Unexpected CO Dependencies, Catalyst Speciation, and Single Turnover Hydrogenolysis Studies of Hydroformylation via High Pressure NMR Spectroscopy

Article abstract of DOI:10.1021/jacs.6b12533

Rhodium bis(diazaphospholane) (BDP) catalyzed hydroformylation of styrene is sensitive to CO concentration, and drastically different kinetic regimes are affected by modest changes in gas pressure. The Wisconsin High Pressure NMR Reactor (WiHP-NMRR) has e

Full text of DOI:10.1021/jacs.6b12533

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Article
Unexpected CO Dependencies, Catalyst Speciation,
and Single-Turnover Hydrogenolysis Studies of
Hydroformylation via High Pressure NMR Spectroscopy
Anna C. Brezny, and Clark R. Landis
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Jan 2017
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Unexpected CO Dependencies, Catalyst Speciation, and
Single Turnover Hydrogenolysis Studies of Hydroformylation
via High Pressure NMR Spectroscopy
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Anna C. Brezny and Clark R. Landis*
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706
Catalysis, hydroformylation, rhodium, bis(diazaphospholane), hydrogenolysis, kinetics, mechanistic studies.
ABSTRACT: Rhodium bis(diazaphospholane) (BDP) catalyzed hydroformylation of styrene is sensitive to CO
concentration and drastically different kinetic regimes are affected by modest changes in gas pressure. The Wisconsin
High Pressure NMR Reactor (WiHP-NMRR) has enabled the observation of changes in catalyst speciation in these
different regimes. The apparent discrepancy between catalyst speciation and product distribution led us to report the first
direct, non-catalytic quantitative observation of hydrogenolysis of acyl dicarbonyls. Analysis and modeling of these
experiments show that not all catalyst is shunted through the off-cycle intermediates and this contributes to the drastic
mismatch in selectivities. The data herein highlight the complex kinetics of Rh(BDP) catalyzed hydroformylation. In this
case the complexity arises from competing kinetic and thermodynamic preferences involving formation and
isomerization of the acyl mono- and dicarbonyl intermediates and their hydrogenolysis to give aldehydes.
INTRODUCTION
Hydroformylation (Scheme 1) is one of the largest
scale organotransition metal catalyzed reactions in
chemical industry. The transformation of an alkene to an
aldehyde with 1:1 CO/H2 (syngas) is a one-carbon
homologation that adds considerable functionality in a
1
single step.
Figure 1. Structure of (S,S)-3,4-bis(diazaphospholane) (BDP).
This work uses racemic ligand with R = H.
Scheme 1. Hydroformylation of Alkenes
In 1961, Heck and Breslow proposed a mechanism
for cobalt-catalyzed hydroformylation that remains
generally accepted for rhodium systems (Scheme 2).
5
Although this mechanism outlines the sequence of
transformations that constitute the overall reaction, only
more detailed kinetic and extra-kinetic analyses can
reveal the origins of regioselectivity, enantioselectivity,
and rate control. Such analyses include applications of
isotopic labels, interception and characterization of
catalyst intermediates, operando examination of catalyst
speciation, and kinetic studies of the catalytic reaction.
For example, deuterioformylation studies probe the
reversibility of the formation of Rh-alkyls (4). With some
catalysts and reaction conditions, this step is irreversible,
thus indicating that selectivity is fixed at the alkene
Although commodity scale applications primarily
focus on the linear aldehyde, the chiral, branched
aldehydes are attractive precursors for fine-chemical
2
products such as pharmaceuticals. In the last 25 years
there have been great advances in the development of
3
chiral ligands for asymmetric hydroformylation (AHF). A
challenge in this reaction is the ability to obtain both
high regio- and enantioselectivity while maintaining
useful rates. The class of 3,4-bis(diazaphospholane)
(
BDP) ligands have shown excellent selectivity for a wide
range of structurally diverse alkenes with turnover
4
6
frequencies greater than one per second (Figure 1).
insertion step.
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Vogt’s work combined kinetic and operando IR
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spectroscopic studies of the hydroformylation of 3,3-
dimethylbut-1-ene as catalyzed by rhodium complexes of
monodentate phosphites demonstrated that (1) catalyst
primarily populates the acyl dicarbonyl 7 with hydrido
dicarbonyl 1 appearing in greater concentration as the
alkene is consumed; (2) at high alkene concentrations the
catalytic reaction obeys type-II kinetics with the rate of
aldehyde appearance strictly correlating with the steady-
state concentration of acyl dicarbonyl 7; (3) the
linear:branched ratio of the acyl dicarbonyl species
remained in the range of 1-2:1 over the 298–342 K while
the linear:branched ratio of the aldehyde product
remained constant over an individual experiment and
ranged from ca 6-22:1 over a 320–370 K temperature
Scheme 2. General Mechanism for Hydroformylation
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range.
These data were interpreted as indicating that
hydrogenolysis of the linear acyl dicarbonyl 7 is faster
than the branched acyl dicarbonyl and that “the rate-
limiting step for both the linear and branched aldehydes
was shown to be the hydrogenolysis of the Rh-acyl
1
0
species.”
Selent
hydroformylation of 3,3-dimethylbut-1-ene using
and
coworkers
also
studied
the
a
different bulky monophosphite ligated rhodium catalyst.
This work utilizes a Michaelis-Menten analysis in which
However, in Rh(BDP)-catalyzed hydroformylation,
the alkyl intermediates are known to isomerize for a
variety of olefin substrates. Reversible formation of 4 has
been demonstrated under catalytic conditions by analysis
“
the rate of product formation is limited by the
hydrogenolytic step of the mechanism over the entire
8c
conversion range.”
Garland’s examination of the
hydroformylation of styrene by an unmodified rhodium
catalyst also led to a similar conclusion, “hydrogenolysis
of the the two acyl rhodium intermediates represents the
of product isotope distributions in the presence of D and
2
CO. Under non-catalytic conditions the acyl dicarbonyl
8
a
isomers (7) have been intercepted, characterized, and
rate-limiting step for aldehyde formation.”
6j,7
observed to interconvert.
According to the Heck and
However the observed off-cycle acyls, 7, do not lie
on the catalytic cycle, which raises a fundamental
question that is general to all catalytic reactions: to what
extent is the catalytic rate controlled by conversion of off-
cycle species to the product? Because the acyl dicarbonyls
are present as both linear and branched isomers, the role
of off-cycle species in the control of regioselectivity, also,
naturally arises.
Breslow mechanism, such interconversion must proceed
via alkyl species. In such cases, the product selectivity
cannot be attributed to the control of a single elementary
step.
In many studies of bisphosphine-modified rhodium
catalysts for hydroformylation the rate laws can be
classified as type-I or type-II as coined by van Leeuwen
1
b
and Claver. Characteristics of type-I kinetics include a
Herein we report kinetic studies of the non-
asymmetric hydroformylation of styrene as catalyzed by
racemic Rh(BDP) complexes. Our report begins with a
summary of prior operando studies of hydroformylation
kinetics and catalyst speciation. We then describe new
catalytic results obtained by operando NMR using the
Wisconsin High Pressure NMR Reactor (WiHP-NMRR)
that demonstrate unexpected overall kinetics. The data
presentation concludes with kinetic characterization of
the non-catalytic hydrogenolysis of linear and branched
isomers and the development of a robust kinetic model
that describes both catalytic and non-catalytic kinetic
data. We finish with an analysis of direct vs. shunted
pathways to product formation that demonstrates the
confusion that may result when a catalyst primarily
accumulates as off-cycle species.
rate law (equation 1) that is independent of [H ], first-
2
order in [catalyst] and [alkene], and inhibited by [CO]
and observation of RhH(CO) (L) as the primary resting
2
2
state. For type-II kinetics the reaction rate (equation 2)
commonly exhibits first-order dependence on [H ] and
2
inhibition by [CO] with catalyst pooling in the form of
Rh(acyl)(CO) (L) 7 at high [alkene]. These observations
2
2
are interpreted to mean that the overall rate is controlled
by the rate of hydrogenolysis of 7.
k[cat][alkene]
(
1)
Type– I Rate =
[
CO]
k[cat][H2 ]
CO]
Type– II Rate =
(2)
[
Of particular interest to the themes of this manuscript
are recent studies of hydroformylation catalysts that
feature elegant, quantitative, and simultaneous analysis
RESULTS AND DISCUSSION
8
of catalyst speciation and reaction rates. For example,
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Operando Spectroscopy and Hydroformylation.
pressure from 115 psia CO to 200 psia results in
approximate halving of the reaction rate. However, the
changes upon decreasing the CO pressure from 115 psia
CO to 20 psia are unexpected: a dramatic decrease of both
the reaction rate and regioselectivity is observed. Does
the catalyst change resting state over the three different
kinetic regimes represented?
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The two most common operando methods for study of
catalytic hydroformylation are IR and NMR spectroscopy.
IR is a natural choice due to the relatively high sensitivity
(
detection of less than 1mM concentrations) afforded by
the strongly absorbing C–O and M–H stretches, the lower
expense of IR spectrometers, and the development of
principal component decompositions that enable the
extraction of spectra for individual components from
The reactions described in Figure
2
use
concentrations of catalyst that enable direct observation
31
1
complex spectra.
kinetic/operando
Excellent examples of combined
IR spectroscopic studies of
of catalyst speciation by P{ H} NMR spectroscopy. In
these experiments, the branched and linear acyl
dicarbonyl species are the primary catalyst resting states
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hydroformylation are provided by recent work of
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,11
Garland, Selent, and Vogt (vide supra). NMR methods,
while less sensitive and more expensive, bring tools for
elucidating detailed structures, simple correlation of peak
areas with concentrations, and applicability for cases
where IR spectra are crowded or structurally insensitive.
The Wisconsin High Pressure NMR Reactor (WiHP-
NMRR) enables the observation of reactions under
known, constant gas concentration with active gas-liquid
(
Figure 3). Under low CO pressures (20 psia, plot A),
rhodium pools primarily as the linear acyl dicarbonyl 7l,
but under higher CO pressures (115 and 200 psia, plots B
and C), it sits as a ~3:1 7b:7l mixture. These data are
consistent with thermodynamic control of the 7b:7l ratio
at the lowest CO pressure and kinetically controlled
ratios at the two higher pressures. Low CO pressures
allow sufficiently rapid interconversion of linear and
branched acyls 7 such that an equilibrium distribution is
attained. Previous non-catalytic studies established a
strong thermodynamic preference for 7l over 7b, yielding
a 33:1 ratio of 7l:7b at –20 °C. For the catalytic conditions
of Figure 2 it is reasonable that higher CO pressures
suppress isomerization of the Rh-alkyls 4l and 4b because
CO trapping of 4 , ultimately to yield 6, is more efficient.
Additionally, isomerization by reversion of the acyl 6 to
the alkyl 4 likely is slower at high pressure because such
reversion requires CO dissociation. We have conducted
deuteroformylation studies at 40 and 80 psia CO, the
results of which are consistent with this interpretation:
deuterium scrambling, hence alkyl isomerization, is
inhibited by increased CO pressure and decreased
temperatures (see Supporting Information). There are
three observations that stand out with the data in Figures
2 and 3: (1) the rate law is not described fully by either
type-I or type-II scenarios; (2) different conditions lead to
large differences in rate and catalyst speciation; (3) the
steady-state ratio of the acyls (7b:7l) does not equal the
ratio of aldehyde products (b:l).
1
2
mixing and injection of reagents under pressure.
Previously we have shown that key intermediates can be
intercepted and rigorously characterized by NMR under
low-pressure conditions; these assignments facilitate the
interpretation of data collected by operando NMR
7
methods.
Operando
Study
of
the
Catalytic
Hydroformylation of Styrene as Studied by WiHP-
NMRR at 313K. In our previous studies of the Rh(BDP)-
catalyzed hydroformylation of styrene, several alkyl and
acyl on- and off-cycle intermediates were characterized in
the absence of H and low CO pressure without active
2
7a
gas-liquid mixing at low temperature. Formation of the
branched acyl dicarbonyl (7b) is kinetically favored, but
isomerizes to the thermodynamically preferred linear
species (7l) under these CO-starved conditions. For
quantitative analysis of the kinetic selectivity, see Figure
S9. These studies demonstrate intrinsic kinetic and
thermodynamic selectivities for acyl formation but do not
necessarily apply to catalytic conditions.
Data collected for catalytic hydroformylation by
1
operando H NMR spectroscopy at 313 K and 20 psia H2
The difference in overall rates between the reactions
at 115 and 200 psia CO most simply is attributed to CO
inhibition consistent with type-II kinetics. The common
interpretation is that acyl dicarbonyl species (7) or
hydrido dicarbonyl (1) must lose one ligand to re-enter
the cycle, thus at higher pressures of CO, the rate is
slower.
are presented in Figure 2. The data of plots B and C are
1b
consistent with type-II kinetics for which the resting
state is an acyl dicarbonyl (7) and the reaction rate is
dependent on [H ] with inhibition by CO (see Supporting
2
Information for the dependence of the rate on
dihydrogen concentration). Thus, increasing the CO
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Figure 2. Effect of CO pressure on rates and selectivity in hydroformylation. Time course data were collected using the
Wisconsin High Pressure NMR reactor (WiHP-NMRR) (1.4 M styrene, 6 mM Rh(H)(CO) (BDP), 313 K, 20 psia H , and varied CO
pressures: 20 psia CO (A), 115 psia CO (B), and 200 psia CO (C)).
2
2
Figure 3. Catalyst speciation observed during hydroformylation reactions in the WiHP-NMRR under same conditions
shown in Figure 2 (1.4 M styrene, 6 mM Rh(H)(CO) (BDP), 313 K, 20 psia H , and varied CO pressure: 20 psia CO (A), 115
2
2
psia CO (B), and 200 psia CO (C)).
The dramatic differences in rate between the low
CO pressure (20 psia, Figure 2A) versus the higher
pressure reactions (115 psia or 200 psia, Figure 2B,C)
clearly correlates with changes in the catalyst resting
state. Interestingly, at low (20 psia) CO pressures the
ratio 7l:7b is ~20:1 but yields a 1:1 b:l ratio of product
aldehydes. Only at low CO pressures do the catalytic data
of Figures 2 and 3 superficially appear to correspond to
Curtin-Hammett kinetics for which there is rapid
isomerization between the acyl dicarbonyls (7) and the
rates of product formation are described by equations 3-4
In order to explain the 1:1 ratio of linear and branched
aldehyde
products,
7b
must
undergo
faster
13
hydrogenolysis than 7l. Strictly speaking, at the higher
pressures of Figures 2B, 2C, 3B, and 3C, Curtin-Hammett
behavior does not explain the regioselectivity because 7b
and 7l are not in equilibrium. Regardless of whether or
not the acyls are in equilibrium equations 3 and 4 can still
be true under conditions of turnover-limiting
hydrogenolysis.
(
Figure 4).
d[b]
dt
=
kb[7b]
(3)
(4)
d[l]
=
kl[7l]
dt
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In the WiHP–NMRR, a 1:1 mixture of 7b and 7l was
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7
8
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formed in the absence of hydrogen by allowing 1
equivalent of styrene to react with hydride 1 at 310K and
1
8
psia of CO.
When the 7b:7l ratio reached
approximately 1:1, the reaction was cooled to 290 K and
additional CO and H were added to the reactor with
2
active gas–liquid mixing. Under these conditions the
acyls produce the aldehyde products without any further
interconversion of acyl dicarbonyls, i.e. the initial
concentrations of 7b + 7b’ and 7l correspond to the final
concentrations of branched and linear aldehydes,
respectively (Figure 5). We note that the minor branched
diastereomer 7b’ is barely visible under these conditions
and is ignored in our subsequent analysis. Temperatures
lower than those of the catalytic experiments of Figures 2
and 3 are necessary to slow the rate of hydrogenolysis for
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Figure 4. A Curtin–Hammett free energy scheme that
may describe catalytic data in low [CO] regimes.
Direct Measurement of the Kinetics of
1
31
Hydrogenolysis of Acyl Dicarbonyls at 290K. In
convenient monitoring by H and P NMR spectroscopies.
Data were collected under three CO pressures (18, 35 and
8
b
Vogt’s analysis of hydroformylation, the appearance of
branched and linear products was modeled by equations
3 and 4. The steady state concentrations of 7b and 7l were
determined by direct operando observation; the apparent
rate constants k and k depend on [CO] and [H ]. In
70 psia CO) and a wide range of H pressures ranging
2
from 20 psia to 530 psia. As expected, based on the rate
laws assuming a steady state approximation on 6
(equations 5–10), the pressure of hydrogen enhances the
rate of hydrogenolysis, and CO inhibits the reaction.
These data corroborate the hypothesis that 7b undergoes
hydrogenolysis faster than 7l.
b
l
2
order to evaluate the role of off-cycle species 7b and 7l in
determining the reaction kinetics and selectivity, it is
useful to know their intrinsic rates of hydrogenolysis.
Therefore, we devised single turnover experiments that
directly measure these rates.
Figure 5. Single turnover experiments in the WiHP–NMRR. The branched acyl dicarbonyl undergoes hydrogenolysis faster than
the linear isomer (CO loss and/or reaction with H ). (~22 mM Rh(BDP) as 1:1 mixture of acyls, 290 K, varied CO and H pressures:
2
2
1
8 psi CO, 20 psi H (A); 18 psi CO, 40 psi H (B); 35 psi CO, 40 psi H (C)). The points indicate the experimental data and solid
2
2
2
lines represent the modeled fits.
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k [7b]
Table 1. Computed rate constants for hydrogenolysis
of acyl dicarbonyl complexes.
1
b
[
6b] =
(5)
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7
8
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6
k [H ]+ k [CO]
2
b
2
-1b
d[b]
=
=
k [6b][H ]
(6)
(7)
Value
Standard Deviation
2
b
2
dt
–
2
–1
–3
1 x10
d
[
b
]
k k [7b][H2 ]
k1b
2.3 x10 (s )
2
b 1b
dt
k [H ]+ k-1b[CO]
2
b
2
–3 –1
6.4 x10 (s )
–4
5 x10
k1l
k [7l
]
1
l
[
6l] =
(8)
k–1b/k2b
k /k
8.2
0.2
0.3
k [H ]+ k [CO]
2
l
2
-1l
0
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0
d[l]
10.5
–
1l 2l
=
=
k [6l][H ]
(9)
2l
2
dt
These data quantitatively show that CO loss from
d
[
l
]
k k [7l][H2 ]
2l 1l
the branched acyl dicarbonyl is approximately four-fold
faster than from the linear isomer. At equal
concentrations of H2 and CO, the branched acyl
monocarbonyl (6b) is just eight times more likely to be
trapped by CO than react with dihydrogen; the linear acyl
monocarbonyl (6l) is ten times more likely to be trapped
by CO. These data indicate just modest differences
(10)
dt
k [H ]+ k [CO]
2l 2 -1l
The data show that increasing pressures of H effect
saturation of the rate of hydrogenolysis. Such saturation
indicates efficient competitive trapping of
dihydrogen vs. reassociation of CO. In this limit, the rate
of hydrogenolysis is controlled by the rate of CO
dissociation from 7 (k1b and k , see Figure 6). Global
modeling of all the empirical kinetic data for the single
turnover hydrogenolysis experiments with the program,
2
6
by
(
factors of 4-5) in the hydrogenolysis rates of 7b and 7l.
1l
Application of these rates to catalytic data at 313 K cannot
account for the mismatch between steady-state acyl
concentrations and the aldehyde product distributions.
In order to draw quantitative conclusions and because
the rates of the single turnover experiments are too fast at
1
4
COPASI,
in accordance with the kinetic model
represented by equations 5–10 led to values for the rate
constants k , k , k /k and k /k (Table 1). Because the
1
b
1l
–1b 2b
–1l 2l
3
13 K, we chose to examine catalytic data at 290 K.
acyl monocarbonyl species (6b and 6l) are not observed
by NMR, the ratios k–1b/k2b and k /k , only, but not the
values of the individual rate constants, can be
determined. Representative modeled fits are shown in
Figure 5; for all modeled data, see Supporting
Information.
WiHP-NMRR Catalytic Hydroformylation at
–1l
2l
290K. In order to compare the rates of non-catalytic
hydrogenolysis with catalytic rates, operando NMR
studies of the catalytic reaction were performed. Both
the catalyst speciation and the rates of linear and
branched aldehyde were followed over a range of CO and
Rh(H)(CO) (BDP)+ styrene
2
H pressures (20 or 200 psia of each gas) (Figure 7). The
2
k3b
catalytic data at 290 K were successfully modeled using
the kinetic model of Figure 6 and the rate constants
O
O
obtained
from
single-turnover
hydrogenolysis
Ph
Rh CO
k
1b
Ph
H2
k2b
OC
-CO
O
experiments. For this simplified model, the reaction of 1
and styrene to form 6b and 6l are represented as
irreversible pseudo-elementary steps. Because the effect
of [CO] on these pseudo-elementary steps is not known,
the phenomenological rate constants, k and k for these
P
Rh CO
Ph
P
+CO
k-1b
P
P
H
b
7b
6b
+
Rh(H)(CO)(BDP)
3
b
3l,
Ph
Ph
steps were fitted for each set of catalytic reaction
conditions. The results are shown in Table 2 and Figure 7.
Consistent with CO inhibition, the apparent rate
O
O
k1l
H2
OC
-CO
O
Ph
Rh CO
P
P
Rh CO
P
constants for acyl formation (k3b/l
)
are inversely
P
+CO
k2l
H
proportional to CO pressure, i.e. increasing the CO
pressure from 20 psia to 200 psia decreases the rate
constant by an order of magnitude. These rate constants
are approximately independent of [H2].
k-1l
l
6
l
7l
+ Rh(H)(CO)(BDP)
k3l
Rh(H)(CO) (BDP)+ styrene
2
Interpretation of the Difference in Catalytic
Kinetics at 313 K and 290 K. In Figure 2, catalytic data at
Figure 6. Kinetic model for hydrogenolysis of acyl dicabonyl
complexes 7b and 7l. Species indicated with solid boxes are
directly observable by NMR spectroscopy; reactions
indicated with dashed boxes are only relevant to catalytic
reactions.
3
13 K show large and complex changes in selectivity and
rate upon changing the CO pressure. In contrast, the data
at 290 K (Figure 7) exhibit much smaller effects; for the
CO pressure ranges explored, the product selectivity
remains almost constant. As discussed above,
deuteroformylation experiments show greater H/D
scrambling at higher temperatures and lower CO
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Journal of the American Chemical Society
isomerization is slowed such that the majority of the
pressures (see Supporting Information). Therefore, the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reactions at higher temperature (313 K) and low CO
pressure (20 psia) allow for greater isomerization of the
catalyst to the thermodynamically favored acyl
dicarbonyl, but overall slower linear pathway. The result
is low regioselectivity (b:1 = 1:1) and slow product
formation. At higher CO pressures (115 or 200 psia), the
catalyst remains on the faster, branched pathway. In
contrast, at 290 K, even at the low CO pressures, the
isomerization of alkyls is slow enough such that the
product distribution is relatively unaffected and the rates
display the expected CO inhibition.
.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 7. Time courses for hydroformylation of styrene collected in the WiHP-NMRR at 290 K. (0.06 M styrene, 0.01M
Rh(H)(CO) (BDP), 290 K, and varied gas pressures: 20 psia CO, 200 psia H (A), 20 psia CO, 20 psia H (B), 200 psia CO, 200 psia
2
2
2
H (C), 200 psia CO, 20 psia H (D). Experimental data shown as points; modeled fits displayed as lines. Plots B and D show
2
2
expansions for clarity of low concentration species.
Table 2. Computed rate constants (k , k , see Figure 6) for formation of acyl monocarbonyl complexes.
3b
3l
–
1
–
–1 –
value (M s
Pco
20
PH
2
k
)
value (M s
Standard
Deviation
k
)
Standard
Deviation
3b
3l
1
1
20
20
0.110
0.003
0.0070
0.00061
0.0083
0.00066
0.0003
2
2
2
00
0.0151
0.122
0.0113
0.0003
0.005
0.00005
0.0006
0.00003
0
200
200
00
0.0002
Does the observed catalytic rate correspond to
rate-limiting hydrogenolysis of the acyl dicarbonyls?
Comparison of the non-catalytic hydrogenolysis rate
mM and [7l] =1.36(6) mM seen over the first 50%
ss
conversion in catalytic experiments) with the catalytic
rate over the first 50% conversion conclusively
demonstrates that the catalytic rate is faster than
(
using the steady-state concentrations of [7b] =4.8(5)
ss
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Journal of the American Chemical Society
Page 8 of 11
hydrogenolysis. For example, at 20 psia CO and 20 psia
k [7b
]
+
k4b[4b][CO]
1
b
[
6b] =
(11)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
H the catalytic rates for making linear and branched
2
k [H ]+ k-1b[CO]
2
b
2
–
7
–1
–5
–1
products are 8.3(1)x10
Ms
and 1.8(1)x10
Ms ,
respectively, whereas the hydrogenolysis rates are
d
[
b
]
(k [7b]+ k [4b][CO])k [H ]
1b 4b 2b 2
–
7
–1
–6
–1
=
(12)
(13)
(14)
computed to be 3.6(3)x10 Ms and 5.2(6)x10 Ms ,
dt
k [H ]+ k-1b[CO]
2b 2
1
5
respectively . In other words, the hydrogenolysis rates
are just 44(4)% and 29(4)% of the catalytic rates for
branched and linear products, respectively. We conclude
that the catalytic rates are not controlled solely by the
hydrogenolysis of 7.
k [7l]+ k [4l][CO]
1
l
4l
[6l] =
k [H ]+ k [CO]
2
l
2
-1l
d[l] (k [7l]+ k [4l][CO])k [H ]
1
l
4l
2l
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
If the catalyst pools in the form of the acyl
dicarbonyls 7b and 7l and the observed rate law is
dt
k [H ]+ k [CO]
2l 2 -1l
independent of [alkene], first order in [H ], and inhibited
2
by CO, why is the rate not predicted by a model of rate-
limiting hydrogenolysis? Although intermediates 6b and
6l
precede product formation in both catalytic
hydroformylation and non-catalytic, single turnover
hydrogenolysis experiments, steady-state concentrations
of these intermediates differ in catalytic and non-catalytic
experiments. Under the single-turnover conditions, 6 can
only be formed by dissociation of CO from the acyl
dicarbonyl (7). In contrast, under catalytic conditions, 6
can also be formed directly from the alkyl 4. Thus, there
is a more efficient pathway to aldehyde in which the
catalyst goes directly from 6 to aldehyde product without
being diverted off-cycle to 7. Applying the steady state
approximation to [6], the concentrations and rate laws in
equations 11–14 result for the model depicted in Figure 8.
This kinetic model represents the CO association and
insertion steps that convert the alkyl monocarbonyl (4) to
the acyl monocarbonyl (6) as a single pseudoelementary
Figure 8. Simplified model for catalytic hydroformylations
highlighting the importance of [alkyl] (4) in the rate of
formation of aldehyde.
step with the composite rate constant k . The reaction of
4
2
and styrene to give the alkyl (4) is represented without
th
The analysis above describes scenarios that apply to
any catalytic reaction with off-cycle species. The most
efficient catalysis occurs for the scenario whereby all of
the catalytic species are on-cycle. Any distribution of
catalyst off-cycle, or even to the slower of concurrent
cycles, must decrease the catalytic rate. As catalyst and
substrate circuit the catalytic cycle there are junctions
where the catalyst temporarily may go off-cycle (e.g.
intermediates 2 and 6). We refer to these as a “shunted”
pathways to product, in opposition to the “direct”
pathway for which the catalyst remains on-cycle. The
direct pathway may contribute substantially to the overall
rate even under conditions in which the only detectable
catalyst is off-cycle. For the hydroformylation catalysts
and conditions examined here, even though all detectable
catalyst species lie off-cycle (as 7l, 7b, and 1) and the
catalytic rate law appears to indicate rate-limiting
hydrogenolysis, detailed analysis reveals that the majority
of products (55% of the linear and 70% of the branched
aldehydes) originate from direct, on-cycle pathways.
These percentages vary with reaction conditions. For
example, the reaction at 200 psia CO (Figure 7D) using
the same analysis reveals that only 20% of the branched
acyl monocarbonyl reacts directly while 80% is shunted
off-cycle.
a rate constant because it is presumed to be fast by the 0
order dependence on styrene and no observation of 2
during catalysis. The forms of the catalytic rate law
demonstrate that the rates of linear and branched
aldehyde formation under catalytic conditions are (a)
controlled by the steady-state concentrations of 6l and
6b, respectively, (equations 12 and 14) and that (b) the
steady-state concentrations of 6 are greater under
catalytic than non-catalytic conditions (equations 11 and
1
3). Indeed, relative to the single turnover conditions, the
catalytic steady-state concentration of 6b increases more
that of 6l. This differential increase occurs because
formation of the branched alkyl 4b is kinetically preferred
over the linear alkyl 4b, as conclusively demonstrated by
7a
our previous studies.
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Journal of the American Chemical Society
The hydroformylation data presented herein
The Supporting Information is available free of charge on the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ACS Publications website.
demonstrate that it is inappropriate to identify the
reaction as rate-limited by the hydrogenolysis of acyl
dicarbonyls. Such dissection of the rates into “direct” and
Experimental procedures, plots, and modeling data (PDF)
“
shunted” components could be made only because
elementary steps of the full catalytic reaction could be
characterized independently.
AUTHOR INFORMATION
The analysis given above directly relates to
Corresponding Author
“
Halpern’s rules” which cast doubt on the role of
observable catalyst-derived species under catalytic
conditions: species sufficiently stable to accumulate are
likely to lie off-cycle. For the example of Rh(BDP)-
catalyzed hydroformylation under the conditions
reported above, many of the alkene molecules are
transformed to aldehyde without ever existing as the off-
cycle 7, even though the acyl dicarbonyls are the primary
observed catalyst species.
*landis@chem.wisc.edu
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Science Foundation
CHE-1152989. Computations were supported in part by NSF
CHE-0840494. NMR instrumentation was supported by NSF
CHE-9709065.
CONCLUSIONS
Operando observation of hydroformylation by
WiHP-NMRR reveals complex kinetics and an apparent
mismatch between the b:l ratio of the acyl resting states
and the product distribution. This discrepancy led us to
study the rates of hydrogenolysis of branched and linear
acyls via single turnover experiments. Although the
branched acyl dicarbonyl (7b) undergoes faster
hydrogenolysis than the linear isomer (7l), these
differences in rates cannot fully explain the observed
catalytic behavior. Detailed analysis distinguishes
between direct and shunted pathways to product.
Shunted pathways are those in which intermediates go
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(k6l->1[7l][H ])/(K6l->7b[CO]). In situ
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2
])/(K6b->7b[CO]); d[l]/dt =
2
high-pressure IR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
1
2
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0
-
4
dimethyl-1-butene] = 0.54 M, [Rh] = 3.14x10 M, L/Rh = 26, PCO
29.75–35.15 bar, 3.75–6.59 bar. Deuteroformylation
experimental conditions: T = 323–373 K, [3,3-dimethyl-1-butene]
=
P
H2
=
-
4
= 2.7 M, [Rh] = 1.0x10 M, L/Rh = 27, PCO = 20 bar, PD2 = 20 bar.
Semibatch experimental conditions: 334–363 K, [3,3-
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L/Rh = 15–30, PCO = 9–35.9 bar, PH2 = 20–42 bar.
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Petrovich, L. M. J. Am. Chem. Soc. 1995, 117, 6007-6014. (f)
Lazzaroni, R.; Uccello-Barretta, G.; Scamuzzi, S.; Settambolo, R.;
Caiazzo, A. Organometallics 1996, 15, 4657-4659. (g) Horiuchi,
T.; Shirakawa, E.; Nozaki, K.; Takaya, H. Organometallics 1997,
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G.; Caiazzo, A.; Scamuzzi, S. J. Mol. Catal. A: Chem. 1999, 143,
(13) We refer to hydrogenolysis as the overall reaction from
resting state 7 to aldehyde; it includes the (reversible) loss of CO
and the irreversible reaction with hydrogen to form aldehyde
(14) Hoops, S.; Sahle, S.; Gauges, R.; Lee, C.; Pahle, J.; Simus,
N.; Singhal, M.; Xu, L.; Mendes, P.; Kummer, U. Bioinformatics
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(15) The errors for the predicted rate constants were
calculated by propagation from the rate constants and the
estimated [7b] and [7l] at the steady state. In the range from 0 to
2000 seconds, the concentrations of the acyl dicarbonyls remain
constant: [7b] = 4.8(5) mM and [7l] = 1.36(6) mM. The observed
rate constants and associated errors were obtained from the
experimental data in the same linear region.
1
23-130. (i) van der Slot, S. C.; Duran, J.; Luten, J.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M. Organometallics 2002, 21, 3873-3883.
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(
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