Chapter 3 — Further Reading

Textbook treatments of acids, bases, and $pK_a$

• Anslyn, E. V., and Dougherty, D. A. (2006). Modern Physical Organic Chemistry. University Science Books. Chapter 3 has the definitive undergraduate-beyond treatment of acidity and basicity, including linear free-energy relationships, Hammett correlations, and solvent effects.
• Clayden, Greeves, Warren. (2012). Organic Chemistry, 2nd edition (Oxford). Chapter 8 covers acids and bases with Clayden's trademark depth and elegance.
• Carey, F. A., and Sundberg, R. J. (2007). Advanced Organic Chemistry, Part A, 5th edition. Springer. For those headed to graduate school, the definitive advanced treatment. Chapter 4 handles bond energies and acidity in depth.

On $pK_a$ tables and references

• Bordwell, F. G. (1988). Equilibrium acidities in dimethyl sulfoxide solution. Accounts of Chemical Research, 21(12), 456–463. The canonical survey of $pK_a$ values in DMSO (an aprotic solvent where many weak-acid measurements are possible that are difficult in water).
• Perrin, D. D., Dempsey, B., and Serjeant, E. P. (1981). pKa Prediction for Organic Acids and Bases. Chapman and Hall. An older but still-useful guide to estimating $pK_a$ values when an experimental number is not available.
• IuPAC (2024). Digital pKa Reference. Online resource; searchable.

On enzyme catalysis and $pK_a$-tuning in proteins

• Fersht, A. (1999). Structure and Mechanism in Protein Science. W. H. Freeman. The standard graduate-level textbook. Chapter 1 on catalysis by proximity and orientation, and Chapter 2 on acid-base catalysis, are outstanding.
• Warshel, A. (1991). Computer Modeling of Chemical Reactions in Enzymes and Solutions. Wiley. For those interested in how proteins manipulate $pK_a$ electrostatically.
• Polgár, L. (2005). The catalytic triad of serine peptidases. Cellular and Molecular Life Sciences, 62(19–20), 2161–2172.

On drug design and pharmacokinetics

• Lipinski, C. A., Lombardo, F., Dominy, B. W., and Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 46(1-3), 3–26. The classic "rule of five" paper.
• Manallack, D. T. (2007). The pKa distribution of drugs: application to drug discovery. Perspectives in Medicinal Chemistry, 1, 25–38.
• Wermuth, C. G. (ed.) (2008). The Practice of Medicinal Chemistry, 3rd edition. Academic Press. Chapters on physicochemical properties and drug absorption.

On the Henderson-Hasselbalch equation and physiology

• Hasselbalch, K. A. (1917). Die Berechnung der Wasserstoffzahl des Blutes. Biochemische Zeitschrift, 78, 112–144. The original paper — in German, but historically important.
• West, J. B. (2000). Respiratory Physiology: The Essentials, 6th edition. Lippincott. For a physiology-side treatment of pH regulation and acid-base chemistry in humans.

Pedagogical and historical

• Brønsted, J. N. (1923). Einige Bemerkungen über den Begriff der Säuren und Basen. Recueil des Travaux Chimiques des Pays-Bas, 42, 718–728. The original Brønsted-Lowry proposal (published near-simultaneously by Lowry in English).
• Lewis, G. N. (1923). Valence and the Structure of Atoms and Molecules. Chemical Catalog Co. Lewis's original monograph proposing the electron-pair theory of acids and bases.
• Pauling, L. (1933). The concept of the chemical bond. Chemical Reviews, 12(1), 87–122. Includes the development of electronegativity and its relation to bond polarity.

Online resources

• ChemAxon's Chemicalize (chemicalize.com): online tool that predicts $pK_a$ values for any drawn structure.
• PubChem (pubchem.ncbi.nlm.nih.gov): experimental $pK_a$ values for thousands of compounds, searchable.
• Evans' pKa table (evans.rc.fas.harvard.edu): Harvard professor David Evans's widely-used compact $pK_a$ table. Available as a PDF.

A note on practice

$pK_a$ intuition is the kind of skill that can only be built by repeated practice. The best thing you can do — genuinely the most time-efficient investment for succeeding in this course — is to take a compound list (your exercise set, or a set of drug structures from a pharmacology textbook) and methodically:

1. Identify every acidic proton.
2. Estimate its $pK_a$ using ARIO reasoning.
3. Look up the actual value.
4. Analyze any discrepancy.

Do this for fifty compounds over a few hours. By the end, $pK_a$ estimation will be second nature. Every chapter after this one will reward the investment.