Reactions of Grignard reagents

Grignard reagents behave both as bases and as nucleophiles. The basicity leads to the requirement that water be rigorously excluded from the reaction mixture both in the preparation and in the use of the Grignard reagent. 

Basicity refers to the ability of a Grignard reagent to react with proton donors, including weak donors like water. The carbanion is the conjugate base of a very weak acid (K = 1(H° - 10 °). This process is 

Weak acids (WA) have strong conjugate bases (SB), while strong acids (SA) have weak conjugate bases (WB). The weaker the acid or base, the stronger its conjugate. 

A Grignard reagent behaves as a base towards water (an acid). An example of this reaction is 

Another example illustrating the basicity of Grignard reagents is 

Purpose To demonstrate the preparation of a tertiary alcohol by the reaction of a 

Review the Safety Alert for Preparation of Grignard Reagents (Sec. 19.2). 

Preparation Sign in at www.cengage.com/login to answer Pre-Lab Exercises, access videos, and read the MSDSs for the chemicals used or produced in this procedure. Review Sections 2.10, 2.11, 2.13, 2.17, 2.21, 2.22, and 2.29. 

Apparatus Glass apparatus from the miniscale experimental procedure of Section 19.2, separatory funnei, ice-water bath, and apparatus for magnetic stirring, simple 

Setting Up While the reaction mixture for the preparation of phenylmagnesium bromide (Sec. 19.2) is cooling to room temperature, dissolve 1.2 mL of methyl benzoate in about 5 mL of anhydrous diethyl ether, and place this solution in the separatory funnel with the stopcock closed. Cool the reaction flask containing the phenylmagnesium bromide in the ice-water bath. 

Kharasch and O. Reinmuth, Grignard Reactions of Nonmetallic Substances, Prentice-Hall, New York, 1954, p. 1274. 

Lecher and his co-workers, for instance, obtained diphenyl sulfide and phenyl p-tolyl sulfide from benzene- and /Koluene-sulfenyl chloride, respectively.39 

Sulfinic acids are formed by reaction of sulfur dioxide498 or sulfuryl chloride499 with Grignard compounds, but yields rarely exceed 60%. Side reactions that may occur can be repressed by passing in the sulfur dioxide at temperatures below 0° and by not using an excess thereof. 

General directions for preparation of sulfinic acids 498 500 Sulfur dioxide is led into a well cooled ethereal solution of the alkylmagnesium halide until no more precipitation occurs. After removal of the ether, the white crystalline residue of the magnesium sulfinate can be recrystallized directly from water, and the magnesium salts of ethane-, propane-, butane-, isopentane-, cyclohexane-, and benzene-sulfinite were prepared in this way magnesium 1-dodecanesulfinite501 was prepared at —35° to —40°. 

For preparation of the free sulfinic acids498 the magnesium sulfinite is suspended in a little water and treated under good cooling with concentrated hydrochloric or sulfuric acid. The oil that separates is taken up in ether, the sulfinic acid is removed from the ether by sodium carbonate solution, liberated again by acid, and taken up again in ether. Finally the ether is removed in a current of air at a low temperature. 

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These compounds are soluble in ether, are comparatively stable, and exhibit many of the reactions of Grignard reagents but are more reactive. Because of their greater reactivity, organohthium compounds can often be used where Grignard reagents fail thus they add to the azomethine linkage in pyridines or... 

The reaction of Grignard reagents with a carbonyl group can be understood as an insertion reaction of an unsaturated C=0 bond of the carbonyl group into... 

Organolithium and -magnesium compounds. Compared with extensive studies carried out on the Ni-catalyzed transmetallation reaction of Grignard reagents[43I,432], few examples of the Pd-catalyzed reactions of Mg are... 

Alcohol synthesis via the reaction of Grignard reagents with carbonyl com pounds (Section 14 6) This is one of the most useful reactions in synthetic organ ic chemistry Grignard reagents react with formaldehyde to yield primary alco hols with aldehydes to give secondary alcohols and with ketones to form terti ary alcohols... 

Reaction of Grignard reagents with es ters (Section 14 10) Tertiary alcohols in which two of the substituents on the hy droxyl carbon are the same may be pre pared by the reaction of an ester with two equivalents of a Grignard reagent... 

Reaction of Grignard reagents with aldehydes and ketones (Section 14 6)... 

We saw an example of nucleophilic ring opening of epoxides in Section 15 4 where the reaction of Grignard reagents with ethylene oxide was described as a synthetic route to primary alcohols... 

The reaction of Grignard reagents with epoxides is regioselective m the same sense Attack occurs at the less substituted carbon of the ring... 

The reaction of Grignard reagents with the keto group of 5a-cholestan-3-one (7) was first described in 1937/ In a later study, Barton obtained the two epimeric tertiary alcohols (8) and (9), in a ratio of 40 60 by exposing (7) to the action of methyl Grignard reagent. 

Beal and Kagan have shown that reaction of Grignard reagent with 15-ketones (45) gives the 15a-methyl carbinols (46). 

Reactions of Grignard Reagents with Aldehydes and Ketones... 

Section 19.11 Carboxylic acids can be prepared by the reaction of Grignard reagents with carbon dioxide. 

Reaction of Grignard Reagents with Iminium Salts... 

Many other routes are now available but the most used involve the reaction of Grignard reagents or lithium alkyls on orthoborates or boron trihalides ... 

More usually they are made by the reaction of Grignard reagents on HgCl2 in thf ... 

Secondary aziridines bearing a trifluoromethyl group were prepared via the Hoch-Campbell reaction of Grignard reagents and oximes bearing a trifluoromethyl... 

The reaction of Grignard reagents with carbonyl compounds has no direct biological counterpart, because organomagnesium compounds are too... 

Methods of synthesis for carboxylic acids include (1) oxidation of alkyl-benzenes, (2) oxidative cleavage of alkenes, (3) oxidation of primary alcohols or aldehydes, (4) hydrolysis of nitriles, and (5) reaction of Grignard reagents with CO2 (carboxylation). General reactions of carboxylic acids include (1) loss of the acidic proton, (2) nucleophilic acyl substitution at the carbonyl group, (3) substitution on the a carbon, and (4) reduction. 

TABLE 8. Formation of sulphoxides, R2S=0, from the reaction of Grignard reagents with sulphurous acid derivatives, SOX2... 

Few racemic alkyl p-tolyl sulphoxides were prepared in rather low yields (16—40%) by the reaction of Grignard reagents with mixed anhydrides 108, 109 and compound HO formed in situ from p-toluenesulphinic acid and 3-phthalimidoxy-l,2-benzoisothiazole 1, 1-dioxide167 (equation 59). The mixed anhydrides 109 or 110 when reacted with cyclopen-tene and cyclohexene enamines 111 gave the corresponding a-ketocycloalkyl sulphoxides 112 in low yields (10-41%) along with small amounts of several by-products such as disulphides and thiosulphonates167 (equation 60). 

TABLE IRON CATALYZED CROSS COUPLING REACTIONS OF GRIGNARD REAGENTS WITH (HETEROJARYL CHLORIDES OR -TRIFLATES... 

Polarization also occurs in coupling and disproportionation reactions of Grignard reagents with alkyl halides. The vinyl protons of isobutene produced in the reaction of t-butylmagnesium chloride with t-butyl bromide show A/E polarization as do the methyl protons of isobutane (Ward et al., 1970). Similar results arise in the reaction of diethyl-magnesium with organic halides (Kasukhin et al., 1972). 

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