Aliphatic electrophiles

These reactions are likely to occur by oxidative addition through a radical mechanism, as evidenced by the loss of stereochemistry of the starting alkyl halide during the coupling process (Equation 19.14b). Despite the radical mechanism, some reactions of benzylic electrophiles have been conducted enantioselectively (Equation 19.14c). Even reactions of alkylboron reagents witti secondary alkyl halides catalyzed by nickel complexes have now been reported. These reactions were conducted with nickel precursors in combination with trflns-l,2-cyclohexanediamine (Equation 19.14d).  

A series of papers have also reported the coupling of alkyl and aryl electrophiles with aryl Grignard reagents catalyzed by iron (Equation 19.15) and cobalt complexes. These reactions build upon Kochi s and Molander s early results on coupling reactions catalyzed by complexes of these metals. The recent reactions have been conducted with simple metal salts in many cases and with discrete metal complexes as catalyst precursors in others. Although little recent mechanistic data is available on these reactions, they have earlier been shown to involve radical intermediates. Kochi concluded that the catalytic process occurs by an Fe(I)-Fe(III) couple reactions of optically active alkyl halides generate racemic coupled products and reactions of diastereomerically pure aUcyl halides generate equal ratios of diastereomeric products, as depicted in Equations 19.16 and 19.17.  

The final common class of coupling reactions to form C-C bonds described here is the coupling of an aryl halide with an olefin to cleave the C-H bond of the olefin and replace it with an aryl group. This reaction, which is shown generically in Equation 19.18, was first reported by Mizoroki the synthetic utility of this process and e most useful conditions for this process at the time were reported by Heck. ° This process is often called the Heck reaction, or more appropriately the Mizoroki-Heck reaction. The Heck reaction is most commonly conducted with electron-deficient olefins, such as styrene or acrylate derivatives. The electronic properties of these substrates tend to favor formation of the conjugated products. The reaction can also be conducted effectively with ethylene a Heck reaction between 6-methoxy-2-bromonaphthalene and ethylene is one step of a short, catalytic commercial synthesis of naproxen. In contrast, intermolecular reactions of internal olefins typically form mixtures of regioisomeric products. Intramolecular Mizoroki-Heck reactions with intemal olefins are more common. Mizoroki-Heck reactions of aliphatic electrophiles have been reported, but remain rare. Applications of the Mizoroki-Heck reaction have been reviewed.  

Catalysts containing chelating ligands and conditions that limit the concentration of cyanide have allowed the development of the coupling of cyanide with aryl halides with improved catalyst lifetimes. Recent procedures have been devised that slowly release cyanide from a cyanohydrin or trimethylsilylcyanide or that include less reactive cyanide reagents, such as zinc cyanides. High-yield reactions have also been reported with potassium hexacyanoferrate(II) as a safe cyanide source (Equation 19.19). This reagent releases little free cyanide, but does transfer cyanide in the catalytic process. It has such little toxicity that it is even used as a food additive. 

-Umaturated Carbonyl Compounds. Most nucleophiles attack a,/3-unsaturated ketones faster at the carbon atom of the carbonyl group (e.g. 4.140 4.139) than at the f3 position. Attack at the (3 carbon (e.g. 4.140 — 4.141) is commonly the result of a slower, but thermodynamically more favourable, reaction. For this mode of reaction to show up, the first step must be reversible. Conjugate attack is therefore most straightforward when the nucleophile is a well-stabilised anion, making the first step easily reversible, as it is when the nucleophile is a cyanide ion.373 

Similarly, the simple lithium enolate 4.143 reacts with cyclohexenone at -78 °C to give the product 4.142 of direct attack, but warming the reaction mixture to room temperature allows this step to revert to the starting materials, and they then form the thermodynamically more stable product 4.144 of conjugate attack.374 /3-Dicarbonyl enolates, commonly used in Michael reactions, usually do not allow the isolation of the product of direct attack, since the first step is even more easily reversible in such cases. 

Moving to a,3-unsaturated esters, hydroxide ion and alkoxide ion (hard nucleophiles) react with ethyl acrylate 4.145 by direct attack at the carbonyl group to give ester hydrolysis and ester exchange, respectively, whereas the /3-dicarbonyl enolate ion 4.146 (a softer nucleophile) undergoes a Michael reaction.381 There is no certainty in this latter reaction that the attack of the enolate anion on the carbonyl group, in a Claisen-like condensation, is not a more rapid (and reversible) process.382 

The ease with which sulfur nucleophiles add to Q,.3-unsaturatcd esters 4.145 4.147 is also ambiguous thiolate anions do not react with esters to give thioesters 4.148, because the equilibrium lies in the other direction so we cannot tell what are the relative rates of attack at the two sites of an a,/3-unsaturated ester, although it is likely that /3 attack is kinetically controlled. 

One case, however, is clear—ammonia and amines do react with ordinary esters to give amides, and it is known383 that the attack at the carbonyl group is rate-determining and effectively irreversible above pH 7. Ammonia (neutral and therefore a relatively soft nucleophile) reacts in methanol with methyl acrylate 4.149 kinetically at the (3 position to give the primary amine 4.150, and reaction continues in the same sense to give successively the secondary and tertiary amines 4.151 and 4.152.384 

The more a carbonyl group is like that of protonated acrolein (Fig. 4.12), the more likely it is that all nucleophiles will attack directly at the carbonyl carbon atom. In agreement with this perception, and in contrast to its behaviour with methyl acrylate, ammonia reacts with acryloyl chloride at the carbonyl carbon atom to give acrylamide. 

2 Allyl Halides. In bimolecular substitutions on allyl halides, direct displacement of the halide ion (S 2) almost always occurs, and conjugate attack (Sn2 ) is rare. It is perhaps significant that the few examples of conjugate reaction 

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For aliphatic electrophilic substitution, we can distinguish at least four possible major mechanisms, which we call Sgl, 8 2 (Iront), Se2 (back), and Sgi. The Sgl is unimolecular the other three are bimolecular. 

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