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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: xshadow on March 13, 2021, 12:52:00 PM

Title: Knoevenagel mechanism doubt
Post by: xshadow on March 13, 2021, 12:52:00 PM
Hi

I've a doubt about the Knoevenagel mechanism, in the Verley Doebner variation

Mechanism:  ( the one at page 8 of the file)
https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.tandfonline.com%2Fdoi%2Fpdf%2F10.1080%2F17518253.2020.1851398&psig=AOvVaw3rl58-58X9yq58v1tpSPsG&ust=1615743994318000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCNCOtMzpre8CFQAAAAAdAAAAABAD

(http://data:image/png;base64,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)

Don't understand why the enolate attack the imine and not for example the C=O of the carboxilic group...
Is the imine more electrophilic??

thanks
Title: Re: Knoevenagel mechanism doubt
Post by: rolnor on March 13, 2021, 03:38:25 PM
The imine is protonated so its very reactive, a carboxylic acid is less reactive.
Title: Re: Knoevenagel mechanism doubt
Post by: xshadow on March 14, 2021, 08:21:00 AM
The imine is protonated so its very reactive, a carboxylic acid is less reactive.

Ok thanks!!

One last thing:

usually I know that aldehydes are more reactive than ketones that are more reactive than ester that are more reactive than amides

Now where imines are located ?
Are imines more reactive than ketone towards reaction with nucleophile (for example LiAlH4 or NaBH4)??
THANKS
Title: Re: Knoevenagel mechanism doubt
Post by: rolnor on March 14, 2021, 01:31:50 PM
No, non-protonated imines are less reactive.  The negative charge after addition will be on the nitrogenatom and that is not ideal I think. I am not sure if you can reduce ketones selective when an imine is in the molecule but I think so. If you have an protonated imine this will be more easily reduced by NaBH3CN than a aldehyde, thats why you can do reductive amination with this reagent. It has been debated if reductive amination can be proceed via the hemiaminal and not the imine so, I am not 100% sure about this either.
https://en.wikipedia.org/wiki/Reductive_amination