The Synthesis, Isolation, and Purification of Methyl Salicylate

Kevin Bobeck Organic Chemistry Lab Chemistry213

Introduction: Steam distillation is separation of compounds with high boiling points, such as aromatic compounds. In steam distillation, water is introduced to into the apparatus in order to decrease the boiling point of the compounds present. This type of distillation is based on the principle of partial pressures. The immiscible liquid and water will each give off their own vapor pressure. These vapor partial pressures will combine and once the vapor pressure is greater than atmospheric pressure, boiling results.1 Therefore, the boiling temperature of the compounds being distilled will always be near but lower than 100C, the boiling point of water, because most of the vapor pressure will be from water. Steam distillation results in a two phase distillate, the organic layer and the aqueous layer. The product can then be isolated via extraction using a separatory funnel. Steam distillation is very important laboratory technique due to its many applications in chemistry. Steam distillation can be used to purify a product from a starting material or other impurities in a synthesis reaction, such as in the case of purifying methyl salicylate from methyl anthranilate. Diazotization reactions are reactions in which a heterocyclic amine reacts with nitrate to form a diazonium salt. The diazonium salt then reacts with a nucleophile to form an aryl halide or aryl hydroxide. The Diazotization reactions are important because they produce substitutions that one would not be able to obtain by direct substitution. Diazotization reactions are also commercially important for their ability to produce isosatins. Isosatins have been shown to possess antiviral, anticancer, anti-inflammatory, and anticonvulsant properties.2 A diazotization reaction is also used to produce the wintergreen oil, methyl salicylate. Methyl salicylate has a strong wintergreen odor and has a pale yellow color. Methyl Salicylate is used as a flavoring agent and also as a perfume. Methyl Salicylate is also used as a

pharmaceutical agent in pain relieving gels, sprays, and patches.3 However, it must be used in very small quantities because it is highly toxic. Methyl salicylate can also be used as an attractant in insect traps due to its pleasant odor. Studies have shown insect populations around methyl salicylate traps were significantly lowered.4 The balanced chemical equation for the synthesis of methyl salicylate from methyl anthranilate can be seen below:

The electron pushing mechanism for the synthesis of methyl salicylate from methyl anthranilate can be seen below:

The synthesis of methyl salicylate from methyl anthranilate is a two step synthesis, which involves the formation of a diazonium salt intermediate. The synthesis is begun by the nitrite group losing a water molecule and becoming positive. The lone pair on the amine group then adds into the positive nitrogen and forms a nitrogen-nitrogen single bond. Then, the oxygen that was part of the nitrite group removes the two hydrogens from the amine, which makes the oxygen a good leaving group. A triple bond is formed between the two nitrogens and the water molecules gets kicked out. This results in the formation of the diazonium salt intermediate. The nitrogen bonded to the aromatic group is positive, thus it is a good leaving group. Once the N2

molecule leaves the compound a positively charged radical is formed on the aromatic ring. Water is added to the reaction and the nucleophilic oxygen of water joins the aromatic compound through radical addition. The conjugate base of the H2SO4 extracts a hydrogen from the oxygen, thus producing a hydroxyl group and the overall product, methyl salicylate. The purpose of this experiment was to synthesize, purify, and isolate methyl salicylate from methyl anthranilate. The methyl salicylate was formed using an amine diazotization reaction. The purification of the product was carried out using steam distillation. The purified product was isolated from water using a separatory funnel and washing with ether. The organic layer was then tested by TLC to see if the product was successfully isolated and purified from the starting material. The product was analyzed using 60MHz H NMR, IR, GC, and GC-MS. Experimental: Distilled water (14mL), concentrated sulfuric acid (4mL, 7.86g), methyl anthranilate (1.6g, .0106mol), and ice (14mL, .778mol) were added together and stirred. A precipitate formed. The solution was cooled to 4C. Sodium Nitrate (1.6g, 0.023mol) in water (10mL, 0.55mol) was added through drop wise addition. The solution was monitored with thermometer to keep the temperature of the solution at 5C. The precipitate cleared and the solution was stirred for an additional fifteen minutes. The solution then underwent steam distillation with the Varistat set to 60. The solution was steam distilled until the distillate turned clear. The distillate was then poured into a separatory funnel and washed with ether (3 X 10mL). After each wash, the organic layer was drained. The organic layers were combined and dried using anhydrous sodium sulfate. The solution was decanted and a TLC test was performed using 75% hexanes25% ethyl acetate as the mobile phase.

TLC Data for Methyl Salicylate Synthesis Compound Starting Material Co-spot Co-spot Product Mixture Rf Value 0.3774 0.3774 0.5094 0.5094

The ether was then evaporated under a nitrogen stream and an oil product was formed. The color of the oil was yellow. The product was weighed and recorded. The product was then subjected to 60MHz NMR, IR, GC, and GC-MS. H1 NMR Data for Methyl Salicylate Functional Group Methyl Aromatic Hydroxyl Chemical Shift(ppm) 3.949 6.886-7.916 10.749

IR Data for Methyl Salicylate Functional Group Aromatic Carbonyl Wavelength (1/cm) 1481.9 1673.8

Hydroxyl

3183.2

GC Data for Methyl Salicylate Retention Time (min) Peak 1 Peak 2 2.2 8.87 Area 427 10125

GC-MS Data for Methyl Salicylate Retention Time (min) Peak 1 Peak 2 Discussion: In this experiment, methyl salicylate was synthesized from methyl anthranilate via an amine diazotization reaction, also known as a Sandmeyer reaction. In the synthesis of methyl salicylate, the concentrated sulfuric acid served to protonate the oxygen in the nitro group in order to make the oxygen a good leaving group. This allowed for nitrogen to become an electrophile and for the nucleophilic amine to add to it. The heat was added to the second step of the reaction in order to give the water enough energy to add into the positively charged radical on the aromatic group. The purification process was carried out using steam distillation. In this technique, the methyl salicylate and water vaporized and condensed together, thus forming a two phase distillate. The methyl salicylate was isolated from the water using a separatory funnel. The 2.73 13.88 Area 178290 1994142

funnel was washed with ether because ether provided an organic layer for methyl salicylate to dissolve in. Thus, the ether made it easier to isolate methyl salicylate and could be easily evaporated under a nitrogen stream. The TLC test proved that methyl salicylate was synthesized and purified from methyl anthranilate. This can be concluded because the product mixture had a higher Rf value than the starting material. Also, there was complete separation of the starting material and product mixture in the co-spot. The methyl salicylate has a higher Rf value because it is slightly less polar than methyl anthranilate. The amino group on methyl anthranilate makes it more polar than methyl salicylate because methyl salicylate has a hydroxyl. The amino group is more polar than the hydroxyl group. The NMR, IR, and GC data also proved that methyl salicylate was synthesized and purified successfully. The NMR data showed 3 peaks. The first peak (a) was a singlet with a chemical shift of 3.949ppm, which shows the presence of a methyl attached to an ester group. The second peak (b) was a multiplet with a chemical shift range of 6.886ppm 7.916ppm. This indicates the presence of aromatic hydrogens. The third peak (c) was a singlet with a chemical shift of 10.749ppm, which demonstrates that a hydroxyl is present. The IR data shows also shows three major peaks. The first peak was 1481.9cm-1 which proves the presence of an aromatic group. The second peak at 1673.89cm-1 shows that a carbonyl is present. The third peak at 3183.29cm-1 concludes that a hydroxyl is present in the compound. The GC analysis concludes that the final product was 96% pure methyl salicylate. The other 4% must have been starting material or diazonium salt. It can be concluded that methyl salicylate was formed because its functional groups appeared on both the NMR and IR and also that it was purified because 96% was methyl salicylate.

The percent yield of this reaction was high. The theoretical weight of methyl salicylate was 1.61g and the actual weight was 1.521. The percent yield of the reaction was 94.47%, which shows that his experiment is very efficient. This reaction was not a 100% efficient because it had by products of the reaction, such as the two molecules of water. Steam distillation is an important laboratory technique because it can be used to purify immiscible compounds with high boiling points. In this experiment, steam distillation was used to purify methyl salicylate from its starting materials. Methyl salicylate was successfully synthesized from methyl anthranilate by way of an amine diazotization reaction. The TLC, NMR, IR, GC, and GC-MS all supported this conclusion of methyl salicylate synthesis. This experiment is important because it successfully synthesizes methyl salicylate with a high efficiency. References:
1

http//:courses.chem.psu.edu/chem213. Synthesis of Methyl Salicylate Via Amine

Diazotization, Experiment #11

2.

Silva, BV, FA Violante, AC Pinto, and LS Santos. "The Mechanism of Sandmeyer's

Cyclization Reaction by Electrospray Ionization Mass Spectrometry." Rapid Communications in Mass Spectrometry (2011). Vol 25.3: 423-28.
3

Chile Pharmaceuticals & Healthcare Report. Rep. Business Monitor International.

(2011).

Mallinger, Rachel E., David B. Hogg, and Claudio Gratton. "Methyl Salicylate Attracts

Natural Enemies and Reduces Populations of Soybean Aphids (Hemiptera: Aphididae) in Soybean Agroecosystems." Journal of Economic Entomology .(2011). Vol.104.1: 115-24.