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All 11 posts   Subject: P2P / Benzylchlorid / Mg powder , Acetonitril   Please login to post   Down

 
    Radiumhero
(Stranger)
11-06-04 21:15
No 540066
      P2P / Benzylchlorid / Mg powder , Acetonitril     

Well Swim just wanted to have some neat P2P and he had the stuff at hand to do the Grignard Benzyl-mg- Chlorid , Acetonitril Stuff.
Unfortunately he fergot to buy new Mg Turning (he used up all) and he had only Powder at hand , but he started to work couriously whats gonna happen when using Powder instead of Turings . At the beginning it lokked pretty bad.
Because the reaktion didnt want to start ... added iodine ...heated ... no reaktion , but then swim thougt about his Mag.stirrer and placed the flask on it started stirring and voila the thing began to react really heavily !
When the reaktion was complete Swim made an mixture of Acetonitril and Et2O .
Cooled Benz Mag Chlorid and added the before made mixture . All of sudden an really ugly Stuff appeared on the bottom
A Pretty hard ( Salt ???) white with a tint of grey .

What the F*** swim thought and wondered what that could be when the addition was complete he thought about disposing all of the ""produkt"" but he wanted to know what happens if he added Hcl . said , done the whole mess dissolved und enourmous masses of Gas and building up 2 Layers , a yellow neon green Top layer and a white , foam bubblin on the bottom !
Can anybody tell me what this mess could be ?

well since noone wanted to tell me , i had to search myselfe  and found sth really nice .... Poodles intructions / writeups and he said this solid was formed in his reaktion too!! well sounds good swir thought and read on .. but he filtered this solid out and exposed it to water (well better than my tries ) to get P2P forming ! well the only thing i have to do now is to extract with a little bit of Et2o and evaporat it . to gin crude P2P. Wow damn simple .....
 
 
 
 
    Bandil
(The Archetypical "Good Guy")
11-08-04 20:06
No 540467
      Noone here at the-hive has ever documented...     

Noone here at the-hive has ever documented satisfactory results using that method. Poodles results are generally thought to be a wee bit optimistic wink The best credibly sounding results report max. 20% yield using Et2O as solvent, and 40% using benzene.

The short chained alkylnitrile is simply not reactive enough towards the grignard reactant. With benzylnitrile and a methylhalide grignard the results are much better.

The white stuff that precipitates is the HCl salt of benzylmethylimine along with different byproducts. When exposed to acid, the imine will decompose into a ketone.

All in all i'd advise you to use another route, unless you want to dedicate your work to real science and figure out how to boost the yields here. When you allready have benzylchloride and master grignard reactions, i'd advice you to use the acetylacetonate route. It gives excellent yields, and is quite simple.

Rhodium> Wouldn't it be appropriate to insert a short warning into poodles p2p writeup, warning people that the presented results are a bit "unique"?

Kind regards
Bandil

Only one way leads to Valhalla - Running amok with TOTAL VIKING POWER
 
 
 
 
    Radiumhero
(Stranger)
11-08-04 21:14
No 540477
      OK Extraction done .     

Well i extracted the P2P and i have to say that the yield is not as bad as exspected ~ 24 ml P2P. And I used 63 ml Benzylchlorid and little more than 38 ml Acetonitril. But my P2P is really dark ! dark brown colored , with a really lets call it unpleasant smell , ( little bit like some sort of plant but this must be an ugly one ...)
 
 
 
 
    Bandil
(The Archetypical "Good Guy")
11-08-04 21:27
No 540479
      How did you extract it and verify that it is...     

How did you extract it and verify that it is P2P?

In my experience with this method, you get something from the distillation, with a b.p. not too far for that of P2P (cant remember the exact b.p., lost the notes). It is however NOT p2p...

Regards
Bandil

Only one way leads to Valhalla - Running amok with TOTAL VIKING POWER
 
 
 
 
    Radiumhero
(Stranger)
11-08-04 22:34
No 540497
      workup :     

Well started with acidifation of this funny white salt  followed by 3 times extraction with 35 ml Et2O( NaCl has been added to mixture .) to remove the yellow color from the bottom (water ) Layer. Et2O extracts pooled together and washed with Water .
Water removed by Dropping funnel and heatng to 110 C. Well ill make a sample with anilin acrylation and compare Products by chromatography. by the way ( wich solvent dont know the english word for it // Fließmittel // works best ?)
And i also looked at the pics by xicori (Meerwein acrylisation...) and his crude >Keton looks exactly like mine !! the only Problem is my Vakuumpump broke . ( u can still turn it on but it makes really unpleasant sounds like sth is scraping insinde ...) Can i destill it without too much loss @ atmospheric pressure ?
 
 
 
 
    moo
(Hive Addict)
11-09-04 16:11
No 540660
      The problem isn't the reactivity of the ...     

The problem isn't excactly the reactivity of the nitrile. One major problem is the fact that the nitrile is acidic enough to protonate the Grignard reagent, turning your precious benzylmagnesium chloride to plain toluene. The deprotonated acetonitrile then goes on and forms different side reaction products. I have a reference to back this up somewhere. Of course one can argue that it is about reactivity because if the reaction with the nitrile was much faster than a proton transfer, this problem would not exist. But proton transfers are known to be very fast reactions.

I think that another problem is the addition of a second molecule of the Grignard reagent to the formed salt of the imine (iminate?), the reason why Grignard reagent should be added to an excess of the nitrile and not the other way around.

However, the reaction is proven to give P2P in literature several times, yields are the problem.

fear fear hate hate
 
 
 
 
    Novice
(Hive Bee)
11-09-04 18:30
No 540678
      If the problem is deprotonation of ...     

If the problem is deprotonation of acetonitril, then the exact same reaction but instead of hydrolysis with acid, reduction with NaBH4 to amphetamine is consulted should not give an 80% yield1. Am I wrong in my reasoning? As the reduction step comes post-imin formation...

1 JACS 109, 3378-3387 (1987) Procedure adapted from the synthesis of #49 (https://www.rhodium.ws/chemistry/amphetamine.html)
 
 
 
 
    moo
(Hive Addict)
11-12-04 18:45
No 541265
      Thanks for asking, an interesting example...     

Thanks for asking, an interesting example which I had overlooked, even though I've seen it several times before. That preparation is obviously tried and true. I'm convinced that steric factors play a major role here as phenylacetonitrile is more acidic than acetonitrile, and methylmagnesium iodide more basic than benzylmagnesium chloride. Also note the inverted addition. So, I must take my word back about the reactivity of the nitrile group not being the issue. Here is another example of a Grignard addition to nitrile, propionitrile in this case: Post 475862 (moo: "one pot 1-phenyl-2-butanamine etc", Novel Discourse).

Here is the reaction scheme from the original article JACS 109 3378-3387:

Grignard.png

fear fear hate hate
 
 
 
 
    Rhodium
(Chief Bee)
11-13-04 00:27
No 541306
User Picture 
      Nitrile + Grignard + NaBH4 -> Amphetamine
(Rated as: excellent)
    

Novel diacid accelerated borane reducing agent for imines
Zhi-Hui Lu, Nandkumar Bhongle, Xiping Su, Seth Ribe and Chris H. Senanayake
Tetrahedron Letters 43, 8617–8620 (2002) (https://www.rhodium.ws/pdf/grignardimine.amph-2002.pdf)



Abstract
A remarkable effect of diacids in modulating the reactivity of borane has been discovered. This novel process provides a rapid and excellent access for reduction of a variety of imines with different functionalities.
____ ___ __ _

New resolution approach for large-scale preparation of enantiopure didesmethylsibutramine (DDMS)
Zhengxu Han, Dhileepkumar Krishnamurthy, Q. Kevin Fang, Stephen A. Wald and Chris H. Senanayake
Tetrahedron: Asymmetry 14, 3553–3556 (2003) (https://www.rhodium.ws/pdf/grignardimine.amph-2003.pdf)

.gif

Abstract
An improved synthesis and efficient resolution method to prepare both enantiopures of DDMS using crystallization of enantiomerically pure tartaric acid salts of racemic DDMS are disclosed.

Experimental
A 1 L three-necked round-bottomed flask was charged with 1-(4-chlorophenyl)-1-cyclobutylcarbonitrile (CCBC, 50.0 g, 261 mmol) and toluene (150 mL), followed by iso-butyl magnesium chloride (395 mL, 1.0 M in MTBE), and the resulting mixture was distilled until the internal temperature reached 105°C. After stirring at that temperature for 2 h, the mixture was cooled to 0°C and methanol was added slowly (295 mL), followed by sodium borohydride (10.4 g, 1.06 equiv.) portion-wise. The resulting mixture was stirred at rt for 15 min and was added to a 2N HCl solution (330 mL) slowly, stirred for 15 min and the phases were separated. The aqueous phase was extracted with toluene (300 mL), the combined organic phases were distilled to remove methanol, and then washed with aqueous NaOH solution (1.5 M, 100 mL) and water (100 mL) twice. The resulting organic phase was heated to 50–60°C, followed by an addition of D-tartaric acid (40.0 g) in water (80 mL) and acetone (40 mL) slowly. The reaction mixture was azeotrope distilled until the internal temperature reached 92°C and then cooled to ambient temperature in 1–2 h. The slurry was filtered, and the wet cake was washed with MTBE (100 mL) and dried at 40–45°C under reduced pressure to afford (RS)-DDMS·D-TA (100.5 g) in 95.8% yield.

____ ___ __ _

A Study and Identification of Potential By-Products of Sibutramine
G. Om Reddy, M. R. Sarma, B. Chandrasekhar, J. Moses Babu, A. S. R. Prasad, and C. M. Haricharan Raju
Organic Process Research & Development 3, 488-492 (1999) (https://www.rhodium.ws/pdf/grignardimine.byproducts.pdf)

Abstract
In the synthesis and process development of sibutramine (9), the isolation and characterization of two potential by-products namely heptane dinitriles (4a-b) and bis-cyclobutyl alkylamine (10) have been studied. The key steps in the synthesis of sibutramine which have contributed to the formation of above by-products are cycloalkylation of 4-chlorophenyl acetonitrile (1) and tandem Grignard reduction on 1-(4-chlorophenyl)-cyclobutyl carbonitrile (3).
____ ___ __ _

Synthesis of sibutramine, a novel cyclobutylalkylamine useful in the treatment of obesity, and its major human metabolites
J.E. Jeffery, F.Kerrigan, T.K. Miller, G.J. Smith and G.B. Tometzki, J. Chem. Soc. Perkin Trans. 1, 2583-2589 (1996)
DOI:10.1039/P19960002583

Abstract
Synthetic routes to N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine (sibutramine) 1 and its demethylated and hydroxylated human metabolites N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine 2, 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine 3, 4-amino-4-[1-(4-chlorophenyl)cyclobutyl]-2-methylbutan-1-ol 4 and c-3-(1-amino-3-methylbutyl)-3-(4-chlorophenyl)cyclobutan-r-1-ol 5a are described. Key steps are tandem Grignard–reduction reactions on 1-(4-chlorophenyl)cyclobutanecarbonitrile 7 and its 3-(tetrahydropyran-2-yloxy)-substituted analogue 14 and a convenient one-pot conversion of 4-chlorophenylacetonitrile 6 into the 3-hydroxycyclobutanecarbonitrile 13.

The Hive - Clandestine Chemists Without Borders
 
 
 
 
    Novice
(Hive Bee)
11-14-04 01:04
No 541455
      Methinks ether is the problem.     

Thanks for those great articles Rhodium!

You see, SWIN tried out the preparation of amphetamine by this specific route (BnMgCl + MeCN), and it yielded the very same white sludge/crystal mass that sticks to the inside of the flask (it renders stirring impossible).

The formation of this in ether insoluble goo occured during or after the addition of BnMgCl to MeCN. The reaction took SWIN by such surprise that SWIN decided to stop right there, and not spend any NaBH4 on what seemed to be a failing attempt to ampetamine. But when you stop to think about it, the intermediate imin-magensium salt IS probably insoluble in diethyl ether, and the article never mentions the behaviour of this intermediate compound in any other solvent then THF.

SWIN's guess is that the goo is the magnesium imine-salt, that it's insoluble in Et2O, and at least more soluble in THF. This is the reason it's never mentioned as a problem in the article.

Radiumhero also used Et2O in his attempt, and it gave the same result as for SWIN. Is there anyone who has had any success with grignard reactions involving nitriles using ether as the solvent?

Neither of the article Rhodium posted above employs Et2O as the solvent, only THF.

Next time SWIN'll RTFM and use THF instead.

smile
 
 
 
 
    Radiumhero
(Stranger)
11-14-04 19:39
No 541537
      did you keep the Sludge ?     

Novice did you keep your product ?
Well i tried a second miniscale reaction wich yielded
this white stuff again , wich was washed 2 times with little
bit ET2O and was coverd with Etoh( 95) with Hcl gassed
After ca 2 h a nice light yellow toplayer has been saved
and stored for further purification . ( product has most likely ET2O and acetonitril contaminations)
Ill destill it ( @ normal pressure ) and tell you the Bp
of the main fraction .
 
 

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