The Preparation of Methyl Benzoate and Methyl Salicylate on Silica Gel Column

Full Length Research Paper

The preparation of methyl benzoate and methyl salicylate on silica gel column

O. M. Ameen* and G. A. Olatunji

Department of Chemistry, University of Ilorin, PMB 1515, Ilorin, Nigeria.

Accepted 29 May, 2009.

An investigation of the acid catalyzed esterification of benzoic acid and salicylic acid with methanol on silica gel solid support system was carried out. The method involved distilling continuously or refluxing the alcohol over the packed column. The conventional method of esterification was also carried out to assess the advantages of the packed column method on improved yield and easier work-up procedure. This modified method minimized the lengthy and cumbersome work – up associated with the conventional method. Although the yields obtainable from the packed column methods compared favourably with yields from conventional method, the new method will require further modification to bring about optimal yields of the desired esters.

Key words: Esters, esterification reaction, salicylate, packed column, modification.

INTRODUCTION

Many esters are known today which may either be natu- mediates. This was demonstrated when its thermal de- ral or synthetic. Many of the esters have found use in composition generated ortho-quinoketene, a benzyne diverse areas of human needs: medicine, ointments, precursor, (Badea et al., 1992). foods, preservatives, lacquers etc. Sodium benzoate is an ester used in the modification of Many of the important esters include the salicylates alkyd resin, (Gwiatek and Zadernowski, 1993), as well as which are useful in the preservation of foods, pain con- in the treatment of hyperammonemia, (Tremblay and Qu- trol, and fever control. They have also been found to reshi, 1993). Similarly, benzocaine, the ethyl ester of p- inhibit aldose reductase in the lens of the eye and as amino benzoic acid widely used as local anesthetic has such they can retard the development of cataracts. For demonstrated relieve of pain in patients with spontaneous instance, sodium salicylate is the chief ingredient used in toothache pain from an open tooth cavity, (Hersh et al., the preparation of antirheumatic and antiseptic drugs. It 1993). Lactate esters are versatile solvents that are was also used in the manufacture of dyes and in the pre- biodegradable, nontoxic and applicable to a wide range paration of preservatives, McGraw – Hill (1997). of industrial and consumer use, (Hidetoshi et al., 2004). Acetyl salicylic acid (aspirin) is an effective analgesic, However, the preparation of ester involved lengthy work- antipyretic and anti-inflamatory drug, and it also prevents ups and sometimes the products may contain some cer- the aggregation of platelets and stroke, (McGraw – Hill tain impurities. Several modifications have been under-ta- 1997; Kurlkarmi et al., 1993). Methyl salicylate, a consti- ken for the preparation of esters in order to minimize tuent of wintergreen and other plants such as Ambyoma lengthy work-ups and to improve yields. One of such met- variegatum and A. hebraeum (Lusby et al., 1991), Law- hods is the one reported by Krbechek, (1993) in which sonia inermis (Wong and Teng, 1995) is another ester sulphuric acid was employed as a catalyst as well as to used as a local anesthetic agent and disinfectant com- remove or immobilize the water produced. Using this mercially used in toothpaste, mouthwash, perfumes as method, isooctanoic acid was esterified with methanol in well as flavouring agents, Finar (1993). Methyl salicylate the presence of excess sulfuric acid both as catalyst and is also useful in synthesis as a generator of reactive inter- as desiccants affording 95% yield of ester. A method reported by Nelson, et al (1992) involved pro- viding a mixture of a monohydric alcohol and a lower carboxylic acid in a reaction vessel equipped with a fractio- *Corresponding author. E-mail: [email protected]. nating column connected to a condenser and a collecting 120 Afr. J. Pure Appl. Chem.

ira et al., 2003). From the foregoing, we decided to investigate a modified esterification technique in which the esterification reaction would be carried out on a packed silica gel column with the alcohol being distilled or refluxed over the column. We aimed at minimizing lengthy and cumbersome solvent extraction work-up associated with the preparation of esters by conventional method. Methyl esters of benzoic acid and salicylic acid have hereby been prepared as case studies.

MATERIALS AND METHOD

Materials

All reagents used in this study were of analytical grade. These include benzoic acid, sodium bicarbonate, sodium carbonate, salicylic Figure 1. Distillation of alcohol over silica gel. acid. Benzoic acid was purified by recrystalizing from boiling water. The solvents used include, diethyl ether, methanol, ethanol, petroleum spirit, etc, the solvent were redistilled before use. vessel. Heating technique and a device for passing small bubbles of gas through the reactants were incorporated. Preparation of methyl benzoate The alcohol/carboxylic acid mixture was maintained at a temperature of at least about the boiling point of the alco- A column [30 cm; Ø3 cm] was packed with silica gel to about half of hol, but below the boiling point of the carboxylic acid, a the column, then silica gel mixed with 2 drops of concentrated sul- gas inert to the esterification reaction was bubbled thro- phuric acid (H2SO4) was packed into the column and separated with some silica gel, and this was followed by silica gel mixed with ben- ugh the mixture to remove the esterification product that zoic acid and packed into the column and finally the column was was formed. The removed vapour was collected and con- topped with silica gel. The column was then connected to a flask densed yielding the esterification product with a high per- containing methanol and the other end was connected to a con- centage conversion and purity. Using this method, they denser and finally to a receiver. The methanol was heated over were able to produce ethyl acetate resulting from three water bath until all the excess methanol had been collected in the receiver at the other end (Figure 1). After all the methanol has been cycles of esterification of ethanol with acetic acid at 85°C distilled over the column and the excess methanol collected in the with air bubbling at a rate not exceeding 200 ml/min re- receiver, the set up was left overnight to allow silica gel embedded sulting in 85 - 90% conversion efficiency in terms of ace- methanol drain back in to the flask. tic acid consumption. The column was emptied into three beakers viz the upper layer Similarly, 0.5 mole phthalic anhydride and 1.1 mole bu- containing the benzoic acid, the silica gel/H2SO4 layer and the lower tanol had been dropped into a mixture of various ratios of silica gel part of the column. The methanol that had drained into the flask was also collected for TLC analysis. alumina gel, silica gel and or active carbon. The mixtures The silica gel and the silica gel mixtures were extracted with di- were then heated at 250°C, and the reaction was main- ethyl ether, concentrated and collected in sample bottles labeled tained for 6 hours. Dibutyl phthalate was obtained in a 1A-4A. The four samples were spotted on a TLC plate along with yield of approximately 30 - 52% with the maximum yield benzoic acid and developed with 1:1 mixture of diethyl ether and petroleum ether. obtained when the mixed catalysts comprise 80% Al2O3 gel and 20% SiO gel or active carbon, (Shigeri and Shi- Sample 2A and 3A were combined. The combined sample was 2 washed with water until neutral, dried over anhydrous magnesium ro, 1954). In another preparation, n-butanol and butyric sulphate (MgSO4) and concentrated. It was then spotted on TLC acid were esterified in a batch reactor using amberlyst plate along with benzoic acid and developed with 1:2 mixture of di- macro porous cation exchange resin as a catalyst. It was ethyl ether petroleum ether. observed that the reaction rate increased with increasing The esterification reaction was repeated with packed column, but catalyst concentration and reaction temperature, (Bhatna- this time around the benzoic acid and concentrated H2SO4 were mixed together before packing with silica gel. The column was then gar et al., 1994). In a recent finding, Hidetoshi et al fitted with a condenser for refluxing. This was carried out for 3 h (Fi- (2004) reported the use of water – permeable – zeolite T gure 2). membranes for the esterification reaction of lactic acid The set up was then left overnight. The following day, excess met- with ethanol yielding an almost complete conversion with- hanol was distilled off and the residue was collected. The column in 8 h while a similar result was recorded for the esterifi- was emptied into two beakers viz the mixture of the acid layer and cation of glycol and fumaric acid within 4 hours. Another the lower part of the column. The samples were extracted with diethyl ether, concentrated and labeled 1B - 3B. Sample 1B that is, report is that of Pereira et al, in which lipase was immo- the layer of the mixture of the organic acid and H2SO4 was washed bilized on a chitosan support and was used for the syn- with water until neutral before extraction. The samples were spot- thesis of n – butyl butyrate with an optimum yield, Pere- ted, developed with the same solvent system as in the first experi- Ameen and Olatunji 121

H3C

HO O + O H3C OH + H + H H

O O Benzoic acid Methyl benzoate Methanol Water

Figure 3. Catalysed esterification of benzoic acid with ethanol

RESULTS AND DISCUSSION

Result of the preparation of methyl benzoate

Experiment A1: Distillation experiment of alcohol over the column

The melting point of the re – crystallized benzoic acid was determined before the commencement of the experi-

ment. The melting point was found to be 123°C. Figure 2. Refluxing of alcohol over silica gel column. The acid catalyzed esterification of benzoic acid with methanol can be represented as in Figure 3. The product of the first experiment in which methanol ment. The products were stored in labeled sample bottles. was continuously distilled over the column gave 2 spots The esterification reaction was repeated using the conventional refluxing method. This involved refluxing 1 g of benzoic acid, 2 (with poor separation) on the TLC plate, indicating that drops of concentrated H2SO4 and excess methanol for 3 h. The ex- there was a partial conversion of the acid to the ester (Fi- cess methanol was distilled off, the residue was washed with ex- gure 4). cess water until neutral and the ester was extracted with diethyl Spot 1A corresponding to the benzoic acid zone on the ether. The solvent was removed and the TLC was carried out. The column indicates the absence of the ester but only the product was stored in a labeled sample bottle. unreacted benzoic acid. However, 2A and 3A (the extracts from mineral acid layer and the lower part of the Preparation of methyl salicylate column respectively) showed the presence of the ester formed as well as the unreacted acid. The ester being an Methyl Salicylate was prepared described as previously i.e. in the oil, drained down the column as it was being formed. On preparation of methyl benzoate. However, the preparation of methyl salicylate was repeated with a combination of samples 2A and 3A and after the work-up longer column [50 cm; Ø3 cm] in which anhydrous MgSO4 (20 g) followed by TLC (reducing the polarity of the developing was incorporated into the lower part of the column, this was re- solvent system) with benzoic acid as reference, the mi- fluxed with methanol for 4 h after which it was left overnight. It was neral acid spot disappeared and the spot (with better se- also worked up and analyzed as described earlier. paration) showed the presence of the ester and trace

amount of unreacted benzoic acid (Figure 5). Melting point determination The percentage yield was 21.04. The low percentage yield can be attributed mainly to the low conversion of the The melting points of solid acid samples were determined using the benzoic acid. On investigation, the melting point of the Galenkamp melting point apparatus. solid substance formed from the extracts of 1A was found

to be 119°C. Infrared analysis

The infrared (IR) analysis was carried out using Buck Scientific Experiment A2: Refluxing experiment (model 500) i.r. spectrophotometer, at Obafemi Awolowo University, Ile-Ife. The products from the second experiment in which meth- 122 Afr. J. Pure Appl. Chem.

Rf VALUES KEY BA = 0.47 Rf VALUES BA = Benzoic acid 1A = 0.47 BA = 0.27 1A = Organic acid zone 2A (1) = C (1) = 0.27 2A = M ineral acid zone 0.47 C (2) = 0.68 3A = Lower part of the 2A (2) = colum n 0.78 4A = Extracts of flask

Figure 4. TLC of product of the distillation experiment.

Figure 7. TLC of the product of conventional method experiment.

Rf VALUES BA = 0.40 CS (1) = 0.41 CS (2) = 0.90 (CS = Com bined sam ples)

Figure 5. TLC of the combined extracts.

KEY BA = Benzoic acid Appendix 1. The IR spectrum for the methyl benzoate.

1B = The m ixture of the acids 2B = Lower part of the colum n conventional method of preparing the ester) also showed 3B = Extract of the flask that benzoic acid was only partially converted to its me- colum n thyl ester, (Figure 7). The low yield from this experiment, (10.35%), can be

explained, since the esterification was not carried out with Rf VALUES concurrent removal of water example, azeotropic distil- BA = 0.48 lation.

Figure 6. TLC of the product of reflux experiment. The i.r. spectrum (Appendix 1) of the product showed absorptions characteristics of the important stretching fre- quencies of the functional groups in the ester, John, anol was refluxed over the packed column gave a mixture (1965). There is sharp band at 1722.2 accounting for C = of spots on TLC indicating also partial conversion of the O (aryl esters) stretching and a medium band at 1250.9 organic acid (Figure 6). and 1190 accounting for C – O (aryl esters) stretching. This TLC result revealed that the ester was formed at the layer containing the mixture of the organic and inor- ganic acids (i.e. benzoic and sulphuric acids). The per- The results of the preparation of methyl salicylate centage yield was 15.23. Experiment B1: Continuous distillation

Experiment A3: conventional method experiment The melting point of recrystallized salicylic acid was determined and found to be 160°C. Methanol and salicylic The TLC results of the third experiment (that is, the acid react according to Figure 8. Ameen and Olatunji 123

HO HO

HO O + O H3C OH + H + H H

O O

CH3 Methanol Salicylic acid Methyl salicylate Water

Figure 8. Reaction of methanol and salicylic acid

Rf VALUES KEY SA = 0.13 SA = Salicylic acid 1G = 0.13 KEY Rf VALUES 1G = Organic acid zone 2G (1) = 1H = Organic acid zone 2G = M ineral acid zone 0.13 SA = 0.38 2H = M ineral acid zone 3G = Lower part of the 2G (2) = 4H (1) = 3H = Lower part of the colum n 0.13 0.38 CM E =Com m ercial m ethyl 3G (1) = colum n 4H (2) = 4H = Extract from the flask 0.78

CM E = 0.78 Figure 9. TLC of the product of continuous distillation experiment. Figure 10. TLC of the product of refluxing experiment.

The TLC analysis result for the continuous distillation of alcohol over packed, column indicates partial conversion of the acid to its ester (Figure 9). The organic acid was packed at the upper part of the Rf VALUES column and as such the esterification was expected to take place at that point. But the fact that the ester was SA = 0.43 found from the extracts of the lower part of the column I (1) = 0.42 and in the residue in the flask indicates that the ester drained down the column along with the embedded alco- I (2) = 0.85 hol. The yield (10.23%) was rather low and unsatisfac- CM E = 0.85 tory. The crystals that formed from the extracts of 1 G melted at 158°C, which meant that it was the unreacted salicylic acid.

Experiment B2: Refluxing experiment Figure 11. TLC of the product of conventional method experiment. The result of the reflux experiment showed that the organic acid was partially converted to its ester. The ester as well as the unreacted acid washed down the column into as by-product impeded further formation of the ester. the distillation flask and no product was found on the co- Whereas, in the continuous distillation experiment the lumn as shown by the TLC analysis result, (Figure 10). reaction occurred on the column, and water formed as by The yield was very low (2.82%). product was entrained in the lower segment of the silica Comparing the two methods adopted for the esterifica- gel packing. tion reaction (that is, continuous distillation and refluxing) the yield of the ester produced from the continuous distil- Experiment B3: conventional method lation experiment was higher than that of the refluxing experiment. This can be explained on the assumption that The conventional method of preparation gave slightly im- the bulk of the reaction in the refluxing experiment was in proved (13.45%) yield, though still lower than would have the distillation flask (the contents of the column was been the case with continuous removal of water (Figure washed down by the methanol), and as such, the water 11). 124 Afr. J. Pure Appl. Chem.

Rf VALUES SA = 0.36 J (1) = 0.36 J (2) = 0.89 CM E = 0.89

Figure 12. TLC of the products of Experiment B4. Appendix 2. The IR spectrum for the methyl salicylate.

The crystalline residue obtained from this experiment melted at 162°C, confirming that it is the unreacted orga- Jessop et al., 1995; Fermin and Bruno (1993), as well as nic acid. the use of enzymes such as immobilized lipase catalyst, The incorporation of anhydrous MgSO4 into the silica gel (Rizzi et al., 1992; Berghund et al., 1995). Esters have al- packing (experiment B4) as a way of trapping the water so been produced in the presence of microorganism or produced as by product failed to improve the yield of the their products, Garcia et al., (1993). ester and the TLC analysis of the results (Figure 12) indi- These ideas prompted the present investigation of este- cates that the conversion and yield were low with the bulk rification on a silica gel column. of the products found in the distillation flask. The results obtained as far as percentage conversion The reversibility of the esterification reaction is a factor and yields are concerned would suggest that the method contributing to the low yields of the ester. Once the reac- may be suitable for micro – scale preparation. Other solid tion attains equilibrium, the rate of forward reaction support systems or their combination may bring about equals that of the backward reaction, and the overall suc- some improvement as shown by the report of Shigeri and cess of the reaction seems therefore contingent on the Shiro (1954) for the esterification of phthalic anhydride. continuous removal of the by–products. This was the ba- sis of incorporating anhydrous MgSO4 into the system, REFERENCES which did not achieve the desired result. The i.r. spectrum (Appendix 2) of the product showed Badea HD, Iordache H, Matei V, Oniciu DC (1992). Thermal Decompo- absorptions characteristics of the important stretching fre- sition of methyl salicylate, evidence for orthoquinokotene generation, quencies of the functional groups in the ester, John Sci. Bull. Poletech. Inst. Bucharest Chem. Mater. Sci. 54(1-2): 89-95. -1 Berghund P, Honquist M, Hult K, Hoegberg HE (1995). Alcohols as (1965). The band at 3200 - 3600 cm on the i-r spectrum enantioselective inhibitors in a lipase catalyzed esterification of a chiral accounts for the presence of hydrogen bonded hydroxyl acyl donor, Biotechnol. Lett. 17(1): 55 – 60. (-OH) group characteristic of phenolic compounds. Simi- Bhatnagar R, Arvid R, Bhatia S (1994). Esterification of n-butanol with butyric acid using Amberlyst-15 (macro porous) resin as catalyst. A ki- larly, the presence of the carbonyl (-C=O) functional netic study, Indian Chem. Eng. Sect-A, 36(3): 120-123. group is shown on the i.r spectrum as a strong, sharp Fermin MC, Bruno JW (1993). Oxygen atom transfer niobocene ke- -1 band at wavelength 1646 cm indicating that it is in con- tones; Baeyer – Villiger chemistry with unusual regioselectivities, Te- trahedron Lett. 34(47): 7545 – 7548. jugation with an aromatic system. The -C-O- stretching th characteristics of aromatic ester is depicted on the i.r. Finar IL (1993). Organic chemistry: The fundamental principles, 6 -1 edition, Longman group Ltd, UK, 1: 66-68. spectrum at wavelength 1241 cm , but was weak. Also, a Garcia DM, Avalos M, Cameselle JC (1993). Alcohol esterification reac- -1 weak band at 1380.9 cm could be as a result of O-H tion and mechanisms of snake venom 51 – nucleotide phosphor-dies- bending, and C-O stretching characteristic of phenols, terase, Eur. J. Biochem. 213(3): 1139 – 1148. Gwiatek L Zadernowski R (1993). Occurrence of aromatic acids and su- John (1965). gars in flower of contaurea cyanus L., Acta. Acad. Agric. Tech. Olste- nensis. Technol. Alimenth 422(25): 231-239. Hersh EV, Cooper SA, Segal H, Greene J (1993). Analgesic on-settime Conclusion and Recommendation as a measure of topical anesthetic efficacy in spontaneous toothache pain. A pilot study, J. Chin. Dent. 4(2): 52-54. Some methods have been tried to improve the yield in Hidetoshi K, Yusuke Y, Ryuhei Y, Kazuhiro T, Kenichi O (2004). Appli- esterification reaction. These include the use of mineral cation of zeolite membrane to esterification reactions; available at http://www.che.utoledo.edu/nams/2004/viewpaper.cfm?ID=687 retriev- acid in excess of the catalytic amount required, Krbech- ed on Feb 12th, 2008. eck (1993) employing different catalysts and catalyst mix- Jessop PG, Hsiao Y, Ikariya T, Noyori R (1995). Methyl formate syn- ture, (Shigeri and Shiro, 1954; Bhatnagar et al., 1994; thesis by hydrogenation of supercritical carbon dioxide in the pre- Ameen and Olatunji 125

sence of methanol, J. Chem. Soc. Chem. Commun. 6: 707 – 708. Pereira EB, Zanin GM, Castro HF (2003). Immobilization and catalytic John RD (1965). Applications of absorption spectroscopy of organic properties of lipase on chitosan for hydrolysis and esterification reac- compounds, Prentice – Hall, New York, pp 33 – 52. tions, also available at http://www.scielo.br/scielo.php?script=sci_art Krebecheck LO (1993). Esterification of carboxylic acid with alcohols in- text&pid=S0104-66322003000400002, retrieve on Feb. 12th, 2008. volving the use of sulfuric acid as catalyst and desiccants [Chem. Braz. J. Chem. Eng. 20(4): 343 – 355. Abstr. 121, #1, 8689n, p.925 (1990)]. Rizzi M, Stylos P, Riek A, Reus M (1992). A kinetic study of immobilized Kurlkarmi GA, Guldsorkar VR, Shete JS (1993). Evaluation of Com- lipase catalyzing the synthesis of isoamyl acetate by transesterification mercial aspirin tablets, East Pharm. 36(431): 119-121. in n- hexane, Enzyme – Microb. Technol. 14(9): 709 – 714. Lusby WR, Soreshine DE, Yunker CE, Norval RA, Buridge MJ (1991). Shigeri T, Shiro N (1954). Vapor-liquid phase esterification of phthalic Comparison of known and suspected pheromoral constituent in males anhydride, J. Chem. Soc. Jpn. Ind. Chem. Sect. 57: 71-73. African tick, Anbyomma hebraeum kock and Amblyoma variegatum Tremblay GC, Qureshi IA (1993). The biochemistry and toxicology of (fabricius), Exp. Appl. Acarol 13(2): 143-152. benzoic acid metabolism and its relationship to the elimination of McGraw-Hill (1997). Encyclopaedia Of Science And Technology, 8th edi- waste nitrogen, Pharmacol-Ther. 60(1): 63-90. tion, McGraw-Hill Inc, New York 2: 177 – 178, 16:6. Wong KC, Teng VE (1995). Volatile components of Lawsonia inermis L. Nelson PE, Ekanayake A (1992). A process for the manufacture of ester flowers, J. Essent. Oil Res., 7(4): 425-428. by esterification of carboxylic acid with alcohols accompanied by bubbling. [Chem. Abstr. 121, #1, 8689u, p.925, (1994)]