Acylation substitution effects

Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated m Table 20 2 Because a more highly stabilized carbonyl group must result m order for nucleophilic acyl substitution to be effective acid anhydrides are readily converted to carboxylic acids esters and amides but not to acyl chlorides... 

Nucleophilic acyl substitution (Sections 20 4 20 6 and 20 12) Acylation of am monia and amines by an acyl chloride acid anhydride or ester is an excep tionally effective method for the for mation of carbon-nitrogen bonds... 

The net effect of nucleophilic acyl substitution is the replacement of the leaving group by the entering nucleophile. We ll see in Chapter 21, for instance, that acid chlorides are rapidly converted into esters by treatment with alkoxide ions (Figure 4). 

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. 

Esters can also be synthesized by an acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol, a process called the Fischer esterification reaction. Unfortunately, the need to use an excess of a liquid alcohol as solvent effectively limits the method to the synthesis of methyl, ethyl, propyl, and butyl esters. 

Conversion of Acid Chlorides into Alcohols Reduction Acid chlorides are reduced by LiAJH4 to yield primary alcohols. The reaction is of little practical value, however, because the parent carboxylic acids are generally more readily available and can themselves be reduced by L1AIH4 to yield alcohols. Reduction occurs via a typical nucleophilic acyl substitution mechanism in which a hydride ion (H -) adds to the carbonyl group, yielding a tetrahedral intermediate that expels Cl-. The net effect is a substitution of -Cl by -H to yield an aldehyde, which is then immediately reduced by UAIH4 in a second step to yield the primary alcohol. 

Another example of a nucleophilic acyl substitution reaction, this one a substitution by hydride inn to effect partial reduction of a thioester to an aldehyde, occurs in the biosynthesis of mevaldehyde, an intermediate in terpenoid... 

The reactivity of the various azolides as well as the order of reactivities within this group can be explained on the basis of the quasi-aromatic character of the azole rc-system the lone electron pairs on the acyl-substituted nitrogens N(l) are part of the cyclic tc-system of the azole units, leading to a partial positive charge on N(l) that interferes with the normal carboxamide resonance and exerts an electron-withdrawing effect on the... 

J(P1)720>. These cyclizations were mediated with sodium acetate-acetic acid buffers affording moderate to good yields (52-86%) and low to moderate yields (10-60%) of 7-acyl-substituted 1H- and (mesoionic) 2//-pyrrolote-trazole derivatives 67a-g, and 70a-d and 70f-h, respectively. In most cases, deacylation of pyrrolotetrazoles 67 and 70 could be effected easily by heating with HC1 affording moderate to excellent yields of 68a-e and 71a-e. 

Minisci-type substitution is one of the most useful reactions for the synthesis of alkyl- and acyl-substituted heteroaromatics. The acyl radicals are formed by the redox decomposition from aldehyde and /-butyl hydroperoxide or by silver-catalyzed decarboxylation of a a-keto acid with persulfate. Synthesis of acylpyrazines 70 as ant pheromones are achieved by this methodology using trialkyl-substituted pyrazines 69 with the acyl radicals generated from aldehydes or a-keto acids (Equation 10) <1996J(P1)2345>. The latter radicals are highly effective for the acylation. Homolytic alkylation of 6-chloro-2-cyanopyrazine 71 is performed by silver-catalyzed decarboxylation of alkanoic acids to provide 5-alkyl-substituted pyrazines 72 (Scheme 18) <1996CCC1109>. 

As noted in Section 4.2.1, the gas phase has proven to be a useful medium for probing the physical properties of carbanions, specifically, their basicity. In addition, the gas phase allows chemists to study organic reaction mechanisms in the absence of solvation and ion-pairing effects. This environment provides valuable data on the intrinsic, or baseline, reactivity of these systems and gives useful clues as to the roles that solvent and counterions play in the mechanisms. Although a variety of carbanion reactions have been explored in the gas phase, two will be considered here (1) Sn2 substitutions and (2) nucleophilic acyl substitutions. Both of these reactions highlight some of the characteristic features of gas-phase carbanion chemistry. 

Penicillin interferes with the synthesis of the bacterial cell wall. A nucleophilic OH group of the glycopeptide transpeptidase enzyme cleaves the P-lactam ring of penicillin by a nucleophilic acyl substitution reaction. The opened ring of the penicillin molecule remains covalently bonded to the enzyme, thus deactivating the enzyme, halting cell wall construction, and killing the bacterium. Penicillin has no effect on mammalian cells because they are surrounded by a flexible membrane composed of a lipid bilayer (Chapter 3) and not a cell wall. 

Kappe, T., Aigner, R., Roschger, P., Schnell, B., Stadbauer, W. A simple and effective method for the reduction of acyl substituted heterocyclic 1,3-dicarbonyl compounds to alkyl derivatives by zinc-acetic acid-hydrochloric acid. Tetrahedron 1995, 51,12923-12928. 

Cu-diimine macrocycle compounds (31) are formed by Jaeger template condensations of diamines with acyl-substituted /3-keto imines (30) (Scheme 9). The acyl substituents on the macrocycles are labile and undergo a variety of reactions. Reaction with trifluoromethyl sulfonate produces reactive methoxy ethylidene diimine compounds (32), which react with amines to form saddle-shaped cyclidenes. With bulky substituents these compounds have a hydrophobic void above the metal ion which can accommodate a guest molecule, an effect enhanced when the... 

The overall effect of the reaction results in the addition of R-X to the metal. Substrate types that will undergo this mode of OA are generally limited to R = benzyl, allyl, and methyl. Some acyl compounds [R(C=0)-X] also readily undergo OA. These are the same substrates that are most reactive in SN2 displacements or in nucleophilic acyl substitution. Other characteristics of these OA reactions associated with the SN2 pathway include the following ... 

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