Stability of Grignard Reagents

Chapter 8. Nucleophilic Species That Form Carbon-Carbon Bonds 

If there is steric bias in a molecule and if the addition of a Grignard reagent generates diastereomers, the products will be formed with good diastereoselectivity in many cases. The rationale for diastereoselectivity discussed for reduction in section 4.8 generally applies to reaction of Grignard reagents and carbonyl 

Assuming that Grignard reagent addition to a carbonyl is a diastereoselective reaction that produces racemic products, it is important to ask if it is possible for the reaction to be enantioselective. If we rely on the carbon bearing the magnesium atom, the answer is no. If we incorporate a stereogenic center elsewhere in the molecule, however, the answer may be yes. For purposes of this discussion, the relative merits of the four cases listed above will be discussed. 

In some cases, it is possible to form a chiral, nonracemic alcohol from a prochiral ketone and a Grignard reagent by adding an asymmetric ligand (a chiral additive) to the reaction mixture, which is differentiated from 

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Complex formation with molecules of ether is an important factor in the formation and stability of Grignard reagents. 

In most text-books this point of view is scarcely considered, and few cases are reported. A frequent example is the stabilization of Grignard reagents by electron donor solvents (usually by lone pairs of the oxygen atoms of ethers), as shown in 1. This lack of attention is a simplification which generates little interest about the real nature of the starting materials and their energy levels, when reactions take place. 

Strong nucleophiles such as Grignard reagents. In general, ortho esters are difficult to prepare directly from acids and are therefore more often prepared from the nitrile. Simple ortho esters derived from normal alcohols are the least stable in terms of acid stability and stability toward Grignard reagents, but as the ortho ester becomes more constrained its stability increases. 

Use of the imonium group for protection of enones was explored. Stability to peracids, lead tetraacetate, bromine, and acetic anhydride was claimed (727). The usual resistance of enamines (but not their salts) to additions of Grignard reagents was used for selective addition to a 3,17-diketosteroid by formation of the usual 3-monoenamine 728). 

Stabilization of intermediates by strong adsorption will frequently be a necessary precondition for synthesis. Thus, in the case of the Kolbe reaction, further oxidation of the radicals is prevented the formation of metal-carbon bonds in the reduction of alkyl halides (Fleischmann et al., 1971a Galli and Olivani, 1970) or oxidation of Grignard reagents (Fleischmann et al., 1972c) is shown by the isolation of organometallic... 

A peroxide-free grade o anhydrous tetrahydrofuran (stabilized by 0.025% of 2,6-di- -butyl-4-methyl phenol) is available currently (1966) from Fisher Scientific Co. in 1-lb. bottles. This product as obtained from freshly opened bottles has been found to be suitable for reactions such as the formation of Grignard reagents in which purity of solvent is critical (du Pont Co., unpublished observations). It is standard practice in at least one laboratory to use only tetrahydrofuran (Fisher) from freshly opened bottles and to discard whatever material is not used within 2-3 days. 

The most conspicuous property of aliphatic amines, apart from their fishy smell, is their high basicity, which usually precludes N-alkylations under acidic reaction conditions (last reaction, Scheme 6.3). Hence, alkylation of amines with tertiary alkyl groups is not usually possible without the use of highly stabilized carbocations which can be formed under basic reaction conditions. Rare exceptions are N-alkyla-tions of amines via radicals (Scheme 4.2), copper-catalyzed propargylations (Scheme 6.3), and the addition of amines to some Michael acceptors and allyl palladium or iridium complexes. Better strategies for the preparation of tert-alkylamines include the addition of Grignard reagents to ketone-derived imines [13] or the reduction of tert-alkyl nitro compounds. 

The secondary -deuterium kinetic isotope effects in reactions of -perdeuterated ethyl-, isopropyl- and rm-butylmagnesium halides with four different ketones were described [24] and were found to be small (within 5%). There, too, hyperconjugative stabilization was supposed to play a role, but this effect was opposed by the steric effects. The role of hyperconjugation in reactions of Grignard reagents, therefore, seems complicated and requires further studies. 

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