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ORGANOMAGNESIUM COMPOUNDS

For many years the most important organometallic compounds for synthetic purposes have been the organomagnesium compounds or halides, or Grignard reagents. They are named after Victor Grignard, who discovered them and developed their use as synthetic reagents, for which he received a Nobel Prize in 1912. As already mentioned, these substances customarily are prepared in dry ether solution from magnesium turnings and an organic halide:


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Chlorides often react sluggishly and, in addition, may give an unwelcome precipitate of magnesium chloride, which, unlike magnesium bromide and iodide, is only very slightly soluble in ether. Organomagnesium fluorides eluded preparation until quite recently.

Although we usually write the structure of a Grignard reagent as RMgX, in which X is a halogen, the structure of the reagent in ether solution is more complex. There is a rapidly established equilibrium between the organomagnesium coumpoundS – organomagnesium halide (RMgX) and the corresponding dialkylmagnesium (RMgR):

Both of these species, RMgX and R2Mg, are reactive, and in ether solvents are solvated by coordination of the ether oxygen to magnesium. They further associate as dimers or higher polymers in solution. Although it is an oversimplification to regard a Grignard reagent as RMgX, most of the reactions can be rationalized easily by this simple structure.

 

ORGANOMAGNESIUM COMPOUNDS AND ORGANOLITHIUM COMPOUNDS IN SYNTHESIS

Organomagnesium compounds are widely used in the preparation of various types of organic compounds. The industrial synthesis of certain organosilicon compounds, aromatic substances, and Pharmaceuticals is carried out with the aid of organomagnesium compounds.

Additions to Carbonyl Groups. Synthesis of Alcohols

The most important synthetic use of Grignard reagents and organolithium reagents is to form new carbon-carbon bonds by addition to polar multiple bonds, particularly carbonyl bonds. An example is the addition of methyl-magnesium iodide to methanal:

The yields of addition products in reactions of this kind are generally high. The adducts have metal-oxygen bonds that can be broken readily by acid hydrolysis to give the organic product. Grignard reagents seldom add to carbon-carbon multiple bonds (however, see Section 14-12D).

With suitable variations of the carbonyl compound, a wide range of compounds can be built up from substances containing fewer carbon atoms per molecule. The products formed when several types of carbonyl compounds react with Grignard reagents are listed in Table 14-4. The sequence of reactions starting with an organic halide, RX, amounts to the addition of R—H across a carbonyl bond.

Primary alcohols can be prepared by the addition of RMgX or RLi to methanal, CH2=O,

Alcohols of formula RCH2CH2OH can be prepared by addition of RMgX to oxacyclopropane (oxirane):

It is not possible to add RH to    directly because AG° generally is somewhat unfavorable [+5 kcal for CH4 + (CH3)2C=0-> (CH3)3COH]. How we get around this unfavorable equilibrium in practice provides an interesting example of how energy can be (and is) squandered to achieve some particular desired result; for example, the reaction CH3CH3 + CH3CHO-> CH3CH2CH(CH3)OH has    kcal but . A possible sequence is

The overall result is the expenditure of 10 + 76 + 71 = 157 kcal to achieve a reaction that itself has AH° — —12 kcal, but an unfavorable AG°. (Li is used in this example rather than Mg because the heat of formation of C2H5MgBr is not available.)

 

Table 14-4

Products from the Reaction of Grignard Reagents (RMgX) with Carbonyl Compounds

 

Secondary alcohols are obtained from aldehydes, whereas ketones give tertiary alcohols:

Hydrolysis of the intermediate R—OMgX compound is achieved best with aqueous ammonium chloride solution. Addition of water gives an unpleasant mess of Mg (OH) 2, whereas addition of strong acids such as HCl or H2SO4 can lead to side reactions of dehydration and so on, especially with tertiary alcohols:

Tertiary alcohols also are obtained from both acyl halides, RCOCl, and esters, RCO2R, by the addition of two moles of Grignard reagent. The first mole of RMgX adds to the carbonyl bond to give the adducts 13 or 14:

However, these first-formed adducts are unstable and decompose to a ketone, CH3COR, and magnesium salts, MgXCl or MgXOC2H5. The ketone usually cannot be isolated, but reacts rapidly with more RMgX ultimately to give a tertiary alcohol:

Organolithium compounds behave very much like Grignard reagents, but with increased reactivity. They offer advantages over the magnesium compounds when the R group or the carbonyl compound is highly branched. For instance, isopropyllithium adds in good yield to 2,4-dimethyl-3-pentanone,whereas isopropylmagnesium bromide fails completely to give the normal addition product:

Failure of Grignard reagents to add in the normal way generally is because reactions by alternative paths occur more rapidly. If the Grignard reagent has a hydrogen on the carbon adjacent to the point of attachment of—MgX (i.e., a (β hydrogen), then reduction can occur, with the effect of adding H2 to the carbonyl group.

Furthermore, if the carbonyl compound has a hydrogen located on the carbon next to the carbonyl group, the Grignarjl reagent can behave as a base and remove this hydrogen as a proton. The result is that the compound becomes an enolate salt and RMgX becomes RH.

Apparently, the complicating side reactions observed with RMgX are not nearly as important with RLi. The reasons for this difference are not well understood.

Synthesis of Carboxylic Acids

The reaction of carbon dioxide with Grignard reagents initially gives a magnesium salt of a carboxylic acid, RC02MgX:

This salt, which has a carbonyl group, in principle could add a second RMgX. However, further addition is usually slow, and for most practical purposes the reaction stops at this stage. If the reaction can go further, the worst way to run it is by bubbling CO2 into the Grignard solution. This exposes the first-formed RCO2MgX to excess RMgX and may lead to further addition reactions. The easy way to avoid this problem is to pour the RMgX solution onto powdered Dry Ice (solid CO2). Hydrolysis of the product (here a stronger acid than NH4Cl is required) generates the carboxylic acid, RCO2H:

Synthesis of Ketones

Although organomagnesium compounds are not sufficiently reactive to add to carboxylate anions, alkyllithium compounds add quite well. A useful synthesis of methyl ketones involves the addition of methyllithium to the lithium salt of a carboxylic acid:

Other methods begin with acid chlorides or esters and attempt to add only one mole of RMgX:

The disadvantage of using Grignard reagents for this purpose is that they add very rapidly to the ketone as it is formed. There are two ways in which this disadvantage can be minimized. First, one can add the Grignard solution to an excess of acid chloride solution (the so-called “inverse addition” procedure) to keep the concentration of RMgX in the reaction mixture low, and hope that the reaction will stop at the ketone stage. However, this device seldom works very well with acid chlorides. Better results can be obtained with RMgX and R’CON(CH3)2. The second method is to use a less reactive organometallic compound —one that will react with RCOCl but not with R2C=O. One easy way to do this is to add cadmium chloride to the Grignard solution, whereby an organocadmium compound, R2Cd, is formed, Method 3). In the presence of magnesium halides, R2Cd reacts moderately rapidly with acid chlorides, but only slowly with ketones. The addition therefore can be arrested at the ketone stage:

Alkylcopper compounds, R—Cu, also are selective reagents that react with acid chlorides to give ketones, but do not add to esters, acids, aldehydes, or ketones. The R—Cu compounds can be prepared from CuI and the alkyllithium. With an excess of the alkyllithium, the alkylcopper is converted to R2CuLi:

 

 

1,4 Additions to Unsaturated Carbonyl Compounds

A conjugated alkenone, , can react with an organometallic reagent by a normal 1,2 addition across the carbonyl group, or by 1,4 addition to the conjugated system.

On hydrolysis, the 1,4 adduct first yields the corresponding enol, but this is normally unstable and rearranges rapidly to the ketone. The final product therefore corresponds to addition of R—H across the carbon-carbon double bond:

Organomagnesium and organolithium compounds can add both 1,2 and 1,4 to alkenones, and the relative importance of each mode of addition depends on the structure of the reactants. This sort of dual behavior can be a nuisance in synthetic work because it leads to separation problems and low yields. Organocopper compounds are a great help in this situation because they show a very high selectivity for 1,4 addition and add to unsaturated ketones in excellent yield:

There are compounds which react with organolithium but not with organomagnesium compounds as there are functional groups which undergo reaction with organolithium compounds but not with organomagnesium compounds.

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