Basic Hydrolysis of Esters – Saponification

When esters are treated with hydroxide ion, followed by neutralization with acid, they are converted into carboxylic acids.

This process is called basic hydrolysis of esters. Another name for it is saponification, since the carboxylate salts initially formed through hydrolysis are often used as soaps (sapon = soap in Latin).

Many different hydroxide salts can be used. In the laboratory, lithium hydroxide in a mixture of THF and water is commonly used. For soap making, lye (usually NaOH but sometimes KOH) from wood ashes is traditionally used.

Diagrams here will use Li(+) but the precise identity of the alkali counter-ion is not crucial.

2. The Mechanism for Basic Hydrolysis

The first step in saponification is nucleophilic addition of the hydroxide ion to the carbonyl carbon of the ester to form a tetrahedral intermediate. (See post: Nucleophilic Addition) This is followed by elimination of alkoxide (RO – ) from the tetrahedral intermediate to give a carboxylic acid.

This two step addition-elimination process is an example of nucleophilic acyl substitution (See post: Nucleophilic acyl substitution)

Since base is present, however, and since carboxylic acids (pKa around 4-5) are much more acidic than alcohols (pKa around 15-16), the carboxylic acid is then quickly deprotonated to give the conjugate base of the carboxylic acid, called a carboxylate salt.

To obtain the neutral carboxylic acid, one generally adds strong acid to the aqueous solution of carboxylate until the carboxylic acid precipitates out, and we then perform an extraction with an organic solvent.

3. Saponification Is Irreversible Under Basic Conditions

If we can obtain carboxylic acids from esters under basic conditions, it’s worth asking if can we go in the opposite direction and obtain esters from carboxylic acids by using an alkoxide (RO(-) ?

The answer is no. Saponification of an ester with HO(-) is irreversible.

Getting the ester back is highly unfavorable under basic conditions. (Note 1– it can be done under acidic conditions, however, using the Fischer esterification ).

It’s instructive to walk through why this is.

Under basic conditions, the first thing to happen will be an acid-base reaction between the alkoxide and the carboxylic acid to give the carboxylate salt. Alcohols are at least 10 pKa units less acidic than carboxylic acids, so this is a very favorable (and essentially irreversible) acid-base reaction.

The next step that would have to occur is addition of the alkoxide RO(-) to the carboxylate to give the tetrahedral intermediate RC(OR)(O2) 2- . This is not a misprint – this species would bear two negative charges, making it a di-anion.

Generally, species become more unstable as the number of point charges increases, so we’d already expect this to be quite unfavorable relative to the mono-anionic carboxylate and alkoxide. (See article: 5 Key Factors That Influence Acidity)

Still, for the sake of argument, let’s allow that this might happen to a tiny extent.

What would have to happen next to get the ester from here? Well, the extremely strong di-anion O( 2- ) would have to be eliminated from the tetrahedral intermediate.

Remember the Principle of Acid-Base Mediocrity? (See post: How To Use a pKa Table). Strong acid plus strong base gives weaker acid and weaker base?

This reaction is disfavored because it would result in the conversion of a moderately strong base into an extremely strong base.

It’s like asking a river to run uphill!

Far, far more likely is elimination of RO(-) from the tetrahedral intermediate to regenerate the carboxylate and the alkoxide. And that is essentially what happens. No net reaction is observed, except for deprotonation of the carboxylic acid.

4. Basic Hydrolysis of Lactones

Any time you learn a new reaction it is worth the time to explore the intramolecular version. It involves no new concepts, but it looks weird, and for this reason intramolecular reactions make for good exam problems.

In this case a cyclic ester, called a lactone, can be converted into an acyclic hydroxy-acid (Note 2) through addition of hydroxide ion.

The reaction looks like this:

The mechanism is completely identical to that of the intermolecular version. The bonds that form and break are exactly the same. The only thing to remember is that since the OR group is attached to the carboxylic acid via a carbon chain, we end up with one molecule instead of two.

5. Saponification of Fats

The origin of the term saponification comes from the Latin sapo for soap.

Fats contain a molecule of glycerol attached to three long-chain carboxylic acids via ester linkages.

At some point in human history, some bright spark it discovered that lye (essentially NaOH) undergoes reaction with fats to give molecules that can act as detergents and soaps.

When these long chain fatty acid carboxylates are added to water, they spontaneously form spherical entities called micelles that organize themselves such that the hydrophilic carboxylate “heads” face out towards the water, and the hydrophobic alkyl tails are arranged inward.

These micelles are excellent at sequestering oils and other non-polar contaminants from skin and dishware in a way that pure water is not.

Notes

Related Articles

Note 1. The Fischer esterification is the conversion of a carboxylic acid to an ester under acidic conditions (See post: The Fischer Esterification)

Note 2. Sometimes called a “seco-acid” from the Latin seco, secaris, secare “to cut, sever”.

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(Advanced) References and Further Reading

  1. On the mechanism of hydrolysis. The alkaline saponifications of amyl acetate
    Polanyi and A. L. Szabo
    Trans. Faraday Soc.,1934, 30, 508-512
    DOI:10.1039/TF9343000508
    One of the first mechanistic studying of saponification, or ester hydrolysis. These authors were the first to find that alkaline hydrolysis of amyl acetate occurs with acyl-oxygen bond fission. Also noted that amyl alcohol had not undergone O 18 -exchange with the solvent water after 2 days at 70°C.
  2. Mechanisms of Catalysis of Nucleophilic Reactions of Carboxylic Acid Derivatives.
    Myron L. Bender
    Chemical Reviews1960,60 (1), 53-113
    DOI: 10.1021/cr60203a005
    This review describes evidence supporting kinetic studies that show a dependence on pH and isotopic labeling studies that prove it is the acyl-oxygen, not the alkyl-oxygen bond that is cleaved during hydrolysis.
  3. Rate-limiting deprotonation in tetrahedral intermediate breakdown
    Robert A. McClelland
    Journal of the American Chemical Society1984,106 (24), 7579-7583
    DOI:10.1021/ja00336a044
    This paper describes mechanistic studies that show that alkyl benzoate esters give only a small amount of exchange under basic hydrolysis conditions, indicating that reversal of OH- addition must be slow relative to the forward breakdown of the tetrahedral intermediate.
  4. Alkyl–oxygen heterolysis in carboxylic esters and related compounds
    G. Davies and J. Kenyon
    Q. Rev. Chem. Soc.,1955, 9, 203-228
    DOI: 10.1039/QR9550900203
    This review describes studies that show that the mechanism of saponification can change based on the stability of the tertiary carbocation formed by alkyl-oxygen cleavage, when using an ester formed from a tertiary alcohol.
  5. General Base Catalysis of Ester Hydrolysis 1
    William P. Jencks and Joan Carriuolo
    Journal of the American Chemical Society1961,83 (7), 1743-1750
    DOI: 10.1021/ja01468a044
  6. General base catalysis of ester hydrolysis
    Dimitrios Stefanidis and William P. Jencks
    Journal of the American Chemical Society1993,115 (14), 6045-6050
    DOI    : 10.1021/ja00067a020
    These two papers by Prof. William P. Jencks, an influential figure in Physical Organic Chemistry, show that general base catalysis has been observed in the case of esters in which the acyl group carries electron-attracting substituents.
  7. General Basic Catalysis of Ester Hydrolysis and Its Relationship to Enzymatic Hydrolysis 1
    Myron L. Bender and Byron W. Turnquest
    Journal of the American Chemical Society1957,79 (7), 1656-1662
    DOI: 10.1021/ja01564a035
  8. Catalysis in ester cleavage. II. Isotope exchange and solvolysis in the basic methanolysis of aryl esters. Molecular interpretation of free energies, enthalpies, and entropies of activation
    Carl G. Mitton, Richard L. Schowen, Michael Gresser, and John Shapley
    Journal of the American Chemical Society1969,91 (8), 2036-2044
    DOI:10.1021/ja01036a029
    There has been a good deal of study of substituent effects, solvent effects, isotopic exchange, kinetics, and the catalysis of ester hydrolysis, as these two papers illustrate.
00 General Chemistry Review
01 Bonding, Structure, and Resonance
02 Acid Base Reactions
03 Alkanes and Nomenclature
04 Conformations and Cycloalkanes
05 A Primer On Organic Reactions
06 Free Radical Reactions
07 Stereochemistry and Chirality
08 Substitution Reactions
09 Elimination Reactions
10 Rearrangements
11 SN1/SN2/E1/E2 Decision
12 Alkene Reactions
13 Alkyne Reactions
14 Alcohols, Epoxides and Ethers
15 Organometallics
16 Spectroscopy
17 Dienes and MO Theory
18 Aromaticity
19 Reactions of Aromatic Molecules
20 Aldehydes and Ketones
21 Carboxylic Acid Derivatives
22 Enols and Enolates
23 Amines
24 Carbohydrates
25 Fun and Miscellaneous
26 Organic Chemistry Tips and Tricks
27 Case Studies of Successful O-Chem Students