/gm min

200 W 300 W 400 W 117 0.0581 0.0962 0.1521 120 0.095 0.1434 0.1935 126 0.1634 0.2147 0.282

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Slope of the curve lnk vs 1/T gives -E/R, from which activation energy can be calculated. Putting rate constants values, given in table-I, in Arrhenius equation, activation energies at different power supplies were calculated. At 400 W, minimum activation energy required 84.48 kJ/mol is indeed much less than the reaction in the absence of MW. Decrease in activation energy value was attributed to electrostatic interactions (or dipole-dipole types) of polar molecules with the electrical field. At higher values of power (300W & 400W) activation energy for this reaction is achieved within shorter time period compared to lower value of power supply (200W).With increase of power consumption reaction rate constant increases as activation energy decreases (fig.5). Conclusion The method is environmentally friendly as acetic acid was used as an acetylating agent in the stoichiometric proportion and a catalytic amount of H2SO4 which leads to minimum effluent generation. It has been observed that N-acetyl-p-anisidine can be produced from acetylation of p-A with high values of conversion (98%) at 126 ºC and 400 W power in much less time, 12-15 minutes as compared to conventional process. Here the use of acetic acid, a precursor for acetic anhydride are extremely convenient from a practical and economic point of view, which avoids wasting reagents and allow a simple work up procedure. MW assisted acetylation provides more precise and controlled volumetric heating, faster heating rates, lower energy consumption and improved quality and properties of the processed materials. Kinetics of the reaction showed that overall order of reaction in p-anisidine concentration is of 1st order and activation energy from about 84 to 138 kJ/mol. Nomenclature p-A species p-A, p-Anisidine A species A, acetic acid S species S, Sulfuric acid k1 reaction rate constant, gmol/gm min k0 initial rate constant, gmol/gm min n order of reaction E activation energy, kJ/mol Ac2O species Ac2O, acetic anhydride

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References Braibante, H.T.S., Braibante, M.E.F., Rosso, G.B., Oriques, D.A., “Preparation of β-Enamino Carbonylic Compounds using Microwave Irradiation/K-10”, J. Braz. Chem. Soc., Vol.14, 994-997(2003). Corma, A., Climent M.J., Garcia H., Primo, J., “Design of synthetic zeolites as catalysts in organic reactions Acylation of Anisole by Acyl Chlorides or Carboxylic Acids Over Acid Zeolites”, Appl. Catal., Vol 49, 109-123 (1989). Das S.K., Reddy, K.A., Krovvidi, V.L.N.R, Mukkant, K. “InCl3 as a powerful catalyst for the acetylation of carbohydrate alcohols under microwave irradiation” Carbohydr. Res. ,Vol 340,1387-1392 (2005). Deka N., Mariotte, A.M., Boumendjel, A., “Microwave mediated solvent-free acetylation of deactivated and hindered phenols”, Green Chem., Vol.3, 263-264 (2001). Fromentin, E.,Coustard, J.M., Guisnet, M.,“Acetylation of 2-methoxynaphthalene with acetic anhydride over a HBEA zeolite” J. Mol. Catal. A: Chem. Vol. 159 377-388 (2000). Guignard, C., Pèdron, V., Richard, F., Jacquot, R., Spagnol, M., Coustard, J. M., Pérot, G., “Acylation of veratrole by acetic anhydride over Hβ and HY zeolites Possible role of di- and triketone by-products in the deactivation process” Appl. Catal. A, Vol. 234, 79-90 (2002). Gupta, R., Paul, S., Nanda, P., Loupy, A., “Ac2O-Py/basic alumina as a versatile reagent for acetylations in solvent-free conditions under microwave irradiation” Tetrahedron Lett., Vol.43, 4261-4265 (2002). Guidotti, M., Canaff, C., Magnoux, J. P., Guisnet, M.. “Acetylation of aromatic compounds over H-BEA zeolite: the influence of the substituents on the reactivity and on the catalyst stability”, J. Catl., Vol. 230, 375-383 (2005). Gronnow, M.J., Macquarrie, D.J., Clark, J.H., Ravenscroft, P.“A study into the use of microwaves and solid acid catalysts for Friedel-Crafts acetylations”, J. Mol. Catal. A: Chem., Vol.231, 47-51(2005). Heravi, M.M., Behbahani, F.K., Shoar, R.H., Oskooie, H.A. “Catalytic acetylation of alcohols and phenols with ferric perchlorate in acetic acid”, Catal. Commun., Vol. 7, 136-139 (2006). Heravi, M.M., Behbahani, F.K., Bamoharram, F.F. “H14[NaP5W30O110 : A Heteropoly acid catalysed acetylation of alcohols and phenols in acetic anhydride”, J. Mol. Catal. A: Chem., Vol. 253, 8-10 (2006). Jain D., Soni M.D.,Vardia, J., Punjabi, P. B., Ameta, S.C., “Acetylation of some organic compounds under microwave irradiation” J.Indian Chem. Soc., Vol. 84, 188-188 (2007). Kirk-Othmer Encyclopedia of Chemical Technology “Nitrite value method”, Vol 2, 3rd Ed., (1978)

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Koningsveld, H.V., Scheele J.J., Jansen, J.C., “Structure of 4-tert-butyl-2,6-dimethylacetophenone and comparison with its FeCl3 complex”, Acta Crystallogr. C., Vol..43, 294-296(1987). Kidwai, M.,. “Dry Media reactions” Pure Appl. Chem., Vol. 73,147-151(2001). Kappe,C.O. “Controlled Microwave heating in Modern Organic Synthesis”, Angew. Chem. Int. Ed., Vol.43, 6250-6284 (2004). Levenspiel, O., “Chemical reaction engineering”, John wiley & sons, New York, 3rd Ed.(2001). Marwah, P., Marwah, A., Lardy H.A., “Lardy Microwave induced selective enolization of steroidal ketones and efficient acetylation of sterols in semisolid state” Tetrahedron Vol. 59, No. 13, 2273-2287 (2003). Raston, C.L. “Versatility of alternative reaction media: solventless organic synthesis”, Chem. Aust., May 11(2004). Smith, K., El-Hiti, G.A., Jayne, A., Butters, J M., “Acetylation of aromatic ethers using acetic anhydride over solid acid catalysts in a solvent-free system. Scope of the reaction for substituted ethers”, Org. Biomol.Chem., Vol.1, 1560-1564 (2003). Spagnol, M., Gilbert, L., In., D.A., Desmurs, J.R., Ratton, S., “The Roots of Organic Development, Elsevier, Amsterdam (1996). Umigarh, V., Chakraborty, M, Parikh, P.A., “Microwave assisted sulfonation of 2-Naphthol by Sulfuric acid: Cleaner production of Schaeffer’s acid”, Ind. Eng. Chem. Res., Vol. 46, 6217-6220 (2007). Verma, R.S., Namboodiri, V. V.,“Solvent-free preparation of ionic liquids using a household microwave oven” , Pure Appl. Chem. Vol 73, 1309- 1313 (2001). Vishnoi, N.K., “Advanced Practical Organic Chemistry”, Vishal publishing house, New Delhi, 2nd Ed. (1996)

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