Chapter 11: Nucleophilic Substitution at C=O with Loss of Carbonyl Oxygen

Hemiacetal and acetal formation from aldehydes and alcohols demonstrates the importance of acid catalysis in both forward and reverse directions, with special attention to oxonium ions as highly reactive intermediates. Cyclic acetals such as dioxolanes are emphasized for their synthetic stability and utility as protecting groups, while practical methods for driving equilibrium reactions—including water removal via Dean-Stark apparatus, molecular sieves, and excess reagent strategies—are detailed. The chapter then covers carbonyl-amino reactions, beginning with imine formation from aldehydes or ketones reacting with primary amines through hemiaminal intermediates under mildly acidic conditions where optimal pH ranges from four to six. Secondary amines follow a different pathway, yielding enamines characterized by nitrogen adjacent to a carbon-carbon double bond. Both imines and enamines are evaluated for their reactivity, stability, and susceptibility to hydrolysis. Reductive amination emerges as a powerful synthetic method using sodium cyanoborohydride or sodium triacetoxyborohydride to convert imines to secondary and tertiary amines, with connections drawn to biosynthetic pathways such as alanine formation via pyridoxamine intermediates. The Strecker synthesis is introduced as a method for amino acid preparation involving cyanide nucleophilic attack on iminium ions followed by hydrolysis. The chapter concludes with the Wittig reaction, which replaces carbonyl oxygen with a carbon-carbon double bond through the intermediacy of phosphonium ylides and four-membered oxaphosphetane intermediates, driven by formation of the exceptionally stable phosphine oxide product.