Author Topic: Grignard trouble  (Read 1060 times)

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zero_nrg

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Grignard trouble
« on: January 08, 2004, 03:26:00 PM »
The following happened recently:


125 grams of distilled benzyl chloride (prepared using benzyl alcohol + HCl synth) was mixed with 250ml dry diethyl ether.  10% of this mix was added to 24 grams clean and dry magnesium turnings in 100ml diethyl ether in a 1000 ml 3 necked RBF with stirbar, condenser (reflux), and calcium chloride guard tube.  Heat, from a warm water bath, was applied to the bottom of the flask to begin the Grignard reaction.  Gentle boiling started and the rest of the ether and benzyl chloride mix was added to the flask. Everything OK thus far and slow stirring started.  Elapsed time=5 minutes, boiling started to get slightly more vigorous and an ice bath was applied to control reaction rate.  Seemed to work.  Ice bath was removed and after 1 minute or so the reaction again was too vigorous.  Ice bath applied once again and this time it seemed to have little effect.  Stirring stopped and ice bath continued with little effect.  The ether could be seen condensing far too high in the condenser.  Reaction was out of control at this point and the two glass stoppers in the RBF popped out with some liquid as a result of ether boiling over.  At this point the decision was made to plunge the entire RBF into a tub of water nearby.  Total failure. This reaction was performed successfully at 1/10th the scale. 
Question: Could the reaction be controlled better by adding the magnesium a little at a time?  Any ideas are appreciated.  -zero

Rhodium

  • Guest
proper grignard prep
« Reply #1 on: January 08, 2004, 03:48:00 PM »
The preferred way of making a grignard reagent is to cover the activated Mg turnings with ether, then add only 1/4 or 1/5 of your alkyl halide soulution in ether to the Mg/ether. Then, when the reaction starts and the ether starts to boil, you begin adding the rest of the etheral alkyl chloride solution *dropwise* and then carefully adjust the addition speed so that the boiling happens at a controllable rate, but not so slowly as to allow the reaction to subside.


lugh

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Grignard Tips and Procedures
« Reply #2 on: January 08, 2004, 05:49:00 PM »
From Chapter 12 of Migrdichian's Organic Synthesis 

Preparation of Organomagnesium Compounds
The general procedure followed in preparing an organomagnesium halide is as follows:

The required quantity of magnesium; in the form of turnings, 3 mm long and 0.6 mm thick, is placed in a dry flask provided with a sealed stirrer and a reflux condenser; the air is displaced with a current of dry nitrogen, a little ether and a crystal of iodine are added, then a small amount of the halide is introduced to initiate the reaction. If reaction fails to proceed spontaneously, the mixture is heated to 45°, although more frequently it is necessary to apply external cooling in order to moderate the reaction. After the initial vigorous reaction has subsided to some extent, the halide, mixed with 1 to 3 volumes of ether, is added slowly and at a constant rate, while the liquid in the flask is stirred. After the addition of all the halide mixture, the flask is heated until the reaction is complete.
It is important that both the reflux condenser and the dropping funnel used for the in­troduction of the halide-ether mixture, be protected from atmospheric moisture by means of calcium chloride tubes. The magnesium turnings must be clean and, in particular, free from any oily matter. Commercial magnesium in the form of turnings or of coarse powder may be used. The quality of magnesium employed may greatly affect the yields obtained_ The magnesium should be stored dry and, if desirable, it may be washed with pure, dry ether by decantation. The impurities present in the metal remain as a dark powder alter the completion of the reaction. The metal is used in an amount corresponding to the halide or in slight excess. The ether must be anhydrous and free from alcohol. Com­mercial alcohol-free ether distilled over phosphorus pentoxide is satisfactory. The ether may also be dried by storing it over sodium wire. The halide must be in a very pure form and free from acids, water or alcohol.
It is important that the halide be added slowly in order to avoid the presence of any large excess of unreacted halide and thus to prevent the reaction
RMgX + XR -. R.R + MgX2
which proceeds quite readily when iodides are employed. This reaction is favored if an excessive amount of iodine is used for initiation of the reaction.


and

Procedure in Carrying out Grignard Reaction

The Grignard reaction is carried out in the following manner:
The compound dissolved in ether is added to the solution of the organomagnesium halide at such a rate that the solution boils continuously. If the compound is insoluble in ether, it may be dissolved in benzene, petroleum ether, etc. Solid compounds may be added to an ethereal solution of the organomagnesium halide in the form of a powder. If there is a possibility of reduction, any temporary excess of the organomagnesium halide is avoided, by gradually adding the solution of the Grignard reagent to the solution of the compound. The reaction generally proceeds quite rapidly in most cases The magnesium complex resulting from the reaction is then decomposed, carrying out the operation with great care in order to assure the success of the preparation and to avoid danger. Rapid dilution and cooling by the addition of water and ice generally ac­complishes the desired result. Decomposition with water results in the formation of mag­nesium hydroxide. The formation of this compound may be avoided by adding dilute hydrochloric or sulfuric acid to the diluted, cooled reaction mixture. It is preferable to pour the reaction mixture on ice, and then to add the acid. If the reaction product is sensitive to acids and likely to polymerize when decomposi­tion is carried out with an acid, ammonium chloride may be used in place of the acid.
The success of the Grignard reaction often depends upon the rapidity with which the operation is carried out.
The ether, as well as other reagents must be quite dry. The ether is best kept dry by storing it over metallic sodium. The reaction often proceeds only when ether dried over phosphorus pentoxide is employed, though it has been carried out successfully in some cases with moist ether, using an excess of the re­agent.
If it becomes necessary to employ a high-boiling solvent as the reaction medium, the ether used in the preparation of the organomagnesium halide is re­moved as much as possible by distillation under vacuum at 100-105°, and the desired solvent is added. Benzene and ethers of higher alcohols are suitable solvents. Among the latter, methyl benzyl, methyl cyclohexyl, amyl and butyl ethers are often employed. The use of rubber stoppers should be strictly avoided, since rubber inhibits the reaction. Glass, or new, paraffin coated cork stoppers are satisfactory.
The rate of reaction is proportional to the concentration of the organomag­nesium halide in the solution. The optimum concentration of the reagent appears to be 30-40%, although occasionally concentrations as high as 70% are employ­ed.
High molecular products may be formed and may separate out in the course of the reaction; if they are liquids, sufficient benzene is added to bring them into solution. Solids, if they appear, are not readily brought into solution and may cause considerable difficulty.


Note that according to Gilman, rubber stoppers inhibit the Grignard reaction, so unless that's not an issue, they should be avoided  ;)  More details are in the file:




stratosphere

  • Guest
as everyone else seemed to indicate, the ...
« Reply #3 on: January 09, 2004, 11:55:00 AM »
as everyone else seemed to indicate, the problem was likley adding all your BzCl solution at once, most procedures ive read they add it slowly with a drop funnel.

zero_nrg

  • Guest
grignard success
« Reply #4 on: January 19, 2004, 04:13:00 PM »
Thanks everyone.  Slow addition is key to success and this newbee also sucessfully carbonanted the reagent to yield 55 grams of very pretty phenylacetic acid.  Yield seems low compared to writeup on Rhod´s site (100 grams), but I´ll work on the technique.  Will try next one with  undistilled benzyl chloride made from benzyl alcohol + HCl synth which by the way, is extremely easy. -zero

chemotype

  • Guest
dropwise and maybe use dry THF instead...
« Reply #5 on: January 20, 2004, 02:39:00 PM »
I guess that you learned that dropwise is the correct method.  Learn from your mistakes.  :)   You might also try using dry THF if you have it.  It is safer than ether because it has a higher bp.  It is less likely to boil out of coontrol.

zero_nrg

  • Guest
Grignard starting
« Reply #6 on: January 20, 2004, 04:02:00 PM »
Tried the above synth using undistilled  benzyl chloride from the benzyl alcohol + HCl synthesis.  Post reaction work-up for the benzyl chloride synth. consisted of only drying over MgSO4.  The Grignard failed to start with the undistilled benzyl chloride.  Wanted to try this just for the hell of it as vacuum distilling the benzyl chloride leaves very little residue in the distilling flask.  Another reason this was tried with only drying of the benzyl choride was that washing it with water, sodium carbonate, or sodium bicarbonate leaves the benzyl chloride a chalky white color and it seems water washes will not remove it (3-300ml water washes of 300 ml benzyl chloride).  Anyone have any suggestions for a post reaction work-up that does not involve vac distilling and leaves the benzyl chloride clear?  Also, will try the THF replacement for diethyl ether in this reaction as ether is definitely a pain due to the bp (will search for Grignard/THF refs)Thanks.  -zero

Rhodium

  • Guest
benzyl chloride purification
« Reply #7 on: January 20, 2004, 05:39:00 PM »
leaves the benzyl chloride a chalky white color and it seems water washes will not remove it

That would surprise me, as the chalky white color is most likely due to suspended water.

If you do not distill the benzyl chloride, you won't remove all acid/water/alcohol which prevents the grignard from starting.


zero_nrg

  • Guest
You´re right Rhod, the distilled benzyl ...
« Reply #8 on: January 23, 2004, 09:16:00 AM »
You´re right Rhod, the distilled benzyl chloride works and undistilled does not.  Also, the chalky looking benzyl chloride (washed with a saturated sodium carbonate solution and then with water) turns into a clear liquid again when heated to approx. 45C.  Also, it does not look as though any water seperates out of the benzyl chloride when heated and no water comes over into the condenser during vacuum distillation.  Dreaming of giving that benzyl chloride/acetaldehyde/methyl imine synth a shot as per Leno Latrunculus as acetaldehyde is readily available. Will consult with wise bees for this one.  -zero

Rhodium

  • Guest
I still think it's water, and my thoughts are thus
« Reply #9 on: January 23, 2004, 11:48:00 AM »
Very little water is needed to give a haze, and I suspect that the solution clears because the solubility of water in benzyl chloride increases. That no water condenses upon initiated distillation is then either because the amount is so small that the water vapor can flow out of the condenser without turning into liquid - the alternative is aqueous hydrolysis of the benzyl chloride to benzyl alcohol and hydrogen chloride.


albert_grieves

  • Guest
benzyl chloride / acetaldehyde/ methylamine synth
« Reply #10 on: January 23, 2004, 03:53:00 PM »
on page 13 paragraph 2 of this document (you need deja vu plugin)

https://www.thevespiary.org/rhodium/Rhodium/djvu/clandestine.drug.synthesis.djvu


it states that the benzyl chloride / acetaldehyde / methylamine synth described in "the underground literature" was incorrect.  I don't know what synth it refers to but the reference the article uses is from 1983.

Rhodium

  • Guest
wrong addition order
« Reply #11 on: January 23, 2004, 04:34:00 PM »
Yes, the description in "the underground literature" called for bubbling methylamine gas through the resulting solution from the addition of benzylmagnesium chloride to acetaldehyde, as that has been mentioned in a british patent. There is no way methylamine could add to the magnesium salt of phenyl-2-propanol (the actual adduct) just like that.


Scooby_Doo

  • Guest
You were doing ok, I've tried starting that...
« Reply #12 on: January 28, 2004, 08:37:00 PM »
You were doing ok, I've tried starting that reaction just dripping in the BzCl/ether at the beginning and usually it would take a long time to start if at all, and only after about 5 to 10% had been added anyway.

Adding 5-10% of the Benzyl chloride/ether sol to start is the easier way especially when your going to start scaling up. I would suggest better cooling through your condenser 0 to -10 deg C Also don't fuck around pulling the flask in and out of the ice bath. Once in leave it. Usually stirring would not have started yet to let the Grignard begin. Don't start stirring until the reaction subsides.  Then only slowly still in the ice bath if it gets wild stop stirring and wait. This reaction takes a bit of time to get used to. After a few you will get the hang of it.

The biggest SWIM could get it was around 4lt before the sol would become to thick to stir properly THF would probably fix that. Look at the procedure in Vogel's 3rd on this reaction and benzoic acid prac you follow this and you won't go wrong.

You will get better yields making PAA using Vogel's ratio of dry ice to Mg complex. Use recrystallization with water to seperate  the oil form PAA crystals (they look pretty cool). On a larger scale make the carboxylate salt to sep out the shit by extraction.

If your going down the one pot shot by adding methylimine/acetalaldehyde to the BzMgCl don't use ether as the grignard solvent, during the reflux it becomes burnt crusty brown poo. (Again it solidifies and can't be stirred) DEFINITELY use THF it solvates better and the higher temp speeds it up. Goodluck  :)