Michael McBride continues Yale's Freshman Organic Chemistry II by reframing acid-base chemistry as a case of nucleophilic substitution at hydrogen. He starts with the ionic dissociation of water, then shows how relative pKa values, largely insensitive to solvent, reveal the roles of energy match, orbital overlap, and resonance. A titration of alanine demonstrates how pKa values are measured experimentally and how buffering works in practice. McBride then explains how switching to other solvents extends the usable pKa scale far beyond what water allows, giving chemists a tool to quantify many organic reaction effects. The lecture closes by connecting nineteenth century organic reactions and biochemical processes to the general framework of nucleophilic substitution. Chapters run from solvent effects through the alanine titration to this broader synthesis, filmed as part of Yale's Open Yale Courses series recorded in spring 2011.