Nucleophiles in Sn2 reaction

The reaction of phenyllithium and allyl chloride using a label reveals that allylic rearrangement occurs. About three-fourths of the product results from bond formation at C—3 rather than C—1. This can be accounted for by a cyclic transition state.  

The portion of the product formed by reaction at C—1 in allylic systems may form by direct substitution, but it has also been suggested that a cyclic transition state involving an aryllithium dimer might be involved. 

These mechanisms ascribe importance to the Lewis acid-Lewis base interaction between the allyl halide and the organolithium reagent. When substitution is complete, the halide ion is incorporated into the lithium cluster in place of one of the carbon ligands. Substituted allylic halides give product mixtures resulting from bond formation both at C—1 and C—3 of the allylic system, with the ratio of products favoring reaction at the less substituted site. 

From a synthetic point of view, direct alkylation of lithium and magnesium organometallic compounds has been supplanted by transition metal-catalyzed processes. We will discuss these reactions in Part B, Chapter 8. 

The alkylation reactions of enolate anions of both ketones and esters have been extensively utilized in synthesis. Both very stable enolates, such as those derived from )8-ketoesters, )8-diketones, and malonate esters, as well as less stable enolates, such as those derived from monofunctional ketones, esters, and nitriles, are reactive. Many aspects of the relationships between reactivity, stereochemistry, and mechanism have been clarified. A starting point for the discussion of these reactions is the 

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We will begin with an exanination of the reactivity of amines as nucleophiles in Sn2 reactions. 

The remarkable enhancement of anion nucleophilicity in Sn2 reactions carried out in dipolar aprotic solvents is a solvation effect.Solvents like DMF and DMSO are very polar owing to the charge separation indicated in 1 and 2. 

Organic solvents such as benzene, ether, and chloroform are neither protic nor strongly polar. What effect would you expect these solvents to have on the reactivity of a nucleophile in SN2 reactions ... 

We commented earlier in this chapter that carboxylic acids are similar in some respects to both alcohols and ketones. Like alcohols, carboxylic acids can be depro-tonated to give anions, which are good nucleophiles in SN2 reactions. Like ketones,... 

Ammonia and other amines are good nucleophiles in SN2 reactions. As a result, the simplest method of alkylamine synthesis is by Sn2 alkylation of ammonia or an alkylamine with an alky) halide. If ammonia is used, a primary amine results if a primary amine is used, a secondary amine results and so on. Even tertiary amines react rapidly with alkyl halides to yield quaternary ammonium salts, R4N+ X-... 

The LU MO of ethyl chloride (trans form) extends in the region of the a carbon to the direction opposite the side of the chlorine atom and also in the region of the hydrogen atom trans coplanar to the chlorine atom 124>. The former is responsible for the attack of nucleophile in Sn2 reactions, and the latter for the attack in E 2 reactions. 

Though this topic is treated here under a separate heading, alkylation of enolate anions is nothing other than enolate anions acting as carbanion nucleophiles in Sn2 reactions. We deferred this topic... 

Examples of replacement of fluorine in saturated aliphatic perfluorinated compounds by alkoxy and aryloxy groups are relatively scarce since such fluorine atoms are generally inert toward nucleophiles in SN2 reactions. 

Sulfur occurs directly beneath oxygen in the periodic table. Therefore, sulfur compounds are weaker bases but better nucleophiles than the corresponding oxygen compounds. Sulfur compounds are excellent nucleophiles in SN2 reactions, and because they are relatively weak bases, elimination reactions are not usually a problem. Yields are good with primary and secondary substrates. For similar reasons, phosphorus compounds also give good yields when treated with primary and secondary substrates in Sn2 reactions. The following equations provide examples of the use of these nucleophiles ... 

Enolate anions generated from ketones, esters, and nitriles can be used as nucleophiles in Sn2 reactions. This results in the attachment of an alkyl group to the a-carbon in a process termed alkylation. Aldehydes are too reactive and cannot usually be alkylated in this manner. Alkylation of cyclohexanone is illustrated in the following equation ... 

The dithiane anion is a good nucleophile in SN2 reactions. After it has been alkylated, the thioacetal group can be removed by hydrolysis using Hg2+ as a Lewis acid catalyst. 

Sulfur nucleophiles are better than oxygen nucleophiles in Sn2 reactions... 

RCOO- acts as a nucleophile in SN2 reactions with RX to give esters. 

Correlation of nucleophilic rate data for phenyldimethylsulfonium ions with common nucleophiles, with pXj values shows that the slopes of the lines, correlate qualitatively with the Edwards hardness parameter for the nucleophile and not with the Swain-Scott n parameter. " " d5,d5-2,4,6-Trimethyl-l,3,5-triammocyclohexane is weakly basic in aqueous solution, because of steric inhibition to solvation of the conjugate acid. " The three NH2 groups are axial and the steric effect also results in reduced reactivity as a nucleophile in Sn2 reactions. Highly stereoselective syntheses of P-C-, N-, and O-glycosides have been carried out by addition of anionic nucleophiles to glycosyl iodides. " 5n2 reactions are involved, but some substrates are susceptible to E2 elimination when treated with highly basic anions. 

In contrast to the behavior of the foregoing nickel(I) complexes as catalysts, the catalytic reactions of alkyl halides with cobalt(I) species such as vitamin Bi2s, cobaloximes(I), and cobalt(I) salen exhibit a significant difference. Cobalt(I) species, acting as potent nucleophiles in Sn2 reactions with alkyl halides, give stable alkylcobalt(III) intermediates. Lexa and coworkers [318] have discussed this mechanistic scheme for the catalytic reduction of l-bromobutane by the electrogenerated cobalt(I) tetraphenylpor-phin complex, where TPP denotes the ligand. Reversible one-electron reduction of the parent cobalt(II) species... 

Thiolate anions make excellent nucleophiles in Sn2 reactions on alkyl halides. It is enough to combine the thiol, sodium hydroxide, and the alkyl halide to get a good yield of the sulfide. 

Ph)jP, is a good nucleophile in SN2 reactions, and yields of the resultant alkyl-triphenylphosphonium. salts are high. The hydrogen on the carbon next to the positively charged phosphorus is weakly acidic and can be removed by a base such as butyllithium (BuLi) to generate the neutral ylide. For example ... 

Second, and as discussed in Part A, Chapter 5, nucleophilicity in Sn2 reactions is associated with polarizability. The more easily a nucleophile s electronic cloud can be distorted to permit bond formation, the stronger an Sn2 nucleophile it will be. Comparison of the oxygen and carbon ends of an ambident enolate ion with regard to nucleophilicity leads to the conclusion that the less electronegative carbon atom is more polarizable and to the prediction that the carbon end of the anion will be more nucleophilic. 

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