Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile

A modified Steglich esterification reaction was used to synthesize a small library of ester derivatives with primary and secondary alcohols. The methodology uses a non-halogenated and greener solvent, acetonitrile, and enables product isolation in high yields without the need for chromatographic purification.

The overall goal of this experiment is to provide a greener methodology for a common esterification reaction, which could serve useful for estro-synthesis in academic and industrial applications. Our method can be used for efficient and mild synthesis of esters by coupling carboxylic acids with primary or secondary alcohols or phenols. The main advantage of this technique is that it eliminates the use of hazardous chlorinated or amide reaction solvents and it minimizes solvent waste during purification without sacrificing reaction rate or product purity.

Demonstrating the procedure will be Andrew Lutjen and Mackenzie Quirk, undergraduate researchers from my laboratory. First, combine trans-Cinnamic acid, DMAP, and EDC in a 50-milliliter round-bottom flask. Add 15 milliliters of acetonitrile, and 98 microliters of 3-Methoxybenzyl alcohol to the mixture, along with a magnetic stir bar.

Clamp the flask in a 40-degree Celsius water bath and stir the reaction. Monitor the reaction by TLC, using ethyl acetate and hexanes. Once the reaction is complete, remove the acetonitrile under reduced pressure using a rotary evaporator to obtain a crude solid.

To the residue, add 20 milliliters each of diethyl ether and one molar of hydrochloric acid. Swirl the flask to dissolve the residue into the solvent layers. Next, pour the solution into a separatory funnel.

Rinse the evaporating flask with five milliliters of diethyl ether, and add the rinse to the separatory funnel. Gently shake the separatory funnel to extract the product into the ether layer, venting periodically. Allow the layers to separate, and then remove the aqueous layer by draining it out the bottom of the funnel into an Erlenmeyer flask.

To the organic layer remaining in the separatory funnel, add 20 milliliters of one molar hydrochloric acid and gently shake the separatory flask, venting periodically. Allow the layers to separate and then remove the aqueous layer by draining it out from the bottom of the funnel into an Erlenmeyer flask. Repeat the washing procedure with saturated sodium bicarbonate and saturated sodium chloride.

After completing the washing steps, transfer the organic layer from the separatory funnel into a clean Erlenmeyer flask. Dry the layer with magnesium sulfate. Then gravity filter the solution through filter paper into a masked evaporation flask.

Following this, remove the diethyl ether solvent under reduced pressure, using a rotary evaporator. Analyze a sample of the product by proton and carbon NMR Spectroscopy in deuterated chloroform, and by mass spectrometry. In a 50-milliliter round-bottom flask, combine trans-cinnamic acid, DMAP, and EDC.

Add 15 milliliters of acetonitrile and 157 milligrams of Diphenylmethanol to the mixture, along with a magnetic stir bar. Clamp the flask and stir the reaction at room temperature for 24 hours. Insert an air condenser into the flask neck to minimize solvent evaporation.

Once the reaction is complete, follow the extraction workup and washing procedure as previously described. In a 50-milliliter round-bottom flask, combine decanoic acid, DMAP, and EDC. Add 15 milliliters of acetonitrile and 157 milligrams of Dithenylmethanol to the mixture, along with a magnetic stir bar.

Clamp the flask and stir the reaction at room temperature for 24 hours. Insert an air condenser into the flask neck to minimize solvent evaporation. Once the reaction is complete, follow the extraction workup and washing procedure as previously described.

Using the modified Steglich esterification reaction, 3-Methoxybenzyl cinnamate was obtained in 90%yield without the need for column chromatography, as confirmed by proton and carbon NMR Spectroscopy. Compounds nine to 17 were synthesized using a similar protocol, with yields of 77 to 90%All compounds were analyzed by NMR Spectroscopy and high resolution mass spectrometry, and found to be of similar purity to 3-Methoxybenzyl cinnamate by NMR analysis. Slight changes to the protocol for primary alcohols were made to obtain optimal yields and purity for compounds 12 to 17.

Secondary alcohol reactions were run for longer to allow the reaction to go to completion. In the decanoic acid reactions, for ester compounds 12 and 17, using 1.2 equivalents of carboxylic acid to one equivalent of alcohol for both primary and secondary alcohols, yielded esters with a decanoic acid impurity. The impurity issue was solved by using a one to one molar ratio of decanoic acid to alcohol with a slightly longer reaction time.

These conditions yielded pure ester products, indicated by a loss of the impurity signal at 2.35 parts per million in the proton NMR spectrum. As with any organic synthesis method, safety data sheets for chemicals should be consulted and proper personal protective equipment and facilities should be used when performing this procedure.