Author Topic: Arylmagnesium bromides/chloroketones reaction  (Read 13231 times)

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Arylmagnesium bromides/chloroketones reaction
« on: October 07, 2002, 06:32:00 PM »
The following is a summary of the reaction between zinc and magnesium organometallic aryl halides and chloroketones:

Taken from J.O.C., pp. 2539-2540 (1954)

This is an interesting paper covering the specifics of the Grignard reaction of chloroacetone.  Apparantly, it is the carbonyl group that is attacked by the phenylmagnesium bromide.  This intermediate can be hydrolyzed by water to form a chlorohydrin, or, it can be refluxed in benzene or toluene, the heat of which rearranges the Grignard complex, which, after hydrolysis, furnishes the ketone.  Cool.

Here are the best parts of the paper:

"The reaction of 2-chlorocyclohexanone with aryl Grignard reagents . . . proceeds by normal addition of the reagent to the carbonyl group; the resulting complex can then give rise to either the chlorohydrin . . . or the rearranged ketone . . . according to whether R is of low or high electropositivity, respectively.  It seemed of interest to study the same reaction with chloroacetone, the simplest member of the chloroketones and free from steric complications. . . .

"It is known that chloroacetone on reaction with phenylmagnesium bromide and subsequent hydrolysis furnishes the normal addition product, namely, the chlorohydrin . . . but that heating of the magnesium complex before hydrolysis results in a rearranged product, phenylacetone (Tiffeneau, Ann. Chim., 1907, 10, p. 367).  The action of chloroacetone of a two-fold excess of Grignard reagent containing the typical aromatic groups has now given the following results. . . .

". . . strongly electron-releasing groups (p-ethoxyphenyl and p-methoxyphenyl) yield exclusively the substituted stilbenes . . . undoubtedly derived from the alcohols . . . by dehydration.  When, however, only a 0.5 mole excess of the [phenylmagnesium bromide] reagent was used, the ketone . . . also was isolated in small yields. . . .

"Weakly electron-releasing groups (m- and p-chlorophenyl) furnished the chlorohydrins . . . only.  And ortho- substituted aryl group (o-methoxyphenyl) also yielded the chlorohydrin . . .

"As with 2-chlorocyclohexanone, therefore, the ultimate product of the reaction depends on the nature of the aryl group, highly electropositive groups leading to rearranged products [ketones].  In the former case, however, the cyclohexanone . . . was obtained, and it is not clear whether rearrangement had taken place before or after hydrolysis of the magnesium complex.  With chloroacetone it appears probable that this complex had undergone rearrangement to the ketone . . . which then reacted with more Grignard reagent to give the alcohol [which then dehydrated to form the stilbene].  This rearrangement might proceed via a free-radical intermediate . . . which could be generated from the complex . . . by a one-electron transfer to the chlorine atom either from unchanged magnesium in the Grignard reagent, or from a component of the equilibrium 2RMgX <<<>>> R2Mg =MgX2.  The fact that a filtered Grignard solution did not alter the course of the reaction, however, excludes the former possibility."

J.A.C.S., Vol. 56, pp. 1990-1994

In this article, they give a few examples of the reaction above using methylmagnesium bromide instead of phenylmagnesium bromide to form 2-methylcyclohexanone.  There is considerable detail provided as to the reaction mechanism.  Good paper.

Taken from J.A.C.S., Vol. 66, pp. 1550-1552 (1944)

This is another example of the various reactions described above:

2-Phenylcyclohexanone, I.---A solution of 280 g. of 2-chlorocyclohexanone in 750 cc. of dry ether was added with stirring to 750 cc. of 3.22 M phenylmagnesium bromide at a rate which caused gentle refluxing (one hour).  The ether was distilled until the foaming viscous residue almost filled the flask.  After addition of 700 cc. of dry benzene the mixture was refluxed for eight hours.  The reaction mixture was then hydrolyzed in the cold with water and the pure ketone, I, was obtained after vacuum fractionation as a colorless solid, b.p. 136-137 at 5-6 mm., f.p. 53-55, in 58% yield.

J.A.C.S., Vol. 72, pp. 1995-2000 (1950)

This paper details the synthesis of ring substituted 2-Phenylcylohexanones as intermediates to unsaturated lactones formed by glyoxalation. 

"With the appearance of the paper by Newman and Farbman (J.A.C.S., 66, 1550 Post 1944 (not existing); previous citation) describing a convenient preparation of 2-phenylcyclohexanone from phenylmagnesium bromide and 2-chlorocyclohexanone, we extended the reaction to the preparation of 2-(p-anisyl)-cyclohexanone and other 2-aryl-cyclohexanones.  The m-anisyl compound required a higher temperature and the p-anisyl compound a lower temperature than the phenyl compound for satisfactory yields." 

Yields in this paper for 2-phenylcylcohexanone were 60%.
2-(p-Anisyl)-cyclohexanone.--To an ice cold solution of the Grignard reagent prepared from 32.8 g. of p-bromoanisole and 4.5 g. of magnesium in 150 ml. of ether a solution of 23 g. of 2-chlorocyclohexanone in 100 ml. of ether was added slowly with stirring.  After standing for fifteen hours at room temperature the mixture was poured into a cold saturated solution of ammonium chloride.  The organic layer was washed with water and dried over magnesium sulfate, and the ether was removed.  The ketone which distilled at 134-135 and 0.2 mm. solidified to a colorless mass; weight, 18.2 g.; m.p. 80-85.  After several recrystallizations from 60-75 petroleum ether the 2-(p-anisyl)-cyclohexanone formed clusters of fine colorless needles; m.p. 89-89.2.  The crystalline ketone was unchanged after exposure to air for three years.
2-(m-Anisyl)-cyclohexanone.--To the Grignard reagent prepared from 15 g. of m-bromoanisole in 50 ml. of ether was added a solution of 14 g. of 2-chlorocyclohexanone in 50 ml of ether at such a rate that the solution boiled gently.  The ether was removed, 50 ml of toluene was added, and the mixture was refluxed for twenty-four hours.  The 2-(m-anisyl)-cyclohexanone was obtained as a colorless liquid which was not analytically pure; weight, 4.8; b.p. 150-158 at 0.2 mm.

2-(p-Isopropylphenyl)-cyclohexanone.--To a solution of the Grignard reagent prepared from 40 g. of p-bromocumene in 250 ml. of ether, cooled in an ice-salt bath, a solution of 27 g. of 2-chlorocyclohexanone in 100 ml. of ether was added with stirring.  After about one-half of the ether had been removed by distillation, 100 ml. of benzene was added and the mixture was refluxed for two hours and then hydrolyzed with an ice cold solution of ammonium chloride.  The ketone (21.5 g.) distilling at 140-145 and 0.1 mm. solidified when triturated with petroleum ether and crystallized from petroleum ether in colorless plates; m.p. 68-69.

Here are some examples of zinc-organic reactions taken from the most recent edition of Vogel's (The one with the reddish-orange cover), page 732:


BrCH2-CO2Et + Zn >>> BrZnCH2-CO2Et >>>(Ph-CHO) >>>

   Ph-CH(OZnBr)-CH2-CO2Et >>> (H3O+)>>> Ph-CH(OH)-CH2-CO2Et

It is essential that all the apparatus and the reagents be scrupulously dry for successful results (compare Grignard reaction).  Equip a 500-ml three-necked flask with a 250-ml separatory funnel, a mechanical stirrer and a double surface condenser; insert calcium chloride guard-tubes in the funnel and condenser.  Place 40 g (0.61 mol of zinc dust (previously dried at 100 C) (Section 4.2.80, p. 467) in the flask, and a solution of 83.5 g (55.5 ml, 0.5 mol) of ethyl bromoacetate (CAUTION:  lacrymatory) (1) and 65 g (62 ml, 0.615 mol) of purified benzaldehyde (Expt. 6.133) in 80 ml of sodium-dried benzene and 20 ml of sodium-dried ether in the separatory funnel.  Add about 10 ml of the solution to the zinc and warm the flask gently until the reaction starts.  When the reaction has commenced, but not before, stir the mixture and add the remainder of the solution at such a rate that moderate refluxing occurs (about 1 hour).  Reflux the reaction mixture on a water bath for a further 30 minutes.  Cool the flask in an ice bath, and add 200 ml of cold 10 per cent sulfuric acid, once with 25 ml of 10 per cent sodium carbonate solution and finally with two 25 ml portions of water.  Extract the combined solutions with 100 ml of ether, and dry the combined benzene and ether solution with 5 g of anhydrous calcium sulfate.  Filter from the desiccant, remove the solvent by distillation under atmospheric pressure and distil the residue under reduced pressure.  Collect the ethyl 3-phenyl-3-hydroxypropanoate at 152-154 C/12 mmHg.  The yield is 60 g (62%).

Note. (1) Great care must be exercised in handling ethyl bromoacetate.  Keep a 10 per cent aqueous ammonia solution available to react with any bromoester which may be spilled.

Cognate preparation.  Ethyl 1'-hydroxycyclohexylacetate.  Place 65 g (1 mol) of clean dry zinc dust and a few crystals of iodine in a 2.5-litre three-necked flask, equipped with an efficient reflux condenser with drying tube, a mechanical stirrer and a dropping funnel.  Prepare a mixture of 400 ml of sodium-dried benzene and 350 ml of sodium-dried toluene with 167 g (111 ml, 1 mol) of ethyl bromoacetate and 98 g (103.5 ml, 1 mol) of pure dried and redistilled cyclohexanone.  Transfer 150 ml of this mixture to the flask, start the stirrer and heat the flask in a boiling water bath.  A vigorous reaction soon sets in.  Add the remainder of the mixture through the dropping funnel at such a rate that gentle refluxing is maintained.  Continue the stirring for an additional 2 hours: practically all the zinc dissolves.  Cool the mixture, add sufficient 10 per cent sulfuric acid with stirring to dissolve all the zinc hydroxide.  Separate the benzene-toluene layer, dry it with anhydrous sodium sulfate, remove the solvent using a rotary evaporator and distil the residue under reduced pressure.  Collect ethyl 1'-hydroxycyclohexylacetate at 86-89 C/2 mmHg.  The yield is 125 g (67%).

This is cool in that it seems very true that zinc organic reactions really can take place in such solvents as toluene and/or xylene.

So I guess in a nutshell, substituted or unsubstituted phenylmagnesium halides react with chloroketones by attacking the carbonyl function to form a magnesium chlorohydrin intermediate which can--depending upon the aryl structure being either electronegative or electropositive--either immediately or upon addition of heat, rearrange, furnishing after hydrolysis the desired ketone.  Correct?

I would like to know if the zinc analog to this reaction would react in the same way.  That is, does the phenylzinc bromide react directly with the halogen of halogenoketones or does it react with the carbonyl group first, as in the manner specified for phenylmagnesium bromide?

Also, can aryl bromides efficiently replace aryl iodides as precursors to arylzinc compounds?  If so, what would be the required experimental conditions to facilitate high yields?

Hope the above information has been of some help.


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« Reply #1 on: October 08, 2002, 10:02:00 AM »
Nice... but did you notice

Post 346231

(Antoncho: "Zealot: a new zincorganic synthesis of P2P's", Novel Discourse)


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What I'm interested in knowing is if phenyl-zinc ...
« Reply #2 on: October 09, 2002, 04:02:00 AM »
What I'm interested in knowing is if phenyl-zinc made from iodobenzene will react with the schiff base of cyclohexanone/ethylamine(or its toluenesulfonic acid salt) to produce PCE? I can't locate any refs that invole the reaction of phenyl or anisyl-zinc with the schiff base of cyclohexanone and any type of amine.. Oh well, in the words of a well known bee, "Arrr fuckin!!" 8)

Love my country, fear my government.


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If you use Rieke Zn * (made from refluxing ...
« Reply #3 on: October 09, 2002, 08:32:00 AM »
If you use Rieke Zn* (made from refluxing potassium in a solution of ZnCl2) I am sure that would do.

Alcohol, an unconsciousness-expanding drug


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Rieke Zn
« Reply #4 on: October 12, 2002, 04:20:00 PM »
Cool. Do you know of any patents/refs that deal with the production of Rieke Zn and its applications? Is it usually reacted with salts(carbonitriles or imminium salt from p-tosic acid), or is it more like lithium? Thanks!

Love my country, fear my government.


  • Guest
« Reply #5 on: October 12, 2002, 05:13:00 PM »
There is a good review article of Rieke metals in Aldrichimica Acta Vol 33, No 2, found at


  • Guest
« Reply #6 on: October 13, 2002, 04:14:00 AM »
Thanks. Found an interesting book there; Organozinc Reagents in Organic Synthesis - E. Erdick, 1996. :)

Love my country, fear my government.


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To Bwiti
« Reply #7 on: October 13, 2002, 04:48:00 AM »
Are you planning on buying that book? If so, can you pretty pretty please PM me when you get it, I want the table of contents and your personal opinion on the book, even before you read it.

The title alone is enough to make me buy it, but if you plan on purchasing it, I would love to get info from you about the book before I buy it.

Sorry for being off topic.


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I'm fucking broke right now, but when I do get ...
« Reply #8 on: October 15, 2002, 02:25:00 AM »
I'm fucking broke right now, but when I do get it, I'll be sure to post the table of contents and a few synths from it.

Love my country, fear my government.