1) Kinetic isotope effects occur when the rate of a chemical reaction is different for molecules that only differ in their isotopic substitution. This is because isotopes can alter vibrational zero-point energies. 2) Primary kinetic isotope effects involve bonds made or broken in the rate-determining step, arising from differences in zero-point vibrational energies between reactants and transition states. Secondary effects involve isotopes near but not at the reaction center. 3) The magnitude of primary kinetic isotope effects depends on factors like the symmetry and geometry of the transition state, with more linear transition states giving larger effects. Secondary effects depend more on hybridization changes and hyperconjugation effects.

1. Kinetic Isotope effect
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2. Sources
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Kinetic Isotope Effects in Organic Chemistry
Rob Knowles
https://macmillan.princeton.edu/wp-content/uploads/RRK-
KIE.pdf
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3. Origin of Primary Kinetic Isotope Effects
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➢ Isotopes may differ chemically, because some chemical properties do depend on atomic mass. However, this difference is
only significant for hydrogen—no other element has one isotope twice as massive as another!
➢ To a good approximation, substitution of one isotope for another does not alter the potential energy surface.
➢ Reactions in which C–H bonds break go faster than reactions in which C–D bonds break, providing the bond to H (or D) is
involved in the rate-determining step.
Why ZPE?
Even in its lowest energy state a covalent bond never stops
vibrating. If it did it would violate Heisenberg’s uncertainty
principle, which states that position and momentum cannot
be known exactly at the same time: a non-vibrating pair of
atoms have precisely zero momentum and precisely fixed
locations.
Origin
Difference in frequencies of various vibrational
modes , which is in turn dependent inversely on
square root of reduced mass (μ).
Greater the mass, the lower will be the ZPE
Unimolecular reactions
but most org rxn not
unimolecular
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4. Magnitude of Primary Kinetic Isotope Effects
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➢ To understand any kinetic phenomenon, one always compares reactant with transition state. For isotope effects we compare
the ZPEs of the various vibrations of the reactant and the activated complex
➢ ΔZPE's in the GS & TS determine the magnitude of the kinetic isotope effect.
➢ ZPE changes between GS & TS: Force constant of the bond changes (k is lower for TS so diff b/w ZPE for H & D is less)
H(D) substitution is most widely studied
H(D) (2 vs 1 in mass-100%),
13C/12C (13 vs 12 in mass-8%)
value of 7 determined assumed that the
bond was freely dissociated thus went
from a bond to no bond
➢ Variation in KIE: Neglect bending, Tunneling
➢ Magnitude of the observed KIE:
I. Max at symmetric TS
II. Geometry of the TS: In general primary KIE's for nonlinear TS are lower than those for more linear TS
III. Higher temperatures produce smaller KIE
IV. Steric isotope effect is therefore an ideal way of estimating the steric crowding of the TS relative to the GS
V. Hybridization changes
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5. Hammond Postulate and Isotope Effects
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❖ Hammond Postulate states that TS structure most resembles the molecule that it is closest in energy
If the transition state occurs
early, the C—H or C—D bond will
be broken only slightly in the
transition structure. The
stretching vibration in the
transition state will be affected
by the mass of the hydrogen (or
deuterium) atom in much the
same way as in the reactant.
Therefore, the difference in
transition state energy for the
C—H or C—D species will be
nearly the same in the transition
structure as in the reactant.
10
20
C-D
C-H
C-D
C-D
C-D
C-H
C-H
C-H
70
68
40
50
62
70
Reaction Ground State Transition
State
Δ ΔΔ
Exothermic C-D 40u 62u 22u 2u
C-H 50u 70u 20u
Thermoneutral C-D 10u 68u 58u 8u
C-H 20u 70u 50u
* Values just for understanding
Hydrogen atom does not move in the vibrational
mode so the frequency of the vibration does not
depend on its mass.
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6. Symmetrical & Non-linear Transition states
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❖ In general primary KIE's for nonlinear TS's are lower than those for more linear TS’s
❖ Reason: TS with bent bonds, the bending vibrational modes become more important. bending modes are much lower
energy than stretching modes in linear TS's.
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7. Secondary Kinetic Isotope effects
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➢ Deuterium labelled molecule has a stronger bond to carbon, participates in hyperconjugation to a lesser extent
➢ β-secondary isotope effect is strongly dependent on geometric factors (not always
Ideally oriented)
➢ secondary kinetic isotope effect arises from differences in bending vibrations.
Reaction Ground State Transition State Δ
Sp3 to sp2 C-D 10u 40u 30u C-H > C-D
Normal
KIE
C-H 20u 48u 28u
sp2 to Sp3 C-D 15u 40u 25u C-D > C-H
Inverse KIE
C-H 20u 48u 28u
10u
20u
40u
48u
48u
40u
15u
20u
C-D
C-D
C-D
C-D
C-H
C-H
C-H
C-H
The biggest (energy)
change occurs in the out-
of-plane bending motion
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8. Steric Isotope Effect
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➢ Steric Isotope Effect: C-D bond is slightly shorter than the C-H bond, deuterium atom feels more 'comfortable' in a
sterically congested environment than a hydrogen
➢ If the GS more crowded than the TS, KIE will be normal
➢ TS is more crowded, a deuterium can be accommodated more easily in it so observed KIE will then be inverse
➢ In the planar transition structure the smaller space requirement of D atoms in the deuterated compounds needs a lower
energy of activation, and therefore an inverse kinetic isotope effect is observed.
The steric isotope effect is therefore an ideal way of estimating the steric crowding of the transition state relative to the
ground state.
Drawbacks to using KIE's
➢ difficulty in synthesizing isotopically labelled compounds
➢ Getting accurate kinetic data
Solution: As the reaction progresses, the starting material
becomes enriched in the slower reacting component
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Hydrogen-containing molecule
undergoes conformational change
slower than the deuterium-substituted
molecule

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Kinetic
Isotope
Effect
(rate
of
a
reaction
changes
with
an
isotopic
substitution)
Primary Kinetic Isotope
Effect (1° KIE)
Secondary Kinetic Isotope
Effect (2° KIE)
KH/KD Value
Normal (KH/KD >1)
Sp3 sp2 or sp2 sp
Inverse(KH/KD <1)
Sp sp2 or sp2 sp3
Different isotopic positions
α (atom undergoing
reaction has the associated
isotope)
β (neighboring atom has
the isotope)
PKIE: labelled bond is made or
broken in the RDS, arise mainly
from differences in ZPE
SKIE: labelled bond not made or
broken in the RDS, labelled atoms are
proximal to the reaction center, arise
mainly from changes in hybridization
and hyperconjugation, generally
smaller than PKIE
What is primary & secondary Kinetic Isotope effects? Ifos 2013
Protonation of alkene
Ionization of an alkyl halide
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