KINETIC ISOTOPE EFFECT (KIE)
➢ Kinetic isotope effects are the changes in rate observed when a (1H) hydrogen atom is replaced by a (2H)
deuterium atom in the same reaction. For any reaction, the kinetic isotope effect is defined as the ratio of
rate constant when substrate contains 1H with the rate constant when substrate contains 2H.
How do kinetic isotope effects come about?
Even in its lowest energy state a covalent bond never stops vibrating.
If it did it would violate a fundamental physical principle,
Heisenberg’s uncertainty principle, which states that position and
momentum cannot be known exactly at the same time: a
nonvibrating pair of atoms have precisely zero momentum and
precisely fixed locations. The minimum vibrational energy a bond
can have is called the zero-point energy (E0) given by the expression
E0 = 0.5hν.
In order to break a covalent bond, a certain amount of energy is
required to separate the nuclei from their starting position. This
energy has to raise the vibration state of the bond from the zero-
point energy to the point where it breaks. Because the zero-point energy of a C–H bond is higher than that for a C–D
bond, the C–H bond has a head start in energy terms. The energy required to break a C–H bond is less than that
required to break a C–D bond, so reactions breaking C–H bonds go faster than those breaking C–D bonds, provided
bond breaking is occurring in the rate-determining step.
KIE can be primary or secondary. Primary kinetic isotope effects are those in which a bond to the isotopically
substituted atom is broken in the rate-determining step. Changing H for D can affect the rate of the reaction
only if that H (or D) is involved in the rate-determining step. The theoretical maximum is about 7 for
reactions at room temperature in which a bond to H or D is being broken.
Primary isotope effects can provide two very useful pieces of information about a reaction mechanism-
➢ The existence of a substantial isotope effect, i.e., kH/ kD > 2, is strong evidence that the bond to that
particular hydrogen is being broken in the rate-determining step.
➢ The magnitude of the isotope effect provides a qualitative indication of where the TS lies with regard to
product and reactant. A relatively low primary isotope effect implies that the bond to hydrogen is either
only slightly or nearly completely broken at the TS. That is, the TS must occur quite close to reactant or
to product. An isotope effect near the theoretical maximum is good evidence that the TS involves strong
bonding of the hydrogen to both its new and old bonding partner.
Isotope effects may also be observed when the substituted hydrogen atom is not directly involved in the
reaction. Such effects, known as secondary kinetic isotope effects, are smaller than primary effects and are
usually in the range of kH /kD = 0.7 – 1.5. They may be normal (kH / kD > 1) or inverse (kH / kD < 1), and are
also classified as α or β, etc., depending on the location of the isotopic substitution relative to the reaction site.
Secondary isotope effects result from a tightening or loosening of a C−H bond at the TS. The strength of the
bond may change because of a hybridization change or a change in the extent of hyperconjugation. For
example, if an sp3 carbon is converted to sp2 as reaction occurs, a hydrogen bound to the carbon will
experience decreased resistance to C−H bending. The freeing of the vibration for a C−H bond is greater than
@Rasayan Academy-Jagriti Sharma @Jagriti Sharma-Rasayan Academy @jagriti.rasayan_Academy
, that for a C−D bond because the former is slightly longer, and the vibration has a larger amplitude. This will
result in a normal isotope effect.
An inverse isotope effect will occur if coordination at the reaction centre increases in the TS. The bending
vibration will become more restricted. Secondary isotope effects at the β-position have been especially
thoroughly studied in nucleophilic substitution reactions. When carbocations are involved as intermediates,
substantial β -isotope effects are observed because the hyper conjugative stabilization by the β -hydrogens
weakens the C−H bond. The observed secondary isotope effects are normal, as would be predicted since the
bond is weakened.
Formulas
𝐻
𝐸 − 𝐸𝑎 𝐷
𝑘𝐻 − 𝑎
• =𝑒 𝑘𝑇
𝑘𝐷
1 𝑘
Here, Ea= 0.5 hv or 0.5hcṽ and 𝑣 = √𝜇
2𝜋
𝑘 𝑘
ℎ( 𝐶−𝐻 − 𝐶−𝐷 )
𝜇𝐶−𝐻 𝜇𝐶−𝐷
𝑘𝐻
• =𝑒 4𝜋𝑘𝑇
𝑘𝐷
•
@Rasayan Academy-Jagriti Sharma @Jagriti Sharma-Rasayan Academy @jagriti.rasayan_Academy
➢ Kinetic isotope effects are the changes in rate observed when a (1H) hydrogen atom is replaced by a (2H)
deuterium atom in the same reaction. For any reaction, the kinetic isotope effect is defined as the ratio of
rate constant when substrate contains 1H with the rate constant when substrate contains 2H.
How do kinetic isotope effects come about?
Even in its lowest energy state a covalent bond never stops vibrating.
If it did it would violate a fundamental physical principle,
Heisenberg’s uncertainty principle, which states that position and
momentum cannot be known exactly at the same time: a
nonvibrating pair of atoms have precisely zero momentum and
precisely fixed locations. The minimum vibrational energy a bond
can have is called the zero-point energy (E0) given by the expression
E0 = 0.5hν.
In order to break a covalent bond, a certain amount of energy is
required to separate the nuclei from their starting position. This
energy has to raise the vibration state of the bond from the zero-
point energy to the point where it breaks. Because the zero-point energy of a C–H bond is higher than that for a C–D
bond, the C–H bond has a head start in energy terms. The energy required to break a C–H bond is less than that
required to break a C–D bond, so reactions breaking C–H bonds go faster than those breaking C–D bonds, provided
bond breaking is occurring in the rate-determining step.
KIE can be primary or secondary. Primary kinetic isotope effects are those in which a bond to the isotopically
substituted atom is broken in the rate-determining step. Changing H for D can affect the rate of the reaction
only if that H (or D) is involved in the rate-determining step. The theoretical maximum is about 7 for
reactions at room temperature in which a bond to H or D is being broken.
Primary isotope effects can provide two very useful pieces of information about a reaction mechanism-
➢ The existence of a substantial isotope effect, i.e., kH/ kD > 2, is strong evidence that the bond to that
particular hydrogen is being broken in the rate-determining step.
➢ The magnitude of the isotope effect provides a qualitative indication of where the TS lies with regard to
product and reactant. A relatively low primary isotope effect implies that the bond to hydrogen is either
only slightly or nearly completely broken at the TS. That is, the TS must occur quite close to reactant or
to product. An isotope effect near the theoretical maximum is good evidence that the TS involves strong
bonding of the hydrogen to both its new and old bonding partner.
Isotope effects may also be observed when the substituted hydrogen atom is not directly involved in the
reaction. Such effects, known as secondary kinetic isotope effects, are smaller than primary effects and are
usually in the range of kH /kD = 0.7 – 1.5. They may be normal (kH / kD > 1) or inverse (kH / kD < 1), and are
also classified as α or β, etc., depending on the location of the isotopic substitution relative to the reaction site.
Secondary isotope effects result from a tightening or loosening of a C−H bond at the TS. The strength of the
bond may change because of a hybridization change or a change in the extent of hyperconjugation. For
example, if an sp3 carbon is converted to sp2 as reaction occurs, a hydrogen bound to the carbon will
experience decreased resistance to C−H bending. The freeing of the vibration for a C−H bond is greater than
@Rasayan Academy-Jagriti Sharma @Jagriti Sharma-Rasayan Academy @jagriti.rasayan_Academy
, that for a C−D bond because the former is slightly longer, and the vibration has a larger amplitude. This will
result in a normal isotope effect.
An inverse isotope effect will occur if coordination at the reaction centre increases in the TS. The bending
vibration will become more restricted. Secondary isotope effects at the β-position have been especially
thoroughly studied in nucleophilic substitution reactions. When carbocations are involved as intermediates,
substantial β -isotope effects are observed because the hyper conjugative stabilization by the β -hydrogens
weakens the C−H bond. The observed secondary isotope effects are normal, as would be predicted since the
bond is weakened.
Formulas
𝐻
𝐸 − 𝐸𝑎 𝐷
𝑘𝐻 − 𝑎
• =𝑒 𝑘𝑇
𝑘𝐷
1 𝑘
Here, Ea= 0.5 hv or 0.5hcṽ and 𝑣 = √𝜇
2𝜋
𝑘 𝑘
ℎ( 𝐶−𝐻 − 𝐶−𝐷 )
𝜇𝐶−𝐻 𝜇𝐶−𝐷
𝑘𝐻
• =𝑒 4𝜋𝑘𝑇
𝑘𝐷
•
@Rasayan Academy-Jagriti Sharma @Jagriti Sharma-Rasayan Academy @jagriti.rasayan_Academy
