Acyl carbon, substitution reactions

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. 

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. 

Nucleophilic acyl substitution reaction (Section 21.2) A reaction in which a nucleophile attacks a carbonyl compound and substitutes for a leaving group bonded to the carbonyl carbon. 

This is a typical nucleophilic acyl substitution reaction, with the amine of the amino acid as the nucleophile and tot-butyl carbonate as the leaving group. The tor-butyl carbonate then loses C02 and gives toi-butoxide, which is protonatecl. 

Nucleophilic substitution at an alkyl carbon is said to alkylate the nucleophile. For example, the above reaction between RI and NMe3 is an alkylation of tri-methylamine. Similarly, nucleophilic substitution at an acyl carbon is an acylation of the nucleophile. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Electrophilic substitution reactions on the carbon atoms of 1,3,4-thiadiazoles are rare due to the low electron density of ring carbons. G-Acylation can be accomplished via rearrangement of intermediate W-acylthiadiazolium salts while radical halogenation can give chlorinated or brominated 2-halo-5-substituted thiadiazoles. Examples can be found in CHEC(1984) <1984CHEC(6)545> and in Houben-Weyls Science of Synthesis <2004HOU(13)349>. 

Intermolecular nucleophilic acyl substitution is a fundamental carbon—carbon bondforming reaction. In spite of its high synthetic potential, however, its intramolecular version, that is, intramolecular nucleophilic acyl substitution (INAS) is rather rare because of the intrinsic difficulties involved in carrying it out. One difficulty associated with the INAS reaction is that a reactive nucleophilic species must be generated in the presence of carbonyl functionality, and at the same time this nucleophile is expected to react only with... 

If aspartic acid-52 acts as a nucleophile in lysozyme reactions a glycosyl enzyme intermediate will be formed [60]. There is no evidence, kinetic or otherwise, for substituted enzyme intermediates, but rapid breakdown might preclude attainment of detectable concentrations. Formation of a substituted enzyme could explain the observed retention of configuration at the anomeric carbon in transglycosidation reactions, provided backside attack in a subsequent reaction is chemically reasonable. It has therefore been important to attempt to understand the chemistry of acylal hydrolysis so as to assess the properties that would be expected of an acylal intermediate in reactions catalysed by the enzyme. 

By far the most generally useful synthetic application of allyltributyltin is in the complementary set of transition metal- and radical-mediated substitution reactions. When the halide substrates are benzylic, allylic, aromatic or acyl, transition metal catalysis is usually the method of choice for allyl transfer from tin to carbon. When the halide (or halide equivalent) substrate is aliphatic or alicyclic, radical chain conditions are appropriate, as g-hydrogen elimination is generally not a problem in these cases. 

Carboxylic acid and its derivatives undergo nucleophilic acyl substitution, where one nucleophile replaces another on the acyl carbon. Nucleophilic acyl substitution can interconvert all carboxylic acid derivatives, and the reaction mechanism varies depending on acidic or basic conditions. Nucleophiles can either be negatively charged anion (Nu ) or neutral (Nu ) molecules. 

The enolate anion attacks the carbonyl carbon of a second molecule of ester and gives a P-ketoester. Thus, the Claisen condensation is a nucleophilic acyl substitution reaction. Eor example, two molecules of ethyl acetate condense together to form the enolate of ethyl acetoacetate, which upon addition of an acid produces ethyl acetoacetate (P-ketoester). 

Organometallic complexes frequently are susceptible to nucleophilic attack by an external reagent. In some instances the attack takes place on the metal center (see substitution reactions, page 686). while in others it occurs on a bound ligand. Already in this chapter we have seen many instances in which coordinated carbon monoxide undergoes nucleophilic attack. Examples include reactions with H to produce a formyl complex (Eq. 15.19). with R to form an acyl complex (Eq. 15.49). and with OH to give a hydroxycarbonyl complex (Eq. 15.21). 

Substitution reactions at sp2 hybridized carbon atoms of acyl halides to amides... 

Because of the contribution of structures such as the one on the right to the resonance hybrid, the a-carbon of an enamine is nucleophilic. However, an enamine is a much weaker nucleophile than an enolate anion. For it to react in the SN2 reaction, the alkyl halide electrophile must be very reactive (see Table 8.1). An enamine can also be used as a nucleophile in substitution reactions with acyl chlorides. The reactive electrophiles commonly used in reactions with enamines are ... 

Moving from rearrangements, condensation reactions were also presented. Condensation reactions occur when two reactive species condense with one another forming a new compound. The first was the aldol condensation (Scheme 8.9). Later, a more complex application of the aldol condensation was presented in the form of the Robinson annula-tion (Scheme 8.10). For both of these reactions, the underlying lessons relate to the ability to induce reactions and incorporate substitutions at carbon atoms adjacent to carbonyl groups. Similar reactivities of such carbon atoms can be utilized for alkylation (SN2) and acylation (addition-elimination) reactions as illustrated in Scheme 8.11. 

According to the electrostatic potential maps, the carbonyl carbon of acetyl azide is more electron-poor and therefore more reactive in nucleophilic acyl substitution reactions. Resonance donation of nitrogen lone-pair electrons to the carbonyl group is greater in an amide than in an acyl azide. 

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