Fischer Esterification – Carboxylic Acid to Ester Under Acidic Conditions

Carboxylic Acid to Ester Under Acidic Conditions (Fischer Esterification)

• The conversion of a carboxylic acid to an ester under acidic conditions is commonly known as the Fischer esterification
• In this reaction there is an equilibrium between the starting materials (carboxylic acid + alcohol) and the products (ester + water).
• The equilibrium is driven to the right (ester side) through using a large excess of alcohol and also through removing any water that is formed either through use of a drying agent (dessicant) or through removal with a Dean-Stark type apparatus
• Cyclic esters can be formed under these conditions, which are known as lactones.
• The mechanism for this reaction is Protonation-Addition-Deprotonation-Protonation-Elimination-Deprotonation (PADPED).
• The reaction can be run in the reverse direction by treating the ester with excess water in the presence of acid. This is acidic ester hydrolysis.

Table of Contents

1. Conversion of Carboxylic Acids to Esters (Fischer Esterification)
2. Intramolecular Fischer Esterification
3. Mechanism of the Fischer Esterification
4. Comparing Fischer Esterification With Saponification
5. What Is The Driving Force?
6. Using a Large Excess of Reagent
7. Removing Water As It Is Formed
8. Summary
9. Notes
10. Quiz Yourself!
11. (Advanced) References and Further Reading

1. Conversion of Carboxylic Acids To Esters (Fischer Esterification)

Carboxylic acids can be converted to esters with an acid catalyst and an excess of alcohol.

This is known as Fischer esterification. or just “esterification of acids”.

Common choices for acids include sulfuric acid (H₂SO₄), tosic acid (TsOH) and hydrochloric acid HCl among others. For our purposes these conditions can be considered to be equivalent.

Here are some examples of the Fischer esterification.

Notice in this reaction that we form a new C-O bond and we break a C-O bond.

Importantly, we are forming and breaking the bond from the oxygen to the carbonyl, not the bond from the oxygen to the R group.

The Fischer esterification is therefore an example of nucleophilic acyl substitution.

We also form two new O-H bonds to generate a molecule of water.

2. Intramolecular Fischer Esterification

The Fischer esterification can also be used to make cyclic esters (lactones).

This is an example of an intramolecular reaction. The bonds that form and break are exactly the same! But since the nucleophile and electrophile are attached to the same molecule, we obtain a cyclic product.

Ring formation works best for the formation of 5- and 6-membered rings. [Note 1] Three and four membered rings are generally too strained to form through this method, although there are other methods for the formation of 4-membered lactone rings [Note 2].

Note that in this reaction an equivalent of water is formed.

3. Mechanism of the Fischer Esterification

So how does this reaction work?

The Fischer esterification mechanism has six steps. Each step is reversible and the starting materials and final product are all in equilibrium.

In the first step of the Fischer esterification, the carbonyl oxygen is protonated with acid to give an oxonium ion.

The resulting protonated carbonyl is an even better electrophile than a neutral carbonyl carbon.

The second step is addition of the neutral nucleophile (ROH) to the protonated carboxylic acid (Form C-O, break C-O (pi)). This results in a tetrahedral intermediate. (See post: Nucleophilic Addition to Carbonyls)

The next two steps together are known as “proton transfer” since they result in the net movement of H+ from one oxygen to another.  Deprotonation of the O-H from the alcohol is followed by protonation of the O-H oxygen.

This results in formation of a good leaving group (H₂O). Elimination of H₂O (Form C-O (pi), break C-O) gives the protonated ester. Deprotonation of the ester then gives us the neutral ester product (and water).

A useful mnemonic for the full mechanism is the acronym PADPED.

(Protonation-addition-deprotonation-protonation-elimination-deprotonation).

This is also the mechanism of acid-catalyzed transesterification (See post: Tranesterification), as well ass acidic ester hydrolysis, imine formation, and several other reactions (See post: Learn 6 mechanisms For The Price Of One)

4. Comparing Fischer Esterification With Saponification

Why does esterification of acids work well under acidic conditions, but fails under basic conditions?

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Recall that a key driving force for nucleophilic acyl substitution reactions is that they are strongly favorable when the nucleophile is a stronger base than the leaving group. [See post: Nucleophilic Acyl Substitution]

When we employ acidic conditions our nucleophile is ROH and our leaving group is H₂O. There isn’t a very strong driving force one way or the other, but at least it’s not unfavorable.

The key elimination step is extremely difficult under basic conditions.

If RO(-) just led to the displacement of HO(-), it would be a fine nucleophilic acyl substitution. But since carboxylic acids are acids, an acid-base reaction between the carboxylic acid and RO(-) occurs first, giving the carboxylate RCO₂(-).

In order for nucleophilic acyl substitution to happen on a carboxylate, the leaving group would have to be O(^2-). That’s far too unfavorable, since it’s a much stronger base than RO(-)! So getting this reaction to work is like expecting a river to flow backwards.

So using acid for this reaction makes all the difference. Since the conjugate acid is a better leaving group (See post: What Makes A Good Leaving Group) using an acid catalyst enables us to perform nucleophilic acyl substitution in situations where base alone would fail.

5. What is The Driving Force?

There’s one last question worth asking. What’s the actual driving force for the Fischer esterification?

Usually, nucleophilic acyl substitution reactions follow the Principle of Acid-Base Mediocrity. That means that reaction proceeds in the direction in which the stronger base (nucleophile) displaces a weaker base (leaving group). [See post: Nucleophilic Acyl Substitution]

But here, the leaving groups in the forward direction (H₂O) and reverse direction (ROH) have roughly the same leaving group ability .

So why should it follow any direction at all?

Good question! Since there is no inherently strong driving force for the reaction, we will have to choose our reaction conditions well such that equilibrium will flow in the direction of the desired product.

There are two main ways to do this, and these two methods can be combined.

• Use a large excess of the nucleophile (alcohol) – preferably, make it the solvent.
• Remove the byproduct (water) as it is formed, which will slow down the reverse reaction.

6. Large Excess of Reagent

One study on this reaction [Note 3] used acetic acid and ethanol in the presence of an acid catalyst.

It was found that running the Fischer esterification using equal amounts of acetic acid and ethanol gave a 65% yield of the ester at equilibrium.

Not bad. But the reaction could be driven even further to the right by using a 10-fold excess of the alcohol. In this case they obtained a 97% yield of the ester.

By using a 100 fold excess, they were even able to drive the reaction toward a 99% yield.

7. Removing Water With A Dean-Stark Trap

Another way to ensure the reaction runs in the direction of ester formation is to remove the water as it is formed. This pushes the equilibrium towards the right via Le Chateliers’ principle.

A clever way to do it is to use an apparatus called a Dean-Stark trap.

In this process, a solvent such as benzene or toluene is used. These molecules co-distill together to form what is called an azeotrope. The vapor condenses at the base of the reflux condenser. At this point, the liquid drops down, and the water, being more dense than toluene, sinks to the bottom of the trap.

With water removed from the reaction mixture, the reverse reaction (ester hydrolysis) is rendered impossible.

For an example, see: this (free) article (Org Syn 1949, 29, 33)

8. Summary

The Fischer esterification is one of those classic reactions in organic chemistry that is never going away.

It is one of the cheapest and most effective processes for the formation of esters from carboxylic acids, especially on large scale.

All of the steps in the Fischer esterification are potentially reversible. The six steps in the mechanism (Protonation-Addition-Deprotonation-Deprotonation-Elimination-Deprotonation) are also the six steps for the reverse reaction, the acid-catalyzed hydrolysis of esters.

Notes

Note 1. The equilibrium for the formation for unstrained, five- and six-membered rings is highly favorable for entropic reasons. A molecule of the leaving group (e.g. H₂O) is released into solution with attendant increase in translational entropy (three degrees of translational entropy and up to three degrees of rotational entropy). This is sometimes known as the chelate effect. [Ref]

Note 2. Beta-lactones cannot be formed through the Fischer esterification as the four-membered ring has too much ring strain. However, beta-lactones can be formed through intramolecular closure of an alcohol onto an acid chloride or similar carboxylic  acid derivative with an excellent leaving group. Beta-lactones are also found in some natural products.

Note 3. This table is adapted from page 499 of “Introduction to Organic Chemistry” (4th ed.), editors Streitweiser, Heathcock, Kosower. [link]

Note 4. Some physical properties of carboxylic acids.

Quiz Yourself!

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(Advanced) References and Further Reading

References

1. First example
   Emil Fischer, Arthur Speier (1895). “Darstellung der Ester”.
   Chemische Berichte. 28: 3252–3258
   DOI: 1002/cber.189502803176
   Original paper by Emil Fischer and Arthur Speier describing acid-catalyzed esterification of carboxylic acids and alcohols.
2. Protonic States and the Mechanism of Acid‐Catalysed Esterification
   Dr. H. Zimmermann Dr. J. Rudolph
   Angewandte Chemie Int. Ed., Volume 4, Issue 1, January 1965, Pages 40-49
   DOI: 10.1002/anie.196500401
   Considerations of proton mobility in the condensed phase suggest a two-step mechanism of esterification, which proceeds via a tetrahedral intermediate.
3. Ethyl Adipate
   M. Micovic
   Org. Synth. Coll. Vol. 2, 264
   DOI: 10.15227/orgsyn.000.0001
   One of the first procedures in Organic Syntheses, a reliable source for reproducible organic transformations. This uses a Fischer esterification to convert adipic acid, a diacid and precursor to nylon-6,6, to ethyl adipate.
4. Mechanisms of Catalysis of Nucleophilic Reactions of Carboxylic Acid Derivatives.
   Myron L. Bender
   Chemical Reviews 1960 60 (1), 53-113
   DOI: 10.1021/cr60203a005
5. Phenyl acetate preparation from phenol and acetic acid: Reassessment of a common textbook misconception
   M. B. Hocking
   Journal of Chemical Education 1980 57 (7), 527
   DOI: 10.1021/ed057p527
6. Recent developments in methods for the esterification and protection of the carboxyl group
   Edwin Haslam
   Tetrahedron, Volume 36, Issue 17, 1980, 2409-2433
   DOI: 10.1016/0040-4020(80)80219-5
7. Entropic Contributions To Rate Accelerations in Enzymic and Intramolecular Reactions and the Chelate Effect
   Michael A. Page and William P. Jencks
   Proc. Nat. Acad. Sci. 1971, 68(8), 1678-1683
   DOI: 10.1073/pnas.68.8.1678
   Discussion of the chelate effect. When a new ring forms, there is a reduction in the entropy arising from restriction of the rotation alongt C-C bonds (about 4.5 entropy units per bond) but this is more than made up for by the large increase in translational degrees of freedom afforded by the release of an additional molecule into solution.