Some practical questions about Grignard reactions

Quote: Originally posted by SplendidAcylation

1) How long does the Grignard reagent need to be refluxed with the nitrile? Both of these seem to use rather a long period of reflux (6 hours, and 3 days(!) respectively), is that really necessary? [\rquote] Yes. Grignard with nitriles can take days. Nitrile group is less reactive than carbonyl to Grignard reagents. [rquote] 2) Is it OK to pour the reagents down the condenser? [\rquote] I don't know if it is bad practice, but I do it all the time, but only for solvents. But for this reaction you should have a moisture trap at the end of the condenser. If you want to briefly remove it, I suppose you can. But everything, including the condenser, needs to be dry of course.

@tsjerk

Thanks! That's interesting indeed, I suppose if it works for an unreactive halide like chlorobenzene then it should work with anything (I hope!).

I decided to do it the simpler way and use the 250mL RBF and pour the reagents down the condenser, it seems to have worked so far

@wxyz

Oops! So the reaction can take a long time... Let's hope I haven't messed up too badly, then.



I tried the reaction yesterday, I'll probably do a write-up on the topic later, but here's a summary:

The 250mL RBF, 3 pipettes (one for the solution of benzonitrile, one for the ether itself, and one for the solution of halide), the Liebig condenser, stir bar, and a rubber bung with a tube through it, were dried in the oven at 140c for 45 mins.

The magnesium was also dried in the oven, after having been sanded to remove oxide and cleaned with isopropanol.

Once removed from the oven, the magnesium, along with a tiny crystal of iodine, was placed in the flask alongside the stir bar, the condenser was then attached, and a drying tube containing CaCl2 was attached to the top via the rubber bung (I don't have a QuickFit drying tube).

The flask was then heated with a heat-gun to vapourize the iodine, forming purple vapour in the flask and coating the magnesium.

Without any coolant in the condenser, a small quantity of the ethyl bromide solution was poured down the condenser, and the bung was replaced.

Within seconds, bubbling was observed, evidently the Grignard reagent was forming!

Unfortunately I took a little too long to fill the condenser with cold water, and I think most of the ether escaped.

Once the condenser was connected to a pump recirculating ice water, the bromide solution was added ~1mL at a time, the flask had to be cooled in an ice-bath for the first few additions, but as the solution became more dilute, this was not necessary, and external heat actually had to be applied at one point to speed up the reaction.

After all of the bromide was added (~30 mins), most of the Mg had dissolved, and a brown solution had formed.

This was left to stir and reflux for 30 mins or so, whereupon I began adding the benzonitrile solution.

(In each case, dry ether was used to rinse out the bottle)

The addition of the nitrile was surprisingly uneventful, it caused the solution to boil, but no change in appearance was observed.

After all of the nitrile had been added (again, ~30 mins), the solution looked just the same, brown and clear, so I began to heat the flask with warm water; Quite quickly, a precipitate formed.

The precipitate seems to be white, but there also seems to be an orange oily substance (maybe).

The mixture was allowed to reflux for ~1 hour, but no longer, as unfortunately I was running out of ice to cool the condenser water, and water straight from the tap is much too warm to condense the ether effectively using a Liebig condenser.

Because of this faux pas, the reaction was suspended, the flask was disconnected from the condenser and stoppered with a rubber bung.

Before I stoppered it, I quickly removed a small quantity of the white precipitate; Once the ether evaporated, it seemed to be odourless, I then added it to water, and a peculiar smelling compound was formed at once (the solution was cloudy).

I'm not sure if this is what propiophenone should smell like, it's quite unpleasant, kind of acrid...

Now I have a bit of a problem it seems, as I had initially assumed that what looks like a fairly large quantity of precipitate (which I assumed to be the =NMgBr imine salt) was an indicator that the Grignard addition was complete, but as wxyz says, these reactions can take a long time.

Without a truck-load of ice, I'm going to struggle with keeping the condenser cool for more than a few hours, so my best option at this stage is to use a different type of condenser.

Unfortunately, the only other condenser I have is a Graham condenser (the kind where the condensate goes through the coil), and these are not advisable for use in reflux, as the condensate can form a droplet which gets pushed up through the coil.

Still, I have used it before for refluxing chloroform with no problem whatsoever, so it's maybe worth a try.


Thanks for your help everyone, I'll let you know how it goes!

P.S. Does anyone have any ideas what the precipitate might be if it isn't the imine salt?


Edit:

I have swapped the Liebig condenser for my Graham condenser, and the solution is refluxing as we speak.

If the reflux rate gets too vigorous, a column of ether gets pushed up the coils, which is why Graham condensers aren't ideal for refluxing, however, at a lower reflux rate (2 or 3 drops per second), this problem doesn't seem to arise.

The good news is that even fridge-cooled water is sufficient to condense the ether in just the first two or three coils!



[Edited on 6-5-2022 by SplendidAcylation]

Quote: Originally posted by zed

To my recollection, this type synthesis calls for an addition of the Grignard Reagent to the Nitrile. If you add the Nitrile to the Grignard Reagent, it is possible that 2 moles of Grignard Reagent will react with each mole of Nitrile, producing the wrong product.