Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile

Summary

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.

Abstract

The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the reaction is commonly performed using chlorinated or amide solvent systems, which are hazardous to human health and the environment. Our methodology utilizes acetonitrile as a greener and less hazardous solvent system. This protocol exhibits rates and yields that are comparable to traditional solvent systems and employs an extraction and wash sequence that eliminates the need for the purification of the ester product via column chromatography. This general method can be used to couple a variety of carboxylic acids with 1° and 2° aliphatic alcohols, benzylic and allylic alcohols, and phenols to obtain pure esters in high yields. The goal of the protocol detailed here is to provide a greener alternative to a common esterification reaction, which could serve useful for ester synthesis in both academic and industrial applications.

Introduction

Ester compounds are widely used for the applications such as flavor compounds, pharmaceuticals, cosmetics, and materials. Commonly, the use of carbodiimide coupling reagents is used to facilitate an ester formation from a carboxylic acid and an alcohol¹. For example, in the Steglich esterification, dicyclohexylcarbodiimide (DCC) is reacted with a carboxylic acid in the presence of 4-dimethylaminopyridine (DMAP) to form an activated acid derivative, generally in a chlorinated solvent system or dimethylformamide (DMF)^2,3,4. The activated acid derivative ....

Protocol

Caution: Consult Safety Data Sheets (SDSs) prior to the use of the chemicals in this procedure. Use appropriate personal protective equipment (PPE) including splash goggles, lab coat, and nitrile or butyl gloves as many of the reagents and solvents are corrosive or flammable. Carry out all reactions in a fume hood. It is unnecessary to dry glassware or to use a nitrogen atmosphere for this protocol.

1. Carbodiimide Coupling Reaction for Primary Alcohols

1. In a 50 mL round bottom flask, combine (E)-cinnamic acid (151 mg, 1.02 mmol, 1.2 equiv), DMAP (312 mg, 2.55 mmol, 3 equiv), and EDC (244 mg, 1.28 mmol, 1.5 equiv). ....

Results

Using the modified Steglich esterification in acetonitrile followed by an acid-base extraction workup, 3-methoxybenzyl cinnamate (8) was obtained as a light-yellow oil (205 mg, 90% yield) without the need for column chromatography. ¹H and ¹³C NMR spectra are presented in Figure 2 to confirm the structure and to indicate purity.

Compounds 9-

Discussion

The methodology presented here was developed to minimize the hazards from solvent associated with a traditional Steglich esterification by using a greener solvent system and by reducing the need for column chromatography^8,9. Comparable reaction yields and rates can be achieved with the use of acetonitrile in place of dry chlorinated solvents or DMF²².

Several key steps enable the efficient purification of produc.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
trans -cinnamic acid	Acros Organics	158571000
butyric acid	Sigma-Aldrich	B103500	Caution: corrosive
hexanoic acid	Sigma-Aldrich	153745-100G	Caution: corrosive
decanoic acid	Sigma-Aldrich	21409-5G	Caution: corrosive
phenylacetic acid	Sigma-Aldrich	P16621-5G
3-methoxybenzyl alcohol	Sigma-Aldrich	M11006-25G
diphenylmethanol	Acros Organics	105391000	Benzhydrol
chloroform-d	Acros Organics	166260250	99.8% with 1% v/v tetramethylsilane, Caution: toxic
hexane	BDH Chemicals	BDH1129-4LP	Caution: flammable
ethyl acetate	Sigma-Aldrich	650528	Caution: flammable
diethyl ether	Fisher Scientific	E138-500	Caution: flammable
acetonitrile	Fisher Scientific	A21-1	ACS Certified, >99.5%, Caution: flammable
4-dimethylaminopyridine	Acros Organics	148270250	Caution: toxic
magnesium sulfate	Fisher Scientific	M65-3
hydrochloric acid, 1 M	Fisher Scientific	S848-4	Caution: corrosive
sodium chloride	BDH Chemicals	BDH8014
sodium bicarbonate	Fisher Scientific	S25533B
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride	Chem-Impex	00050	Caution: skin and eye irritant
thin layer chromatography plates	EMD Millipore	1055540001	aluminum backed sheets
Note: All commercially available reagents and solvents were used as received without further purification.