Kinetic hydrogen/deuterium effects in the direct hydrogenation of ketones catalyzed by a well-defined ruthenium diphosphine diamine complex

Article abstract of DOI:10.1021/ja9043104

The trans-dihydride complex trans-RuH₂(NH₂CMe ₂CMe₂NH₂)((R)-binap) (1) is an active catalyst for the homogeneous hydrogenation of ketones in benzene under pressure of H ₂ gas. The mechanism

Full text of DOI:10.1021/ja9043104

Published on Web 07/16/2009
Kinetic Hydrogen/Deuterium Effects in the Direct
Hydrogenation of Ketones Catalyzed by a Well-Defined
Ruthenium Diphosphine Diamine Complex
Marco Zimmer-De Iuliis and Robert H. Morris*
DaVenport Laboratory, Department of Chemistry, UniVersity of Toronto, Toronto,
Ontario M5S 3H6, Canada
Received May 28, 2009; E-mail: rmorris@chem.utoronto.ca
Abstract: The trans-dihydride complex trans-RuH
for the homogeneous hydrogenation of ketones in benzene under pressure of H
2
(NH
2
CMe
2
CMe
2
NH
2
)((R)-binap) (1) is an active catalyst
gas. The mechanism of
2
the catalysis is proposed to occur through a rapid transfer of a hydride from the ruthenium and a proton
from the amine on 1 to the carbonyl of the ketone to give the product alcohol and a hydrido-amido
intermediate RuH(NHCMe CMe NH )((R)-binap) (2). The dihydride is then regenerated by the turnover-
2 2 2
limiting heterolytic splitting of dihydrogen by complex 2. In this work the kinetic isotope effect (KIE) is
measured to be 2.0 ((0.1) for the reduction of acetophenone to 1-phenylethanol catalyzed by 1 using 8.0
atm of H
simplified catalyst RuH(NHCH
This supports the observation that deuterium scrambles into the catalyst when a pressure of D
We discuss the significance of these results relative to the KIE of 2 that was reported by Sandoval et al.
2
versus D
2
gas. DFT calculations predict a KIE of 2.1 for the described mechanism using the
CH NH )(PH with H or the catalyst RuD(NDCH CH ND )(PH with D
is used.
2
2
2
3
)
2
2
2
2
2
3
)
2
2
.
2
(
J. Am. Chem. Soc. 2003 125, 13490) for the hydrogenation/deuteriation of acetophenone catalyzed by
1
trans-RuH(η -BH
4
)((S)-tolbinap)((S,S)-dpen) in basic isopropanol/isopropanol-d
8
.
Introduction
variability in the value. Under highly basic conditions (KOtBu/
catalyst ) 200/1), a value of 2 was reported, while in the
absence of added KOtBu, a large value of 55 was reported. The
small value was proposed to result from the rate-determining
splitting of dihydrogen across a ruthenium-amido bond (struc-
The substitution of deuterium for hydrogen is a useful
technique in the study of the mechanism of catalytic hydrogena-
1
-16
17-19
tion reactions. Labeling the gas,
the substrate,
the
2
0,21
7,22-24
catalyst,
or the solvent
with deuterium is practical
25-29
ture I, Figure 1)
or by a proton shuttle involving the alcohol
and has yielded important mechanistic insights.
2
5
solvent (structure II, Figure 1). The large value was proposed
to result from the rate-limiting deprotonation of a cationic
dihydrogen complex by the alcohol solvent (B) (Figure 1,
structure III) although recent work by Hamilton and Bergens
suggests that such a dihydrogen complex is not found within
The measurement of kinetic isotope effects for catalytic
processes by use of dihydrogen and dideuterium is less common.
Noyori and co-workers measured the kinetic isotope effect (KIE)
of the asymmetric hydrogenation (or deuteriation) of acetophe-
none catalyzed by trans-RuH(η -BH
1
4
)((S)-tolbinap)((S,S)-dpen)
2
2,30
25
the catalytic cycle.
8
in isopropanol or isopropanol-d (Table 1). They found a large
(
(
(
1) Smith, G. V.; Musoiu, M. J. Catal. 1979, 60, 184–192.
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1843–1853.
1
1703–11714.
(
(
(
(
(
(
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1894.
1
998, 120, 10115–10125.
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Phys. Chem. A 2001, 105, 6305–6310.
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0, 379–381.
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2
(21) Ralph, C. K.; Hamilton, R. J.; Bergens, S. H. In The Handbook of
Homogeneous Hydrogenation; de Vries, J. G., Elsevier, C. J., Eds.;
Wiley-VCH: New York, 2007; Vol. 1, pp 359-371.
(22) Hamilton, R. J.; Bergens, S. H. J. Am. Chem. Soc. 2006, 128, 13700–
13701.
7
58.
(
10) Solladie-Cavallo, A.; Hoernel, F.; Schmitt, M.; Garin, F. J. Mol. Cat.
A 2003, 195, 181–188.
(
(
(
11) Dahlenburg, L.; Gotz, R. Eur. J. Inorg. Chem. 2004, 31, 888–905.
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1434.
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10.1021/ja9043104 CCC: $40.75  2009 American Chemical Society
J. AM. CHEM. SOC. 2009, 131, 11263–11269 9 11263

A R T I C L E S
Iuliis and Morris
Table 1. Kinetic Isotope Effects for Reactions of Dihydrogen Versus Dideuterium
a
reaction
RDS
k(H )/k(D
2
2
)
ref
1
II
b
H
2
+ PhCOMe + trans-RuH(η -BH
4
)((S)-tolbinap)((S,S)dpen) + KOtBu
)((S)-tolbinap)((S,S)-dpen)
H
H
H
H
H
2
+ N-Ru , TS I of Figure 1 or
2
25
II
2
+ N-Ru + ROH, TS II
+ HN-Ru
1
II
c
H
H
H
2
2
2
+ PhCOMe + trans-RuH(η -BH
4
2
2
2
55
1.22
1.23 ( 0.05
25
31
2
I
+ trans-IrCl(CO)(PPh
3
)
2
+ Ir
I
+ (Z)-PhHCdC(NHCOMe)(COOH) +
+ Rh
+
[
Rh(PPh
2
CH
+ (Z)-R-(acetamido)cinnamate + Ru(OAc)
+ 2-phenylpyrroline catalyzed by a chiral titanocene complex
2 2 2 2
CH PPh )(MeOH) ]
II
H
H
2
2
((R)-binap)
H
H
2
2
+ C-Ru
+ N-Ti
1.2
1.5
40
3
IV
2
a
b
c
Rate determining step. iPrOH solvent and KOtBu. iPrOH solvent without base.
3
6,37
38
iridium complexes
and chromium group complexes. Parkin
3
9
has reviewed EIE values for a variety of other reactions. The
turnover-limiting hydrogenolysis of a ruthenium-alkyl bond
was proposed for the hydrogenation of methyl (Z)-(R)-(aceta-
mido)cinnamate catalyzed by Ru(OAc)
2
((R)-binap), and this was
supported by a KIE of 1.2. In the hydrogenation of the imine
-phenylpyrroline catalyzed by a chiral titanocene complex, a
4
0
2
KIE of 1.5 ( 0.2 was attributed to the turnover-limiting
3
hydrogenolysis of a titanium-amido bond. The theoretical
maximum isotope effect for the gases themselves, neglecting
Figure 1. Three transition states proposed by Noyori and co-workers (ref
5) for the formation of the trans-dihydride in the presence of added KOtBu
I or II) and in the absence of added KOtBu (III) where the base is proposed
to be the alcohol solvent. P-P is (S)-tolbinap and the diamine is (S,S)-
dpen.
2
(
tunneling, is 20 where the H-H bond versus the D-D bond is
4
1
completely broken in the transition state.
Our research group had previously demonstrated that the
heterolytic splitting of dihydrogen is the turnover-limiting step
in the catalytic hydrogenation of acetophenone using trans-
Other relevant kinetic isotope effect (KIE) values are listed
in Table 1. In 1966 Chock and Halpern reported a KIE of 1.22
RuH
2
(NH
2
CMe
2
CMe
2
NH
2
27,28
)((R)-binap) (1) in benzene in the
Here we both measure and calculate
absence of added base.
3
1
for the oxidative addition of H
2 2 3 2
/D to trans-IrCl(CO)(PPh ) .
the kinetic isotope effect for this well-defined catalyst system.
To the best of our knowledge the current report is the first to
calculate by use of DFT the isotope effects for the catalytic
This and other data provided evidence for a side-on interacting
32,33
dihydrogen in the transition state.
Zhou et al. used empirical
methods to estimate the relative importance of tunneling, zero-
point energy, vibrational, translational and rotational partition
2
H -hydrogenation of ketones based on ruthenium phosphine/
diamine systems and a rare example where the results of both
experiment and theory of the KIE for catalytic hydrogenation
are compared. While dihydrogen splitting is turnover-limiting
3
4
functions that make up this small KIE value. Significantly,
Brown and Parker found that the KIE for the hydrogenation of
+
(
Z)-acetamidocinnamic acid catalyzed by [Rh(dppe)(OHMe)
2
]
42a
in our system, in a related study Comas-Vives et al. utilized
2
in methanol is identical at 1.23 ( 0.05. Landis and co-workers
proposed that this value, on the basis of DFT calculations, results
from the combined isotope effects of three steps, first the
addition of dihydrogen to rhodium(I) to give a dihydrogen
complex in a rapid equilibrium step (with an inverse equilibrium
isotope effect (EIE) of 0.8) followed by oxidative addition in a
second equilibrium step to give a rhodium(III) dihydride (inverse
EIE of 0.8) followed by a slow migratory-insertion of the olefin
into the rhodium-hydride bond (KIE of 1.8), giving an overall
DFT methods to calculate the isotope effects for the transfer of
hydrogen or deuterium from a Shvo-type ruthenium catalyst to
formaldehyde. They found that the concerted outer-sphere
transfer transition state that was proposed by Casey and co-
42b
workers was most consistent with the calculated and experi-
42c
mentally observed KIE.
Experimental Details
3
5
KIE of 1.15. The source of the inverse equilibrium isotope
effect (0.65-0.8) for H coordination has been explained for
General. Unless otherwise stated, all manipulations were carried
out under Ar using standard Schlenk and glovebox techniques. The
2
27,28
2
literature method for the preparation of RuH (tmen)((R)-binap),
where tmen is NH CMe CMe NH , was modified to provide a better
yield (see below). All of the solvents were distilled under argon
2
2
2
2
(
(
(
(
25) Sandoval, C. A.; Ohkuma, T.; Mu n˜ iz, K.; Noyori, R. J. Am. Chem.
Soc. 2003, 125, 13490–13503.
26) Abdur-Rashid, K.; Lough, A. J.; Morris, R. H. Organometallics 2000,
1
9, 2655–2657.
(36) Abu-Hasanayn, F.; Krogh-Jespersen, K.; Goldman, A. S. J. Phys.
Chem. 1993, 97, 5890–5896.
27) Abdur-Rashid, K.; Faatz, M.; Lough, A. J.; Morris, R. H. J. Am. Chem.
Soc. 2001, 123, 7473–7474.
28) Abdur-Rashid, K.; Clapham, S. E.; Hadzovic, A.; Harvey, J. N.; Lough,
A. J.; Morris, R. H. J. Am. Chem. Soc. 2002, 124, 15104–15118.
29) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40–73.
30) Hamilton, R. J.; Leong, C. G.; Bigam, G.; Miskolzie, M.; Bergens,
S. H. J. Am. Chem. Soc. 2005, 127, 4152–4153.
(37) Abu-Hasanayn, F.; Krogh-Jespersen, K.; Goldman, A. S. J. Am. Chem.
Soc. 1993, 115, 8019–8023.
(38) Bender, B. R.; Kubas, G. J.; Jones, L. H.; Swanson, B. I.; Eckert, J.;
Capps, K. B.; Hoff, C. D. J. Am. Chem. Soc. 1997, 119, 9179–9190.
(39) Parkin, G. J. Labelled Compd. Radiopharm. 2007, 50, 1088–1114.
(40) Kitamura, M.; Tsukamoto, M.; Bessho, Y.; Yoshimura, M.; Kobs, U.;
Widhalm, M.; Noyori, R. J. Am. Chem. Soc. 2002, 124, 6649–6667.
(41) Johnson, H. S. Gas Phase Reaction Rate Theory; The Ronald Press
Company: New York, 1966.
(
(
(
(
(
31) Chock, P. B.; Halpern, J. J. Am. Chem. Soc. 1966, 88, 3511.
32) Halpern, J. Acc. Chem. Res. 1970, 3, 386–392.
33) Hyde, E. M.; Shaw, B. L. J. Chem. Soc., Dalton Trans. 1975, 765–
7
67.
(42) (a) Comas-Vives, A.; Ujaque, G.; Lled o´ s, A. Organometallics 2007,
26, 4135–4144. (b) Casey, C. P.; Bikzhanova, G. A.; Cui, Q.; Guzei,
I. A. J. Am. Chem. Soc. 2005, 127, 14062–14071. (c) Casey, C. P.;
Singer, S. W.; Powell, D. R.; Hayashi, R. K.; Kavana, M. J. Am. Chem.
Soc. 2001, 123, 1090–1100.
(
34) Zhou, P.; Vitale, A. A.; San Filippo, J., Jr.; Saunders, W. H., Jr. J. Am.
Chem. Soc. 1985, 107, 8049–8054.
(
35) Landis, C. R.; Hilfenhaus, P.; Feldgus, S. J. Am. Chem. Soc. 1999,
1
21, 8741–8754.
1
1264 J. AM. CHEM. SOC. 9 VOL. 131, NO. 31, 2009

Mechanism of Catalytic Hydrogenation Reactions
A R T I C L E S
using sodium/benzophenone ketyl. Acetophenone was purchased
from Aldrich and distilled under argon and dried over P
2 5 2
O . D
(
99.8% D) gas was purchased from Cambridge Isotope Laboratories.
Chromatography was carried out on a Perkin-Elmer Autosystem
XL with Chrompack capillary column (Chirasil-Dex CB 25 m ×
0
2
.25 mm) utilizing an H carrier gas at a column pressure of 5 psi,
an oven temperature of 130 °C, an injector temperature of 250 °C,
and an FID temperature of 275 °C. The retention times were 5.0
min for acetophenone, 8.4 min for (R)-1-phenylethanol, and 9.1
min for (S)-1-phenylethanol.
trans-RuH
charged with 150 mg (0.17 mmol) of RuHCl((R)-binap)(tmen), 172
mg of KHB(sec-Bu) (1.0 M solution in THF, 0.19 mmol) and 1
mL of THF, yielding a dark-red solution. The mixture was stirred
under 1 atm of H for 3 h and then filtered over a pad of Celite.
Pentane (8 mL) was added to the filtrate, and the mixture was stirred
under H
2
((R)-binap)(tmen) (1). A 50 mL Schlenk flask was
3
2
2
for 3-4 h, after which time an orange-red precipitate
Figure 2. Simplification made for 1 and 2 for the calculation of the
structures shown in Scheme 1.
formed in the light-orange solution. The bright-orange solid was
filtered, washed twice with 1 mL of pentane, and then dried for 10
1
performed on the optimized structure to obtain values of ∆G, ∆H,
and ∆S at 1 atm and 298 K. The QST2 or QST3 method was
utilized to locate transition states. All transition states were found
to have one imaginary frequency. The calculated Atomic Polar
Tensor (APT) charges were used. The APT charge is the derivative
of the forces on the atoms with respect to an applied external electric
field and yield atomic charges that more accurately reflect the charge
min under vacuum. Yield: 108 mg, 76%. H NMR (C
6 6
D ) δ: -4.80
2
(
0
t, JHP ) 17.2 Hz, 2H, RuH), 0.22 (s, 6H, Me), 1.00 (s, 6H, Me),
2
2
.90 (d, JHH ) 10.2 Hz, 2H, NH) 3.11 (d, JHH ) 10.0 Hz, 2H,
31 1
NH), 6.50-8.75 (m, 32H). P{ H} (C
agree well with previously reported values.
Kinetics. All of the hydrogenation reactions were carried out at
constant pressures of H or D using a stainless steel 50 mL Parr
6 6
D ) δ: 89.6 (s). These values
27
2
2
5
0
distribution rather than individual atomic charges. Owing to the
large size of 1 and 2, (R)-binap was modeled as two cis-PH groups,
hydrogenation reactor with a glass liner. The reactor was modified
such that in one of the ports a stainless steel sampling tube was
added. Please see the Supporting Information for further details
regarding the modifications to the reactor and the method of
sampling used. The reactor was degassed by evacuation for 15 min,
3
and 2,3-dimethyl-2,3-diaminobutane was simplified to ethylene
diamine (Figure 2). In order to calculate the isotope effect, the
keyword “ISO)2” was added next to the required protons in the
input file and then a full optimization and vibrational analysis was
performed again to determine the free energy of the deuterated
model species.
followed by refilling with 8.0 atm of H
2 2
or D gas, and this was
repeated three times. Standard solutions of acetophenone (0.833
-
3
M) and RuH
2
(tmen)((R)-binap) (2.28 × 10 M) were prepared by
Predicting the Kinetic Isotope Effect. Kinetic isotope effects
dissolving the appropriate amount of compound in 10 mL of C
H .
6 6
(
(
KIE) were calculated using conventional transition state theory
TST). For the reaction in which reactant, R, goes to the transition
Reaction mixtures were prepared by pipetting the appropriate
amount of substrate stock solution into a 3 mL volumetric flask
and catalyst stock solution into a 2 mL volumetric flask and diluting
5
1,52
state, TS, we may write the following equations.
6 6
with C H , to give a total volume of 5 mL upon mixing. Substrate
kH
k T
H
D
H
B
◦q
and catalyst solutions were taken up via separate syringes and then
injected into the reactor against a flow of gas. Samples were taken
every two minutes. Concentrations of 1-phenylethanol were deter-
mined via gas chromatography.
R
R
98 TS , k )
exp(-∆G /RT)
(1)
(2)
H
H
h
kD
k T
D
B
◦q
98 TS , k )
exp(-∆G /RT)
D
D
h
Computational Details
In eq 1, k
transition state for the protio species, respectively. The analogous
, RH and TSH are the rate constant, reactant and
H
4
3
General. All calculations were performed using Gaussian03.
Calculations used the mPW1PW91 density functional method.
4
4,45
°q
°q
equations when D
respectively the activation barriers for the protio and deutero species
at a given temperature T, h is Planck’s constant and k is
Boltzmann’s constant. If eqs 1 and 2 are combined, then we can
2 H D
is used are shown in eq 2. ∆G and ∆G are
4
6
Ruthenium was treated with the SDD basis set to include
relativistic effects and an effective core potential, and H, C, N,
and P were treated with the triple-ꢀ basis set 6-311++G** which
includes diffuse functionals and additional p-orbitals on H as well
as additional d-orbitals on C, N, O, and P. It has been previously
demonstrated that this combination of functional is superior to the
B
H D
express the KIE as the ratio of k /k as shown below.
kH
◦q
◦q
H
KIE )
) exp((∆GD - ∆G )/RT)
(3)
4
7,48
B3LYP functional and other ECP.
In addition, Lynch et al.
kD
have reported that the mPW1PW91 functional is better for the
prediction of transition states and energy barriers. All structures
were optimized in the gas phase. Full vibrational analyses were
4
9
It should be noted that the conventional TST adopted in the
current study assumes that the geometry of the protio and deutero
TS in the proposed reaction mechanisms stays the same. Also,
tunneling and recrossing effects have not been accounted for since
such a treatment is beyond the scope of the present study.
(
43) Frisch, M. J.; et al. Gaussian 03, Revision C.02 ed; Gaussian Inc.:
Wallingford, CT, 2004.
(
(
44) Adamo, C.; Barone, V. J. Chem. Phys. 1998, 108, 664–675.
45) Burke, K.; Perdew, J. P.; Wang, Y. Electronic Density Functional
Theory: Recent Progress and New Directions; Plenum: New York,
Results and Discussion
The new sampling method and reactor charging method
allowed the economical use of deuterium gas so that the kinetics
1
997.
(
46) Leininger, T.; Nicklass, A.; Stoll, H.; Dolg, M.; Schwerdtfeger, P.
J. Chem. Phys. 1996, 105, 1052–1059.
(
(
47) Gusev, D. G. J. Am. Chem. Soc. 2004, 126, 14249–14257.
(50) Cioslowski, J. J. Am. Chem. Soc. 1989, 111, 8333–8336.
(51) Laidler, K. J. Chemical Kinetics, 3rd ed.; Harper & Row: New York,
1987.
48) Zhang, Y.; Guo, Z.; You, X.-Z. J. Am. Chem. Soc. 2001, 123, 9378–
9
387.
(
49) Lynch, B. J.; Truhlar, D. G. J. Phys. Chem. A 2001, 105, 2936–2941.
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J. AM. CHEM. SOC. 9 VOL. 131, NO. 31, 2009 11265

A R T I C L E S
Iuliis and Morris
a
The rate constant for H
2
is 2.5 ( 0.1 M-1 s-1 which is slightly
Table 2. Kinetic Data Determined for Complex 1
-
1
-1 28
lower than that of the literature value of 3.6 M s . The
P(H
[H
2
or D
or D
2
), atm;
], M
k ) ν
0
/[Ru]/
2
or D ], M
-1
-1 -1
gas
[Ru], M
2
2
0
v , M s
[H
2
s
rate constant using D
under the same conditions is 1.32 ( 0.05
taking into account the slightly higher solubility of D
than that of H in benzene. Therefore, the kinetic isotope effect
2
-
1
-1
-
-
4
4
-2
-2
-5
M
s
H
D
2
4.6 × 10
4.6 × 10
8.0; 2.1 × 10
8.0; 2.3 × 10
2.4 ((0.1) × 10
2.5 ((0.1)
1.25 ((0.05)
2
b
-5
2
1.32 ((0.05) × 10
2
is 2.0 ( 0.1. The magnitude of this isotope effect is indicative
of an early transition state in which there is only a little
weakening of the H-H bond.
a
b
2
93 °C, benzene, 0.166 M acetophenone. The solubility of D
2
is
5
3
2
about 1.09 times greater than that of H .
The mechanism of hydrogenation using 1 has been proposed
2
7,28
to occur as shown in Scheme 1.
As the catalysis proceeds
using D gas, eventually all of the N-H protons and the Ru-H
2
hydrides will be replaced with deuterium according to this
mechanism. The time for the replacement of these hydrogens
for deuteria can be estimated from the turnover frequency of
-
1
-5
-1
the reaction with D
×
2
gas of 0.028 s (1.32 × 10 M s /4.6
10 M) or 36 s per turnover. After the first addition of D
to 2 to give trans-RuD(H)((R)-binap)(NDHCMe CMe NH ), D
can be added to a ketone from the side of the molecule
containing the DRuND unit, or H can be added from the
HRuNH unit on the other side of the otherwise C -symmetrical
-
4
2
2
2
2
2
2
2
trans-dihydride (ignoring the H vs D distinction when determin-
ing the symmetry). The HRuNH transfer should be faster so
that after less than 16 cycles of 36 s (480 s), the catalyst will
be in the form trans-RuD
2
((R)-binap)(ND
2
CMe
2 2 2
CMe ND ). The
Figure 3. Plot of the average concentration of 1-phenylethanol determined
using 1 with H and D . The data points represent the average of results of
four experiments for the H line (gray squares) and, three experiments for
the D line (black circles).
rapid deuteration of 1 in toluene under D
2
gas has been reported
2
2
27
previously. Therefore, complete deuteration in these positions
of the catalyst actually takes place much earlier than 480 s. Thus,
the deuteration of the catalyst must be taken into account when
calculating the kinetic isotope effect for the catalytic process
by use of the DFT method (see below).
2
2
Scheme 1. Mechanism for the Heterolytic Splitting of Dihydrogen,
a
Starting with B and the Outer-sphere Hydrogenation of Acetone
Often alcohols are the best solvents for the hydrogenation of
ketones catalyzed by ruthenium complexes containing primary
7
,29,54,55
amines and phosphines.
that, as alcohol is produced in the hydrogenation of acetophe-
none catalyzed by RuH(NHCMe py)(((R)-binap) in benzene, the
In one case our group showed
2
56
reaction speeds up in an autocatalytic fashion. An explanation
for all of these observations is a proton-shuttle transition state
analogous to II shown in Figure 1. Calculations have shown
that this six-membered transition state has a lower barrier to
dihydrogen splitting than the four-membered one analogous to
5
6,57
I.
However, the rate of the hydrogenation of acetophenone
catalyzed by 1 remains constant as the 1-phenylethanol con-
2
8
centration increases (Figure 3) so that an alcohol-assisted
splitting of dihydrogen is not operative in this case. The bulkier
diamine of 1 might destabilize the hydrogen-bonded network
required for the transition state II of Figure 1.
Another possible complication in understanding the mecha-
nism of the hydrogenation of acetophenone catalyzed by 1 is
the formation of the alkoxide complex trans-RuH(OCHMePh)
(
binap)(tmen) by the known, reversible reaction of 1-phenyle-
2
8
a
thanol with the amido complex 2. This reaction does not
appear to be important under the catalytic conditions of low
concentrations of catalyst and substrate utilized in this work.
In addition the 1-phenylethanol is very weakly acidic in benzene,
a low dielectric solvent, disfavoring the protonation of the amido
complex to give a cationic complex that might lead to the
formation of a transition state like III of Figure 1. The work of
P
2
3 2
) (PH ) .
of the reactions shown in eq 4 could be made at 8 atm pressure,
0 °C. The results are shown in Table 2 and Figure 3.
2
(
(
(
54) Rautenstrauch, V.; Hoang-Cong, X.; Churlaud, R.; Abdur-Rashid, K.;
Morris, R. H. Chem.sEur. J. 2003, 9, 4954–4967.
55) Genov, D. G.; Ager, D. J. Angew. Chem., Int. Ed. 2004, 43, 2816–
2
819.
56) Hadzovic, A.; MacLaughlin, C. M.; Song, D.; Morris, R. H. Orga-
nometallics 2007, 26, 5987–5999.
(
53) Muccitelli, J.; Yen, W.-Y. J. Soln. Chem. 1978, 7, 257.
1266 J. AM. CHEM. SOC. 9 VOL. 131, NO. 31, 2009
1

Mechanism of Catalytic Hydrogenation Reactions
A R T I C L E S
Figure 4. Calculated structures of models B and C.
2
2,58
Hamilton and Bergens
shows that, when isopropanol is the
solvent, the alkoxide complexes trans-RuH(OR)(binap)(dpen)
are the resting states for this catalyst system.
Calculations
The Catalytic Cycle. The cycle shown in Scheme 1 has been
explored previously by use of DFT methods, but different
methods and basis sets were employed and the isotope effects
2
8,57,59
were not predicted.
We present here the results of our
calculation of the geometries and energies of the species using
the mPW1PW91 functional in combination with the SDD basis
set for Ru and the triple-ꢀ basis set 6-311++G** functional
for H, N, C, and P. The results match well the experimentally
determined geometries of analogous complexes where available,
and the activation barrier for the catalytic reaction and the kinetic
isotope value.
Figure 5. Reaction coordinate diagram for the heterolytic splitting of H
gray squares) or D gas (black circles, energies shown in italics). The
2
reaction starts with B + H or D , followed by formation of an η -
2
(
2
2
2
The cycle begins with the amido, B, which reacts with
2
dihydrogen/η -dideuterium adduct, C. This leads to the transition state, D*,
followed by formation of the trans-dihydride/trans-dideuteride A. Energies
2
dihydrogen to form an η -dihydrogen complex, C. The calcu-
lated structures of B and C are shown in Figure 4. The amido
bond in B between Ru and N1 is notably shorter (1.97 Å) than
the Ru-N2 amino bond (2.17 Å). Further evidence of Ru-N1
multiple bond character is that N1 is essentially planar since
2 2
are reported relative to free B and free H or D .
the gas phase (Figure 5). Deuterium equilibrium isotope effects
have been studied for the reversible addition of H and D to a
2
2
the sum of the angles around N1 (θRu-N1-H4 + θH4-N1-C1
+
number of complexes in solution, and it was found that
deuterium binds more strongly than does dihydrogen.
2
38,60
θ
C1-N1-Ru ) 355.2°) is nearly 360°. This shows that N1 is sp
hybridized which would allow the free lone pair to donate into
an empty d orbital on the Ru. Also of note is the basicity of
N1, as evidenced by the APT charge of -0.51 ESU (cf. APT
of -0.27 ESU on amino N2). The incoming dihydrogen can
coordinate to the vacant site on Ru trans to H3. The H1-H2
distance in C is 0.81 Å, indicating that the dihydrogen is not
The dihydrogen adduct C leads directly to the transition state
D* for the heterolytic splitting of H (Figure 6). In the transition
2
state, the H1-H2 distance has increased from 0.81 in C to 1.00
Å in D*. The magnitude of the negative charge on N1 has also
increased from -0.52 to -0.62 ESU. The dihydrogen is now
polarized, with H1 assuming a positive charge of 0.44 ESU,
and H2, a negative charge of -0.20 ESU. The transition-state
very activated at this stage. The Ru-H1 and Ru-H2 distances
2
are nearly identical: 1.84 and 1.83 Å, respectively. The η -H
2
-1
motion associated with the imaginary frequency (1172i cm )
ligand is coordinated in such a way as to orient itself parallel
to the Ru-N1 bond with H1 closer to N1. The coordination of
2
the H in C also results in the loss of multiple bond character
involves the simultaneous lengthening of the H1-H2 bond and
the pyramidalization of N1. There is also evidence of the trans-
influence that H2 has on H3 as the Ru-H3 bond forms since
the Ru-H3 bond elongates from 1.63 in D* to 1.7 Å in A. The
structure of D* with an H1-H2 distance of 1.00 Å can be
between Ru and N1. The Ru-N1 bond distance is elongated to
2
.11 Å and the sum of the angles around N1 is far from planar,
3
which would be expected for an sp hybridized nitrogen
considered as a completely unstable elongated dihydrogen
(
θ
Ru-N1-H4 + θH4-N1-C1 + θC1-N1-Ru ) 328.9°). Thus, the
60-64
complex.
Furthermore, no bond has yet been formed
calculated structure of C is consistent with the cartoon shown
in Scheme 1, in which the dative π-bond from the amido group
is lost and the lone pair has been pushed back onto the nitrogen.
between N1 and H1, as indicated by the N1-H1 distance of
.42 Å.
1
Compared to free H
increases to 7.78 kcal/mol for H
2
or D
2
and B, the relative energy of C
and 7.33 kcal/mol for D , in
(
(
60) Kubas, G. J. Metal Dihydrogen and Sigma-Bond Complexes; Kluwer
Academic/Plenum: New York, 2001.
61) Kubas, G. J. Chem. ReV. 2007, 107, 4152–4205.
2
2
(
(
(
57) Hedberg, C.; K a¨ llstr o¨ m, K.; Arvidsson, P. I.; Brandt, P.; Andersson,
P. G. J. Am. Chem. Soc. 2005, 127, 15083–15090.
58) Hamilton, R. J.; Bergens, S. H. J. Am. Chem. Soc. 2008, 130, 11979–
1987.
59) Chen, Y.; Tang, Y.; Lei, M. Dalton Trans. 2009, 2359–2364.
(62) Albinati, A.; et al. J. Am. Chem. Soc. 1993, 115, 7300-7312.
(63) Hasegawa, T.; Li, Z.; Parkin, S.; Hope, H.; McMullan, R. K.; Koetzle,
T. F.; Taube, H. J. Am. Chem. Soc. 1994, 116, 4352–4356.
1
(64) Klooster, W. T.; Koetzle, T. F.; Jia, G.; Fong, T. P.; Morris, R. H.;
Albinati, A. J. Am. Chem. Soc. 1994, 116, 7677–7681.
J. AM. CHEM. SOC. 9 VOL. 131, NO. 31, 2009 11267

A R T I C L E S
Iuliis and Morris
Figure 6. Calculated structures of the models D* and A. Selected bond lengths (Å) and angles (deg): D*: Ru-P1 ) 2.23, Ru-P2 ) 2.25, Ru-N1 ) 2.17,
Ru-N2 ) 2.18, Ru-H3 ) 1.63, H1-H2 ) 1.01, Ru-H1 ) 1.80, Ru-H2 ) 1.82, N1-H1 ) 1.41, P1-Ru-P2 ) 93.4. Selected APT charges (ESU) of
D*: P1 ) 1.03, P2 ) 1.04, N1 ) -0.62, N2 ) -0.28, H1 ) 0.44, H2 ) -0.20, H3 ) -0.15.
The relative free energy of D* at 298 K, which corresponds
to the activation barrier for H heterolytic splitting, is 16.57
kcal/mol for H and 17.00 kcal/mol for D . The calculated
energy barrier for H agrees fairly well with the experimentally
determined activation barrier (∆G 293 K) of 14.5 kcal/mol when
Table 3. Isotope Effects Calculated for the Heterolytic Splitting of
Dihydrogen According to Scheme 1 by Various Isotopomers of the
Ruthenium Complex 2
2
2
2
q
∆G
D
293 K
2
q
D
q
H
q
entry
isotopomer
kcal/mol ∆G
- ∆G
KIE
2
8
using catalyst 1. For comparison the activation barrier for the
dihydride complex A transferring dihydrogen to acetone in the
six-membered Ru-H-C-O-H-N transition state shown in
Scheme 1 is calculated to be only 9.9 kcal/mol (see the
Supporting Information). This low-barrier hydrogenation step
completes the cycle of Scheme 1.
1
2
3
4
5
RuD(NDCH
RuH(NHCH
RuD(NHCH
RuH(NDCH
RuD(NDCH
2
2
2
2
2
CH
CH
CH
CH
CH
2
2
2
2
2
ND
NH
NH
ND
ND
2
2
2
2
2
)(PH
)(PH
)(PH
)(PH
)(PH
3
)
3
)
3
)
3
)
3
)
2
2
2
2
2
17.00
16.72
16.89
16.96
0.43
0.15
0.32
0.39
0.53
2.1
1.3
1.7
1.9
2.5
+ MeOD 10.45
5
7
59
Hedberg et al. and Chen et al. have also calculated the
activation barrier for the cleavage of H based on model complex
determined KIE would be larger. The magnitude of the
experimentally determined KIE suggests an early transition state;
that is, the H-H bond is not completely broken, and the
2
B. Hedberg et al. used single-point energy calculations deter-
mined with the B3LYP functional and the triple-ꢀ basis set
2
structure of D* also supports an incomplete cleavage of H in
LACV3p+** and determined that the activation barrier for H
2
the transition state.
cleavage was 17.2 kcal/mol. This value is also close to the
experimentally reported value. Chen et al. used the same
functional with the LANL2DZ basis set for ruthenium and
The isotope effect was also calculated for the catalyst in
progressive states of deuteration (Table 3). The KIE for no
deuteration of the catalyst (1.3) is not consistent with the
observations. When only the Ru-D bond is present in
6
-31+G** for H, N, C, and P. They calculated the activation
barrier for H cleavage to be 22.0 kcal/mol.
2
2 2 2 3 2
RuD(NHCH CH NH )(PH ) , the KIE increases to 1.7. Deu-
The structure following transition state D* in Scheme 1 is
the trans-dihydride A. The H1 · · ·H2 distance is now 2.54 Å
teration of the ethylene diamine N-H groups only (entry 4)
results in an increase in KIE to 1.9. The KIE calculated for the
(
Figure 6), showing that there is no longer a bond between the
proton-shuttle transition state II (Figure 1) involving H
2
and
two atoms. Of note is that both H1 and H2 are aligned to
accommodate an interaction with the polar multiple bond of an
incoming substrate such as a carbonyl or imine moiety in a
hydrogenation reaction. The charge on the proton H1 is positive,
MeOH versus D and MeOD is 2.5 (entry 5). In the latter case
2
the catalyst will be completely deuterated as shown in Table 3.
Therefore, the best agreement is the value for entry 1 as
discussed.
0
.14 ESU, while that on the hydride H2 is negative, -0.22 ESU.
Comparison with the Results from Noyori and Co-workers.
Sandoval et al. reported KIE values that greatly depended on
the conditions of the hydrogenation or deuteriation of acetophe-
2
5
This charge distribution would also aid in the orientation of
the incoming substrate, since the more electronegative atom of
the polar multiple bond (O or N) would preferentially interact
with H1, while the electropositive atom (C) would interact with
H2. The energy of A is -1.47 kcal/mol as a dihydride and -2.76
none in isopropanol or isopropanol-d
8
catalyzed by the complex
1
4
trans-RuH(η -BH )((S)-tolbinap)((S,S)-dpen) (Table 1). The KIE
value of 2 for their system with excess base added (KOtBu)
kcal/mol as a dideuteride relative to the energy of A plus H
, indicating that this reaction is thermodynamically favorable.
Calculation of the Kinetic Isotope Effect. This isotope effect
2
or
best matched our value of 2.0. The value of 55 for the system
-
D
2
in the absence of base (other than the BH
4
ligand which is, in
2
2
fact, a base ) is not consistent with our result.
was calculated for the system RuH(NHCH
plus H
CH ND
2
CH
2
NH
2
)(PH
3
)
2
(B)
2
Noyori and co-workers reported that the KIE of 2 corresponds
to the neutral hydrido-amido complex RuH((S)-tolbinap)(dpen-
amido) reacting with H either via the four-membered TS I of
2
2
versus the partially deuterated catalyst RuD(NDCH
q
2
2
)(PH
3
)
2
plus D
2
in the gas phase. The ∆G
H
value
needed for eq 3 above refers to the free energy of the transition
Figure 1 or the six-membered, proton-shuttle TS II of Figure
1. Our results indicate that the four-membered transition state
I is more likely.
q
state D* minus the free energy of B plus H
2
. Similarly the ∆G
D
value refers to the free energy difference for the corresponding
deuterated species (Table 3). The calculated KIE effect for the
The low-temperature observation by NMR of intermediates
5
8
heterolytic splitting of H
2
is 2.1 (Table 3). This value agrees
8
in isopropanol-d reported by Hamilton and Bergens and our
well with that of the measured value for 1 (KIE ) 2.0 ( 0.1).
Therefore, quantum mechanical tunneling of hydrogen through
the barrier to hydrogen splitting does not appear to be important
in the catalytic reaction of 1; otherwise, the experimentally
group’s observations on the effect of iPrOH and base on the
2
8
activity of catalyst 1 suggest that the presence of base favors
the formation of the amido complex. The resting state of the
catalysts in neutral iPrOH are the complexes trans-RuH(OiPr)
1
1268 J. AM. CHEM. SOC. 9 VOL. 131, NO. 31, 2009

Mechanism of Catalytic Hydrogenation Reactions
A R T I C L E S
(
diphosphine)(diamine). Our use of benzene, a low dielectric
using catalyst 1 in the hydrogenation of acetophenone in
constant solvent, disfavors the formation of cationic species such
as the cationic transition state III of Figure 1 that are formed
by reaction with acidic alcohols. The alcohol in our study is
the product, 1-phenylethanol, which is a much weaker acid in
benzene than is neat isopropanol in the Noyori and Bergens
systems.
2
benzene. For the first time, the activation barrier for D splitting
by the deuterated model complex B is calculated to be 17.0
kcal/mol.
The predicted KIE value of 2.5 by DFT methods for an
alternative mechanism for the catalysis involving the alcohol-
assisted splitting of dihydrogen is not consistent with the
observed value of 2.0. The value of 2.0 is the same as the isotope
Conclusions
effect observed by Sandoval et al. for the hydrogenation/
1
In summary, the kinetic isotope effect has been determined
experimentally to be 2.0 ( 0.1 for the homogeneous hydrogena-
deuteration of acetophenone catalyzed by trans-RuH(η -BH
4
)((S)-
tolbinap)((S,S)-dpen) in isopropanol/deuterated isopropanol
when KOtBu is added. This might indicate that the transition
state for the Noyori system is also the splitting of dihydrogen
directly over the ruthenium-amido bond as observed for our
catalyst 1.
tion of acetophenone catalyzed by trans-RuH
2
(NH
2
CMe
2
CMe
) at
2
NH
2
)((R)-binap) in benzene under 8 atm of gas (H
2
or D
2
room temperature. The KIE was also calculated by use of DFT
methods to be 2.1 on the basis of the previously proposed
mechanism involving the turnover-limiting, heterolytic splitting
of dihydrogen or dideuterium across the ruthenium-amido bond
Acknowledgment. NSERC is thanked for a Discovery and a
Research Tools (reactor) Grant to R.H.M.
of the model complex RuH(NHCH
2
CH )(PH
2
NH
2
3 2
) (B) or the
deuterated form RuD(NDCH
ment and theory agree well.
2
CH
2
ND )(PH ) . Thus, the experi-
2
3 2
Supporting Information Available: Complete refs 43 and 62,
a detailed procedure for the catalytic reaction, and coordinates
and energies from the DFT calculations including those for the
hydrogenation of acetone. This material is available free of
charge via the Internet at http://pubs.acs.org.
The splitting of dihydrogen proceeds via transition state D*
which has a four-membered Ru · · ·H· · ·H· · ·N ring as proposed
2
8
earlier. The activation barrier at 298 K calculated using H
2
gas is 16.6 kcal/mol, agreeing reasonably well with the measured
value of 14.5 kcal/mol for the activation barrier (∆G 293 K) when
q
JA9043104
J. AM. CHEM. SOC. 9 VOL. 131, NO. 31, 2009 11269