Amides nucleophilic substitution reactions

Arynes are intermediates in certain reactions of aromatic compounds, especially in some nucleophilic substitution reactions. They are generated by abstraction of atoms or atomic groups from adjacent positions in the nucleus and react as strong electrophiles and as dienophiles in fast addition reactions. An example of a reaction occurring via an aryne is the amination of o-chlorotoluene (1) with potassium amide in liquid ammonia. According to the mechanism given, the intermediate 3-methylbenzyne (2) is first formed and subsequent addition of ammonia to the triple bond yields o-amino-toluene (3) and m-aminotoluene (4). It was found that partial rearrangement of the ortho to the meta isomer actually occurs. 

An a ,/3-epoxycarboxylic ester (also called glycidic ester) 3 is formed upon reaction of a a-halo ester 2 with an aldehyde or ketone 1 in the presence of a base such as sodium ethoxide or sodium amide. Mechanistically it is a Knoevenagel-type reaction of the aldehyde or ketone 1 with the deprotonated a-halo ester to the a-halo alkoxide 4, followed by an intramolecular nucleophilic substitution reaction to give the epoxide 3 ... 

Bonds typically hydrolyzed include carboxylic and phosphoric esters, amides, acetals, amidines, as well as metal ion complexes. (When a nucleophilic substitution reaction uses the solvent as the nucleophile, the reaction is often referred to as solvolysis.)... 

A variety of protonic and Lewis acids initiate the cationic polymerization of lactams [Bertalan et al., 1988a,b Kubisa, 1996 Kubisa and Penczek, 1999 Puffr and Sebenda, 1986 Sebenda, 1988]. The reaction follows the mechanism of acid-catalyzed nucleophilic substitution reactions of amides. More specibcally, polymerization follows an activated monomer mechanism. Initiation occurs by nucleophilic attack of monomer on protonated (activated) monomer (XXIV) to form an ammonium salt (XXV) that subsequently undergoes proton exchange with monomer to yield XXVI and protonated monomer. The conversion of XXIV to XXV involves several steps—attachment of nitrogen to C+, proton transfer from... 

In order to learn how to generate a complete mechanistic sequence for a complex reaction, we consider now a nucleophilic substitution reaction of esters, amides and so on, shown in Equation 6.23,... 

Sulfonic acids, like sulfuric acid, are much stronger acids than carboxylic acids. However, their chemical behavior resembles that of carboxylic acids in many other respects. Sulfonic acids form the same type of derivatives, sulfonyl chlorides, esters, amides, and so on, as do carboxylic acids. These derivatives are intercon-verted by nucleophilic substitution reactions that resemble those of carboxylic acid derivatives. 

The charge distribution in pyridine leads to deactivation for electrophilic substitution, the least for the position 3 (formation of 3-bromopyridine) at higher temperatures mainly 2-bromo-pyridine is produced by radical substitution. With sodium amide 2-aminopyridine is produced as a nucleophilic substitution reaction. 

Ambident anions are mesomeric, nucleophilic anions which have at least two reactive centers with a substantial fraction of the negative charge distributed over these cen-ters ) ). Such ambident anions are capable of forming two types of products in nucleophilic substitution reactions with electrophilic reactants . Examples of this kind of anion are the enolates of 1,3-dicarbonyl compounds, phenolate, cyanide, thiocyanide, and nitrite ions, the anions of nitro compounds, oximes, amides, the anions of heterocyclic aromatic compounds e.g. pyrrole, hydroxypyridines, hydroxypyrimidines) and others cf. Fig. 5-17. 

A similar approach was described by Kim et al. <01MI1403> to build the Furstner synthon from the vinylogous amide 9, previously described, and the commercially available dimethyl aminomalonate hydrochloride as building block for pyrrole systems. The cyclocondensation reaction between the vinylogous amide 9 and dimethyl aminomalonate hydrochloride was performed in acetic acid at room temperature to yield the presumed Intermediate 12 via an acid-catalyzed nucleophilic substitution reaction. The mixture was then diluted with additional acetic acid and heated under reflux to facilitate the intramolecular ring closure and the loss of the methoxycarbonyl moiety to produce the desired pyrrole. Formation of lamellarin O dimethyl ether was achieved as in the Furstner approach <95JOC6637>. 

Nucleophilic substitution reactions of 5-chlorop5Tazoles 48 with amines and thiols under mild conditions provided 5-alkyl amino and thioether pyrazoles 49 as selective COX-2 inhibitors <03TL7629>. 4-Chloromethylpyrazoles 50 reacted readily with amides, carbamates, urea, azoles, alcohols, and thiols under neutral conditions to give substituted benzylic products 51 in moderate yields <03H(60)167>. 

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. 

The acetylide ion is a strongly basic and nucleophilic species which can induce nucleophilic substitution at positive carbon centres. Acetylene is readily converted by sodium amide in liquid ammonia to sodium acetylide. In the past alkylations were predominantly carried out in liquid ammonia. The alkylation of alkylacetylenes and arylacetylenes is carried out in similar fashion to that of acetylene. Nucleophilic substitution reactions of the alkali metal acetylides are limited to primary halides which are not branched in the -position. Primary halides branched in the P-position as well as secondary and tertiary halides undergo elimination to olefins by the NaNH2. The rate of reaction with halides is in the order I > Br > Cl, but bromides are generally preferred. In the case of a,o)-chloroiodoalkanes and a,to-bromoiodoalkanes. 

Commercially available alkali amides can also be used in nucleophilic substitution reactions to form anilines, although the reaction mechanisms differ greatly from those of direct nucleophilic substitution reactions conducted with weak bases. The reactions generally occur rapidly at room temperature, and even at temperatures as low as — 33 °C in the case of amination in liquid ammonia. A mixture of products often results, but the entering amine is rarely found more than one carbon atom away from the leaving halogen (equation 2). 

Hydrolases catalyze the addition of water to a substrate by means of a nucleophilic substitution reaction. Hydrolases (hydrolytic enzymes) are the biocatalysts most commonly used in organic synthesis. They have been used to produce intermediates for pharmaceuticals and pesticides, and chiral synthons for asymmetric synthesis. Of particular interest among hydrolases are amidases, proteases, esterases, and lipases. These enzymes catalyze the hydrolysis and formation of ester and amide bonds. 

Several natural products, for example siderophores, contain the N-hydroxy amide Y[CON(OH)] motif [138], Within a peptide backbone, this group increases the stability to enzyme degradation and induces characteristic conformational behavior [139]. In addition to the synthesis in solution of N-hydroxy amide-containing peptides (which is not trivial), a new solid-phase approach has recently been developed [140]. To explore the features of the N-hydroxy amide moiety using automated and combinatorial techniques, a method for the preparation of v /[CON(OH)] peptide ligands for MHC-I molecules has been elaborated [140], The strategy for the parallel preparation of these peptidomimetics on a solid support is illustrated in Scheme 7.9. The key step is the nucleophilic substitution reaction of resin-bound bromocarboxylic acids by O-benzylhydroxylamine, which requires several days. 

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. 

Cyclopropylphosphine oxides (140) react with the sodium salts of amides, presumably via cyclopropane ring-opening and intramolecular olefination, to give dihydropyrrole derivatives in moderate to good yield. Vicarious nucleophilic substitution reactions of a variety of substituted nitrobenzene derivatives with the carbanion of chloromethyldiphenylphosphine oxide to give o-(141) and p-(142)-nitrobenzyldiphenylphosphine oxides have been investigated. ... 

This route is especially convenient because no over-alkylation of the anion of acetonitrile occurs. Over-alkylation can be a problem in attempts to methylate the anion of diethyl cyano-methylphosphonate (4) directly a mixture of unalkylated, monoalkylated and dialkylated products in a ratio of 1 2 1 is formed. The same problem arises with the alkylation of triethyl phosphonoacetate (11). For the preparation of a Ca-ester synthon, an alternative method to the propionitrile route is used (Scheme 7). This method has been used in the synthesis of labelled Cio-central units, described in the next Section. The starting material is acetic acid (9) which is converted into ethyl bromoacetate (10) as described above (Scheme 3). The ethyl bromoacetate (10) is reacted with triphenyl phosphine in a nucleophilic substitution reaction the phosphonium salt is formed (yield 97%). The phosphonium salt is deprotonated in a two-layer system of dichloromethane and an aqueous solution of NaOH. After isolation, the phosphorane 22 is reacted at room temperature with one equivalent of methyl iodide (19) the product consists mainly of the monomethylated phosphonium salt (>90%) which is deprotonated with NaOH, to give the phosphorane 23 in quantitative yield relative to phosphorane 22, and 23 is reacted with the aldehyde in dichloromethane. The ester product 12 can subsequently be reduced to the corresponding alcohol and reoxidized to the aldehyde 8. An alternative two-step sequence for this has also been used. First, the ester 12 is converted into the A -methyl-iV-methoxyamide (16) quantitatively by allowing it to react with the anion of A, 0-dimethylhydroxylamine as described above (Scheme 5). This amide 16 is converted, in one step, into the aldehyde 8 by reacting it with DIB AH in THF at -40°C [46]. 

The nucleophilic substitution reaction may take place when a durable synthetic polymer is mixed with agar or yeast, cellulose, amides and water. The hydroxyl groups present in the cellulose become attached to the hydroxyl groups of agar and yeast in a link resembling a glycosidic linkage. 

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