Chapter 6: Methods of

Studying Organic Reactions

• Problems: 1, 3, 7, 8, 11, 16, 18

Mechanism
• The order of events in going from reactant
to product.
– An “event” is a breaking of a bond, the making
of a bond, or the simultaneous making and
breaking of a bond.

Reaction Products
• Products of the reaction must be explained
by the mechanism.
CH2 Cl
- CH2 OH
HO

G G
N O2

CH2 Cl
-
HO
O 2N
O2 N

• Often minor products give a clue to the

mechanism
3

1
 Intermediates
• Single step (elementary) bond are formed
and broken simultaneously.

PE

A+ B

C+ D

rxn coordin ate

Multiple Step Reactions

• High energy intermediates (low conc...)

PE

A+ B
D + E

rxn coordin ate

Demonstrating the Existence of

an Intermediate.
• Generate by a different reaction and look
for the same products.
CH 3O OCH 3
EtOH O
O the r p ro duct s
O Ts OEt

1 1%

Pro posed int eremedi ate

O
O
EtO H
O Et
TsOH

2
 Spectroscopic Methods
• Olah NMR of carbocations.
– Are the cations in SO2 FCl-SbF 5 the same as the
ones in solvolysis reactions?
• EPR might show signal for a radical if the
concentration is high enough.
• IR of reaction may detect an intermediate
that can not be isolated.
– Cyclobutadiene in Ar matrix at low temp.
7

Trapping
• A reagent might be added to a reaction that
would be expected to react rapidly with the
proposed intermediate.
Br Br - Br H
CH 3 H Br2 CH3 H C H3
CH 3
H Br
H CH3 H CH3
Racemic

Br H
CH3 H Br2 C H3
C H3
H N3
H CH3 Na N3
Racemic

Intermediates
• Can infer the nature of the intermediate.
OH OH
OH
-
H -
mande late CO O
COO racemase CO O - H

(R) prop osed (S)

OH OH

H -
mand elate H -
COO racemase CO O

BrC H2 CH3
OH OH
-
COO -
CO O
BrC H2 CH2

3
 Crossover
• Fries Rearrangement
O CH3 AlCl3 OH OH
C
O CH3 CH3
C C
O O

O CH3 -
C O AlCl
+
O -
CH 3
AlCl3 C
+
O
OH OH

CH3
CH3 CH 3 C
O
Ad d Loo k for 10

Isotopic Labeling
14
• C is can be used and followed by
counting.
- -
RCOO + BrCN RCN + CO 2 + Br

- -
RCOO + BrCN RCN + CO 2 + Br

11

Stereochemistry
• Inversion was used to understand SN2
mechanism.
• Retention is rather unusual
O HO H PC l5
OH (-) C hl orosuccinic a cid
HO
O
(+) M ali c Aci d
SOC l2
(+) Chl orosuccinic a cid

12

4
 Solvent Effects
• Change in solvent can tell you something
about the polarity of intermediates.
• Rate of SN1 solvolysis increases as you go
to a more polar solvent.
– Consistent with the formation of ions during
reaction.
• Diels-Alder not influenced much by
solvent.
13

Solvent Polarity
• Difficult to define.
– Dielectric constant (ε) is often used.
– It is a mix of polarity and polarizability
• Many empirical scales (Table 6.1)
– Solvatochromism - change in UV-Vis with
change in solvent. C OO CH 3

– Kosower Z - based on
N I
C H2 CH3

14

Kinetics
• Major tool for understanding mechanisms.
• Follow the concentration of a reactant or
product as a function of time.
d [A]
Rate = change in concentration with time
dt

If A is a reactant then there is a negative sign s ince

the rate is decreasing with time.

15

5
 Kinetic Goal
• Relate quantitatively the concentration of a
reactant with time.
• Kinetic Order is the relationship of the
concentration of a reactant with respect to
time
• One hopes to obtain a rate equation which
relates the rate and the concentration of the
reactants.
16

Organic Reaction Mechanism

• Rate equation
k1
A + B C
k-1

rate = k1[A][B] - k-1[C]

d[C]
= k1[A][B] - k-1[C]
dt

17

Multi-step Reactions
k1 k2 k3
A+B C D E+ F
k-1
First step

rate = k 1 [A][B] - k-1 [C]

d[C]
= k 1[A][B] - k-1 [C] - k 2 [C]
dt

Second step

d[D]
= k 2[C] - k3 [D]
dt

18

6
 Multi-step Reactions
• Rate for the third step.
d[D] d[E] d[F]
- = =
dt dt dt

• Be careful of sign. Negative sign means

decrease in concentration and positive
sign means increase in concentration.

19

Multi-step Reactions
• The importance of terms in the rate equation
depends on the magnitude of the rate
constants.
ex. If k3 >>k2 then the second step is rate
determining
If k -1>>k1 >k2 then the concentration of C will be
very small and C must be an unstable
intermediate.

20

Equations need to be expressed

in measurable species
• Thermodynamic relationships can be used.
• Suppose second step is rate determining.
(k2 <<k1 and k-1) d[A] d[B]
= = -k 2 [C]
dt dt
[C]
Keq =
[A][B]

[C] = k 1 [A][B]
k-1

d[A] - k2 k 1[A][B]
= k
dt -1

k2 k 1
The reaction would be second order. kobs =
k-1

21

7
 Need Integrated Form of Rate
Equation
• First order reaction
k1
A B

d[A]
= - k 1[ A ]
dt
d[A]
= - k 1d t
[A]

[ A ]o
ln [ A ]t = kt

A plot of ln(Ao/At ) vs time should give a straight line of slope -k

22

Second Order Reaction

k1
A+B C

d[A]
= - k1[A][B]
dt

If Ao does not equal Bo then Ao -A = Bo - B

or B = Bo - Ao +A
d[A]
- = k1[A][B o - Ao +A]
dt

23

Differential Equations
• To solve the differential equation you must apply
the method of partial fractions.
1 Ao 1 Bo - Ao + A
ln + ln = k 1t
Bo - Ao A Bo - Ao Bo

1 Ao( Bo - A o + A)
ln = k1 t
Bo - A o B oA

1 A oB
ln = k1 t
Bo - A o Bo A

24

8
 Bimolecular Kinetics
• We can simplify if Ao = Bo
dA
- = k [ A][B]
dt
dA 2
- = k [ A]
dt
Integration

1 1
- = kt
A Ao

• Plot 1/A vs. t. Intercept is 1/Ao

25

Example
+ k1 +
ROH + H RO H2
k-1

+ - k2
ROH2 + Br RBr + H2 O

+
[RO H2 ] k1
Keq = =
+ k- 1
[ROH][H ]

d[ROH] + - + -
- = k2[ROH2 ][Br ] = k2Keq[RO H][H ][Br ]
dt

26

Steady State Approximation

k1
A + B C
k-1

k2
C + D E+ F

• If C is reactive it’s concentration will not be

very large and it will be consumed as fast as
it is formed. Under these conditions the rate
of formation is equal to the rate of
consumption
27

9
 Derivation
k1
A + B C
k-1

k2
C + D E + F

k 1[A][B] = k2 [C][D ] + k-1 [C] St eady state approx.

k 1[A][B] = [C](k 2[D] + k -1)

k1 [A][B]
[C] = k2 [D] + k 1

Rate o f Seco nd st ep

rate = k2 [C][D ]

k2 k 1[A][B][D]
rate = [C] is no t in th e equ atio n
k2 [D] + k 1

28

How does one use kinetics?

• Several mechanism are proposed and the
rate equations are derived. Hopefully,
different equations will result.
• The rate dependence for the reactants is
studied and tested to see if the data fits the
derived equations.
• More than one mechanism may fit the data.

29

Case Study: Nitration of

Benzene
N O2
H NO 3 H 2 SO 4 H2 O
A.
k1
2 HN O3 H2 O+N O2 N O3
-

k-1
H
NO 2
H2 O+N O2 k2 H2 O

H N O2
N O2 k3 +
H

k3 >>k2
k1 and k-1>>k2

30

10
 Cont....
k2 k1[HNO 3]2[φH]
rate = k2[H2 O+ NO 2][φH] = k-1[NO 3-]

kobs [HNO3 ]2[φH]

=
[NO 3-]

31

Second Mechanism
k1
2 HNO 3 H2 O +NO 2 -
NO 3
k-1
+ k2
B. H2 O NO 2
slow
H 2O
H
NO 2
+

NO 2
NO 2+ k3

H N O2
N O2 k4
H+

k3 and k 4 >>k2
k1 and k -1 >>k2

+
k2 k1 [HNO 3 ]2
rate = k2 [H2 O N O2 ] = -
k-1 [NO 3 ]

k o b s[HN O3 ]2
= -
[N O3 ]
32

Third Mechanism k1 +
2 HNO 3 H 2O NO 2 NO 3 -
k- 1

C. H 2O +NO 2
k2
k -2
H2 O N O2
+

H
NO 2
N O2 + k3
k-3

H NO 2
N O2 k4
H+

k1 , k 2 , k3 >>k4

rat e = k4 [φ NO 2 ]
+
but [ φ+N O2 ] = k1 k2 k3 [ φH][HN O3 ] 2-
k-1 k- 2k -3 [H2 O ][N O3 ]

therefo r rate = ko b s[ φH ][HNO 3 ]2

[H2 O][NO 3 -]

k4 k1 k2 k3
ko b s =
k-1 k-2 k- 3 33

11
 How do the rate equation
differ?
ko b s[HN O3 ]2 [φ H]
A. rat e = -
[ NO 3 ]

k o b s[HNO 3] 2
B. rat e =
[N O3 -]

k o b s[ φH] [H NO 3] 2
C. rate =
[H 2O ][ NO 3 -]

The rate is found to be independent of the benzene concentration

34

Transition State Theory

• How do we judge the effects of a change in
structure on rates?
• Rate depends on the Ea for the reactions.
• Make some assumptions regarding the T.S.
– Unstable and proceeds rapidly to product.

35

Rate of Decay of T.S.

• Transmission coefficient, κ (usually 1)
• Boltzmann’s Constant, k
• Planck’s Constant, h
• Absolute temp. (of T.S.) T
ΚkT
Rate of decomposition = [T.S.]
h

36

12
 For a Reactions
• Simple reactions
A + B C

A + B T. S. C

• Equilibrium with T.S.

[T. S.]
K* = and ∆G * = -RT l n K *
[A ] [B]

• Where ∆G* is the free energy change

necessary to attain the T.S.
37

Combining
• Substituting for [T.S]
rate = Κ kT Κ k T K* [A] [B]
h [T.S] = h

But K* = e - ∆G */RT

So rate = = Κ k T e- ∆G*/R T [A] [B]

h

• Comparing rate equations we can see that

the rate of the reaction depends on the free
energy of activation. 38

P.E. Curve

∆G* ki ne ti c

∆G thermodyna mic
∆G*
PE

A+ B

rxn c oordi na te

39

13
 Two Step Process
• C is an intermediate.

∆G*
PE

A+ B
D

rxn coordin ate

• The T.S. has a life time < one vibrations

40

Principle of Microscopic
Reversibility
• The same path that is traveled for reactants
to products will be used in going from
products to reactants.
• The free energy of activation can be
measured but the structure of the T.S. can
not be measured.
• MO methods can be applied to the structure
of the T.S.
41

T.S. Approximations
• Look at effect of temperature on rates.
-∆G*/RT
kr = Κk T e
h
* * *
∆G = ∆H -T∆S

Substituting and reorganizing the equation

- ∆H*/ RT ∆S*/R
kr = Κ kT e e
h

*
We now assume that ∆S does not vary much with temperature so
*
the major change is due to ∆H because of the exponential function

42

14
 Continue
• A good approximation is:
kr Κk
= C e-∆H*/RT C=
T h

kr
ln = -∆H* + C'
T RT

• A plot of ln kT v s. r 1
T

• Slope of -∆H*/R.

43

∆S*
• Now can calculate ∆S* from the equation
* ∆H* R ln k r
∆S = +
T ΚkT

∆H* 4.58 log k r -47.4

= +
T T

44

Another Derivation
• Arrhenius Equations
k r = A e-Ea/RT

Ea
ln kr = - + ln A
RT

• Plot of ln kr vs 1/T should have a slope of

-Ea/R.
• Ea is the Arrhenius activation energy
45

15
 Continued
• At constant pressure
*
Ea = ∆H + RT

• A is the pre-exponential factor

A = ΚkT e
∆S*/R
h

46

What do we get?
• The magnitude and sign of ∆H* and ∆S* tell
us something about the T.S.
• Large ∆H* indicate that the T.S. is more
highly strained than the reactants.
• Negative ∆S* indicate that the T.S. is more
highly ordered that the reactants.
• Positive ∆S* indicate that the T.S. is more
disordered than the reactants.
47

Example
• For the Diels-Alder reaction

T.S.

∆H = 1 5.5 Kcal/ mo l
*
Bon d breaki ng and maki ng si mu ltan eous
∆S* = -34 cal/ mo l-d eg. Hig hly ordered T.S.

48

16
 Another
• Decomposition of diazoalkane
CH 3CH2 CH 2 CH 2 N=N CH2 CH 2CH 2CH3

*
∆H = 52 Kcal/mol In dividu al Bond b reaking
∆S * = +19 cal/mol-d eg. Mor e p articles

49

∆S* includes solvent

• Be careful in interpreting ∆S* in is for the
whole system including solvent.
CH3 CH3
CH3 C Cl CH3 C Cl
CH3 CH3

Might expect DS * to be positive

*
∆S = -6. 6 cal/mol-deg.

• Solvent is highly ordered around ions.

50

Isotope Effects
• Change in rate as a result in a change from
one isotope to another.
• Only significant for H, D, and T.
– Change in mass is significant

51

17
 Simple Model
• Frequency 1 k
ν=
2π m

– k is force constant
– m is reduced mass.
• Quantum mechanical model gives energy
levels. ε = (n + 1/2)hν n=0, 1, 2, 3, . ... .
n
∆ ε = hν

52

Continue
• Lowest level would be 1/2 hν above
minimum P.E.

n=3
n=2
n =1
n =0

53

Primary Isotope Effect

• The stretching vibration of the reacting
bond is converted to the translational
motion over the barrier, and the zero-point
energy disappears for that degree of
freedom in the T.S.
• Therefore, since the C-H compound starts
out higher in energy than the C-D, the Ea is
lower
54

18
 P.E Diagram
• C-H should react faster than C-D.

P.E. n=3
n=2
n =1 C-H
n =0 C-D

r C-H

kH
kD > 1

55

Magnitude
X H Y
X D Y

X-H Y X H -Y

X -D Y X D -Y

• We can calculate the magnitude

1 1 1
= 1.4 1 cl oser to
2 1 .35

56

Continue
• Change in εo with change in isotope
∆εο = 1 hc(νH - νD) = 1 hc(1 - 1/1.35) νH

kH hν 0.1 865
k D ~ exp - 2kT (1 - 1/ 1.3 5) νH = exp - T νH

• Since νH is ~ 3000 cm-1 and T= 300 o K

kH 0 .186 5
= exp - 3 000 = 6.4
kD 30 0

57

19
 The Reacting Bond
• The heavier isotope will bond more tightly
to the reactant and the lighter isotope will
bond tighter to the T.S. where the force
constant is weaker.
• C-H will react faster than C-D

58

Secondary Isotope Effect

• An isotope effect that occurs from
substitution at a bond that is not being
broken during the reactions.
• Must result from changes in zero-point
energy with the ordinary vibrations
kH 1 (u * - u * ) - (ν - ν )
kD = ex p - 2
H D H D

kH 0 .18 65 (ν ∗ - ν )
kD = ex p - T
H H

59

So?
• Any vibration which decreases on going to
the T.S. contributes a factor greater than 1
to kH/k D and any vibration for which the
frequency increases in the T.S. contributes a
factor less than one.

60

20
 Changes in Hybridization
• sp3 to sp2 or sp2 to sp3
R' R'
+
C X C X-
R R
H (D) H (D)
sp 3 sp
2

3
sp2 sp

61

Vibrations
• Streitwieser
+
C H C H

3 -1 2 -1
sp 2900 cm sp 2800 cm
+
C H C H

3
sp 1350 cm
-1 sp 2 1350 cm- 1

C H C+ H Maj or out of pla ne

2 -1
sp3 1350 cm- 1 sp 800 c m

62

Cont....
• Estimate
kH 0 .1865 (800 -1350)
= exp - = 1 .41
kD T

• Actual effect is smaller 1.15 to 1.25

• For sp 2 to sp3 kH/kD < 1;
• Max 0.71; usual about 0.8 - 0.9.
• β isotope effect about 1.1.
63

21
 Examples
kH/kD

φ CH2H* + Br φ CH2 + HBr 4.6

O -
O
(CH3) 2C C C (CH3)2 + HO - (CH3)2C C C (CH3) 2 6.1
* * *
H H H
O OH
C * C *
H + HCN H 0. 73
CN
CH3O CH3O

64

Linear Free Energy

Relationships
For a reation

A+ B C + D

K eq will depend on the free energy change for the reaction.

∆Go = -RT ln K eq

Looking at a specific reaction

O O
+
OH + H 2O O- + H 3O

∆Go = -RT ln K eq

65

Substituted Benzoic Acids

K eq for the substituted benzoic acid will be slightly different depending on the
nature of the substutuent.
∆G xo = -RT ln K x

O O
-
OH + H2 O O + H 3 O+

X X

∆∆G o = ∆G Xo - ∆GH o

H -φ -CO O H
X -φ -CO O H ∆G Ho

H- φ -CO O
-
∆G Xo

Go X -φ -CO O -

66

22
 Substituent Constant
∆∆ G o = ∆G X o - ∆ GH o = - 2.303 RT σ x

− ∆ G X o = - ∆G o o + 2.303 RT σx

Since
−∆ Go = 2.303 RT log K

2.303 RT log K x = 2.303 RT log K o + 2.303 RT σ

or
log K x = log K o + σx
Kx
log
Ko
= pK o - pK x = σx

67

Sigma Values

68

Different Reaction
• Rate of Ester Hydrolysis
O O
k
O CH3 HO- O- C H3 OH

X X

69

23
 Linear Free Energy
If there is a relationship it might be

Kx kx
m log = log k
Ko o

m ( log Kx - log Ko ) = ( log kx - log ko )

m ( -∆Gx/RT -∆G o/RT ) = ∆Gx+ /2.3RT - ∆G o/2.3RT)

m ( -∆Gx -∆Go ) = ∆G x - ∆G o

m ∆∆G = ∆∆G
Acid strength Rate of reaction
Does this relationship exist?

70

pKa vs Rate of Ester

Hydrolysis

71

Reaction Constant (ρ)

If there is a relationship it might be

Kx kx
m log = log
Ko ko

kx Kx
log
ko = σx ρ m= ρ log
Ko
= σx

σ x = substituent constant
ρ = reaction constant

72

24
 Ramifications
• If we plot log kx /k H vs σ the we should get a slope
of ρ. This tells us how similar in sensitivity to
substituents the new reaction is when compared to
benzoic acid ionization.
ρ = 1 : substituent influences reaction in the same
way as benzoic acid ionization
ρ > 1 : substituent has a greater effect on the
reaction.
ρ < 1 (negative) : the effect of the group is the
opposite to that of benzoic acid ionization 73

ρ Tables

74

Where do the effects come

from?
• Resonance F
F

Yδ+ Yδ- Yδ
+
Yδ
-

• Field Effect X X X X

unfavorable favorable favorable unfavorable

Yδ Yδ
+ -
Yδ Yδ
+ -

+ +
δδ δδ δδ
-
δδ
-

+ - -
δ δ+ δ δ

• Induction X X X X

unfavorable favorable favorable unfavorable

75

25
 Hammett Equation and
Reaction Mechanisms
kx
log
kH = σx ρ
log kx = log k +
H
σx ρ
Plot of log k z vs σx has slope of ρ

O OH
R R
C O I R R II
R R N O
H2 N NH C NH2 NH O N H C N H2
N H C NH2

76

Observations
• The rate of semicarbazone formation is a
function of pH. Lowering from slightly
alkaline to slightly acidic increases the rate.
Further lowering the pH decreases the rate
• Change in R.D. step
• At slightly alkaline acid dehydration is rate
limiting (II)
• Further lowering causes attack on carbonyl
to be rate limiting (I)
77

Hammett Plot

78

26
 Interpretation
ρ = 0.91 same effect as with benzoic acid.
Reasonable if rate determining step is attack
by amine.

79

At pH =7.0

80

• In neutral solution the rate limiting step is

acid cat. dehydration. Under these
conditions the rate of semicarbazone
formation depends on both eq. conc... if
intermediate and the rate of its
decomposition ( kobs = k1k 2/k-1).
• electron donating increase the rate of
formation of the intermediate and electron
withdrawing increases the rate of
decomposition of the intermediate.

81

27
 pH = 3.9

82

• Since addition is made more difficult, and

dehydration is facilitated by electron
donating groups, at intermediate pH the rate
determining step is the addition step.
• For aldehydes with electron withdrawing
groups the addition is favorable and
dehydration is difficult.
• One ρ for electron donating groups and a
different ρ for electron withdrawing groups.

83

σ+ and σ-
• A problem arises if the reaction is such that
resonance interacts directly with the reaction
OH O- O
site. -
O +
N
-
O +
N
-
O
N+
O O -
O

• Effect of NO2 greater than then predicted by

σ NO2
84

28
 New Standard Reaction
CH 3
k C H3
C Cl Cl
-
C H3 C
90% aq. ac etone C H3
X
X

kx
l og k
H
= σ x+ ρ = 1 by definit ion

σ - from el ect on wit hdrawing groups and σ+ from ele ctron dona ting

Used when direct resonance interaction with

reaction site.
85

Sigma Minus
• Where there is a negative charge at the
reaction site
OH -
O H+

X
X

kx
log
kH = σ x- ρ = 1 by defin itio n

86

How do we use sigma values?

• You may not know what sigma to use.
• Plot and find which gives the best
correlation.

87

29
End of Chapter 6

88

30