1st Edition

Computational Approaches for the Prediction of pKa Values

By George C. Shields, Paul G. Seybold Copyright 2014
    175 Pages 25 B/W Illustrations
    by CRC Press

    175 Pages 25 B/W Illustrations
    by CRC Press

    The pKa of a compound describes its acidity or basicity and, therefore, is one of its most important properties. Its value determines what form of the compound—positive ion, negative ion, or neutral species—will be present under different circumstances. This is crucial to the action and detection of the compound as a drug, pollutant, or other active chemical agent. In many cases it is desirable to predict pKa values prior to synthesizing a compound, and enough is now known about the salient features that influence a molecule’s acidity to make these predictions.

    Computational Approaches for the Prediction of pKa Values describes the insights that have been gained on the intrinsic and extrinsic features that influence a molecule’s acidity and discusses the computational methods developed to estimate acidity from a compound’s molecular structure. The authors examine the strengths and weaknesses of the theoretical techniques and show how they have been used to obtain information about the acidities of different classes of chemical compounds.

    The book presents theoretical methods for both general and more specific applications, covering methods for various acids in aqueous solutions—including oxyacids and related compounds, nitrogen acids, inorganic acids, and excited-state acids—as well as acids in nonaqueous solvents. It also considers temperature effects, isotope effects, and other important factors that influence pKa. This book provides a resource for predicting pKa values and understanding the bases for these determinations, which can be helpful in designing better chemicals for future uses.


    Absolute pKa Calculations
    Thermodynamic Cycles
    Gas Phase Gibbs Free Energy Calculations
    Solvation Gibbs Free Energy Calculations
    Pitfalls and Lessons from the Literature
    Concluding Remarks on Absolute pKa Calculations

    Relative pKa Calculations

    Quantitative Structure-Acidity Relationships (QSARs)
    Basic Principles of the QSAR approach
    Hammett and Taft Constants
    The Search for Useful Quantum Chemical Descriptors
    Alternative Approaches
    Commercial and Free Programs

    Oxyacids and Related Compounds
    Alcohols, Phenols, and Carboxylic Acids
    Phosphonic Acids
    Hydroxamic Acids and Oximes

    Nitrogen Acids
    Aliphatic Amines
    Azoles and Some Other Heterocyclics
    Amino Acids
    Pyridines and Related Heterocyclics
    Purines and Pyrimidines

    Additional Types of Acids
    Carbon Acids
    Inorganic Acids
    Polyprotic Acids
    Excited State Acids

    Acids in Non-aqueous Solvents
    Deuterium Oxide
    Dimethyl Sulfoxide
    Other Solvents and Commentary

    Additional Factors Influencing Acidity and Basicity
    Temperature Effects on Acidity
    Steric Effects and Hydrogen Bonding
    Isotope Effects



    George Shields, Ph.D., is currently a professor of chemistry and dean of the College of Arts and Sciences at Bucknell University. His research uses computational chemistry to investigate atmospheric and biological chemistry.

    Paul Seybold, Ph.D., has been has been a faculty member and department chair (1999–2004) in the Department of Chemistry at Wright State University in Ohio and a visiting scholar and visiting professor at a number of universities in the United States and Europe. His research interests center on chemical and biochemical applications of quantum chemistry, molecular structure-activity relationships, luminescence spectroscopy, and cellular automata models of complex systems.