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11: Nucleophilic Acyl Substitution Reactions

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    • 11.1: Prelude to Nucleophilic Acyl Substitution Reactions
      Understanding the reactivity of carboxylic acid derivative groups will allow us to appreciate why penicillin is so prone to degradation, and why - very significantly for all of us - the era of not having to worry about bacterial infections may be near an end, as common toxic bacterial species such as Staphylococcus develop increasingly robust resistance to antibiotics.
    • 11.2: Carboxylic Acid Derivatives
      The functional groups at the heart of this chapter are called carboxylic acid derivatives: they include carboxylic acids themselves, carboxylates (deprotonated carboxylic acids), amides, esters, thioesters, and acyl phosphates.
    • 11.3: The Nucleophilic Acyl Substitution Mechanism
      The fact that one of the atoms adjacent to the carbonyl carbon in carboxylic acid derivatives is an electronegative heteroatom – rather than a carbon like in ketones or a hydrogen like in aldehydes - is critical to understanding the reactivity of carboxylic acid derivatives.
    • 11.4: The Relative Reactivity of Carboxylic Acid Derivatives
      In carboxylic acid derivatives, the partial positive charge on the carbonyl carbon is stabilized by electron donation from nonbonding electrons on the adjacent heteroatom, which has the effect of decreasing electrophilicity.
    • 11.5: Hydrolysis of Thioesters, Esters, and Amides
      So far we have been looking at the formation of thioesters, carboxylic esters, and amides, starting from carboxylates. In hydrolytic acyl substitution reactions, nucleophilic water is the incoming nucleophile and a carboxylate group is the final product. Because carboxylates are the least reactive among the carboxylic acid derivatives, these hydrolysis reactions are thermodynamically favorable, with thioester hydrolysis the most favorable of the three.
    • 11.6: Nucleophilic Acyl Substitution Reactions in the Laboratory
      All of the biological nucleophilic acyl substitution reactions we have seen so far have counterparts in laboratory organic synthesis. Mechanistically, one of the biggest differences between the biological and the lab versions is that the lab reactions usually are run with a strong acid or base as a catalyst, whereas biological reactions are of course taking place at physiological pH.
    • 11.7: Nucleophilic Acyl Substitution Reactions (Exercises)
    • 11.8: Nucleophilic Acyl Substitution Reactions (Summary)