Tough time brominating quite a basic ketone

[fireoncells]

Hello !

I am doing some research on thiazole chemistry. I have to brominate 1-(2-(pyridin-4-yl)thiazol-5-yl)ethanone to obtain the corresponding bromoketone. I've tried this with elemental bromine in CCl4 (stirring, r.t) and obtained a red powder after vacuum filtration . The problem is that this molecule has to 2 aromatic N atoms and the bromine is actually incorporated into the molecule (probably like in pyridinium tribromide?). The 1HNMR spectra shows that there has no bromination occured.

I have tried to brominate it with NBS/CCl4 + 2 drops HCl conc under reflux. TLC shows that the bromination is incomplete.

I don't like CCl4 at all-it is toxic and it doesn't work so I have to try some other system like NBS/MeCN or NBS/DMF with an appropriate catalyst. One of them is HBr but I don't have HBr so I have to make it. TsOH might also be a very good idea but the problem is that can form salt with my haloketone complicating isolation.

 

So my questions are: Which is the best method to brominate this molecule with pronounced basicity ? (no Br2 please ! ) ) and how to isolate the product (in base form not pyridinum salt) ?

 

I really need the oppinion of an expert....

 

Sorry for my English...Thank you very much !

Edited September 23, 2011 by fireoncells

[hypervalent_iodine]

Hello !

I am doing some research on thiazole chemistry. I have to brominate 1-(2-(pyridin-4-yl)thiazol-5-yl)ethanone to obtain the corresponding bromoketone. I've tried this with elemental bromine in CCl4 (stirring, r.t) and obtained a red powder after vacuum filtration . The problem is that this molecule has to 2 aromatic N atoms and the bromine is actually incorporated into the molecule (probably like in pyridinium tribromide?). The 1HNMR spectra shows that there has no bromination occured.

I have tried to brominate it with NBS/CCl4 + 2 drops HCl conc under reflux. TLC shows that the bromination is incomplete.

I don't like CCl4 at all-it is toxic and it doesn't work so I have to try some other system like NBS/MeCN or NBS/DMF with an appropriate catalyst. One of them is HBr but I don't have HBr so I have to make it. TsOH might also be a very good idea but the problem is that can form salt with my haloketone complicating isolation.

 

So my questions are: Which is the best method to brominate this molecule with pronounced basicity ? (no Br2 please ! ) ) and how to isolate the product (in base form not pyridinum salt) ?

 

I really need the oppinion of an expert....

 

Sorry for my English...Thank you very much !

 

 

Firstly, I'm not sure I understand the aversion to Br₂; why won't you use it? It's toxic and corrosive, sure, but it's fairly easy to use.

 

To answer your question, a SciFinder search showed that most use HBr, Br₂ or a combination thereof. You should do a SciFinder search yourself and see which one you are most comfortable with; all of the reactions I saw gave yields over 70% (or they claimed to, anyway).

[fireoncells]

Firstly, I'm not sure I understand the aversion to Br₂; why won't you use it? It's toxic and corrosive, sure, but it's fairly easy to use.

 

To answer your question, a SciFinder search showed that most use HBr, Br₂ or a combination thereof. You should do a SciFinder search yourself and see which one you are most comfortable with; all of the reactions I saw gave yields over 70% (or they claimed to, anyway).

 

You really don't understand do you? I have a particular problem with this molecule, Br2 is excluded ! I cannot brominate with Br2 because it reacts on a different manner with the Py N...

[hypervalent_iodine]

You really don't understand do you? I have a particular problem with this molecule, Br2 is excluded ! I cannot brominate with Br2 because it reacts on a different manner with the Py N...

 

 

No need to get snarky, I was simply asking why. I did actually come back here with a solution for you, but seeing as you think being rude to the only member offering an answer (to a question quite easily solved with a quick SciFinder search, really) is an acceptable way to approach matters, I think I'll just keep it to myself.

 

Edit to add: I doubt it is reacting with the pyridine N. Just FYI.

Edited September 23, 2011 by hypervalent_iodine

[fireoncells]

No need to get snarky, I was simply asking why. I did actually come back here with a solution for you, but seeing as you think being rude to the only member offering an answer (to a question quite easily solved with a quick SciFinder search, really) is an acceptable way to approach matters, I think I'll just keep it to myself.

 

Edit to add: I doubt it is reacting with the pyridine N. Just FYI.

 

Why do you doubt it is reacting with the Py N ?? It is very clear that it does react. Are you an organic chemist? In CCl4 you form a ionic compound which leaves the system...simple.

[hypervalent_iodine]

I am a PhD level organic chemist. Yourself?

 

CCl₄ is a polar, aprotic solvent. The only way I can see your suggestion working is if the chlorine attacked the pyridine N to give a salt, which doesn't really make sense since the nitrogen is (as you pointed out) basic and reactive towards Lewis acids rather than Lewis bases. CCl₄ used to be the 'go-to' solvent in electrophillic halogenations of alkenes due to it being completely inert under the conditions. Given that this reaction uses similar conditions, I just can't see how this would be the case. Additionally, why would it choose to form a salt with CCl₄ and not react directly with the Br₂, which is considerably more likely to react there? Or perhaps more poignantly, why do you think the bromine is reacting at the nitrogen and not on one of the ring carbons? Even with that said, I still don't see why it would do that over reacting with the alpha position next to the ketone. Unless I am misinterpreting what you said in your OP (which is likely due to the English barrier; no offense meant), NMR indicated no bromination. So what proof do you have except that the colour of your compound looking a little off (which by the way, is proof of nothing)?

 

It is quite likely that carbon-tet isn't even dissolving your compound given how aliphatic it is; to be honest, I have no idea why you used CCl₄ at all given how impractical it is over other perfectly viable solvents like DCM or similar.

 

A search of your thiazole component, which still contains an aromatic N, in SciFinder will show you that bromination at the ketone is not only possible, but possible in high yields. Additionally I thought I should point out something you learn here in second year that you may like to refresh yourself on: if you take pyridine by itself, bromination with Br₂ in the presence of a Lewis acid gives substitution meta to the nitrogen as the major product, rather than substitution on the nitrogen.

Edited September 24, 2011 by hypervalent_iodine

[fireoncells]

I am a PhD level organic chemist. Yourself?

 

CCl₄ is a polar, aprotic solvent. The only way I can see your suggestion working is if the chlorine attacked the pyridine N to give a salt, which doesn't really make sense since the nitrogen is (as you pointed out) basic and reactive towards Lewis acids rather than Lewis bases. CCl₄ used to be the 'go-to' solvent in electrophillic halogenations of alkenes due to it being completely inert under the conditions. Given that this reaction uses similar conditions, I just can't see how this would be the case. Additionally, why would it choose to form a salt with CCl₄ and not react directly with the Br₂, which is considerably more likely to react there? Or perhaps more poignantly, why do you think the bromine is reacting at the nitrogen and not on one of the ring carbons? Even with that said, I still don't see why it would do that over reacting with the alpha position next to the ketone. Unless I am misinterpreting what you said in your OP (which is likely due to the English barrier; no offense meant), NMR indicated no bromination. So what proof do you have except that the colour of your compound looking a little off (which by the way, is proof of nothing)?

 

It is quite likely that carbon-tet isn't even dissolving your compound given how aliphatic it is; to be honest, I have no idea why you used CCl₄ at all given how impractical it is over other perfectly viable solvents like DCM or similar.

 

A search of your thiazole component, which still contains an aromatic N, in SciFinder will show you that bromination at the ketone is not only possible, but possible in high yields. Additionally I thought I should point out something you learn here in second year that you may like to refresh yourself on: if you take pyridine by itself, bromination with Br₂ in the presence of a Lewis acid gives substitution meta to the nitrogen as the major product, rather than substitution on the nitrogen.

 

You are anything but a chemist (no offense meant) as long as you state CCl4 is polar. Also, it does NOTHING to do with any reaction with CCl4. In the first step there is a little bromination which forms HBr. HBr + Py...+ Br2 ---> Br3 - +HNPy...Now the reaction stops. Any bromoketone formed is removed perhaps during purification. The Py and Th rings are strongly electron deficient so it will not react AT ALL. Reaction of Py with Br2 has very low yield as far as I know. Anyway, thank you for your oppinion

[John Cuthber]

Could you two stop the ad hom attacks please.

I rather suspect that what you have is a communication problem.

 

While CCl4 is not polar overall, it has a lot of very polar bonds so it will dissolve polar things quite well.

 

My best guess is that when you say "In CCl4 you form a ionic compound which leaves the system...simple. " you mean that the reaction of the brominating agent and /or the by product (HBr) with the pyridine gives a pyridinium salt which is insoluble.

 

I don't think there's any suggestion of a reaction with CCl4 so this bit " The only way I can see your suggestion working is if the chlorine attacked the pyridine N to give a salt, which doesn't really make sense since the nitrogen is (as you pointed out) basic and reactive towards Lewis acids rather than Lewis bases."

is, as far as I can tell, a misunderstanding.

[fireoncells]

Could you two stop the ad hom attacks please.

I rather suspect that what you have is a communication problem.

 

While CCl4 is not polar overall, it has a lot of very polar bonds so it will dissolve polar things quite well.

 

My best guess is that when you say "In CCl4 you form a ionic compound which leaves the system...simple. " you mean that the reaction of the brominating agent and /or the by product (HBr) with the pyridine gives a pyridinium salt which is insoluble.

 

I don't think there's any suggestion of a reaction with CCl4 so this bit " The only way I can see your suggestion working is if the chlorine attacked the pyridine N to give a salt, which doesn't really make sense since the nitrogen is (as you pointed out) basic and reactive towards Lewis acids rather than Lewis bases."

is, as far as I can tell, a misunderstanding.

 

Sorry.. I didn't attack anyone. The only thing I want is a professional answer to my question. My question is stated very clearly. It also very clear what the product is

so we shouldn't argue about that. How can I brominate and isolate using NBS ? I am new in this field so please help me. I didn't want to be mean but come on !

I am becoming frustrated not because I dont get any help, but because I receive some stupid answers from somebody who clearly doesn't know basic chemistry. And

(s)he also states is a PhD organic chemist. COME ON !

[Cap'n Refsmmat]

Cut it out, please. If you would work with the people who try to help you, rather than insulting them, you might get somewhere. If there's a problem with their explanation, you could ask for clarification, instead of attacking their intelligence.

[hypervalent_iodine]

1316874906[/url]' post='628130']

You are anything but a chemist (no offense meant) as long as you state CCl4 is polar. Also, it does NOTHING to do with any reaction with CCl4. In the first step there is a little bromination which forms HBr. HBr + Py...+ Br2 ---> Br3 - +HNPy...Now the reaction stops. Any bromoketone formed is removed perhaps during purification. The Py and Th rings are strongly electron deficient so it will not react AT ALL. Reaction of Py with Br2 has very low yield as far as I know. Anyway, thank you for your oppinion

 

 

Attacking me is not going to get you an answer. Your post lead me to believe that you thought the CCl₄ was reacting with the pyridine, so that's where my response came in to it. Additionally, nowhere did I say CCl₄ was polar. In fact, I do believe I said the opposite.

 

 

The above sequence of events you've drawn - I take it that's with the NBS/carbon-tet/HCl system? It would make sense to me that if this system was forming the tribromide salt (which I am still not convinced about) you mentioned that it would act as a source of Br₃^-, which should be able to react with another molecule of your ketone to give you product (depending on reaction rates I suppose). What makes you so sure that reaction didn't give you product? Did you try purify and isolate it at all?

 

 

Believe me about doing my PhD, don't believe me; it doesn't really bother me. As you are new to the field, let me give you some advice: being rude to people who try to help you will not make your career, whatever that may be, a smooth one and nor will it make it an easy one. There was a misunderstanding on my part in my initial response, likely due to what I assume is an English barrier, which could have been quite easily remedied with a simple clarification rather than questioning my credentials (which I can promise you are real).

 

 

I have one final question for you, which I can assure you will be my last since you don't seem to want my help; why have you still not gone and looked up SciFinder, as I suggested in my first post? You would have answered your own question before you even got to typing your second reply to this thread. As another piece of friendly advice, usually SciFinder is the first port of call when you're looking up protocol for reactions (which makes me want to question why you didn't go there in the first place).

 

Edit: I just re-read my post and saw the bit where I said CCl₄ was polar. I would just like to clarify that this was a typo and I had meant to say non-polar.

 

 

1316879874[/url]' post='628136']

Sorry.. I didn't attack anyone. The only thing I want is a professional answer to my question. My question is stated very clearly. It also very clear what the product is

so we shouldn't argue about that. How can I brominate and isolate using NBS ? I am new in this field so please help me. I didn't want to be mean but come on !

I am becoming frustrated not because I dont get any help, but because I receive some stupid answers from somebody who clearly doesn't know basic chemistry. And

(s)he also states is a PhD organic chemist. COME ON !

 

 

While you stated your question clearly, your post was a little convoluted. You'll also find that I did point you in the direction of an answer in my first post, which you are clearly yet to consult.

Edited July 5, 2012 by hypervalent_iodine

[fireoncells]

Periodinane, you really have to understand that I try to work scientifically because I am not a technician okay? I have access to sciencedirect and I do consult a lot of articles. I don't know how to use your SciFinder. I am sure that it doesn't tell me how to brominate my specific ketone. This is a science forum where I ask for opinions not for links. Sorry if I was a bit rude with you...as this is an internet forum it is impossible to clarify immediately any misconceptions. However everything was very clear. I told you how the reaction proceeds with elemental bromine. Yes, I did isolate product and made lots of analysis. There is no doubt that is a pyridinium tribromide. My Q was how to brominate with NBS ! I did not asked you to tell me the reaction product with bromine. As you are just a student, please don't post here anymore. I really don't need your opinion okay? This topic is closed for you. Thank you.

 

 

 

Hello. Any organic chemist with experience in this field ? I try to figure out how to brominate my ketone with NBS. I'll go to the lab next week to research new methodology but I'll wait for comments and suggestions. Thank you all !

[hypervalent_iodine]

Periodinane, you really have to understand that I try to work scientifically because I am not a technician okay? I have access to sciencedirect and I do consult a lot of articles. I don't know how to use your SciFinder. I am sure that it doesn't tell me how to brominate my specific ketone. This is a science forum where I ask for opinions not for links. Sorry if I was a bit rude with you...as this is an internet forum it is impossible to clarify immediately any misconceptions. However everything was very clear. I told you how the reaction proceeds with elemental bromine. Yes, I did isolate product and made lots of analysis. There is no doubt that is a pyridinium tribromide. My Q was how to brominate with NBS ! I did not asked you to tell me the reaction product with bromine. As you are just a student, please don't post here anymore. I really don't need your opinion okay? This topic is closed for you. Thank you.

 

 

 

I gave you the SciFinder suggestion because it is the easiest way to get more specific information on brominating similar compounds to yours. It would be advisable for you to learn how to use it as it is a very useful tool for chemists. Most universities and institutions will have a license to it, all you have to do is register an account.

 

I have no idea what level you are, so it is perfectly reasonable that I ask for further clarification on points I am unsure of in your post so that I may better help you. If you didn't want someone to comment on it, then why did you bother writing it?

 

Calling my expertise into question (again) does nothing to get you an answer, as I have already stated. You also have no authority to tell me where I can and cannot post. FYI, just after my first post I went and consulted a colleague with a great deal of experience in NBS bromination reactions in substrates somewhat similar to yours. Unfortunately for you, I don't feel obliged to share the information. He's just a PhD student after all, so what could he possibly know?!

[macarena]

Hi there ! Try to brominate using DMF as a solvent and TsOH as a catalyst (Lewis acids such as anhydrous ZnCl2 might also work). Succinimide is easily soluble in cold water so you should be able to separate it from your haloketone. There might also be an option to block the Py nitrogen but I think that is just too complicated. Hope you got something out of it.

Edited September 26, 2011 by macarena

[Cap'n Refsmmat]

Give me a break. Registering multiple accounts to (a) answer your own questions, presumably in hopes of making hypervalent_iodine look bad, and (b) give yourself some reputation points is quite clearly against the rules. Don't try to make up for your rudeness with trickery. We're not that stupid.

 

Also, if you're going to pretend to be someone else, try changing your punctuation habits; the extra space before your exclamation marks is a bit distinctive.