Leaving group in nucleophilic substitution reactions

Methyl bromide slowly hydrolyzes in water, forming methanol and hydrobromic acid. The bromine atom of methyl bromide is an excellent leaving group in nucleophilic substitution reactions and is displaced by a variety of nucleophiles. Thus methyl bromide is useful in a variety of methylation reactions, such as the syntheses of ethers, sulfides, esters, and amines. Tertiary amines are methylated by methyl bromide to form quaternary ammonium bromides, some of which are active as microbicides. 

Isopentenyl pyrophosphate and dimethylallyl pyrophosphate are structurally similar—both contain a double bond and a pyrophosphate ester unit—but the chemical reactivity expressed by each is different. The principal site of reaction in dimethylallyl pyrophosphate is the carbon that bears the pyrophosphate group. Pyrophosphate is a reasonably good leaving group in nucleophilic substitution reactions, especially when, as in dimethylallyl pyrophosphate, it is located at an allylic carbon. Isopentenyl pyrophosphate, on the other hand, does not have its leaving group attached to an allylic carbon and is far- less reactive than dimethylallyl pyrophosphate toward nucleophilic reagents. The principal site of reaction in isopentenyl pyrophosphate is the carbon-carbon double bond, which, like the double bonds of simple alkenes, is reactive toward electrophiles. 

The -R and -H in these compounds can Tact as leaving groups in nucleophilic substitution reactions. 

The -OH, -X, -OR, -SR, -NH2, -0C0R, and -0P032- in these compounds can act as leaving groups in nucleophilic substitution reactions. 

Tosylate (Section 11.1) A p-toluenesulfonate ester useful as a leaving group in nucleophilic substitution reactions. 

Recall that p-toluenesul Innate (tosylate) is a good leaving group in nucleophilic substitution reactions. The nucleophile that displaces tosylate from carbon is the alkoxide ion derived from the hydroxyl group within the molecule. The product is a cyclic ether, and the nature of the union of the two rings is that they are spirocyclic. 

The combination of addition and elimination reactions has the overall effect of substituting one nucleophile for another in this case, substituting an alcohol for water. The rate of these nucleophilic substitution reactions is determined by the ease with which the elimination step occurs. As a rule, the best leaving groups in nucleophilic substitutions reactions are weak bases. The most reactive of the carboxylic acid derivatives are the acyl chlorides because the leaving group is a chloride ion, which is a very weak base (ATb KT20). 

The preparation of tosylate and other sulfonate esters for use as leaving groups in nucleophilic substitution reactions (see Section 8.9) employs the reaction of a sulfonyl chloride (an acid chloride of a sulfonic acid) with an alcohol. Another example is shown in the following equation. Note the similarity of this reaction to the reaction of an acyl chloride with an alcohol to form an ester. 

Three kinds of sulfur substituents are used as leaving groups in nucleophilic substitution reactions in the pyrimidine moiety of pyrido[2,3-d]pyrimidines, i.e. the free sulfanyl group,29,249,364,365 alkylsulfanyl,7,335,366 and alkylsulfonyl substituents.326,367... 

Why are thioesters superior to ordinary esters as acyl-transfer agents Part of the answer lies in the acidity difference between alcohols and thiols (Sec. 7.1 7). Since thiols are much stronger acids than are alcohols, their conjugate bases, SR, are much weaker bases than OR. Thus, the —SR group of thioesters is a much better leaving group, in nucleophilic substitution reactions, than is the —OR group of ordinary esters. Thioesters are not so reactive that they hydrolyze in cellular fluid, but they are appreciably more reactive than simple esters. Nature makes use of this feature. 

---