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:
The energies of a molecule’s Highest Occupied Molecular Orbital’s (HOMO’s) and the Lowest Unoccupied Molecular Orbitals (LUMO’s) tell us alot about that molecules reactivity. In general, molecules with high HOMO’s are good nucleophiles, bases, and reductants while molecules with low LUMO’s are good electrophiles, Lewis acids and oxidants. Unfortunately, the absolute magnitudes of “high” or “low” are very rarely treated. In the figure above, we plotted absolute values of HOMO and LUMO energies to convey more of a global understanding of reactivity trends.
Figure 1 A. Chemical Functional Groups organized by pKa (y-axis) and acidic atom (x-axis: oxygen, nitrogen, carbon, other.) B. Key for using A given a solution pH. First, mark the position of the solution pH on the pKa axis (dotted horizontal line). all functional groups above it are neutral or positively charged while all functional groups below it are negative or neutral. Second, the pKa axis is useful in further categorizing functional groups by their ability to participate in hydrogen bonds.
The pKa value of a chemical functional group (Figure 1A) is very useful because it can directly give you the approximate charged state of that functional group (in the context of drugs, proteins, membranes, DNA, etc.) at a specific solution pH. As such, the pKa is critical to an intuitive understanding of electrostatics in chemical and biological contexts.