4. Structural Effects on Reactivity 4.1 Electronic Effects: 4.1.1 Inductive and field effects 4.1.2 Resonance effect 4.2 Steric Effects 4.2.1 Steric hindrance 4.2.2 Strain 4.2.3 Stereo electronic effect 4.3 Linear Free Energy Relationships 4.3.1 Hammett equation 4.3.2 Mechanistic implication of LFER

4.1 Electronic Effects 4.1.1 Inductive and field effect: Inductive effect is a polarization through -bond; drop off rapidly with number of -bonds. Field effect is a polarization through space; drop off rapidly with the distance. In most cases, inductive and field effects operate together and difficult to separate them. The following sytem is designed to show only the field effects e.g. pKa = 6.07 5.67

4.1.1 Inductive and field effects (continued) Electron donating group (+I): O-, COO-, CR3, CHR2, CH2R, CH3, D Electron withdrawing group (-I): NR3+, SR2+, NH3+, NO2, SO2R, CN, SO2Ar, CO2H, F, Cl, Br, I, OAr, COOR, OR, COR, SH, SR, OH, CCR, Ar, CH=CR2

4.1 Electronic Effects 4.1.2 Resonance effect (mesomeric effect) is caused by electron delocalization of -bond; drop off gradually with the number of -bonds. Electron donating group (+M): O-, S-, NR2, NHR, NH2, NHCOR, OR, OH, OCOR, SR, SH, Br, I, Cl, F, (R), Ar Electron withdrawing group (-M): NO2, CN, COOH, COOR, CONH2, CONHR, CONR2, CHO, COR, SO2R, SO2OR, NO, Ar Electronic effect on reactivity can be considered by comparison of the effects on transition state and reactants e.g.

Electronic effect on reactivity (continued) Electron withdrawing groups (-I and –M) or Ar will lower the free energy of T.S. These groups have much less effects on the free energy of reactants. The free energy of activation is thus lowered with the electron withdrawing groups.

4.2 Steric Effects 4.2.1 Steric hindrance (front strain, F-strain) Relative rates of sovolysis of RBr with ethanol R = CH3 CH3CH2 CH3CH2CH2 (CH3)2CHCH2 (CH3)3CCH2 Relative Rate: 17.6 1 0.28 0.030 4.2 x 10-6 4.2.2 Strain caused by steric repulsion Relative rates of hydrolysis of RCl in 80% ethanol R = Me3C Me2EtC MeEt2C Et3C Me2(i-Pr)C Me(i-Pr)2C Relative Rate: 1 1.7 2.6 3.0 0.9 13.6 ------Hyper conjugation-------------- B-strain (back strain) R = Relative Rate: 43.7 0.35 I- strain (internal strain)

4.2 Steric Effects 4.2.3 Stereo electronic effects Conformational analysis

4. 3 Linear free energy relationship (LFER) 4.3.1 Hammett equation For thermodynamic evaluation, log K/K0 =  whereas  is the substituent constant and  is the reaction constant Hammett arbitrarily assigned  = 1 for the ionization of substituted benzoic acids to determine p and m . log K/K0 = p log K/K0 = m  = 0 for X = H

Hammett equation (continued) When the resonance effect of an electron withdrawing substituent can directly affect the reaction center the substituent constants are correlated to - better than p. - is determined from the ionization of p-substituted phenol.  = 1 When the resonance effect of an electron donating substituent can directly affect the reaction center the substituent constants are correlated to + better than p. + is determined from the rate constants (log k/k0 = ) of the following reaction in which  is assigned as -1

The substituent constants () Group p  m  p+  m+  p- O- -0.81 -0.47 -4.27 -1.15 - NMe2 -0.63 -0.10 -1.7 - - NH2 -0.57 -0.09 -1.3 -0.16 OH -0.38 0.13 -0.92 - - OMe -0.28 0.10 -0.78 0.05 - CMe3 -0.15 -0.09 -0.26 -0.06 - Me -0.14 -0.06 -0.31 -0.10 - H 0 0 0 0 0 Ph 0.05 0.05 -0.18 0 - COO- 0.11 0.02 -0.41 -0.10 - F 0.15 0.34 -0.07 0.35 - Cl 0.24 0.37 0.11 0.40 - Br 0.26 0.37 0.15 0.41 - I 0.28 0.34 0.14 0.36 - Group p  m  p+  m+  p- N=NPh 0.34 0.28 0.17 - - COOH 0.44 0.35 0.42 0.32 0.73 COOR 0.44 0.35 0.48 0.37 0.68 COMe 0.47 0.36 - - 0.87 CF3 0.53 0.46 - - 0.57 NH3+ 0.60 0.86 - - - CN 0.70 0.62 0.66 0.56 1.00 SO2Me 0.73 0.64 - - - NO2 0.81 0.71 0.79 0.73 1.27 NMe3+ 0.82 0.88 0.41 0.36 - N2+ 1.93 1.65 1.88 - 3 Electron withdrawing groups have positive . Electron donating groups have negative .

Hammett equation (continued)  can be categorized into three groups using inductive (I) and resonance (mesomeric, M) effects (- I): Me, Et, Me3C (+M,+I): Ac, CN, NO2, CF3, Me3N+ (-M, +I): AcNH, AcO, NH2, Br, Cl, F, OH, MeO, EtO, Ph Hammett Equation is an LFER G0 = -RT ln K0 Gx = -RT ln Kx G0 - Gx = RT ln K0/Kx = 2.3 RT  Gx = G0 - 2.3 RT  G0 and 2.3 RT are constant at a specific temperature. If changing of the substituent on the substrate does not change the reaction mechanism  is also constant and Gx has linear relationship with .

4.4 Mechanistic implication of LFER If a plot of log k/k0 against an appropriate set of  give a linear line, the LFER is valid and the slope of the plot is  (the reaction constant). The linear line obtained from the plot indicates that the reaction mechanism and the coordination of the transition states do not change upon the variation of the substituent. The  values can be used to give information about the structures of the transition states A positive  indicates that the reaction center in the transition state becomes more negative comparing to the starting material. A negative  indicates that the reaction center in the transition state becomes more positive comparing to the starting material.

4.4 Mechanistic implication of LFER The size of  suggests how well the charge on the reaction center in the transition state can be transferred to the substituent. Exercise: Propose a reasonable mechanism for saponification of methylbenzoate ( = +2.38) and specify the rate determining step of the reaction. Exercise: Match the following  values i.e. +2.45, +0.75, -2.39 and -7.29 to the following reactions. (a) nitration of substituted benzene (b) ionization of substituted benzenethiols (c) ionization of substituted benzenephosphonic acids (d) reaction of substituted N,N-dimethylanilines and methyl iodide Exercise: What is the isokinetic temperature?

4.4 Mechanistic implication of LFER A plot of log k/k0 against an appropriate set of  is sometime not linear. The curved line obtained from the plot indicates that the coordination of the transition states are shifted upon the variation of the substituent. The reflected line obtained from the plot usually indicates that change of the rate determining step upon the variation of the substituent. Exercise: Propose a reasonable mechanism for the following reaction and specify the rate determining step that agrees with the  values

Answer to the exercise (a) Nitration of substituted benzene –7.29 (b) ionization of substituted benzenethiols +2.45 (c) ionization of substituted benzenephosphonic acids +0.75 (d) reaction of substituted N,N-dimethylanilines with methyl iodide –2.39

Answer to the exercise