Sciencemadness Discussion Board

Can williamson ether synthesis be performed with lewis acids?

Electra - 10-3-2014 at 08:26

I have seen these williamson ether synthesis's almost exclusively performed with NaOH, KF, and sometimes CuO as a catalyst, but rarely with lewis acids.

Would the lewis acid not be more effective than NaOH and KF if it were made to organic-soluble with a ptc? I know NaOH typically form catecholates, though I am not sure if NaOH directly activates the halogen. Would a lewis acid not activate the halogen more effectively and simultaneously deprotanate the H in the OH group, allowing for a much more swift and effective reaction? Instead of relying on the halogen simply leaving on its own by its natural leaving ability? HX (x = halide) would be formed instead of NaX as is with the use of NaOH.

I am curious to try this. If a lewis acid would have the above effects, it could mean higher yields and fewer by products, right?

[Edited on 10-3-2014 by Electra]

Marvin - 10-3-2014 at 08:51

You are going a mile a minute and not making a lot of sense. Point us to what you are talking about.

Electra - 10-3-2014 at 11:12

Sorry? What is there not to understand?

http://en.wikipedia.org/wiki/Williamson_ether_synthesis

Very well known reaction.

Alcohol group is deprotonated, hydrogen is substituted in from some halide, at which point the halogen leaves, forming an ether. Typically a base is used for the deprotonation, but a lewis acid can accomplish this same task by a different mechanism. I am asking if a lewis acid can be used in the place of a base, since it should perform a double function of not only deprotonating but also acting as an electrophile towards the halogen, allowing it to leave easier so the substitution reaction can precede and form the ether.

DraconicAcid - 10-3-2014 at 11:22

You're asking if a Lewis acid can deprotonate an alcohol to give an alkoxide?

Electra - 10-3-2014 at 12:35

The Lewis Acid is an electron acceptor, so it should be able to deprotonate the alcohol. Correct me if I am wrong.

What I am asking is whether or not a lewis acid would be a better catalyst for this reaction instead of a base like Sodium Hydroxide, since the Lewis Acid can act to deprotonate the alcohol and activate the halogen, where as the base only deprotonates the the alcohol.

I'm probably answering my own question here but I would just like confirmation on whether or not I am missing something.

Marvin - 10-3-2014 at 12:41

A proton has no electrons, you can deprotonate with a Lewis base.

DraconicAcid - 10-3-2014 at 12:41

Quote:
The Lewis Acid is an electron acceptor, so it should be able to deprotonate the alcohol. Correct me if I am wrong.


An electron acceptor is not a proton acceptor.
Quote:
What I am asking is whether or not a lewis acid would be a better catalyst for this reaction instead of a base like Sodium Hydroxide, since the Lewis Acid can act to deprotonate the alcohol and activate the halogen, where as the base only deprotonates the the alcohol.


Sodium hydroxide is not a catalyst for this reaction, but a reactant. The base deprotonates the alcohol to form an alkoxide, the alkoxide reacts with the alkyl halide.

Net reaction: NaOH + ROH + R'X -> NaX + H2O + R'OR.

If you added a Lewis acid (do you have a specific one in mind? FeCl3? AlCl3? SbF5?) to the alcohol and the alkyl halide, the Lewis acid would probably accept electrons from the alcohol to form some sort of complex, but then that complex would not be nucleophilic enough to react with even an activated alkyl halide.



[Edited on 10-3-2014 by DraconicAcid]

Electra - 10-3-2014 at 12:48

I was intending to use Nickel Chloride as a lewis acid, since it has never failed me in other reactions, and it is super cheap.

An electron acceptor is not a proton acceptor but when a electrophile accepts an electron from a hydrogen it activates it, creating a better leaving group. Lewis Acids as electrophilic hydrogen-bond activators is very well documented.

Though like you said, whether or not it will be activated enough to leave the molecule is the question. It just needs to be activated enough so that a hydrogen from the haloalkane can substitute in. The halogen activated would merge with the activated hydrogen and form HCl (or another halogen), the moment the haloalkane substitutes in place of the hydrogen that was activated.

These mechanisms are well documented. Though the question is, as you said, whether or not the activation of the hydrogens will be strong enough to allow the reaction to happen

DraconicAcid - 10-3-2014 at 13:09

You need to take a serious look at the mechanism for the ether synthesis, because what you have written does not correspond with the reaction you are hoping for.

Lewis acids will make alcohols easier to deprotonate, but that's by stabilizing the alkoxide. You don't *want* a stabilized alkoxide, because you want it nucleophilic enough to react with the alkyl halide.
Quote:
It just needs to be activated enough so that a hydrogen from the haloalkane can substitute in. The halogen activated would merge with the activated hydrogen and form HCl (or another halogen), the moment the haloalkane substitutes in place of the hydrogen that was activated.


You do not remove HCl as part of this reaction, and the hydrogen from the haloalkane doesn't enter into it. You need to generate a strong Lewis base (something Lewis acids are notoriously poor at) and react it with the haloalkane.

The only time a Lewis acid will help with a reaction such as this is in the Sn1 reaction of an alcohol with a tertiary alkyl halide-addition of silver ions will help abstract the halide, allowing the alcohol to react with the carbocation left.

Marvin - 10-3-2014 at 13:11

(Electra) You have this completely backwards and should review acid base theory.

For example, say you create a good leaving group out of the hydrogen, where is going to leave *to*?

If it protonates water then it is moving from a weak acid to a stronger one. That isn't going to be favoured. A Lewis base is a proton acceptor, it has all the electrons required for the bond, but no proton.

Edit, I can't improve on DraconicAcid's answer.

[Edited on 10-3-2014 by Marvin]

Electra - 10-3-2014 at 14:27

Edit: On second thought, while this reaction would definitely work, it could result in Friedel Crafts Alkylations to take place, where as this would not occur using a bronsted base.

I don't think there is anything backwords. Perhaps I explained above poorly, in any case, I have answered my own question...read on if you are curious. This is simple Electrophilic activation at work here, which Lewis Acids are known to induce. If you want to learn more about this, google the following terms:
Quote:
"electrophilic activation" AROUND(20) "hydroxyl"

Quote:
"electrophilic activation" AROUND(20) "c-h"


Lets use the well known methylenation of catechols reactions as an example. Also take a look at this. http://www.erowid.org/archive/rhodium/chemistry/methylenatio...

While the yields are low ^, presumably due to lack of solubility of the catalyst, copper oxide has lewis acidic properties.
Quote:
"copper oxide" AROUND(20) "lewis acid"

"copper oxide particles can act as Lewis acid sites"

"This increase, according to Acta Crystallography, because CuO is a metal oxide that has only weak Lewis acid site, which is according to data from the state of the copper oxide crystallography is one of the metal oxides which have only weak Lewis acid site"


A lewis acid definitely would catalyze this reaction and allow it to happen, with the degree of completion being dependent upon catalyze-substrate contact. Lewis Acids can also be used in place of Bronsted bases in Henry/Nitroaldol reactions as well - this is well documented.

In the traditional methylenation (williamson ether) reaction, NaOH forms a catecholate with the catechol by deprotonating it, allowing dihalomethane to substitute in. When the dihalomethane substitutes electrons get pulled away from the halides, forcing them to leave, at which point they immediately swap places with the catecholate forming NaCl, as the OH pop off the NaOH and merge with the proton to form water in addition.

In an electrophillicly catalyzed methylenation, the mechanism is different, but results in the same end result Lewis Acids are known to be electrophilic activators of many types of bonds by attracting electrons, thus weakening/activating the bonds involved. Hydroxyl groups are known nucleophiles. The Lewis Acid will pull an electron away from the OH group, activating/weakening the bond, opening it up to a substitution. Since the halogens on the dihalomethane are nucleophilic they too should also be activated by the lewis acid. At this point all the necessary bonds are activated enough to where the reaction can take place. Instead of NaCl and H2O forming, the halogens would react with the activated protons from the hydroxyl group's forming the respective Hydrohalide Acids. Like the traditional NaOH based reaction, the yields should remarkably improve with the addition of a PTC.

I should have remembered that above study. Research has shown that many reactions involving bonsted bases can have lewis acids used instead, depending on the mechanism. Feel free to continue posting, but I have answered my own question. I would love to further discuss this mechanism, but it is pretty clear cut.


[Edited on 10-3-2014 by Electra]

[Edited on 10-3-2014 by Electra]

Marvin - 11-3-2014 at 07:34

Hopefully when you mark your answer you will have done well.
Quote: Originally posted by Electra  

Lets use the well known methylenation of catechols reactions as an example. Also take a look at this. http://www.erowid.org/archive/rhodium/chemistry/methylenatio...


Potassium carbonate is a base.