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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: Acyl Phosphates
      Acyl phosphates, because they are so reactive towards acyl substitutions, are generally seen as reaction intermediates rather than stable metabolites in biochemical pathways. Acyl phosphates usually take one of two forms: a simple acyl monophosphate, or acyl-adenosine monophosphate.
    • 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.
    • 11.6: Acyl Phosphates
      Thioesters, which are themselves quite reactive in acyl substitution reactions (but less so than acyl phosphates), play a crucial role in the metabolism of fatty acids The ‘acyl X group’ in a thioester is a thiol.
    • 11.7: 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.
    • 11.8: Protein Synthesis on the Ribosome
      Let’s take a look at the chemistry behind the formation of a new peptide bond between the first two amino acids - which we will call aa-1 and aa-2 - in a growing protein molecule. This process takes place on the ribosome, which is essentially a large biochemical 'factory' in the cell, composed up of many enzymes and RNA molecules, and dedicated to the assembly of proteins.
    • 11.9: Nucleophilic Substitution at Activated Amides and Carbamides
      In discussing the nucleophilic acyl substitution reactions of acyl phosphates, thioesters, esters, and amides, we have seen many slight variations on one overarching mechanistic theme. Let’s now look at a reaction that can be thought of as a ‘cousin’ of the nucleophilic acyl substitution, one that follows the same general pattern but differs in several details.
    • 11.E: Nucleophilic Acyl Substitution Reactions (Exercises)
    • 11.S: Nucleophilic Acyl Substitution Reactions (Summary)
    • 11.10: 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.
    • 11.11: A Look Ahead - Acyl Substitution Reactions with a Carbanion or Hydride Ion Nucleophile
      Although we have seen many different types of nucleophilic acyl substitutions in this chapter, we have not yet encountered a reaction in which the incoming nucleophile is a carbanion or a hydride. Recall that in the previous chapter on aldehydes and ketones, we also postponed discussion of nucleophilic carbonyl addition reactions in which a carbanion or a hydride is the nucleophile.