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

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

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)



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