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Author: Subject: Grignard reaction work up with concentrated sulfuric acid?
FireLion3
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[*] posted on 24-7-2014 at 19:16
Grignard reaction work up with concentrated sulfuric acid?


I am working on a synth right now that is theoretically sound, but the only thing I am running into problems with is the grignard work up. I actually plan to use Zinc in place of Magnesium, which should behave in the same manner, it is just less exothermic and less nucleophilic - but this shouldn't matter due to the nature of my reagents being very electrophilic.

The problem is my product itself is extremely electrophilic, so much so that it would instantly undergo a substitution reaction with water, ruining it, and with a large number of organic solvents as well. Can I just add concentrated sulfuric acid, which should hydrolyze the addition product forming a mixture of sulfate and halide salts? All references I encounter say to use dilute sulfuric acid, or other halide acid, but the water will simply not do.
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[*] posted on 24-7-2014 at 23:38


I'm not sure I've ever heard of doing this before. How confident are you that the acid won't ruin your product? I would be worried about producing some tar.
What solvent are you using? One of my concerns would be ether cleavage with Grignard nucleophile.

[Edited on 25-7-2014 by Chemosynthesis]
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[*] posted on 25-7-2014 at 00:35


in general zinc is not a suitable replacement for magnesium in grignard type reactions. Quenching anything owith conc. sulfuric acid isn't too smart and probably just leads to issueof how to get yourcompound out from conc acid. One suitable wayof isolating labile compounds is by doing a one pot synthesis-protection sequence. Ther are also methods where the cold rxn mixture is very rapidly quenched with cold organic solvent with a tiny bit of water added. This has been applied in LDA reductions and wittig reactions. It's hard to say what would be a suitable plan of attack without knowing the substrates. Have you done a literature search on the compound, what approaches have been applied previously and how it has been isolated?

[Edited on 25-7-2014 by kavu]
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[*] posted on 25-7-2014 at 01:00


Quote: Originally posted by kavu  
in general zinc is not a suitable replacement for magnesium in grignard type reactions.

Really? I was under the impression Barbier reactions were analogous to Grignard and aklyl lithium reactions from reading old works of Paul Knochel.
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[*] posted on 25-7-2014 at 01:38


Barbier belongs to the "not in general" group, mosly I just wanted to emphasize this because the procedure is severely different from your typical 1. Make MgXR nucleophile 2. Add electrophile.

[Edited on 25-7-2014 by kavu]
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[*] posted on 25-7-2014 at 01:49


Quote: Originally posted by kavu  
Barbier belongs to the "not in general" group, mosly I just wanted to emphasize this because the procedure is severely different from your typical 1. Make MgXR nucleophile 2. Add electrophile.


Oh! I didn't notice it appears the OP isn't intending to work the reaction one-pot, with an in-situ organometallic, rather than form an organozinc separately then react it.
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[*] posted on 25-7-2014 at 03:16


Use acetic acid.
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[*] posted on 25-7-2014 at 05:44


Quote: Originally posted by Chemosynthesis  
I'm not sure I've ever heard of doing this before. How confident are you that the acid won't ruin your product? I would be worried about producing some tar.
What solvent are you using? One of my concerns would be ether cleavage with Grignard nucleophile.

[Edited on 25-7-2014 by Chemosynthesis]


Lots of questions...good ones. Pretty sure the acid won't react with it, or other electrophiles for that matter. The compound I am creating is basically an extremely electrophilic alkylating agent. Solvent is an issue. I need something that can dissolve organics that will not react to the extreme electrophilicity. Even Something like Benzene is too nucleophilic with respect to the target product. It would effortlessly alkylate benzene. I've thought of something like Nitrobenzene perhaps, but I am not familiar with its solvent properties and whether it not it could react with the nucleophilic Organozinc intermediate. I basically need something so stable that it is not electrophilic enough to react with the electrophilic organozinc, and electron poor-enough to withstand the final product, or else I would have to run the reaction dry, which, the compounds should be air stable.


Quote: Originally posted by kavu  
in general zinc is not a suitable replacement for magnesium in grignard type reactions. Quenching anything owith conc. sulfuric acid isn't too smart and probably just leads to issueof how to get yourcompound out from conc acid. One suitable wayof isolating labile compounds is by doing a one pot synthesis-protection sequence. Ther are also methods where the cold rxn mixture is very rapidly quenched with cold organic solvent with a tiny bit of water added. This has been applied in LDA reductions and wittig reactions. It's hard to say what would be a suitable plan of attack without knowing the substrates. Have you done a literature search on the compound, what approaches have been applied previously and how it has been isolated?


I thought it wouldn't be a suitable replacement, but the only real information I could find in comparison to Mg-Grignard reactions was zinc-halide intermediates being less nucleophilic (thus stable in water) - which in my case is irrelevant since the reactant that would be added to is a strong electrophile on its own.

You mention not being able to separate my compound from the isolated acid, but why would there be any unreacted acid? Would it not react and eventually just be left with Magnesium (or Zinc) Halide and Sulfate? I could always separate from those with a simple filtration, or work around their presence with an overhead stirrer.

The compound as I am designing does not exist, yet. I've run the structure through a number of structure search engines and no results, but I didn't expect it to be there anyways.

The structural concept that would allow for extreme alkylating properties is derived from the behavior of various halogenating agents that utilize the labile bond properties and molecular polarity that results in electron withdrawing groups adjacent to Nitrogen-Halide bonds. These bonds are very conjugated and reactive. I know for a fact that replacing the halide with carbon electrophile that is already electrophilic can be easily done by a number of synthetic methods, right now I am just testing the theoretical ground to identify the best one.

Quote: Originally posted by forgottenpassword  
Use acetic acid.

Thought about it, but it wont work. Acetic Acid is a carboxylic acid, and my starting reagent prior to the Zinc addition is already extremely electrophilic. It has often been used to form acyl halides from acetic acid, and these would only interfere with the reaction.

If you are referring to using the acetic acid to do the work up, that won't work either, because being a carboxylic acid, the end product, a very electrophilic alkylating agent, will effortlessly react with the acetic acid.

---

Running a dry reaction is an option as the target is air stable, but this would just be tedious.If I can't work out this particular pathway then it's no issue. I have about 6 other theoretical pathways laid out that less involved, but pose other potential issues unique to each.

The only real advantage to forming this target compound as an alkylating agent would be for its extreme reactivity, yet extreme inability to form by products when used with the correct substrate, resulting in extremely high and clean yields and easy work up. As far as alkylating is concerned, there are far easier methods. I am just interested in seeing if I can use this as its own novel pathway.
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[*] posted on 25-7-2014 at 06:01


Can you be more specific as to what the substrate is?



As below, so above.
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[*] posted on 25-7-2014 at 07:07


I am mulling about an awkward possible answer to your problem, but would want to know your substrates and product first. Any reason you're keeping it secret?
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[*] posted on 25-7-2014 at 07:19


If the specific compound is not found try searching with similar structural motifs. In the case of highly reactive products you want to know as much beforehand as possible not to screw up the reaction. Considering what you are claiming this compound could do, I'd say making/isolating it is damn near impossible if no literature can be found to back it up.

[Edited on 25-7-2014 by kavu]
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[*] posted on 25-7-2014 at 08:53


Draw a picture of it and upload it.
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