CHAPTER 5 SYNTHESIS OF 7-HYDROXY-4-METHYLCOUMARIN OVER ZAPO-5 AND LEWIS ACID METAL ION-EXCHANGED ZAPO-5 MOLECULAR SIEVES

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1 79 CHAPTER 5 SYNTHESIS F 7-HYDRXY-4-METHYLCUMARIN VER ZAP-5 AND LEWIS ACID METAL IN-EXCHANGED ZAP-5 MLECULAR SIEVES 5.1 INTRDUCTIN Coumarins are an important group of naturally occurring compounds widely distributed in the plant kingdom. However, they have been produced synthetically for many years for commercial use. Coumarin and its derivatives have been studied for physiological activity. The coumarin derivatives find their applications in pharmaceutical, fragrance, agrochemical industries, optical brightening agent, dispersed fluorescent and anticoagulant (Gunnewegh et al 1995). Among the various coumarin derivatives, 7-hydroxy-4-methylcoumarin is the most widely used one in fine chemical industries. It is used as fluorescent brightener and as a standard for fluorometric determination of enzymatic activity. It acts as a starting material in the preparation of insecticide hymecromone. Pechmann reaction is the most widely applied method for the preparation of substituted coumarins since it proceeds from very simple starting materials and also offers good yield. Mineral acids like H 2 S 4, HCl, H 3 P 4 and CF 3 CH and Lewis acids such as ZnCl 2, FeCl 3, SnCl 4, TiCl 4 and AlCl 3 were used as catalysts in the conventional methods of coumarin synthesis (Horning 1955). This route causes formation of by-products, longer reaction time and corrosion problems. For these reasons, there have been efforts to find alternative,

2 80 environmentally benign and heterogeneously catalysed synthetic routes. The use of heterogeneous acid catalysts presumes advantages like ease of operation conditions, reduced equipment corrosion and minimised contamination of waste streams combined with reusability. Nafion-H, zeolites β, Amberlyst 15 and other solid acids have been employed for this purpose in the Pechmann reaction (Hoefnagel et al 1995, Gunnewegh et al 1995 and Li et al 1998). Pechmann reaction of resorcinol and ethyl acetoacetate produced 7-hydroxy-4-methylcoumarin over regenerable Hβ in toluene solvent (Gunnewegh et al 1995). In the case of Amberlyst-15, special equipment for accelerating this reaction by microwave irradiation was used (de la Hoz et al 1999). Potdar et al (2005) reported the synthesis of 7-hydroxy-4-methylcoumarin over neutral ionic liquids ([bmim] PF 6 /PCl 3 ), but it required the presence of PCl 3 which is also a hazardous one. Adopting the principles of green chemistry, we have established dramatic improvement in the yield using solvent-free condition for Knoevenagel and Pechmann reactions. Synthesis of coumarins directly catalysed by Lewis acid ion-exchanged MeAP-5 has not been reported so far. In the present work we describe an eco-friendly procedure for the synthesis of coumarins via Pechmann reaction catalysed by metal ion-exchanged ZAP-5. We report the preparation of 7-hydroxy- 4-methylcoumarin using resorcinol and ethyl acetoacetate as the reactants over ZAP-5 and Lewis acid metal ion-exchanged ZAP-5 in the liquid phase. The structure of 7-hydroxy-4-methylcoumarin is shown in Figure 5.1.

3 81 H C= Figure 5.1 Structure of 7-hydroxy-4-methylcoumarin 5.2 SYNTHESIS F 7-HYDRXY-4-METHYLCUMARIN The liquid phase intermolecular condensation between resorcinol and ethyl acetoacetate was carried over ZAP-5 and La 3+, Ce 3+, In 3+ and Ga 3+ ion-exchanged ZAP-5 catalysts. The reaction was carried out by changing the reaction parameters viz., temperature, catalyst weight, feed ratio and reaction time to obtain good yield at maximum conversion. The only product obtained was 7-hydroxy-4-methylcoumarin Effect of Temperature Intermolecular condensation of resorcinol and ethyl acetoacetate was carried over ZAP-5 and metal ion-exchanged ZAP-5 catalysts in order to correlate the effect of Lewis acid sites on resorcinol conversion and product selectivity. The reaction was carried at 100, 125, 150 and 175 ºC in the liquid phase. The feed ratio was kept at 1:3 (resorcinol: ethyl acetoacetate) and the reaction was carried for 6 h in all the cases. The major product was found to be 7-hydroxy-4-methylcoumarin. The results of resorcinol conversion, selectivity and yield of products over all the catalysts are presented in Table 5.1. The resorcinol conversion and selectivity to 7-hydroxy-4- methylcoumarin increased with increase in temperature. The possible pathways for the formation of coumarin derivative are illustrated in Schemes 5.1 and 5.2. It is visualised as shown in the reaction Scheme 5.1 that

4 82 ethyl acetoacetate is activated by protonation at the ester carbonyl which facilitates nucleophilic attack of resorcinol yielding the precursor of the final product. Table 5.1 Effect of temperature on resorcinol conversion, yield and selectivity of products over various catalysts Catalyst ZAP-5 LaZAP-5 CeZAP-5 InZAP-5 Temperature ( o C) Resorcinol conversion Selectivity of 7-hydroxy- 4-methyl coumarin hydroxy- 4-methyl coumarin other products GaZAP Reaction conditions: Catalyst amount: 0.1 g; Time: 6 h; Feed ratio: 1:3 (Resorcinol: Ethyl acetoacetate)

5 83 CC 2 H 5 2- Zn H + + P + H 2 C CC 2 H 5 H 2 C 2- Zn H C CH P C H H H C= H 2 C =C H C= C H MAP-5 H + H + C C-H CH H C C H C H H H C= Scheme 5.1 Intermolecular cyclisation of resorcinol and ethyl acetoacetate over ZAP-5

6 84 H H H 2 C C C CH 2 M + MAP-5 H 3 C C CH 2 M + C CH 2 H C= CH C= H M + H H M + H M= H C M= + H + H2 -H 2 H C= Scheme 5.2 Intermolecular cyclisation of resorcinol and ethyl acetoacetate over M +. The precursor undergoes enolisation and the enolised product is also activated by protonation at the ester carbonyl. The resulting species undergoes intermolecular cyclisation and subsequent dehydration to form the product.

7 85 In the reaction Scheme 5.2, it is presumed that ethyl acetoacetate co-ordinates to M +. This is attacked by resorcinol yielding the precursor. This precursor undergoes enolisation and rearrangement of electronic cloud to form species that readily undergo intermolecular cyclisation. The conversion of cyclised species into final product is also catalysed by M +. Since the precursor is not observed as product, cyclisation appears to be more rapid. The conversion increased with increase in temperature over ZAP-5. The selectivity of product is above 90% at all temperatures. This revealed that the intermediates formed immediately reacted further to form the final product. Comparison of the results of resorcinol conversion and product yield revealed that ZAP-5 is the least active among the catalysts. This presumed that the reaction is largely controlled by Lewis acid sites. LaZAP-5 showed higher conversion of resorcinol and yield of 7-hydroxy-4- methylcoumarin than ZAP-5. Though LaZAP-5 exhibited 48% reduction of strong acid sites, the enhanced conversion compared to ZAP-5 clearly established the active role of La + sites. These Lewis acid ions like Bronsted acid sites also activate ester thus facilitating nucleophilic reaction of ester with resorcinol as shown in the reaction Scheme 5.1. Though they are lesser in number than the total number of strong Bronsted acid sites, they may catalyse with higher activity. Co-ordination of both reactants to La + may be possible as it possesses higher co-ordination capability than H +. The important observation is that ion-exchange of La 3+ mainly occured on strong acid sites leaving weak acid sites unaffected as discussed above. Hence, the metal ion dependent route may be more pronounced than Bronsted acid sites dependent route. The reaction over CeZAP-5 exhibited nearly similar trend in conversion and product yield as that of LaZAP-5. However, there is further

8 86 enhancement in the conversion of resorcinol, yield and selectivity of 7-hydroxy-4-methylcoumarin over CeZAP-5. Therefore Ce 3+ may play similar role as that of La 3+. The high conversion and yield over CeZAP-5 are due to more ion-exchange of Ce 3+ (70%) than La 3+ (48%) in ZAP-5. The results over In 3+ and GaZAP-5 exemplify higher conversion than the previous catalysts. This is again due to more ion-exchange of In 3+ (90%) and Ga 3+ (96%) than La 3+ and Ce 3+ in ZAP-5. Hence it could be concluded that M + sites (where M = La 3+, Ce 3+, In 3+ and Ga 3+ ) are more active for intermolecular cyclisation of resorcinol and ethyl acetoacetate than Bronsted acid sites. The yield of the product is also higher over GaZAP-5 than other catalysts. Palaniappan and ChandraShekhar (2004) have reported the synthesis of 7-hydroxy-4-methylcoumarin using polyaniline supported sulphuric acid. They reported 74% yield of the product for a feed ratio of 1:2 (resorcinol: ethyl acetoacetate) at 170 C. The yield of the product in our study is 17% higher than the already reported value although the catalyst weight was 0.1 g less than the amount used by them. Hence ion-exchanged ZAP-5 is found to be better than others for this reaction. In addition, HY and HZSM-5 zeolites have been used for the synthesis of 7-hydroxy-4- methylcoumarin (Sabou et al 2005). The yield of the product with HY and HZSM-5 was found to be 12% less than our report with ion-exchanged ZAP-5. Comparison of these results revealed that ion-exchanged ZAP-5 with Lewis acid metal ion in the form M + species may catalyse this reaction better than Bronsted acid sites Effect of Feed Ratio The effect of feed ratio (resorcinol: ethyl acetoacetate) viz., 1:1, 1:3 and 1:5 on resorcinol conversion, product yield and selectivity was studied over GaZAP-5 at 160 C and the results are shown in Table 5.2 and

9 87 Figure 5.2. The conversion increased when the feed ratio increased from 1:1 to 1:3. This observation suggests enhanced adsorption and activation of ethyl acetoacetate on the active sites of the catalyst. In order to facilitate nucleophilic attack of resorcinol, ethyl acetoacetate should be first chemisorbed on the active sites through the ester carbonyl group. This is the prerequisite step for the subsequent intermolecular cyclisation. But the conversion decreased with 1:5 feed ratio. There may be enhanced adsorption of ethyl acetoacetate even at this feed ratio. But nucleophilic attack of resorcinol on this could be suppressed due to the presence of excess free ethyl acetoacetate. Although feed ratio changed the conversion, selectivity was not much affected as all three feed ratios gave selectivity more than 90%. Table 5.2 Effect of feed ratio on resorcinol conversion, product selectivity and yield over GaZAP-5 Feed ratio Resorcinol conversion Selectivity of 7-hydroxy-4- methylcoumarin 7-hydroxy-4- methylcoumarin other products 1: : : Reaction conditions: Temperature: 150 ºC; Catalyst amount: 0.1; Time: 6 h

10 Conversion Selectivity Yield Distribution Figure 5.2 1:1 1:3 1:5 Feed ratio Effect of feed ratio on resorcinol conversion, product selectivity and yield of 7-hydroxy-4-methylcoumarin Effect of Catalyst Loading The effect of catalyst loading on resorcinol conversion and product selectivity was studied using 0.05, 0.1 and 0.15 g catalyst with a constant feed ratio of 1:3 at 150 C and the results are presented in Table 5.3. The conversion increased with increase in the catalyst amount. Hence, it is presumed that once the product formed it should be immediately desorbed from the catalyst surface without allowing to chemisorb again. The selectivity of 7-hydroxy-4-methylcoumarin also increased with increase in catalyst amount from 0.05 to 0.15 g. Hence, the formation of intermediate and its cyclisation to coumarin derivative require enough number of active sites to increase resorcinol conversion as well as product selectivity. GaZAP-5 with

11 89 more number of active sites is better than other catalysts. This study clearly revealed that the reaction still depends on the number of active sites. Thus the optimum amount of catalyst is found to be 0.1 g. Table 5.3 Effect of catalyst amount on resorcinol conversion, product selectivity and yield over GaZAP-5 Catalyst amount (g) Resorcinol conversion Selectivity of 7-hydroxy-4- methylcoumarin 7-hydroxy-4- methylcoumarin other products Reaction conditions: Temperature: 150 ºC; Time: 6 h; Feed ratio: 1:3 (Resorcinol: Ethyl acetoacetate) Effect of Reaction Time The sequential formation of intermediate and the product is evident from the effect of reaction time on resorcinol conversion and product selectivity as shown in Table 5.4. The selectivity to 7-hydroxy-4- methylcoumarin increased with increase in the reaction time upto 8 h, beyond which the selectivity remained steady illustrating the attainment of equilibrium. Since the selectivity of others also increased with increase in time, they should include only the intermediates of 7-hydroxy-4- methylcoumarin. This supported clearly the formation of intermediates first and their cyclisation to coumarin derivative in a sequential manner.

12 90 Table 5.4 Effect of reaction time on resorcinol conversion, product selectivity and yield over GaZAP-5 Selectivity of Time (h) Resorcinol conversion 7-hydroxy-4- methylcoumarin 7-hydroxy-4- methylcoumarin other products Reaction conditions: Temperature: 150 ºC; Catalyst amount: 0.1 g; Feed ratio: 1:3 (Resorcinol: Ethyl acetoacetate) 5.3 CNCLUSIN The study concludes that ion-exchanged ZAP-5 catalysts are more active for intermolecular cyclisation of resorcinol and ethyl acetoacetate in the synthesis of 7-hydroxy-4-methylcoumarin than the parent ZAP-5. The yield of the product is higher over ion-exchanged ZAP-5 than those catalysts already reported in the literature. The M + sites (where M = La 3+, Ce 3+, In 3+ or Ga 3+ ) are found to be more active than Bronsted acid sites. The formation of minimal amount of side product is an important observation in this study. Thus, Lewis acid metal ion exchanged ZAP-5 catalysts could be an eco-friendly alternative for the industrial production of coumarin derivatives from the appropriate precursors. Further, ZAP-5 is suitable for selective ion-exchange of Bronsted acid sites by trivalent metal ions. Such ion-exchanged catalysts may find applications in the selective organic transformations requiring only Lewis acid sites or weak Bronsted acid sites.