Substitution nucleophilic addition elimination

Addition-elimination Nucleophilic substitution with a carboxylic acid or acid derivative by means of a tetrahedral intermediate. 

Other reactions where the cluster core remains intact are based on nucleophilic addition, elimination, and substitution reactions, as well as electrochemical interconversions. Some examples are given in Equations (47) and (48) 2714 3216... 

Nucleophilic Addition-Elimination (Nucleophilic Acvl Substitution)... 

Know the meaning of Fischer esterification, nucleophilic addition-elimination (nucleophilic acyl substitution), tetrahedral intermediate, saponification, ammonolysis, acyl transfer. 

The author believes that students are well aware of the basic reaction pathways such as substitutions, additions, eliminations, aromatic substitutions, aliphatic nucleophilic substitutions and electrophilic substitutions. Students may follow undergraduate books on reaction mechanisms for basic knowledge of reactive intermediates and oxidation and reduction processes. Reaction Mechanisms in Organic Synthesis provides extensive coverage of various carbon-carbon bond forming reactions such as transition metal catalyzed reactions use of stabilized carbanions, ylides and enamines for the carbon-carbon bond forming reactions and advance level use of oxidation and reduction reagents in synthesis. 

In addition to nucleophilic substitution of aromatics by the addition-elimination mechanism, nucleophilic substitution is also possible through the effect of a strong base (BI via an elimination-addition mechanism. Arynes occur as intermediates in such a process. 

A typical retrosynthesis of a P-keto ester involves making a disconnection from one of the carbonyls to the alpha carbon between the two carbonyls. The alpha carbon will be introduced as a nucleophilic enolate. The P-keto carbon used to be a carbonyl (E+), but how can it still be a carbonyl after being attacked by a nucleophile The P-keto carbonyl must have had a leaving group attached to it in order for the addition-elimination acyl substitution mechanism to take place. The alkoxy group is the preferred leaving group to select, since esters are stable, easy to work with, and commercially available. 

The Pd—C cr-bond can be prepared from simple, unoxidized alkenes and aromatic compounds by the reaction of Pd(II) compounds. The following are typical examples. The first step of the reaction of a simple alkene with Pd(ll) and a nucleophile X or Y to form 19 is called palladation. Depending on the nucleophile, it is called oxypalladation, aminopalladation, carbopalladation, etc. The subsequent elimination of b-hydrogen produces the nucleophilic substitution product 20. The displacement of Pd with another nucleophile (X) affords the nucleophilic addition product 21 (see Chapter 3, Section 2). As an example, the oxypalladation of 4-pentenol with PdXi to afford furan 22 or 23 is shown. 

Pd(II) compounds coordinate to alkenes to form rr-complexes. Roughly, a decrease in the electron density of alkenes by coordination to electrophilic Pd(II) permits attack by various nucleophiles on the coordinated alkenes. In contrast, electrophilic attack is commonly observed with uncomplexed alkenes. The attack of nucleophiles with concomitant formation of a carbon-palladium r-bond 1 is called the palladation of alkenes. This reaction is similar to the mercuration reaction. However, unlike the mercuration products, which are stable and isolable, the product 1 of the palladation is usually unstable and undergoes rapid decomposition. The palladation reaction is followed by two reactions. The elimination of H—Pd—Cl from 1 to form vinyl compounds 2 is one reaction path, resulting in nucleophilic substitution of the olefinic proton. When the displacement of the Pd in 1 with another nucleophile takes place, the nucleophilic addition of alkenes occurs to give 3. Depending on the reactants and conditions, either nucleophilic substitution of alkenes or nucleophilic addition to alkenes takes place. 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

The Addition-Elimination Mechanism of Nucleophilic Aromatic Substitution... 

THE ADDITION-ELIMINATION MECHANISM OF NUCLEOPHILIC AROMATIC SUBSTITUTION... 

The generally accepted mechanism for nucleophilic aromatic substitution m nitro substituted aryl halides illustrated for the reaction of p fluoromtrobenzene with sodium methoxide is outlined m Figure 23 3 It is a two step addition-elimination mechanism, m which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group Figure 23 4 shows the structure of the key intermediate The mech anism is consistent with the following experimental observations... 

These results rule out substitution by addition-elimination because that mechanism requires the nucleophile to attach itself to the carbon from which the leaving group departs... 

Section 23 6 Nucleophilic aromatic substitutions of the type just shown follow an addition—elimination mechanism... 

Other aryl halides that give stabilized anions can undergo nucleophilic aromatic substitution by the addition-elimination mechanism Two exam pies are hexafluorobenzene and 2 chloropyridme... 

The product of this reaction as its sodium salt is called a Meisenheimer complex after the Ger man chemist Jacob Meisenheimer who reported on their formation and reactions in 1902 A Meisenheimer complex corresponds to the product of the nucleophilic addition stage in the addition-elimination mechanism for nucleophilic aromatic substitution... 

Addition-elimination mechanism (Section 23 6) Two stage mechanism for nucleophilic aromatic substitution In the addition stage the nucleophile adds to the carbon that bears... 

Cycloalkene (Section 5 1) A cyclic hydrocarbon characterized by a double bond between two of the nng carbons Cycloalkyne (Section 9 4) A cyclic hydrocarbon characterized by a tnple bond between two of the nng carbons Cyclohexadienyl anion (Section 23 6) The key intermediate in nucleophilic aromatic substitution by the addition-elimination mechanism It is represented by the general structure shown where Y is the nucleophile and X is the leaving group... 

Nucleophilic aromatic substitution (Chapter 23) A reaction m which a nucleophile replaces a leaving group as a sub stituent on an aromatic nng Substitution may proceed by an addition-elimination mechanism or an elimination-addition mechanism... 

There are alternatives to the addition-elimination mechanism for nucleophilic substitution of acyl chlorides. Certain acyl chlorides are known to react with alcohols by a dissociative mechanism in which acylium ions are intermediates. This mechanism is observed with aroyl halides having electron-releasing substituents. Other acyl halides show reactivity indicative of mixed or borderline mechanisms. The existence of the SnI-like dissociative mechanism reflects the relative stability of acylium ions. 

SECTION 10.5. NUCLEOPHILIC AROMAHC SUBSTITUTION BY THE ADDITION-ELIMINATION MECHANISM... 

Nucleophilic Aromatic Substitution by the Addition-Elimination Mechanism... 

There are several mechanisms by which net nucleophilic aromatic substitution can occur. In this section we will discuss the addition-elimination mechanism and the elimination-addition mechanism. Substitutions via organometallic intermediates and via aryl diazo-nium ions will be considered in Chapter 11 of Part B. 

The addition-elimination mechanism uses one of the vacant n orbitals for bonding interaction with the nucleophile. This permits addition of the nucleophile to the aromatic ring without displacement of any of the existing substituents. If attack occurs at a position occupied by a potential leaving group, net substitution can occur by a second step in which the leaving group is expelled. 

Kinetic studies have shown that the enolate and phosphorus nucleophiles all react at about the same rate. This suggests that the only step directly involving the nucleophile (step 2 of the propagation sequence) occurs at essentially the diffusion-controlled rate so that there is little selectivity among the individual nucleophiles. The synthetic potential of the reaction lies in the fact that other substituents which activate the halide to substitution are not required in this reaction, in contrast to aromatic nucleophilic substitution which proceeds by an addition-elimination mechanism (see Seetion 10.5). 

The first three chapters discuss fundamental bonding theory, stereochemistry, and conformation, respectively. Chapter 4 discusses the means of study and description of reaction mechanisms. Chapter 9 focuses on aromaticity and aromatic stabilization and can be used at an earlier stage of a course if an instructor desires to do so. The other chapters discuss specific mechanistic types, including nucleophilic substitution, polar additions and eliminations, carbon acids and enolates, carbonyl chemistry, aromatic substitution, concerted reactions, free-radical reactions, and photochemistry. 

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