Case Study 1: Catalytic
Hydrogenation of Enamides
The Nobel Prize for 2002 was awarded to Noyori,
Knowles, and Sharpless for their pioneering work in
asymmetric catalysis. This case study focuses on the
techniques utilized to unravel the mechanism of
asymmetric hydrogenation of prochiral enamides.
Useful References:
Knowles, W. S. Acc. Chem. Res. 1983, 16, 106-112.
Halpern, J. Science 1982, 217, 401.
Halpern, J.; Riley, D. P.; Chan, A. S. C.; Pluth, J. J.
Am. Chem. Soc. 1977, 99, 8055.
Chan, A. S. C.; Pluth, J. J.; Halpern, J. Inorg. Chim.
Acta 1979, 37, L477.
Chan, A. S. C.; Halpern, J. J. Am. Chem. Soc. 1980,
102, 838.
Chan, A. S. C.; Pluth, J. J.; Halpern, J. J. Am. Chem.
Soc. 1980, 102, 5952.
Landis, C. R.; Halpern, J. J. Am. Chem. Soc. 1987,
109, 1746-1754.
In 1975 Knowles and coworkers reported that in situ
reaction of [Rh(DIPAMP)(COD]+BF4- with
acetamidocinnamic acid in alcohol solutions and
under an H2 atmosphere led to rapid hydrogenation of
the C=C bond with 95% enantioselectivity.
MeO2C
H
N
[Rh(DIPAMP)(COD)]+
O
Ph
MAC
+ H2
(3.5-27atm)
MeO2C
H
N
O
Ph
(R-S)/(R+S)=95.7%
enantiomeric excess
O
P
P
DIPAMP
O
Substrates: Good ee if they can chelate and have an
electron withdrawing group in  position.
Interesting observation: e.e. was lowered by higher
pressure of H2 but this effect could be offset by using
higher temperature.
Fundamental Mechanistic Issues
1.
2.
3.
4.
Hydride Route or Unsaturate Route?
Rate Controlling Step?
Selectivity Controlling Step?
Origin of Enantioselection?
Mechanistic Starting Point: Simple
Achiral Model Complexes
P
P
DIPHOS
Strategy:
1. Study reaction of catalyst precursor with H2
2. Study reaction of catalyst precursor with
substrate
3. Measure alkene binding constants and rates
4. Determine rate law of catalytic reaction.
1. Reactions with H2
Ph Ph
P
Rh
P
Ph Ph
yellow
+ H2
methanol
solution
orange
31
P NMR:  60, JRh-P 160Hz
31
P NMR: d 60, JRh-P 203
Hz
Gas Uptake: 2 H2 /Rh
1
H NMR: norbornane, no
Rh-H (<0 ppm)
contrasts with
Ph Ph
Ph P
Ph P Rh
Ph Ph
orange
colorless
+ H2
methanol
solution
31
P NMR: d 47.2, JRh-P 121
Hz
Gas Uptake: 3 H2 /Rh
1
H NMR: norbornane,
-12.4, JRh-H =23Hz,
JP-H=15Hz
These data are consistent with the products shown
below:
Ph Ph H
OMe
P
Rh
P
OMe
H
Ph Ph
Ph Ph H H
OMe
P
Ph
Rh
Ph
P
H
Ph
MeO
Ph
H
Apparently the trans influence of H is large enough to
preclude formation of a dihydride from the reaction of
H2 with [(DIPHOS)Rh(norbornadiene)]+.
Crystals of the product formed from H2 and
[(DIPHOS)Rh(norbornadiene)]+ revealed an unusual
dimeric structure shown below:
Ph
PPh2
P
2+
Rh
Rh
Ph2 P
P
Ph
2. Binding of Unsaturates
A number of unsaturates bind to the di-solvate, 1.
Ph Ph H
OMe
P
Rh
+
P
OMe
H
Ph Ph
1
Ph Ph
P
Rh
P
Ph Ph 2
This can be monitored by NMR or by changes in the
visible spectrum. The unsaturates do not absorb in
the visible region whereas 1 and 2 do. Beginning with
a solution of 1 before the addition of benzene:
Abs0=1[1]0 initial absorbance
After addition of some benzene
Abs=1[1] + 2[2]
Often the value of 2 is not known. The equilibrium
constant is given by:
[2]
K
[1][benzene]
[2]

[1]0  [2] [benzene]0  [2]



solve for [2]
-([1]0  [benzene]0  K 1)  ([1]0  [benzene]0  K 1)2  4[benze
[2] =
2
The concentration of 1 at any point in the titration is
given by
[1]  [1]0  [2]


 Abs  1 [1]0  [2]  2 [2]
Substitution of the expression for [2] into this equation
leads to a description of the absorbance in terms of
known values ([1]0, 1, and [benzene]0) and unknowns
(K and 1). Nonlinear least squares analysis allows
one to fit the unkowns to the observed absorbance
data.
Using this method the following data are obtained for
binding different unsaturates.
Ph Ph H
OMe
P
Rh
+
P
OMe
H
Ph Ph
1
Unsaturate
Benzene
Toluene
p-Xylene
Methyl acrylate
1-Hexene
Styrene
O
OMe
H
N
MAC
O
Ph
Ph Ph
P
Rh
P
Ph Ph 2
K (M-1)
18
97
500
3
2
20
5.3x103
The binding of simple alkenes is weak; only one
alkene binds to the Rh center as indicated by the
inequivalent phosphines ligands in the 31P NMR
spectrum:
Ph Ph H
OMe
P
Rh
+
P
OMe
H
Ph Ph
1
Ph Ph
P
Rh
P
Ph Ph
H
OMe
3. Measurement of the Kinetics of Approach to
Equilibrium
A) One approach to measure the binding rates is
stopped-flow measurement of absorbance time
profiles accumulated upon addition of excess MAC to
1.
Ph Ph H
OMe
P
Rh
+ MAC
P
OMe
H
Ph Ph
1
k1
k-1
Ph Ph
O
P
Rh
NH
P
MeO
Ph
Ph
Ph
O
According to 1st-Order Approach to Equilibrium
Kinetics
k1 [MAC]k1 t
[A]t  [A]  ([A]0  [A] )e
using non-linear least squares analysis one can
optimize [A], [A]0, and kobs = k1[MAC]+k-1. From a
series of experiments at different [MAC] one obtains
kobs
MAC
Analysis of k1[MAC] + k-1 as a function of MAC
concentration gives well-determined values of k1 but
not k-1. The value of k1[MAC] is so large that the
value of k-1 is subsumed.
k1=2.7x104M-1s-1
B) The rate of MAC dissociation can be determined
from K and k1. Independent verification of this rate
comes from the kinetics of displacement of MAC by
arenes.
Trapping Approach