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Topic: Conjugating carboxyl and pyridine groups  (Read 2352 times)

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Offline Sabu

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Conjugating carboxyl and pyridine groups
« on: September 11, 2014, 03:51:34 AM »
It’s been a long time since I have done any organic chemistry, so I apologise in advance if I have said anything crazy…

I just need to know whether there is a simple way to conjugate one of the pyridine groups from the TPEN molecule (a metal chelator; see below), to a terminal carboxyl group of another compound, either directly or through a linker molecule. I also need the TPEN to remain functional as a weak Ca2+ or Mg2+ chelator once conjugated.
c1ccc(nc1)CN(CCN(Cc1ccccn1)Cc1ccccn1)Cc1ccccn1
TPEN

I do quite a bit of copper catalysed “click chemistry” between azide/alkyne terminated compounds. So it would be awesome if it were possible to add either of those groups to the pyridine/carboxyl groups. My only worry with this would be if the TPEN permanently chelated the copper catalyst and was no longer sensitive to Ca2+/Mg2+….

In short I'm trying to achieve something like this:
c1ccc(nc1)CN(CCN(Cc1ccccn1)Cc1ccccn1)Cc1ccccn1 + [*:0]C(=O)O = c1ccc(nc1)CN(CCN(Cc1ccccn1)Cc1ccccn1)Cc1cc([*:0])ccn1
 

TPEN + "R" linked carboxyl = Linked TPEN-"R" composite

It doesn't matter where or how the secondary molecule "R" binds as long as TPEN is still functional.

I would be very grateful if anyone could help me out with this, I’ve been stuck for a while.
All suggestions welcome!
Thanks in advance.  ;D

Offline gritch

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Re: Conjugating carboxyl and pyridine groups
« Reply #1 on: October 11, 2014, 01:26:17 AM »
The lab I'm working in does a lot of pyridine chemistry. Most of this is off the top of my head ideas. I don't have the resources at this moment to search the literature but hopefully this will give you a starting point. Make sure to do a throughout literature search before proceeding.

I would recommend aiming for a halogenated TPEN that can be functionalized in multiple different ways. Once a halogen is in place you can experiment with various coupling reactions and/or nucelophilic substitutions. If you don't care about the position or amount of halogenation you could probably try to halogenate TPEN directly but you'll probably get a hellish mixture of various halogenated compounds. You could then add an alkyne to the halogenated pyridine via a simple nucleophilic substitution reaction.

I would not recommend trying to lithiate the halopyridine as if report however. As tempting as it is, a strong base introduced to the TPEN will run into complications with the rather acidic methylene linkers (a lesson I had to learn the hard way).

If you're looking for a more controlled functionalization you could place your desired functional group on a simpler synthetic fragment. TPEN can likely be synthesized by a condensation as shown below:
2BrC1=NC(CNCC2=NC=CC=C2)=CC=C1+BrCCBr[K+].[O-]C([O-])=O :rarrow:BrC3=CC=CC(CN(CC4=CC=CC=N4)CCN(CC5=NC=CC=C5)CC6=CC=CC(Br)=N6)=N3

The monobromo starting material it should be possible to synthesize again with reductive amination as such:
[Na+].[BH3-]C#N+NCC1=CC=CC=N1.O=CC2=CC=CC(Br)=N2:rarrow:BrC3=NC(CNCC4=NC=CC=C4)=CC=C3

All of those starting materials I believe are commercially available.

I stumbled upon a nice website summarizing various pyridine chemistry while I was looking up some of this stuff. Hope it helps (I learned about a few more nifty reactions while I was at it too).
http://www.uio.no/studier/emner/matnat/kjemi/KJM5220/h07/undervisningsmateriale/Kap4-5.pdf

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