You are on page 1of 13

Kinetic isotope eect

For instance, changing a hydrogen atom (H) to its isotope deuterium (D) represents a 100% increase in mass,
whereas in replacing carbon12 with carbon-13, the
mass increases by only 8 percent. The rate of a reacfaster
An example of the kinetic isotope eect. In the reaction of tion involving a CH bond is typically 610 times
reacmethyl bromide with cyanide, the kinetic isotope eect of the cartion is only 4 percent faster than the corresponding 13 C
bon in the methyl group was found to be 1.082 0.008.[1][2]
reaction (even though, in both cases, the isotope is one
The kinetic isotope eect (KIE) is the change in the atomic mass unit heavier).
rate of a chemical reaction when one of the atoms in the Isotopic substitution can modify the rate of reaction in a
reactants is substituted with one of its isotopes. Formally, variety of ways. In many cases, the rate dierence can
it is the ratio of rate constants for the reactions involving be rationalized by noting that the mass of an atom afthe light (kL) and the heavy (kH) isotopically substituted fects the vibrational frequency of the chemical bond that
it forms, even if the electron conguration is nearly identiKIE =

cal. Heavier isotopes will (classically) lead to lower vibration frequencies, or, viewed quantum mechanically, will
have lower zero-point energy. With a lower zero-point
energy, more energy must be supplied to break the bond,
resulting in a higher activation energy for bond cleavage,
which in turn lowers the measured rate (see, for example,
the Arrhenius equation).



The kinetic isotope eect is considered to be one of the

most essential and sensitive tools for the study of reaction
mechanisms, the knowledge of which allows the improve- 2 Classication
ment of the desirable qualities of the corresponding reactions. For example, kinetic isotope eects can be used
to reveal whether a nucleophilic substitution reaction fol- 2.1 Primary kinetic isotope eects
lows a unimolecular (SN1) or bimolecular (SN2) pathA primary kinetic isotope eect may be found when a
bond to the isotopically labeled atom is being formed or
In the reaction of methyl bromide and cyanide (shown in broken. For the previously mentioned nucleophilic subintro section), the observed methyl carbon kinetic isotope stitution reactions, primary kinetic isotope eects have
eect indicates an SN2 mechanism.[1] Depending on the been investigated for both the leaving groups, the nuclepathway, dierent strategies may be used to stabilize the ophiles, and the -carbon at which the substitution octransition state of the rate-determining step of the reac- curs. Interpretation of the leaving group kinetic isotope
tion and improve the reaction rate and selectivity, which eects had been dicult at rst due to signicant contriare important for industrial applications.
butions from temperature independent factors. Kinetic
isotope eects at the -carbon can be used to develop
some understanding into the symmetry of the transition
state in SN2 reactions, although this kinetic isotope effect is less sensitive than what would be ideal, also due to
contribution from non-vibrational factors.[1]

2.2 Secondary kinetic isotope eects

A secondary kinetic isotope eect is observed when no
Isotopic rate changes are most pronounced when the bond to the isotopically substituted atom in the reactant is
relative mass change is greatest, since the eect is re- broken or formed in the rate-determining step of a reaclated to vibrational frequencies of the aected bonds. tion. By its denition, secondary kinetic isotope eects


which resides the transition state.[5][6] The kinetic isotope

eect arises largely from the changes which the isotopic
perturbation produces along the minimum energy pathway on this reaction energy surface, which may only be
accounted for with quantum mechanical treatments of the
For the aforementioned nucleophilic substitution reac- system. Depending on the mass and energy of the retions, secondary hydrogen kinetic isotope eects at the acting species, quantum mechanical tunneling may also
-carbon provide a direct means to distinguish between make a[5]large contribution to an observed kinetic isotope
SN1 and SN2 reactions. It has been found that SN1 reactions typically lead to large secondary kinetic isotope ef- Of the various theoretical treatments of kinetic isotope
fects, approaching to their theoretical maximum at about eects, Bigeleisens seems to be the most popular. His
1.22, while SN2 reactions typically yield kinetic isotope basic general equation for the hydrogen/deuterium kieects that are very close to or less than unity. Kinetic netic isotope eects is given below, neglecting tunnelling
isotope eects that are greater than 1 are referred to as contributions which can be introduced as a separate facnormal kinetic isotope eects, while kinetic isotope ef- tor. The subscripts H and D refer to hydrogen and deufects that are less than one are referred to as inverse ki- terium substituted substrates, respectively.[4]
netic isotope eects. In general, smaller force constants
in the transition state are expected to yield a normal ki(
)3/2 (
netic isotope eect, and larger force constants in the tran

sH sD
sition state are expected to yield an inverse kinetic isotope


sD sH
eect when stretching vibrational contributions dominate kD


the kinetic isotope eect.


i=1 1e iH 1/2( i=1 (uiH uiD ) i=1 (uiH uiD ))
3N 6
tend to be much smaller than primary kinetic isotope effects; however, since kinetic isotope eects can be calculated and measured to very high precision, secondary
kinetic isotope eects are still very useful for elucidating
reaction mechanisms.


The magnitudes of such secondary isotope eects at the

-carbon are largely determined by the C-H(D) vibrations. For an SN1 reaction, since the carbon is converted
into an sp2 hybridized carbenium ion during the transition
state for the rate-redermining step with an increase in CH(D) bond order, an inverse kinetic isotope eect would
be expected if only the stretching vibrations were important. The observed large normal kinetic isotope eects
are found to be caused by signicant out-of-plane bending vibrational contributions when going from the reactants to the transition state of carbenium formation. For
SN2 reactions, bending vibrations still play an important
role for the kinetic isotope eect, but stretching vibrational contributions are of more comparable magnitude,
and the resulting kinetic isotope eect may be normal or
inverse depending on the specic contributions of the respective vibrations.[1][3][4]


The theoretical treatment of isotope eects relies heavily

on transition state theory, which assumes a single potential energy surface for the reaction, and a barrier between
the reactants and the products on this surface, on top of


The S factors are the symmetry numbers for the reactants and transition states. The M factors are the molecular masses of the corresponding species, and the I factors are the moments of inertia about the three principal axes. The u factors are determined from the corresponding vibrational frequencies, , through u = h /kT.
N and N are the number of atoms in the reactants and
the transition states, respectively.[4] The complex expression given above can be represented as the product of four
separate factors, as shown below, from which some possible simplications for hydrogen/deuterium kinetic isotope eects can be more easily seen.[4]

The S factor is the ratio of the symmetry numbers for the
various species. These symmetry numbers do not lead
to isotopic fractionation, so the S factor can be set to be
1.000. The MMI factor refers to the ratio of the molecular masses and the moments of inertia. Since hydrogen
and deuterium tend to be much lighter compared to most
reactants and transition states, the MMI factor is usually
also approximated as unity. The EXC factor corrects for
the kinetic isotope eect caused by the reactions of vibrationally excited molecules. The contribution of this factor
is also negligible when the reactions are carried out at or
near room temperature. Hence, for hydrogen/deuterium
kinetic isotope eects, the observed values are typically
governed by the zero-point energy contributions, which
can be represented as follows:[4]







kH 1/2{





(uiH uiD )



(uiH uiD )}

ui }

If the zero-point energy dierence between the stretching

vibrations of a carbon-hydrogen and carbon-deuterium
bond is allowed to disappear in the transition state, the
expression given above predicts a maximum for kH/kD
as 6.9. If the weakening of two bending vibrations are
also taken into account, kH/kD values as large as 15-20
can be predicted. Bending frequencies are very unlikely
to vanish in the transition state, however, and quite few
kH/kD values exceed 7-8 near room temperature. Furthermore, it is often found that tunneling is a major factor
when they do exceed such values. Hence, more often than
not, weakening of bending frequencies is not an important cause of large kinetic isotope eects.
For isotope eects involving elements other than hydrogen, most of these simplications are not valid, and may
depend largely on some of the neglected factors. In many
cases and especially for hydrogen-transfer reactions, contributions to kinetic isotope eects from tunneling are
signicant (see below).

ZPE energy dierences and corresponding dierences in the activation energies for the breaking of analogous C-H and C-D

above using some simplications:[5][8]


ln( kkH

ln( kkH
( )


mH /mT
1 1/3

= 1.44
1 mH /mD
1 1/2



In deriving these expressions, symmetry terms are omitted. The subscript s refers to these semiclassical kinetic isotope eects, which disregard quantum tunneling.
Tunneling contributions must be treated separately as a
As mentioned, especially for hydrogen/deuterium substi- correction factor.
tution, most kinetic isotope eects arise from the dierence in zero-point energy (ZPE) between the reactants
and the transition state of the isotopologues in question, 3.1 Tunneling
and this dierence can be understood qualitatively with
the following description: within the BornOppenheimer In some cases, an additional rate enhancement is seen for
approximation, the potential energy curve is the same for the lighter isotope, possibly due to quantum mechanical
both isotopic species. However, a quantum-mechanical tunnelling. This is typically only observed for reactions
treatment of the energy introduces discrete vibrational involving bonds to hydrogen atoms. Tunneling occurs
levels onto this curve, and the lowest possible energy state when a molecule penetrates through a potential energy
of a molecule corresponds to the lowest vibrational en- barrier rather than over it.[9][10] Although not allowed by
ergy level, which is slightly higher in energy than the min- the laws of classical mechanics, particles can pass through
imum of the potential energy curve. This dierence, classically forbidden regions of space in quantum mereferred to as the zero-point energy, is a manifestation chanics based on waveparticle duality.[11]
of the Heisenberg uncertainty principle that necessitates
an uncertainty in the C-H or C-D bond length. Since
the heavier (in this case the deuterated) species behaves
more classically, its vibrational energy levels are closer
to the classical potential energy curve, and it has a lower
zero-point energy. The zero-point energy dierences between the two isotopic species, at least in most cases, diminish in the transition state, since the bond force constant decreases during bond breaking. Hence, the lower
zero-point energy of the deuterated species translates into
a larger activation energy for its reaction, as shown in
the following gure,leading to a normal kinetic isotope The potential energy well of a tunneling reaction. The dash-red
arrow shows the classical activated process, while the red arrow
shows the tunneling path.

The following simple expressions relating deuterium and

tritium kinetic isotope eects, which are also known as Analysis of tunneling can be made using Bells modicathe Swain equation (or the Swain-Schaad-Stivers equa- tion of the Arrhenius equation, which includes the additions), can be derived from the general expression given tion of a tunneling factor, Q:


3.2 Transient kinetic isotope eect

Main article: Transient kinetic isotope fractionation

k = QAeE/RT

where A is the Arrhenius parameter, E is the barrier Isotopic eect expressed with the equations given above
only refer to reactions that can be described with rstheight and
order kinetics. In all instances in which this is not possible, transient kinetic isotope eects should be taken into
account using the GEBIK and GEBIF equations.[25]

(e e )

where =


and =

2a 2 (2mE)1/2

Examination of the term shows exponential dependency

on the mass of the particle. As a result, tunneling is much
more likely for a lighter particle such as hydrogen. Simply doubling the mass of a tunneling proton by replacing
it with its deuterium isotope drastically reduces the rate
of such reactions. As a result, very large kinetic isotope
eects are observed that can not be accounted for by differences in zero point energies.

4 Kinetic isotope eect experiments

Simmons and Hartwig refer to the following three cases

as the main types of kinetic isotope eect experiments
involving C-H bond functionalization:[26]
A) KIE determined from absolute rates of two parallel
reactions In this experiment, the rate constants for the

normal substrate and its isotopically labeled analogue are

determined independently, and the KIE is obtained as a
ratio of the two. The accuracy of the measured KIE is
severely limited by the accuracy with which each of these
rate constants can be measured. Furthermore, reproducing the exact conditions in the two parallel reactions can
be very challenging. Nevertheless, this measurement of
the kinetic isotope eect is the only one that may tell that
C-H bond cleavage occurs in the rate-determining step
without a doubt.
B) KIE determined from an intermolecular competition
In this type of experiment, the same substrates that are

Donor-Acceptor Model of a proton transfer.[12]

In addition, the term depends linearly with barrier

width, 2a. As with mass, tunneling is greatest for small
barrier widths. Optimal tunneling distances of protons
between donor and acceptor atom is 0.4 .[13]

used in Experiment A are employed, but they are allowed

in to react in the same container, instead of two separate
containers. The kinetic isotope eect from this experiment is determined by the relative amount of products


Evaluation of Rate Constant Ratios from Intermolecular Competition Reactions

formed from C-H versus C-D functionalization (or it can

be inferred from the relative amounts of unreacted starting materials). It is necessary to quench the reaction before it goes to completion to observe the kinetic isotope
eect (see the Evaluation section below). This experiment type ensures that both C-H and C-D bond functionalizations occur under exactly the same conditions, and
the ratio of products from C-H and C-D bond functionalizations can be measured with much greater precision
than the rate constants in Experiment A. Moreover, only
a single measurement of product concentrations from a
single sample is required. However, an observed kinetic isotope eect from this experiment is more dicult to interpret, since it may either mean that C-H bond
cleavage occurs during the rate-determining step or at
a product-determining step ensuing the rate-determining
step. The absence of a kinetic isotope eect, at least according to Simmons and Hartwig, is nonetheless indicative of the C-H bond cleavage not occurring during the
rate-determining step.

energy prole, in which the C-H or C-D bond cleavage

is irreversible but occurs after the rate-determining step
(RDS), no signicant kinetic isotope eect will be observed with Experiment A, since the overall rate is not
aected by the isotopic substitution. Nevertheless, the irreversible C-H bond cleavage step will give a primary kinetic isotope eect with the other two experiments, since
the second step would still aect the product distribution.
Therefore, with Experiments B and C, it is possible to observe the kinetic isotope eect even if C-H or C-D bond
cleavage occurs not in the rate-determining step, but in
the product-determining step.

C) KIE determined from an intramolecular competition

This type of experiment is analogous to Experiment B,

Reaction energy prole for when the C-H bond cleavage occurs
at a product-determining step after the RDS

except this time there is an intramolecular competition for

the C-H or C-D bond functionalization. In most cases, the
4.1 Evaluation of Rate Constant Ratios
substrate possesses a directing group (DG) between the
from Intermolecular Competition ReC-H and C-D bonds. Calculation of the kinetic isotope
eect from this experiment and its interpretation follow
the same considerations as that of Experiment B.
In competition reactions, the kinetic isotope eect is calApart from the dierences in feasibility and precision be- culated from isotopic product or remaining reactant ratween the dierent kinds of experiments, they may also tios after the reaction, but these ratios depend strongly
dier in terms of the information they may provide. For on the extent of completion of the reaction. Most comexample, if a reaction follows the following energy pro- monly, the isotopic substrate will consist of molecules lale, all three experiments will yield a signicant primary beled in a specic position and their unlabeled, ordinary
kinetic isotope eect:
counterparts.[5] It is also possible in case of 13 C kinetic
isotope eects, as well as similar cases, to simply rely on
the natural abundance of the isotopic carbon for the kinetic isotope eect experiments, eliminating the need for
isotopic labeling.[28] The two isotopic substrates will react through the same mechanism, but at dierent rates.
The ratio between the amounts of the two species in the
reactants and the products will thus change gradually over
the course of the reaction, and this gradual change can be
treated in the following manner:[5] Assume that two isotopic molecules, A1 and A2 , undergo irreversible competition reactions in the following manner:
The kinetic isotope eect for this scenario is found to be:
Reaction energy prole for when C-H cleavage occurs at the RDS

ln(1 F1 )
On the other hand, if a reaction follows the following KIE = k2 = ln(1 F2 )


isotope eects, and much of the previously covered theory refers to primary kinetic isotope eects. When there
is adequate evidence that transfer of the labeled hydrogen occurs in the rate-determining step of a reaction, if a
fairly large kinetic isotope eect is observed, e.g. kH/kD
of at least 5-6 or kH/kT about 10-13 at room temperature, it is quite likely that the hydrogen transfer is linear and that the hydrogen is fairly symmetrically located
in the transition state. It is usually not possible to make
comments about tunneling contributions to the observed
isotope eect unless the eect is very large. If the primary kinetic isotope eect is not as large, it is generally
Where F1 and F2 refer to the fraction of conversions for considered to be indicative of a signicant contribution
the isotopic species A1 and A2 , respectively.
from heavy-atom motion to the reaction coordinate, alIsotopic enrichment of the starting material can be cal- though it may also mean that hydrogen transfer follows a
culated from the dependence of R/R0 on F1 for various nonlinear pathway.[5]
kinetic isotope eects, yielding the following gure. Because of the exponential dependence, even very low kinetic isotope eects lead to large changes in isotopic com- 5.2 Secondary hydrogen isotope eects
position of the starting material at high conversions.
The secondary hydrogen isotope eects or secondary kinetic isotope eect (SKIE) arises in cases where the isotopic substitution is remote from the bond being broken.
The remote atom, nonetheless, inuences the internal vibrations of the system that via changes in the zero point
energy (ZPE) aect the rates of chemical reactions.[31]
Such eects are expressed as ratios of rate for the light
isotope to that of the heavy isotope and can be normal
(ratio is greater than or equal to 1) or inverse (ratio is
less than 1) eects.[32] SKIE are dened as , (etc.) secondary isotope eects where such prexes refer to the position of the isotopic substitution relative to the reaction
center (see alpha and beta carbon).[33] The prex refers
to the isotope associated with the reaction center while
the prex refers to the isotope associated with an atom
neighboring the reaction center and so on.
The isotopic enrichment of the relative amount of species 2 with
respect to species 1 in the starting material as a function of conversion of species 1. The value of the kinetic isotope eect
(k1 /k2 ) is indicated at each curve.

In physical organic chemistry, SKIE is discussed in terms

of electronic eects such as induction, bond hybridization, or hyperconjugation.[34] These properties are determined by electron distribution, and depend upon vibrationally averaged bond length and angles that are not
When the products are followed, the kinetic isotope eect
greatly aected by isotopic substitution. Thus, the use
can be calculated using the products ratio RP along with
of the term electronic isotope eect while legitimate is
R0 as follows:
discouraged from use as it can be misinterpreted to suggest that the isotope eect is electronic in nature rather
than vibrational.[33]
ln(1 F1 )
SKIEs can be explained in terms of changes in orbital
ln[1 (F1 RP /R0 )]
hybridization. When the hybridization of a carbon atom
changes from sp3 to sp2 , a number of vibrational modes
(stretches, in-plane and out-of-plane bending) are af5 Case studies
fected. The in-plane and out-of-plane bending in an sp3
hybridized carbon are similar in frequency due to the
5.1 Primary hydrogen isotope eects
symmetry of an sp3 hybridized carbon. In an sp2 hybridized carbon the in-plane bend is much stier than the
Primary hydrogen kinetic isotope eects refer to cases out-of-plane bending resulting in a large dierence in the
in which a bond to the isotopically labeled hydrogen is frequency, the ZPE and thus the SKIE (which exists when
formed or broken in the rate-determining step of the re- there is a dierence in the ZPE of the reactant and tranaction. These are the most commonly measured kinetic sition state).[9] The theoretical maximum change caused


Secondary hydrogen isotope eects

by the bending frequency dierence has been calculated them to choose which pathway was most likely based on
as 1.4.[9]
the observed isotope eect.[36]
When carbon undergoes a reaction that changes its hybridization from sp3 to sp2 , the out of plane bending force
constant at the transition state is weaker as it is developing sp2 character and a normal SKIE is observed with
typical values of 1.1 to 1.2.[9] Conversely, when carbons
hybridization changes from sp2 to sp3 , the out of plane
bending force constants at the transition state increase and
an inverse SKIE is observed with typical values of 0.8 to

Secondary hydrogen isotope eects from the methylene

hydrogens were also used to show that Cope rearrangement in 1,5-hexadiene follow a concerted bond rearrangement pathway, and not one of the alternatively proposed
allyl radical or 1,4-diyl pathways, all of which are presented in the following scheme.[37]

More generally the SKIE for reversible reactions can be

normal one way and inverse the other if bonding in
the transition state is midway in stiness between substrate and product, or they can be normal both ways if
bonding is weaker in the transition state, or inverse both
ways if bonding is stronger in the transition state than in
either reactant.[32]
An example of an inverse secondary kinetic isotope
eect can be seen in the work of Fitzpatrick and Kurtz
who used such an eect to distinguish between two proposed pathways for the reaction of d-amino acid oxidase with nitroalkane anions.[35] Path A involved a nucleophilic attack on the coenzyme FAD, while path B involves a free-radical intermediate. As path A results in
the intermediate carbon changing hybridization from sp2
to sp3 an inverse a SKIE is expected. If path B occurs
then no SKIE should be observed as the free radical intermediate does not change hybridization. An SKIE of 0.84
was observed and Path A veried as shown in the scheme



Path A

X = H or D



5.2.1 HSteric isotope eects


Alternative mechanisms for the Cope rearrangement of

1,5-hexadiene: (from top to bottom), allyl radical, synchronous concerted, and 1,4-dyil pathways. The middle
pathway is found to be the predominant one.[37]

The steric isotope eect is a SKIE that does not involve

bond breaking or formation. This eect is attributed to
the dierent vibrational amplitudes of isotopologues.[38]
An example of such an eect is the racemization of
9,10-dihydro-4,5-dimethylphenanthrene.[39] The smaller
amplitude of vibration for deuterium as compared to
hydrogen in CH (carbonhydrogen), CD (carbon
deuterium) bonds results in a smaller van der Waals raO
dius or eective size in addition to a dierence in the
ZPE between the two. When there is a greater eective
Probing radical vs. nucleophilic mechanisms bulk of molecules containing one over the other this may
be manifested by a steric eect on the rate constant. For
Another example of a SKIE is the oxidation of benzyl althe example above deuterium racemizes faster than the
cohols by dimethyldioxirane where three transition states
hydrogen isotopologue resulting in a steric isotope eect.
for dierent mechanisms were proposed. Again, by considering how and if the hydrogen atoms were involved Another example of the steric isotope eect is in the
in each, researchers predicted whether or not they would deslipping reaction of rotaxanes. The deuterium isotope,
expect an eect of isotopic substitution of them. Then, due to its smaller eective size, allows easier passage of
analysis of the experimental data for the reaction allowed the stoppers through the macrocycle, resulting in faster
rates of deslipping for the deuterated rotaxanes.[40]
Path B

5.4.1 Compensating for variations in


C natural

Often, the largest source of error in a study that depends

on the natural abundance of carbon is the slight variation
in natural 13 C abundance itself. Such variations arise because the starting materials used in the reaction are themselves products of some other reactions that have kinetic
isotope eects and corresponding isotopic enrichments
in the products. To compensate for this error when NMR
spectroscopy is used to determine the kinetic isotope effect, the following guidelines have been proposed:[29][30]
Choose a carbon that is remote from the reaction
center that will serve as a reference and assume it
does not have a kinetic isotope eect in the reaction.
In the starting material that has not undergone any
reaction, determine the ratios of the other carbon
NMR peak integrals to that of the reference carbon.

Inverse kinetic isotope eects

Obtain the same ratios for the carbons in a sample

of the starting material after it has undergone some

Reactions are known where the deuterated species

reacts faster than the undeuterated analogue, and
these cases are said to exhibit inverse kinetic iso The ratios of the latter ratios to the former ratios
tope eects (IKIE). IKIEs are often observed in the
yields R/R0 .
reductive elimination of alkyl metal hydrides, e.g.
(Me2 NCH2 CH2 NMe2 )PtMe(H). In such cases the C-D If these as well as some other precautions listed by
bond in the transition state, an agostic species, is highly Jankowski are followed, kinetic isotope eects with prestabilized relative to the CH bond.
cisions of three decimal places can be achieved.[29][30]


Solvent hydrogen kinetic isotope eects

5.5 Isotope eects with elements heavier

than carbon

For the solvent isotope eects to be measurable, a nite fraction of the solvent must have a dierent isotopic
composition than the rest. Therefore, large amounts of
the less common isotopic species must be available, limiting observable solvent isotope eects to isotopic substitutions involving hydrogen. Detectable kinetic isotope
eects occur only when solutes exchange hydrogen with
the solvent or when there is a specic solute-solvent interaction near the reaction site. Both such phenomena are
common for protic solvents, in which the hydrogen is exchangeable, and they may form dipole-dipole interactions
or hydrogen bonds with polar molecules.[5]

Interpretation of carbon isotope eects are usually complicated by simultaneously forming and breaking bonds
to carbon. Even reactions that involve only bond cleavage
from the carbon, such as SN1 reactions, involve strengthening of the remaining bonds to carbon. In many such
reactions, leaving group isotope eects tend to be easier to interpret. For example, substitution and elimination reactions in which chlorine act as a leaving group are
convenient to interpret, especially since chlorine acts as
a monoatomic species with no internal bonding to complicate the reaction coordinate, and it has two stable isotopes, 35 Cl and 37 Cl, both with high abundance. The major challenge to the interpretation of such isotope aects
is the solvation of the leaving group.[5]


Owing to experimental uncertainties, measurement of

isotope eect may entail signicant uncertainty. Often isotope eects are determined through complementary studies on a series of isotopomers. Accordingly,
it is quite useful to combine hydrogen isotope eects
with heavy-atom isotope eects. For instance, determining nitrogen isotope eect along with hydrogen
isotope eect was used to show that the reaction of
2-phenylethyltrimethylammonium ion with ethoxide in

Carbon-13 isotope eects

Most organic reactions involve the breaking and making of bonds to a carbon; thus, it is reasonable to expect detectable carbon isotope eects. When 13 C is used
as the label, the change in mass of the isotope is only
~8%, though, which limits the observable kinetic isotope
eects to much smaller values than the ones observable
with hydrogen isotope eects.


Other Examples

ethanol at 40o C follows an E2 mechanism, as opposed

to alternative non-concerted mechanisms. This conclusion was reached upon showing that this reaction yields a
nitrogen isotope eect, k14 /k15 , of 1.01330.0002 along
with a hydrogen kinetic isotope eect of 3.2 at the leaving

these exotic species, the reaction of H with 1 H2 was investigated. Rate constants from reacting the lightest and
the heaviest hydrogen analogues with 1 H2 were then used
to calculate the k./k. kinetic isotope eect, in which
there is a 36.4 fold dierence in isotopic masses. For
this reaction, isotopic substitution happens to produce an
report a
Similarly, combining nitrogen and hydrogen isotope ef- inverse kinetic isotope eect, and the authors
is the
fects was used to show that syn eliminations of simple amsmallest kinetic isotope eect ever reported.[41]
monium salts also follow a concerted mechanism, which
was a question of debate before. In the following two The kinetic isotope eect leads to a specic distribution
reactions of 2-phenylcyclopentyltrimethylammonium ion of deuterium isotopes in natural products, depending on
with ethoxide, both of which yield 1-phenylcyclopentene, the route they were synthesized in nature. By NMR specboth isomers exhibited a nitrogen isotope eect k14 /k15 troscopy, it is therefore easy to detect whether the alcoat 60o C. Although the reaction of the trans isomer, which hol in wine was fermented from glucose, or from illicitly
follows syn elimination, has a smaller nitrogen kinetic iso- added saccharose.
tope eect (1.0064) compared to the cis isomer which Another reaction mechanisms that was elucidated usundergoes anti elimination (1.0108), both results are ing the kinetic isotope eect is the halogenation of
large enough to be indicative of weakening of the C-N toluene:[42]
bond in the transition state that would occur in a concerted process.


Other Examples

Since kinetic isotope eects arise from dierences in isotopic masses, the largest observable kinetic isotope effects are associated with isotopic substitutions of hydrogen with deuterium (100% increase in mass) or tritium
(300% increase in mass). Kinetic isotope eects from
isotopic mass ratios can be as large as 36.4 using muons.
They have produced the lightest hydrogen atom, 0.11 H
(0.113 amu), in which an electron orbits around a positive muon (+ ) nucleus that has a mass of 206 electrons.
They have also prepared the heaviest hydrogen atom analogue by replacing one electron in helium with a negative
muon ( ) to form He with an atomic mass of 4.116
amu. Since the negative muon is much heavier than an
electron, it orbits much closer to the nucleus, eectively
shielding one proton, making He to behave as 4.1 H. With

In this particular intramolecular KIE study, a benzylic

hydrogen undergoes radical substitution by bromine using N-bromosuccinimide as the brominating agent. It was
found that PhCH3 brominates 4.86x faster than PhCD3 .
A large KIE of 5.56 is associated with the reaction of
ketones with bromine and sodium hydroxide.[43]



In this reaction the rate-limiting step is formation of the [11] Silbey, R. J.; Alberty, R. A.; Bawendi, M. G. (2005).
Physical Chemistry. John Wiley & Sons. pp. 326338.
enolate by deprotonation of the ketone. In this study the
ISBN 0-471-21504-X.
KIE is calculated from the reaction rate constants for regular 2,4-dimethyl-3-pentanone and its deuterated isomer
[12] Borgis, D.; Hynes, J. T. (1993). Dynamical theby optical density measurements.
ory of proton tunneling transfer rates in solution: Gen-

See also
Chemical kinetics
Reaction mechanism
Transient kinetic isotope fractionation
Magnetic isotope eect
Crossover experiment


[1] Westaway, Kenneth C. (2006). Using kinetic isotope effects to determine the structure of the transition states of
SN2 reactions. Advances in Physical Organic Chemistry
41: 217273. doi:10.1016/S0065-3160(06)41004-2.
[2] Lynn, K. R.; Yankwich, Peter E. (5 August 1961). Journal of the American Chemical Society 83 (15): 3220
3223. doi:10.1021/ja01476a012. Missing or empty |title= (help)
[3] Poirier, Raymond A.; Wang, Youliang; Westaway, Kenneth C. (March 1994). A Theoretical Study of the
Relationship between Secondary .alpha.-Deuterium Kinetic Isotope Eects and the Structure of SN2 Transition
States. Journal of the American Chemical Society 116 (6):
25262533. doi:10.1021/ja00085a037.
[4] Buncel, E.; Lee, C.C. Isotopes in Organic Chemistry. Elsevier: Amsterdam, 1977, Vol. 5.
[5] Melander, L.; Saunders, W.H., Jr. Reaction Rates of Isotopic Molecules. Wiley: New York, 1980.
[6] Bigeleisen, J.; Wolfsberg, M. Adv. Chem. Phys. 1958, 1,
[7] Carpenter, B.K. Nature Chem. 2010, 2, 80.
[8] Swain, C. Gardner; Stivers, Edward C.; Reuwer, Joseph
F.; Schaad, Lawrence J. (1 November 1958). Use of
Hydrogen Isotope Eects to Identify the Attacking Nucleophile in the Enolization of Ketones Catalyzed by Acetic
Acid. Journal of the American Chemical Society 80 (21):
58855893. doi:10.1021/ja01554a077.
[9] Anslyn, E. V.; Dougherty, D. A. (2006). Modern Physical
Organic Chemistry. University Science Books. pp. 435
437. ISBN 1-891389-31-9.
[10] Razauy, M. (2003). Quantum Theory of Tunneling.
World Scientic. ISBN 981-238-019-1.

eral formulation. Chemical Physics 170 (3): 315

346. Bibcode:1993CP....170..315B. doi:10.1016/03010104(93)85117-Q.
[13] Krishtalik, L. I. (2000). The mechanism of the proton transfer: An outline. Biochimica et Biophysica Acta
1458: 627. doi:10.1016/S0005-2728(00)00057-8.
[14] Zuev,
P. S. (2003).
Carbon tunneling
from a single quantum state.
Science 299
doi:10.1126/science.1079294. PMID 12574623.
[15] Atkins, P.; de Paula, J. (2006). Atkins Physical Chemistry.
Oxford University Press. pp. 286288, 816818. ISBN
[16] Fujisaki, N.; Ruf, A.; Gaeumann, T. (1987). Tunnel effects in hydrogen-atom-transfer reactions as studied by the
temperature dependence of the hydrogen deuterium kinetic isotope eects. Journal of Physical Chemistry 91
(6): 1602. doi:10.1021/j100290a062.
[17] Lewis, E. S.; Funderburk, L. (1967). Rates and isotope
eects in the proton transfers from 2-nitropropane to pyridine bases. Journal of the American Chemical Society 89
(10): 23222327. doi:10.1021/ja00986a013.
[18] Dewar, M. J. S.; Healy, E. F.; Ruiz, J. M. (1988).
Mechanism of the 1,5-sigmatropic hydrogen shift in 1,3pentadiene. Journal of the American Chemical Society
110 (8): 26662667. doi:10.1021/ja00216a060.
[19] von Eggers Doering, W.; Zhao, X. (2006). Eect
on Kinetics by Deuterium in the 1,5-Hydrogen Shift
of a Cisoid-Locked 1,3(Z)-Pentadiene, 2-Methyl-10methylenebicyclo[4.4.0]dec-1-ene: Evidence for Tunneling?". Journal of the American Chemical Society 128 (28):
90809085. doi:10.1021/ja057377v. PMID 16834382.
[20] In this study the KIE is measured by sensitive proton
NMR. The extrapolated KIE at 25 C is 16.6 but the margin of error is high
[21] Kohen, A.; Klinman, J. P. (1999). Hydrogen tunneling in biology. Chemistry & Biology 6 (7): R191198.
doi:10.1016/S1074-5521(99)80058-1. PMID 10381408.
[22] Wilde, T. C.; Blotny, G.; Pollack, R. M. (2008). Experimental evidence for enzyme-enhanced coupled motion/quantum mechanical hydrogen tunneling by ketosteroid isomerase. Journal of the American Chemical
Society 130 (20): 65776585. doi:10.1021/ja0732330.
PMID 18426205.
[23] Truhlar, D. G.; Gao, J.; Alhambra, C.; Garcia-Viloca, M.;
Corchado, J.; Snchez, M.; Vill, J. (2002). The Incorporation of Quantum Eects in Enzyme Kinetics Modeling. Accounts of Chemical Research 35 (6): 341349.


[24] Kohen, A.; Klinman, J. P. (1998). Enzyme Catalysis:

Beyond Classical Paradigms. Accounts of Chemical Research 31 (7): 397404. doi:10.1021/ar9701225.
[25] Maggi, F.; Riley, W. J. (2010). Mathematical treatment
of isotopologue and isotopomer speciation and fractionation in biochemical kinetics. Geochimica et Cosmochimica Acta 74 (6): 1823. Bibcode:2010GeCoA..74.1823M.
[26] Simmons, E.M.; Hartwig, J.F. Angew. Chem. Int. Ed.
2012, 51, 3066-3072.
[27] Buncel, E.; Lee, C.C. Isotopes in Organic Chemistry. Elsevier: Amsterdam, 1977, Vol. 3.
[28] Singleton, Daniel A.; Thomas, Allen A. (September
1995). High-Precision Simultaneous Determination of
Multiple Small Kinetic Isotope Eects at Natural Abundance. Journal of the American Chemical Society 117
(36): 93579358. doi:10.1021/ja00141a030.
[29] Jankowski, S. Ann. Rep. NMR Spec. 2009, 68, 149.
[30] Kwan, Eugene. CHEM 106 Course Notes - Lecture 14 Computational Chemistry. Retrieved 2 November 2013.
[31] Hennig, C.; Oswald, R. B.; Schmatz, S. (2006).
Secondary Kinetic Isotope Eect in Nucleophilic
A Quantum-Mechanical Approach.
Journal of Physical Chemistry A 110 (9): 30713079.
[32] Cleland, W. W. (2003). The Use of Isotope Effects to Determine Enzyme Mechanisms. Journal
of Biological Chemistry 278 (52): 5197551984.
doi:10.1074/jbc.X300005200. PMID 14583616.
[33] IUPAC, Compendium of Chemical Terminology, 2nd ed.
(the Gold Book) (1997). Online corrected version:
(2006) "Secondary isotope eect".
[34] Denition of isotope eect, secondary. Chemistry Dictionary.
[35] Kurtz, K. A.; Fitzpatrick, P. F. (1997). pH and Secondary Kinetic Isotope Eects on the Reaction of DAmino Acid Oxidase with Nitroalkane Anions: Evidence
for Direct Attack on the Flavin by Carbanions. Journal
of the American Chemical Society 119 (5): 11551156.
[36] Angelis, Y. S.; Hatzakis, N. S.; Smonou, I.; Orfanopoulos, M. (2006). Oxidation of benzyl alcohols by dimethyldioxirane. The question of concerted
versus stepwise mechanisms probed by kinetic isotope
eects. Tetrahedron Letters 42 (22): 37533756.
[37] Houk, K.N.; Gustafson, S.M.; Black, K.A. JACS 1992,
114, 8565.
[38] IUPAC, Compendium of Chemical Terminology, 2nd ed.
(the Gold Book) (1997). Online corrected version:
(2006) "steric isotope eect".

[39] Mislow, K.; Graeve, R.; Gordon, A. J.; Wahl, G. H.

(1963). A Note on Steric Isotope Eects. Conformational Kinetic Isotope Eects in The Racemization
of 9,10-Dihydro-4,5-Dimethylphenanthrene. Journal
of the American Chemical Society 85 (8): 11991200.
[40] Felder, T.; Schalley, C. A. (2003). Secondary Isotope Eects on the Deslipping Reaction of Rotaxanes: High-Precision Measurement of Steric Size.
Angewandte Chemie International Edition 42 (20): 2258
2260. doi:10.1002/anie.200350903. PMID 12772156.
[41] Fleming, D. G.; Arseneau, D. J.; Sukhorukov, O.; Brewer,
J. H.; Mielke, S. L.; Schatz, G. C.; Garrett, B. C.; Peterson, K. A.; Truhlar, D. G. (27 January 2011). Kinetic Isotope Eects for the Reactions of Muonic Helium
and Muonium with H2. Science 331 (6016): 448450.
doi:10.1126/science.1199421. PMID 21273484.
[42] Wiberg, K. B.; Slaugh, L. H. (1958). The Deuterium Isotope Eect in the Side Chain Halogenation of Toluene.
Journal of the American Chemical Society 80 (12): 3033
3039. doi:10.1021/ja01545a034.
[43] Lynch, R. A.; Vincenti, S. P.; Lin, Y. T.; Smucker, L. D.;
Subba Rao, S. C. (1972). Anomalous kinetic hydrogen
isotope eects on the rat of ionization of some dialkyl
substituted ketones. Journal of the American Chemical
Society 94 (24): 83518356. doi:10.1021/ja00779a012.



Text and image sources, contributors, and licenses



Kinetic isotope eect Source: Contributors: Stevenj, Ehn,

Stone, Bearcat, Sndrsn, Centrx, Nunh-huh, Herbee, Cantus, Christopherlin, DragonySixtyseven, Pt, HenkvD, Gene Nygaard, Japanese
Searobin, Woohookitty, Chochopk, V8rik, Rjwilmsi, Physchim62, Bgwhite, YurikBot, Tony1, Itub, Jclerman, Slashme, Bluebot, Colonies
Chris, Thezookeeper, Smokefoot, DMacks, Saippuakauppias, Pinktulip, Knights who say ni, Dl2000, CmdrObot, Rieman 82, Dynaow, Epbr123, Headbomb, Pjvpjv, Dirac66, R'n'B, CommonsDelinker, Leyo, Pelirojopajaro, Someguy1221, SieBot, LeadSongDog,
SallyForth123, Matdrodes, Unimaginatively, DumZiBoT, Addbot, DOI bot, Element16, Queenmomcat, Ronhjones, AndersBot, Tassedethe, AnomieBOT, Crystal whacker, Citation bot, LilHelpa, J04n, Maxus96, Citation bot 1, PigFlu Oink, DrilBot, Trappist the monk,
Chem540f09grp3, RjwilmsiBot, Jagbag777, Tes12, Fm74, Ryanpeter, Headheadjj, Tomsdearg92, Bomazi, Louisajb, ClueBot NG, Snotbot, MrsPotiron, Helpful Pixie Bot, Bibcode Bot, Cowburn, BG19bot, Ollieinc, Roshan220195, Ruby Murray, Lukabri, Aykutaydin,
Monkbot, SantiLak and Anonymous: 33



File:Alcohol_dehydrogenase.png Source: License:

Public domain Contributors: Own work Original artist: Chem540f09grp3
File:C-H_and_C-D_bond_breaking.png Source:
breaking.png License: CC BY-SA 3.0 Contributors: Own work Original artist: Aykutaydin
File:Chemicalrotaxane.svg Source: License: Public domain Contributors: Own work Original artist: <a href='//' title='User:Ronhjones'>
Ronhjones </a>(Talk)
File:Cope_rearrangement_mechanisms.png Source:
mechanisms.png License: CC BY-SA 3.0 Contributors: Own work Original artist: Aykutaydin
File:Donor_Acceptor_Model.png Source: License:
Public domain Contributors: Own work Original artist: Chem540f09grp3
File:Edit-clear.svg Source: License: Public domain Contributors: The
Tango! Desktop Project. Original artist:
The people from the Tango! project. And according to the meta-data in the le, specically: Andreas Nilsson, and Jakub Steiner (although
File:Elimination_reactions_of_2-phenylcyclopentyltrimethylammonium_isomers.png Source:
wikipedia/commons/d/dd/Elimination_reactions_of_2-phenylcyclopentyltrimethylammonium_isomers.png License: CC BY-SA 3.0
Contributors: Own work Original artist: Aykutaydin
File:Energy_Well_Model.png Source: License: Public
domain Contributors: Own work Original artist: Chem540f09grp3
File:F2_vs._F1_in_KIE_Competition_Reactions.png Source:
KIE_Competition_Reactions.png License: CC BY-SA 3.0 Contributors: Own work Original artist: Aykutaydin
File:KIE_Competition_Reactions.png Source:
png License: CC BY-SA 3.0 Contributors: Own work Original artist: Aykutaydin
File:KIE_General_Background_Hypothetical_Reaction.png Source:
General_Background_Hypothetical_Reaction.png License: CC BY-SA 3.0 Contributors: Own work Original artist: Aykutaydin
File:KIE_determined_from_absolute_rates_of_two_parallel_reactions.png Source:
commons/f/f0/KIE_determined_from_absolute_rates_of_two_parallel_reactions.png License: CC BY-SA 3.0 Contributors: Own work
Original artist: Aykutaydin
File:KIE_determined_from_an_intermolecular_competition.png Source:
KIE_determined_from_an_intermolecular_competition.png License: CC BY-SA 3.0 Contributors: Own work Original artist: Aykutaydin
File:KIE_determined_from_an_intramolecular_competition.png Source:
KIE_determined_from_an_intramolecular_competition.png License: CC BY-SA 3.0 Contributors: Own work Original artist: Aykutaydin
File:KIE_effect_iodination.png Source: License:
CC-BY-SA-3.0 Contributors: Transferred from en.wikipedia to Commons. Original artist: The original uploader was V8rik at English
File:KIE_effect_sigmatropicReaction_2006.png Source:
sigmatropicReaction_2006.png License: CC-BY-SA-3.0 Contributors: Transferred from en.wikipedia to Commons. Original artist: V8rik
at English Wikipedia
KineticIsotopeEffectEnolateFormation.png License: CC-BY-SA-3.0 Contributors: en:Image:KineticIsotopeEffectEnolateFormation.png
Original artist: V8rik
KineticIsotopeEffectHalogenation.png License:
Original artist: V8rik

CC-BY-SA-3.0 Contributors:

File:Kinetic_isotope_effect_(reaction_mechanism).png Source:
isotope_effect_%28reaction_mechanism%29.png License: CC BY-SA 3.0 Contributors: Own work Original artist: Aykutaydin


Content license


File:Kinetic_isotope_effect_(reaction_mechanism)_(2).png Source:

isotope_effect_%28reaction_mechanism%29_%282%29.png License: CC BY-SA 3.0 Contributors: Own work Original artist: Aykutaydin
File:Methylamine_dehydrogenase.gif Source:
License: Public domain Contributors: Own work Original artist: Chem540f09grp3
File:R_to_R0_vs._F1_in_KIE_Competition_Reactions.png Source:
R0_vs._F1_in_KIE_Competition_Reactions.png License: CC BY-SA 3.0 Contributors: Own work Original artist: Aykutaydin
File:Racemization.svg Source: License: Public domain Contributors: Self-made with bkchem, mysids script and inkscape Original artist: User:Slashme
File:Reaction_energy_profile_for_when_C-H_cleavage_occurs_at_the_RDS.png Source:
commons/4/4c/Reaction_energy_profile_for_when_C-H_cleavage_occurs_at_the_RDS.png License: CC BY-SA 3.0 Contributors: Own
work Original artist: Aykutaydin
png Source:
occurs_at_a_product-determining_step_after_the_RDS.png License: CC BY-SA 3.0 Contributors: Own work Original artist: Aykutaydin
File:SN1_vs_SN2.png Source: License: CC BY-SA 3.0 Contributors: Own work Original artist: Aykutaydin
Secondaryradicalneucleophilicdetermination.svg License: Public domain Contributors: Own work Original artist: Louisajb (<a
href='//' title='User talk:Louisajb'>talk</a>) 13:14, 15 December 2011 (UTC)


Content license

Creative Commons Attribution-Share Alike 3.0