Kinetic Isotope Effects (K.I.E.

):

o The rate of a reaction changes with an

isotopic substitution
o How does it therefore affect the rate of a
reaction?
o What an isotopic substitution does affect is
the vibrational energy of a bond consider a
vibrational coordinate for a single bond

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 Isotope Effects

Due to uncertainty principle, the lowest vibrational energy

is not at bottom of energy well (and thus the bond
dissociation energy does not occur from bottom of well)
In addition, the vibrational energy levels are quantized
En = (n + 1/2) ho Where n = 0, 1, 2, etc.
The lowest energy level is thus Eo = 1/2 ho
To determine the frequency (o) of the bond vibration:
For simplicity assume a simple two body vibration attached
by a spring

IR Stretching Frequencies of two bonded atoms:

What Does the Frequency, , Depend On?

h k
E h clas
2
= frequency
k = spring strength (bond stiffness)
= reduced mass (~ mass of largest atom)

is directly proportional to the strength of the bonding between

the two atoms ( k)
is inversely proportional to the reduced mass of the two
atoms (v 1/) 51

2
 Stretching Frequencies

Frequency decreases with increasing atomic weight.

Frequency increases with increasing bond energy.
52

Kinetic Isotope effects

Deuterium isotope effects (kH/kD) is the ratio between
the rate of reaction of the protonic substrate and that of
the corresponding deutero substrate.
A normal isotope effect has kH/kD > 1 indicating that
the reaction of the protonic substrate is faster than the
reaction of the corresponding deutero substrate.
An inverse isotope effect has kH/kD < 1 indicating that
the reaction of the protonic substrate is slower than
the reaction of the corresponding deutero substrate.
Primary isotope effect is observed in the reaction that
its rate determining step involves the breaking of the
bond connecting to the isotopic H.
The primary isotope effects usually have 6 2 kH/kD 7.

3
 Primary isotope effects
Origin of the primary isotope effects
R H X kH/kD < 7 (late T.S)
R H X maximum kH/kD ~ 7
R H X kH/kD < 7 (early T.S)

1 k
E0
4
m A mB
AB mA
R H m A mB
R D E0D E0H
7

Primary Kinetic Isotope

Effect:
Typical Values
Nuclide k light k hea vy o
(at 25 C )

C-H/C-D 6-8

C-H/C-T 15 - 16
12 13
C/ C 1.04
12 14
C/ C 1.07
14 15
N/ N 1.03
16 18
O/ O 1.02
32 34
S/ S 1.01

35 37
Cl/ Cl 1.01

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 Primary isotope effects
Alcohol oxidation

R OH R
+ H2CrO4 O
R H (D) R

Gives kH/kD = 6.9

The transition stateRproposed for the rds. is as follow
O CrO3H

R H base

Exercise

Write a reasonable mechanism and specify the rate

determining step for the following reaction which
shows kH/kD 7
O O
H+
CH3CCH3 + Br2 CH3CCH2Br

10

5
 Kinetic Isotope effects

Secondary isotope effect is observed in the reaction that its

rate determining step does not involve the breaking of any
bond connecting to the isotopic H.
-secondary isotope effect usually has kH/kD in the range
0.7-1.5. It is the result of the greater vibration amplitude of
C-H bond comparing to C-D bond.
A normal -secondary isotope effect (kH/kD > 1)
generally suggests a rehybridization of the carbon
connecting to the isotopic H from sp3 to sp2 in the rate
determining step.
An inverse -secondary isotope effect (kH/kD < 1) generally suggests a
rehybridization of the carbon connecting to the isotopic H from sp2 to sp3 in
the rate determining step.
-secondary isotope effect has kH/kD > 1. It is11 mainly attributed to
hyperconjugation.

Secondary isotope effect

Solvolysis of cyclopentyl tosylate
OTs
H (D)
H (D)
sp3C-H sp2C-H (kH/kD = 1.17)

Addition on aldehyde normal

O O
CN-
Ph H (D) Ph H (D)
CN
sp2C-H sp3C-H (kH/kD = 0.833)
12
inverse

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 Summary of primary and secondary
kinetic isotope effects

(CH3)3CD + X (CH3)3C. + DBr primary

+
(CH3)2CDX (CH3)2CD + X- -secondary (normal)
+
(CH3)2C=CD2 + H+ (CH3)2CCD2H -secondary (inverse)

+
(CD3)2CHX (CD3)2CH + X- -secondary

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Kinetic Isotope effects

Solvent isotope effects
Generally observed when a protic solvent e.g. D2O
or ROD is used.
kH/kD < 1 when the reaction involves a rapid
equilibrium protonation because the acidity of
D3O+ is greater than H3O+ (specific acid catalysis
can be used for confirmation)
kH/kD > 1 when proton transfer is the rate
determining step (general acid catalysis can be
used for confirmation)
Secondary solvent isotope effect can interfere the
interpretation. Solvent isotope effect is thus used
only as a supporting evidence.

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 Examples of
Kinetic Isotope Effects
Consider the following dehydrohalogenation reactions:
NaOC 2 H 5 H 3C
CH 3 CH 2 CH 2 Br C CH 2
C2 H 5 OH H k H / k D = 6.7
Case I:
NaOC 2 H 5 H 3C 1o KIE for C-H/C-D
CH 3 CD2 CH 2 Br C CH 2
C2 H 5 OH D

CH 3
H 2O H 3C CH 3
CH 3 CH 2 C Br C C
H CH 3
CH 3 k H / k D = 1.4
Case II:
CH 3 o
2 KIE for C-H/C-D
H 2O H 3C CH 3
CH 3 CD 2 C Br C C
D CH 3
CH 3
Rationale:
Transition State for Case I (E-2) Transition State for Case II (E-1)
-
C2 H 5 O
+ CH 3 CH 3
H
H (D) H H (D) H (D)
C CH 3 C CH 3
C
+
C C rds C
- -

(D) H Br (D) H Br (D) H
H 3C H 3C H 3C Br -

More Examples of Kinetic

Isotope Effects
Consider the following decomposition of an azo compound:

R N N R R N N R 2 R + N2 k 14 k 15 = 1.02
N N

Rationale: Although the above rate enhancement is small in absolute terms,

for the nitrogen nuclides indicated, the enhancement is indicative
of a primary kinetic isotope effect.

Consider the nitration of benzene shown below:

HNO 3 /H 2 SO 4
C6 H 6 C6 H 5 NO 2 rate
H
HNO 3 /H 2 SO 4
C6 D6 C6 D5 NO 2 rate D

Observation: rate ~ rate

=
H D

Conclusion to be drawn: A C-H (C-D) bond is not being broken in the

rate determining step of electrophilic aromatic
nitration.

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Secondary Kinetic Isotope
Effects

Differences in steric demand

Hyperconjugative effects
Differences in inductive effect

Examples of Secondary
Kinetic Isotope Effects
Differences in Steric demand
Example I: CH 3 Cl + H 2 O CH 3 OH + HCl k
H

CD3 Cl + H 2 O CD3 OH + HCl kD

Observation: kH / kD = 0.97

H In order to initiate bond making, the

incoming nucleophile must be able to
Rationale: H 2O C approach the substrate from the rear.
H
Cl
H The shorter C-D bonds (relative to C-H
bonds) permit a closer approach by H 2O
Example of an inverse and bond making can begin sooner.
-isotope effect

Example II: (CH 3 )2 CHOTs + H 2 O (CH 3 )2 CHOH + TsOH kH

(CH 3 )2 CDOTs + H 2 O (CH 3 )2 CDOH + TsOH kD

Observation: k H / k D = 1.13
H
Rationale: C+ In the transition state leading to the
H 3C CH 3 isopropyl carbocation, there is a greater
relief of strain for C-H relative to C-D.

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 Secondary Kinetic
Isotope Effects
Example III: + CH 3 I
N N+ I-
CH 3

Observatio ns: Pyridine Substrate k D / kH

CD3

1.0 01
N
CD3
1.0 09
N

1.0 30
N CD3

1.0 95
D3 C N CD3

Secondary Kinetic Isotope

Effects
Hyperconjugative effects
Example: -Isotope effect

(CH 3 )3 C Cl + H 2 O (CH 3 )3 C OH + HCl kH

(CD3 )3 C Cl + H 2 O (CD3 )3 C OH + HCl kD

Observation: k H / k D = 1.21

+
Rationale: CH 3 CH 2 H
C+ C
H 3C CH 3 H 3C CH 3

Whereas a C-D bond is slightly stronger than a C-H bond, hyperconjugation as

shown above is not quite as effective at stabilizing the carbocationic intermediate
for the reaction using deuterated reactant relative to that using unlabeled reactant.

Another view: Whereas C-H bonds at a given temperature are slightly longer than
corresponding C-D bonds, formation of a carbocationic intermediate
provides more relief from steric strain for unlabeled reactant
compared with that experienced by deuterated reactant.

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 Secondary Kinetic Isotope
Effects

Inductive effects
Example: CH 3 COOH CH 3 COO - + H + KH
- + KD
CD3 COOH CD3 COO + H

Observation: KH / KD = 1.06

Rationale: Hydrogen is slightly more electronegative than deuterium.

Related Question: Which one of the following is more basic?

CH 2 NH 2 vs. CD2 NH 2

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