goldberg
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Conditions for reductive amination
I'm trying to understand actual conditions for reductive amination.
Solomons' textbook for organic chemistry gives 7-step mechanism for imine formation
that is clear for me. I understand why pH between 5 and 4 is needed.
From this i conclude that this reaction takes place in aqueous medium like water solution of some buffer. Imine is formed and then we can reduce it to
amine.
I'm confused because i found procedures for reductive amination that uses water-free medium like ammonia saturated methanol.
Vogel in preparation of pentylamine tells to use ammonia saturated alcohol and apropiate aldehyde, then add Raney nickel and hydrogen at pressure.
Other preparation that i found tells to also use methanolic solution of amine and aldehyde/ketone and then reduce it with NaBH4.
So if there is non-aqueous medium how carbonyl compund can be protonated and form imine? This is what confuse me.
Is it issue with solubility? I can imagine carbonyl compound that is not soluble in water or aqueous buffers. But then how it can react with amine to
form shiff base?
More over how about equilibrum between shiff base and mixture of amine and carbonyl compound in non aqueous medium?
I'm not planning to use this reaction for synthesising particular compound but i would like to understand how and why it is done in practice.
Also how imine formation looks like? Are there any easily observable changes like separation of new liquid phase, change in colour or heating of
reaction mixture?
And how fast this reaction is?
For preparation of amine in aqueous phase should i first mix amine and aldehyde/ketone and then add acid (which one? hydrochloric? phosphoric? or
buffer?)
to this mixture? or should i make buffer from my amine and some acid and then add carbonyl compound?
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monolithic
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http://chemistry2.csudh.edu/rpendarvis/imineform.html
http://chemistry2.csudh.edu/rpendarvis/iminemech.GIF
In practice an acid isn't always used to speed up the reaction. Notice how water is formed. Many procedures employ a non-aqueous environment, and
other implements like a Dean Stark apparatus or sieves to continuously remove water (Le-Chatelier's principle.) I don't think I've ever performed an
amination reaction but my guess is that you would monitor it with TLC like any other reaction, to determine if the imine has been fully formed. And
I'm guessing if you wanted to use an acid to speed it up, you should use a strong acid that is largely free of water i.e. not HCl. But I could be
completely wrong.
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Sigmatropic
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I've done a couple by liberating an ammonium salt in situ with sodium acetate, or buffered with acetate if you will. Then add ketone followed by the
reducing agent.
There are preps where the imine is formed first and then reduced but the power of reductive amination is that you don't need to do that. You can do
imine formation in situ if your reducing agent is selective for imines/iminium ions. Sodium cyanoborohydride and triacetoxyborohydride are used for
this. Note that reductive aminations can also be done with Borohydride but reduction of the ketone competes with imine reduction. Doesn't have to be
completely selective, imines/iminium ions are reduced faster and in this way you get kinetic selectivity.
I think what you are confused about is that there is also a pH in organic solutions. It's just the concentration of protons. Buffering is also
possible in organic solutions.
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goldberg
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Thanks for explaination i get clearer picture. Should i wait between adding ketone/aldehyde to amine and starting reduction or i can
just mix them and immediately add reducing agent?
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Sigmatropic
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How I was doing it, no, I just mixed amine and ketone then added reducing agent and started heating.
Reductive amination in that way works, I believe, by removing the imine/iminium from the equilibrium and slowly driving it forward by le Chatelier's
principle until amine or ketone is consumed.
What I mean to say is that reductive amination under these conditions is reversible until reduction occurs. And this equilibrium (mildly acidic
THF-water) is probably heavily leaning towards the amine side. So there shouldn't be a need to incubate amine and ketone in order to reach the
equilibrium state, that'll happen during the reaction anyway.
If anyone has different thoughts/experiences, I'd love to hear them!
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deep_dreamer
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It all depends on your substrate, reducing agent and all the other parameters!
Best is to just search the literature for close examples of the aminations you want to do.
A small example:
If you reduce with NaBH4, you will have to wait for the complete imine formation (before adding the NaBH4) because the hydride is reactive enough to
reduce the starting ketone/aldehyde to the alcohol.
You wouldn't need to do this NaBH3CN.
"Reductive Amination" is a very large field and there are a lot of quite different methods...
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