Alkylation reaction nucleophilic molecules

In the synthesis of molecules without functional groups the application of the usual polar synthetic reactions may be cumbersome, since the final elimination of hetero atoms can be difficult. Two solutions for this problem have been given in the previous sections, namely alkylation with nucleophilic carbanions and alkenylation with ylides. Another direct approach is to combine radical synthons in a non-polar reaction. Carbon radicals are. however, inherently short-lived and tend to undergo complex secondary reactions. Escheirmoser s principle (p. 34f) again provides a way out. If one connects both carbon atoms via a metal atom which (i) forms and stabilizes the carbon radicals and (ii) can be easily eliminated, the intermolecular reaction is made intramolecular, and good yields may be obtained. 

You may have noticed that aldehydes were conspicuously absent from the examples of alkylation reactions presented in Sections 20.3 and 20.4. This is due to the high reactivity of the carbonyl carbon of an aldehyde as an electrophile. When an enolate anion nucleophile is generated from an aldehyde, under most circumstances it rapidly reacts with the electrophilic carbonyl carbon of an un-ionized aldehyde molecule. Although this reaction, known as the aldol condensation, interferes with the alkylation of aldehydes, it is a very useful synthetic reaction in its own right. The aldol condensation of ethanal is shown in the following equation ... 

Perhaps the single most important reaction of enolate ions is their alkylation by treatment with an alkyl halide or tosylate. The alkylation reaction is useful because it forms a new C-C bond, thereby joining two smaller pieces into one larger molecule. Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide in an Sn2 reaction and displaces the leaving group by back-side attack. 

This reaction is an intramolecular alkylation of a ketone. Although alkylation of a ketone with a separate alkyl halide molecule is usually difficult, intramolecular alkylation reactions can be carried out effectively. The enolate formed by proton abstraction from the a-carbon atom carries out a nucleophilic attack on the carbon that bears the leaving group. 

In SAM-dependent alkylation reactions, when the methyl acceptors are carbon atoms, the enzymatic reaction mechanisms are more complicated and depend on the electronic properties of the acceptor molecules. The generation of C-alkyl linkages requires the formation of a nucleophilic carbon. An interesting SAM-dependent... 

Because an alkyl group is added to the original alkyne molecule, this type of reaction is called an alkylation reaction. We limit our discussion in this chapter to reactions of acetylide anions with methyl and primary haloalkanes. We will discuss the scope and limitation of this type of nucleophilic substitution in more detail in Chapter 7. For reasons we will discuss there, alkylation of nucleophilic acetylide anions is practical only for methyl and primary halides. While this alkylation reaction can be used with limited success with secondary haloalkanes, it fails altogether for tertiary haloalkanes. 

These molecules bear large numbers of nucleophilic groups that can be alkylated by other molecules (electrophiles) in what seem to be simple Sn2 reactions (Fig. 13.78). 

This is the first of three chapters dealing with an in-depth study of the organic reactions of compounds containing C-Z a bonds, where Z is an element more electronegative than carbon. In Chapter 7 we learn about alkyl halides and one of their characteristic reactions, nucleophilic substitution. In Chapter 8, we look at elimination, a second general reaction of alkyl halides. We conclude this discussion in Chapter 9 by examining other molecules that also undergo nucleophilic substitution and elimination reactions. 

Baylis-Hillman alcohols and their derivatives represent a particularly useful group of regents widely utilized in the synthesis of a-aUcylidene y and 8-lactones and lactams. These attractive synthetic intermediates easily undergo alkylation reactions of various nucleophiles resulting in the introduction of ester and alkylidene moieties into the target molecules. 

The influence of hydrophobicity in the equations is likely related to the influence of hydrophobicity on the internal concentrations. An influence of electronic descriptors, related to the distribution of electrons in the molecules, could be expected because they represent the charge distribution in the organophosphorus compounds. The substituents on the aromatic ring directly influence the positive charge on the central phosphorus atom or on the carbon atom in the common methoxy groups and, as a consequence, the tendency of nucleophiles to attack the carbon atom in alkylation reactions or to attack the phosphorus atom in the phosphorylation reactions or in hydrolysis. 

Since allylation with allylic carbonates proceeds under mild neutral conditions, neutral allylation has a wide application to alkylation of labile compounds which are sensitive to acids or bases. As a typical example, successful C-allylation of the rather sensitive molecule of ascorbic acid (225) to give 226 is possible only with allyl carbonate[l 37]. Similarly, Meldrum s acid is allylated smoothly[138]. Pd-catalyzed reaction of carbon nucleophiles with isopropyl 2-methylene-3,5-dioxahexylcarbomite (227)[I39] followed by hydrolysis is a good method for acetonylation of carbon nucleophiles. 

We can extend the general principles of electrophilic addition to acid catalyzed hydration In the first step of the mechanism shown m Figure 6 9 proton transfer to 2 methylpropene forms tert butyl cation This is followed m step 2 by reaction of the car bocation with a molecule of water acting as a nucleophile The aUcyloxomum ion formed m this step is simply the conjugate acid of tert butyl alcohol Deprotonation of the alkyl oxonium ion m step 3 yields the alcohol and regenerates the acid catalyst... 

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