Name: synthesis of esters via a greener steglich esterification in acetonitrile
Uploaded: 2018-10-30T15:00:00.000+00:00
Duration: 6 min 52 s
Description: Watch this Scientific Journal Video about Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile at JoVE.com

This research was supported by Siena College and the Center for Undergraduate Research and Creative Activity. We thank Dr. Thomas Hughes and Dr. Kristopher Kolonko for helpful conversations, Ms. Allycia Barbera for early stage work on this methodology, and the Siena College Stewart&#39;s Advanced Instrumentation and Technology (SAInT) Center for instrumentation resources.

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
<ol>
	<li>In a 50 mL round bottom flask, combine (E)-cinnamic acid (151 mg, 1.02 mmol, 1.2 equiv), DMAP (312 mg, 2.55&#160;mmol, 3 equiv), and EDC (244 mg, 1.28 mmol, 1.5 equiv). Add acetonitrile (15 mL) and 3-methoxybenzyl alcohol (98 &#956;L, 0.85 mmol, 1 equiv) to the mixture along with a stir bar. 
	CAUTION: Acetonitrile is a flammable solvent.</li>
	<li>Clamp the flask in a 40 &#176;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.</li>
</ol>
2. Extraction Workup
<ol>
	<li>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 evaporator24,25.</li>
	<li>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.</li>
	<li>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.</li>
	<li>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 funnel24,25.</li>
</ol>
3. Washing Procedure
<ol>
	<li>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.</li>
	<li>Repeat the washing procedure with saturated sodium bicarbonate solution (2 x&#160;20 mL) and then with saturated sodium chloride solution (20 mL).</li>
	<li>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 agent24,25.</li>
	<li>Remove the diethyl ether solvent under reduced pressure using a rotary evaporator.</li>
	<li>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 analysis24,25.</li>
</ol>
4. Carbodiimide Coupling Reaction for Secondary and Electron-deficient Alcohols
<ol>
	<li>In a 50 mL round bottom flask, combine (E)-cinnamic acid (151 mg, 1.02 mmol, 1.2 equiv), DMAP (312 mg, 2.55&#160;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.</li>
	<li>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.</li>
	<li>Follow the extraction workup and washing procedure described in Steps 2-3 above.</li>
</ol>
5. Carbodiimide Coupling Reaction for Long-Chain or Hydrophobic Carboxylic Acids
<ol>
	<li>In a 50 mL round bottom flask, combine decanoic acid (146 mg, 0.85 mmol, 1 equiv), DMAP (312 mg, 2.55&#160;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.</li>
	<li>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 &#176;C for 1 h.</li>
	<li>Follow the extraction workup and washing procedure described in Steps 2-3 above.</li>
</ol>

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The authors have nothing to disclose.

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 chromatography8,9. 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...

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 alcohols2,5,6. 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 demonstrated14,15,16,17,18,19,20,21; 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.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/58803/58803fig1.jpg" /> 
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. <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/58803/58803fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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

synthesis of esters via a greener steglich esterification in acetonitrile

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&#176; and 2&#176; 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.

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-<str...

Watch this Scientific Journal Video about Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile at JoVE.com

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 Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the ...

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35.1K Views.  Siena College. 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.

Video: Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile

Esterification

<h4>Esters</h4>
The structure of an ester is a carbonyl with an alkyl or aryl group (R) on one side, and an oxygen bound to another alkyl or aryl group (R&#8217;) on the other side, represented by the general formula: RCOOR&#8217;. Esters can be commonly derived by an esterification reaction between a carboxylic acid and an alcohol. The hydroxyl group of the carboxylic acid is replaced by an alkyl or aryl group. Simple esters, which have low molecular weight and small R and R&#8217; functional groups, have smells and flavors of fruits and flowers.
The simplest carboxylic acid is formic acid (HCOOH), with the simplest alcohol being methanol. Thus, the simplest ester formed from the esterification of these two molecules is methyl formate (HCOOCH3). Methyl formate is considered a derivative of formic acid because the OH group is replaced by the OCH3 group. The structural differences between methyl formate and formic acid dictate the difference in their properties. This is because the properties of the molecule depend heavily on the R and R&#8217; groups.
Esters that are found in fruits and flowers are known as simple esters due to the low complexity of their structure in comparison to other esters. The alkyl and aryl groups found on these esters greatly influences the fragrance they emit; thus, the addition of a carbon or a different functional group can impact the scent produced by the ester. For example, propyl acetate (C5H10O2) has the scent of pears. However, butyl acetate (C6H12O2), which has only one more carbon in its chain, smells like apples.
Long-chain esters, meaning those with long alkyl chains, are called fatty acids. Fatty acids are important biological compounds that are essential for certain biological processes. Fatty acids are also a biological form of energy storage. When three fatty acids react with glycerol, they form a triglyceride &#8212; the most common form of fatty acids. Triglycerides have a very high molecular weight and can be highly branched. Their function and properties are dependent on the length and types of alkyl chains incorporated into their structure. One of the most common industrial uses for triglycerides is in the production of soaps and detergents.
<h4>Esterification Reaction</h4>
Esters are formed from an esterification reaction, with simple esters being formed through Fisher esterification. This reaction converts a carboxylic acid and alcohol into an ester with water as a by-product. Fisher esterification is a reversible reaction that proceeds very slowly. An acid catalyst, typically in the form of sulfuric acid, is added to increase the rate of the reaction while also acting as a dehydrating agent.
The mechanism of action for a Fisher esterification begins by the carbonyl oxygen attacking the sulfuric acid and deprotonating its OH group. This leads to a positively charged carbonyl oxygen. To better stabilize the positive charge, one electron pair of the carbonyl double bond is pushed to the carbonyl oxygen while simultaneously creating an electron-poor carbon center. Next, the hydroxy group of the alcohol acts as a nucleophile and attacks the electron-poor carbon &#8212; the electrophile &#8212; forming an intermediate. Then, the positively-charged hydroxyl group from the alcohol is deprotonated by the hydroxyl group of the carboxylic acid, stabilizing the oxygen atom of the alcohol. In the last step, the carbonyl oxygen is deprotonated by the conjugated base, and the free electron pair is moved towards the carbonyl center while the protonated carboxyl group leaves as a water molecule.
Since the esterification reaction is reversible, a 1:1 mixture of the carboxylic acid and the alcohol will reach equilibrium with about 70% yield of the ester. However, as with any equilibrium process, the reaction can be driven in one direction by changing the concentration, pressure, temperature, or volume of the reagents. This change causes the reaction to adjust to a new equilibrium to counteract the change, which is the basis of Le Chatelier&#8217;s principle.
When the concentration of one of the reactants is increased, the equilibrium shifts in the direction that will decrease its concentration. Thus, by increasing the concentration of one reactant, the equilibrium produces more of the product, thereby resulting in a higher yield of the ester product.
One common method utilized in organic chemistry labs is to provide an excess of one of the reagents, typically the alcohol. As mentioned earlier, Fisher esterification can utilize sulfuric acid as a catalyst. However, one of the other functions of sulfuric acid is to act as a dehydrating agent, sequestering water molecules away from the reaction. Applying Le Chatelier&#8217;s principle demonstrates that as one of the products is removed &#8212; in this case, water &#8212; the reaction is pushed to making more product. This increases the yield of the ester formed.
<h4>Reference</h4>
<ol>
	<li style="font-size:17px">Streitwieser, A., Heathcock, C.H., Kosower, E.M. (1998). Introduction to Organic Chemistry. Upper Saddle River, NJ: Prentice Hall.</li>
</ol>

Esterification: Synthesis of Ester by Fischer Esterification - Concept

Esters
The structure of an ester is a carbonyl with an alkyl or aryl group (R) on one side, and an oxygen bound to another alkyl or aryl group (R&#8217;) ...

JoVE Lab Manual

Highly Stereoselective Synthesis of 1,6-Ketoesters Mediated by Ionic Liquids: A Three-component Reaction Enabling Rapid Access to a New Class of Low Molecular Weight Gelators

In organic chemistry ionic liquids (ILs) have emerged as safe and recyclable reaction solvents. In the presence of a base ILs can be deprotonated to form catalytically active N-Heterocyclic Carbenes (NHCs). Here we have used ILs as precatalysts in the addition of &#945;,&#946;-unsaturated aldehydes to chalcones to form 1,6-ketoesters, incorporating an anti-diphenyl moiety in a highly stereoselective fashion. The reaction has a broad substrate scope and several functional groups and heteroaromatics can be integrated into the ketoester backbone in generally good yields with maintained stereoselectivity. The reaction protocol is robust and scalable. The starting materials are inexpensive and the products can be obtained after simple filtration, avoiding solvent-demanding chromatography. Furthermore, the IL can be recycled up to 5 times without any loss of reactivity. Moreover, the 1,6-ketoester end product is a potent gelator in several hydrocarbon based solvents. The method enables rapid access to and evaluation of a new class of low molecular weight gelators (LMWGs) from recyclable and inexpensive starting materials.

Ionic liquids (ILs) mediate fast, simple and cheap access to 1,6-ketoesters in high diastereoselectivities and good yields. The reaction protocol is robust and the 1,6-ketoesters can be obtained in gram scale after a simple filtration protocol. Moreover, the 1,6-ketoesters are potent gelators in hydrocarbon solvents.

In organic chemistry ionic liquids (ILs) have emerged as safe and recyclable reaction solvents. In the presence of a base ILs can be deprotonated to form ...

Facile Preparation of (2Z,4E)-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

Direct cross-coupling between two alkenes via vinylic C-H bond activation represents an efficient strategy for the synthesis of butadienes with high atomic and step economy. However, this functionality-directed cross-coupling reaction has not been developed, as there are still limited directing groups in practical use. In particular, a stoichiometric amount of oxidant is usually required, producing a large amount of waste. Due to our interest in novel 1,3-butadiene synthesis, we describe the ruthenium-catalyzed olefination of electron-deficient alkenes using allyl acetate and without external oxidant. The reaction of 2-phenyl acrylamide and allyl acetate was chosen as a model reaction, and the desired diene product was obtained in 80% isolated yield with good stereoselectivity (Z,E/Z,Z = 88:12) under optimal conditions: [Ru(p-cymene) Cl2]2 (3 mol %) and AgSbF6 (20 mol %) in DCE at 110 &#186;C for 16 h. With the optimized catalytic conditions in hand, representative &#945;- and/or &#946;-substituted acrylamides were investigated, and all reacted smoothly, regardless of aliphatic or aromatic groups. Also, differently N-substituted acrylamides have proven to be good substrates. Moreover, we examined the reactivity of different allyl derivatives, suggesting that the chelation of acetate oxygen to the metal is crucial for the catalytic process. Deuterium-labeled experiments were also conducted to investigate the reaction mechanism. Only Z-selective H/D exchanges on acrylamide were observed, indicating a reversible cyclometalation event. In addition, a kinetic isotope effect (KIE) of 3.2 was observed in the intermolecular isotopic study, suggesting that the olefinic C-H metalation step is probably involved in the rate-determining step.

Facile Preparation of 2Z,4E-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

The ruthenium-catalyzed olefination of electron-deficient alkenes with allyl acetate is described here. By using aminocarbonyl as a directing group, this external oxidant-free protocol has high efficiency and good stereo- and regioselectivity, opening a novel synthetic route to (Z,E)-butadiene skeletons.

Direct cross-coupling between two alkenes via vinylic C-H bond activation represents an efficient strategy for the synthesis of butadienes with high ...

Carboxylic Acids to Esters: Acid-Catalyzed (Fischer) Esterification Overview

The Fischer esterification reaction was developed by the German chemist Emil Fischer&#160;in 1895. It is a condensation reaction between carboxylic acids and alcohols in an acidic medium to give esters and water.
<img alt="Figure1" src="/files/ftp_upload/12348/12348_PT_Figure_1.svg" style="text-align: center; height: 80px;" />
Hydroxy-functionalized carboxylic acids undergo intramolecular Fischer esterification to form lactones. The cyclic five- and six-membered lactones are formed spontaneously.
<img alt="Figure2" src="/files/ftp_upload/12348/12348_PT_Figure_2.svg" style="text-align: center; height: 100px;" />
The reaction rate of Fischer esterification is greatly dependent on steric factors. Primary alcohols react fastest with carboxylic acids to form esters, while tertiary alcohols undergo Fischer esterification at a slower rate, forming alkene by-products.
Fischer esterification is an inherently slow reaction with a low equilibrium constant value and never attains completion. During the reaction, an equilibrium is always established between the reactant and the product. Consequently, traces of unreacted acid are always present along with the product ester. Using excess alcohol as a solvent directs the equilibrium towards the product, according to Le Chatelier&#39;s principle. Alternatively, removing the water from the reaction mixture using a Dean&#8211;Stark trap can also drive the reaction to completion.

Carboxylic Acids to Esters: Acid-Catalyzed Fischer Esterification Overview

The Fischer esterification reaction was developed by the German chemist Emil Fischer&#160;in 1895. It is a condensation reaction between carboxylic acids ...

Carboxylic Acids

KEY TERMS AND CONCEPTS

Carboxylic Acids to Esters: Acid-Catalyzed (Fischer) Esterification Mechanism

Carboxylic acids react with alcohols to yield esters via an&#160;acid-catalyzed condensation reaction called Fischer esterification. This is a nucleophilic acyl substitution reaction that proceeds via&#160;a tetrahedral intermediate, where a&#160;water molecule is eliminated as the leaving group.
<img alt="Figure1" src="/files/ftp_upload/13088/13088_PT_Figure_1.svg" style="text-align: center; height: 68px;" />
The mechanism of this reaction was confirmed by Robert and Urey (1938) through a radioisotope labeling experiment, where&#160;esterification of a carboxylic acid was carried out using 18O-labeled alcohol. The resulting ester was found to be labeled with an&#160;18O atom, establishing the fact that the &#8211;OH group of the carboxylic acid was replaced by&#160;the &#8211;OR group from the alcohol.
<img alt="Figure2" src="/files/ftp_upload/13088/13088_PT_Figure_2.svg" style="text-align: center; height: 55px;" />
Modifications of Fischer esterification&#160;use either a boron trifluoride ether complex or an organotin complex as the catalyst in an acid-free condition.
<img alt="Figure3" src="/files/ftp_upload/13088/13088_PT_Figure_3.svg" style="text-align: center; height: 48px;" />

Carboxylic Acids to Esters: Acid-Catalyzed Fischer Esterification Mechanism

Carboxylic acids react with alcohols to yield esters via an&#160;acid-catalyzed condensation reaction called Fischer esterification. This is a ...

Esters to Carboxylic Acids: Acid-Catalyzed Hydrolysis

Hydrolysis of esters under acidic conditions proceeds through a nucleophilic acyl substitution. In the presence of excess water, the reaction proceeds in a reversible manner, forming carboxylic acids and alcohols.
During hydrolysis, the ester is first activated towards nucleophilic attack through the protonation of the carboxyl oxygen atom by the acid catalyst. The protonation makes the ester carbonyl carbon more electrophilic. In the next step, water acts as a nucleophile and adds to the carbonyl carbon, followed by the loss of a proton to give the tetrahedral addition intermediate. Further, the protonation of the alkoxy group converts it into a better leaving group. Subsequently, the carbonyl group is reconstructed with the expulsion of alcohol as a leaving group. Finally,&#160;deprotonation yields a carboxylic acid&#160;as the final product and regenerates the acid catalyst.
<img alt="Figure1" src="/files/ftp_upload/12369/12369_PT_Figure_1_.svg" style="text-align: center; height: 225px;" />
An acid catalyst protonates the carbonyl oxygen, thereby increasing the formation rate of the tetrahedral intermediate. Moreover, the catalyst decreases the basicity of the leaving group. Notably, the reaction is exactly the reverse of a Fischer esterification reaction.

Hydrolysis of esters under acidic conditions proceeds through a nucleophilic acyl substitution. In the presence of excess water, the reaction proceeds in ...

Esters to &beta;-Ketoesters: Claisen Condensation Overview

Regular Claisen condensation is a base-promoted reaction involving identical esters with two &#945; hydrogens, condensing to produce &#946;-ketoesters. It is a nucleophilic acyl substitution reaction wherein one of the ester molecules, upon deprotonation by the base, forms a nucleophilic enolate ion, while the other molecule serves as an electrophile.
<img alt="Figure1" src="/files/ftp_upload/12390/12390_Figure_1.svg" style="text-align: center; height: 70px;" />
The condensation reaction requires specific nonaqueous bases, such as alkoxide, which must be similar to the alkoxy group of the ester molecule. The use of different alkoxide ions often leads to the transesterification product. Also, the use of hydroxide bases is avoided as they result in irreversible hydrolysis of the esters to carboxylate ions.
<img alt="Figure2" src="/files/ftp_upload/12390/12390_Figure_2.svg" style="text-align: center; height: 150px;" />

Esters to &amp;#946;-Ketoesters: Claisen Condensation Overview

Regular Claisen condensation is a base-promoted reaction involving identical esters with two &#945; hydrogens, condensing to produce &#946;-ketoesters. It ...

&alpha;-Carbon Chemistry: Enols, Enolates, and Enamines

&alpha;-Hydroxy Ketones via Reductive Coupling of Esters: Acyloin Condensation Overview

The pinacol and McMurry reactions involve the reductive coupling of ketones or aldehydes. Similarly, the bimolecular reductive coupling of two ester molecules in the presence of sodium metal in an aprotic solvent yields an &#945;-hydroxy ketone product. The &#945;-hydroxy ketone is also called acyloin, so the reaction is referred to as &#8216;acyloin condensation.&#8217;
<img alt="Figure1" src="/files/ftp_upload/12908/12908_PT_Figure_1.svg" style="text-align: center; height: 65px;" />
In the acyloin condensation reaction, esters are converted to ketyls, which undergo radical dimerization to form an unstable tetrahedral intermediate. Further, this intermediate collapses to give a 1,2-diketone intermediate. The 1,2-diketones are comparatively more reactive than ketones towards electrophiles and reducing agents because of lower &#960;* energy. Consequently, two electrons sequentially transfer to the 1,2-diketone to form an enediolate. Lastly, the enediolate intermediate is quenched with acid to yield an &#945;-hydroxy ketone with a good yield.
Often some by-products are obtained alongside the major product because of the reactivity of nucleophilic enediolate. To overcome the side reactions and improve the yield of an acyloin, trimethylsilyl chloride is used to silylate the enediolate. This results in a bis-silyl ether, further hydrolyzed with aqueous acid to give &#945;-hydroxy ketones.

&amp;#945;-Hydroxy Ketones via Reductive Coupling of Esters: Acyloin Condensation Overview

The pinacol and McMurry reactions involve the reductive coupling of ketones or aldehydes. Similarly, the bimolecular reductive coupling of two ester ...

Radical Chemistry

Esters to &beta;-Ketoesters: Claisen Condensation Mechanism

Regular Claisen condensation involves the synthesis of &#946;-ketoesters by combining identical ester molecules bearing two &#945; hydrogens in the presence of an alkoxide base. The reaction commences with the deprotonation of the acidic &#945; hydrogen by the base to form a resonance stabilized ester enolate. This nucleophilic ion then attacks the carbonyl center of another ester molecule to generate a tetrahedral alkoxide intermediate. Next, the expulsion of the alkoxide group from the intermediate restores the carbonyl center and produces an acyl-substituted ester. The alkoxide by-product subsequently abstracts the second &#945; proton from the &#946;-dicarbonyl compound to form a doubly-stabilized enolate ion. This step is the driving force of the reaction to completion and suggests the essential requirement of two &#945; protons in starting ester. Finally, acidification of the enolate produces the desired &#946;-ketoester. The utility of the Claisen condensation process is also observed in biological systems. For instance, the synthesis of acetoacetyl-CoA from the condensation of acetyl-CoA in the presence of thiolase enzyme.

Esters to &amp;#946;-Ketoesters: Claisen Condensation Mechanism

Regular Claisen condensation involves the synthesis of &#946;-ketoesters by combining identical ester molecules bearing two &#945; hydrogens in the ...

Alkylation of &beta;-Ketoester Enolates: Acetoacetic Ester Synthesis

Acetoacetic ester synthesis is a method to obtain ketones from alkyl halides and &beta;-keto esters. The reaction occurs in the presence of an alkoxide base that abstracts the acidic proton of the &beta;-keto esters. The step results in an enolate ion which is doubly stabilized. The enolate then reacts with an alkyl halide via the SN2 process to produce an alkylated ester intermediate with a new C&#8211;C bond. The hydrolysis of the intermediate, followed by acidification, results in an alkylated &beta;-keto acid. Under high-temperature conditions, the &beta;-keto acid undergoes decarboxylation to form a ketone. However, if the alkylation is repeated before hydrolysis and decarboxylation steps, a disubstituted ketone is obtained.

Alkylation of &amp;#946;-Ketoester Enolates: Acetoacetic Ester Synthesis

Acetoacetic ester synthesis is a method to obtain ketones from alkyl halides and &beta;-keto esters. The reaction occurs in the presence of an alkoxide ...

Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile

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Chapters in this video

Esterification

Highly Stereoselective Synthesis of 1,6-Ketoesters Mediated by Ionic Liquids: A Three-component Reaction Enabling Rapid Access to a New Class of Low Molecular Weight Gelators

Facile Preparation of (2Z,4E)-Dienamides by the Olefination of Electron-deficient Alkenes with Allyl Acetate

Carboxylic Acids to Esters: Acid-Catalyzed (Fischer) Esterification Overview

Carboxylic Acids to Esters: Acid-Catalyzed (Fischer) Esterification Mechanism

Esters to Carboxylic Acids: Acid-Catalyzed Hydrolysis

Esters to β-Ketoesters: Claisen Condensation Overview

α-Hydroxy Ketones via Reductive Coupling of Esters: Acyloin Condensation Overview

Esters to β-Ketoesters: Claisen Condensation Mechanism

Alkylation of β-Ketoester Enolates: Acetoacetic Ester Synthesis