Rational Optimization of Supramolecular Catalysts for the Rhodium-Catalyzed Asymmetric Hydrogenation Reaction

Article abstract of DOI:10.1002/anie.201707670

Rational design of catalysts for asymmetric transformations is a longstanding challenge in the field of catalysis. In the current contribution we report a catalyst in which a hydrogen bond between the substrate and the catalyst plays a crucial role in determining the selectivity and the rate of the catalytic hydrogenation reaction, as is evident from a combination of experiments and DFT calculations. Detailed insight allowed in silico mutation of the catalyst such that only this hydrogen bond interaction is stronger, predicting that the new catalyst is faster. Indeed, we experimentally confirmed that optimization of the catalyst can be realized by increasing the hydrogen bond strength of this interaction by going from a urea to phosphine oxide H-bond acceptor on the ligand.

Full text of DOI:10.1002/anie.201707670

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Accepted Article
Title: Rational Design of Supramolecular Catalysts for the Rhodium-
Catalyzed Asymmetric Hydrogenation Reaction
Authors: Julien Daubignard, Remko Detz, Anne Jans, Bas De Bruin,
and Joost Reek
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707670
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10.1002/anie.201707670
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Rational Optimization of Supramolecular Catalysts for the Rhodium-
Catalyzed Asymmetric Hydrogenation Reaction
Julien Daubignard,[a] Remko J. Detz,[a] Anne C. H. Jans,[a] Bas de Bruin,[a] Joost N. H. Reek*[a]
Abstract: Rational design of catalysts for asymmetric
transformations is a longstanding challenge in the field of catalysis.
In the current contribution we report a catalyst in which a hydrogen
bond between the substrate and the catalyst plays a crucial role in
determining the selectivity and the rate of the catalytic hydrogenation
reaction, as is evident from a combination of experiments and DFT
calculations. Detailed insight allowed in silico mutation of the catalyst
such that only this hydrogen bond interaction is stronger, predicting
that the new catalyst is faster. Indeed, we experimentally confirmed
that optimization of the catalyst can be realized by increasing the
hydrogen bond strength of this interaction by going from a urea to
phosphine oxide H-bond acceptor on the ligand.
reaction pathway. Subsequently, the relevant supramolecular
interactions between the substrate and the catalyst were
optimized in silico, resulting in the rational design of a second
generation of catalysts. Catalytic and kinetic experiments with
the newly prepared catalysts confirmed that both the activity and
the selectivity is improved.
The asymmetric hydrogenation reaction is undoubtedly the most
powerful asymmetric transformation for the fine chemical
industry as it provides a rather general strategy to create chiral
centers in organic molecules.[1] As the synthesis of the desired
products cannot always be reached using the existing catalysts,
the search for new methods and concepts has received
considerable attention.[2] Combinatorial chemistry approaches
and high throughput catalyst screenings have been
demonstrated to be increasingly important.[3] For the generation
of catalyst libraries based on chiral ligands, the use of
supramolecular ligand building blocks that form bidentate
ligands by self-assembly is a powerful strategy as the number of
catalysts grows exponentially with the number of synthesized
building blocks.[4] Next to interactions between the two ligand
building blocks, hydrogen bonding between functional groups of
the substrate and the ligands at the metal complex can
contribute to catalyst selectivity.[5] One of the holy grails in the
area of asymmetric hydrogenation, or more general in the field
of catalysis, would be the rational design of transition metal
catalysts. Although for several catalyst systems detailed
knowledge on the reaction mechanism has been obtained,[6]
prediction of the catalyst properties is still very challenging.[7]
However, when the selectivity of a catalytic reaction is controlled
by supramolecular interactions, further rational optimization
could be performed, guided by theoretical prediction. Herein we
report the first example of rational design of a catalyst for the
asymmetric hydrogenation reaction by optimization of the
supramolecular interactions between the substrate and the
catalyst, leading to enhanced activity and superior selectivity in
the hydrogenation of hydroxyl-functionalized di- and
trisubstituted alkenes. In order to allow a rational approach, the
reaction mechanism of the supramolecular catalyst used was
investigated by means of X-ray crystallography, NMR
spectroscopy, kinetic studies, and DFT calculations of the
Scheme 1. The chemical structures of the ligand building blocks with H-bond
acceptors (L1-L4) and H-bond donor (L5), and a typical example of a self-
assembled bidentate ligands around a rhodium complex (6).
We previously reported the use of complex [Rh(L1)(L5)(cod)]BF4
as
a new selective catalyst based on a self-assembled
supramolecular hetero-bidentate ligand, formed by a single
hydrogen bond between the NH group of a phosphoramidite and
the urea carbonyl of a urea-functionalized phosphine.[8] This
complex affords the highest enantioselectivity (>99% ee)
reported up to now for the hydrogenation of methyl 2-
hydroxymethacrylate (and several of its derivatives), which upon
hydrogenation forms the so-called “Roche ester”, an important
intermediate in the preparation of several biologically active
compounds. Catalysis results show that hydrogen bonding
between the catalyst and the substrate plays an important role
achieving this high selectivity (Table 1).
Table 1. Asymmetric hydrogenation of methyl-2-hydroxymethylacrylate
derivatives S1-S4 catalyzed by supramolecular [Rh(cod)(L1)(L5)]BF4.[a]
Substrate
S1b
R1
OH
R2
Me
tBu
Me
Me
R3
H
Conv (%)
100
ee (%)
99
[a]
Dr. J. Daubignard, Dr. R. Detz, A C. H. Jans, Prof. Dr. Bas de Bruin
Prof. Dr. J.N.H. Reek*
S2b
OH
H
100
99
Homogeneous, Bioinspired and Supramolecular Catalysis, van ‘t
Hoff Institute for Molecular Sciences University of Amsterdam
Science Park 904, 1098 XH Amsterdam, the Netherlands
E-mail: j.n.h.reek@uva.nl
S3b
OH
Ph d
Ph d
83
96[c](S)
S4
OMe
67
25 (S)
[a] [Rh(1)(5)(cod)2]= 0.2 mM, [substrate]
= 0.1 M, solvent: CH2Cl2, reaction
performed at 10 bar H2 pressure at 25°C for 16 h [b] Results previously reported in
[7]. [c] ee obtained for this substrate varies between 96 and 99%.[d] E isomer
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201707670
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In the context of further rational optimization by computational
strategies we decided to study the origin of the high selectivity in
detail. The X-ray analysis of [Rh(L1)(L5)(cod)]BF4 as the
precatalyst as well as the solvento complex that is formed after
hydrogenation of the cod (1,5-cyclooctadiene), confirmed the
presence of the hydrogen bond between the PNH group of the
phosphoramidite and the carbonyl group of the urea-
functionalized phosphine, as predicted by the DFT computed
structures. (These structures will be published in a full paper).
The acetonitrile complex that was obtained after hydrogenation
of the cod was also characterized in solution and in the solid
state. This complex appeared to be sufficiently stable to allow
further substrate coordination studies.
constants obtained for these substrates again confirmed a
stronger binding of S3 to the rhodium complex compared to S4.
Interestingly, also Vmax appeared to be higher for S3,
suggesting that the hydrogen bond also resulted in an overall
lower energy barrier. This was further studied by computing the
reaction pathways using DFT calculations.
A
detailed
computational study of the different reaction pathways
(unsaturated pathway, dihydride pathway and semi-dihydride
pathway) revealed that the unsaturated pathway is energetically
favored. Importantly, for the lowest energy pathway, the
hydrogen bonds between the substrate and the ligands are
present throughout the reaction. The rate-determining transition
state is represented by the hydride migration step B (Scheme 2
and Fig. 3), in line with the kinetic studies, and is stabilized by
the hydrogen bond to a larger extent than the substrate complex,
explaining the higher Vmax obtained for the substrate that can
form hydrogen bonds. (Figure 1). Inspection of the structures in
detail shows that the geometry of transition state is more suited
to accommodate the hydrogen bonds as is reflected in the
shorter NH-O and OH-carbonyl distances.
Upon addition of the trisubstituted alkene S3 to a solution of the
solvento-complex in dichloromethane (see sup info), the
substrate-catalyst complex A in which both the carbonyl and the
alkene of the prochiral substrate are coordinated to the rhodium
center was identified by NMR spectroscopy as the major species.
Additional 2D 1H-1H COSY experiments and DFT calculations
revealed that the hydrogen bond between the substrate and the
functional group is not with the ester group of L5, as previously
proposed.[8] Instead, the OH group inserts in the existing
hydrogen bond between L1 and L5, leading to the formation of
two hydrogen bonds between the substrate and the complex.
(Figure 1). This complex was found to be 5.45 kcal/mol more
stable than the alternative complexes that were computed, and
as such is the major catalyst-substrate species observed in
solution. The binding of substrate S3 and S4, the methoxy
protected analogue of S3 that cannot form hydrogen bonds, to
the solvento-complex was also studied by UV-vis titrations. The
binding of S3 was found to be 2 kcal/mol stronger than for S4 in
line with the proposed hydrogen bond formation.
Scheme 2. Proposed catalytic cycle for the supramolecular rhodium-
catalyzed asymmetric hydrogenation reaction of hydroxyl-functionalized
alkenes
Figure 1. Optimized structure of the catalyst-substrate Rh(L1)(L5)(S3) (left)
and the rate determining transition state of the hydride migration step (right) in
which two hydrogen bonds are formed between the catalyst and S3
From this mechanistic study it is clear that hydrogen bonds
between the substrate and the ligands play a crucial role in
determining both the selectivity and the activity. With this
knowledge in mind, we wondered if it would be possible to
generate a better catalyst based on rational design by targeting
these interactions. As phosphine-oxides are known to be the
strongest hydrogen bond acceptors, we aimed for replacing
In order to further unravel the mechanism of the hydrogenation
reaction with this complex as catalyst, in situ 31P-NMR
experiments were performed, indicating that the solvento-
complex was the resting state of the reaction. As no hydrides
could be detected when the complex was pressurized, the
reaction follows the unsaturated pathway (as displayed in
scheme 2), meaning substrate coordination is required prior to
oxidative addition of molecular hydrogen.[9] Next, a series of
kinetic experiments were performed, monitored by gas-uptake,
to elucidate the kinetics of the reaction, which confirmed the
earlier described reaction mechanism. The kinetic data obtained
for both substrates S3 and S4 could be fitted using the
Michaelis-Menten rate equation. The Michaelis-Menten
urea-phosphine building block L1 in the complex for
a
phosphine-oxide analogue. DFT-optimized structures of catalyst
substrate complexes based on building block L2 and L3 showed
that ligand L3 forms complexes that are structurally most similar
to the parent complex (see fig 2). Clearly, the phosphine oxide
takes the role of the urea group: forming a hydrogen bond with
the OH-group of the substrate. Additionally, we could further
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10.1002/anie.201707670
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optimize the strength of the hydrogen bond by changing the
substituents on the phosphine oxide group for methyl groups.
NMR studies on a solution of complex Rh(L3)(L5)(cod)BF4 and
Rh(L4)(L5)(cod)BF4 showed that indeed complexes are formed
that are very similar to that of Rh(L1)(L5)(cod)BF4. In line with a
stronger binding between the ligands, a large shift of the NH in
1H NMR was observed with the bis-phosphine monoxide ligands
(BPMO). Importantly, 2D COSY NMR experiments showed that
the hydrogen bonds between the catalyst and the substrate in
complex [Rh(L3)(L5)(S3)]BF4 are similar to those found for the
analogues urea-based system.
To verify our prediction, the performance of various rhodium
complexes based on self-assembled ligands, using hydrogen
bond donor L5 and one of the hydrogen bond acceptors from
L1-L4, was evaluated in the asymmetric hydrogenation of
substrate S3 by monitoring the reaction rate by gas-uptake
experiments (Table 2). In line with the prediction from the
computational studies, the reaction is much faster when the
phosphine oxide-based catalyst [Rh(L3)(L5)]BF4 is applied,
compared to the parent [Rh(L1)(L5)]BF4 and also the selectivity
significantly improved (entry 1 vs 2). Using L5 in combination
with L2 results in lower activity, as in this complex the geometry
is not suited to form the optimal hydrogen bond (calculated
structure in supporting information). In contrast, when
[Rh(L4)(L5)]BF4 is applied the activity is even higher, as in this
case the geometry of the hydrogen bond is the same, but the
dimethyl phosphine oxide is a stronger hydrogen bond acceptor
as the methyl groups are more electron donating than the phenyl
groups. Interestingly, experiments performed at 45°C resulted in
a drop in selectivity for [Rh(L1)(L5)]BF4 to 93% ee, while the
phosphine oxide-based catalyst [Rh(L3)(L5)]BF4 still produced
the product in 96% ee.
Table 2. Hydrogenation of substrate S3 by complexes [Rh(L1)(L5)],
[Rh(L2)(L5)], [Rh(L3)(L5)] and [Rh(L4)(L5)].[a]
Figure 2. Rational optimization of supramolecular interactions in
a
Entry
Complex
Conv. [%]b
TOFc
875
eed [%]
96
transition metal catalysts. The crucial hydrogen bond acceptor (urea of L1)
in the catalyst-substrate complex A (left structure) is replaced by a phosphine-
oxide (L3, complex C, right) without changing the basic structure of catalyst-
substrate complex.
1
2
3
4
Rh(L1)(L5)(cod)BF4
Rh(L3)(L5)(cod)BF4
Rh(L2)(L5)(cod)BF4
Rh(L4)(L5)(cod)BF4
98
100
39
3644
335
>99
96
To confirm that the stronger hydrogen bond also translates in
better catalysis, we computed the reaction pathway of the
hydrogenation of substrate S3 by complex Rh(L3)(L5)BF4 using
DFT methods. As for the first generation catalyst, the energy
profile of the reaction displays an uphill profile and the rate-
determining step is also represented by the hydride migration
transition state structure D. The calculated pathways of the
hydrogenation of substrate S3 by complex [Rh(L1)(L5)]BF4 and
[Rh(L3)(L5)]BF4 are plotted on the same graph in Figure 3 and it
is clear that the predicted overall energy barrier is lower by 2.34
kcal mol-1 for [Rh(L3)(L5)]BF4. Therefore, the stronger hydrogen
bond acceptor, by going from the urea to the phosphine oxide
group, is predicted to provide faster catalysis.
99
4561
>99
[a] Reagents and conditions: [Rh] = 0.2 mM, S/C ratio = 1000, 25°C, 20 hours, pH2
10 bar. [b] determined by 1H NMR [c] turnover frequencies calculated at 15%
=
conversion [d] determined by HPLC.
In conclusion, whereas previously it has been demonstrated that
the inclusion of hydrogen bonding in catalyst development can
lead to unprecedented selectivity in catalysis by appropriate
substrate organization at the metal complex[5], we now show for
the first time the successful in silico optimization of such catalyst.
The rational approach relies on mechanistic understanding of
the role of the hydrogen bonds, and subsequent in silico
optimization of this specific interaction. In the current example,
new supramolecular bidentate ligands were used, in which the
urea functional group was replaced by the stronger hydrogen
bond acceptor phosphine oxide in one of the building blocks.
According to DFT calculations and experiments two hydrogen
bonding interactions between the catalyst and the substrate
exist. Increasing the strength of this hydrogen bond interaction
results in a reaction pathway with a lower overall energy barrier,
which as a consequence results in higher reaction rates found
experimentally. In addition, the product is also produced in
higher selectivity (>99% ee) with the rationally optimized catalyst.
The development of catalysts by rational approaches is based
on long-standing established parameters such as steric effects,
electronic effects and bite angle effects.[10] The flourishing
number of supramolecular strategies implies that non-covalent
interactions should also be taken into account in the design of a
catalyst. This work highlights the potential of catalyst fine-tuning
Figure 3. Normalized energy profiles of the unsaturated pathways for the
urea-based supramolecular catalyst (blue path) and the phosphine oxide-
based supramolecular catalyst Rh(L3)(L5) (red path).
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by means of modification of the supramolecular interactions that
can be used as a new tool to improve catalyst performance.
Birkholz, N. V. Dubrovina, H. Jiao, D. Michalik, J. Holz, R. Paciello, B.
Breit, A. Borner, Chem. Eur. J. 2007, 13, 5896-5907; l) FA. J. Sandee,
A. M. van der Burg, J. N. H. Reek, Chem. Commun. 2007, 864-866; m)
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Jin, X. Fan, M. Geng, Y. Zhou, S. Wen, X. Wang, L.W. Cheng, X.-Q.
Dong, X. Zhang, Angew. Chem. Int. Ed. 2017, 56, 6808-6812.
Acknowledgements
This work was financially supported by a TOP grant to JNHR,
provided by the Dutch national science foundation (NWO). We
would like to thank Vivek Sinha for his help on the DFT
calculations.
[5]
for reviews see; a) P. Dydio, J.N.H. Reek, Chem. Sci. 2014, 5,
2135−2145 b) H.J. Davis, R.J. Phipps, Chem. Sci, 2017, 8, 864-877.
For some examples see c) T. Šmejkal, D. Gribkov, J. Geier, M. Keller,
B. Breit, Chem. Eur. J. 2010, 16, 2470-2478; d) P. Dydio. C. Rubay, T.
Gadzikwa, M. Lutz, J. N. H. Reek, J. Am. Chem. Soc. 2011, 133,
17176-17179. e) P. Dydio, W. Dzik, M Lutz, B. de Bruin, J.N.H. Reek,
Angew. Chem. Int. Ed. 2011, 50, 396–400 f) W. I. Dzik, X. Xu, X. P.
Zhang, J. N. H. Reek and B. de Bruin, J. Am. Chem. Soc., 2010, 132,
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N. Reek, Angew. Chem., Int. Ed., 2013, 52, 3878-3882
Keywords: Supramolecular ligands • ligand design •
asymmetric hydrogenation • dft calculations • Catalyst prediction
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Layout 2:
COMMUNICATION
Julien Daubignard, Remko J. Detz, Anne
C. H. Jans, Bas de Bruin, Joost N. H.
Reek*
Page No. – Page No.
Rational optimization of
Supramolecular Catalysts for the
Rhodium-Catalyzed Asymmetric
Hydrogenation Reaction
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