Sciencemadness Discussion Board
Not logged in [Login ]
Go To Bottom

Printable Version  
 Pages:  1  
Author: Subject: grignard reagent to o-Chlorophenyl cyclopentyl ketone
RabbitTy
Harmless
*




Posts: 16
Registered: 19-9-2019
Member Is Offline


[*] posted on 19-9-2019 at 01:31
grignard reagent to o-Chlorophenyl cyclopentyl ketone


I just cant repeat the ketamine synthesis from Zealot.
The only difference is that I bought Cyclopentyl magnesium bromide 1mol/L in THF instead of synthesizing myself.
Ive tried several times but no target product generated.
CuBr added as catalyst but only made the system more complex without product.
ref also uploaded
could anyone help me out please

Also have few quetions:
1. Dose solvent type crucial to this reaction.I cant get diethyl ether
2. Is there any pratical way to sythesize this product

Attachment: Synthesis of carbon-14 labeled ketamine and norketamine.pdf (640kB)
This file has been downloaded 77 times

View user's profile View All Posts By User
Cactuar
Harmless
*




Posts: 28
Registered: 25-7-2014
Location: Denmark
Member Is Offline

Mood: No Mood

[*] posted on 19-9-2019 at 12:24


What's the purity of your nitrile?

Have you triturated your grignard solution?

Explain your procedure. Aromatic nitriles are quite resilient both to the grignard addition and the subsequent hydrolysis.
View user's profile View All Posts By User
DavidJR
International Hazard
*****




Posts: 701
Registered: 1-1-2018
Location: Scotland
Member Is Offline

Mood: Anxious

[*] posted on 19-9-2019 at 14:50


I don't think you mean triturated....
View user's profile View All Posts By User
RabbitTy
Harmless
*




Posts: 16
Registered: 19-9-2019
Member Is Offline


[*] posted on 19-9-2019 at 16:40


Quote: Originally posted by DavidJR  
I don't think you mean triturated....


U mean titration?
View user's profile View All Posts By User
RabbitTy
Harmless
*




Posts: 16
Registered: 19-9-2019
Member Is Offline


[*] posted on 19-9-2019 at 16:52


Quote: Originally posted by Cactuar  
What's the purity of your nitrile?

Have you triturated your grignard solution?

Explain your procedure. Aromatic nitriles are quite resilient both to the grignard addition and the subsequent hydrolysis.


I havent confirmed the purity of my meterial.

procedure as follow:
1. Nitrile in THF in the flask under N2.
2. Grignard reagent dropwise to the solution around 0℃。
3. after adding, warm to r.t. then stir for three days.

P.S Ive changed the order of adding but turned out to be se same consequence.
Catalyst CuBr also applied but noithing changed.
View user's profile View All Posts By User
monolithic
Hazard to Others
***




Posts: 146
Registered: 5-3-2018
Member Is Offline

Mood: No Mood

[*] posted on 19-9-2019 at 18:17


Quote: Originally posted by RabbitTy  
I just cant repeat the ketamine synthesis from Zealot.
The only difference is that I bought Cyclopentyl magnesium bromide 1mol/L in THF instead of synthesizing myself.
Ive tried several times but no target product generated.
CuBr added as catalyst but only made the system more complex without product.
ref also uploaded
could anyone help me out please

Also have few quetions:
1. Dose solvent type crucial to this reaction.I cant get diethyl ether
2. Is there any pratical way to sythesize this product


I think, in general, dry diethyl ether or THF are necessary for Grignard reagent formation. I believe the same holds true for the Grignard reaction itself.

Quote:
Ethyl ether or THF are essential for Grignard reagent formation. Lone pair electrons from two ether molecules form a complex with the magnesium in the Grignard reagent (As pictured below). This complex helps stabilize the organometallic and increases its ability to react.


Source: https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_(Organic_Chemistry)/Aldehydes_and_Ketones/Synthesis_of_Aldehydes_and_Ke tones/Grignard_and_Organolithium_Reagents

[Edited on 9-20-2019 by monolithic]
View user's profile View All Posts By User
RabbitTy
Harmless
*




Posts: 16
Registered: 19-9-2019
Member Is Offline


[*] posted on 19-9-2019 at 19:06


Quote: Originally posted by monolithic  
Quote: Originally posted by RabbitTy  
I just cant repeat the ketamine synthesis from Zealot.
The only difference is that I bought Cyclopentyl magnesium bromide 1mol/L in THF instead of synthesizing myself.
Ive tried several times but no target product generated.
CuBr added as catalyst but only made the system more complex without product.
ref also uploaded
could anyone help me out please

Also have few quetions:
1. Dose solvent type crucial to this reaction.I cant get diethyl ether
2. Is there any pratical way to sythesize this product


I think, in general, dry diethyl ether or THF are necessary for Grignard reagent formation. I believe the same holds true for the Grignard reaction itself.

Quote:
Ethyl ether or THF are essential for Grignard reagent formation. Lone pair electrons from two ether molecules form a complex with the magnesium in the Grignard reagent (As pictured below). This complex helps stabilize the organometallic and increases its ability to react.


Source: https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_(Organic_Chemistry)/Aldehydes_and_Ketones/Synthesis_of_Aldehydes_and_Ke tones/Grignard_and_Organolithium_Reagents

[Edited on 9-20-2019 by monolithic]


I dried the THF with molecular sieves,however i suppose its not enough right?
View user's profile View All Posts By User
draculic acid69
National Hazard
****




Posts: 442
Registered: 2-8-2018
Member Is Offline


[*] posted on 19-9-2019 at 23:11


I read mol.sieves do a much more thorough job of drying than sodium does.
View user's profile View All Posts By User
Cactuar
Harmless
*




Posts: 28
Registered: 25-7-2014
Location: Denmark
Member Is Offline

Mood: No Mood

[*] posted on 20-9-2019 at 00:15


Quote: Originally posted by RabbitTy  
Quote: Originally posted by DavidJR  
I don't think you mean triturated....


U mean titration?


Haha, yes, sorry.

Quote: Originally posted by RabbitTy  
I havent confirmed the purity of my meterial.

procedure as follow:
1. Nitrile in THF in the flask under N2.
2. Grignard reagent dropwise to the solution around 0℃。
3. after adding, warm to r.t. then stir for three days.

P.S Ive changed the order of adding but turned out to be se same consequence.
Catalyst CuBr also applied but noithing changed.


1:1 molar equivalents? I always add the nitrile to the grignard solution and not the other way around. It takes a few minutes to react but then quickly starts to reflux (ether).
View user's profile View All Posts By User
RabbitTy
Harmless
*




Posts: 16
Registered: 19-9-2019
Member Is Offline


[*] posted on 20-9-2019 at 01:53


Quote: Originally posted by Cactuar  
Quote: Originally posted by RabbitTy  
Quote: Originally posted by DavidJR  
I don't think you mean triturated....


U mean titration?


Haha, yes, sorry.

Quote: Originally posted by RabbitTy  
I havent confirmed the purity of my meterial.

procedure as follow:
1. Nitrile in THF in the flask under N2.
2. Grignard reagent dropwise to the solution around 0℃。
3. after adding, warm to r.t. then stir for three days.

P.S Ive changed the order of adding but turned out to be se same consequence.
Catalyst CuBr also applied but noithing changed.


1:1 molar equivalents? I always add the nitrile to the grignard solution and not the other way around. It takes a few minutes to react but then quickly starts to reflux (ether).


1:1.7 molar equivalents.I cant get ether sadly.I test THF for moist,its around 0.1% which may lead to the failure.
View user's profile View All Posts By User
RabbitTy
Harmless
*




Posts: 16
Registered: 19-9-2019
Member Is Offline


[*] posted on 20-9-2019 at 01:56


Quote: Originally posted by draculic acid69  
I read mol.sieves do a much more thorough job of drying than sodium does.


mol.sieves is better? however Ive tested THF dried by mol.sieves. Moist is around 0.1%.is it too much for grignard reaction?
View user's profile View All Posts By User
Prepic
Harmless
*




Posts: 13
Registered: 23-4-2019
Member Is Offline


[*] posted on 20-9-2019 at 03:13


You can always make diethyl ether :
( see https://www.sciencemadness.org/whisper/viewthread.php?tid=97...)

I do believe that THF is preferred over diethy ether however so this shouldnt be an issue. Water, however, is a massive issue with regards to performing grignard reagents.

I've seen on SM the use of ultrasound to help with grignard reactions in the presence of water and according to other literature ultrasound does indeed help. Perhaps give ultrasound a try?

Link: https://www.sciencemadness.org/whisper/viewthread.php?tid=65...
View user's profile View All Posts By User
monolithic
Hazard to Others
***




Posts: 146
Registered: 5-3-2018
Member Is Offline

Mood: No Mood

[*] posted on 20-9-2019 at 03:26


Can you follow the reaction with TLC? I haven't performed a Grignard since undergrad, but shouldn't there be exothermia when you add the Grignard reagent to your substrate? Do you observe any exothermia, or some other indication of the Grignard reaction taking place?
View user's profile View All Posts By User
draculic acid69
National Hazard
****




Posts: 442
Registered: 2-8-2018
Member Is Offline


[*] posted on 20-9-2019 at 07:20


Diethyl ether can be gotten off from starting fluid spray cans.when I was asking round bout grignards is some rxn's happen like 10x better in diethyl ether than they do in thf.
One person said that one rxn they do ends in 80% in ether but only 10% in thf so it might be worth trying to get ether.available in most car supply stores.
View user's profile View All Posts By User
Pumukli
National Hazard
****




Posts: 452
Registered: 2-3-2014
Location: EU
Member Is Offline

Mood: No Mood

[*] posted on 21-9-2019 at 01:17


I would like to second draculic's statement: some Grignards are picky about the solvent! For some THF is better, for some diethyl is the way to go. I even seen di-n-butil-ether used for some for the greatest yield! There's an article about the solvent effect in these reactions somewhere, of course I can't find it now - when would be useful. :(
View user's profile View All Posts By User
Cactuar
Harmless
*




Posts: 28
Registered: 25-7-2014
Location: Denmark
Member Is Offline

Mood: No Mood

[*] posted on 21-9-2019 at 03:42


For your pleasure I just tried the reaction myself but with chlorocyclopropane and m-tolunitrile since I didn't have the other starting materials. Still a 1M THF solution though. I had to add CuI to get the reaction to start, both for the grignard formation and the alkylation.


Prep:
0.53 Mg turnings (21.8 mmol, 1.1eq) was fused with a small crystal of iodine with a heat gun in a 50mL flat-bottomed RB-flask. 10mL of THF (dried over mol. sieves) was added and the purple mixture was stirred (pic 1). Chlorocyclopentane (2.08g, 19.89 mmol, 1 eq) was dissolved in 10mL THF and added dropwise by pipette. After half of it was added and still no reaction had occurred the solution was brought to a boil with a heat gun. The iodine-color disappeared (pic 2) and the solution became clear but still no sign of the reaction commencing. A very small amount of CuI was added with the tip of a glass pipette and the reaction started immediately (pic 3). The rest of the chloride was added to keep the mixture refluxing. After it had finished reacting the whole mixture was again brought to reflux with the help of a heat gun.

m-Tolunitrile (2.25g, 19.20 mmol, 0.97 eq) was dissolved in 5mL THF and was added dropwise by pipette. No reaction occurred even after all the nitrile had been added. Once again a small amount of CuI was added and the mixture started to violently reflux, almost boiling over (pic 4). After it had calmed down it was refluxed for 5 minutes and then decanted into 100mL of 1M HCl. The left-over turnings were washed with Et2O 2 times and the washings decanted into the acid. This was vigorously stirred (pic 5) for 30 minutes and then separated. The aqueos phase was extracted once with Et2O. The organic phases were combined, dried over MgSO4 and reduced on the rotavap. This gave 3.46g of a golden oil which on TLC (20% EtOAc/pet. Ether) showed (in descending order) assumed product, starting nitrile, an unknown polar compound and some polymerized stuff that didn't move (pic 6).

The residue was mixed with pet. ether which caused the polymerized stuff to crash out (pic 7). Everything was then ran through a 4 cm silica plug and the silica eluated with 50mL 20% EtOAc/Pet. ether. This gave a 3.04g of a light yellow oil (pic 8) which was quite pure by TLC (84% yield). A small band of starting material could still be seen and a faint smell of the nitrile could be noted (pic 9).

---

This was all done in less than two hours with no protecting atmosphere and the nitrile could probably be easily removed by distilling the product. Or just leave it there. I added 1 eq of bromine neat and stirred for 5 minutes and then reduced it on the rotavap. After adding pet. ether and evaporating it two times together with the excess bromine and HBr I had an orange oil (pic 10) that crashed out as light yellow crystals upon addition of methanol. Any nitrile that followed from the previous steps can easily be removed here by filtration. (If the 2'-chloro-bromoketone does crystallize that is, this is 3'-methyl).




grignard1.jpg - 178kB grignard2.jpg - 161kB grignard3.jpg - 194kB grignard4.jpg - 167kB quench.jpg - 169kB crude-tlc.jpg - 196kB crude-petether.jpg - 214kB silica.jpg - 217kB pure-tlc.jpg - 184kB brominated.jpg - 194kB
View user's profile View All Posts By User
Pumukli
National Hazard
****




Posts: 452
Registered: 2-3-2014
Location: EU
Member Is Offline

Mood: No Mood

[*] posted on 21-9-2019 at 06:16


Nice work, Cactuar!

It seems that not the solvent is the culprit, then what?

Maybe the trick is in the CuI what you used? You wrote that this catalyst made the difference between no reaction - almost boiling over. :) And was needed both in the Grignard formation and the actual coupling.

Do you have experience with o-substituted nitriles? Don't you think that this subst. pattern may slow down the reaction and make it even harder to start?
View user's profile View All Posts By User
Cactuar
Harmless
*




Posts: 28
Registered: 25-7-2014
Location: Denmark
Member Is Offline

Mood: No Mood

[*] posted on 22-9-2019 at 12:28


Quote: Originally posted by Pumukli  
Nice work, Cactuar!

It seems that not the solvent is the culprit, then what?

Maybe the trick is in the CuI what you used? You wrote that this catalyst made the difference between no reaction - almost boiling over. :) And was needed both in the Grignard formation and the actual coupling.

Do you have experience with o-substituted nitriles? Don't you think that this subst. pattern may slow down the reaction and make it even harder to start?


Thanks :)

I'm quite certain CuBr, which OP used, should be sufficient. And I don't know if it's actually needed, I just got impatient.

No experience from o-substituted nitriles, there's more steric hinderance and also with the chloro, maybe the more electron deficient molecule is even harder to react. But the paper which OP cites makes it work so it's obviously something else. His procedure seems correct so it's something with the materials. My guess it's the Grignard solution.
View user's profile View All Posts By User
RabbitTy
Harmless
*




Posts: 16
Registered: 19-9-2019
Member Is Offline


[*] posted on 22-9-2019 at 16:48


Quote: Originally posted by monolithic  
Can you follow the reaction with TLC? I haven't performed a Grignard since undergrad, but shouldn't there be exothermia when you add the Grignard reagent to your substrate? Do you observe any exothermia, or some other indication of the Grignard reaction taking place?


When I added the Grignard reagent to the substrate, I observed the exotherm.
TLC shows almost nothing before hydrolysis. After that, few new spot shows but none of them are my pruduct. The reaction have been hydrolyzed by HCl NH4Cl and H2SO4 separately. however, turned out to be the same consequence.
View user's profile View All Posts By User
RabbitTy
Harmless
*




Posts: 16
Registered: 19-9-2019
Member Is Offline


[*] posted on 22-9-2019 at 16:52


Quote: Originally posted by draculic acid69  
Diethyl ether can be gotten off from starting fluid spray cans.when I was asking round bout grignards is some rxn's happen like 10x better in diethyl ether than they do in thf.
One person said that one rxn they do ends in 80% in ether but only 10% in thf so it might be worth trying to get ether.available in most car supply stores.


I googled it and find some reactions do only proceed in ether. Thats important. Thx!
View user's profile View All Posts By User
RabbitTy
Harmless
*




Posts: 16
Registered: 19-9-2019
Member Is Offline


[*] posted on 22-9-2019 at 16:56


Quote: Originally posted by Pumukli  
I would like to second draculic's statement: some Grignards are picky about the solvent! For some THF is better, for some diethyl is the way to go. I even seen di-n-butil-ether used for some for the greatest yield! There's an article about the solvent effect in these reactions somewhere, of course I can't find it now - when would be useful. :(


Ive read about it. Different grignard reagents can form different complex with solvent to stabilize it.
View user's profile View All Posts By User
RabbitTy
Harmless
*




Posts: 16
Registered: 19-9-2019
Member Is Offline


[*] posted on 22-9-2019 at 17:24


Quote: Originally posted by Cactuar  
For your pleasure I just tried the reaction myself but with chlorocyclopropane and m-tolunitrile since I didn't have the other starting materials. Still a 1M THF solution though. I had to add CuI to get the reaction to start, both for the grignard formation and the alkylation.


Prep:
0.53 Mg turnings (21.8 mmol, 1.1eq) was fused with a small crystal of iodine with a heat gun in a 50mL flat-bottomed RB-flask. 10mL of THF (dried over mol. sieves) was added and the purple mixture was stirred (pic 1). Chlorocyclopentane (2.08g, 19.89 mmol, 1 eq) was dissolved in 10mL THF and added dropwise by pipette. After half of it was added and still no reaction had occurred the solution was brought to a boil with a heat gun. The iodine-color disappeared (pic 2) and the solution became clear but still no sign of the reaction commencing. A very small amount of CuI was added with the tip of a glass pipette and the reaction started immediately (pic 3). The rest of the chloride was added to keep the mixture refluxing. After it had finished reacting the whole mixture was again brought to reflux with the help of a heat gun.

m-Tolunitrile (2.25g, 19.20 mmol, 0.97 eq) was dissolved in 5mL THF and was added dropwise by pipette. No reaction occurred even after all the nitrile had been added. Once again a small amount of CuI was added and the mixture started to violently reflux, almost boiling over (pic 4). After it had calmed down it was refluxed for 5 minutes and then decanted into 100mL of 1M HCl. The left-over turnings were washed with Et2O 2 times and the washings decanted into the acid. This was vigorously stirred (pic 5) for 30 minutes and then separated. The aqueos phase was extracted once with Et2O. The organic phases were combined, dried over MgSO4 and reduced on the rotavap. This gave 3.46g of a golden oil which on TLC (20% EtOAc/pet. Ether) showed (in descending order) assumed product, starting nitrile, an unknown polar compound and some polymerized stuff that didn't move (pic 6).

The residue was mixed with pet. ether which caused the polymerized stuff to crash out (pic 7). Everything was then ran through a 4 cm silica plug and the silica eluated with 50mL 20% EtOAc/Pet. ether. This gave a 3.04g of a light yellow oil (pic 8) which was quite pure by TLC (84% yield). A small band of starting material could still be seen and a faint smell of the nitrile could be noted (pic 9).

---

This was all done in less than two hours with no protecting atmosphere and the nitrile could probably be easily removed by distilling the product. Or just leave it there. I added 1 eq of bromine neat and stirred for 5 minutes and then reduced it on the rotavap. After adding pet. ether and evaporating it two times together with the excess bromine and HBr I had an orange oil (pic 10) that crashed out as light yellow crystals upon addition of methanol. Any nitrile that followed from the previous steps can easily be removed here by filtration. (If the 2'-chloro-bromoketone does crystallize that is, this is 3'-methyl).






Nice work!Thx!
Ive tried both with or without CuBr in my reactions. When CuBr applied, the reaction time reduced to near 20hours. It took almost 3 days without the CuBr.I guess the o-sub make the reaction more difficult to proceed. On the other hand, analysis the moist of th solvent showd its contain near 0.1% moist in the THF , I wonder is there any standard of the moist in the solvent used in grignard reaction.
View user's profile View All Posts By User
RabbitTy
Harmless
*




Posts: 16
Registered: 19-9-2019
Member Is Offline


[*] posted on 22-9-2019 at 17:31


Quote: Originally posted by Cactuar  
For your pleasure I just tried the reaction myself but with chlorocyclopropane and m-tolunitrile since I didn't have the other starting materials. Still a 1M THF solution though. I had to add CuI to get the reaction to start, both for the grignard formation and the alkylation.


Prep:
0.53 Mg turnings (21.8 mmol, 1.1eq) was fused with a small crystal of iodine with a heat gun in a 50mL flat-bottomed RB-flask. 10mL of THF (dried over mol. sieves) was added and the purple mixture was stirred (pic 1). Chlorocyclopentane (2.08g, 19.89 mmol, 1 eq) was dissolved in 10mL THF and added dropwise by pipette. After half of it was added and still no reaction had occurred the solution was brought to a boil with a heat gun. The iodine-color disappeared (pic 2) and the solution became clear but still no sign of the reaction commencing. A very small amount of CuI was added with the tip of a glass pipette and the reaction started immediately (pic 3). The rest of the chloride was added to keep the mixture refluxing. After it had finished reacting the whole mixture was again brought to reflux with the help of a heat gun.

m-Tolunitrile (2.25g, 19.20 mmol, 0.97 eq) was dissolved in 5mL THF and was added dropwise by pipette. No reaction occurred even after all the nitrile had been added. Once again a small amount of CuI was added and the mixture started to violently reflux, almost boiling over (pic 4). After it had calmed down it was refluxed for 5 minutes and then decanted into 100mL of 1M HCl. The left-over turnings were washed with Et2O 2 times and the washings decanted into the acid. This was vigorously stirred (pic 5) for 30 minutes and then separated. The aqueos phase was extracted once with Et2O. The organic phases were combined, dried over MgSO4 and reduced on the rotavap. This gave 3.46g of a golden oil which on TLC (20% EtOAc/pet. Ether) showed (in descending order) assumed product, starting nitrile, an unknown polar compound and some polymerized stuff that didn't move (pic 6).

The residue was mixed with pet. ether which caused the polymerized stuff to crash out (pic 7). Everything was then ran through a 4 cm silica plug and the silica eluated with 50mL 20% EtOAc/Pet. ether. This gave a 3.04g of a light yellow oil (pic 8) which was quite pure by TLC (84% yield). A small band of starting material could still be seen and a faint smell of the nitrile could be noted (pic 9).

---

This was all done in less than two hours with no protecting atmosphere and the nitrile could probably be easily removed by distilling the product. Or just leave it there. I added 1 eq of bromine neat and stirred for 5 minutes and then reduced it on the rotavap. After adding pet. ether and evaporating it two times together with the excess bromine and HBr I had an orange oil (pic 10) that crashed out as light yellow crystals upon addition of methanol. Any nitrile that followed from the previous steps can easily be removed here by filtration. (If the 2'-chloro-bromoketone does crystallize that is, this is 3'-methyl).






furthermore, I can also get the top spot compound on TLC after hydrlyzing. However, it turned out they arent my product after analyzing by LC-MS. I wonder didu confirm the structure of ur product.
View user's profile View All Posts By User
Cactuar
Harmless
*




Posts: 28
Registered: 25-7-2014
Location: Denmark
Member Is Offline

Mood: No Mood

[*] posted on 22-9-2019 at 22:38


Quote: Originally posted by RabbitTy  
furthermore, I can also get the top spot compound on TLC after hydrlyzing. However, it turned out they arent my product after analyzing by LC-MS. I wonder didu confirm the structure of ur product.


I never did. But it did brominate, form an imine, reacted with HCl in iPrOH and rearranged in benzyl acetate. I'm recrystallizing it right now but have no intention of tasting it.

What did your LC/MS say?
View user's profile View All Posts By User
RabbitTy
Harmless
*




Posts: 16
Registered: 19-9-2019
Member Is Offline


[*] posted on 22-9-2019 at 23:29


Quote: Originally posted by Cactuar  
Quote: Originally posted by RabbitTy  
furthermore, I can also get the top spot compound on TLC after hydrlyzing. However, it turned out they arent my product after analyzing by LC-MS. I wonder didu confirm the structure of ur product.


I never did. But it did brominate, form an imine, reacted with HCl in iPrOH and rearranged in benzyl acetate. I'm recrystallizing it right now but have no intention of tasting it.

What did your LC/MS say?


TLC(20%etoac/pet ether),the top spot like ur. I purified by column chromatography.However LC-MS showed more than one compound in it.After that i changed to 2%EtOAc/Pet ether. And it shows three spots instead.
LC-MS file been loaded

Attachment: JLX1904-SM3-19090201.PDF (45kB)
This file has been downloaded 24 times

View user's profile View All Posts By User
 Pages:  1  

  Go To Top