Steric parameters taft’s steric factor (es)

Steric parameters
Taft's steric factor
es

1. STERIC PARAMETERS- Taft’s steric factor ( Es )

2. STERIC PARAMETERS stearic features of drug markedly effect the drug receptor interactions reflecting the change In onset and duration of biological action . eg : buprenorphine As it is more lipophilic it enters CNS more rapidly , rapid onset and duration of action, because of bulky substituent's it needs time to orient in favorable confirmation and bulky substituent's also delays detachment of drug from receptor. This leads to late onset and duration of action. 3

3. 1/19/2022 much harder to quantitate Examples are:    Taft’s steric factor ( Es ) (~1956), an experimental value based on rate constants  Molar refractivity (MR)--measure of the volume occupied by an atom or group--equation includes the MW, density, and the index of refraction— Verloop steric parameter--computer program uses bond angles, van der Waals radii, bond lengths Steric Effects

4. The Taft equation is a linear free energy relationship (LFER) used in physical organic chemistry in the study of reaction mechanisms and in the development of quantitative structure activity relationships for organic compounds. It was developed by Robert W. Taft in 1952 as a modification to the Hammett equation. While the Hammett equation accounts for how field, inductive, and resonance effects influence reaction rates, the Taft equation also describes the steric effects of a substituent. The Taft equation is written as: where log(k s /k CH3 ) is the ratio of the rate of the substituted reaction compared to the reference reaction σ* is the polar substituent constant that describes the field and inductive effects of the substituent, E s is the steric substituent constant, ρ* is the sensitivity factor for the reaction to polar effects δ is the sensitivity factor for the reaction to steric effects. Taft Equation 5

5. The hydrolysis of esters can occur through either acid and base catalyzed mechanisms , both of which proceed through a tetrahedral intermediate . In the base catalyzed mechanism the reactant goes from a neutral species to negatively charged intermediate in the rate determining (slow) step, while in the acid catalyzed mechanism a positively charged reactant goes to a positively charged intermediate . Due to the similar tetrahedral intermediates, Taft proposed that under identical conditions any steric factors should be nearly the same for the two mechanisms and therefore would not influence the ratio of the rates. However, because of the difference in charge buildup in the rate determining steps it was proposed that polar effects would only influence the reaction rate of the base catalyzed reaction since a new charge was formed.

6. Although the acid catalyzed and base catalyzed hydrolysis of esters gives transition states for the rate determining steps that have differing charge densities, their structures differ only by two hydrogen atoms . Taft thus assumed that steric effects would influence both reaction mechanisms equally. Due to this, the steric substituent constant E s was determined from solely the acid catalyzed reaction, as this would not include polar effects. E s was defined as : where ks is the rate of the studied reaction and KCH3 is the rate of the reference reaction (R = methyl). δ is a reaction constant that describes the susceptibility of a reaction series to steric effects. For the definition reaction series δ was set to 1 and Es for the reference reaction was set to zero. This equation is combined with the equation for σ* to give the full Taft equation.

7. 1/19/2022 Steric Effects The third major factor that often must be considered in QSAR involves steric effects. For studies involving reactivity of organic compounds, a steric parameter, Es , was defined by Taft as : where k is the rate constant for the acid hydrolysis of esters of the type

8. 1/19/2022 Assuming the electronic effects of substituent X can be ignored, the size of X will affect the transition state and hence the rate of reaction. By definition Es = 0 for X=H. Tables of values of Es for other substituents are available.

9. Steric Effects The Taft Equation

10. Here, the size of R affects the rate of reaction by blocking nucleophilic attack of water .                      Taft quantified the steric (spatial) effects using the hydrolysis of esters: In this case , the steric effects were quantified by the Taft parameter E s : k is the rate constant for ester hydrolysis. This expression is analogous to the Hammett equation. Steric effects

11.           t-Bu -2.78 : large resistance to hydrolysis             Me -1.24: little steric resistance to hydrolysis            H    0.00 the reference substituent in the Taft equation Compare some extreme values: E s Values for Various Substituents H Me Pr t -Bu F Cl Br OH SH NO 2 C 6 H 5 CN NH 2 0.0 -1.24 -1.60 -2.78 -0.46 -0.97 -1.16 -0.55 -1.07 -2.52 -3.82 -0.51 -0.61 Note : H is usually used as the reference substituent (E s (0)), but sometimes when another group, such as methyl (Me) is used as the reference, as in the chemical equation above, the value becomes 1.24.

12.         Organophosphates must be hydrolysed to be active and it is observed that their biological activity is directly related to the Taft steric parameter E S for the substituent R by the equation: E s may be used in other chemical reactions and to explain biological activities, for example the hydrolysis of inhibitors of acetylcholine esterase. Steric effects

13. Steric Factors Taft’s Steric Factor ( E s ) Measured by comparing the rates of hydrolysis of substituted aliphatic esters against a standard ester under acidic conditions E s = log k x - log k o k x represents the rate of hydrolysis of a substituted ester k o represents the rate of hydrolysis of the parent ester Limited to substituents which interact sterically with the tetrahedral transition state for the reaction Cannot be used for substituents which interact with the transition state by resonance or hydrogen bonding May undervalue the steric effect of groups in an intermolecular process (i.e. a drug binding to a receptor)

14. Thank you !!!