Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: quantumnumber on August 24, 2014, 08:36:05 AM
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Hi guys,
an easy one:
How could I carry out a bromination of a ketone on the less substitued side?
I know that bromination in acidic conditions will give the not-desired product... And no other simple way comes to my mind.
Thanks!
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I've thought this, trying to control the halogenation with an enolate equivalent, but I think there could still be problems with deprotonation of the most acidic hydrogen (the one next to the bromine), and so further halogenation... Maybe with stoichiometric control and low temperature would work.
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Quantum,
I don't think that last halogenation step would actually work. Starting with Butane, I would either add Br2 and UV light or NBS and heat. Then a big sterically hindered base to get almost all ( if not all of) the E2 Product and also the Hoffman product. Then from the Hoffman product add Br2, h20 and then A strong oxidizing agent like chromic acid to turn that secondary alcohol into the ketone. The final product would be your 1,-bromo-2,-butanone
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This looks like a product from a longer series of steps. If bromine and catalyst doesn't give bromination in the less substituted position, how was that accomplished in your class or textbook?
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This looks like a product from a longer series of steps. If bromine and catalyst doesn't give bromination in the less substituted position, how was that accomplished in your class or textbook?
I don't know really... Nowadays I'm preparing an exam about retrosynthetic analysis, so I was doing an excercise, trying to figure out how to get the target molecule, and I ended up needing this reagent (according to my plan of synthesis). I thougt this halo-ketone would be easy to prepare, but I realized it isn't.
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Quantum,
I don't think that last halogenation step would actually work. Starting with Butane, I would either add Br2 and UV light or NBS and heat. Then a big sterically hindered base to get almost all ( if not all of) the E2 Product and also the Hoffman product. Then from the Hoffman product add Br2, h20 and then A strong oxidizing agent like chromic acid to turn that secondary alcohol into the ketone. The final product would be your 1,-bromo-2,-butanone
Interesting, but you made me think... Wouldn't it be easier if you start with 1-butene, then Br2 and H2O to get the bromohydrin? And finally, oxidation...
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I don't know why you guys are not liking the bromination of an enolate. I would trap it into a silyl enol ether to be sure though - so 1) LDA 2) TMSCl (this will form a kinetic silyl enol ether), then Br2 should be ok (see e.g. http://pubs.acs.org/doi/abs/10.1021/jo00925a051) or NBS if need be?
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Edit
Re: bromination of enolate
What do you think might happen mid-reaction? Does your product know it shouldn't react? Why does basic bromination give bromoform? Would you get monobromomethyl ketone if only one equivalent of bromine were used?
@quantum, could you make the bromoketone in two steps from acetylene?
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Who are you asking these questions orgopete? They don't apply to method, yet you're not quoting anyone else and writing under my post...
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Quantum,
Yup, your right it would be easier to start with 1-butene. I was just starting from a bare bones molecule to sort of methodically work our way up to the target molecule.
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I don't know why you guys are not liking the bromination of an enolate. I would trap it into a silyl enol ether to be sure though - so 1) LDA 2) TMSCl (this will form a kinetic silyl enol ether), then Br2 should be ok (see e.g. http://pubs.acs.org/doi/abs/10.1021/jo00925a051) or NBS if need be?
Many thanks! That was my first plan, I write it down.
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Edit
Re: bromination of enolate
What do you think might happen mid-reaction? Does your product know it shouldn't react? Why does basic bromination give bromoform? Would you get monobromomethyl ketone if only one equivalent of bromine were used?
@quantum, could you make the bromoketone in two steps from acetylene?
I know basic bromination would get bromoform, but isolating the enolate equivalent (lithium enolate) and then mixing it with Br2 I thought it could work, because it's supposed you don't have base anymore...
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Edit
Re: bromination of enolate
What do you think might happen mid-reaction? Does your product know it shouldn't react? Why does basic bromination give bromoform? Would you get monobromomethyl ketone if only one equivalent of bromine were used?
@quantum, could you make the bromoketone in two steps from acetylene?
I know basic bromination would get bromoform, but isolating the enolate equivalent (lithium enolate) and then mixing it with Br2 I thought it could work, because it's supposed you don't have base anymore...
I thought an enolate or enolate equivalent would react with the product as the reaction took place. A second reaction might be since the product is a stronger acid than starting material, I also expected proton exchange. I presume that is why haloform reaction is able to attack least substituted carbon over other reactions. If bromination of enolate worked as proposed, I would have expected it to be the preferred route.
@rview, you are correct. I had failed to read your post completely and discover you had linked it to a successful lit procedure. Mia culpea.
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What about starting with 1-butene, making the bromohydrin with NBS in aqueous DMSO, then oxidizing the alcohol to a ketone? Offhand, I don't have an oxidant picked out.
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I thought an enolate or enolate equivalent would react with the product as the reaction took place. A second reaction might be since the product is a stronger acid than starting material, I also expected proton exchange. I presume that is why haloform reaction is able to attack least substituted carbon over other reactions. If bromination of enolate worked as proposed, I would have expected it to be the preferred route.
@rview, you are correct. I had failed to read your post completely and discover you had linked it to a successful lit procedure. Mia culpea.
I see - the attack on the product by the enolate is a reasonable worry, as is proton exchange - but I'd argue that the enolate should be so reactive that if you flood it with a few equivalents of the brominating agent, whatever it'd be, the bromination should be by far the fastest route available. Also, this is why I went for the silyl ether- it should decrease the reactive of the enolate for those potential side reactions and give you a clean attack on the desired electrophile.
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What about starting with 1-butene, making the bromohydrin with NBS in aqueous DMSO, then oxidizing the alcohol to a ketone? Offhand, I don't have an oxidant picked out.
This. 1-butene>1,2-epoxybutane>swern oxidation with catalytic MeOH will generate the desired product in one step with decent yield and far less side products.
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phth, That looks very interesting. Is the difference between chlorine and bromine a trivial one?
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Phth,
This looks/sounds like a pretty cool reaction, unfortunately I have never heard of it until now. Do you have any other literature I can read about it or can you post the link to that paper the picture is from? So I can read more about it?
8)
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Phth,
Cool reaction, but you're getting halogenation on the more substituted side, which is not what we wanted to do here, no?
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Babcock Hall: I believe it is a trivial difference, and oxalyl chloride is more stable, so more widely used. I read that reaction from the book called 'Oxidaiton of Alcohols to Aldehydes and Ketones' (http://link.springer.com/book/10.1007%2Fb135954). The paper referenced is (http://www.sciencedirect.com/science/article/pii/004040209401111C) DOI:10.1016/0040-4020(94)01111-C. I haven't had a chance to read through the paper because I'm not at the university today. Rwiew: I doubt the reaction is extremely regioselective, but I think there will be more opening at the less substituted side which we want. My reasoning behind the result is that the tertiary SN1 transition state requires less energy than the secondary SN2/1 transition state does, and the substituted side leads to a alcohol that cant oxidize.
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Def. use some kind of hindered base to afford a Hoffman product intermediate.
-Zack
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Def. use some kind of hindered base to afford a Hoffman product intermediate.
-Zack
Huh? It is an acid catalyzed epoxide opening followed by a DMSO oxidation (Swern in this case). The triethylamine is to make the sulfur ylide.
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Def. use some kind of hindered base to afford a Hoffman product intermediate.
-Zack
Huh? It is an acid catalyzed epoxide opening followed by a DMSO oxidation (Swern in this case). The triethylamine is to make the sulfur ylide.
Where is that acid coming from if you're working in triethylamine? I'd say the epoxide is most likely not protonated when opened. What I think Zack is saying is using a hindered base to first attack at the less substituted end and then be displaced by the halide - there's no room for a mention of Hoffmann though, this is not an elimination.
I still don't see how this is better than brominating a silyl ether though, especially with the lack of regioselectivity.
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Where is that acid coming from if you're working in triethylamine? I'd say the epoxide is most likely not protonated when opened. What I think Zack is saying is using a hindered base to first attack at the less substituted end and then be displaced by the halide - there's no room for a mention of Hoffmann though, this is not an elimination.
I still don't see how this is better than brominating a silyl ether though, especially with the lack of regioselectivity.
The experiment shows phosgene plus methanol, which should give some HCl and open the epoxide. The alcohol in the presence of the sulfonium salt should give a new sulfonium salt (the ylide precursor) and HCl. So this part of the reaction can be catalytic in HCl. After all of this occurs, the triethylamine is added.
If the reaction is run from an epoxide, I agree acid catalyzed opening of an epoxide should give the wrong isomer.
This same procedure can be run directly on 1-butene by doing the bromination in DMSO, but I didn't look up the reference. That is simply an alternative one pot bromohydrin formation and oxidation. I don't know it is necessarily better than doing it in two steps, or a one step bromohydrin from 1-butyne to the product. This should give the desired regions electricity.
Re: bromination of silly enol either
I'm sure that is a fine method. If this is from air, fire, and water problem, then I don't know which is going to be better, a priori. For the purpose of the original poster's question, probably all of the answers are useful chemistry.
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Sorry….misread post….disregard my invalid comments. THEY ARE WRONG
-Z
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Sorry….misread post….disregard my invalid comments. THEY ARE WRONG
-Z
Been there, done that too many times!