Master Organic Chemistry Reaction Guide

Conversion of carboxylic acids to esters using acid and alcohols (Fischer Esterification)

Description: When a carboxylic acid is treated with an alcohol and an acid catalyst, an ester is formed (along with water). This reaction is called the Fischer esterification.

1-reaction of carboxylic acid with alcohol to make ester fischer esterification.gif

Notes: The reaction is actually an equilibrium. The alcohol is generally used as solvent so is present in large excess. Many different acids can be used; it’s common to see just “H+”, although H2SO4 (sulfuric acid) and TsOH (tosic acid) are also often used.

Examples:

Notes: The byproduct of each of these reactions is water. Note that the third and fourth examples are intramolecular reactions that form a cyclic ester. Cyclic esters are also called lactones.

The fifth example shows that without any added alcohol, the only thing that happens is protonation of the carbonyl!

The sixth example is a double Fischer esterification.

Mechanism:

For such a seemingly simple reaction (replacement of OH by OR) there are actually a lot of steps. Protonation of the carbonyl oxygen by acid (Step 1, arrows A and B) makes the carbonyl carbon a much better electrophile. It undergoes 1,2-addition by the alcohol (Step 2, arrows C and D) whereupon the proton from the alcohol is transferred to one of the OH groups (Step 3, arrows E and F). Subsequent 1,2-elimination of water (Step 4, arrows G and H) leads to the protonated ester, and the ester is then deprotonated (Step 5, arrows I and J).

mechanism-for-fischer-esterification-full-arrow-pushing-between-carboxyilc-acid-and-alcohol-giving-ester-reversible-equilibrium

Notes:

  • All of these steps are in equilibrium

Note that the acid is a catalyst here (regenerated at the end) and serves two purposes. First, it makes the carbonyl carbon a better electrophile (Setting up step 2) and also allows for the loss of H2O as a leaving group (much better leaving group than HO–)


(Advanced) References and Further Reading

  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.

 

 

 

Comments

Comment section

194 thoughts on “Conversion of carboxylic acids to esters using acid and alcohols (Fischer Esterification)

  1. I came in expecting an expulsion of the OH similar to the Grignard addition to an Ester – the Electrons rise up the Carbonyl to make C-O(-), then slam back down to make the carbonyl again, and then the O-R leaves because the C-O bond breaks.

    Why isn’t this the case here? Is it due to the acidic conditions? Is there a basic version of this reaction that would, in fact, do this addition-elimination reaction?

    1. It’s because -OR is a bad leaving group. If to say that it was -OCl or -OTs, then your thought process would most likely be valid. As is, it would be hard to generate an alkoxide (-OR) in acidic conditions too. I am not sure this reaction would work in base (well not with these starting materials) as it wont go very far from a simple acid-base reaction at the first step.

  2. Hello,
    I actually have a question, what would happen if excess watr were added to the ester product and the solution was refluxed under acidic conditions?
    I believe that the rxn would occur in the reverse because the rxn is an equilibrium rxn and follows le chatalier’s principle.
    Thank you in advance!

      1. I know if you were to remove the water from the product as it forms, it would drive the reaction towards ester formation, but would the addition of ether to the reactant side of the equation have any effect???

      2. I have this problem too. I got excess water as my side result. How to remove the excess of water? Because it will decrease the %yield of ester. I added the drying agent, such us sodium sulphate and magnesium sulphate, but it was not doing well. Thank you.

    1. Hi Collin –

      Diazomethane is great on small scale, and if you want to make the methyl ester. Probably one of my favorite reactions to run because it’s so darn easy.

      However the higher analogs of diazomethane (e.g. diazoethane, diazopropane) are not stable enough for routine use. So it’s limited to methyl esters for the most part.

      The Fischer esterification is one of those robust, old school, tried and true reactions that can be used to make a huge variety of esters.

      Hope that answers your question! James

    1. Its due to resonance stabilization of the “Carbonyl-oxygen protonated” intermediate and hence proceeds further unlike that in case of protonation of hydroxyl oygen.

      1. Resonance? the carboxyl oxygen has a resonance that puts negative charge on it so it easily picks up a positive hydrogen.
        What confuses me though, is carboxylic acid is a much less stable acid than an alcohol and so it seems counterintuitive that it would soak up the extra acid in solution.

  3. How many mole of acid catalyst that we need to use in this esterification, and is the amount of acid used will effect the reaction?

    1. This page will show you the reaction including the H2SO4 showing you why it is used as a catalyst there are probably many more catalysts that work but sulphuric acid is mass produced and very cheao

    2. This page will show you the reaction including the H2SO4 showing you why it is used as a catalyst there are probably many more catalysts that work but sulphuric acid is mass produced and very cheap.

    3. Sulphuric acid is also a very good dehydrating agent..So the water produced during the reaction gets absorbed and hence the reaction equilibrium gets shifted in forward direction….

  4. Minor typo: it’s the fourth example reaction that’s an intramolecular reaction, not the third. Great job, as always!

  5. Can fischer esterification happen in aqueous solution? In other words, can the protonation in step 1 and deprotonation in step 5 happen via hydrogen ions and hydroxide ions of water, respectively?

    Thanks

    1. Hey Ted – the Fischer esterification is in equilibrium with the reverse reaction (acidic hydrolysis of esters to give carboxylic acids).

      In order to get the reaction to proceed from acid —> ester, you need to add a large excess of alcohol so that the concentration of alcohol will be much greater than water . This is what drives the reaction toward the ester [think Le Chatelier]

      So if you use water as the solvent, nothing will happen to the carboxylic acid. It will just sit there. You need to use an alcohol solvent.

      For example if you want to make a methyl ester, add methanol as solvent.

      Hope this helps – James

  6. Hi, sorry…This is not related to ester.
    Can you suggest me a test to distinguish between chlorobenzene and benzyl chloride?

    Thanks :)

      1. how the reaction between alcohol and TsOH is reversible and the differenne between Pka value is 19 unit (approxomatly)

        1. Hi Harith – the number you need to be looking at is not the pKa of the alcohol (which measures the equilibrium for formation of its conjugate base ROH –> RO- + H+ ) but instead protonation of the alcohol to give its conjugate acid (ROH + H+ —> ROH2+ ). The pKa of that species is about -2 , which is roughly equivalent to that of tosic acid. Hence TsOH is in equilibrium with protonated alcohol, as well as protonated carbonyl and protonated water. Hope this helps – James

  7. 1. Why is the carboxylic acid and alcohol not reacted in equimolar amounts
    2. Why is it necessary that the aqueous solution is basic?

    1. 1. The reaction is an equilibrium. Using an excess of alcohol drives it to the right (ester) side.

      2. The aqueous solution is ACIDIC in order to 1) speed up addition of the nucleophile to the C=O group, and 2) convert OH into OH2+, making it a better leaving group.

      1. How about in the case of mevalonate forming a cyclic ester to become mevalolactone? Mevalonate is in its carboxylate form…I am trying to understand the proton transfers that occur in this cyclization reaction/equilibrium under physiological conditions.

      1. That’s not entirely correct – thionyl chloride/alcohol is also an effective way to carry out esterification (see Tetrahedron Letters, Vol. 37, No, 35, pp. 6375-6378). Thionyl chloride reacts with alcohol to generate the requisite acid catalyst in situ.

  8. Hi, do you by any chance know some examples of research where Fischer esterification is used? What are its real life applications?
    Thank you.