Nucleophilic aromatic substitution elimination process

The addition-elimination mechanism for nucleophilic aromatic substitution requires strong electron-withdrawing substituents on the aromatic ring. Under extreme conditions, however, unactivated halobenzenes react with strong bases. For example, a commercial synthesis of phenol (the Dow process ) involves treatment of chlorobenzene with sodium hydroxide and a small amount of water in a pressurized reactor at 350 °C ... 

Mechanistically, the one-pot transformation can be rationalized by a sequence of chemoselective coupling of ort/to-halogenated (hetero)aromatic acid chlorides 81 and electron rich terminal alkynes 4, followed by nucleophilic addition of the sulfide ion to the a,p-unsaturated system 86 to furnish the anionic Michael adduct 87, and finally an intramolecular nucleophilic aromatic substitution in the sense of an addition-elimination process concludes the sequence (Scheme 46). 

This equation also describes the overall reaction of either an 5 2 or a nucleophilic aromatic substitution process. In some cases, the only way to distinguish an reaction from these processes is that an is inhibited by radical inhibitors. Another distinguishing feature is that the order of the relative leaving group abilities of halides are opposite that found for nucleophilic aromatic substitution by the addition-elimination mechanism (see Chapter 3). 

One of the features of the current state of heterocyclic chemistry is a growing interest in the so-called Sn methodology (nucleophilic aromatic substitution of hydrogen) and related processes initiated by a nucleophilic attack at unsubstituted carbon in 7t-deficient azaaromatics addition of nucleophiles (An), oxidative elimination of hydrogen from cr -adducts, or auto -aromatization of cr -adducts, the tandem addition (An-An) or substitution (Sn -Sn ) reactions, and other transformations . All aspects of this relatively new branch of the chemistry of 1,2,4-triazines are discussed in detail in this chapter. 

Two examples of nucleophilic aromatic substitution for hydrogen reactions were described from which we have proposed two new atomically efficient processes for the manufacturing of commercially relevant aromatic amines. Our mechanistic studies have revealed that the direct oxidation of a-complex intermediates by either nitro groups or O2 can eliminate the need for chlorination of benzene as a starting point for the manufacturing of aromatic amines. Accordingly, these reactions demonstrate the key objective of alternate chemical design which is not to make the waste in the first place. 

Elimination of Chlorine in the Synthesis of 4-Aminodiphenylamine A New Process That Utilizes Nucleophilic Aromatic Substitution for Hydrogen... 

A critically important reaction used to manufacture a wide range of chemical products is nucleophilic aromatic substitution. Unfortunately, this reaction generates a large amount of toxic waste associated with synthesis of both intermediates and products. Of special concern are chlorinated species, the large-scale chemical synthesis of which has come under intense scrutiny. Solutia, Inc. (formerly Monsanto Chemical Company), one of the world s largest producers of chlorinated aromatics, funded research to explore alternative synthetic reactions for manufacturing processes that do not require the use of chlorine and that represent new atom-efBcient chemical reactions. Monsanto s Rubber Chemicals Division (now Flexsys America L.P.) has developed a new method for manufacturing a rubber preservative that eliminates chlorine waste at the source. 

The mechanism that operates in these reactions is an addition-elimination mechanism involving the formation of a carbanion with delocalized electrons, called a Meisenheimer intermediate. The process is called nucleophilic aromatic substitution (SnAc). 

Many synthetically important aromatic substitutions are effected by nucleophilic reagents. Unlike nucleophilic substitution at saturated carbon, aromatic substitution rarely, if ever, occurs as a single step. Rather, intermediates are involved. Three broad mechanistic classes can be recognized addition-elimination, elimination-addition, and radical or electron-transfer processes. Undoubtedly the most broadly useful substrates for nucleophilic aromatic substitution are the aryl-diazonium salts and these compounds will be the first topic. 

The outcome of the regioconservative reactions is vaguely attributed to a "direct displacement" process or to a "chelation-driven nucleophilic aromatic ipso substitution". Presumably both times the authors refer to the well-known two-step addition/elimination mechanism of nucleophilic aromatic substitution. However, to make this option practically feasible, the haloarene has to be activated by powerful electron-acceptors, in particular, nitro groups (as in 2- or 4-halonitroarenes) or by ring-incorporated nitrogen (as in 2- or 4-halopyridines). Without that, the crucial Meisenheimer complex is energetically out of reach. 

Neutral borabenzene-PMe3, generated through the route described in Scheme 2, reacts with a variety of anionic nucleophiles to furnish 5-substituted borataben-zenes (Scheme 7).15 This approach provides efficient access to boratabenzenes that bear a range of boron substituents (H, C, N, O, P) with diverse electronic and steric properties.16 Mechanistic studies establish that this novel aromatic substitution process follows an addition-elimination pathway. 

Two other important modes of substitution require mention here. They are the SNAr and elimination-addition reactions. Actually, it is sometimes difficult to distinguish between true aromatic nucleophilic substitutions and addition-elimination processes. The second group involves pyridyne intermediates (Scheme 53). Both of these reaction types are discussed fully under substituent reactions (Chapter 2.06). 

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. 

Aromatic substitution is an analogous addition/elimination process in which an electrophilic, nucleophilic, or radical reagent attaches itself to one... 

Self-Assessment Exercises 79a. Nucleophilic substitution corresponds to a substitution (either Sxjl or S[.j2) for aliphatic compounds. Electrophilic aromatic substitution is typical for aromatic compounds (an atom is replaced by an electrophile) 79b. An addition reaction is the opposite of an elimination reaction. In an addition reaction, two or more atoms (molecules) combine to form a larger one. 79c. S[,jl reaction involves the formation of carbocation. Sf.j2 reaction, on the other hand, is a one-step process in which bond breaking and bond making occur simultaneously at a carbon atom with a suitable leaving group. 79d. El reactions are unimolecular elimination reactions that proceed via carbocation intermediates. E2 reactions are bimolecular, one-step reactions that require an antiperiplanar conformation at the time of rr-bond formation and /3-bond breaking and do not involve carbocations. 

Synthetically important substitutions of aromatic compounds can also be done by nucleophilic reagents. There are several general mechanism for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, and metal-catalyzed processes. (See Section 9.5 of Part A to review these mechanisms.) We first discuss diazonium ions, which can react by several mechanisms. Depending on the substitution pattern, aryl halides can react by either addition-elimination or elimination-addition. Aryl halides and sulfonates also react with nucleophiles by metal-catalyzed mechanisms and these are discussed in Section 11.3. 

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