Chapter 8: Acylation Reactions at Carbon and Heteroatom Centers

Students learn how this hierarchy determines selectivity in synthetic transformations and influences reaction conditions. The chapter progresses to acylation of carbon nucleophiles via organometallic reagents, particularly lithium dialkylcuprates, which enable selective formation of ketones and aldehydes while avoiding overacylation and competing side reactions. Heteroatom-centered acylation reactions are explored in depth, covering the formation of amides from amine nucleophiles, ester synthesis from alcoholic hydroxyl groups, and carboxylic acid generation through hydrolysis. Electronic effects, including resonance stabilization and inductive withdrawal, and steric factors governing nucleophile accessibility are analyzed to explain reactivity differences across substrates. The chapter addresses practical coupling methodologies employing carbodiimides and other activating agents that enhance reaction efficiency and synthetic utility. Peptide bond formation is presented as a key application, illustrating how controlled acylation under physiologically relevant conditions constructs polypeptides without unwanted side products. Protecting group strategies are discussed to manage functional group compatibility in multistep syntheses. Throughout, mechanistic insights are reinforced through synthetic examples demonstrating how acylation reactions generate complex molecules with high regio- and chemoselectivity in laboratory and industrial contexts.