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.
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).
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
- 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. - 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. - 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.
The ester volatility temperature is high. For example PEG400 oleate. In this reaction, for the transport of water, toluene and nitrogen gas and water are collected in the dean stark and returned to the toluene reaction medium with reflux. Toluene at 175 degrees is removed by vacuum. But the toluene smell remains in the ester. Which solvent would be as suitable as toluene to carry water and no odor in this process?
If we use toluene to carry the water from the reaction, which solvent do you think I should use so that there is no toluene odor in the ester formed after vacuum? Should it form an azeotrope like toluene and separate easily after esterification? I will be glad if you answer.
How volatile is your ester? If you have traces of toluene left in your ester after the reaction, you could always take it up in a little bit of n-pentane or diethyl ether to get rid of any traces of toluene.
If we want to use dean starck setup, it means we have to use Toluene as solvent?
then what what would be nucleophile source if I want to make methyl ester?
please reply.
Hello, I use diethyl ether as a solvent to extract chlorinated Herbicides. In order to get rid of the water that could probably get into the sample, I let my sample sit in Acidified Na2So4 before concentration and Esterification. is there anything better I could do (if Dean-Stark trap isn’t an option)? Also, the standard method suggests using a mixture of methanol/2,2,4-Trimethylpentane/ ethyl ether/diazomethane, and silicic acid added respectively but I don’t understand the role of the iso-octane and the silicic acid in the reaction!! should I be adding them or the diazomethane and methanol would be enough?
Thanks in advance
Without seeing your specific example I can’t give you a good answer. From what you’ve written I don’t know the structure. I can tell you that diazomethane is something you absolutely should not work with unless you have been properly trained in its use by an expert. It is potentially very explosive.
Is it Sn1 or Sn2 ….and how to determine nucleophilicity of alchohol ,that is which alcohol will react first.
Side reactions?
Depends on the substrate. A very high yielding reaction with simple starting materials, but if you have acid-sensitive functional groups that aren’t protected, inevitably there will be complications.
i couldn’t understand what’s OTs there?
Tosylate, or p-toluenesulfonate. https://www.masterorganicchemistry.com/2015/03/10/tosylates-and-mesylates/
Hye, im wondering why does esterification process starts at 30°C?
Where did you get that information from?
If my alcohol is solid, what solvent can i use ?
Uh oh. What solid are you trying to use? Phenol?
Why don’t you convert the carboxylic acid to an acid halide and then take it up in an appropriate solvent and add your solid alcohol.
Hi,
I am going to write my extended essay on chemistry, and I came up with a topic which is “what is the effect of different concentrations of sulfuric acid as a catalyst of esterification on the yield of ester when ethanol is reacted with ethanoic acid”, but my teacher said that it is too easy for an extended essay. And I am considering about the other methods that increases the yield of ester and make comparisons with the esterification that uses sulfuric acid. So any suggestions to me to make my topic more complicated?
Thank you so much
I don’t have a good answer for you. One thing you could look at is the effect of various substituents on the para position of benzoic acid and how the affect the rate of the Fischer esterification with an alcohol like ethanol. This is referred to as a Hammett plot and it gives useful information about the mechanism.
Hi,
I am synthesizing dimethyl malate with dl-Malic acid and excess methanol with sulphuric acid as the acid catalyst. Using HPLC, I can identify 3 peaks (depending on my reaction condition). Using a standard as a check, the major peak is the dimethyl ester and another is definitely a dimethyl fumarate. The other peak based on GC is speculatively dimethyl succinate. The standard almost agreed with this but my mole balance based on yield% for each does not add up and the so-called succinate seems to be the problem. Truth is, I do not know how a succinate could be produced following traditional reaction mechanisms for fischer esterification reactions. Based on the wealth of your experience, what do you think the other side product is? I have scoured the internet and journals for ideas and everything seems to be a blur.
Probably not dimethyl succinate. You could do a michael addition of methanol to dimethyl fumarate and you’d get a very similar molecular mass to dimethyl succinate.
Hey!
I’m about to venture into synthesizing different esters for perfume and lotion and soap production.
What should I ensure?
Thanks
If you have to ask, I’d suggest you buy them instead of making them.
Hello, I need to make a esterification using allylic alcohol that is very reactive with sulfuric acid, there is any other substances like acid resine that I could use. Thank you very much.
Why don’t you just convert the carboxylic acid to the acid chloride and do it under basic conditions?
Hi. How do I compare the rates of acid catalysed esterification for different carboxylic acid reagents? What role do electronic effects play in determining the reactivity of a carboxylic acid towards Fischer esterification?
One way you could do it is by looking at the linear free energy relationship (LFER) for the Fischer esterification reaction and then getting the Hammett parameters for the substituents. That would provide you with your answer. It would require some digging through the primary literature.
Is Fischer esterification an SN1 reaction or an SN2 reaction?
Please explain…
It is neither – it is an acyl substitution reaction!
Why basic medium is not taken instead acidic medium…
It’s possible to use basic conditions but that would be “transesterification”. The Fischer employs acid.
What is the difference in using a Dowex-resin and sulfuric acid as a catalyst? Would the isolation of the product need to be different?
Well the nice part about using the resin is that you just filter it off, instead of having to neutralize the solution during workup.
If i wanted to turn a fully organic Carboxylic acid into its corresponding methyl-ester, which is regarding safety and environment the better method: 1) Fisher esterification or 2) Alkylation with Methyl iodide in basic circumstances? And because of which safety and environmental reasons exactly?
Well, you probably want to use the Fischer. Methyl iodide can be effective but it isn’t a lot of fun to work with, it’s a mutagen and will alkylate your DNA if you get a few drops on your hand.
Why is there removal of -OH from carboxylic acid but not from alcohol to give water?
In order to have water as a leaving group you have to form two O-H bonds. That’s not possible with the alcohol because you’d have to break an O-C bond, which would be much more difficult.
Hi, two questions,
when the water is eliminated, is there any preference for it being oxygen from the carbonyl or from the hydroxyl of the carboxyl group?
and is there evidence for the proton transfer involving an external (e.g. alcohol) molecule rather than an internal transfer?
Thanks!
No, in experiments with isotopically labelled oxygen scrambling of the isotopic label is observed, meaning that there is no preference. As far as proton transfer, it’s probably an external molecule but that’s a tough question to answer.
Why can’t the Fischer esterification take place under basic catalysis?
Because your leaving group would be O (2-) which is a terrible leaving group.
Why doesn’t salicylic acid undergo intramolecular esterification?
It’s way too strained. Look at a model. 4 membered ring, it would break apart too easily.
Why is it necessary to add sulphuric acid in the synthesis of esters?
Otherwise your leaving group would be HO- , which would be a very slow reaction.
I am doing esterification with ethanol getting conversion 95 to 96 %area purity by HPLC. but i am getting yield 81 to 82 %.
please suggest work-up conditions of esterification.
It’s not uncommon to see a drop in yield comparing HPLC yields to isolated yields. Workup is just a standard wash with saturated bicarb followed by 3x extraction with appropriate solvent. Search the literature, you’ll find hundreds of examples.
Is esterification a nucleophilic substitution reaction or electrophilic substitution reaction?
Nucleophilic acyl substitution.
Why benzoyl chloride is used instead of carboxylic acid with phenol in synthesis of phenyl benzoate