Grignard reactions in solvents other than ether

From Grignard Reactions of Non-metallic Substances, by M.S. Kharasch and Otto Reinmuth (1954)

"Tertary Amines. Tschelinzeff¹⁴⁶ remarked the simarity betwwen the reactions of Grignard reagents with many oxygen compounds, on the one hand and their nitrogen analogs, on the other hand, e.g. water and ammonia, alcohols and amines (primary and secondary), ketones and nitriles, esters and amides. From this he reasoned that the nitrogen analog of an ether (e.i. a tertiary amine) might well play the same role as an ether in the preparation of a grignard reagent." [In short this worked. Specificly he speaks of dimethylaniline.¹⁴⁶

"Hydrocarbons. ...Tschelinzeff149 attempted the preparation of of Grignard reagents from a series of iodides (not specified) in benzene, both thiophene-free and thiophene contaminated, but noted no preceptible reaction after forty-eight hours at the boiling point. In xylene, he was able to prepare reagents from, ethyl, n-propyl, n-butyl, and n-amyl iodides without the use of a "catalyst".

When a few drops of a tertiary amine (suitable dimethylaniline) was added such preparations could be carried out in benzene, toluene, xylene, hexane, petroleum ether, benzine, and terpenoid hydrocarbons. Reaction often begin spontaneously, but always could be initiated by warming to 30-40 , or by adding a crystal of iodine.... Simialr tertiary amine promoted Grignard reagents preparations in hydrocarbon solvents are described b Tschelinzeff¹⁵⁰, by Stadnikoff¹⁵¹, and Hess and Rheinboldt¹⁵².

...A comparative study of the effectiveness of various ethers and their sulfur analogs in facilitating Grignard reagent formation in benzene solution has been made by Hepworth¹⁵⁶.... In general oxygen compounds are much more effective thantheir sulfur analogs. Open-chain compounds are more effective than the related hetrocycles: e.g. ethyl n-propyl ether is more effective than pentamethylene oxide; ethyl n-propyl sulfide is more effective than pentamethylene sulfide...

Gilman and McCracken¹⁵⁷ have reviewed earlier work on the preparation of Grgnard reagents in solvents other than ethyl ether, and have investigated the effect on Grignard yields of various hydrocarbon-ethyl ether mixtures. They conclude that in general, the use of a mixed solvent results in a drop in yeild of about 10% below that obtained with the optmum ethyl ether concentration.

Barr'e and Repentigny¹⁶⁰ describe the preparation of several Grignard reagents in hydrocarbon solvents with dimethylaniline as "catalyst".

"TABLE II-XII:
Preparations Of Several Griganrd Reagents In Hydrocarbon Solvents With The Aid Of Dimethylaniline

Benzyl chloride in refluxing benzene (14h, 80°C) with the addition of 1.25g PhNMe₂ as catalyst results in a 20-30% yield of Benzyl Magnesium Chloride, but the Benzyl Chloride also quaternizes to some extent; neither allyl bromide nor t-butyl chloride give appreciable yeilds of Grignard reagent."

References

• 146: Tschelinzeff, Ber., 37, 2081-5 (1904)
• 149: Tschelinzeff, Ber., 37, 4534-40, (1904)
• 150: Tschelineff, Ber., 3664-73, (1905)
• 151: Stadnikoff, Ber., 44, 1157, (1911)
• 152: Hess and Rheinboldt, Ber., 54B, 2043-55, (1921)
• 156: Hepworth, J. Chem. Soc., 119, 1249-56, (1921)
• 157: Gilman and McCracken, Rec. Trav. Chim., 46, 463-72, (1927)
• 160: Barr'e and Repentigny, Can. J. Research, 27B, 716-20, (1949)

Also, concerning ketone formation by Grignard reagent addition to an excess of acid halide...

"'The order of activity of the three acid halides, benzoyl flouride, chloride, and bromide,...Since the acid flouride is actually found to be the most reactive, it is obvious that the reaction occurs through addition to the carbonyl group not through a metathetical reaction of the halogen atom...

It may or may not be significant in this connection that the order of reactivity of acyl halides toward the organoainc, -cadmium, and -mercury compounds (Which do not under go carbonyl double bond addition, which is very slowly indeed) is said to be the reverse of that toward Grignard reagents...

Preparation Of Ketones By Grignard-Halide Interaction

For that purpose low operating tempatures, reverse adition (i.e. addition of the Grignard reagent to the acid chloride, or it's solution), and the use of an excess of the acid chloride are obviously indicated. The reaction has indeed been employed by, amoung others, Gilman et al¹³, Helferich and Malkomes¹⁴, Darzens and Rost¹⁵, Acree¹⁶, Schmidlin¹⁷, Karrer¹⁸, and Whitmore and Badertscher¹⁹...

When applicable, however, the organozinc halides or the diorganocadmium, compounds give superior results.

Ketone Preparation With The Aid Of Zinc And Cadmium Salts

The advantage claimed for the use of organocadmium compounds are: that they are readily prepared form from Grignard reagents and the relativly economical, nonhydroscoopic cadmium chloride; that the preparation and subsequent reaction can be carried out in ether solution (although benzene, or toluene is preferred solvent for acid chloride reactions); that, although they react readily with acid chloride and acid anhydrides, they are are very unreactive towards other functional groups (including the carbonyl) that react more or less readily with Grignard reagents. The R₂Cd and RCdX compounds appear to be equally satisfac- tory, but the former are most often used as requiring less cadmium chloride.

The Organozinc compounds are similar in chemical properties to the corresponding organocadmium compounds, but notwithstanding the recommondations of Blaise²⁵, who gives no experimental detail, are alleged to to be comparatively disadvant- ageous because of greater difficultly of preparation; the undesireableity of using ether as a solvent in acid chloride reactions )because of ether cleavage and ester formation); and the geatwerreactivity of the zinc compounds particularly towards carbonyl groups. ...It is possible, however, to affect the preparation by a method analogous to that commonly employed for the preparation of organocadmium compounds, namely, the addition of anhydrous zinc chloride to a Grignard reagent solution, a method that has been used with good sucess by Jones²⁷ and others."

TABLE IX-I:
Preparation Of Ketones From Acid Halides With The Aid Of Cadmium Or Zinc Salts

CH₃COCl + C₆H₅CH₂MgCl + CdCl₂ → Phenyl-2-Propanone (18%)

Conclusion: Ketone preparation from Cd or Zn SUCKS, no matter how you do it...

References

• 13: Gilman, "Organic Chemistry", 2nd Ed,Chapter 5, page 501-2,1943
• 14: Chem. Abstr., 41, 41, 3444, 1947
• 15: Rec. trav. chim., 48, 748-51, 1929
• 16: Ber.,625-8, 1904
• 17: Ber., 42, 2377-92, 1909
• 18: Ber., 50, 1499-508, 1917
• 19: J. Amer. Chem. Soc., 55, 1559-67, 1933
• 25: Bull. soc. chim., [4], 9, I-XXVI, 1911
• 27: J. Amer. Chem. Soc., 69, 2350-4, 1947