Substitution, electrophilic addition-elimination

Electrophilic Substitution by Addition-Elimination. Electrophilic attack has a parallel series of events, which is best known in the electrophilic substitution of vinylsilanes. The electrophile attacks from above (or below) the u bond in the vinylsilane 5.67, with the creation of an intermediate carbocation 5.68 (with the cationic carbon behind). Rotation about the a bond can take place... 

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. 

There are two possible mechanisms for cyclometallation oxidative addition or electrophilic substitution followed by reductive elimination of a small molecule. The balance of electronic and steric effects determines the course of the reaction. The metallation of 8-methylquinoline is the prototype of most cyclometallation reactions. It can be viewed in two ways, as shown in reactions (ar) and (as). 

True electrophilic substitution is very difficult in pyridopyridazines. For example, the [3,4-d] parent (286) is inert to hot 65% oleum (68AJC1291), and although formation of a 3-bromo derivative (308) was reported in the [2,3-d] series, it seems to have arisen by an addition-elimination reaction via the dibromide (309) (69AJC1745). Attempted chlorination led to ring opening. A similar effect was observed in the [3,4-d] system, where an 8-bromo derivative was obtained (77BSF665), and in iV-oxides of the pyrido[2,3-c]pyridazine and fused pyridazino[3,4-c]isoquinoline series (72JHC351). The formation of (311) from (310)... 

Chlorination. Electrophilic chlorination of quinoline (66) in neutral medium showed a positional selectivity order of 3 > 6 > 8. The 5- and 8-positions should be sterically hindered to some extent. Hammett cr+ values predict an order for electrophilic substitution of 5 > 8 = 6 > 3. Treatment with chlorine at 160-190°C converted quinoline into a mixture of 3-chloro-, 3,4-dichloro-, 3,4,6- and 3,4,8-trichloro-, 3,4,6,8-tetrachloro-, and 3,4,6,7,8-pentachloro-quinolines. At lower temperatures ( 100°C) the major product was 3-chloroquinoline, albeit in low yield. The 4-substituted species may have arisen from an addition-elimination or radical process (70JHC171). 

Volume 8 Volume 9 Volume 10 Volume 12 Volume 13 Proton Transfer Addition and Elimination Reactions of Aliphatic Compounds Ester Formation and Hydrolysis and Related Reactions Electrophilic Substitution at a Saturated Carbon Atom Reactions of Aromatic Compounds Section 5. POLYMERISATION REACTIONS (3 volumes)... 

In Part 2 of this book, we shall be directly concerned with organic reactions and their mechanisms. The reactions have been classified into 10 chapters, based primarily on reaction type substitutions, additions to multiple bonds, eliminations, rearrangements, and oxidation-reduction reactions. Five chapters are devoted to substitutions these are classified on the basis of mechanism as well as substrate. Chapters 10 and 13 include nucleophilic substitutions at aliphatic and aromatic substrates, respectively, Chapters 12 and 11 deal with electrophilic substitutions at aliphatic and aromatic substrates, respectively. All free-radical substitutions are discussed in Chapter 14. Additions to multiple bonds are classified not according to mechanism, but according to the type of multiple bond. Additions to carbon-carbon multiple bonds are dealt with in Chapter 15 additions to other multiple bonds in Chapter 16. One chapter is devoted to each of the three remaining reaction types Chapter 17, eliminations Chapter 18, rearrangements Chapter 19, oxidation-reduction reactions. This last chapter covers only those oxidation-reduction reactions that could not be conveniently treated in any of the other categories (except for oxidative eliminations). 

Chapters 1 and 2 dealt with formation of new carbon-carbon bonds by reactions in which one carbon acts as the nucleophile and another as the electrophile. In this chapter we turn our attention to noncarbon nucleophiles. Nucleophilic substitution is used in a variety of interconversions of functional groups. We discuss substitution at both sp3 carbon and carbonyl groups. Substitution at saturated carbon usually involves the Sjv2 mechanism, whereas substitution at carbonyl groups usually occurs by addition-elimination. 

The mechanism for electrophilic aromatic substitution is addition-elimination. Using these working hypotheses, Mills and Nixon explained the regioselectivity of electrophilic substitution in 5-hydroxyindan versus 6-hydroxytetralin. 

The electrode reaction of an organic substance that does not occur through electrocatalysis begins with the acceptance of a single electron (for reduction) or the loss of an electron (for oxidation). However, the substance need not react in the form predominating in solution, but, for example, in a protonated form. The radical formed can further accept or lose another electron or can react with the solvent, with the base electrolyte (this term is used here rather than the term indifferent electrolyte) or with another molecule of the electroactive substance or a radical product. These processes include substitution, addition, elimination, or dimerization reactions. In the reactions of the intermediates in an anodic process, the reaction partner is usually nucleophilic in nature, while the intermediate in a cathodic process reacts with an electrophilic partner. 

If we are correct in our assumption that the electrophilic substitution of aromatic species involves such a complexes as intermediates—and it has proved possible actually to isolate them in the course of some such substitutions (p. 136)—then what we commonly refer to as aromatic substitution really involves initial addition followed by subsequent elimination. How this basic theory is borne out in the common electrophilic substitution reactions of benzene will now be considered. 

Attack on aromatic species can occur with radicals, as well as with the electrophiles (p. 131) and nucleophiles (p. 167) that we have already considered as with these polar species, homolytic aromatic substitution proceeds by an addition/elimination pathway ... 

Pyrimidinyl halides are not only precursors for Pd-catalyzed reactions, but also important pharmaceuticals in their own right. One of the most frequently employed approaches for halopyrimidine synthesis is direct halogenation. When pyrimidinium hydrochloride and 2-aminopyrimidine were treated with bromine, 5-bromopyrimidine and 2-amino-5-bromopyrimidine were obtained, respectively, via an addition-elimination process instead of an aromatic electrophilic substitution [4, 5], Analogously, 2-chloro-5-bromopyrimidine (1) was generated from direct halogenation of 2-hydroxypyrimidine [6], Treating 1 with HI then gave to 2-iodo-5-bromopyrimidine (2). In the preparation of 5-bromo-4,6-dimethoxypyrimidine (4), N-bromosuccinimide was found to be superior to bromine for the bromination of 4,6-dimethoxypyrimidine (3) [7]. 

Reactivity toward nucleophiles and comparison with other electrophilic centers 152 Paths for nucleophilic substitution of sulfonyl derivatives 156 Direct substitution at sulfonyl sulfur stereochemistry 157 Direct substitution at sulfonyl sulfur stepwise or concerted 158 The elimination-addition path for substitution of alkanesulfonyl derivatives 166 Homolytic decomposition of a-disulfones 172 10 Concluding remarks 173 Acknowledgement 174 References 174... 

Two substitutions are occurring here H to Br, and Br to MeO. Looking at the order of reagents, the first substitution is H to Br. Br2 is electrophilic, so the a-C of the acyl bromide must be made nucleophilic. This is done by enolization. The substitution of Br with MeO occurs by a conventional addition-elimination reaction under acidic conditions. 

A reaction in which one functional group (see p.lO) is replaced by another is termed substitution. Depending on the process involved, a distinction is made between nucleophilic and electrophilic substitution reactions (see chemistry textbooks). Nucleophilic substitutions start with the addition of one molecule to another, followed by elimination of the so-called leaving group. 

For example, 3-bromopyridine is formed when pyridine is reacted with bromine in the presence of oleum (sulfur trioxide in cone, sulfuric acid) at 130 °C (Scheme 2.4). Direct electrophilic substitution is not involved, however, aszwitterionic (dipolar) pyridinium-A-sulfonate is the substrate for an addition of bromide ion. Subsequently, the dihydropyridine that is formed reacts, possibly as a dienamine, with bromine to generate a dibromide, which then eliminates bromide ion from C-2. It is notable that no bromination occurs under similar conditions when oleum is replaced by cone, sulfuric acid alone instead, pyridinium hydrogensul-fate is produced. 

The addition-elimination mechanism is also very common in the monocyclic oxygen and sulfur heterocycles (e.g. equation 20), a fact frequently cited as evidence for their low aromaticity. Pyran-2-ones can react with electrophiles at the 3- and 5-positions and pyran-4-ones at the 3-position (they also react at the carbonyl oxygen atom, but this is classified as a substituent reaction). Moreover, while the position of substitution can often be predicted on the basis of charge distribution and substituent effects, the choice of experimental conditions can also profoundly affect the outcome of the reaction, as illustrated in Schemes 2 and 3. 

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