Linear Free-Energy Relationships

(Substituent Effects, LFERs, or Hammett Plots)

O OH O O

+ H+

X X

Qualitative question: How does substituent X affect acidity?

As a reminder,
O O O O
resonance- resonance- O O
−
δ destabilized δ+ stabilized

δ− δ− δ+ δ+
induction-
NH2 NO2 stabilized
δ+ −
δ
NO2

Electron-donating groups Electron-withdrawing groups

decrease acidity. increase acidity.
 Linear Free-Energy Relationships
O OH O O

ΔGo
+ H+
Ka
X X

Qualitative question: How does substituent X affect acidity?

pKa Ka ΔG0

X= NH2 less acidic 4.86 1.4 x 10-5 M 6.7 kcal/mol

CH3
H 4.20 6.3 x 10-5 M 5.8 kcal/mol
Br
CF3
NO2 more acidic 3.42 3.8 x 10-4 M 4.7 kcal/mol
 Linear Free-Energy Relationships
O OH O O

ΔGo
+ H+
Ka
X X

Louis Hammett turned this into a quantitative question:

Can we construct a mathematical relationship

between substituent X and acidity? (Can effect of
substituent on ΔG and Ka be expressed
o

mathematically?)

Is relationship for one reaction related to that for

other reactions?
 Linear Free-Energy Relationships
O δ+OH O O

ΔGo
+ H+
Ka
X X

Hammett’s Hypothesis, Part 1:

For each substituent X, there is a characteristic free-energy difference

Ka(X) -ΔΔGo(X)
log10 = = σ(X) X=H
Ka(H) 2.303RT
ΔG (H)
“Hammett o

parameter” X = NO2
ΔG (NO2)
o

ΔΔGo(X) = ΔGo(X) - ΔGo(H)

 Linear Free-Energy Relationships

O OH O O

ΔG
o

+ H+
Ka
X X

Hammett’s Hypothesis, Part 1: X σ

We can define a set of NH2 -0.66 Ka(NH2) < Ka(H)
constants σ such that
H 0 (by definition)
Br 0.23
Ka(X)
log10 = σ(X) NO2 0.78 Ka(NO2) > Ka(H)
Ka(H)
So far, this is just math.
Not a big deal.
 Linear Free-Energy Relationships
O O
Hammett’s Hypothesis, Part 2:
OH O
These exact same Ka
constants σ apply to other + H+
(only somewhat related)
reactions, such that X X

Ka(X)
log10 = ρσ(X)
Ka(H) ρ = 0.489

Ka(X)
Here, different reaction… log10 (ρ < 1 means
but same general Ka(H) less sensitive to
substituent effects! substituents than
benzoic acid Ka)

This is a big deal.

σ
 Linear Free-Energy Relationships
O OH O O
Hammett’s Hypothesis, Part 2:

These exact same Ka

constants σ apply to other + H+
(only somewhat related)
reactions, such that X
X

Ka(X)
log10 = ρσ(X)
Ka(H) ρ = 0.489

(Denominator can actually Ka(X)

be any constant.) log10
ρ = 0.212
Ka(H)

Remarkably, relationship
between substituent σ and
equilibrium stays linear.
σ
 Linear Free-Energy Relationships

Hammett’s Hypothesis, Part 2:

(actually possible to
Ka(X) use any constant in
log10 = ρσ(X) denominator)
K0
Overall:

ρ > 0: Equilibrium has same pattern as benzoic acid Ka’s;

Electron-withdrawing substituents increase Ka,
Electron-donating substituents decrease Ka.

ρ > 1: More sensitive to substituents than benzoic acid Ka’s.

0 > ρ > 1: Less sensitive to substituents than benzoic acid Ka’s.

ρ < 0: Equilibrium has opposite pattern as benzoic acid Ka’s;

Electron-withdrawing substituents decrease Ka,
Electron-donating substituents increase Ka.
 Linear Free-Energy Relationships
O OH O O

Ka
+ H+
X X

If substituent effect is fundamentally

different, then different set of σ values
may be required.

Pattern of stabilization/
O O
destabilization is the same
for σmeta;
δ+/− δ+/−
Resonance less important,
δ+/− X
δ+/− Induction more important.
 Linear Free-Energy Relationships:
Kinetics

Remarkably, σ can be used for

E ΔG (H)
‡
rate constants too.

ΔG‡(X)

ΔΔG‡(X) = ΔG‡(X) – ΔG‡(H)

kX -ΔΔG‡(X)
log10 = = ρσ(X)
kH 2.303RT
reaction coordinate
rate constants!
 Linear Free-Energy Relationships:
Kinetics

O OEt O O For example:

kX
+ OH + EtOH ρ = 2.61

X X

ρ > 0;
‡
kX -ΔΔG (X) As with benzoic acid acidity,
log10 = = ρσ(X)
kH 2.303RT EWGs increase rate constant,
EDGs decrease rate constant.
 Linear Free-Energy Relationships
δ− ‡
O Electron-withdrawing X destabilizes (δ+)C=O.
δ− OEt Destabilizes Csp3 in transition state less.
HO
So, kEWG > kH.

Just like benzoic acid Ka’s. So ρ > 0.

X
kX
log10 = ρσ(X)
ΔG (EWG)
‡
kH

ΔG‡(H)
δ- O O OH
O OEt HO OEt
δ+
HO

X
X X
 Linear Free-Energy Relationships
Direct resonance of changing charge in TS addressed by σ+, σ-.

Resonance stabilization Cl OH
particularly important in TS. H3C CH3 H3C CH3

δ− H3O+
Cl
(SN1)
H 3C CH3
δ+ X X

H3C CH3

Resonant e- donors rate-determining

stabilize TS, step X
increase k.
 Linear Free-Energy Relationships
σ+ accounts for direct Cl OH
resonance with phenyl H3C CH3 H3C CH3
substituents.
H3O+

(SN1)
X X

H3C CH3

rate-determining
step X
kX
Reference is cumyl chloride -log10 = ρσ+(X)
hydrolysis (this reaction). kH
Negative sign (for σ+ only) means
σ values same direction as benzoic acids.
 Linear Free-Energy Relationships

Ka(X) kX
log10 = ρσ(X) or log10 = ρσ(X)
Ka(H) kH

Summary:

ρ > 0: Process has same pattern as benzoic acid Ka’s;

Electron-withdrawing substituents increase Ka or rate k,
Electron-donating substituents decrease Ka or rate k.

ρ < 0: Process has opposite pattern as benzoic acid Ka’s;

Electron-withdrawing substituents decrease Ka or rate k,
Electron-donating substituents increase Ka or rate k.
 Linear Free-Energy Relationships

Keep in mind: For multistep kinetics,

Effect of substituent is between starting
material and rate-determining transition state.

Method is frequently used

to identify rate-determining
ΔG‡(H) step/transition state.
ΔG‡(X)
Can also be used to
identify change in
rate-determining
transition state.