[eb51111]

Hi,

I'm trying to make the molecule below, via esterification of 4,4'-dicarboxy-2,2'-bipyridine and hydroquinone.
I've attempted relfuxing the dicarboxylic acid in SOCl₂, however this didn't work. And because the alcohol is solid - this presents problems doing it the usual way with conc. H₂SO₄


Does anyone have any idea how I could perform this esterification?

[Babcock_Hall]

I have made amides of isonicotinic acid using active ester chemistry.  The active ester was made from isonicotinic acid, DCC, and 4-nitrophenol, probably with catalytic DMAP.  I wonder whether there is the possibility of your quinol reacting at both ends.

[wildfyr]

You have to add the diphenol slowly to get good regioselectivity.

What do you mean the thionyl chloride reflux didn't work? It's about the most bulletproof reaction I know. Could you diophenol have been wet and hydrolyzed your acid chloride?

You can probably do the direct esterification heterogeneously, it just will require some extra trickery.

*edit my suggestion of slow addition is plain wrong

[rolnor]

But if you add the hydroquinone slowly would not that give ester in both ends?
To get the wanted product you want the hydroquinone in excess, no?
I think DCC in DMF could be good.

[eb51111]

You have to add the diphenol slowly to get good regioselectivity.

What do you mean the thionyl chloride reflux didn't work? It's about the most bulletproof reaction I know. Could you diophenol have been wet and hydrolyzed your acid chloride?

You can probably do the direct esterification heterogeneously, it just will require some extra trickery.

The dicarboxy bipy didn't dissolve in the thionyl chloride (50 mg in around 10 mL SOCl₂), refluxed under Ar low flow for 7hrs. Rotavap'd the thionyl chloride left, and NMR still shows dicarboxy 2,2'-bipy.

Without SOCl2 however, what would be the best solvent (&ratio)? e.g. 50 mg dcbipy 1 mL conc. H₂SO₄ in 10 mL DCM?

[wildfyr]

You can do the chlorination in chlorobenzene, or even better in dmf. Distill off the volatiles to get pure products. You probably made the acid chloride but it hydrolyzed when you added it to wet deuterated solvent.

To do direct esteirifcwitons you need catalytic sulfuric acid, 1 mL is WAY too much. Just use an a aprotic solvent that azeotropes well with water (aka benzene). DCM boils too low, you need some heat for this.

[rolnor]

Is SOCl2 compatible with DMF? I am not sure.

[wildfyr]

Yes, in fact DMF is a catalyst for acid chlorinations. But it's quite compatible

[wildfyr]

I was thinking about this and bet your product isn't soluble in organics because it becomes the dipyridine dihydrochloride salt when SOCl2 hits it

Also you're the lab's worst enemy if you're rotovapping thionyl chloride. Give your poor seals and labmates a break and distill it in your hood.

You can't really tell the difference between a carboxylic acid and an acid chloride on nmr. I would use the reflux in thionyl chloride with a drop of DMF as a catalyst overnight, then distill it, then add the diphenol with a bunch of organic base  like triethylamone in dry MeCN.
.

[Babcock_Hall]

I wondered about the protonation of state of this compound, based on my experience with nicotinic and isonicotinic acids.  They seemed difficult to solubilize if I recall correctly.

We patterned our work using DCC after work done by Karl Folkers and collaborators:  Janecka et al., J. Med. Chem. 1994,37, 2238-2241, and other papers in this series.

[eb51111]

I was thinking about this and bet your product isn't soluble in organics because it becomes the dipyridine dihydrochloride salt when SOCl2 hits it

Also you're the lab's worst enemy if you're rotovapping thionyl chloride. Give your poor seals and labmates a break and distill it in your hood.

You can't really tell the difference between a carboxylic acid and an acid chloride on nmr. I would use the reflux in thionyl chloride with a drop of DMF as a catalyst overnight, then distill it, then add the diphenol with a bunch of organic base  like triethylamone in dry MeCN.
.

So do these amounts look right? 50 mg of the dicarboxy bipy in 10 mL SOCl₂ with drop of DMF. Remove SOCl₂, then add 45 mg diphenol, with 15 mL Et₃N/MeCN (50% v/v ET₃N)?
Rotovapping off the solvent should yield the diester... hopefully - only got 3 days to do this.

[wildfyr]

A little overboard on the triethylamine, perhaps do 4.2 equivlanets to TEA compared to dicarboxy 2,2'-bipy (1 for each acid chloride, and 1 for each protonated pyridine, and a little extra just because its typically neccessary). Youre just using it to mop up any HCl or HCl salts from the chlorination part. The main thing here is that everything you add in the second step must be bone dry or your acid chlorides will hydrolyze.

Give this a EtOAc/aqueous bicarb wash afterwards to make sure the product isnt protonated, and it should go into the organic layer.

[OrganicDan96]

should the phenol not be in large excess to stop the other -OH from reacting with the acid chloride?

[wildfyr]

That's a good piece of advice Dan. Large excess of diphenol would prevent oligomerization.

[eb51111]

And is there no alternative way of performing this reaction - without going through acid chloride form?