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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: AlphaScent on May 27, 2020, 10:06:37 AM

Title: Basicity of Substituted Pyridine
Post by: AlphaScent on May 27, 2020, 10:06:37 AM

Hey All,

Have a question for you.  The attached reaction shows a Mitsunobo reaction between cycohexanol and picolinic acid.

My question is do you think the pyridine moiety's nitrogen is sufficiently basic enough (or pKa conjugate acid weakly acidic enough) to be protonated when treated with HCl (pH about 2).

My thought is that I can get the material to be water soluble in order to remove the TPPO and reduced DIAD by products.  I have some literature on this where it is done with a tertiary amine product from the Mitsunobu reaction on scale.

Just wondering what you all think.  Any thoughts would be appreciated.

Hope y'all are staying safe!!

Cheers!

Title: Re: Basicity of Substituted Pyridine
Post by: AlphaScent on May 27, 2020, 10:10:49 AM

I guess I should have put more into why I think this may be an issue.

With the electron withdrawing carbonyl substituent I would think that this may reduce the ability for the material to hold onto that proton (weaker base and conjugate acid stronger). 

I honestly do not know enough about substituted pyridines.  I also realize that my lit source is not a aromatic (less basic) amine.

Just trying to invoke the idea that pyridine itself is readily washed from organic solution with aqueous HCl.

Also realized I didnt post PNG!!

Cheers!

Title: Re: Basicity of Substituted Pyridine
Post by: rolnor on May 27, 2020, 11:24:15 AM

HCl can hydrolyze the ester, I would run a silica column if the scale is not to big.

Title: Re: Basicity of Substituted Pyridine
Post by: hollytara on May 27, 2020, 11:53:32 AM

pKa of the methyl ester of the 4-carboxylic acid isomer is 3.45.  If it is the same for the 2 isomer and the cyclohexyl , then to protonate you will have to bring pH down to 2 or less. 

That can hydrolyze the ester.  I would test on a small amount to make sure and do the process quickly and at low temperature (maybe keep solutions in ice bath).  This will limit the hydrolysis.

Title: Re: Basicity of Substituted Pyridine
Post by: AlphaScent on May 27, 2020, 12:32:52 PM

I thought about acid hydrolysis and would just keep it cold as hollytara said.  I have never had too much trouble with secondary acetates hydrolyzing when I keep it cold. 

Thank you for the input.  I am trying to be able to scale up a reaction to 500 g so I am trying to not have to do any rigorous CC.  Hopefully only a plug at most.

I am doing a rxn tomorrow and will get back to you about how it goes.

Cheers!

Title: Re: Basicity of Substituted Pyridine
Post by: wildfyr on May 27, 2020, 07:45:13 PM

Can remove TPPO with the Zinc chloride ligand trick

https://pubs.acs.org/doi/10.1021/acs.joc.7b00459

What exactly are the DIAD sideproducts you're referring to?