Reactions of Alkyl Halides Grignard Reagents

As the preceding examples indicate, the yields of these SOCI2 and PBr reactions are generally high, and other functional groups such as ethers, carbonyls, and aromatic rings don t usually interfere. We ll look at the mechanisms of these substitution reactions in the next chapter. 

Problem 10.8 How would you prepare the following alkyl halides from the corresponding alcohols  

WeTl see many more uses of Grignard reagents as sources for carbon nucleophiles in later chapters. 

Problem 10.9 How strong a base would you expect a Grignard reagent to be Look at Table 8.1 on page 271, and then predict whether the following reactions will occur as written. (The pKg of NH3 is 35.) 

Problem 10.10 How might you replace a halogen substituent by a deuterium atom if you wanted to prepare a deuterated compound  

Problem 10.9 How strong a base would you expect a Grignard reagent to be Look at Table 8.1 on 

CH3CH2CH2CH2UH2CH28r —— uH3cH2CH2uH2cH2ci-i2MgtJr ——= CH3CH2CH2CH2CH2CH3 1-Bromohexane 1-Hexylmagnesium bromide Hexane (85%) 

Primary and secondary alcohols are best converted into alkyl halides by treatment with either thionyl chloride (SOCI2) or phosphoms tribromide (PBr3). These reactions, which normally take place readily under mild conditions, are less acidic and less likely to cause acid-catalyzed rearrangements than the HX method. 

Alkyl fluorides can also be prepared from alcohols. Numerous alternative reagents are used for the reaction, including diethylaminosulfur trifluoride [(CH3CH2)2NSF3] and HF in pyridine solvent. 

Alkyl halides, RX, react with magnesium metal in ether or tetrahydrofuran (THF) solvent to yield alkylmagnesium halides, RMgX. The products, called Grignard reagents after their discoverer, Victor Grignard, are examples of 

As you might expect from the discussion of electronegativity and bond I polarity in Section 5,4, the carbon-magnesium bond is polarized, making I the carbon atom both nucleophilic and basic. An electrostatic potential map j clearly shows the electron-rich (red) character of the carbon bonded 6 magnesium  

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In some instances the reactions of the indole Grignard reagents resemble those of simple aryl or alkyl magnesium halides, but in many eases they appear to reaet anomalously. 

In the 19.S0 s a number of workers, including Hoshino, Oddo, and Kubota suggested that indolenine-type intermediates (cf. 431) were formed during the reaction of the indole Grignard reagents [depicted as N—MgX derivatives (cf. 432)] with alkyl and arylalkyl halides. Rather surprisingly these were the last reports dealing with... 

Alkanes can also be prepared from alkyl halides by reduction, directly with Zn and acetic acid (AcOH) (see Section 5.7.14) or via the Grignard reagent formation followed by hydrolytic work-up (see Section 5.7.15). The coupling reaction of alkyl halides with Gilman reagent (R 2CuLi, lithium organocuprates) also produces alkanes (see Section 5.5.2). 

Organolithium reagents These reagents are prepared by the reaction of alkyl halides with lithium metals in an ether solvent. Unlike Grignard reagents, organolithiums can also be prepared using a variety of hydrocarbon solvents e.g. hexane, and pentane. 

Sml2 (stoichiometric amount) promotes alkylation of ketones in THF by alkyl hromidcs, iodides, or tosylates. The reaction is slow, but can be accelerated by a catalytic amount of FcClj. This reaction is analogous to reaction of ketones with Grignard reagents. Vinylic and aryl halides do not undergo this alkylation.1... 

Organozinc reagents are not nearly as reactive toward aldehydes and ketones as Grignard reagents and organolithium compounds but are intermediates in certain reactions of alkyl halides. 

Radical addition/cross-coupling products 61 were obtained in 60-91% yield when Ni(dppf)Cl2 was applied as a catalyst in reactions of alkyl halides 60 with 2,3-disubstituted dienes 59 and aryl Grignard or arylzinc reagents (Fig. 12). Competition experiments of n-, sec-, and ferf-butyl bromide with 2,3-dimethylbutadiene... 

Tamura and Kochi studied the cross-coupling reactions of alkyl halides with alkyl Grignard reagents catalyzed by silver compounds first [422, 426, 427]. The coupling of primary alkyl halides with primary Grignard reagents resulted in a mixture... 

Exchange reactions of alkyl halides are synthetically useful mostly in the case of alkyl iodides bearing an a-halogen or a-acyloxy substituent. The resulting Grignard reagents react smoothly with various electrophiles (Scheme 24)69,72,72a,72b... 

X-Substituted Allyl Anions. Allyl anions with alkyl substituents almost always react with carbonyl electrophiles at the more substituted a position, as in the reaction of the prenyl Grignard reagent with aldehydes to give the product 4.39, presumably because the metal attaches itself preferentially to the less-substituted end of the allyl system and then delivers the electrophile in a six-membered transition structure 4.38. In contrast, alkylation of a similar anion with an alkyl halide gives mainly the product 4.40 of y attack, which is normal for an X-substituted allyl anion when a cyclic transition structure is not involved. 

Reduction of carbon-halogen bond by metal yields carbanion. Reaction of alkyl halide with Mg in the presence of anhydrous ether as solvent generates Grignard reagent. The Grignard reagent behaves like a carbanion. Alkyllithiums are also obtained from alkyl halides and behave as carbanions. 

Metal insertion reactions of alkyl halides produce organometal-lic derivatives such as Grignard reagents, which are synthetically useful sources of carbanions and change the reactive character of the carbon atom of the alkyl halide. 

Organophosphorus compounds find wide use in the chemical industry as catalysts, intermediates, complexes, and end-use products. Arylphosphines and phosphine oxides are often produced by the reaction of a preformed Grignard reagent with a halophosphine or phosphine oxide. Yields are reduced by the production of unwanted side-reaction products such as biaryls. These unwanted products are reduced when the reaction is conducted under Barbier conditions. When alkyl and aryl halides are reacted with magnesium metal, a trihalophosphine or phosphine oxide, a metal halide or amine catalyst, in THE benzene mixtures, at reflux, good yields of phosphines or phosphine oxides are obtained [74]. For example, triphenylphosphine can be prepared in a 97.2% yield from the reaction of bromobenzene, trichlorophosphine, magnesium metal, aluminum chloride, and sodium chloride in THF-benzene at 70 80 C. 

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