Anhydrides nucleophilic substitution reactions

The kinetics of the nucleophilic substitution reactions of benzoic anhydrides with anilines in acetonitrile-water have been studied.74 A frontside 5 k2 mechanism with a four-membered ring transition state has been proposed. 

Since sulfonation of pyridine iV-oxide is about as difficult as is that of pyridine itself and takes place at the 3-position,17 it has been assumed18 that, in fuming sulfuric acid, pyridine iV-oxide reacts only in the salt form (3), when the prediction is that substitution at C-3 would take place. It is, however, difficult to account for the fact that bromination, even at 110° in the presence of iron powder, does not occur.17 Bromination in chloroform solution in the presence of acetic anhydride and sodium acetate (when the O-acetate is the the probable substrate) take place readily, however, to give 3,5-dibromopyridine JV-oxide.19 The predicted order of nucleophilic reactivity, on the basis of both atom localization energies and ground-state v-electron density calculations, is 4 > 2 > 3. The same order is predicted for the nucleophilic substitution reactions of the salts of pyridine JV-oxide. In actual practice, iV-alkoxypyridinium derivatives undergo nucleophilic attack preferentially at C-2.20-23 The reaction of some pyridine iV-oxides with phosphorus pentachloride may involve the formation... 

These reactions are used to make anhydrides, carboxylic acids, esters, and amides, but not acid chlorides, from other acyl compounds. Acid chlorides are the most reactive acyl compounds (they have the best leaving group), so they are not easily formed as a product of nucleophilic substitution reactions. They can only be prepared from carboxylic acids using special reagents, as discussed in Section 22.10A. 

Although somewhat less reactive than acid chlorides, anhydrides nonetheless readily react with most nucleophiles to form substitution products. Nucleophilic substitution reactions of anhydrides are no different than the reactions of other carboxylic acid derivatives, even though anhydrides contain two carbonyl groups. Nucleophilic attack occurs at one carbonyl group, while the second carbonyl becomes part of the leaving group. 

Hydrolysis reactions are a kind of nucleophilic substitution reaction in which the oxygen of a water molecule serves as the nucleophile. The electrophile is usually the carbonyl group of an ester, amide, or anhydride. 

One of the most important reactions in the production of industrial aromatics is electrophilic aromatic substitution another prominent type of reaction is nucleophilic substitution, which is favored for aromatics with electron-withdrawing groups. Free radical reactions, which occur especially in thermal pyrolysis processes and in side-chain oxidation and chlorination reactions, are even more important, in quantitative terms, than electrophilic and nucleophilic substitution reactions. Typical examples are thermal cracking of naphtha and gas-oil fractions, the oxidation of naphthalene to phthalic anhydride, and the side-chain chlorination of toluene. Rearrangement reactions are less significant. 

Because both the carboxylate anion and ATP are negatively charged, they caimot react with each other unless they are at the active site of an enzyme. One of the functions of the enzymes that catalyze these reactions is to neutralize the negative charges of ATP so it can react with a nucleophile (Figure 16.5). Another function of the enzyme is to exclude water from the active site where the reaction takes place. Otherwise, hydrolysis of the mixed anhydride formed by the reaction of a carboxylate ion and ATP would compete with the desired nucleophilic substitution reaction. 

Esters undergo nucleophilic substitution reactions by means of addition-elimination pathways, albeit with reduced reactivity relative to halides and anhydrides. Thus, catalysis by acid or base becomes a frequent necessity. For example, esters are cleaved to carboxylic acids and alcohols in the presence of excess water and strong acid, and the reaction requires heating to proceed at a reasonable rate. The mechanism of this transformation is the reverse of acid-catalyzed esterification (Section 19-9). As in esterification, the acid serves two purposes It protonates the carbonyl oxygen to make the ester more reactive toward nucleophilic attack, and it protonates the alkoxy oxygen in the tetrahedral intermediate to make it a better leaving group. 

Previous efforts for attaching sugar moieties onto preformed polymers relied on the nucleophilic substitution reaction of aminated sugars with polymeric activated carbonyl compounds. Polymeric backbones containing active carbonyl compounds such as carboxylic acid, acid chloride, carbonate, N-hydroxysuccinimide ester and anhydride react readily with aminated sugar under mild reaction conditions to afford glycopolymers via an amide linkage (Scheme 1.11). 

Monomer Reactivity. The poly(amic acid) groups are formed by nucleophilic substitution by an amino group at a carbonyl carbon of an anhydride group. Therefore, the electrophilicity of the dianhydride is expected to be one of the most important parameters used to determine the reaction rate. There is a close relationship between the reaction rates and the electron affinities, of dianhydrides (12). These were independendy deterrnined by polarography. Stmctures and electron affinities of various dianhydrides are shown in Table 1. 

The most useful syntheses of pyridazines and their alkyl and other derivatives begins with the reaction between maleic anhydride and hydrazine to give maleic hydrazide. This is further transformed into 3,6-dichloropyridazine which is amenable to nucleophilic substitution of one or both halogen atoms alternatively, the halogen(s) can be replaced by hydrogen as shown in Scheme 110. In this manner a great number of pyridazine derivatives are prepared. 

Conversion of Acid Halides into Anhydrides Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion gives an acid anhydride. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way. 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

Like all anhydrides (Section 21.5), the mixed carboxylic-phosphoric anhydride is a reactive substrate in nucleophilic acyl (or phosphoryl) substitution reactions. Reaction of 1,3-bisphosphoglycerate with ADR occurs in step 7 by substitution on phosphorus, resulting in transfer of a phosphate group to ADP and giving ATP plus 3-phosphoglycerate. The process is catalyzed by phospho-gjvcerate kinase and requires Mg2+ as cofactor. Together, steps 6 and 7 accomplish the oxidation of an aldehyde to a carboxylic acid. 

The above transformations show a few of the many inorganic esters that can be prepared by attack of an inorganic acid or, better, its acid halide or anhydride, on an alcohol. Although for convenience all these similar reactions are grouped together, these are not all nucleophilic substitutions at R. The other possible pathway is nucleophilic substitution at the inorganic central atom ... 

Nitration of furfuryl alcohol (2-furylmethanol) in acetic anhydride yields the nitro-nitrate 57 which possesses both a reactive methylene group able to undergo aldol reactions, etc., and also a nitrate ion leaving group for nucleophilic substitutions.137 Detailed studies of the nitration disclose various products resulting from the addition of one or even two acetic acid residues to the furan nucleus in competition with the nitrations.138,139... 

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