-1-
PHYSICAL ORGANIC NOTES
Kinetic Isotope Effect
The Kinetic Isotope Effect (KIE) is a useful tool for establishing mechanistic pathways. It
comes about by considering the isotopic substitution of D for H in a C-H bond. This
causes a change in reaction rate which indicates the involvement of the C-H bond in the
mechanism’s rate determining step (terminal KIE).
The effect is brought about by the different vibrational
frequencies of C-H vs. C-D (lower frequency due to increased
reduced mass). Frequency is linked to energy by E= ½ hv, and
hence is linked to rate. Thus when a C-H bond breakage is
involved in the rate determining step (RDS), we see a change
in Activation Energy due to the KIE. Potential Energy is not
dependent on KIE.
Considering Primary Kinetic Isotope Effect (PKIE) – when the C-H bond is key to the
rate determining step. This gives a value of kH/kD of up to approx 7. The maximum
possible value is 8.8 at 298K, which is brought about by complete vibrational loss of a
stretch + 2 bending frequencies. The value does vary with temperature, such that as T
decreases, we would expect the ratio to increase in value.
Some examples of where PKIE would be noticeable are any mechanisms where C-H
bond dissociation is of prime importance. For example, in the oxidation of secondary
alcohols (e.g. by CrO3), the kH/kD = 7.0, indicating that C-H bond cleavage is the RDS.
Conversely, in aromatic nitration, the value drops to 1.0, implying that the RDS is
addition of NO2+, not loosing H. kh/kD > 2 usually indicates the breaking of C-H in the rate
determining step.
The magnitude of the value can indicate either reactant-like or product-like Transition
States (see Hammond Postulate below). A low pKIE implies that the C-H bond is either
nearly completely broken (close to product), or only slightly broken (close to reactant).
There are also secondary KIE’s possible. In this case the C-H bond is either α or β to the
reaction centre. The value of these is usually between 0.7 and 1.5. A value below 1
indicates an inverse KIE, i.e. the rate for C-D is faster than C-H.
The secondary KIE involves tightening or loosening of the C-H bond in the Transition
State, but not breaking. It is then labelled as either α or β depending on which carbon
the bond is formed with (α being the reaction centre).
α-SKIE results from a change in stretching frequency due to loss of CH to dominate all
other terms. The change in rate ratio is usually between 1.15 and 1.2, showing the loss
of magnitude compared to the primary KIE. An example of this effect would be
something like:
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -2-
This is typically seen for sp3Æsp2 rehybridisation (e.g. in SN1 reactions) and the factors
affecting C+ stability are usually apparent. The KIE comes about because of the
decreased resistance to bending experienced on the drop to sp2 hybridisation. This has
more effect on the freedom of the C-H bond vibration than C-D (since it is longer – see
above) so the effect is usually normal (i.e. > 1).
It is possible for inverse KIEs to occur here, e.g. the attack on a carbonyl. This is
because in the Transition State the coordination around Cα has increased, which
restricts bending. Again this affects C-H more than C-D, but this time in a negative way,
so the rate for C-D is greater because it is less destabilised.
β-SKIE is an even more remote effect. It is usually apparent due to conjugated system,
where electrons are transferred away from the C-H bond, which weakens it
(hyperconjugation):
This is thus a normal KIE. An important point in this case is the conformational
dependence which can be useful, e.g. antiperiplanar alignment shows a greater effect
than SPP as the orbitals line up appropriately for a greater overlap (and hence more
hyperconjugation in effect).
Solvent KIEs are also useful. This would be for example, using D2O instead of H2O. This
is often used to determine whether the solvent is in fact a reagent, since this would give
a large PKIE. It may also have secondary effects, e.g. in exchange with acidic centres or
solvent-solute interactions (affects the energy of the Transition State).
A typical example is where protonation is involved in catalysing a reaction. D3O+ is less
stable relative to D2O (due to higher viscosity, and loss of H-bonding) when compared to
H3O+ vs. H2O (i.e. the D3O+ is a stronger acid). This means the rate is increased for D
relative to H. This leads to an inverse effect. However, H+ transfer in the rate determining
step is a primary KIE and so is favoured by H over D (a normal KIE).
Specific
(i.e. not
RDS with
H+) AAC2 mechanism
Solvent KIEs can be useful for spotting General and Specific Acid Catalysis, by using the
normal vs. inverse results:
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
PHYSICAL ORGANIC NOTES
Kinetic Isotope Effect
The Kinetic Isotope Effect (KIE) is a useful tool for establishing mechanistic pathways. It
comes about by considering the isotopic substitution of D for H in a C-H bond. This
causes a change in reaction rate which indicates the involvement of the C-H bond in the
mechanism’s rate determining step (terminal KIE).
The effect is brought about by the different vibrational
frequencies of C-H vs. C-D (lower frequency due to increased
reduced mass). Frequency is linked to energy by E= ½ hv, and
hence is linked to rate. Thus when a C-H bond breakage is
involved in the rate determining step (RDS), we see a change
in Activation Energy due to the KIE. Potential Energy is not
dependent on KIE.
Considering Primary Kinetic Isotope Effect (PKIE) – when the C-H bond is key to the
rate determining step. This gives a value of kH/kD of up to approx 7. The maximum
possible value is 8.8 at 298K, which is brought about by complete vibrational loss of a
stretch + 2 bending frequencies. The value does vary with temperature, such that as T
decreases, we would expect the ratio to increase in value.
Some examples of where PKIE would be noticeable are any mechanisms where C-H
bond dissociation is of prime importance. For example, in the oxidation of secondary
alcohols (e.g. by CrO3), the kH/kD = 7.0, indicating that C-H bond cleavage is the RDS.
Conversely, in aromatic nitration, the value drops to 1.0, implying that the RDS is
addition of NO2+, not loosing H. kh/kD > 2 usually indicates the breaking of C-H in the rate
determining step.
The magnitude of the value can indicate either reactant-like or product-like Transition
States (see Hammond Postulate below). A low pKIE implies that the C-H bond is either
nearly completely broken (close to product), or only slightly broken (close to reactant).
There are also secondary KIE’s possible. In this case the C-H bond is either α or β to the
reaction centre. The value of these is usually between 0.7 and 1.5. A value below 1
indicates an inverse KIE, i.e. the rate for C-D is faster than C-H.
The secondary KIE involves tightening or loosening of the C-H bond in the Transition
State, but not breaking. It is then labelled as either α or β depending on which carbon
the bond is formed with (α being the reaction centre).
α-SKIE results from a change in stretching frequency due to loss of CH to dominate all
other terms. The change in rate ratio is usually between 1.15 and 1.2, showing the loss
of magnitude compared to the primary KIE. An example of this effect would be
something like:
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -2-
This is typically seen for sp3Æsp2 rehybridisation (e.g. in SN1 reactions) and the factors
affecting C+ stability are usually apparent. The KIE comes about because of the
decreased resistance to bending experienced on the drop to sp2 hybridisation. This has
more effect on the freedom of the C-H bond vibration than C-D (since it is longer – see
above) so the effect is usually normal (i.e. > 1).
It is possible for inverse KIEs to occur here, e.g. the attack on a carbonyl. This is
because in the Transition State the coordination around Cα has increased, which
restricts bending. Again this affects C-H more than C-D, but this time in a negative way,
so the rate for C-D is greater because it is less destabilised.
β-SKIE is an even more remote effect. It is usually apparent due to conjugated system,
where electrons are transferred away from the C-H bond, which weakens it
(hyperconjugation):
This is thus a normal KIE. An important point in this case is the conformational
dependence which can be useful, e.g. antiperiplanar alignment shows a greater effect
than SPP as the orbitals line up appropriately for a greater overlap (and hence more
hyperconjugation in effect).
Solvent KIEs are also useful. This would be for example, using D2O instead of H2O. This
is often used to determine whether the solvent is in fact a reagent, since this would give
a large PKIE. It may also have secondary effects, e.g. in exchange with acidic centres or
solvent-solute interactions (affects the energy of the Transition State).
A typical example is where protonation is involved in catalysing a reaction. D3O+ is less
stable relative to D2O (due to higher viscosity, and loss of H-bonding) when compared to
H3O+ vs. H2O (i.e. the D3O+ is a stronger acid). This means the rate is increased for D
relative to H. This leads to an inverse effect. However, H+ transfer in the rate determining
step is a primary KIE and so is favoured by H over D (a normal KIE).
Specific
(i.e. not
RDS with
H+) AAC2 mechanism
Solvent KIEs can be useful for spotting General and Specific Acid Catalysis, by using the
normal vs. inverse results:
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
