Resonance and Inductive Effects
Functional groups in drug molecules can affect the ionization equilibrium, i.e., can make an acid a stronger or a weaker acid. These electrostatic effects of functional groups are classified as resonance and inductive effects and represent the contribution that resonance stabilization and electronegativity have on ionization.
The C-C bond in ethane (CH3-CH3) has no polarity because it involves two equivalent carbon atoms. However, the C-C bond in chloroethane (Cl-CH2-CH3) is polarized by the presence of the electronegative chlorine atom. This polarization is the sum of two effects: first the Cl atom (electronegativity of 3.0) takes some of the electron density of the carbon atom (electronegativity of 2.5) it is attached to, i.e., it polarizes that covalent bond so that the electrons spend more time close to the Cl atom than to the C atom. The carbon attached to chlorine then compensates this withdrawal of electron density by drawing the electrons from the C-C bond closer to itself. This results in the polarization of the C-C bond.
Inductive Effect is the polarization of one bond caused by the polarization of an adjacent bond.
The effect is greatest for adjacent bonds, but can also be felt farther away.
The inductive effect of a substituent in a drug molecule makes it a stronger or weaker acid (relative to the unsubstituted acid), depending on whether the substituent is electron-donating or electron-attracting relative to hydrogen. Polarization of bonds is an effect through space, therefore it decreases in strength the larger the distance from the acidic group.
Functional groups can be classified as electron-withdrawing (-I) or electron-donating (+I) relative to hydrogen. A nitro group (NO2, -I), for example will draw electrons to itself more than a hydrogen atom would if occupying the same position in the drug molecule. Table 2.2 shows functional groups commonly found in drug molecules that can have -I or +I effects.
-I groups increase the acidity of uncharged acids such as acetic acid because they spread the negative charge of the anion. However, -I groups increase the acidity of any acid, no matter what the charge. For example, if the acid has a charge of +1, as in RNH3+Cl-, a -I group destabilizes the positive center by increasing and concentrating the positive charge of the acid. This destabilization is relieved when the proton is lost, therefore the neutral, deprotonated CB form of the acid is favored and the ionization equilibrium shifts towards it. A –I group substitution in RNH3+Cl- makes the parent amine a weaker base.
In general we may say that, groups that withdraw electrons by the inductive effect increase acidity and decrease basicity, while electron-donating groups act the opposite way.
Resonance or conjugative effects result from the high mobility of p-electrons and their delocalization in a system of conjugated double bonds. Functional groups that increase the electron density of conjugated systems are called +R (electron-donating), and those that decrease electron density are called –R (electron-withdrawing). An example of resonance effects is found in the higher acidity of carboxylic acids compared to primary alcohols.
The carboxylate anion (RCOO-) is stabilized by resonance not available to the RCH2O- ion or to RCOOH. The RCOO- is stabilized not only by the fact that there are two resonance structures, but also by the fact that the negative charge is spread over two oxygen atoms, rather than concentrated on a single oxygen atom as in RCH2O-. Table 3 shows functional groups commonly found in drug molecules that can have -R or +R effects.