Acidic cleavage of ethers (SN2)

by James

Description: When ethers are treated with strong acid in the presence of a nucleophile, they can be cleaved to give alcohols and alkyl halides. If the ether is on a primary carbon this may occur through an SN2 pathway.

Notes: Common acids for this purpose are HI and other hydrogen halides, as well as H2SO4 in the presence of H2O.

In the case where the ether being cleaved is secondary and has a stereocenter, there will be inversion of configuration.

Examples: 

Notes: The third example could also be written “H3O+”

Mechanism: Strong acid (HI) protonates the ether oxygen, which turns it into a better leaving group (Step 1, arrows A and B). Next, the iodide ion attacks the carbon in an SN2 reaction (Step 2, arrows C and D) to give the alcohol and methyl iodide.

Notes: In cases  where the ether being cleaved is secondary and has a stereocenter, there will be inversion of configuration.

Another example: Opening of tetrahydrofuran (THF) with aqueous acid:

THF opening

{ 24 comments… read them below or add one }

Hao Luo

Is HI a stronger nucleophile than HCl? If asked to list all the hydrogen halides in terms of their cleavage speed with an ether without side chains, what order should you arrange them? I always thought HF is the strongest and as you go down it gets weaker. But that wasn’t the case right? Could you please explain to me why.

Thanks,
Hao

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Jake the Dog

HI is a better nucleophile than HCl because the Iodine atom is more polarizable and hence more able to take place in SN2 reaction. As you go down the halide group, the electron shells get larger and farther away from the nucleus and therefore more polarizable. Thus they get more nucleophilic down gorup as well

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Gitesh

You must be thinking that F being for electronegative stabilizes the negative charge on it the most. But remember thats not the only basis on which u decide the acidity. H-F bonds are hydrogen bonds(Very strong) so cleaving it would be the most difficult. While for the others hydration energy also plays a role. So the correct series is:
HI> HBr> HCl> HF

According to their acidic strength.

So I- acts as a very good nucleophile because it is a stable nucleophile.

Reply

sotos

But what about steric hindrance ? I would expect the chloride ion to be more reactive than the iodide due to its considerably smaller size. Also, that becomes even more important considering the fact that the reaction is Sn2.

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James

Steric hindrance isn’t really an issue with halides because the size is generally inversely proportional to the length of the bond they form with carbon [i.e. small Cl, shorter bond length, large I, longer bond length] and these two factors largely cancel out. More important is the type of solvent. In polar protic solvents (solvents that can hydrogen bond) iodide is a better nucleophile than chloride. See this posthttp://www.masterorganicchemistry.com/2012/06/18/what-makes-a-good-nucleophile/

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Biki Das

First of all we have to understand the bond distribution for take place in the any type of neucleophilic reaction #
H-F (least tendency to distribution of ions) due to smallest surface area
H-I (quick or good/fast tendency to distribution of ions) due to greatest surface area
Above in basis of reactivity order
F>CL>BR>I OR H-F<H-CL<H-Br<H-I

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Madhu88

what about unsymmetrical ether cleavage???????

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Petr Menzel

Hi, in the mechanism is produced Ph-OH + CH3I. Why is not produced Ph-I + CH3-OH? Thx, P.

Reply

James

Because that would involve an SN2 of I- on an sp2 hybridized carbon, which is very slow – not to mention that “backside attack” would have to occur from the middle of the benzene ring!

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Yuvraj

Suppose I have a polymeric structure, with multiple ether linkages, say for instance, an ether of polyethlene glycol. What is the probability of the cleavage affecting only the terminal linkage and not the other ether bonds??? Thanx.

Reply

Carli

This was so helpful! Thank you so much! Do you have anything on epoxide ring opening?

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Zach W

In regards to reactivity, are more substituted carbon centers less reactive because during the backside attack there is more steric hinderance?

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James

Yes, exactly! (for SN2 reactions, anyway)

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Isaac

Does this method work for complex molecules like LIGNIN which contain a lot of ether linkages?

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Amy Nguyen

For the first example with the clevage of C6H5OCH3, how come C6H5I and CH3OH don’t form ?

Reply

James

Ah! This is an SN2 reaction…. and SN2 reactions require a backside attack. A backside attack would have to occur from inside the aromatic ring which is impossible (very crowded). Also, SN2 reactions don’t work on sp2 hybridized carbons (like alkenyl halides)

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kristin

will you please go over the reaction between thf and h3o+?

Reply

James

Great question. Added it as an “addendum”, see above.

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Neha

If the reaction, say for a tertiary ether, takes place at high temperature in an acidic medium, can an alkene be formed via elimination (provided the anion is a weak nucleophile) ?

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Abby Almonte

What happens when you put a reagent with THF? How does it react?

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Wouter

Hello James,
can you also do this cleaving of ethers quantitative to make an analysis for determining monomeric components in a poly-ether?

Reply

James

In theory yes, but I imagine that it would be very difficult on a practical level.

Reply

James

Hi, do the cyclic ethers (not epoxides) too follow these type of reactions?

Reply

James

Yes, they do. For example the cyclic ether tetrahydrofuran (THF) can be opened with strong acid in the presence of a nucleophile. The Lewis acid titanium tetrachloride also does a particularly good job….

Reply

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