Understanding Reactivity with Hard-Soft Acid-Base Theory

Hard-Soft Acid-Base(HSAB) theory one of the most useful rules of thumb for explaining and predicting chemical reactivity trends. Hard molecules tend to be small/non-polarizable and charged while soft molecules tend to be large/polarizable and uncharged. Both acids/electrophiles and bases/nucleophiles can be hard and soft and the defining reactivity rule of HSAB theory is:

•  hard acids  prefer to react with  hard bases  forming ionic bonds
•  soft acids  prefer to react with  soft bases  forming covalent bonds

HSAB REGIOSELECTIVITY:
These rules are especially useful for rationalizing regioselectivity in ambident molecules (molecules that have more than one reactive site) such as enols and enones (see figure above):

•  hard acids  react with the oxygen of the enolate
•  soft acids  react with the carbon of the enolate
   

•  hard bases  react with the carbonyl carbon of the enone
•  soft bases  react with the β-carbon of the enone

KLOPMAN EQUATION EXPLAINS HSAB THEORY:
Finally, though these rules were originally derived empirically, there is quantum mechanical explanation for these trends in the Klopman equation:

This equation shows how chemical reactivity is defined by two terms: (1) an electrostatics (ionic) term and (2) orbital (covalent) term. In general:

• hard/hard interactions maximize the electrostatic term (i.e. highly charged molecules are very attracted to each other)
• soft/soft interaction maximize the orbital overlap term (i.e. molecules with similar energy HOMO’s and LUMO’s most easily make covalent bonds)

REFERENCES: 

1. Pearson, R.G. Hard and Soft Acids and Bases. J. Am. Chem. Soc. 1963, 85, 3533-3539.
2. Pearson, R.G.; Songstad,J. Application of the Principle of Hard and Soft Acids and Bases to Organic Chemistry J. Am. Chem. Soc. 1966, 89, 1827-1836.
3. Klopman, G. Chemical Reactivity and the Concept of Charge- and Frontier-Controlled Reactions. J. Am. Chem. Soc. 1968, 90, 223-234.
4. Pearson, R.G. Hard and Soft Acids and Bases, HSAB, Part II. J. Chem. Educ. 1968, 45, 643-648.
5. Fleming, I. Frontier Orbitals and Organic Chemical Reactions, Wiley-Interscience, 2004
6. McQuarrie, D.A.; Simon, J.D. Physical Chemistry: A Molecular Approach. University Science Books, 1997
7. Carey, F.A.; Sundberg, R.J. Advanced Organic Chemistry, Part A: Structure and Mechanisms. Springer 2008

This work by Eugene Douglass and Chad Miller is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.