Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: Jfalken on May 16, 2019, 10:13:06 AM
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So I am doing this solvent free reaction, or trying to at least, but due to the shape of the round bottom flask not everything reacts with the reagent, which is added dropwise.
One solution would simply be to find a proper solvent for the reaction to take place in but if anyone has any idea or tips on how to make sure that all of the SM reacts with the reagent, and not only the part directly under the funnel, I would really appricate it as a solvent could hold back the yield and will just add additional costs.
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Can you give some details about your chemistry?
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Can you give some details about your chemistry?
What do you wish to know?
It's an amine (the solid SM) that reacts with an acyl chloride (the liquid reagent).
The problem is not that it does not react, it does react very violently with the material that it comes in contact with.
The problem is that it does not seem to come in contact with all of the SM since the funnel is placed directly above it.
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Why dont you want to use a solvent? Do you have any base present to pick up the liberated HCl?
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Just dissolve the amine in DCM or ether or dioxane or THF whatever, add base such as triethylamine and add solution of chloride to the other solution dropwise, cool if needed and dont forget stirring.
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You need a proton trap like triethylamine to get it to full conversion. All the amine will be protonated by evolved HCl at some point, and won't be reactive with acyl chloride.
This can be overcome like in nylon synthesis but some more complicated setups are required.
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Pyridine is better then triethylamine in my book.
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Pyridine is better then triethylamine in my book.
This is my experience as well. My understanding is that TEA can participate in side reactions through deprotonation of α protons and suppress product yield, whereas pyridine is too weak.
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Ok, ya guys got me, but the essential point of needing a base to fully convert the amination reaction stands.
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Ok, ya guys got me, but the essential point of needing a base to fully convert the amination reaction stands.
You can sometimes get away without. I have performed these reactions neat without base in the past when doing the same reaction in solvent with base didn’t work, but it’s certainly not a universally compatible method. In general I would definitely agree, these reactions tend to go much better with than without.
OP, another thing to consider is the purity of your reagents, particularly the acid chloride. You may wish to distil it if it isn’t fresh.
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You need a proton trap like triethylamine to get it to full conversion. All the amine will be protonated by evolved HCl at some point, and won't be reactive with acyl chloride.
I should really look into this properly before heading out to the lab, I just thought that by adding it dropwise I'd get away from. At least to some extent.
Why dont you want to use a solvent? Do you have any base present to pick up the liberated HCl?
I'm slowly coming to the realization that I need to use a solvent even though the reaction itself can take place at STP without a solvent. Green chemistry looks nice in papers, but in the lab, the solvent def. fulfil a purpose here.
I'll be monitoring the reaction with TLC and then, after completion, use a proper base before adding water.
Just dissolve the amine in DCM or ether or dioxane or THF whatever, add base such as triethylamine and add solution of chloride to the other solution dropwise, cool if needed and dont forget stirring.
Yeah, that's what I am left with here I suppose..
Guessing I'll just have a go with a few diffrent solvents and see how it affects the yield.
OP, another thing to consider is the purity of your reagents, particularly the acid chloride. You may wish to distil it if it isn’t fresh.
It should be fine, we just got it from our supplier last week. But I appreicate the tip!
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I suggest you use dichloromethane as solvent, THF can react with acid chlorides.
You need to have the base present as the reaction take place in most cases as described.
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Dont worry, I learned about the difference in reactions with TEA vs Py in 2nd year graduate study just by accident when prof. mentioned it during lecture on something totally different. Anyway, to sum it up for you: triethylamine is stronger base therefore it can deprotonate the α-proton of the acyl chloride which forms ketene during the reaction. The ketene can react witht he amine to form amide easily but it can also do other kinds of side reactions. That is especially problem when you are using α-chiral acid chloride (like mandelic acid chloride).
If you worry about green chem, you might want to try adding the solid amine in small chunks into the liquid acid chloride and see whats going on (It might not work well but might be worth trying). Also, using pyridine as a base and a solvent seems like a green option as well.
I'm slowly coming to the realization that I need to use a solvent even though the reaction itself can take place at STP without a solvent. Green chemistry looks nice in papers, but in the lab, the solvent def. fulfil a purpose here.
I'll be monitoring the reaction with TLC and then, after completion, use a proper base before adding water.
No, you need the base during the reaction. The reaction liberates HCl and you need to trap it because otherwise it will protonate your amine which wont react most of the time
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I suggest you use dichloromethane as solvent, THF can react with acid chlorides.
You need to have the base present as the reaction take place in most cases as described.
Cheers, I'll be giving DCM a try then with pyridine as the base of choice.
See how it goes.
No, you need the base during the reaction. The reaction liberates HCl and you need to trap it because otherwise it will protonate your amine which wont react most of the time
Alright thanks, we only had dimethylaminopyridine in stock but I'm getting some pyridine tomorrow.
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DMAP is actually a terrific base for aminations, but probably not necessary here.
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DMAP is actually a terrific base for aminations, but probably not necessary here.
its not just abase but an activator as it's nucleophillic
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DMAP is actually a terrific base for aminations***, but probably not necessary here.
its not just abase but an activator as it's nucleophillic
Completely true, it creates a transient activated ester, as in DCC/DMAP amidation.
**this should say amidation, not amination.
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You get a acylpyridinium ion, pyridine is similar as DMAP.
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DMAP is a better nucleophile than plain pyridine. Also it doesn't stink as bad and is often used in subequimolar amounts. .
Quick tip for anyone trying to remove pyridine or other pyridine like molecules from a reaction that is acid sensitive: copper sulfate extraction.
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DMAP is a better nucleophile than plain pyridine. Also it doesn't stink as bad and is often used in subequimolar amounts. .
Quick tip for anyone trying to remove pyridine or other pyridine like molecules from a reaction that is acid sensitive: copper sulfate extraction.
Could not recommend this enough. Some of my more difficult amidations using pyridine went from ~40% to ~85% yield just by changing the work up to 1M CuSO4.