Case Study for the synthesis of methyl salicylate PDF

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in this case study, introduction , chemical composition, effect on human health and diazotization method for the preparation of methyl salicylate has been discussed....

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The Synthesis of Methyl Salicylate Introduction: 

Methyl salicylate can be found naturally in several plants such as wintergreen (leaves/bark)

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It is also present in fruits such as peaches and strawberries.

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Methyl salicylate can be obtained by chemical organic synthesis.

Wintergreen Plant

Chemical Identity :  Brand names: Methyl salicylate  Chemical name (IUPAC) : Methyl 2‐hydroxybenzoate  Molecular formula : C8H8O3  Molecular weight: 152.15 g/mol  Synonyms: 2‐Hydroxybenzoic acid methyl ester ,Synthetic oil of wintergreen, Synthetic methyl salicylate

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Ata Ur Rehman, 13001140002

The Synthesis of Methyl Salicylate Chemical Structure:

O

OCH 3

HO

Applications:  Methyl salicylate is used as an active pharmaceutical ingre‐ dient, mainly in formulations for its analgesic effect.  It is used in diverse applications in cosmetics and personal care products, as well as in flavoured or scented products.

Health effect: Pure Methyl salicylate is classi‐fied as harmful if swallowed For consumer applications, it is used in suitable concentration according to appropriate regulations. For industrial uses, safety measures must be respected.

Environmental effect:  Methyl salicylate is toxic to aquatic environment but as it is redially biodegradeable and has low potential for bioaccumulation, methyl salicylate is classified as dangerous for environment.  Industrial emissions and disposal, treatment or recycling of industrial waste must comply with applicable regulations to preserve environment.

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Ata Ur Rehman, 13001140002

The Synthesis of Methyl Salicylate

Physical and Chemical properties: Property

Result

Form

Liquid at 20°C

Colour Odour

Colourless to pale yellow Characteristic, aromatic

Boiling point

221 °C

Density

1.18 at 25°C

Vapour pressure

Moderately volatile

Water solubility

Slightly soluble

Octanol water partition

Low potential for bioaccumulation

Methods of Preparation for Methyl salicylate 1. Amine Diazotization 2. Esterification by Continuous distillation Method 3. Esterification by Refluxing experiment

1-Amine Diazotization This experiment, while demonstrating the use of diazonium salts for the replacement of an aromatic amine group by a phenolic hydroxyl, also involves two pleasant‐smelling organic compounds, methyl anthranilate (grape) and methyl salicylate (oil of wintergreen). Along with the usual instrumental techniques of product analysis (i.e., IR), the student's nose serves in this experiment as a means of verifying a successful synthesis. The chemistry of diazonium salts is usually one of the major areas covered in amine chemistry. The formation and replacement of the diazonium salt by a variety of different groups

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Ata Ur Rehman, 13001140002

The Synthesis of Methyl Salicylate (e.g., CN, OH, F) is often the only easy method for the synthesis of compounds containing these substituents. The chemistry utilized in this experiment is given below,

Although this particular synthesis is new, the literature abounds with similar examples. The intermediate diazonium salt is not isolated! The use of starch iodide paper to detect both an initial excess of nitrous acid and its subsequent decomposition is useful since it precludes any unwanted substitution byproducts and insures the complete destruction of the original amine. Finally, yields are quite good (60‐82%) and depending on the length of the laboratory period, three workup methods for the final product are possible.

Experlrnental: Methyl Salicylate. 3 Place 70 mL of water in a 400‐mL beaker, and, while stirring it with a magnetic stirrer (see figure), cautiously add 20g of concentrated sulfuric acid. To the warm acid solution, 13 g of methyl anthranilate is added, resulting in the formation of a dense, white precipitate. Set the beaker into an ice bath, and add 70 g of ice directly to the beaker. Maintain stirring! While the solution is cooling to 2‐5 °C a solution of 8 g of sodium nitrite in 15 mL of water is prepared. The sodium nitrite solution is added to the beaker in small portions, taking care to keep the temperature of the mixture below 10 °C. As the reaction proceeds, the precipitate gradually disappears. After some 10 mL of the nitrite solution has been added, test

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Ata Ur Rehman, 13001140002

The Synthesis of Methyl Salicylate with starch iodide paper for the presence of free nitrous acid (a blue‐black color is positive for nitrous acid). Add enough of the remaining solution to give a positive test. Allow the solution to warm to room temperature with stirring. And sit for 15 min. The excess nitrous acid is then destroyed by adding small portion of solid urea, using starch iodide paper to test. The demonstration is accompanied by a mild effervescence. The reaction mixture is now heated to boiling and maintained there far 5 min. (If product is to be purified by steam distillation, purification procedures, below). At about 80°C, an evolution of nitrogen gas begins! Reddish oil will form. The odor of oil of wintergreen should become apparent. Cool the mixture in an ice bath to just below room temperature to maximize product separation, and transfer it to a 125 mL separatary funnel. Extract with three 50‐mL portions of solvent‐grade ether. Combine and dry the ether extracts with anhydrous sodium sulfate. Using a steam bath as a heat source, distil the ether, and discard. The residue, a reddish oil is methyl salicylate, and its identity can he verified by infra red spectroscopy. The product is pure enough to turn in at this time.

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Ata Ur Rehman, 13001140002

The Synthesis of Methyl Salicylate

Product Purification: The oil can be purified by distilling through an air condenser and collecting the fraction that boils between 221 and 224 °C.

Product Identification: The infrared spectrum should show a characteristic hydroxyl peak (3175 cm‐1) and the complete absence of the amine doublet (3450, 3350 cm‐1.)

2-Esterification by Continuous distillation Method Method reported by Nelson, et al (1992) involved providing a mixture of a monohydric alcohol and a lower carboxylic acid in a reaction vessel equipped with a fractionating column connected to a condenser and a collecting vessel. Heating technique and a device for passing small bubbles of gas through the reactants were incorporated. The alcohol/carboxylic acid mixture was maintained at a temperature of at least about the boiling point of the alcohol, but below the boiling point of the carboxylic acid, a gas inert to the esterification reaction was bubbled through the mixture to remove the esterification product that was formed. The removed vapour was collected and condensed yielding the esterification product with a high percentage conversion and purity. Using this method, they were able to produce ethyl acetate resulting from three cycles of esterification of ethanol with acetic acid at 85°C with air bubbling at a rate not exceeding 200 ml/min resulting in 85 ‐ 90% conversion efficiency in terms of acetic acid consumption. 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.

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Ata Ur Rehman, 13001140002

The Synthesis of Methyl Salicylate

Experlrnental: 

The organic acid was packed at the upper part of the column and as such the esterification was expected to take place at that point.

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But the fact that the ester was found from the extracts of the lower part of the column and in the residue in the flask indicates that the ester drained down the column along with the embedded alcohol.

Distillation of alcohol over silica gel

 The yield (10.23%) was rather low and unsatisfactory.  The crystals that formed from the extracts of 1 G melted at 158°C, which meant that it was the unreacted salicylic acid. The crystals that formed from the extracts of 1 G, melted at 158°C, which meant that it was the unreacted salicylic acid.

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Ata Ur Rehman, 13001140002

The Synthesis of Methyl Salicylate

Reaction of methanol and salicylic acid

Product Identification: The TLC analysis result for the continuous distillation of alcohol over packed, column indicates partial conversion of the acid to its ester

TLC of product of continuous distillation experiment

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Ata Ur Rehman, 13001140002

The Synthesis of Methyl Salicylate

3-Esterification by Refluxing experiment:  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 the distillation flask and no product was found on the column as shown by the TLC analysis result.  The yield was very low (2.82%).  The bulk of the reaction in the refluxing experiment was in the distillation flask.  The contents of the column was washed down by the methanol  The water as by-product hindered further formation of the ester.

Refluxing of alcohol over silica gel column

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Ata Ur Rehman, 13001140002

The Synthesis of Methyl Salicylate Product Identification:

TLC of the product of refluxing experiment.

The IR spectrum for the methyl salicylate

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Ata Ur Rehman, 13001140002

The Synthesis of Methyl Salicylate Conclusion: o Methyl salicylate was synthesized from methyl anthranilate via an amine diazotization reaction, the concentrated sulfuric acid served to protonate the oxygen in the nitro group in order to make oxygen a good leaving group. The percent yield was 94.47%, which shows that this experiment is very efficient. o Comparing the two methods adopted for the esterification reaction (that is, continuous distillation and refluxing) the yield of the ester produced from the continuous distillation experiment was higher than that of the refluxing experiment. This can be explained on the assumption that the bulk of the reaction in the refluxing experiment was in the distillation flask (the contents of the column was washed down by the methanol), and as such, the water as by‐product impeded further formation of the ester. Whereas, in the continuous distillation experiment the reaction occurred on the column, and water formed as by product was entrained in the lower segment of the silica gel packing.

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Dangerous Properties of Industrial Material, 6th ed.; Van Nostrand Reinhold: New York. 1984: pp 291. 1927.2442)

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Badea HD, Iordache H, Matei V, Oniciu DC (1992). Thermal Decomposition of methyl salicylate, evidence for orthoquinokotene generation, Sci. Bull. Poletech. Inst. Bucharest Chem. Mater. Sci. 54(1‐2): 89‐95.

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Berghund P, Honquist M, Hult K, Hoegberg HE (1995). Alcohols as enantioselective inhibitors in a lipase catalyzed esterification of a chiral acyl donor, Biotechnol. Lett. 17(1): 55 – 60.

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Bhatnagar R, Arvid R, Bhatia S (1994). Esterification of n‐butanol with butyric acid using Amberlyst‐15 (macro porous) resin as catalyst. A kinetic study, Indian Chem. Eng. Sect‐A, 36(3): 120‐123.

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The Synthesis of Methyl Salicylate 

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Hersh EV, Cooper SA, Segal H, Greene J (1993). Analgesic on settime as a measure of topical anesthetic efficacy in spontaneous toothache pain. A pilot study, J. Chin. Dent. 4(2): 52‐54.

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Hidetoshi K, Yusuke Y, Ryuhei Y, Kazuhiro T, Kenichi O (2004). Application of zeolite membrane to esterification reactions; available at http://www.che.utoledo.edu/nams/2004/viewpaper.cfm?ID=687 retrieved on Feb 12th, 2008.

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Jessop PG, Hsiao Y, Ikariya T, Noyori R (1995). Methyl formate synthesis by hydrogenation of supercritical carbon dioxide in the presence of methanol, J. Chem. Soc. Chem. Commun. 6: 707 – 708.

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John RD (1965). Applications of absorption spectroscopy of organic compounds, Prentice – Hall, New York, pp 33 – 52.

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Krebecheck LO (1993). Esterification of carboxylic acid with alcohols involving the use of sulfuric acid as catalyst and desiccants [Chem.Abstr. 121, #1, 8689n, p.925 (1990)].

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Kurlkarmi GA, Guldsorkar VR, Shete JS (1993). Evaluation of Commercial aspirin tablets, East Pharm. 36(431): 119‐121.

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