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Topic: Grignard Reagents in DCM  (Read 15285 times)

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Offline lancenti

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Grignard Reagents in DCM
« on: March 23, 2010, 03:45:59 AM »
Hello everyone! I've got a question about grignard reagents in DCM.

I was told that DCM would not react with grignard reagents, but I can't understand why and the person ran off before I could press him for answers. But basically, my reasoning is as follows:

Dichloromethane has an electron-deficient carbon, i.e. it's a delta-positive center. In addition to this, it can't be said to be sterically hindered as its R-groups are hydrogen atoms.

Grignard Reagents are strong nucleophiles which attack delta-positive centers. In the case of DCM, an attack by a grignard should result in kicking out a chloride ion (considered a good leaving group). This reaction can happen twice to give me a G-CH2-G (where G is the organic part of the grignard reagent). Mechanism would probably be via an SN2.

Am I forgetting something?

Offline stewie griffin

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Re: Grignard Reagents in DCM
« Reply #1 on: March 23, 2010, 08:22:25 AM »
Grignards, although nucleophilic as well as basic, are terrible for doing C-C formation from attack on a C-X compound. In other words, you can't take two of the same (or different) alkyl halides, make a grignard of one and then have it attack the other alkyl halide. Grignards just don't react that way. I understand your confusion as your reasoning is very logical. I don't recall if there is a textbook theory type of answer as to why grignards won't do this type of reaction or if it's just what's been observed and taken as is.
Anyway, you may or may not recall that to do the reaction discussed above (connecting two alkyl halides) you CAN do it with Gilman reagents (dialkyl copper lithium reagents, http://en.wikipedia.org/wiki/Gilman_reagent). Just FYI.

Offline Dan

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Re: Grignard Reagents in DCM
« Reply #2 on: March 23, 2010, 04:35:21 PM »
Grignards are probably basic enough to deprotonate DCM - it can be done with LDA to generate dichloromethyllithium, so I suppose a Grignard could do something similar.
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Offline stewie griffin

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Re: Grignard Reagents in DCM
« Reply #3 on: March 23, 2010, 07:16:54 PM »
Good point Dan. Deprotonation of CH2Cl2 crossed my mind, but I could swear that a fellow graduate student in another synthesis lab at my current school had tried a Grignard in DCM.... I vaguely remember something about forming the reagent in THF, concentrating in vacuo, and redissolving in DCM. Something about have a less coordinating solvent for an addition reaction.
I could be totally crazy and dreaming this up but it seems very real.  ??? I'll check in with the student and post if it is indeed true or if I'm crazy....

Offline dunno260

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Re: Grignard Reagents in DCM
« Reply #4 on: March 23, 2010, 08:41:28 PM »
I can tell you that with my experience grignards WILL self couple to an alkyl bromide.  I spent quite a bit of time trying to wrangle out of that before switching to the chloride.  Still get a decent bit of the self coupling though.  I know of others who have run into problems preparing the benzyl magnesium halide reagents and getting self coupled products.

That doesn't mean that you can't do it in DCM.  I haven't ever heard of it as the solvents I have seen are THF, diethyl ether, dibutyl ether, and toluene. 

Offline stewie griffin

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Re: Grignard Reagents in DCM
« Reply #5 on: March 23, 2010, 08:46:36 PM »
re dunno260: Interesting to know that bromides can self couple. I wasn't aware.I suppose the thing to remember then is that if self coupling is the goal then grignards aren't the way to go.
I've sent the fellow grad student an email asking if they did run it in DCM. Hopefully I'll get a response by tomorrow morning...

Offline tmartin

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Re: Grignard Reagents in DCM
« Reply #6 on: March 23, 2010, 09:33:49 PM »
I have run a vinyl grignard addition to an aldehyde in methylene chloride.  It was a while ago, but if I recall correctly, it worked reasonably well ~60% (not quite as high as THF or ether >80%).  The reason I was using it was to increase chelate control in the addition...unfortunately it didn't go any higher.

I'm away from my lab notebook and references right now (at the ACS meeting) but I will try to remember to check back into the rationale later in the week.  It was one of those things the boss said "try this" and it seemed interesting, so I did.

Offline lancenti

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Re: Grignard Reagents in DCM
« Reply #7 on: March 24, 2010, 02:02:52 AM »
Thank you everyone for the responses! It makes much more sense now.

I was always told that you don't run Grignard reactions in anything other than ethers so the idea of using DCM to control the chelate control fascinates me. I would love to be able to try my reaction again in DCM to see if any coupling reaction occurs but as a 1st year undergraduate, it's considered "wasting reagents". Maybe when I get to my third or fouth year I can try it out.

Offline dunno260

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Re: Grignard Reagents in DCM
« Reply #8 on: March 24, 2010, 05:12:52 AM »
What I do wonder is if you want to increase chelation control in the reaction why isn't toluene/benzene an appropriate solvent?  Butyl ether is a whole different beast compared to THF and diethyl ether as well from what I have heard. 

And yeah, the self coupling thing is a royal pain when it can occur.  I see it some with the chlorides but we have been able to sidestep that just by dropping the temperature.  With the bromide nothing helped though.  I never saw formation of the desired grignard reagent using a variety of conditions (dilution, stoichiometric ratios, solvent, temperature, magnesium activation methods).  For future note, we found that the best results to avoid self coupling have come by using magnesium powder activated by stirring for 48 hours (at least overnight, but longer the better) under an inert atmosphere (ideally in a glove box).  This method will also activate turnings if thats all you have. 

My PI hates grignards because of how finicky they can be.  Organolithiums, at least in his experience, behave much more predictably. It would also be interesting to know what organolanthanide species like cerium or ytterbium would do in DCM.  I would imagine that would be a poor idea in general as they are considerably more nucleophilic than their magnesium or lithium counterparts (while being less basic). 

Offline stewie griffin

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Re: Grignard Reagents in DCM
« Reply #9 on: March 24, 2010, 07:35:01 AM »
tmartin thanks for proving I'm not completely crazy  :)
Anyway the student I was referring to wrote back and said he does indeed do a solvent switch to DCM and that at -78 degrees he doesn't observe any problems with deprotonation of the solvent. If he's doing it on a large scale sometimes he'll just dilute the THF solution of grignard with DCM rather than doing the entire solvent switch, and that seems to work ok. He added that now he uses toluene as it actually works a little bit better for his chelation control (as dunno260 even suggested). His last comment was that he loves zinc and from his knowledge if you made the organozinc reagent you can run the reaction in DCM with no risk of deprotonation of solvent. So there you have it..

as a 1st year undergraduate, it's considered "wasting reagents". Maybe when I get to my third or fouth year I can try it out.
Yeah those days sucked. You have to earn trust from the other students and PI that you actually have a good idea and can actually set up reactions properly. My advice: The quickest way to earn your PI's respect/trust is to keep a very detailed and very CLEAN notebook. This way when they have questions you just turn to the page and say "it's all right here". Also don't make claims you can't back up (like don't say "oh yeah the reaction worked!" when all you have is a good looking TLC plate and no actual NMR of an isolated product). Lastly, be honest with your yields... no point in lying about yields.

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