Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: voidSetup on March 01, 2011, 09:38:28 PM
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Hello,
I'm working on an undergraduate senior project right now, and am having a little trouble here. I'm trying to turn a TBDMS protected 9-bromo-1-nonanol into a Grignard reagent for use in a cross-coupling reaction, but the Grignard reagent doesn't seem to form. I ran the reaction at the end of last semester, and the Grignard solution (the alkyl-halide/Mg in THF) was a grey turbid color so I thought that it worked. I tried the coupling, did the workup, and ran GC-MS on the reaction mixture. Only two compounds were present and they were the two starting materials. This means that there were no side reactions (elimination, homocoupling..), or the desired product. The MS shows though that the 9-bromo-1-nonanol still has its halogen on there though. If the Grignard reagent formed then the halogen would have been removed on the NH4Cl workup.
I tried the reaction again today and added a small crystal of iodine to the solution this time. It instantly turned amber. I brought the solution to reflux for about an hour but all the of Mg would not be consumed. The solution turned to a more yellow color but a decent amount of Mg was still present. I tried the cross-coupling again, and worked it up. I'm going to run some analysis on it tomorrow or Thursday but I don't think the Grignard reagent formed again.
Has anyone else ever encountered trouble with this?
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What are you trying to react the Grignard with?
I don't think you can add the iodide whenever you please, you're supposed to mix it with the magnesium first to get the oxidized layer off, THEN add your alkyl halide (anyone who has done this more recently feel free to correct me).
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I'm reacting the Grignard with another primary alkyl halide, so I'm trying to do sp3-sp3 alkyl coupling. I'll try that with the iodide next week when I attempt it again. I think I may need to scrape the top layers off the Mg with a razor blade a little bit more to expose fresh Mg. When I tried it yesterday I wasn't sure if I was going to use the iodide to initiate it so just tossed it in there once the alkyl halide was already added. So I should let the Mg in THF stir for a little while with the iodide before adding the alkyl halide?
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I'm not so sure that your reaction will work that well. I was under the impression that grignards generally don't do SN2 on alkyl halides very well... if they did you would never be able to form the gringard in the first place (since it would just homocouple with any unreacted alkyl halide). I think you may have to consider adding Ni (first two ref's) and/or switching to Zn instead of Mg (last ref):
Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646-5647.
Terao, J.; Watanabe, H.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222-4223.
Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482-10483.
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I tried the Ni catalyzed cross coupling last semester but I think I ran it at too low temperature (-78C) and no product or side products were formed. I'm trying it now under Cu(I) catalysis, but it doesn't seem like the Grignard reagent is forming before I even get to the coupling part. Here's a couple references.
Cahiez, G.; Gager, O.; Buendia, J. SYNLETT 2010, 2, 0299-0303
In this paper they do primary alkyl halide coupling with Cu(I) catalysis and very slow addition of the Grignard reagent to the solution to avoid elimination/homocopuling. In 2000 these guys also published a similar paper but using NMP as a cosolvent which makes the addition rate of the Grignard reagent not important. I think elimination is more of an issue with secondary/tertiary coupling partners.
Grodner, J. Tetrahedron 2009, 65, 1648-1654
This is a pheromone synthesis paper. They do a primary alkyl halide coupling using CuBr catalyst. Its reaction 4.8 in the paper. The piece turned into the Grignard reagent has an aldehyde protected as dioxane so it's kind of similar to mine.
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Yes, let the iodide mix with the Mg first. Alternatively, you can try to crush the Mg up a little bit once it's in the solvent to expose the fresher Mg underneath.
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Ok thanks, I'll try that next time I attempt it. I'll probably let the iodide mix for a little. Might be hard to crush the Mg once it's in the solvent already because the whole setup is under nitrogen and I don't want to take any of the septums off.
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I made a lot of Grignard reagents in my undergrad research and I never had success using iodine as an activator. 1,2-Dibromoethane was always superior. Perhaps more important is the quality of your Mg. I always used Mg turnings in favor of powdered Mg, and I would submerge the turnings in a bit of THF or ether and then squash them a little with a spatula to expose some of the interior of the metal. I also had to reflux my mixture for a few hours to form the reagent (although mine was a particularly difficult system).
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Hm I might be able to try 1,2-dibromoethane if we have some around. The literature I have uses ethyl iodide as an activator. How careful do I have to be about keeping the system dry? I've been drying the glassware and keeping it under nitrogen. Can I open it up for a little to hit the Mg with a spatula? I think I def need to scrape the Mg down with a razor and break it into smaller pieces.
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I've opened them up before to *carefully* (don't want to break your flask) grind at some of the Mg so as to assist in the initiation. Just use a two- or three-necked flask so that you can have your nitrogen entering one neck while you insert a spatula into the other neck. Also, temporarily crank up the flow of nitrogen while you have the one neck exposed so as to avoid any moisture/air getting in there.
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Yup, under a flow of dry N2 or Ar gas should be fine. Be sure your glassware is well-dried by heating under vacuum and backfilling with dry, inert atmosphere before you add the solvent and Mg. Also be sure that you are using good quality dry solvent – it can make a big difference.
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Ok sounds good. Unfortunately I think the only two-neck microscale flask I can find in my lab is one of the pear shaped ones and I don't like that. The Mg kind of just gets stuck in the bottom of it and it doesn't stir well. I can probably order something though. I've been drying the glassware in the oven for an hour or two, letting it cool in the desiccator, then putting septums on and flushing it out with nitrogen. I think the solvent should be good. We ordered it last semester from Fisher and it came sealed and on molecular sieves. I only transfer it with a syringe that's been flushed with nitrogen.
Thank you everyone for the suggestions, I'll let you know if I have any progress.
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… more important is the quality of your Mg.
I second that. I hope you are starting with a fresh bottle of magnesium turnings.
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I may consider ordering some, the stuff I used was acid washed at some point recently but it's not new. Is it not good enough to just scrape the surface with a razor blade or something and break it into smaller pieces after?
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What I love with Grignard reactions ist the fact that they are very tolerant. N2 or even argon is absolutely not necessary. The etheral vapours form a layer which keeps moisture away. Also, ether and THF in p.A. quality is good (and dry!) enough. Even the magnesium turnings can be several years old. I never have problems. Last week, I run a reaction on 4-chlorobromobenzene on 750g scale and got >98% conversion into the magnesiated species. Isolated yield of crystalline 4-chlorophenylboronic acid was 70%.
I always add a small iodine crystal before adding the halogen component. That works fine. Mg doesn´t need to be grinded.
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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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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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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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@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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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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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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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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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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I'm pretty sure tBuLi is pyrophoric, I don't think my advisor would want me working with that.
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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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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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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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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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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.