Quantitative Structure-Activity Relationships (QSAR) PDF

Quantitative Structure-Activity Relationships (QSAR) Patrick Chapter 18 3. Electronic Effects of Substituents: Hammett Substituent Constant (σ) The constant () is a measure of the e-withdrawing or edonating influence of substituents It can be measured experimentally and tabulated (e.g.  for aromat...

Quantitative Structure-Activity Relationships (QSAR) Patrick Chapter 18 3. Electronic Effects of Substituents: Hammett Substituent Constant (σ) The constant () is a measure of the e-withdrawing or edonating influence of substituents It can be measured experimentally and tabulated (e.g.  for aromatic substituents is measured by comparing the dissociation constants of substituted benzoic acids with benzoic acid) X=H KH = Dissociation constant= [PhCO2 ] [PhCO2H] X= electron withdrawing group (e.g. NO2) Charge is stabilised by X Equilibrium shifts to right KX > K H X = log KX = logKX - logKH KH Positive value X= electron donating group (e.g. CH3) X = electron donating group Charge destabilised Equilibrium shifts to left KX < K H X = log KX = logKX - logKH KH Negative value NOTES:  value depends on inductive and resonance effects  value depends on whether the substituent is meta or para ortho values are invalid due to steric factors EXAMPLES: p (NO2) m (NO2) meta-Substitution e-withdrawing (inductive effect only) para-Substitution e-withdrawing (inductive + resonance effects) EXAMPLES: m (OH) p (OH) meta-Substitution e-withdrawing (inductive effect only) para-Substitution e-donating by resonance more important than inductive effect QSAR Equation: 1  log  C 2.282  - 0.348 Diethylphenylphosphates (Insecticides) Conclusion: e-withdrawing substituents increase activity 3. Electronic Effects of Substituents: Electronic Factors R and F R - Quantifies a substituent’s resonance effects F - Quantifies a substituent’s inductive effects σp σm, R and F only for aromatic substituents 3. Electronic Effects of Substituents: Aliphatic electronic substituents Defined by I Purely inductive effects Obtained experimentally by measuring the rates of hydrolyses of aliphatic esters Hydrolysis rates measured under basic and acidic conditions X= electron donating Rate I = negative X= electron withdrawing Rate I = positive Basic conditions: Acidic conditions: Rate affected by steric + electronic factors Gives I after correction for steric effect Rate affected by steric factors only (see Es)