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 then undergoes a nucleophilic acyl substitution with an alcohol to form the ester product, which is usually purified via chromatography. The Steglich esterification enables mild coupling of large, complex carboxylic acids and alcohols, including sterically hindered secondary and tertiary alcohols^2,5,6. The goal of this work is to modify the standard Steglich esterification protocol to provide a greener synthetic option for this common esterification reaction.

One important aspect in the design of new synthetic methodology is to seek to minimize the use and formation of hazardous substances. The Twelve Principles of Green Chemistry⁷ can be used to provide a guideline for creating safer syntheses. Some of these include the prevention of waste generation (Principle 1) and the use of safer solvents (Principle 5). In particular, solvents account for 80-90% of the non-aqueous mass of the materials in pharmaceutical manufacturing⁸. Thus, modifying a protocol to use a less hazardous solvent can make a large impact on the greenness of an organic reaction.

Steglich esterification reactions often use anhydrous chlorinated solvent systems or DMF; however, these solvents are of concern for both the environment and human health. Dichloromethane (CH₂Cl₂) and chloroform (CHCl₃) are probable human carcinogens, and DMF has reproductive toxicity concerns⁹. In addition, CH₂Cl₂ is ozone depleting¹⁰. Thus, a less hazardous solvent for the Steglich esterification would be of great utility. While there are not yet green replacements for polar aprotic solvents, acetonitrile is recommended as a greener replacement for CH₂Cl₂, CHCl₃, and DMF⁹. Acetonitrile is currently produced as a byproduct in acrylonitrile manufacturing; however, a green synthesis of acetonitrile from biomass on an academic scale has been reported¹¹, and potential options for the reuse and recovery from waste streams are being investigated¹². Acetonitrile has previously been used as a greener solvent alternative for carbodiimide coupling reactions in solid-phase peptide synthesis to form amide linkages¹³. The use of acetonitrile as a solvent system for Steglich esterifications has been demonstrated^{14,15,16,17,18,19,20,21}; however, these methods have not focused on the green aspect of the solvent and also employ additional purification via column chromatography.

Reducing the need for column chromatography as a purification step also minimizes hazardous solvent waste⁸. In addition to using a less hazardous reaction solvent, the methodology enables the isolation of highly pure product without the need for chromatography. The traditionally used dicyclohexylcarbodiimide (DCC) coupling reagent is substituted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC). The basic amine functional group on this reagent enables the reaction byproducts and any residual reagents to be removed via acidic and basic wash steps.

The protocol presented herein can be used with a variety of acid and alcohol partners (Figure 1). It was used to synthesize a small library of cinnamyl ester derivatives using primary, secondary, benzyl, and allyl alcohols and phenols²². Additionally, the rate of the esterification reaction in acetonitrile is comparable to that in the chlorinated and DMF solvent systems, without a need to dry or distill the acetonitrile prior to the reaction²². Esters synthesized from tertiary alcohols have not been isolated, which is currently a limitation of the methodology compared to the traditional Steglich esterification in chlorinated solvent²³. In addition, other acid-labile groups could be affected by the acid wash steps, potentially necessitating column chromatography for purification after acetonitrile removal. Despite these limitations, the reaction is a facile and general method for the synthesis of esters in high yields using a range of both alcohol and carboxylic acid components. The use of a greener solvent system and high purity without the need for chromatography steps make this protocol an attractive alternative to a traditional Steglich esterification.

Figure 1. General reaction scheme. The general scheme for the reaction involves the coupling of a carboxylic acid and an alcohol, which is facilitated using a carbodiimide coupling reagent (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, or EDC) and 4-dimethylaminopyridine (DMAP) in acetonitrile. To demonstrate the reaction breadth, esters were formed using various acids (1-5) with either a primary (6) or secondary (7) alcohol. Please click here to view a larger version of this figure.

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). Add acetonitrile (15 mL) and 3-methoxybenzyl alcohol (98 μL, 0.85 mmol, 1 equiv) to the mixture along with a stir bar.
   CAUTION: Acetonitrile is a flammable solvent.
2. Clamp the flask in a 40 °C water bath and stir the reaction.
   NOTE: If the reaction involves an aromatic alcohol, monitor the reaction for the loss of the alcohol via thin-layer chromatography (TLC) using 1:3 ethyl acetate/hexane. The reaction is complete when the alcohol spot is no longer visible on the TLC plate by irradiation with a UV lamp.

2. Extraction Workup

1. Once the reaction is complete as indicated by TLC or after 45 min, remove the acetonitrile under reduced pressure using a rotary evaporator to obtain a crude solid.
   NOTE: Please see additional resources for the information regarding the use of a rotary evaporator^24,25.
2. To the residue, add diethyl ether (20 mL) and 1 M HCl (20 mL). Swirl the flask to dissolve the residue into the solvent layers.
   CAUTION: Diethyl ether is a highly flammable solvent.
   NOTE: To decrease the solvent hazard, ethyl acetate can be used in place of the diethyl ether; however, there is a greater potential for emulsion formation during the extraction and wash steps.
3. Pour the solution into a separatory funnel. Rinse the evaporating flask with additional diethyl ether (5 mL) and add the rinse to the separatory funnel.
4. 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 from the bottom of the funnel into an Erlenmeyer flask or beaker.
   NOTE: Please see additional resources for the information regarding extractions and the use of a separatory funnel^24,25.

3. Washing Procedure

1. To the organic layer remaining in the separatory funnel, add 1 M HCl (20 mL) 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 or beaker.
2. Repeat the washing procedure with saturated sodium bicarbonate solution (2 x 20 mL) and then with saturated sodium chloride solution (20 mL).
3. Pour the organic layer out from the top of the separatory funnel into a clean Erlenmeyer flask, dry the layer with magnesium sulfate, and gravity filter the solution through filter paper into a massed evaporation flask.
   NOTE: Please see additional resources for information regarding extractions and the use of magnesium sulfate as a drying agent^24,25.
4. Remove the diethyl ether solvent under reduced pressure using a rotary evaporator.
5. Analyze a sample of the product by ¹H and ¹³C NMR spectroscopy in CDCl₃ and by mass spectrometry.
   NOTE: Please see additional resources for the information regarding the preparation of samples for NMR analysis^24,25.

4. Carbodiimide Coupling Reaction for Secondary and Electron-deficient 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). Add acetonitrile (15 mL) and diphenylmethanol (157 mg, 0.85 mmol, 1 equiv) to the mixture along with a stir bar.
   CAUTION: Acetonitrile is a flammable solvent.
2. Clamp the flask and stir the reaction at room temperature for 24 h. Insert an air condenser into the flask neck to minimize solvent evaporation.
3. Follow the extraction workup and washing procedure described in Steps 2-3 above.

5. Carbodiimide Coupling Reaction for Long-Chain or Hydrophobic Carboxylic Acids

1. In a 50 mL round bottom flask, combine decanoic acid (146 mg, 0.85 mmol, 1 equiv), DMAP (312 mg, 2.55 mmol, 3 equiv), and EDC (244 mg, 1.28 mmol, 1.5 equiv). Add acetonitrile (15 mL) and diphenylmethanol (157 mg, 0.85 mmol, 1 equiv) to the mixture along with a stir bar.
   CAUTION: Acetonitrile is a flammable solvent.
2. Clamp the flask and stir the reaction at room temperature for 24 h. Insert an air condenser into the flask neck to minimize solvent evaporation. If a primary alcohol is used, stir the reaction in a water bath at 40 °C for 1 h.
3. Follow the extraction workup and washing procedure described in Steps 2-3 above.

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.