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Author: Subject: Methods for preventing over addition of Grignard reagent
Opylation
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[*] posted on 28-1-2020 at 16:39
Methods for preventing over addition of Grignard reagent


Hello all,

I am planning on making a ketone via the grignard reaction with an ester. Now I have read of the weinreb ketone synthesis however I am curious if using stirring within the reaction vessel and adding the organo-magnesium halide reagent to the ester very slowly if it is possible to prevent over addition, stopping at the ketone step instead of continuing on to make a tertiary alcohol

[Edited on 29-1-2020 by Opylation]
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DavidJR
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[*] posted on 28-1-2020 at 17:31


This method does not really work, because the reaction of the ketone with the Grignard reagent is much faster than the reaction of the ester with the Grignard reagent. So even if you only add exactly one equivalent of Grignard reagent you'll still get mostly tertiary alcohol + ester with only a trace of the ketone. You could instead react the Grignard reagent with the appropriate aldehyde to yield a secondary alcohol, which can then be oxidized to a the ketone.

What is the desired product here?

[Edited on 29-1-2020 by DavidJR]
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[*] posted on 28-1-2020 at 20:12


Ah I see now. Thanks for the reply. I have been doing a little more research and it seems like the weinreb ketone synthesis would be the easiest way to proceed. I thought maybe the isopropylmagnesium chloride would be sterically hindered and prevent an additional isopropyl group being added to the ketone but I couldn’t find any supporting information. I did find some mention of isopropylmagnesium chloride not being nucleophillic however which is disheartening...

By the way, the product in question is isobutyrophenone via methyl benzoate. It looks like a basic conversion of methyl benzoate to benzohydroxamic acid and then N,O-methylation via dimethyl sulfate is the way to go. From there, continuing with an isopropylmagnesium chloride Grignard reagent seems preferable
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[*] posted on 28-1-2020 at 21:38


Sometimes the free acid can be treated with two equivalents of the organolithium. The formed geminal dialkoxide being stable in the absence of protic solvents.
See http://www.orgsyn.org/demo.aspx?prep=CV5P0775
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[*] posted on 28-1-2020 at 22:45


Thanks for the reply. I am hoping to avoid air-sensitive reactions though as I don’t have the materials to produce inert atmospheres
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[*] posted on 29-1-2020 at 01:41


you can skip all these reactions and just alkylate the benzene with isobytiric acid and PPA as catalyst work like charm for preparing ketones.
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[*] posted on 29-1-2020 at 02:07


Friedel-Crafts acylation seems like the obvious choice for that product.
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[*] posted on 29-1-2020 at 19:55


" I am hoping to avoid air-sensitive reactions though as I don’t have the materials to produce inert atmospheres"

If you cannot access an inert atmosphere how can you plan to run a Grignard reaction?

You are correct in that isopropyl Grignard reagents are not very reactive in the normal sense. (They are great transmetallation reagents, however.) Why not just go ahead and do the experiment - react methyl benzoate with the i-Pr-Mg-Cl and see what happens. Assuming one mole of the reagent reacts with the ester in the normal sense, it seems doubtful that a second mole of the reagent will subsequently react to any great extent given the poor reactivity and steric bulk of the Grignard. You might get lucky assuming you can create an inert atmosphere. After all, chemistry is an experimental science. If your reaction fails, then you can go on to some of the more demanding methods or maybe even buy your compound.

AvB
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[*] posted on 30-1-2020 at 05:15


Grignards are not oxygen sensitive are they? A drying tube and dry glassware should be enough.
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[*] posted on 30-1-2020 at 09:39


They are very water and CO2 sensitive, and some could react with oxygen (I think) as well. But CO2 will definitely kill them. I will agree that if you have an excess of the grignard, a true inert atmosphere is not needed. But if the Grignard is the limiting reagent (and took 8 steps to make), you will not want to waste any of it.
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[*] posted on 30-1-2020 at 10:01


Quote: Originally posted by AvBaeyer  
If you cannot access an inert atmosphere how can you plan to run a Grignard reaction?


Quote: Originally posted by Tsjerk  
Grignards are not oxygen sensitive are they? A drying tube and dry glassware should be enough.


They are oxygen sensitive, but not to the extent that you absolutely must use inert gas.

In fact, I've done plenty of Grignard reactions in open flasks without even bothering with a drying tube or to oven-dry the glassware. Water fucks with the formation of the reagent by forming a layer of crud on the magnesium which retards further reaction. If you use a cheap ultrasonic cleaner to sonicate the flask, any crud gets knocked right off. This means a small amount of water results only in a correspondingly small loss to hydrolysis, but does not completely inhibit the formation of the reagent. The ultrasonic cleaner also eliminates the need to add any kind of activating agent (iodine, 1,2-dibromoethane, etc).

[Edited on 30-1-2020 by DavidJR]
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[*] posted on 30-1-2020 at 11:33


Quote: Originally posted by DavidJR  

They are oxygen sensitive, but not to the extent that you absolutely must use inert gas.

In fact, I've done plenty of Grignard reactions in open flasks without even bothering with a drying tube or to oven-dry the glassware. Water fucks with the formation of the reagent by forming a layer of crud on the magnesium which retards further reaction. If you use a cheap ultrasonic cleaner to sonicate the flask, any crud gets knocked right off. This means a small amount of water results only in a correspondingly small loss to hydrolysis, but does not completely inhibit the formation of the reagent. The ultrasonic cleaner also eliminates the need to add any kind of activating agent (iodine, 1,2-dibromoethane, etc).

[Edited on 30-1-2020 by DavidJR]


I used magnesium turnings that I crushed a bit in a mortar with a pestle, the other reagents and the glassware were dry. That also works fine without iodine or bromoethane. A drying tube filled with CaCl2 and a bit of NaOH against CO2 could be used just to be sure, as those are cheap anyway.

Edit: or if you don't trust your magnesium, you can give it a quick HCl bath and then an acetone rinse and then an ether rinse. Or skip the acetone if you have enough ether.

[Edited on 30-1-2020 by Tsjerk]
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[*] posted on 31-1-2020 at 07:21


I will add though that good quality (high purity and not oxidised already) magnesium makes a big difference.
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[*] posted on 31-1-2020 at 07:44


Quote: Originally posted by DavidJR  
I will add though that good quality (high purity and not oxidised already) magnesium makes a big difference.


That is definitely correct, but that can be sorted out with a bit of HCl.
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[*] posted on 31-1-2020 at 07:55


Oxidation can be, but purity of the bulk metal cannot.

[Edited on 31-1-2020 by DavidJR]
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[*] posted on 31-1-2020 at 07:59


Quote: Originally posted by DavidJR  
Oxidation can be, but purity of the bulk metal cannot.

[Edited on 31-1-2020 by DavidJR]


That is also true, but have you ever seen an example of impure magnesium?
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[*] posted on 31-1-2020 at 09:29


Yes. Cheap magnesium turnings off of eBay are probably literal waste from machining "magnesium" parts which are in reality some kind of high-magnesium alloy. There are quite a number of these and they might well contain up to about 10% of aluminium, zinc, and other metals including rare earths. With these cheap turnings, and even after degreasing and acid etching, they still react sluggishly with alkyl halides. Sonication helps, but the resulting reagent is nearly opaque black in colour, presumably due to suspended particles of metallic stuff that is not magnesium. I've tried a few different eBay sellers with similar results. In one case the seller described them as 99.9% pure but I'm pretty certain this was a total lie (I've caught the same seller lying about such things before). They were also invariably coated in a light layer of oil.

On the other hand, 99.8% magnesium turnings from Sigma Aldrich (not specifically "Grignard grade", just bog standard) work very well - they react a lot faster with the halide and the Grignard reagent solution is much lighter and less opaque/turbid. Also, I would describe them as irregular granules, even though they were sold as "turnings" they are definitely not turnings in the sense of being chips produced by a lathe.

[Edited on 31-1-2020 by DavidJR]
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[*] posted on 31-1-2020 at 09:56


Quote: Originally posted by DavidJR  
Yes. Cheap magnesium turnings off of eBay are probably literal waste from machining "magnesium" parts which are in reality some kind of high-magnesium alloy. There are quite a number of these and they might well contain up to about 10% of aluminium, zinc, and other metals including rare earths. With these cheap turnings, and even after degreasing and acid etching, they still react sluggishly with alkyl halides. Sonication helps, but the resulting reagent is nearly opaque black in colour, presumably due to suspended particles of metallic stuff that is not magnesium. I've tried a few different eBay sellers with similar results. In one case the seller described them as 99.9% pure but I'm pretty certain this was a total lie (I've caught the same seller lying about such things before). They were also invariably coated in a light layer of oil.

On the other hand, 99.8% magnesium turnings from Sigma Aldrich (not specifically "Grignard grade", just bog standard) work very well - they react a lot faster with the halide and the Grignard reagent solution is much lighter and less opaque/turbid. Also, I would describe them as irregular granules, even though they were sold as "turnings" they are definitely not turnings in the sense of being chips produced by a lathe.

[Edited on 31-1-2020 by DavidJR]


Interesting. I only got magnesium turnings once, I got 500 grams about ten years ago and they performed well a year ago. But yes, they were sold by Boomlab, a reputable seller in the Netherlands.
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[*] posted on 20-2-2020 at 12:27


A coarse magnesium powder for fireworks is suitable for Grignard. At least with isopropyl chloride it works well.
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[*] posted on 21-2-2020 at 03:59


How do you prepare the Grignard? With turnings it is already hard to reflux all ether sometimes.
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[*] posted on 23-2-2020 at 11:56


Aparatus: two neck 500 ml RBF equiped with Dirmroth condenser, dropping funnel and magnetic stirrer.
21g of Mg coarse powder, 10 g of isopropyl chloride and 70 ml of dry ether was loaded. The mixture of 50 g of isopropyl chloride
and 60 ml ether was placed into dropping funnel. The RBF was heated by warm water. The reaction started within minutes. After a
short time the reaction became vigorous. The condenser managed it but wapors of ether condensed almost at the top of condenser.
After short time when reaction became quiet the rest of chloride was added dropwise. The reaction went smoothly, the boiling was
easily regulated by addition of chloride.
The problem is a start of reaction. To put almost 20% of all chloride at the beginning wasn't a good idea. I should have started
with less amount of isopropyl chloride or maybe use dibromoethane for a smooth start the reaction. The advantage of use Mg powder is that you can do reaction as fast as your condenser allow. Every drop of chloride is consumed almost immediately.

[Edited on 23-2-2020 by egret]
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[*] posted on 3-4-2020 at 12:40


"I used magnesium turnings that I crushed a bit in a mortar with a pestle, the other reagents and the glassware were dry. That also works fine without iodine or bromoethane. A drying tube filled with CaCl2 and a bit of NaOH against CO2 could be used just to be sure, as those are cheap anyway."
why did you crush the Mg?? Usually not necessary and complicates workup. Also with Mg Grignard reagents the vapor head of ether excludes air quite effectively.. so no need for N2. With Li reagents I would use Ar atmosphere. I don't like fires.




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