Expt 84

A Floral Fragrance, Methyl Benzoate

Prelab Exercise: Give the detailed mechanism for the synthesis of methyl benzoate by Fischer Esterification. Introduction: The ester group is an important functional group that can be synthesized in a number of different ways. The low-molecular-weight esters have very pleasant odors and indeed are the major components of the flavor and odor aspects of a number of fruits. Although the natural flavor may contain nearly a hundred different compounds, single esters approximate the natural odors and are often used in the food industry for artificial flavors and fragrances (see table below). In snapdragon flowers, the volatile ester methyl benzoate is the most abundant scent compound. It is synthesized by and emitted from only the upper and lower lobes of petals, where pollinators (bumblebees) come in contact with the flower. Emission of methyl benzoate occurs in a rhythmic manner, with maximum emission during the day, which correlates with pollinator activity. (Taken from http://www.plantcell.org/cgi/content/abstract/13/10/2333) In this experiment, you will be synthesizing methyl benzoate via Fischer esterification.

Esters can be prepared by the reaction of a carboxylic acid with an alcohol in the presence of a catalyst such as concentrated sulfuric acid, hydrogen chloride, p-toluenesulfonic acid, or the acid form of an ion exchange resin:
O C H3C + CH OH 3 OH H+ H3C O O CH3 + H O 2

This Fischer esterification reaction reaches equilibrium after a few hours of refluxing. The position of the equilibrium can be shifted by adding more of the acid or of the alcohol, depending on cost or availability. The mechanism of the reaction involves initial protonation of the carboxyl group, attack by the nucleophilic hydroxyl, a proton transfer, and loss of water followed by loss of the catalyzing proton to give the ester. Because each of these steps is completely reversible, this process is also, in reverse, the mechanism for the hydrolysis of an ester. Refer to your lecture textbook for the Fisher esterification mechanism scheme. Other methods are available for the synthesis of esters, most of them more expensive but readily carried out on a small scale. For example alcohols react with acid anhydrides to form esters:

O CH3CH2OH Ethanol + C

O C H3C

O O CH2CH3 + CH3COOH Acetic acid

H3C CH3 O Acetic anhydride

Ethyl acetate

Acid chlorides form esters by reaction with alcohols.

CH2CH2CH3 + HCl

n-Propyl acetate

In the latter reaction, an organic base such as pyridine is usually added to react with the hydrogen chloride. A number of other methods can be used to synthesize the ester group. Among these are the addition of 2-methylpropene to an acid to form t-butyl esters, the addition of ketene to make acetates, and the reaction of a silver salt with an alkyl halide. See scheme below.
O OH Propionic acid + H+ O O 2-Methylpropene t-Butyl propionate

H 2C C O Ketene

CH2OH Benzyl alcohol

O CH2O C CH3 Benzyl acetate

O OAg+ + Br 1-bromo-3-methylbutane

O O Isoamyl acetate

Silver acetate

As noted above, Fischer esterification is an equilibrium process. Consider the reaction of acetic acid with 1-butanol to give n-butyl acetate:
O H3C C OH Acetic acid + HOCH2CH2CH2CH3 n-Butanol

H+

O CH2CH2CH2CH3 C + H2O O H3C n-Butylacetate

The equilibrium expression for this reaction is shown below.

O H3C C O O H3C C OH CH2 CH2CH2 CH3 [H2O]

Keq=

[HOCH2CH2CH2CH3]

For primary alcohols reacting with unhindered carboxylic acids, Keq ~4. If equal quantities of 1butanol and acetic acid are allowed to react, the theoretical yield of ester is only 67% at equilibrium. To upset the equilibrium we can, by Le Chatelier's principle, increase the concentration of either the alcohol or acid, as noted above. If either one is doubled, the theoretical yield increases to 85%. When one is tripled, it goes to 90%. But note that in the example cited the boiling point of the relatively nonpolar ester is only about 8C higher than the boiling points of the polar acetic acid and 1-butanol, so a difficult separation problem exists if either starting material is increased in concentration and the product is isolated by distillation. Another way to upset the equilibrium is to remove water. This can be done by adding to the reaction mixture molecular sieves, an artificial zeolite, which preferentially adsorb water. Most other drying agents, such as anhydrous sodium sulfate or calcium chloride, will not remove water at the temperatures used to make esters. A third way to upset the equilibrium is to preferentially remove the water as an azeotrope. Water can form an azeotrope with certain alcohols at specific concentrations. A special apparatus, called a Dean-Stark apparatus or trap, can be used to distill off the water as as an azeotrope while the ester being is formed. Removing water from the reaction in this way will favor ester formation.

Synthesis of Methyl Benzoate by Fisher Esterification

OH + CH3OH Methanol bp 64.6C MW 32.04 H+

OCH3 + H2O

Benzoic acid mp 122C MW 122.12

Methyl Benzoate bp 198-199C d 1.094 MW 136.15

Use the set-up shown below this paragraph for this synthesis. Place 5.0 g of benzoic acid and 25 mL of methanol in a 100-mL round-bottomed flask, cool the mixture in ice, pour 1.5 mL of concentrated sulfuric acid slowly and carefully down the walls of the flask, and then swirl to mix the components. Attach a reflux condenser fitted with water-inlet tubing, add 3 boiling chips, and reflux the mixture gently for 1 hr.

Isolation and Purification Cool the solution to room temperature, then decant it into a separatory funnel containing 25 mL of water, and rinse the flask with 25 mL of diethyl ether (use wet ether found in a supply bottle in each hood). Add this ether to the separatory funnel, shake thoroughly, and drain off the water layer, which contains the sulfuric acid and the bulk of the methanol. Wash the ether in the separatory funnel with 25 mL of water followed by 25 mL of 10% sodium bicarbonate to remove unreacted benzoic acid. Again shake, with frequent release of pressure by inverting the separatory funnel and opening the stopcock, until no further reaction is apparent; then drain off the bicarbonate layer into a beaker. Wash the ether layer in the separatory funnel with saturated sodium chloride solution, separate the ether solution, and dry the ether solution over anhydrous calcium chloride in a 125-mL Erlenmeyer flask. Add sufficient anhydrous calcium chloride so that it no longer clumps together on the bottom of the flask. After 10 min, decant the dry ether solution into a dry 50-mL Erlenmeyer flask, wash the drying agent with an additional 5 mL of ether, and decant again. Take a TLC of your ether solution. TLC plates should have three spots (or lanes) on the origin: one for the main organic starting material that is being transformed (benzoic acid), one for a cospot (starting material and the reaction mixture), and one for the reaction mixture. Find a suitable mobile phase; start by testing 30% EtOAc in hexanes. Remove the ether by evaporation in the hood until the next lab period; label flask with your name and section number. When evaporation is complete, add 2 to 3 g of anhydrous calcium chloride pellets to the residual oil and heat for about 5 min longer. Clamp a 25-mL roundbottomed flask (with a 14/20 joint neck) to a ring stand and decant the methyl benzoate into the flask. Obtain a microscale distillation kit from the stockroom. Attach to the flask a stillhead, but do NOT equip the stillheads condenser with water-inlet tubing since the boiling point of the ester is so high (199C), the water-cooled condenser may consequently crack. The flask should be placed deep in the sand bath and wrapped with lots of glass wool. Equip the stillhead with the thermometer found in the kit. Equip the receiving end of the stillhead with a 3- or 4- tube cow. Before distilling, have a TA check your set-up. Once the set-up has been approved, start distilling, and collect material boiling above 1900C. A typical yield is about 3 g.

Analysis In addition to TLC analysis, you may be instructed to analyze your final product by IR, NMR or RI. Analyze your sample according to your assignment sheet and prepare it as per the instructions on Sample Preparation in the Lab Guide (inside back cover). Cleaning Up: Pour the sulfuric acid layer into water, combine it with the bicarbonate layer, neutralize it with solid sodium carbonate, and flush the solution down the drain with much water. The saturated sodium chloride layer also can be flushed down the drain. If the calcium chloride is free of ether and methyl benzoate, it can be placed in the nonhazardous solid waste bin. Post Lab Questions: 1. In the preparation of methyl benzoate, what is the purpose of (a) washing the organic layer with sodium bicarbonate solution? (b) washing the organic layer with saturated sodium chloride solution? (c) treating the organic layer with anhydrous calcium chloride pellets? 2. What is the product of the following reaction?
O NH3 OCH3 ether