Alkylation, enolate ions electrophilic addition reactions

A large number of reactions have been presented in this chapter. However, all of these reactions involve an enolate ion (or a related species) acting as a nucleophile (see Table 20.2). This nucleophile reacts with one of the electrophiles discussed in Chapters 8, 18, and 19 (see Table 20.3). The nucleophile can bond to the electrophilic carbon of an alkyl halide (or sulfonate ester) in an SN2 reaction, to the electrophilic carbonyl carbon of an aldehyde or ketone in an addition reaction (an aldol condensation), to the electrophilic carbonyl carbon of an ester in an addition reaction (an ester condensation) or to the electrophilic /3-carbon of an a,/3-unsaturated compound in a conjugate addition (Michael reaction). These possibilities are summarized in the following equations ... 

In a formal sense, the reaction of ascorbic acid (11) with various electrophiles may also be regarded as an intramolecular conjugate addition with subsequent alkylation of the intermediate enolate ion. For example, the reaction of 11 with ( )-2-methyl-2-butenenitrile afforded the natural product piptosidin (12), together with its di-epimer 1351. In a quite similar fashion, leucodrin (14) and delesserin (15) were prepared from the corresponding benzyl alcohols52. 

When an alkyne undergoes the acid-catalyzed addition of water, the product of the reaction is an enol. The enol immediately rearranges to a ketone. A ketone is a compound that has two alkyl groups bonded to a carbonyl (C=0) group. An aldehyde is a compound that has at least one hydrogen bonded to a carbonyl group. The ketone and enol are called keto-enol tautomers they differ in the location of a double bond and a hydrogen. Interconversion of the tautomers is called tautomerization. The keto tautomer predominates at equilibrium. Terminal alkynes add water if mercuric ion is added to the acidic mixture. In hydroboration-oxidation, H is not the electrophile, H is the nucleophile. Consequently, mercuric-ion-catalyzed addition of water to a terminal alkyne produces a ketone, whereas hydroboration-oxidation of a terminal alkyne produces an aldehyde. 

Mannich reaction Alkylation of enols by electrophilic iminium ions, giving f)-aminocarbonyl compounds. Markovnikov rule Regioselectivity in electrophilic addition to alkenes whereby an electrophile attacks... 

The enolate ion is nucleophilic at the alpha carbon. Enolates prepared from aldehydes are difficult to control, since aldehydes are also very good electrophiles and a dimerization reaction often occurs (self-aldol condensation). However, the enolate of a ketone is a versatile synthetic tool since it can react with a wide variety of electrophiles. For example, when treated with an unhindered alkyl halide (RX), an enolate will act as a nucleophile in an Sn2 mechanism that adds an alkyl group to the alpha carbon. This two-step a-alkylation process begins by deprotonation of a ketone with a strong base, such as lithium diisopropylamide (LDA) at -78°C, followed by the addition of an alkyl halide. Since the enolate nucleophile is also strongly basic, the alkyl halide must be unhindered to avoid the competing E2 elimination (ideal RX for Sn2 = 1°, ally lie, benzylic). 

The previous sections have dealt primarily with reactions in which the new carbon-carbon bond is formed in an Sn2 reaction between the nucleophilic carbon species and the alkylating reagent. There is another general and important method for alkylation of carbon that should be discussed at this point. This reaction involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The reaction is applicable to a wide variety of enolates and enamines. The electrophilic reaction partners are typically a,j8-unsaturated ketones, esters, or nitriles, but other electron-withdrawing substituents also activate the carbon-carbon double bond to nucleophilic attack. The reaction is called either the Michael reaction or conjugate addition The process can also occur with other nucleophiles, such as alkoxide ions or amines, but these reactions are outside the scope of the present discussion. 

Bicyclic compounds have apparently never been detected in the products resulting from the carbonium ion reactions of either acyclic precursors [e.g., (33-X) or (34-X)], or monocyclic menthane reactants [e.g., (35-X)] under quite a variety of conditions (77, 84, 86, 87), It appears to be necessary to provide additional driving force as in the acid-catalyzed cyclization of carvone enol acetate (44) 87) or the intramolecular enolate alkylation of keto tosylate (45) 88, 89) in order to overcome the strain energy of the bicyclo[2.2.1]heptane and bicyclo-[3.1.1]heptane rings. An additional factor in the latter case is, of course, increased electrophilic demand at a primary, as opposed to a tertiary, center. 

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