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Topic: Ether side product during Esterification  (Read 1494 times)

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Offline G-Head

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Ether side product during Esterification
« on: December 10, 2021, 06:54:39 AM »
Hi guys,

While peforming esterification reactions with different alcohols (e.g. Methanol, Ethanol, butanol, Isopropanol,...) I always got a significant amount of ether side products, only when using Isopropanol.

The reaction is catalyzed with sulphuric acid.  I know that H2SO4 catalyze etherification as well.

But i don't know, why I get much more ether with Isopropanol than wirh the other alcohols ??
Maybe because it is a secondary alcohol and the other are primary?

How can i suppress the reaction to the ether ?? Maybe with another catalyst?

Thanks for your *delete me*

Offline wildfyr

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Re: Ether side product during Esterification
« Reply #1 on: December 10, 2021, 03:46:47 PM »
Yep, isopropanol can condense with itself in the presence of sulfuric acid to make an ether.

I’m too lazy to check but this is probably how diisopropyl ether is made.

How much acid are you using? Really only need a tiny amount…

Offline spirochete

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Re: Ether side product during Esterification
« Reply #2 on: December 12, 2021, 03:33:09 PM »
I would think probably less acid, and lower temperature maybe, if reaction is possible at the lower temperature. Also I've seen phosphoric acid as an alternative to sulfuric acid that gives less side product.

Also if it is an expensive starting material, doing the process in an entirely different way might be better. About ten years ago when I studied this, Mitsonobu coupling was a standard way to couple carboxylic acid + alcohol and make an ester. This would be more important if you care about stereochemistry at the alcohol carbon.  Mitsonobu would invert stereochemistry at the alcohol, and a Fischer esterification would retain the stereochemistry, or give some racemization depending on the conditions/substrate, I would think. It might not be worth it if your reactants are both very cheap and simple.

Or, alternative way is simple Sn2 with carboxylate ion + alkyl halide + polar aprotic solvent, maybe some HMPA or crown ether or phase transfer catalyst. Mitsonobu might be better because alcohols are more readily available on average than alkyl halides. You could also convert an alcohol to a sulfonate ester such as tosylate or triflate.

Offline wildfyr

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Re: Ether side product during Esterification
« Reply #3 on: December 13, 2021, 08:24:16 AM »
Yes, phosphoric acid will lower this side reaction, but also is not quite as good catalyst.

Industry standard is p-toluene sulfonic acid.

Offline spirochete

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Re: Ether side product during Esterification
« Reply #4 on: December 13, 2021, 06:54:32 PM »
Yes, phosphoric acid will lower this side reaction, but also is not quite as good catalyst.

Industry standard is p-toluene sulfonic acid.

I have always wondered the practical reason behind using pTsOH over sulfuric acid, but I've only heard different people speculating. Is it just because it is easier to work with, and typically include less water than H2SO4? The two acids seem to have about the same pKa, -3 and -2.8. And 99.9% sulfuric acid can be obtained from sigma aldrich, so the lack of water can't be the only reason. pTsOH is a solid, and pure H2SO4 is a liquid. I would imagine pure H2SO4 is just difficult to work with for some reason, and TsOH is easier.

Offline wildfyr

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Re: Ether side product during Esterification
« Reply #5 on: December 14, 2021, 01:59:33 PM »
I don't have a rock solid answer either... but from a purely industrial point of view, pTSOH is definitely safer to handle. They also do not have the same reactivity, but I don't know specifics off the top of my head.

Offline spirochete

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Re: Ether side product during Esterification
« Reply #6 on: December 14, 2021, 03:27:25 PM »
Hi guys,

While peforming esterification reactions with different alcohols (e.g. Methanol, Ethanol, butanol, Isopropanol,...) I always got a significant amount of ether side products, only when using Isopropanol.

The reaction is catalyzed with sulphuric acid.  I know that H2SO4 catalyze etherification as well.

But i don't know, why I get much more ether with Isopropanol than wirh the other alcohols ??
Maybe because it is a secondary alcohol and the other are primary?

How can i suppress the reaction to the ether ?? Maybe with another catalyst?

Thanks for your *delete me*

I feel bad about hijacking your thread before all your questions were answered. Why does a secondary alcohol favor forming the ether more compared to primary? You could probably answer this question yourself if you thought about it. Alcohols have a possible leaving group (in acid, at least), bonded to an sp3 carbon. This means substitutions will take place via Sn2 or Sn1. Are these conditions going to favor Sn2 or Sn1? Is there a strong nucleophile present? Is the solvent polar protic or polar aprotic? Also, if secondary alcohols are doing the ether formation faster, this almost tells you what mechanism is favored. Why would secondary alcohols do this process faster?

Various introductory textbooks have sections about this. Dimerization of alcohols to make ethers in sulfuric acid. It happens less at lower temperatures, and less with primary alcohols. Loudon, a sort of bad textbook IMO, does have a decent discussion of this in the ether chapter.

Offline spirochete

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Re: Ether side product during Esterification
« Reply #7 on: December 14, 2021, 06:00:48 PM »
I don't have a rock solid answer either... but from a purely industrial point of view, pTSOH is definitely safer to handle. They also do not have the same reactivity, but I don't know specifics off the top of my head.

I guess sulfuric acid can lose water/make SO3 and cause unwanted sulfonations or other oxidations. And H2SO4 would have very different ability to dissolve in organic solvents. And H2SO4 might be more hygroscopic. Also if an acid without much water is needed, purified H2SO4 ends up being a viscous liquid, which sounds like nasty stuff.

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