Addition reactions nucleophilic acyl

Biochemistry is carbonyl chemistiy. Almost all metabolic pathways used by living organisms involve one or more of the four fundamental carbonvl-group reactions we ve seen in Chapters 19 through 23. The digestion and metabolic breakdown of all the major classes of food molecules—fats, carbohydrates, and proteins—take place by nucleophilic addition reactions, nucleophilic acyl substitutions, a substitutions, and carbonyl condensations. Similarly, hormones and other crucial biological molecules are built up from smaller precursors by these same carbonyl-group reactions. 

Acid - base reactions Substitution reactions Elimination reactions Addition reactions Nucleophilic acyl addition Oxidation reactions Reduction reactions... 

As with nucleophilic additions and nucleophilic acyl substitutions, many laboratory schemes, pharmaceutical syntheses, and biochemical pathways make frequent use of carbonyl cr-substitution reactions. Their great value is that they constitute one of the few general methods for forming carbon-carbon bonds, thereby making it possible to build larger molecules from smaller precursors. We ll see how and why these reactions occur in this chapter. 

We ve now studied three of the four general kinds of carbonyl-group reactions and have seen two general kinds of behavior. In nucleophilic addition and nucleophilic acyl substitution reactions, a carbonyl compound behaves as an electrophile. In -substitution reactions, however, a carbonyl compound behaves as a nucleophile when it is converted into its enol or enolate ion. In the carbonyl condensation reaction that we ll study in this chapter, the carbonyl compound behaves both as an electrophile and as a nucleophile. 

The presence or absence of a leaving group on the electrophilic carbonyl carbon determines the strucmre of the product. Even though they appear somewhat more complicated, these reactions are often reminiscent of the nucleophilic addition and nucleophilic acyl substitution reactions of Chapters 21 and 22. Four types of reactions are examined ... 

Ketyls generated by the reaction of SmE with aldehydes and ketones have been incorporated into numerous sequential processes in which a radical reaction is involved. Sequential radical processes, radical cyclization/carbonyl additions, radical cyclization/substitution reactions, nucleophilic acyl substitution/radical cyclizations, cyclization/elimination processes, and others have all been realized. Because these types of reactions have been extensively reviewed [2b, 25], further details will not be given here. Needless to say, new sequential processes based on SmE-promoted ketyl/olefin coupling reactions are still being developed (Eq. 75) [88]. 

Up to now, we have studied two of the main types of carbonyl reactions nucleophilic addition and nucleophilic acyl substitution. In these reactions, the carbonyl group serves as an electrophile by accepting electrons from an attacking nucleophile. In this chapter, we consider two more types of reactions substitution at the carbon atom next to the carbonyl group (called alpha substitution) and carbonyl condensations. 

The major difference between nucleophilic acyl addition and nucleophilic acyl substitution is that aldehydes and ketones do not have a group that can leave as a relatively stable anion. They undergo only nucleophilic addition. The four carboxylic acid derivatives we study in this chapter have a leaving group, Lv, that can leave as a relatively stable anion or as a neutral species. Neutral molecules commonly serve as nucleophiles in this reaction, mainly when it is carried out under acid-catalyzed conditions. When these reactions are catalyzed by add, protonation precedes nucleophilic attack similarly, protonation precedes leaving group departure. We will see this sequence numerous times in this chapter. 

Figure21.1 The general mechanisms of nucleophilic addition and nucleophilic acyl substitution reactions. Both reactions begin with addition of a nucleophile to a polar C=0 bond to give a tetrahedral, alkoxide ion intermediate. (a) The intermediate formed from an aldehyde or ketone is protonated to give an alcohol, but (b) the intermediate formed from a carboxylic acid derivative expels a leaving group to give a new carbonyl compound.

The characteristic reaction of acyl chlorides acid anhydrides esters and amides is nucleophilic acyl substitution Addition of a nucleophilic reagent Nu—H to the carbonyl group leads to a tetrahedral mtermedi ate that dissociates to give the product of substitution... 

Ketenes undergo rapid addition by nucleophilic attack at the sp-carbon atom. The reaction of tertiary amines and acyl halides, in the absence of nucleophiles, is a general preparation for ketenes. ... 

An interesting application of the Paal thiophene synthesis was documented for the synthesis of a polystyrene-oligothiophene-polystyrene copolymer. In the Stetter reaction of aldehyde 13 and P-dimethylaminoketone 14, in situ generation of the a,p-unsaturated ketone preceded nucleophilic 1,4-conjugate addition by the acyl anion... 

Both in the laboratory and in living organisms, the reactions of carbonyl compounds take place by one of four general mechanisms nucleophilic addition, nucleophilic acyl substitution, alpha substitution, and carbonyl condensation. These... 

The second fundamental reaction of carbonyl compounds, nucleophilic acyl substitution, is related to the nucleophilic addition reaction just discussed but occurs only with carboxylic acid derivatives rather than with aldehydes and ketones. When the carbonyl group of a carboxylic acid derivative reacts with a nucleophile, addition occurs in the usual way, but the initially formed tetra-... 

Identify each of the following reactions as a nucleophilic addition, nucleophilic acyl substitution, an a substitution, or a carbonyl condensation ... 

As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in A Preview of Carbonyl Compounds and shown in Figure 19.14, the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate... 

The net effect of the addition/elimination sequence is a substitution of the nucleophile for the -Y group originally bonded to the acyl carbon. Thus, the overall reaction is superficially similar to the kind of nucleophilic substitution that occurs during an Sn2 reaction (Section 11.3), but the mechanisms of the two reactions are completely different. An SN2 reaction occurs in a single step by backside displacement of the Leaving group a nucleophilic acyl substitution takes place in two steps and involves a tetrahedral intermediate. 

Both the initial addition step and the subsequent elimination step can affect the overall rate of a nucleophilic acyl substitution reaction, but the addition step is generally the rate-limiting one. Thus, any factor that makes the carbonyl group more reactive toward nucleophiles favors the substitution process. 

We said in Section 17.4 that carboxylic acids are reduced by L1AIH4 to give primary alcohols, but we deferred a discussion of the reaction mechanism at that time. In fact, the reduction is a nucleophilic acyl substitution reaction in which —H replaces -OH to give an aldehyde, which is further reduced to a primary alcohol by nucleophilic addition. The aldehyde intermediate is much more reactive than the starting acid, so it reacts immediately and is not isolated. 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

We said in A Preview ofCnrbonyl Compounds that much of the chemistry of carbonyl compounds can be explained by just four fundamental reaction types nucleophilic additions, nucleophilic acyl substitutions, o substitutions, and carbonyl condensations. Having studied the first two of these reactions in the past three chapters, let s now look in more detail at the third major carbonyl-group process—the a-substitution reaction. 

The Hell-Volhard-Zelinskii reaction is a bit more complex than it looks and actually involves substitution of an acid bromide enol rather than a carboxylic acid enol. The process begins with reaction of the carboxylic acid with PBr3 to form an acid bromide plus HBr (Section 21.4). The HBr then catalyzes enolization of the acid bromide, and the resultant enol reacts with Br2 in an cr-substitution reaction to give an cv-bromo acid bromide. Addition of water hydrolyzes the acid bromide in a nucleophilic acyl substitution reaction and yields the a-bromo carboxylic acid product. 

The following transformation involves a conjugate nucleophilic addition reaction (Section 19.13) followed by an intramolecular nucleophilic acyl substitution reaction (Section 21.2). Show the mechanism. 

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