[Kate]

Hello.

I need an experimental procedure for the addition of a grignard reagent to a nitrile (with later acidic work-up). I've found articles that deal with this, but they're old (80's mainly) and my University doesn't have access to them.

I'd appreciate if anyone has any literature/publication that deals with this.

Does anyone know what sort of concerns should be taken in consideration when performing this reaction in a lab (edit: apart from dryness and an inert atmosphere, obviously)?

Thanks. 

[TheUnassuming]

Heres a J Med Chem paper that has the basic reaction. Link.
No real special considerations beyond those you use with any grignard so far as I've seen.


Mod edit: Copyright material removed. Dan

[Kate]

Thanks, but the yield for the reaction in method A and B was, respectively, 12% and 20%. Somehow, I don't think my teacher will be too pleased.

Is it normal, btw, to have such low yields in a grignard addition?

If anyone has other articles and such, I'd really appreciate.

[TheUnassuming]

The basic procedure is the same in all the papers I've seen so far.  An excess of grignard is added to the nitrile and refluxed in THF until nitrile is gone.  The variance in yield from one paper to another is mostly a function of the exact substrates used.
 Its also good to remember that particularly with med chem papers, the authors (myself included in this group) don't always optimize a given reaction because their priority is getting the final compound.  If it turns out to be a hit that they want to take to the next step then they worry about optimization of the route.   

[Kate]

The basic procedure is the same in all the papers I've seen so far.  An excess of grignard is added to the nitrile and refluxed in THF until nitrile is gone.  The variance in yield from one paper to another is mostly a function of the exact substrates used.

Ok. But I'm using toluene (bp of 110ºC), not THF (bp of 66ºC) and I came across this article does mention the addition without reflux, just at room temperature. So I'm uncertain if it really is necessary to provide heat in order for the reaction to occur.

Have you carried out this reaction with reflux at the lab with success?

Its also good to remember that particularly with med chem papers, the authors (myself included in this group) don't always optimize a given reaction because their priority is getting the final compound.  If it turns out to be a hit that they want to take to the next step then they worry about optimization of the route.   

Makes sense.

[TheUnassuming]

Whether heating is necessary will be determined by your exact substrate, though in toluene odds are you won't need to reflux the reaction. 
If this is a new reaction with no close analogues in the literature you always should start conservatively if the starting material is at all precious.  So for this one you would start at rt and let it go for a while, if no reaction is happening raise the temp by ~10 ºC and let it go for a while again.  Keep doing this until you see reaction taking place then hold until complete. 
If the starting material is relatively cheap then I would go ahead and start at 60 ºC and see what happens.  If you get a lot of decomp then drop the temperature down for your next test reaction, if it isn't going then raise the temp up. 

[Kate]

Ok, but to know if this specific reaction is going I'd have to use TLC, right? Or would there be some color change or bubbling going on?

[TheUnassuming]

Its a very good idea to always be running TLC's of your reactions unless you have a very good reason for not doing so.  Remember that a little color goes a long way in solution, and won't tell you much in a reaction you have never ran before.  Bubbling when not at reflux is interesting and should be accounted for in your notebook, but won't tell you much beyond that gas is being produced.

[Kate]

One final question: how do I monitor the reaction with TLC when air and moisture can destroy the grignard? Do I have to be super quick when opening up the reaction vessel? But seriously, is there any way to do it without breaking the N₂ atmosphere?

[TheUnassuming]

Yes there are a few ways to do it without compromising the reaction.
One is to increase the positive pressure of N2 on the flask, pierce the septum with a large gauge needle and insert your spotter through the needle.  The positive pressure should keep any air from coming into the flask. 
The second way is to take a small syringe and take a few uL's out and TLC that.  I tend to favor this method for most reactions because it feels more "dry" to me, though the other method works just as well. 
If you are doing a large scale roar and pour reaction, you can also just crank up the pressure and crack open the septum enough to take out an aliquot.  If its cranking out gas the amount of air to get in will be minimal and on a large scale you can usually get away with it without even a dip in the yield... I don't recommend this with new reactions because some are far too finicky for that. 

[Kate]

Many thanks.

[TheUnassuming]

Of course!
Let us know how it goes!

[Kate]

Hey.

It went ok, actually. The product was confirmed through NMR, so it's there. But I have a problem now: I got this colored oily product and I really need to make it colorless (the color supposedly doesn't come from the ketone I want), so how can I do this? Chromatography?

[TheUnassuming]

Hello again! Glad to hear it worked.  The default purification method is almost always column chromatography. 
Random question on my part, but is this for an O-chem class/lab or are you working in a lab?

[Kate]

I'm working in a lab under supervision, but I'm quite the newbie (yet ).

I tried activated carbon and didn't work. So chromatography next.