Transcript QSARs and Inorganic Chemistry

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, Keq?”
• 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
-Z
sz
-H
0.00
-CH3
-0.17
-Cl
0.23
-OH
-0.37
-NO2
0.78
-Z
• Plot log (K/K0) vs s
• Slope is r
• If EWG increases K, r =
positive
• If EDG increases K, r =
negative
sz
• These are defined values!
• σz = log Kz – log KH
K
log
= sr
Ko
• The Hammett equation has
been modified to
understand correlations in
rate (k), thermodynamic
values (ΔG, ΔH, ΔS),
coupling constants (J, aH),
etc. in place of equilibrium
constants
Modification of σ
• Substituent constants (σ) are not “one size fits all”
• Formally, σ describes electronic effects seen in parasubstituted benzoic acids
• Includes both inductive and resonance effects
• σ has been modified to separate out these two effects
• These values are redefined as σR and σI , resonance and inductive
respectively
• Additional modifications to σ have been published
• These include:
•
•
•
•
σ. = radical intermediates
σ-= negatively charged intermediates
σ+ = positively charged intermediates
σm = 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)
10
Substituent, Z
σ
p-OCH3
-0.22
6
p-t-Bu
-0.11
4
H
0
m-CN
0.68
0
m-NO2
0.71
-2
p-CN
0.91
-4
p-NO2
1.23
-6
-0.5
Δυ
8
2
0
0.5
σ
1
1.5
Mn(II) complex Δν versus σm, or σ−. Blue squares are the MLCT
transition. Green squares are n π* transition. Δν = νH – νZ.
Sloop, J. C., Shultz, D. A., Marcus, M. B. and Shepler, B. J. Phys. Org. Chem., 2012, 25, 101–109.
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
•
350
Binding constant
300
Toluene
250
200
150
p-fluorotoluene
Benzene
100
50
0
-0.2
Fluorobenzene
-0.15
-0.1
-0.05
0
0.05
Binding stronger for groups with electron
donating groups
• The authors suggest the driving
force for binding is, in part, a chargetransfer interaction between the
electron-rich aromatic guests and
the electron- deficient pyrazine
ligands.
• Guests with electron withdrawing
groups have lower electron transfer
rates.
0.1
σ of guest molecule
Keefe, M.H.; Slone, R.V.; Hupp, J.T.; Czaplewski, K.F.; Snurr, R.Q.; Stern, C.L. Langmuir, 2000, 16, 3964–3970.
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:
Property
Equation
Variance
Statistical
Significance
Covalent Index
Log LC50 = 2.8 – 0.7 Χ2mr
0.79
0.04
Hydrolysis Constant
Log LC50 = 1.1 + 0.4log(KOH)
0.05
0.71
Softness Index
Log LC50 = 1.0 + 0.2σP
0.31
0.33
Ionic Index
Log LC50 = -0.19 + 0.25Z2/r
0.05
0.71
• 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.
Further Reading
• T.H. Lowry, K. S. Richardson. Mechanism and Theory in Organic
Chemistry, 2nd ed. Harper Collins, 1987, pp 143 – 159.
• Walker, J. Newman, M.C., Enache M. Fundamental QSARs for
Metal Ions. Taylor & Francis, Boca Raton, FL, 2012.
• Journals that publish QSAR/SAR related research
• http://www.qsarworld.com/literature-qsar-journals.php
• 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.
• http://pubs.acs.org/doi/abs/10.1021/cr00002a004
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