Академический Документы
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Rob Knowles
MacMillan Group Meeting
Sept. 14, 2005
Key References
Wiberg, K.B. Chem. Rev. 1955, 55, 713
Westheimer, F.H. Chem. Rev. 1961, 61, 295
Saunders, W.H., Melander, L. Reaction Rates of Isotopic Molecules , Wiley, New York, 1981
Dougherty, D.A., Anslyn, E.V. Modern Physical Organic Chemistry, University, Sausalito, 2005
Lowry, T.H., Richardson, K.S. Mechanism and Theory in Organic Chemistry, Harper and Row, New York, 1987
1932 Urey and coworkers reported the first spectroscopic evidence for a
heavy isotope of hydrogen. Shortly thereafter Urey reported the enrichment of
heavy hydrogen in water upon electrolysis.
Urey
isotope
1933 Gilbert Lewis and coworkers isolated a pure sample of heavy water
2H
3H
13C
15N
17O
natural
abundance
0.0015%
0.0001%
1.108%
0.365%
0.037%
O
H3C
CH3
H3C
Br2, H2O
CH2Br
CD3
7.0
cat H+
O
D3C
cat H+
D3C
Br2, H2O
Key Assumptions
Krel
CD2Br
1.0
! Interpretation of the rate differences provides information on the nature of the rate-determining step.
(D)H
R
Me
Me
Cl
Me
NaOEt
E1 or E2?
Me
OsO4
Me3C
3+2 or 2+2?
HO
Me3C
OH
r
C
bond
C-H
0.92
C-D
1.71
12C-12C
6.00
12C-13C
6.24
1
2"c
= m1 m2
Energy
m1 + m2
En = (n + 1) h!
n=3
n=2
n=1
n=0
Zero-Point Energy
! The energy the molecule possesses in the ground vibrational state is known as the zero-point energy, and it
forms the basis for the reactivity differences between isotopomers.
Energy
! Simplest case to treat is the homolytic cleavage of C - H/D bond where the bond is considered to be
fully broken at the transition state. Reaction progress followed by observing the C - H/D bond stretch.
frequency (cm-1)
ZPE (kcal/mol)
C - H stretch
2900
4.15
~6.9
C - D stretch
2100
3.00
1.0
r
Activation energy for
C-D bond homolysis
n=0 (C-H)
n=0 (C-D)
!!G = !ZPE
r
C
! As the C - H/D bond breaks at the transition state the stretch becomes a translation. As a result there is no new
stretch in the TS that corresponds to the stretch of ground state bond. For this mechanism, the isotope
effect is entirely controlled by the difference in the ground state ZPE's.
Wesheimer, F.H. Chem. Rev. 1961, 61, 295
Case 1
E2 elimination
CH3CH2CH2Br
CH3CD2CH2Br
NaOEt
Me
C2H5OH
NaOEt
Me
C2H5OH
EtO
kH/KD = 6.7
Me
Br
! This KIE is consistent with an E2 elimination in which the C - H/D bond is broken in the rate determining step.
Case 2
E1 elimination
Me
Me
Me
Me
Me
Me
Me
Me
Me
CH3CH2 C
CH3CD2 C
Me
H2O, !
Br
kH/KD = 1.4
H
Me
Br
H2O, !
H
H
Br-
! This KIE is consistent with an E1 solvolysis in which the C - H/D bond is not broken in the rate determining step.
Energy
!ZPETS
Reaction Coordinate
! The ZPE changes between the ground state and the transition state because the force constant of the bond is
changing. The difference in energy between the !ZPE's in the ground state and the transition state determine
the magnitude of the kinetic isotope effect.
Exothermic
H
Energy
Thermoneutral
!ZPEGS ~ !ZPETS
!!G is small
Small KIE
!ZPEGS ~ !ZPETS
!!G is small
Small KIE
! In the exothermic and endothermic reactions, the TS is similar to the SM and product respectively. Thus !ZPETS
is very similar to !ZPEGS, yielding a small KIE. In the thermoneutral TS the symetrical stretch is independent of the
mass of the isotope, yielding very small values of !ZPETS which in turn yield very large KIE's.
Me
R-NH2
NO2
Me
R-NH3
NO2
!pKa = 0
11
KH / KD
10
9
8
5
10
11
12
pKa of RNH3+
Thermoneutral
Exothermic
A
13
Endothermic
A
B
Bruice, T.C. JACS 1969, 92, 905
! In general primary KIE's for nonlinear TS's are lower than those for more
linear TS's for two reasons:
1. In going to a TS with bent bonds, the bending vibrational modes become
more important.However, bending modes are much lower energy than
stretching modes in linear TS's and thus the KIE's associated with bending
are diminished.
Stretch
Bend
v = 2900 cm-1
v = 1350 cm-1
H
A
! Generally primary KIE's for proton transfers occuring by non-linear TS's are on
the order of 2.5 - 3.5.
New symmetric stretch
in the TS structure
Out-of-plane Bend
H
sp3
1350 cm-1
sp2
1350 cm-1
1350 cm-1
H
800 cm-1
Expected SDKIE
Rule of Thumb
sp3 to sp2
1.1 - 1.2
sp2 to sp3
0.8 - 0.9
Hyperconjugation
H H
!
R #
H
" Br
H
H
H
KH / KD
"
1.1 - 1.2
1.15 - 1.25
0.92 - 1.02
CH3Cl
CH3OH
HCl
CD3OH
HCl
KH/KD = 0.97
H2O
CD3Cl
SN1 Reactions
H
Me
OTs
H2O
Me
OTs
Me
Me
OH
Me
Me
KH/KD = 1.13
H2O
OH
Me
Me
TsOH
TsOH
O
OH
KH/KD = 1.06
H3C
O
D3C
H+
O
OH
D3C
Case 2
Case 1
Energy
!G = -RT ln Keq
Reaction Coordinate
Case 1
Case 2
1,4 diyl
O
4
bis-allyl
1.0
Key Assumptions
Bond-Breaking
KIE (C4) - 1
EIE (C4) - 1
BMKIE =
KIE (C6) - 1
EIE (C6) - 1
1.092 - 1.0
0.33
0.15
1.27 - 1.0
=
0.976 - 1.0
0.84 - 1.0
0.0
Bond-Making
1.0
aromatic
bis-allyl
BMKIE 1
Reaction
BBKIE 1
Me
1.0
Me
NC
1.85
Ph
Ph
8.1
Ph
NC
NC
Bond-Breaking
NC
Me
Ph
Ph
NC
NC
0.31
Ph
0.0
Bond-Making
1.0
- 14Carbon KIE
O
HO
**
HO
1.076
1.065
15Nitrogen
OH
C
HO
OH
KIE
1.02
37Chlorine
KIE
CN-
CN
Cl
1.0057
Nuclides
1 KIE
C-H/C-D
6-8
C-H/C-T
12C/13C
12C/14C
14N/15N
16O/18O
32S/34S
35Cl/37Cl
15-16
1.04
1.07
1.03
1.02
1.01
1.01
Kinetic Fractionation
R / R0 = (1 - F)(1/KIE - 1)
! As the reaction progresses, the starting material becomes enriched in the slower reacting component. As
the reaction approaches completion the ratio of R/R0 becomes very sensitive to the value of the KIE.
! In the NMR it is possible to evaluate each 13C and 2H individually and simultaneously by using atoms on the
the molecule of interest that will not have isotope effects as an "internal standard"
This method is general for nearly every type of reaction, making the study of
KIE's a practical tool in elucidating even the most ambiguous mechanisms.
Singelton, D.A. JACS 1995, 117, 9357
O
Me
O
O
xylenes, 25 C
Me
O
O
! Substiution on the diene methyl group was not expected to affect the rate. Thus it was used as the internal
standard
0.965
H
1.00*
1.022
Me
H 0.908
1.001
H 0.938
0.990 H 1.00
KH/KD
K12C/K13C
1.017
H
0.968
3+2
O Os
O Os
O Os
O
Sharpless Mechanism
O
2+2
O Os
O
O Os
O Os
L
O
R
! Singelton's method gives 13C KIE's that are convincing evidence that the 3 + 2 pathway is likely operative.
OMe
1.026
1.032
1.045
1.042
NO2
1.027
1.028
CMe3
1.034
1.032
O
OMe
EtO2C
OEt
Rh cat
N2
Me
Key Points
Me
Singelton demonstrates that KIE's point to an early asynchronous TS, inconsistent with 2+2 mechanism
1.010
1.00
H
Me
1.003
Calculated TS structure
Me
O
O
Me
Me
Me
Oxone
! Singelton compared the theoretical KIE's to the experimental KIE's and was able to show that one
TS conformer was likely operative in the Shi epoxidations.
1.006
1.006
0.998
1.001
Me
1.022
1.022
Theoretical KIE
Experimental KIE
KH / KD = 20 - 100
m
1
2a
Tunneling is extremely
sensitive to the width of
the barrier and the mass
of the particle tunneling
through it
Energy
2a
Reaction Coordinate
Tunnel Vision
! Selenoxide eliminations to create double bonds is a commonly used organic reaction that proceeds
via tunneling
Se
OH
D
Se
H
Se
OD
! Kwart and coworkers predicted a barrier width of 0.82 , implying that neither the oxyen or the carbon moved
at all, only the proton was transferred. A typical C - H bond length is roughly 1.1 .
O
H
R
O
Se
H
R
O
Se
Se
! This reaction is facilitated by the long bonds to selenium as compared to the sulfur variant of this reaction, which
proceeds by a normal proton transfer and has a much smaller difference in activation energy (1.15 kcal/mol).
OTBS
Me
Me
OTES
H
Me
OTBS
Tf2O
2,6 di-tBu pyr;
then DBU
Me
OTBS
Me
Me
OTES
H
Me
OTBS
Me
OMe O
Me
Me
OTBS
Me
Me
Tf2O
Me
OTBS
Me
OMe
OTES
H
Me
OMe Me
D D
Me
Me
OMe O
Me
30%
OTES
H
OTBS
Me
OTBS
Me
Me
H
Me
H
66%
OTES
H
OTBS
OTBS
Me
D D
Me
H
O
Me D
OMe Me
Me
OMe
81%
9%
! Mechanistic Rationale
Me
OTBS
D D
Me
Me
Tf
Miyashita, Science 2004, 305, 497
Ph
OCH3 OCH3
OCH3
PhSe
OCH3 OCH3
OCH3
Ph3SnH
AIBN,
PhH
OCH3 OCH3
H2C
Ph
OCH3
OCH3
OCH3 OCH3
OCH3 OCH3
A:B
~1:1
Ph
OCH3
Ph
OCH3
OCH2 OCH3
OCH3 OCH3
Ph
OCH3
OCH3 OCH3
OCH3
OCH3 OCH3
OCH3 OCH3
Ph
OCD3 OCH3
D
O
OCH3
OCH3 OCH3
AIBN,
PhH
Ph
OCD3 OCH3
OCH3
Ph3SnH
PhSe
OCH3
OCH3 OCH3
OCH3
A:B
9 : 91
OCH3 OCH3
TS1
O
1O
H3C
H3C
CD3
CD3
H3C
CD3
(rds)
TS2
OOH
1.38
CD3
H2C
DOO
H3C
CD3
1.00
H3C
CD2
C-H bonds vibrate with greater frequency and with greater amplitudethan do C-D bonds due to their higher
ZPE. This asymmetry in the vibrational modes of each methyl group of the activated complex creates a
perturbation that is sufficiently energetic as to alter the product distribution.
The broader implication is that the long-held notion that any form of selectivity that is not manifested in the
rate-determining step implies the formation of intermediate is not necessarily true
This reiterates the point that reaction mechanisms are truly complex and that even the most minute
perturbations can make truly large differences in reaction outcomes.
Singleton, JACS 2003, 125, 1176
Conclusions
! Kinetic isotope effects arise from intrinsic differences in the physical properties of istopes. This is mainly a
manifestation of the difference in mass on the vibrational energy levels of the isotopomers.
! Primary kinetic isotope effects arise mainly from differences in zero-point energy
! Secondary deuterium isotope effects arise mainly from changes in hybridization and hyperconjugation
! Tunneling is an important contributor to the rate of many proton (or carbon) transfers reactions and
often tunneling reactions exhibit abnormally large kinetic isotope effects
! KIE's provide a uniquely sensitive probe of transition state structures and provide valuable information
about the rate determining step in reaction mechanisms
! Recent practical developments make obtaining detailed KIE profiles for reaction by running a single
experiement which analyzed by NMR in a routine fashion
! KIE's can be used to partition product mixtures in the synthesis of complex molecules.