Expt 32

Synthesis of Methyl Salicylate: Amine Diazotization

Introduction: The synthesis of methyl salicylate is a safe and effective way to observe an amine diazotization. It also includes pleasant smells due to chemicals that are used for artificial flavorings. The synthesis uses diazonium salts to replace the amine group of an aromatic amine with a hydroxyl group. The reaction proceeds as follows: H2SO4 + 2 NaNO2 Na2SO4 + 2 HNO2 NO+ + H2O + Na2SO4

(1)

H2SO4 NaNO2

methyl anthranilate

methyl salicylate

(2)

The mechanism for the formation of the diazonium ion is as follows:

O H3C O C N O

H
+N

N O

-H+

O H3C O C N N O H 5

H 1 4

O H3C O C N N OH H
+

O H3C O C N N OH2

-H2O

O H3C O C N N

O H3C O C

N N+

Prelaboratory Exercises: 1. In your chromatographic behavior comparison PreLab section, be sure to include the triazene product described below. 2. Draw the Lewis structures for the nitrite ion (NO2-), the nitroso group (R-N=O), and the diazonium group (R-NN+). If there are resonance forms possible, show these too. Cautions: Sodium nitrite is toxic. Handle with care! DO NOT allow the benzenediazonium sulfate solution to warm up or it will decompose leading to undesirable side-products. Concentrated H2SO4 is very corrosive. Handle with care and do not spill it on anything. TLC

You are required to run a TLC to monitor the progress of the reaction. Plates should have three spots (or lanes) on the origin: one for the main organic starting material that is being transformed, one for a cospot (starting material and the reaction mixture), and one for the reaction mixture. Synthesis: In a 50-mL Erlenmeyer flask, put 11 mL of distilled water and a 1-inch magnetic stirring bar. While stirring magnetically, slowly add 3 g of concentrated sulfuric acid (approximately 1.5 mL; measure the exact amount you need by transfering from the conc. H2SO4 bottle with a glass Pasteur pipet into a graduated cylinder; dont take more than you need), and then add 2.0 g of methyl anthranilate. Put the flask into a beaker of ice bath and add 9 to 12 g of ice directly to the flask. Continue to stir! A precipitate will form. While this solution is cooling to 2-5C, make up a solution of 2.3 mL of distilled water and 1.2 g of sodium nitrite in a reaction tube. Dropwise, add 23 drops of this solution very slowly to the flask while continuing to stir. Monitor the reaction temperature with a thermometer and if the temperature rises, allow the reaction to cool back down to about 4C before adding more of the nitrite solution. Make sure to keep the mixture below 10C at all times. The precipitate should eventually disappear. Continue to stir for 15 minutes. Add 4 crystals of urea to decompose any excess nitrous acid. Remove the stir bar and add a boiling stick, bring the solution to a boil on a sand bath, and boil for 5 to 10 minutes. A reddish oil that smells of wintergreen should form. Isolation and Purification: Allow the reaction to cool to room temperature and then pour into a 125-mL-separatory funnel. Extract the aqueous phase with three 5-mL-portions of dichloromethane, combine the dichloromethane extracts, and dry this dichloromethane solution of your product over anhydrous sodium sulfate. Analysis of the product will be through TLC. Prepare about 10 mL of a 75% hexane - 25% ethyl acetate solution. On one TLC plate, spot a diluted (1 drop per mL) dichloromethane solution of the starting material (methyl anthranilate) next to the dichloromethane solution of your product. After developing in the hexane / ethylacetate solution, there will be two visible spots (yellow and brown) and one additional spot brightly visible under the UV lamp. The lowest (yellow) spot is the triazene formed from the diazonium salt reacting with the starting material as follows:
O CH 3OC H N: H
+N

O COCH 3 N CH 3OC

O H N N N

O COCH 3

Determine the identity of the remaining two spots by TLC combined with a special olfactory detector--YOUR NOSE! Instead of a single dot, place a heavy band of your product mixture on the origin line by continously applying overlapping spots. The band should have at least a 1/8 margin on each side, as shown below.

1 cm

Product "band"

After developing, allow the mobile phase to evaporate. Starting at one end of the plate, bring the plate under your nose and gently smell along the plate. Methyl anthranilate has a grape odor, while the desired product (methyl salicylate) has the distinct odor of wintergreen. Using your olofactory detector, determine which band coresponds to each of these compounds. For both plates, mark each band and calculate the Rf

values. The product may be purified by first transferring the remaining dichloromethane solution to a 50-mL Erlenmeyer flask, then rinsing the sodium sulfate with 3 mL of fresh dichloromethane, and adding the rinse solution to the flask with the dichloromethane. Then add 3 boiling chips and evaporate solvent by gently boiling on a sandbath to leave a dark red oil. Once the dichloromethane has completely evaporated, the boiling will subside for a few moments as the temperature begins to climb to the boiling point of the methyl salicylate. You may need to turn the Varistat to 65 to 70. When the solution begins to boil, use a fresh pipet with a bulb attached to draw vapors up into the pipet. Squeeze the bulb, insert the tip into the flask just above the level of the liquid, i.e., in the hot organic vapors, and slowly release the bulb. The hot vapors will enter and condense inside of the cool pipet to give a light yellow liquid.* Transfer the yellow liquid to a tared shorty vial. This step can be repeated, combining all of the condensed liquid product, until there is essentially no more vapors to withdraw from the flask.. Weigh the product and calculate a percent yield based on methyl anthranilate. [*Note: This technique is called "instant microscale distillation" (see Lab Guide Chapter 1). Ideally, this is done by transferring the red oil and chips to a reaction tube, and placing the tube into a sand bath, using a pipet to condense the vapors; however, this particular chemical tends to bump too much, even with the boiling chips present, such that a smooth distillation is difficult, and the non-volatile components accidentally get sucked up into the pipet. When possible, the reaction tube is better, as the smaller opening at the top of the tube minimizes the loss of organic vapors to the atmosphere.] Analysis In addition to TLC analysis, you may be instructed to analyze your final product by IR or NMR. Analyze your sample according to your Assignment sheet and the instructions on Sample Preparation in Lab Guide. Final Report: Attach the labeled TLC plates to your final report. At the end of your report answer the following questions: 1. What is the initial precipitate that forms when sulfuric acid is added to methyl anthranilate? Write a balanced equation for the reaction. 2. What role does concentrated sulfuric acid serve in this reaction? 3. Why is diazonium sulfate formed in this procedure used in situ rather than isolated and purified before going on the next step?