Kinetic isotope effect evidence for a concerted hydrogen transfer mechanism in transfer hydrogenations catalyzed by [p-(Me2CH)C6H4Me] Ru-(NHCHPhCHPhNSO2C6H4-p-CH3)

Article abstract of DOI:10.1021/jo0205457

The isotope effects in the reaction of [p-(Me₂CH)-C₆H₄Me]Ru (NHCHPhCHPhNSO₂C₆H₄-p-CH₃) (1) with isopropyl alcohol were 1.79 for transfer of hydrogen from OH to N and 2.86 for transfer from CH to Ru. The isotope effect for transfer of deuterium from doubly labeled material (k_CHoH/k_CDOD = 4.88) was within experimental error of the product of the two individual isotope effects. These isotope effects provide convincing evidence for a mechanism involving concurrent transfer of hydrogen from oxygen to nitrogen and from carbon to ruthenium.

Full text of DOI:10.1021/jo0205457

effect of 1.5 for the reduction of acetophenone by (CH3)2-
CDOH catalyzed by 1; it is not clear whether this isotope
effect is for the transfer of hydrogen from isopropyl alco-
hol to 1 or from 2 to acetophenone or some combination
of the two processes. While this isotope effect is consistent
with the proposed mechanism, we decided that further
mechanistic investigation of this important system was
warranted.
Kin etic Isotop e Effect Evid en ce for a
Con cer ted Hyd r ogen Tr a n sfer Mech a n ism
in Tr a n sfer Hyd r ogen a tion s Ca ta lyzed by
[p-(Me2CH)C6H4Me]Ru -
(NHCHP h CHP h NSO2C6H4-p-CH3)
Charles P. Casey* and J effrey B. J ohnson
Department of Chemistry, University of
Wisconsin-Madison, Madison, Wisconsin 53706
We are interested in catalysts that can simultaneously
transfer hydride and proton to polar substrates. We have
carried out mechanistic studies of Shvo’s catalyst,6 which
can reduce ketones and aldehydes by either a transfer
hydrogenation process with isopropyl alcohol as the red-
uctant or by a direct hydrogenation with H2 as the red-
uctant. On the basis of detailed studies on the related
active reducing agent [2,5-Ph2-3,4-Tol2(η5-C4COH)]Ru-
(CO)2H (3), including observation of primary deuterium
isotope effects for transfer of both OH and RuH hydro-
gens, we proposed a mechanism involving concerted tran-
sfer of proton and hydride to aldehyde outside the coord-
ination sphere of the metal (Scheme 2).7,8
Here we report the application of the same mechanistic
tools and isotope effect measurements to the mechanism
of transfer hydrogenation catalyzed by Noyori’s catalyst
1. Our kinetic isotope effect measurements on the sto-
ichiometric oxidation of isopropyl alcohol by 1 provide
direct experimental support for a simultaneous hydrogen
transfer mechanism.
Ra te La w for Rea ction of 1 w ith Isop r op yl Alco-
h ol. We experienced difficulty in measuring the rate of
the reaction of 1 with isopropyl alcohol by 1H NMR spec-
troscopy because the spectra were dominated by the
methyl resonances of excess isopropyl alcohol, which
limited the dynamic range of the spectrometer and our
ability to accurately integrate the resonances of 1 and 2.
This problem was circumvented by using the deuterated
substrate (CD3)2CHOH and following the conversion of
1 [δ 5.7 (aryl), and δ 2.1 (Me)] to 2 [δ 4.8 and 4.7 (aryl),
and δ -5.8 (RuH)] by NMR integration. Reaction of 1
(0.02 M) with a large excess of (CD3)2CHOH (0.7 M, 35-
fold excess) at -20 °C went to form an equilibrium ratio
of 1:2 of about 10:90 (Scheme 3).
casey@chem.wisc.edu
Received August 15, 2002
Abstr a ct: The isotope effects in the reaction of [p-(Me2CH)-
C6H4Me]Ru(NHCHPhCHPhNSO2C6H4-p-CH3) (1) with iso-
propyl alcohol were 1.79 for transfer of hydrogen from OH
to N and 2.86 for transfer from CH to Ru. The isotope effect
for transfer of deuterium from doubly labeled material
(kCHOH/kCDOD ) 4.88) was within experimental error of the
product of the two individual isotope effects. These isotope
effects provide convincing evidence for a mechanism involv-
ing concurrent transfer of hydrogen from oxygen to nitrogen
and from carbon to ruthenium.
The development of several new transition metal tran-
sfer hydrogenation catalysts is revolutionizing reduction
chemistry. Noyori’s chiral [p-(Me2CH)C6H4Me)]Ru(NHC-
HPhCHPhNSO2C6H4-p-CH3) (1) shows high activity and
excellent enantioselectivity for the conversion of ketones
to alcohols with isopropyl alcohol as the ultimate reduc-
tant (Scheme 1).1 Reaction of 1 with isopropyl alcohol pro-
duces the ruthenium hydride [p-(Me2CH)C6H4Me]RuH-
(NH2CHPhCHPhNSO2C6H4-p-CH3) (2), which then trans-
fers hydrogen to a ketone. The success of Noyori’s catalyst
has triggered extensive studies of isoelectronic Cp*Rh-
(III)(NHCHPhCHPhNSO2C6H4-p-CH3) and Cp*Ir(III)(NH-
CHPhCHPhNSO2C6H4-p-CH3) catalysts by Mashima and
Ikariya.2,3 These new transfer hydrogenation catalysts
provide an alternative to traditional stoichiometric NaBH4
and LiAlH4 reductions, and utilize environmentally
friendly isopropyl alcohol as the terminal reductant, for-
ming acetone as the byproduct.4 The reduction of carbon-
yl groups by 2 and related complexes, which have an elec-
tronically coupled metal hydride and acidic NH proton,
are proposed to transfer a hydride from ruthenium to car-
bon and a proton from nitrogen to the carbonyl oxygen;
these transfers are suggested to occur without prior co-
ordination of the alcohol to the metal center. This mech-
anism is distinctly different from that of the Meerwein-
Ponndorf-Verley reaction in which an aluminum alkox-
ide catalyzes transfer hydrogenations. It is unusual for
a transition metal complex to react with a substrate out-
side the coordination sphere of the metal. Noyori has re-
ported extensive calculations that provide theoretical
support for the concerted six-center transition state for
transfer hydrogenation.5 Noyori also reported an isotope
The rate of approach to equilibrium followed pseudo-
first-order kinetics to over 3 half-lives, indicating a first-
order dependence on ruthenium complex 1 with kobs
)
(9.80 ( 0.30) × 10-4 s-1 for the disappearance of 1. A
linear dependence of kobs on the concentration of (CD3)2-
CHOH between 0.35 and 0.90 M established a first-order
dependence on alcohol concentration (Table 1). These
data established the second-order rate law for disappear-
ance of 1 (eq 1), with kobs/[alcohol] ) (1.39 ( 0.42) × 10-3
(5) Yamakawa, M.; Ito, H.; Noyori, R. J . Am. Chem. Soc. 2000, 122,
1466.
(1) (a) Haack, K.-J .; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori,
R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285. (b) Noyori, R.;
Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (c) Matsumura, K.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J . Am. Chem. Soc. 1997, 119,
8738.
(2) (a) Mashima, K.; Abe, T.; Tani, K. Chem. Lett. 1998, 1199. (b)
Mashima, K.; Abe, T.; Tani, K. Chem. Lett. 1998, 1201.
(3) Murata, K.; Ikariya, T.; Noyori, R. J . Org. Chem. 1999, 64, 2186.
(4) Fehring, V.; Selke, R. Angew. Chem., Int. Ed. 1998, 37, 1827.
(6) (a) Blum, Y.; Czarkie, D.; Rahamin, Y.; Shvo, Y. Organometallics
1985, 4, 1459. (b) Shvo, Y.; Czarkie, D.; Rahamim, Y.; Chodosh, D. F.
J . Am. Chem. Soc. 1986, 108, 7400. (c) Menashe, N.; Shvo, Y.
Organometallics 1991, 10, 3885. (d) Menashe, N.; Salant, E.; Shvo, Y.
J . Organomet. Chem. 1996, 514, 97.
(7) The small square attached to ruthenium in Scheme 2 indicates
an open coordination site.
(8) Casey, C. P.; Singer, S. W.; Powell, D. R.; Hayashi, R. K.; Kavana,
M. J . Am. Chem. Soc. 2001, 123, 1090.
10.1021/jo0205457 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/01/2003
1998
J . Org. Chem. 2003, 68, 1998-2001

SCHEME 1
SCHEME 2
TABLE 1. Ra tes of Ap p r oa ch to Equ ilibr iu m for
Rea ction of Isop r op yl Alcoh ol Isotop om er s w ith 1 a t -20
°C in CD2Cl2
[alcohol]
(M)
kobs (s-1
)
kobs/[alcohol]
× 104
(M-1 s-1) × 104
Keq
CHOH
0.363
0.537
0.707
0.872
0.706
0.702
0.706
5.0 ( 0.1
7.2 ( 0.2
9.8 ( 0.3
11.3 ( 0.4
5.4 ( 0.2
4.2 ( 0.1
2.3 ( 0.1
13.0 ( 0.3
14.2 ( 0.4
13.9 ( 0.4
13.8 ( 0.4
7.7 ( 0.3
5.9 ( 0.2
3.2 ( 0.2
0.181
0.184
0.179
0.178
0.170
0.155
0.148
F IGURE 1. Plot of ln {δt/[δt(1 - K-1) + R]} versus time used
to determine the second-order rate constant for the reaction
of 1 with isopropyl alcohol.
CHOD
CDOH
CDOD
for a forward reaction when a significant amount of start-
ing material remains at equilibrium (eq 2). Plots of ln
{δt/[δt(1 - K-1) + R]} versus time were linear (Figure 1)
and rate constants are presented in Table 2.
TABLE 2. Secon d -Or d er Ra te Con sta n ts for th e
Rea ction of Isop r op yl Alcoh ol Isotop om er s w ith 1 a t -20
°C a n d for Rea ction of Aceton e w ith 2a
k (M-1 s-1) × 104
k (M-1 s-1) × 104
kCHOH
kCHOD
kCDOH
kCDOD
11.8 ( 0.5
6.9 ( 0.1
4.1 ( 0.2
2.4 ( 0.2
kRuHNH
kRuHND
kRuDNH
kRuDND
66 ( 5
41 ( 3
27 ( 2
16 ( 1
ln {δt/[δt(1 - K-1) + R]} ) -kRt + C
(2)
where
R ) [1]eq + [alcohol]eq + K-1([2]eq + [acetone]eq)
and
a
Rate constants for reaction of acetone with 2 determined by
dividing kCHOH by KCHOH
.
M-1 s-1 for (CD3)2CHOH. The equilibrium constants are
also presented in Table 1.
δt ) [1]t - [1]eq
d[1excess
dt
]
≈ kobs[alcohol][1excess
]
(1)
Kinetic measurements were performed between -10
and -35 °C to allow determination of activation param-
eters. The second-order rate constants were the follow-
ing: 19.7 × 10-4 M-1 s-1 at -11.3 °C; 18.1 × 10-4 M-1
We have employed the methods outlined by Espenson9
and King10 for obtaining the second-order rate constant
SCHEME 3
J . Org. Chem, Vol. 68, No. 5, 2003 1999

TABLE 3. Kin etic a n d Equ ilibr iu m Isotop e Effects for
th e Rea ction of Isop r op yl Alcoh ol w ith 1 a n d for th e
Rea ction of Aceton e w ith 2
SCHEME 4
kCHOH
/
1.79 ( 0.07 KCHOH
/
1.05 ( 0.10 kRuHNH
/
1.69 ( 0.18
1.64 ( 0.22
2.46 ( 0.30
2.38 ( 0.27
4.03 ( 0.52
kCHOD
KCHOD
kRuHND
kCDOH
kCDOD
kCHOH
kCDOH
kCHOD
kCDOD
kCHOH
kCDOD
/
1.71 ( 0.16 KCDOH
/
1.05 ( 0.10 kRuDNH
/
KCDOD
kRuDND
/
2.86 ( 0.20 KCHOH
/
1.16 ( 0.11 kRuHNH
/
KCDOH
kRuDNH
/
2.73 ( 0.15 KCHOD
/
1.15 ( 0.11 kRuHND
/
KCDOD
kRuDND
/
4.88 ( 0.41 KCHOH
/
1.21 ( 0.12 kRuHNH
/
KCDOD
kRuDND
reactions of isopropyl alcohol isotopomers with ruthenium
complex 1 and the equilibrium constants for the reac-
tions, the second-order rate constants for the reverse
reaction of acetone with ruthenium hydride 2 were
readily determined by dividing the second-order rate
constants for the forward reactions by the equilibrium
constants (eq 5). The ratios of the rate constants gave
isotope effects for the reverse reactions (Table 3).
s-1 at -14.2 °C; 11.9 × 10-4 M-1 s-1 at -21.4 °C; 9.7 ×
10-4 M-1 s-1 at -26.4 °C; and 6.4 × 10-4 M-1 s-1 at -34.1
°C. An Eyring plot provided the values ∆Hq ) 5.8 ( 1.5
kcal mol-1 and ∆Sq ) -48.4 ( 4.6 eu. The large negative
entropy is indicative of a highly ordered transition state
in which 1 and isopropyl alcohol associate prior to
transfer of hydrogen.
Kin etic Isotop e Effect Mea su r em en ts. The rates of
reaction of 1 with an excess of (CD3)2CHOD, (CD3)2CDOH,
and (CD3)2CDOD were measured at -20 °C at several
different ruthenium concentrations while holding the iso-
propyl alcohol concentration constant. The second-order
rate constants for the forward reaction are presented in
Table 2.
We found primary deuterium isotope effects of 2.7-
2.8 for breaking the CH bond of isopropyl alcohol and of
1.7-1.8 for breaking the OH bond of isopropyl alcohol
(Table 3). These isotope effects are consistent with a
mechanism involving concerted transfer of hydrogen from
carbon to ruthenium and from oxygen to nitrogen.
Equ ilibr iu m Isotop e Effect Mea su r em en ts. The
equilibrium constants for the reaction of each isopropyl
alcohol isotopomer with ruthenium species 1 were de-
termined by measuring the ratio of species after >20 half-
lives (eq 3).11 The amount of acetone was assumed to be
the same as ruthenium hydride 2 because of stoichiom-
etry. At -20 °C the equilibrium constant was Keq ) 0.179
( 0.013 for (CD3)2CHOH, which corresponds to about
90% conversion to 2 under typical reaction conditions.
Equilibrium constants for all the isotopomers are given
in Table 1.
kCHOH
kRuHNH
)
(5)
KCHOH
The observation of isotope effects for transfer of hydro-
gen both from carbon to ruthenium (kCHOH/kCDOH ) 2.86
( 0.20) and from oxygen to nitrogen (kCHOH/kCHOD ) 1.79
( 0.07) in the reaction of isopropyl alcohol with 1 provides
strong evidence for a concerted mechanism. For a concert-
ed mechanism, the isotope effect for transfer of deuterium
from doubly labeled material should be the product of
the two individual isotope effects. The observation that
the combined isotope effect for transfer of deuterium from
carbon and oxygen (kCHOH/kCDOD ) 4.88 ( 0.41) is within
experimental error of the product of the two individual
isotope effects (2.86 × 1.79 ) 5.11 ( 0.41) provides con-
vincing evidence that both transfers occur in the same
step. These results provide strong support for the mech-
anism proposed by Noyori that involves simultaneous
transfer of hydrogen from carbon to ruthenium and from
oxygen to nitrogen outside the coordination sphere of
ruthenium (Scheme 4). These isotope effects provide evi-
dence only for the movement of the hydrogen atoms dur-
ing this reaction and provide no information on the polar-
ity of the hydrogens. However, we suggest that the hydro-
gen transferred from carbon to ruthenium behaves as a
hydride, while the hydrogen transferred from oxygen to
nitrogen behaves as a proton, and that both are trans-
ferred in a concerted process through a single transition
state.
[2][acetone]
Keq
)
(3)
[1][isopropyl alcohol]
The equilibrium isotope effects determined from the
individual equilibrium constants were small (eq 4). The
Stepwise alternatives to the concerted mechanism in
which the hydride and proton are transferred to the
unsaturated ruthenium species 1 in separate steps can
be excluded based on the results reported here. In a two-
step reaction (Scheme 5) in which k-1 and k2 differ by an
order of magnitude or more, a primary kinetic isotope
effect would be seen for only the slower of the two
reactions and an equilibrium isotope effect would be seen
for the reversible step. The magnitude of the equilibrium
isotope effect on the first step in the mechanism should
equilibrium isotope effect for CD substitution (KCHOH
/
KCDOH ) 1.16 ( 0.11) is consistent with the expectation
that deuterium will be concentrated in the stronger bond
(CD favored over RuD). The equilibrium isotope effect
for OD substitution was KCHOH/KCHOD )1.05 ( 0.10.
(Table 3).
KCHOH
KCHOD
CHOH
CHOD
equilibrium isotope effect
)
)
(
)
[2RuHNH][(CD3)2CHOD]
[2RuHND][(CD3)2CHOH]
(4)
(9) Espenson, J . H. Chemical Kinetics and Reaction Mechanisms,
2nd ed.; McGraw-Hill: St. Louis, 1995.
(10) (a) King, E. L. Int. J . Chem. Kinet. 1982, 14, 1285. (b) King, E.
L. J . Chem. Educ. 1979, 56, 580.
(11) Even at long reaction times, no exchange into the ruthenium
hydride position from excess alcohol was seen.
Kin etic Isotop e Effects for Rever se Rea ction s.
Since we know both the second-order rate constants for
2000 J . Org. Chem., Vol. 68, No. 5, 2003

SCHEME 5
glovebox. CD2Cl2 was dried over CaH2 and distilled prior to use.
Solvents were dried with activated alumina purification col-
umns.13 Commercially available starting materials were used
without further purification. NMR spectra were recorded on a
360-MHz spectrometer. NMR spectra are referenced to residual
be similar to the equilibrium isotope effect for the overall
reaction. In the present case, the equilibrium isotope
effects for the overall reaction are small (KCHOH/KCHOD
)
1.05 and KCHOH/KCDOH ) 1.16). Both the observed isotope
effect of 1.79 for transfer of OH to nitrogen and of 2.86
for transfer of CH to ruthenium are much too large to be
equilibrium isotope effects. Stepwise mechanisms of this
type are therefore excluded.
protons in deuterated solvent. Ruthenium catalyst
1 was
prepared according to a literature procedure.1a Deuterated
isopropyl alcohol was prepared by reduction of acetone-d6 (see
Supporting Information).
A stepwise mechanism in which the barriers for proton
transfer followed by hydride transfer are approximately
equal (k-1 ≈ k2 in Scheme 5) would give rise to isotope
effects for transfer of both O-H and C-H hydrogens. For
this two-step mechanism, the isotope effect observed for
doubly labeled material should be smaller than the
product of the individual isotope effects. For example,
assuming no equilibrium isotope effect for protonation
of the amino group and equal barriers for OH and CH
transfer, one must employ isotope effects of 2.62 on OH
transfer and 3.76 on CH transfer to obtain the observed
Gen er a l Kin etic P r oced u r e. The general kinetic procedure
will be illustrated with a specific example. A standard CD2Cl2
solution of 1 containing ferrocene as an internal NMR integra-
tion standard (0.70 mL, 0.031 M, prepared in a nitrogen glovebox
from 44.1 mg of 1, ∼10 mg of ferrocene, and 2.40 mL of CD2Cl2)
in a resealable NMR tube was degassed with 3 freeze-pump-
thaw cycles. The NMR tube was filled with N2 at -78 °C and
isopropyl alcohol (40.0 µL, 0.523 mmol, 25 equiv) was added from
a 50-µL gastight syringe. The NMR tube was resealed, inserted
into an NMR spin collar, shaken for 3 s, and then inserted into
the NMR spectrometer precooled to -20 °C. After locking and
shimming (∼3 min), data acquisition was begun. The disappear-
ance of the ruthenium complex 1 and the appearance of the
ruthenium hydride 2 were both followed by 1H NMR spectro-
scopy for over 2.5 half-lives (∼100 min). The concentration of 1
was followed by measuring the integrations between δ 5.70-
5.79 and δ 2.08-2.14 (cymene aromatic and methyl protons,
respectively) compared to the integration of the ferrocene int-
ernal standard. The concentration of 2 was followed by mea-
suring the integrations from δ 4.82 to 4.88, δ 4.75 to 4.82, and
δ -5.73 to -5.90 (two cymene aromatic and hydride protons,
respectively) compared to the integration of the ferrocene inter-
nal standard. The final equilibrium concentrations were deter-
mined from samples held at -20 °C in a slush bath for at least
8 h.
isotope effects of kCHOH/kCHOD ) 1.79 ( 0.07 and kCHOH
/
kCDOH ) 2.86 ( 0.20 (see Supporting Information). The
combination of the two isotope effects predicts an isotope
effect for doubly labeled material of kCHOH/kCDOD ) 3.17,
which is significantly smaller than the observed value
of 4.88 ( 0.41. Therefore, a two-step mechanism with
equal barriers can be excluded.
In the paper by Ryberg,12 isotope effects for the
catalytic reduction of acetophenone by deuterated iso-
propyl alcohol using a related Ru(cymene)(amino alcohol)
catalyst were measured and evidence was presented that
the rate determining step was hydrogen transfer from
isopropyl alcohol to the ruthenium complex. They found
isotope effects of 2.51 ( 0.22 for OH transfer and 2.69 (
0.30 for CH transfer. The combination of our isotope
effect measurements in stoichiometric reactions with
Ryberg’s isotope effect measurements in catalytic reac-
tions make a convincing case for concerted transfer of
hydrogen from OH to N and from CH to Ru in 1, which
occurs outside the coordination sphere of ruthenium. In
addition, the activation parameters and equilibrium data
presented here increase the overall understanding of this
reaction, and in turn, the catalytic cycle as a whole.
Ack n ow led gm en t. Financial support from the De-
partment of Energy, Office of Basic Energy Sciences, is
gratefully acknowledged. Grants from NSF (CHE-962-
9688) and NIH (I S10 RR04981-01) for the purchase of
NMR spectrometers are acknowledged. We thank Pro-
fessor Per Ryberg for sharing his results prior to pub-
lication.
Su p p or tin g In for m a tion Ava ila ble: Preparation of deu-
terated alcohols, summary of kinetic runs, calculations of
isotope effects assuming a two-step mechanism with equal
barriers, and an Eyring plot. This material is available free of
charge via the Internet at http://pubs.acs.org.
Exp er im en ta l Section
Gen er a l. All syntheses and sample preparations were pre-
pared following Schlenk techniques or in a nitrogen atmosphere
J O0205457
(12) Nordin, S.; Andersson, P. G.; Ryberg, P. J . Org. Chem. Submit-
ted for publication in 2002.
(13) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J . Organometallics 1996, 15, 1518.
J . Org. Chem, Vol. 68, No. 5, 2003 2001