Computational Approaches for the Prediction of pKa Values: 1st Edition (Paperback) book cover

Computational Approaches for the Prediction of pKa Values

1st Edition

By George C. Shields, Paul G. Seybold

CRC Press

175 pages | 25 B/W Illus.

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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.

Table of Contents


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


About the Authors

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.

About the Series

QSAR in Environmental and Health Sciences

The aim of the book series is to publish cutting-edge research and the latest developments in QSAR modeling applied to environmental and health issues. Its aim is also to publish routinely used QSAR methodologies to provide newcomers to the field with a basic grounding in the correct use of these computer tools. The series is of primary interest to those whose research or professional activity is directly concerned with the development and application of SAR and QSAR models in toxicology and ecotoxicology. It is also intended to provide graduate and postgraduate students with clear and accessible books covering the different aspects of QSARs.

Learn more…

Subject Categories

BISAC Subject Codes/Headings:
SCIENCE / Chemistry / General
SCIENCE / Chemistry / Organic
SCIENCE / Chemistry / Physical & Theoretical