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Chapter 6: Acid and Bases, Electrophiles and Nucleophiles I. Acid-Base Dissociation A. Water Acting as a Base. Since for dilute solution the activity of water is constant:. B. Water Acting as An Acid. Proceeding as before:. Since pK W = pH + pOH = 14

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slide1

Chapter 6: Acid and Bases, Electrophiles and Nucleophiles

I. Acid-Base Dissociation

A. Water Acting as a Base

Since for dilute solution the activity of water is constant:

slide2

B. Water Acting as An Acid

Proceeding as before:

slide3

Since pKW = pH + pOH = 14

pKb = 14 - pKa

Conclusion: stronger bases have lower pKb values,

and their conjugate acids are weaker

acids (higher pKa values).

slide4

II. Strengths of Oxygen and Nitrogen Acids

Electron-withdrawing groups have a large effect on the acidity of the OH function.

slide5

Many important intermediates in organic reactions are strong acids.

Reference:

Advanced Organic Chemistry; 4th Ed.; March, J.; John Wiley & Sons: New York, 1992, pp. 250-252.

slide6

Ammonium ions are stronger acids, and therefore their conjugate bases weaker bases, than their oxygen analogs.

slide7

III. Leveling Effects of the Solvent

The strongest acid that can exist in a solvent is the

conjugate acid (lyonium species) of the solvent.

H2SO4 + H2O H3O+ + HSO4-

pKa ~ -4 pKa = -1.7

HCl + H2O H3O+ + Cl-

pKa ~ -7

slide8

The strongest base that can exist in a solvent is the conjugatebase (lyoxide species) of the solvent.

NH2- + H2O NH3 + OH-

(iPr)2N- + H2O (iPr)2NH + OH-

pKW = 14

pKa ~ 35-40 for neutral amines

slide9

IV. Rates of Proton Transfer

A. Oxygen Acids

kD

HA + H2O A- + H3O+

kR

Ka = kD/kR

Rate constants for proton transfer from H3O+ to anionic

bases are diffusion controlled. Values of kR are typically

1 to 5 x 1010 M-1 s-1.

slide12

B. Nitrogen Bases

kR

R3N + H2O R3NH+ + HO-

kD

Kb = kR/kD Ka = Kw/Kb

pKa = 14 - pKb

slide14

V. Acidities of Carbon Acids

a) Table 6.5, p 247 of book. b) Advanced Organic Chemistry; 4th Ed.; March, J.; John Wiley & Sons: New York, 1992, pp. 250-252. c) Amyes, T.L.; Richard, J.P. J. Am. Chem. Soc.1996, 118, 3129-3141. d) Richard, J.P.; Williams, G.; O’Donoghue, A.C.; Amyes, T.L. J. Am. Chem. Soc. 2002, 124, 2957-2968.

slide15

A. Measurement of Weak Acidity

Make a solution of two weak acids and add

a substoichiometric amount of a strong base. Measure the

equilibrium concentrations:

Keq

HA1 + A2- HA2 + A1-

slide18

B. Factors that Affect Carbon Acidity

1. Substituent Effects

Substituents stabilize conjugate base anion by resonance delocalization of negative charge.

slide19

2. Aromaticity

pKa = 15

pKa = 43

slide20

3. Stabilization by d-orbitals

CHCl3 + B: Cl2C--Cl Cl2C=Cl-

pKa = 25

R3P+-CH3 + B: R3P+-CH2- R3P=CH2

R2S+-CH3 + B: R2S+-CH2- R2S=CH2

pKa ~ 30

R3N+-CH3 + B: R3N+-CH2-+ BH

pKa ~ 40

CH3-CH3 + B: CH3-CH2-+ BH

pKa ~ 50

slide22

C. Nitrogen Acids

N-H bond tends to be more acidic than C-H bond due to higher electronegativity of N than C.

slide23

VI. Theories of Proton Transfer

A. Eigen Model

kd kp k-d

A-H + B (A-HB) (A-H-B+) A- + H-B+

k-d k-p kd

kd = 4N(rAH + rB)(DAH + DB)e

slide24

DGp‡

DG‡

B. Marcus Theory

DG‡ = DGp‡+ WR

slide25

WR = work required to form encounter complex from

reactants

WP = work required to form the encounter complex in the

reverse direction from products

GR, GP = free energies of reactants and products,

respectively, within the encounter complex

G‡ = overall free energy of activation

Gp‡ = free energy of activation for proton transfer within

the encounter complex

Go = overall equilibrium free energy of reaction

Gpo = equilibrium free energy of reaction within the

encounter complex

slide26

Derivation of the Marcus Theory Equation:

DGp‡=lx2 =l(x-1)2 +DGpo

lx2 = l(x-1)2 + DGpo

slide27

Since DGp‡=lx2:

DGp‡

Therefore, when DGpo = 0:

DGp‡DG‡int = l/4 andl = 4 DG‡int

Position of the transition state:

x‡= ½ + DGpo/8 DG‡int

slide28

VII. Nucleophilicity and Electrophilicity

A. BrØnsted Linear Free Energy Relationship

A formal similarity is noted between proton transfer and

nucleophilic displacement or nucleophilic addition:

slide29

BrØnsted equation for nucleophilic reactions:

knuc = Gnuc Ka-βnuc

Taking the log transform:

log knuc =bnucpKa + log Gnuc = bnucpKa + C

slide31

Since ki = Gi Ka-bi:

log kobs = (b3+b1-b2) pKa + C123 – log(1 + G23Kab2-b3)

or

log kobs = (b3+b1-b2) pKa + C123 – log(1 + G2310(b3-b2)pKa)

The equation is nonlinear because of the last term.

slide32

Special Cases:

1. k1 is rate-determining:

k3>> k2

k3/k2>> 1

kobs = k1

log kobs = β1pKa + C1

slide33

2. k3 is rate-determining:

k3<< k2

k3/k2~ 0

kobs = k1k3/k2

log kobs = (β3+β1-β2)pKa + C123

slide34

Example 1: reactivity of various imidazoles toward

p-nitrophenyl acetate

Slope =  = 0.8

Reference:

Bruce and Lipinski, J. Am. Chem. Soc.1958, 80, 2265.

slide35

High sensitivity of rate constant to basicity of nucleophile is

consistent with a late transition state with appreciable +-charge

on bonding atom of nucleophile:

Y

CH

3

C

O

N

O

N

+

d

2

N

H

O

-

d

Appreciable bond making

slide36

Example 2: Acetylation of Substituted Pyridines

Castro and Castro, J. Org. Chem.1981, 46, 2939-2943.

slide37

The nonlinear BrØnsted plot is proof of an intermediate:

pKa< 6 Breakdown of T± is rate-determining.

kobs = k1k3/k2βobs = β3 + β1 - β2

pKa> 6 Formation of T± is rate-determining.

kobs = k1 βobs = β1

pKa~ 6 Both k1 and k3 are rate-determining.

slide38

Leaving group abilities match for CH3CO2- (pKa = 4.8) and YPyr when pKa of YPyrH+ is 6.1.

Conclusion: A nonlinear BrØnsted plot requires a

mechanism with at least one intermediate.

Caveat: The converse, that a linear BrØnsted plot requires

a concerted mechanism, is not true.

slide39

Example 3: An unambiguous test for concertedness.

Use nucleophiles of the same structural class as the leaving group.

slide40

Prediction for a stepwise mechanism:

T-

k3 = k2 when

pKa = 0

slide41

, ifreaction is stepwise,

BrØnsted plot must have a

break at pKanuc = 7.

T-

slide42

-

d

O

-

d

C

H

C

O

C

H

N

O

3

6

4

2

O

C

H

Y

6

4

slide43

What is observed?

Ba-Saif, Luthra & Williams

J. Am. Chem. Soc.1987, 109, 6362-6368

slide44

For the equilibrium:

log Keq = C + βeq pKanucβ = 1.7

α = βnuc/βeq = 0.44

α is a measure of the position of the transition state on a

More O’Ferrall-Jencks diagram:

slide45

slide46

C. Hard and Soft Acids and Bases

  • Various observations indicate that the correlation of nucleophilicity with basicity, as measured by conjugate acid pKa values, is not universal:
  • 1. BrØnsted analysis degrades when nucleophiles of different structural classes
  • are used.2. HI is a very strong acid (pKa = -9) whose conjugate base is nonetheless a strong nucleophile:
  • 3. I- is an example of a soft Lewis base, and methyl is an example of a soft Lewis acid.
  • 4. Hard-hard interactions and soft-soft interactions are stronger than hard-soft interactions.
slide47

D. Energetics of Nucleophile-Electrophile Interactions

qn and qe are charges on nucleophile and electrophile, respectively.

cn and ce are orbital coefficients of nucleophile HOMO and electrophile

LUMO, respectively.

β is the resonance integral.

EHOMO = energy of nucleophile HOMO

ELUMO = energy of electrophile LUMO

Electrostatic term: important for interactions of hard acids with hard bases

Orbital interaction term: important for interactions of soft acids with soft bases

slide50

E. Quantitative Measures of Hardness and Softness

Ionization potential measures EHOMO.

Electron affinity measures ELUMO.

Frontier Orbital Energies for Lewis Acids and Bases

soft

hard

slide51

Reactivity Trends:

1. Hg2+ (ELUMO = -448 kJ mol-1, soft electrophile)

HS-> CN-> Br-> Cl-> HO-> F-

Reactivity parallels EHOMO of nucleophile.

2. Ca2+ (ELUMO = 225 kJ mol-1, hard electrophile)

HO-> CN-> HS-> F-> Cl-> Br-> I-

Reactivity parallels pKa of conjugate acid of nucleophile.

slide52

F. Structure-Nucleophilicity Correlations

1. Swain-Scott LFER

n nucleophilicity

parameter

s = sensitivity of studied

reaction (s = 1 for

reaction in H2O)

log kNu/k0 = sn

Reference reaction:

Nu:- + CH3Br NuCH3 + Br-

slide53

n values are for reactions in H2O.

n0 values are for reactions in MeOH.

More values in Table 6.10

Correlations best for nucleophilic displacements at saturated carbon.

slide54

2. Edwards “Oxybase” Equation

log kNu/k0 = aEN + bHN

EN soft nucleophilicity (based on oxidation potentials)

HN  hard nucleophilicity (based on pKa values)

k0 = rate constant for reaction with water

EN and HN parameters are tabulated in Table 6.10.

Examples:

Nu:- + CH3Br NuCH3 + Br-a = 2.50 b = 0.006

Nu:- + HO-OH NuOH + HO-a = 6.22 b = -0.43

slide55

3. Ritchie Nucleophilicity Parameters

log kNu/k0 = N+

Features:

● Not a LFER.

● Provides a scale of nucleophilicities for anion/solvent systems.

● Reference system is H2O.

● Works for reactions with carbocation and carbonyl carbons.

slide56

Ritchie Nucleophilicity Parameters

Conclusions:

Softer Lewis bases (nucleophiles) are more reactive.

Hydroxylic solvents impede nucleophilic reactivity.

slide57

G. Relationship Between Nucleophilicity and Nucleofugacity

105 k2 (M-1 s-1) Ratio

I- + EtI* EtI + I*-6000

1440

Pyr + EtI EtPyr+ + I-4.17

I- + EtBr EtI + Br- 195

269

Pyr + EtBr EtPyr+ + Br- 0.725

slide59

H. α-Effect Nucleophiles

  • ● Hydrazines, hydroxylamines, peroxide anions
  • ● Unusually strong nucleophiles in relation to their weak basicity
  • ● Lone-pair repulsions raise EHOMO.
  • Example:

kHOO-/kHO- = 20

pKa of H2O = 15.7 pKa of H2O2 = 11.6