QSARs and Inorganic Chemistry What is QSAR? Quantitative Structure-Activity Relationship Way to quantitatively correlate structure to physical properties or biological activity Can you correlate systematic changes in structure and/or composition to a measurable trend in properties? Related to the physical-organic chemistry concept of Hammett parameters Hammett asked “How do electronic effects influence reaction equilibria, K eq ?” Original studies used the dissociation of p-substituted benzoic acids As early example of a linear-free energy relationship

Hammett Equation Substituent Constant Quantitative description of electron donating or withdrawing ability of a substituent These are defined values! σ z = log K z – log K H Plot log (K/K 0 ) vs  Slope is  If  EWG increases K,  positive If  EDG increases K,  negative The Hammett equation has been modified to understand correlations in rate (k), thermodynamic values (ΔG, ΔH, ΔS), coupling constants (J, a H ), etc. in place of equilibrium constants -Z zz zz -H0.00 -CH Cl0.23 -OH-0.37-NO

Modification of σ Substituent constants (σ) are not “one size fits all” Formally, σ describes electronic effects seen in para- substituted benzoic acids Includes both inductive and resonance effects σ has been modified to separate out these two effects These values are redefined as σ R and σ I, resonance and inductive respectively Additional modifications to σ have been published These include: σ. = radical intermediates σ - = negatively charged intermediates σ + = positively charged intermediates σ m = meta substituted compounds…

How is this applied to inorganic chemistry? Correlating structure and property relationships can give information regarding: Mechanistic information k/K changes with changing properties Intermediates Predictive power Regular trends can be elucidated Help guide future studies/synthetic efforts Structural changes can be made to: Ligands Metal center

Example 1: Ligand Substitution in Coordination Complexes “Linear free‐energy relationships in semiquinone species and their Mn(II) and Cu(II) complexes” Is there a correlation between substituent and physical properties for semiquinone complexes? Correlation found for electronic transitions (see below) and redox potentials Different strengths of correlations found for Cu(II) and Mn(II) complexes Rationalized on the possible exchange pathways present in Cu(II) vs Mn(II) Sloop, J. C., Shultz, D. A., Marcus, M. B. and Shepler, B. J. Phys. Org. Chem., 2012, 25, 101–109. Substituent, Zσ p-OCH p-t-Bu-0.11 H0 m-CN0.68 m-NO p-CN0.91 p-NO σ Δυ Mn(II) complex Δν versus σ m, or σ −. Blue squares are the MLCT transition. Green squares are n  π * transition. Δν = ν H – ν Z.

Example 2: Property Evaluation “Mesoporous Thin Films of “Molecular Squares” as Sensors for Volatile Organic Compounds” Is there are correlation between electronic structure of guest and binding constant in rhenium-based molecular squares? Rational design of materials for specific guest absorption Keefe, M.H.; Slone, R.V.; Hupp, J.T.; Czaplewski, K.F.; Snurr, R.Q.; Stern, C.L. Langmuir, 2000, 16, 3964–3970. Binding stronger for groups with electron donating groups The authors suggest the driving force for binding is, in part, a charge- transfer interaction between the electron-rich aromatic guests and the electron- deficient pyrazine ligands. Guests with electron withdrawing groups have lower electron transfer rates. σ of guest molecule Binding constant Toluene p-fluorotoluene Benzene Fluorobenzene

Example 3: Properties of Metal Ions “Estimating Bioconcentration Factors, Lethal Concentrations and Critical Body Residues of Metals in the Mollusks… Using Ion Characteristics” Relating metal bioconcentration factors and LC50s to properties of metal Regression plots of acute toxicity vs metal properties were generated: Correlation of LC50 and covalent index is strong and significant! Van Kolck, M.; Huijbregts, M.A.J.; Veltman, K.; Hendriks, A.J. Environmental Toxicology and Chemistry, 27, 2008, 272–276. PropertyEquationVarianceStatistical Significance Covalent IndexLog LC50 = 2.8 – 0.7 Χ 2 m r Hydrolysis ConstantLog LC50 = log(K OH ) Softness IndexLog LC50 = σ P Ionic IndexLog LC50 = Z 2 /r

Further Reading T.H. Lowry, K. S. Richardson. Mechanism and Theory in Organic Chemistry, 2 nd ed. Harper Collins, 1987, pp 143 – 159. Walker, J. Newman, M.C., Enache M. Fundamental QSARs for Metal Ions. Taylor & Francis, Boca Raton, FL, Journals that publish QSAR/SAR related research Review with values of σ for many organic and inorganic substituents C. Hansch, A. Leo and R. W. Taft (1991). "A survey of Hammett substituent constants and resonance and field parameters". Chem. Rev. 91 (2): 165–195. Chem. Rev. 91 (2): 165–195.

Learning Outcomes Define QSAR Describe the Hammett equation including definitions of each variable Give examples of how QSAR can be used to predict properties of inorganic systems