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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
12
than
the
corresponding
CD
bond,
whereas
a
C
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
reactants:
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).

kL
kH

Background

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
way.
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
1

THEORY

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
eect.
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(
)1/2
)(
)3/2 (
netic isotope eect, and larger force constants in the tran

sH sD
MH
MD
IAH
IBH
ICH
kH
IAD IBD ICD
sition state are expected to yield an inverse kinetic isotope
=

IAH IBH ICH


sD sH
MD
MH
IAD
IBD
ICD
eect when stretching vibrational contributions dominate kD


[1]

the kinetic isotope eect.


3N7
1euiD
7
3N
3N
6

u
i=1 1e iH 1/2( i=1 (uiH uiD ) i=1 (uiH uiD ))
3N 6
e
1euiH
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.

i=1

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]

Theory

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

1euiD

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]

kH
= S M M I EXC ZP E
kD
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]

3.1

Tunneling

7
3N

3N
6

i=1

i=1

kH 1/2{
=e
kD

3N
6

1/2{

=e

i=1

(uiH uiD )

ui

7
3N
i=1

(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
bonds

above using some simplications:[5][8]


(

ln( kkH
)
T

ln( kkH
)
D
i.e.,
( )
kH
kT

(
=

mH /mT
1 1/3

=
=
= 1.44
1 mH /mD
1 1/2
1

kH
kD

)1.44
s

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
eect.[7]
[9]
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:

4 KINETIC ISOTOPE EFFECT EXPERIMENTS

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
Q=
(e e )

where =

E
RT

and =

2a 2 (2mE)1/2
h

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

4.1

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
actions
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

k1
ln(1 F1 )
On the other hand, if a reaction follows the following KIE = k2 = ln(1 F2 )

5 CASE STUDIES

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]
k1
ln(1 F1 )
=
SKIEs can be explained in terms of changes in orbital
k2
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

5.2

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
0.9.[9]

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
below.
R
N

O
N

R
N

Path A

N
O
X = H or D

N
O

O
N

5.2.1 HSteric isotope eects

O
O

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
R
the dierent vibrational amplitudes of isotopologues.[38]
N
N
O
An example of such an eect is the racemization of
Nitroethane
9,10-dihydro-4,5-dimethylphenanthrene.[39] The smaller
anion
N
H
N
amplitude of vibration for deuterium as compared to
hydrogen in CH (carbonhydrogen), CD (carbon
O
deuterium) bonds results in a smaller van der Waals raO
X
N
dius or eective size in addition to a dierence in the
O
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 CASE STUDIES
5.4.1 Compensating for variations in
abundance

13

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.
5.2.2

Inverse kinetic isotope eects

Obtain the same ratios for the carbons in a sample


of the starting material after it has undergone some
reaction.

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]

5.3

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]

5.4

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.

5.6

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
hydrogen.[5]

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
4
kinetic
isotope
eect
as
low
as
1.74
x
10
,
which
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.

5.6

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]

10

REFERENCES

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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

References

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12

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