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Author Topic: Grignard initiation with TBDMS group present  (Read 7570 times)

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voidSetup

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Re: Grignard initiation with TBDMS group present
« Reply #15 on: March 15, 2011, 03:41:44 PM »

Hm I'm still having trouble with this.  I did a test run yesterday using 1-bromobutane just to try and get the Grignard to form.  I scraped the Mg down really well with a razor blade and broke it into small pieces, then tossed it into a 10x100 test tube with some THF.  It wouldn't really start at first, but eventually I took the septum off of it and crushed it up with a spatula a little bit.  Then it started to bubble and exotherm, so I slowly added some alkyl halide.  The reaction kept on slowing down though and wouldn't start up again until I took the septum off and crushed it up some more.  Eventually it kind of sped up and all of the Mg was consumed, so I syringed it out and reacted it with some cyclohexanone.  When I syringed it out some white precipitate was left behind (maybe the Grignard reagent as a result of the solvent boiling off?).  So I'm pretty sure the reaction worked.

Anyway today I tried the reaction again with my TBDMS protected 9-bromononanol, and could not get it to initiate.  At one point since it wouldn't start I took the round-bottom off of the condenser for a brief minute to crush up the Mg with a spatula.  A couple of bubbles popped up so I thought it might start and put it back on with the stir bar.  It still wouldn't start after like 30 mins so I took it off again to crush the Mg up some more.  A couple more bubbles but it wouldn't get started.  The third time taking it out to crush it up, I took it out of the hood for a second and some white precipitates formed (MgOHBr I think) which means some air/water got in. So no success today.  I'm going to order some new Mg tomorrow and ethyl iodide as an activator.

Is there anything with Grignards being harder to initiate if the alkyl chain is longer?
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orgopete

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Re: Grignard initiation with TBDMS group present
« Reply #16 on: March 16, 2011, 05:18:58 AM »

I agree with OC Pro that Grignards are tolerant of conditions. I remember making phenyl Grignard in college on open bench tops.

On the practical aspect of making Grignard reagent though, we had a lot of trouble with student preps on a micro scale. I eventually bought commercial phenyl magnesium bromide. I did find that changing to a fresh bottle of magnesium worked. Although I haven't do this, reading Reike's activated magnesium, you can make a Grignard at -78°C. All of this points to the ability of the magnesium to donate electrons. If a freshly reduced magnesium will start at -78°C and a commercial sample of magnesium may need scraping or activation with a more reactive reagent, this all suggests the quality of the magnesium plays a role. I am presuming it will oxidize and reduce the surface activity.

On reactivity, I assume the magnesium is donating electrons to the halogen. Therefore reactivity falls I>Br>>Cl. I should also assume that a tertiary halide should be less reactive than a primary halide or a phenyl halide. Although I don't see why you shouldn't be able to make a Grignard from your bromide, you could convert your bromide (or chloride) to an iodide.
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voidSetup

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Re: Grignard initiation with TBDMS group present
« Reply #17 on: March 16, 2011, 06:36:24 AM »

Ya from what I understand the ether's vapors are supposed to block atmospheric moisture from getting in but it's definitely more of a problem on the microscale. Hopefully the fresh Mg will give me better results.
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OC pro

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Re: Grignard initiation with TBDMS group present
« Reply #18 on: March 16, 2011, 06:53:08 AM »

@voidSetup: I don´t see any probs with your starting material. Should work as usual. Even on "microscale". I once did a Grignard on 250mg scale and it was just fine. I see more of a handling / experience issue. It can be tricky to get a Grignard started and it needs some hands-on-experience. So far, I have performed ~1500 reactions including isolation. Therefore, I get my Grignard´s started everytime even with a 10-year old bottle of Mg...

I do favor orgopete´s idea. Rieke Mg is way more reactive and the "weapon-of-choice" for less reactive alkyl halides (normally chlorides). Stock solutions in THF are availabe from Aldrich. Clean Mg-halogen exchange at -78°C.
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voidSetup

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Re: Grignard initiation with TBDMS group present
« Reply #19 on: March 16, 2011, 07:05:26 AM »

Yea, I appreciate the tips from everyone.  I'm going to try another test run just trying to get 1-bromoundecane initiated.  I've been very careful though about keeping water out of the system. I had my sample on the vacuum pump for like 3 hours before getting started.
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stewie griffin

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Re: Grignard initiation with TBDMS group present
« Reply #20 on: March 16, 2011, 12:59:54 PM »

I agree with OC pro about the experience aspect. I don't have any problems getting grignards to initiate anymore, but I remember being embarassed/frustrated as an undergrad when I wasn't able to get an aryl bromide to form a grignard... I ended up heating the solution of bromide and Mg to reflux in THF though until most of the Mg was gone and then used as it was. It ended up working.
So I guess since your starting material isn't that previous/complicated, it wouldn't hurt to just try the old "heat and beat" method.
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voidSetup

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Re: Grignard initiation with TBDMS group present
« Reply #21 on: April 10, 2011, 01:20:43 PM »

I'm still having a little bit of issues with this.  So last week I did a test run to try and get the Grignard initiated.  I used some 1-bromoundecane that was sitting around in the lab, and I dried it on molecular sieves for a day or two just to see if it might help.  I also have some new Mg turnings that are very shiny so they look good.  I added a drop of the 1-bromoundecane and 50uL of ethyl iodide.  I heated the solution up to reflux, it got cloudy and the Mg turned black.  I added another drop of the alkyl halide and let it reflux for a little bit.  After a few minutes the Mg very quickly turned shiny again, so I figured the reaction had started.  I took the solution off of the heat, and with every drop of the alkyl halide the bubbles would come off of the Mg.  After all the alkyl halide was added i refluxed for another 15 minutes or so and all of the Mg was consumed.  So this one worked very well, I reacted it with cyclohexanone and the IR looked good.

A couple of days later I decided to try it again with my TBDMS-protected 9-bromononanol.  I let the sample sit on the vacuum pump (I think its pulling about 1mmHg vacuum) for about 3 hours or so to try and eliminate any residual moisture.  I went to do the Grignard and the Mg turned black again when I got it to reflux. I let it reflux for like 30 minutes and the Mg did not turn shiny again. I would add another drop here and there but it still wouldn't go. Eventually after all of the alkyl halide was added the Mg was still black and some white precipitates had formed in the solution.  I let it reflux for like an hour and nothing, so I just gave that attempt up at that point.

Is it possible there is still some water in my sample that is preventing it from initiating?  Is the blackness on the magnesium a MgO coating?  Also is it reasonable to dry my sample on molecular sieves or CaCl2, or is the vacuum pump the best way to go when your sample is from a previous step and not something that was bought commercially?
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dunno260

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Re: Grignard initiation with TBDMS group present
« Reply #22 on: April 12, 2011, 07:32:20 PM »

Is there any reason you can't do a lithium/halogen exchange with sBuLi or tBuLi?  If you want to transmetalate to magnesium for whatever reason you can do this by incorporating magnesium bromide diethyl etherate into the reaction. 
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voidSetup

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Re: Grignard initiation with TBDMS group present
« Reply #23 on: April 13, 2011, 08:19:43 AM »

I'm pretty sure tBuLi is pyrophoric, I don't think my advisor would want me working with that.
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Arctic-Nation

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Re: Grignard initiation with TBDMS group present
« Reply #24 on: April 13, 2011, 09:56:07 PM »

Is there any reason you can't do a lithium/halogen exchange with sBuLi or tBuLi?  If you want to transmetalate to magnesium for whatever reason you can do this by incorporating magnesium bromide diethyl etherate into the reaction. 
I've used this method (with n-BuLi) to reasonable success when making a Grignard out of 3-bromothiophene. While it'll work with aryl halides, I'm not sure alkyl halides will behave.

On the other hand, I do remember a labmate of mine having to try two dozen times before her Grignard would work. Poor girl. :-X
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voidSetup

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Re: Grignard initiation with TBDMS group present
« Reply #25 on: April 14, 2011, 10:13:31 AM »

Ya i've attempted it with my actual sample like 6 times, and I had a successful attempt using 1-bromoundecane.  My last attempt resulted in a lot of white salts in the solution which made me think there was either water or homocoupling occuring.
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voidSetup

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Re: Grignard initiation with TBDMS group present
« Reply #26 on: April 20, 2011, 07:59:58 AM »

I think I actually got this to work last night!  I'm pretty sure the Grignard was prepared well, and I added it to a mixture of the other alkyl halide and CuBr in THF.  The solution turned black, I let it stir for a while.  After workup I have a yellow oil with these couple of white little balls in it, which I believe is my product because the molecular weight is about 500.  Thanks for the help everyone!
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CathyCao

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Re: Grignard initiation with TBDMS group present
« Reply #27 on: June 22, 2011, 12:01:10 AM »

Hi. I am also struggling doing the coupling reaction of grignard reagent and halide/tosylates. Did the method in synlett 2010 worked well for you? Have you published the result? As I am looking for some detailed reaction procedure to direct my reaction. Thanks!
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voidSetup

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Re: Grignard initiation with TBDMS group present
« Reply #28 on: June 22, 2011, 04:40:30 PM »

I based my procedure off of the one in that Tetrahedron article, they got 80% yield on it.  I think I got mine to work but the school year ended and I didn't really get a chance to do any analysis on the product.  My professors thought the molecular weight of my desired product was too high for the column we had on our GC/MS and would just clog it up.
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