Adapted from J. Med. Chem. 2019, 62, 4350.

Introduction

Background

Carboxylic acids and their derivatives are widely encountered in nature. Common derivatives include esters, acid anhydrides, acid chlorides, and amides. They are termed “carboxylic acid derivatives” because these functional groups can (in principle) be synthesized from a carboxylic acid and (in principle) hydrolyzed back to the carboxylic acid. Esters, specifically, are a key functional group of fats, oils, waxes, fragrances, and solvents. There are countless methods (and variations thereof) with which to synthesize esters. However, if the starting carboxylic acid is in hand—and the synthetic target is a methyl, ethyl, or propyl ester of the acid—then the Fischer esterification is a popular choice. The Fischer esterification is an equilibrium process in which the carboxylic acid is mixed with an excess of the alcohol and trace mineral acid, which acts as the reaction catalyst (Scheme 1).

Scheme 1. Generic Fischer esterification

The reaction mixture is generally heated to increase the rate of reaction. The problem, of course, is that once an equilibrium is established, no addition product is formed. Two steps can be taken to help drive the reaction toward completion:

(1) You can use a molar excess of the alcohol. Methanol, ethanol, and propanol are inexpensive and serve as the solvent in the reaction as well.

(2) You can remove one or both products can be removed as they are formed to drive the reaction to completion. (Recall Le Chatlier’s Principle!)

Experimental Protocol

FULL DISCLOSURE: This experiment is still in development. It should work; it may not! Chemistry is an adventure.

Obtain the crude yield of your (now dry) carboxylic acid product from the Grignard reaction. Calculate the percent yield in your ILN. Use the tip of a spatula to remove approximately 20 mg of your product (note the exact amount). Place it in a small, labeled test tube or vial. This will be your TLC standard for monitoring your reaction.

Note: You will need to calculate the correct values for the following procedure based on the amount of material you obtained. Remember to account for the material that you removed for your TLC standard. This will also require you to select appropriately sized glassware based on the reaction scale.

To a round-bottom flask, add the carboxylic acid (1.0 equiv.) in MeOH (0.33 M solution). Carefully add concentrated sulfuric acid (1.0 equiv). Assemble a reflux condenser atop the flask (Figure 1). Use a heating mantle to heat your reaction to a gentle reflux with stirring. Monitor the reaction by TLC every half hour. The TA will demonstrate the set-up of a reaction-monitoring TLC plate. Continue to monitor the reaction until about 30 min before the end of lab or until the reaction has reached completion, whichever comes first.

Figure 1. Reflux condenser apparatus; water is always in at the bottom, out at the top.

Then, remove the flask from the heat and allow it to cool to room temperature. Place a septum in the flask and carefully store the mixture in your drawer for ~48 hours.

Dilute the mixture with ~10 mL EtOAc. Add 7 mL RO water to the mixture. Extract the product (2 x 10 mL) with EtOAc. Then, carefully wash the combined organic phases with ~5 mL NaOH (3 M). Do not combine the aqueous washes. Dry the combined organic phases over anhydrous Na₂SO₄, filter, and concentrate. Purify the ester by flash column chromatography.

Characterize the product by ¹H NMR.