[Reddart]

Does anyone have any reviews or other references to quaternary ammonium synthesis and counterion exchange. This is a new area for me, and I am making quats attached to (mostly) hydrophobic molecules.

Amines, a good nucleophile...halides are good leaving groups...solubility???...goopy products....emulsions....ahhhhhhhh!

[TheUnassuming]

I have some experience making a small library of quat amines, though the work hasn't been published yet so I can't shoot you a ref for it.  Precipitation/crystallization/trituration and ion exchange resins were my best friend in purification of the small molecule derivatives.  If your compounds are large enough you might also look into small MW dialysis tubing to help clean it up (and the subsequent lyophilization made the compounds a wonderful fluffy powder). 

[Babcock_Hall]

I have often wondered whether or not solid phase extraction on a hydrophobic support might work for this class of compounds (we make pyridinium derivatives BTW), but I don't recall seeing any papers on this.

[zuriel]

I've made quats at a pyridine ring in some of my compounds. I'd generally just stir the compounds in DMF with an alkyl halide (such as methyl iodide) and it works quite well. I've never done extensive counter ion changes but in the past I have done a finkelstein reaction on 6-bromohexanenitrile to get 6-iodohexanenitrile and used this as my alkyl halide to get a different counter-ion. Not sure if that will be of any help but I hope it is!

[Reddart]

Thanks for the tips.

The reaction looks like its going well (benzyliodide to form the alkyl benzylammonium iodide salt).

Trying to aqueously wash with saturated NaOAc works somewhat, but emulsion makes it slow to work up and eats up a lot of yield.

I've been looking into ion exchange resins, and I think it could work well for this(exchanging an iodide for acetate).

So if I'm thinking correctly, I could take Dowex type 1 chloride resin, treat it with excess sodium acetate to replace the chloride with acetate, wash well, pack a column with this resin and run my product through as the ammonium iodide salt, and end up with the acetate product at the end.

Is that the basic procedure?

[TheUnassuming]

For ion exchange I've had better luck with first taking about 10 molar equiv worth of the activated resin (done much as you said) and stirring it in solution with your compound for an hour or two before loading the whole thing onto the resin column and running it through. 

[Babcock_Hall]

As your message implies, a typical resin is somewhat selective for chloride over acetate.  Some protocols call for conversion of the chloride form to the hydroxide form of the resin with a large excess of NaOH.  Then one adds acetic acid to make the acetate form of the resin.  I suspect that people do it this way because of the relative costs.

[clarkstill]

I don't know what sort of scale you're working on, or what your budget is, but have you tried using silver(I) salts for the counter ion exchange? It's an old trick, but the silver halide should precipitate pretty easily from solvents where your NR4+ X- stays in solution.

[wildfyr]

Ive tried that silver trick, and the conversion is excellent, but removing silver salts from the pdt, then cleaning the glassware afterwards is a nightmare. FYI ammonium hydroxide or nitric acid helps with the glass.

[Reddart]

Just an update: The resin is working well. I switched to the bromide over the iodide, and can get rid of most of the bromide via an aqueous wash in saturated NaOAc/Toluene-IPA (down to ~1%), then a few batch process ion exchange resin treatments to get it down to <200ppm Br-.

I didnt want to use silver because the final product is sensitive to trace metals/ions, and would probably be a no-go for scale-up.

Thanks for the help.