Phosphine Oxide Based Supramolecular Ligands in the Rhodium-Catalyzed Asymmetric Hydrogenation

Article abstract of DOI:10.1021/acs.organomet.9b00484

A series of bisphosphine monoxides and a phosphoramidite have been used for the preparation of supramolecular ligands. A structural analysis of the complexes using NMR spectroscopy and DFT calculations revealed the formation of strong hydrogen bonding between the two ligands. The complexes have been evaluated in the hydrogenation of several functionalized alkenes, leading to very high enantioselectivity for the substrates bearing a hydroxyl group. Also, kinetic studies showed that enhanced reaction rates of hydrogenation are observed in comparison with the supramolecular catalytic systems based on urea groups. In-depth NMR spectroscopy experiments and computational studies have highlighted the crucial role of the hydrogen bond between the phosphine oxide ligands and the substrate during the hydrogenation reaction.

Full text of DOI:10.1021/acs.organomet.9b00484

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Cite This: Organometallics XXXX, XXX, XXX−XXX
Phosphine Oxide Based Supramolecular Ligands in the Rhodium-
Catalyzed Asymmetric Hydrogenation
Julien Daubignard, Remko J. Detz, Bas de Bruin, and Joost N. H. Reek*
Van ‘t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, Amsterdam 1098 XH, The Netherlands
*
S Supporting Information
ABSTRACT: A series of bisphosphine monoxides and a
phosphoramidite have been used for the preparation of
supramolecular ligands. A structural analysis of the complexes
using NMR spectroscopy and DFT calculations revealed the
formation of strong hydrogen bonding between the two
ligands. The complexes have been evaluated in the hydro-
genation of several functionalized alkenes, leading to very high
enantioselectivity for the substrates bearing a hydroxyl group. Also, kinetic studies showed that enhanced reaction rates of
hydrogenation are observed in comparison with the supramolecular catalytic systems based on urea groups. In-depth NMR
spectroscopy experiments and computational studies have highlighted the crucial role of the hydrogen bond between the
phosphine oxide ligands and the substrate during the hydrogenation reaction.
INTRODUCTION
actions influence the reaction by the formation of a hydrogen
bond between the catalyst and the substrate. Such interactions
have been identified as decisive in the stereodiscriminating step
■
The design of new catalysts is very important in the industry,
especially in the field of fine chemicals and pharmaceuticals, in
which time and cost are very important parameters in the
39
of the reaction, and they also influence the rate. Guided by
1
−3
rational design based on mechanistic considerations and
computational studies, we have sought an improved catalyst
that would enhance these supramolecular interactions.
Bisphosphine monoxides (BPMOs) are a class of ligands
constituted of a phosphine group and a phosphine oxide group
separated by a spacer (Figure 1). Due to the presence of both a
development of new drugs.
Therefore, many ways to find
new catalysts have been developed during the last decades. The
high-throughput screening of known bidentate ligands that
form the catalysts is a commonly applied strategy in the
4
−11
industry.
However, the sometimes difficult synthesis of
highly asymmetric catalysts has required the use of new
methods for the development of wide libraries of ligands. The
versatility of monodentate ligands and their high efficiency in
many reactions has quickly lifted them to the rank of privileged
1
2
13−17
ligands. Another approach developed by Reetz
and
1
8−20
Feringa and de Vries
is the use of mixtures of
monodentate ligands in the combinatorial screening of
catalysts, expanding considerably the potential of monodentate
ligands by increasing the number of possible catalysts that can
be evaluated on the basis of a certain number of ligands. In
another approach, several groups have reported the use of
monodentate ligands that act as building blocks able to self-
assemble through noncovalent interactions, leading to the
Figure 1. General structure of the bisphosphine monoxide ligands.
hard (O) and soft (P) donor atom in the same structure,
BPMOs constitute an important class of hemilabile ligands that
21
formation of supramolecular catalysts. Various interactions
can be used for the assembly of ligand building blocks such as
40
can form labile metal chelates.
2
2−28
29−31
hydrogen bonds,
electrostatic interactions,
and
While BPMOs have been efficiently applied to several
3
2−37
metal−ligand association.
on new supramolecular systems is a developing field of
research, and many concepts have to be explored.
The search for catalysts based
41
processes such as the carbonylation of methanol and
42
ethylene polymerization, to the best of our knowledge, this
class of ligand has never been investigated in the formation of
We recently discovered a new series of supramolecular
catalysts based on ligands that form supramolecular complexes
through hydrogen bonding between the PNH group of a
phosphoramidite and the carbonyl group of a urea-function-
Special Issue: Asymmetric Synthesis Enabled by Organometallic
Complexes
3
8
alized phosphine. An extensive experimental mechanistic
study demonstrated that intramolecular noncovalent inter-
Received: July 18, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.9b00484
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Article
supramolecular bidentate ligands. In this paper, we report a
new class of supramolecular rhodium catalysts based on
phosphine oxides as hydrogen bond acceptors combined with a
chiral phosphoramidite to form bidentate supramolecular
ligands. These complexes have been evaluated in the
asymmetric hydrogenation of several benchmark substrates.
While poor to moderate selectivities have been obtained for
most of the substrates, excellent selectivity was observed in the
hydrogenation of functionalized substrates bearing a hydroxyl
group acting as a hydrogen bond directing group. More
importantly, kinetic analysis revealed that this second
generation of catalysts has higher hydrogenation rates in
comparison to the urea-based system, while very high
selectivity is maintained. Finally, by analysis of the contribution
of the phosphine oxide group in the transition state during the
reaction mechanism, these studies have led to a better
understanding of this new class of supramolecular catalysts.
As phosphine oxides are known to display strong HBA
43−47
properties,
we decided to synthesize and evaluate a library
of new BPMOs as HBAs in the formation of supramolecular
bidentate ligands in rhodium complexes. On the basis of
geometrical considerations and molecular modeling, ligands
3−5 were synthesized (Figure 2). The ligands were prepared
in two steps in a fashion similar to that for the reported ligand
UREAPhos (ligand 1, Figure 2). The first step of the synthesis
is the preparation of iodobenzyl derivatives by deprotonation
of the corresponding phosphine oxide and the nucleophile
addition on 3-iodobenzyl bromide. In a second step, the
iodobenzyl derivatives are coupled with diphenylphoshine to
48
give ligands 3−5 (Scheme 1).
Scheme 1. Synthesis of the Ligands 3−5
RESULTS AND DISCUSSION
We previously investigated the activity and the selectivity of
the supramolecular complex [Rh(1)(6)]BF (Figure 2) in the
■
4
Ligands 2−5 were evaluated in the formation of supra-
molecular complexes in combination with phosphoramidite 6
(
Figure 2). Mixing 1 equiv of ligand 3 with 1 equiv of
phosphoramidite 6 and 1 equiv of [Rh(cod) ]BF (with cod =
2
4
1
,5-cyclooctadiene) in CD Cl results in the observation of a
2 2
3
1
single species, as evidenced by P NMR spectroscopy.
As can be seen in Figure 3, the P NMR spectrum displays
classic patterns for a heterocomplex (rhodium bearing two
3
1
Figure 2. Structures of the bisphosphine monoxide ligands (2−5) and
structure of the phosphoramidite ligand 6.
asymmetric hydrogenation of functionalized alkenes. Through
an extensive mechanistic study, we have highlighted the crucial
role of hydrogen bonding in the catalytic hydrogenation of a
series of hydroxyl-functionalized substrates. As a result, the
hydrogen bond acceptor (HBA) group of the urea-function-
alized phosphine ligand has been identified as being actively
involved at several stages of the catalytic cycle. First, this group
is involved in the stabilization of the catalyst−substrate
complex by forming hydrogen bonds with the substrate,
enhancing the stereodiscrimination of the prochiral faces of the
functionalized alkene. Also, computational studies showed that
the same group is involved in the rate-determining step of the
reaction (hydride migration step). Therefore, we anticipated
that the modification of this group for a stronger hydrogen
bond acceptor group would lead to possible beneficial changes
in terms of enantioselectivity and activity.
Figure 3. 31P NMR spectrum of the complex [Rh(3)(6)(cod)]BF in
4
CD Cl (162 MHz).
2
2
different ligands) with two doublets of doublets attributed to
the phosphoramidite and the phosphine ligands and a sharp
1
singlet attributed to the phosphine oxide moiety (δ(P ) dd,
1
2
2
131.9 ppm, J
= 240.8 Hz, J = 31.3 Hz; δ(P ) dd, 34.7
P,Rh
P,P′
1
2
3
ppm, J
= 150 Hz, J = 31.3 Hz, δ(P ) s, 32.4 ppm). In
P,Rh
P,P′
3
1
the P NMR spectrum, a difference in chemical shift was
observed for the PO moiety in comparison to the free ligand
(Δδ = 4.1 ppm downfield shift). The relatively small change in
B
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chemical shift suggests that the phosphine oxide is not
coordinated to the metal center, since much larger chemical
shifts are usually observed in chelating BPMO-rhodium
4
9
complexes. Since no shift of the phosphine oxide moiety is
40
expected upon coordination of the phosphine ligand, the
difference in chemical shift implies the involvement of the PO
moiety in a hydrogen bond. We previously demonstrated by
NMR experiments combined with X-ray crystallography that
1
the H chemical shift of the NH group of the phosphoramidite
can be used as an indicator for the formation of hydrogen
39
bonding between two ligands. Therefore, we also performed
1
1
a 2D H− H COSY NMR experiment on the complex
[
Rh(3)(6)(cod)]BF in CD Cl in order to identify the signal
4
2
2
of the PNH group of the phosphoramidite (δH 7.18 ppm).
This large downfield chemical shift clearly indicates the
50
formation of a hydrogen bond between the two ligands. In
a similar way, the quantitative formation of heterocomplexes
was also observed for the complexes [Rh(2)(6)(cod)]BF4,
[
Rh(4)(6)(cod)]BF , and [Rh(5)(6)(cod)]BF . The chemical
4
4
shifts of the PNH groups in the different complexes as well as
the chemical shifts of the PO groups are reported in Table 1.
Table 1. Chemical Shift of the PNH Group of the
Complexes [Rh(L)(6)(cod)]BF and the Corresponding
4
a
Chemical Shift of the PO Group
ligand
δNH (ppm)
ΔδNH
ΔδPO
PPh3
4.25
4.88
7.18
6.05
7.07
2
3
4
5
0.63
2.93
1.80
2.82
0.11
4.11
1.18
2.28
a
Δδ(PO) = δ(POcomplex) − δ(POfree ligand).
Interestingly, the differences in the chemical shift of the PNH
goups (with and without H bonds) are correlated with the
difference in chemical shift of the corresponding PO group,
suggesting a difference in the strength of the hydrogen bonds
in the formation of supramolecular complexes.
From Table 1, a large difference in Δδ(NH), and thus in the
hydrogen bond strength, is observed between the complexes
Figure 4. DFT optimized structures of the two conformers (with and
without hydrogen bonding) of the different supramolecular
complexes: (a) Rh(2)(6)(cod); (b) Rh(3)(6)(cod), The H-bond
52
length, in green, is given in angstroms.
[
Rh(2)(6)(cod)]BF and [Rh(3)(6)(cod)]BF . In these two
4
4
ligands, the substituents on the phosphine oxide moieties are
phenyl groups. However, the introduction of the methylene
spacer in [Rh(3)(6)(cod)]BF induces an important variation
in the geometry of the ligand. As a consequence, the geometry
of the ligand influences the directionality of the HBA in the
supramolecular complex and therefore leads to a significant
change in the hydrogen bond strength. Interestingly, the
similar change in chemical shift observed for the NH in
complexes [Rh(3)(6)(cod)]BF and [Rh(5)(6)(cod)]BF
suggests that the electronic properties and the bulk of the
phosphine oxide substituents do not significantly influence the
strength of the hydrogen bond between the two ligands.
The stability of the supramolecular complexes [Rh(2)(6)-
displaying a hydrogen bond between the two ligands were
found to be more stable than the corresponding conformers
without a hydrogen bond. Also, the length of the hydrogen
bond was measured and used as an indication of the strength.
It shows that the hydrogen bond in complex [Rh(2)(6)-
4
(cod)]BF is weaker than those in the other complexes, in line
4
51
with the NMR experiments.
The complexes were evaluated in the asymmetric hydro-
genation of several benchmark substrates (substrates A−G,
Figure 6) and compared to the results obtained with the first
generation of catalysts of this type (complex [Rh(1)(6)-
4
4
(cod)]BF ). Since a variation of the hydrogen pressure can
4
influence the selectivity of the catalytic reaction, we evaluated
53
(
[
cod)]BF , [Rh(3)(6)(cod)]BF , [Rh(4)(6)(cod)]BF , and
the performance of the complexes in the range 5−40 bar.
4
4
4
Rh(5)(6)(cod)]BF have been studied by means of DFT
As can be seen from Table 2, all of the catalysts give a similar
trend in the selectivity in the hydrogenation of the substrates
A−E (low selectivity for substrates A−C and E while good
selectivity is obtained for substrate D) with up to 93% ee in the
hydrogenation of substrate D by complex [Rh(4)(6)(cod)]-
BF at 10 bar of H . Notably, substrate D is the only substrate
4
calculations in an examination of geometries in which a
hydrogen bond exists between the two ligands, and these were
compared to analogues in which this was absent. These
structures were optimized, and the free energies of the
corresponding supramolecular complexes were compared
4
2
(
Figures 4 and 5). For each complex, the conformers
next to F and G to have the same ester moiety and no amide,
C
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Table 2. Enantiomeric Excess (%) Obtained in the
Hydrogenation of Substrates A−G by Complexes
a
[
Rh(L)(6)(cod)]BF4
L
substrate
1
2
3
4
5
A
B
C
D
E
F
16
12
34
92
0
30
22
41
88
8
0
0
7
34
44
87
19
99
99
14
30
92
18
99
99
38
36
93
23
99
99
99
99
96
91
b
G
a
Reagents and conditions unless noted otherwise: [Rh] = 0.2 mM,
[
substrate] = 0.1 M, CH Cl , 10 bar H , room temperature, 16 h.
2 2 2
1
Conversions were determined by H NMR or GC analysis. Full
conversions were obtained for all the tested substrates except for
substrate A (conversions ranging from 20 to 50%). The ee values were
b
determined by chiral GC or HPLC analysis. [Rh] = 1 mM.
suggesting that the chelate complex that is formed with
rhodium is similar. Also, the selectivity is rather independent of
the pressure of hydrogen (see the Supporting Information).
Substrates F and G (the substrates bearing a hydroxyl group)
are hydrogenated with very high selectivity by complexes
[
Rh(3)(6)(cod)]BF , [Rh(4)(6)(cod)]BF , and [Rh(5)(6)-
4
4
(
cod)]BF , producing the S product in line with that observed
4
39,55
previously for complex [Rh(1)(6)(cod)]BF4.
Interestingly,
the geometries of the ligands 3−5 are close to that of the urea-
based ligand 1, leading to a similar orientation of the hydrogen
bond donor group involved in the hydrogen-bonding
interactions. On the other hand, in ligand 2 the phosphine
oxide group is directly connected to the phenyl substituent on
the phosphine, inducing an important change in the geometry
of the ligand (in comparison to ligand 1). This difference in
geometry of ligand 2 leads to a different orientation of the
hydrogen bonds between the catalyst and the substrate. This
difference in hydrogen bonding was already deduced from the
NMR experiments and the DFT study performed on the
precatalysts, and it translates to a lower selectivity in the
hydrogenation of substrates F and G by the complex
Figure 5. DFT optimized structures of the two conformers (with and
without hydrogen bonding) of the different supramolecular
complexes: (a) Rh(4)(6)(cod); (b) Rh(5)(6)(cod). The H-bond
52
length, in green, is given in angstroms.
[Rh(2)(6)(cod)]BF . Therefore, the geometry of the ligand
4
bearing the hydrogen bond acceptor has an important role in
the structure of the supramolecular catalyst. Small differences
in the structure of the catalyst can have important
consequences on the outcome of the reaction, but interestingly
the steric hindrance of the substituents on the different
phosphine oxide groups (ligands 3−5) does not influence the
excellent selectivity observed for substrates F and G.
The reaction mechanism of the hydrogenation of substrate
G by the complex [Rh(3)(6)(cod)]BF was studied by means
4
of NMR spectroscopy and DFT calculations (Figure 7). When
a 0.02 M solution of complex [Rh(3)(6)(cod)]BF in CD Cl
4
2
2
3
1
was hydrogenated at −80 °C for 1 h, the signals in the
P
NMR spectrum completely disappeared and only traces of the
precatalyst and traces of the hydrolyzed ligand could be
3
1
detected. The broad signals observed in the P NMR
spectrum are attributed to the formation of undefined
monomeric solvate species in solution, as previously observed
in our experiments performed with the complex [Rh(1)(6)-
39
Figure 6. Substrates evaluated in the asymmetric hydrogenation
reaction.
(cod)]BF4.
Upon addition of 5 equiv of substrate G, new sets of
3
1
doublets of doublets arise in the P NMR spectrum. The new
D
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Figure 7. 31P NMR spectra (162 MHz, CD Cl ) of a sample initially
2
2
containing a solution of [Rh(3)(6)(cod)]BF : (a) starting spectrum,
4
2
98 K; (b) hydrogenation under 5 bar at 193 K for 1 h (the sample
was degassed and the spectrum was taken at 298 K); (c) the same
sample with an additional hydrogenation for 30 min at 193 K (the
sample was degassed and the spectrum was taken at 298 K); (d)
spectrum after the addition of 5 equiv of substrate G at 298 K.
species observed in the 31P NMR spectrum consist of a major
species and two other minor species in the ratio major/
minor1/minor2 of 4/1/1. Due to overlay of the signals of the
minor species, coupling constants and chemical shifts could be
1
established only for the major species (δ(P ) dd, 133.09 ppm,
1
2
2
1
JP,Rh = 307.6 Hz, J = 38.9 Hz; δ(P ) dd, 46.96 ppm, J
Figure 8. Calculated structures of the four possible catalyst−substrate
complexes (optimized with DFT, def2-TZVP/disp3). Most of the
hydrogen atoms have been removed for clarity (except from the
hydrogen atoms involved in hydrogen bonds and the hydrogen atom
on the hydroxyl group).
P,P′
P,Rh
2
=
205.6 Hz, J = 38.9 Hz). On the basis of our previous
P,P′
studies, these signals indicate the formation of substrate−
chelate complexes. Also, integration of the signals allowed us to
assign the singlet at δ 34.45 ppm to the PO group belonging to
31
the major species observed in the P NMR spectrum.
This hardly shifted signal of the PO group means that the
PO group is not coordinated to the metal center but still is
involved in hydrogen bond formation. The difference in
chemical shifts between the PO of the precatalyst and the PO
group in the major species (Δδ = 2.04 ppm with respect to the
PO group in the precatalyst) indicates that the coordination of
the substrate influences the orientation of the PO group. Due
resulting in the stabilization of the catalyst−substrate complex.
Also, we calculated the conformer of structure A in which the
hydroxyl group is not interacting with the catalyst (with the
hydroxyl group pointing away from the catalyst). Interestingly,
−
1
this structure is 8.3 kcal mol higher in energy than structure
A (pro-S face) and also higher in energy than structure C (pro-
R face). This large difference in energy as a result of hydrogen
bond interactions between the catalyst and the substrate
reflects the importance of the interaction, as the order of the
stability of the possible catalyst−substrate adducts would
to the numerous signals in the 3 P and C NMR spectra, no
information could be obtained on the coordination mode of
the substrate. To get more insight into the structure of the
major chelate complex, we optimized the structures of the four
possible diastereoisomers that can be formed upon coordina-
tion of the prochiral substrate to the complex (Figure 8). The
most stable diastereoisomer (structure A, Figure 8) features
two hydrogen bonds between the substrate and the catalyst.
Indeed, the hydroxyl group of the substrate has a hydrogen
bond interaction with the NH group of the phosphoramidite
ligand and with the oxygen of the phosphine oxide group.
Effectively, the hydroxyl group of the substrate is inserted in
the PNH−PO hydrogen bond between the two ligands,
1
13
54
change without H bonding.
1
1
The catalyst−substrate complex was analyzed by 2D H− H
COSY NMR, revealing an upfield shift of the NH group of the
phosphoramidite at δ 5.30 ppm. This chemical shift indicates
that the NH group is still involved in a hydrogen bond in the
catalyst−substrate complex. Also, the difference in chemical
shift between the NH group in the catalyst−substrate complex
and the NH group in the precatalyst (Δδ = 1.88 ppm) suggests
an important modification of the geometry of the hydrogen
bond between the two ligands. As can be seen in the calculated
E
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structure A (Figure 8), the NH group of the phosphoramidite
forms a hydrogen bond with the OH group of the substrate,
which is different from the hydrogen bond to the phosphine
oxide found in the precomplex.
Table 4. Michaelis−Menten Kinetic Parameters for the
Asymmetric Hydrogenation of Substrate G by the
Complexes [Rh(1)(6)(cod)]BF and [Rh(3)(6)(cod)]BF4
4
[Rh(1)(6)(cod)]BF4
[Rh(3)(6)(cod)]BF4
Detailed mechanistic studies on the urea-based system
Vmax (M h−1)
KMM (M)
0.38701
0.04282
0.01449
1.90494
0.26012
0.02371
(
complex [Rh(1)(6)(cod)]BF ) showed how the hydrogen
4
bond interaction between the substrate and the catalyst
55
Ki (M)
influences the rate and the selectivity. To establish that the
phosphine oxide analogue discussed in the current contribu-
tion operates via a similar mechanism, the activity of this
catalyst was studied in more detail by kinetics and DFT
calculations. The reaction progress was monitored under
different conditions by gas uptake during the hydrogenation of
conditions, a larger fraction of the catalyst in solution is present
as the solvate complex. This is in line with the NMR
experiments, as only minor amounts of the catalyst−substrate
complex were observed in solution in the presence of 5 equiv
of substrate G. As the phosphine oxide (ligand 3) is a stronger
hydrogen bond acceptor then the urea function (ligand 1), one
may expect a stronger interaction with the substrate. However,
these better hydrogen bond accepting properties also lead to a
stronger interaction between the two ligands, and this
hydrogen bond needs to be broken upon substrate binding,
which requires more energy. As such, the use of a stronger
hydrogen bond acceptor does not lead to a stronger association
of the hydrogen-bonded substrate. Importantly, the complex
substrate G (complexes [Rh(1)(6)(cod)]BF , [Rh(2)(6)-
4
(
cod)]BF , [Rh(3)(6)(cod)]BF , and [Rh(5)(6)(cod)]BF ;
4 4 4
Table 3). In comparison to the complex [Rh(1)(6)(cod)]BF4
Table 3. Hydrogenation of Substrate G by Complexes
[
[
Rh(1)(6)(cod)]BF , [Rh(2)(6)(cod)]BF ,
4
4
a
Rh(3)(6)(cod)]BF , and [Rh(5)(6)(cod)]BF
4
4
b
c
d
complex
S/C ratio
conversn (%)
TOF
ee (%)
Rh(1)(6)(cod)BF4
Rh(3)(6)(cod)BF4
Rh(2)(6)(cod)BF4
Rh(5)(6)(cod)BF4
1000
1000
1000
1000
98
100
39
875
3644
335
95.5
99.7
96
[
Rh(3)(6)(cod)]BF has a higher maximum reaction rate in
4
comparison to the urea catalyst complex [Rh(1)(6)(cod)]BF4,
suggesting that the stabilization by the hydrogen bond is
stronger (Table 4). In order to confirm this, DFT calculations
were performed.
We studied the influence of the hydrogen bond interactions
on the energy of the intermediates and the transition states
involved in the mechanism of the reaction. Following our
previous computational studies on the urea-based supra-
99
4561
99.2
a
Reagents and conditions: [Rh] = 0.2 mM, S/C ratio = 1000, 25 °C,
0 h, p(H ) = 10 bar. Determined by H NMR. Turnover
2
d
b
1
c
2
frequencies calculated at 15% conversion. Determined by HPLC.
(
first-generation catalyst), higher activities are observed with
molecular system [Rh(1)(6)(cod)]BF , we calculated the
complexes [Rh(3)(6)(cod)]BF4 and [Rh(5)(6)(cod)]BF4,
4
energy profile of the hydrogenation of substrate G by the
while excellent selectivity is retained (up to 99.7% ee). The
complex [Rh(3)(6)(cod)]BF . The similarities between the
TOF observed when complex [Rh(2)(6)(cod)]BF was used
4
4
two supramolecular systems result in similarities in the
mechanism. They both follow an unsaturated pathway in
which the substrate coordinates to the catalyst prior to the
oxidative addition of hydrogen. The calculated energy profiles
is much lower. This complex has a different geometry, as is
clear from the calculated structure, and this has an influence on
the activity of the complex, underlining the importance of the
orientation of the hydrogen bonding groups in the catalyst
of the complexes [Rh(1)(6)(cod)]BF and [Rh(3)(6)(cod)]-
(
entry 3, Table 3).
In order to gain more insight into the mechanism of this new
4
BF were plotted in the same graph to highlight the differences,
4
taking the energy of the major diastereoisomer as a reference
series of catalysts, we performed several kinetic experiments on
the hydrogenation of substrate G by complex [Rh(3)(6)-
(
Figure 9).
As can be seen from Figure 9, the pathway corresponding to
(
cod)]BF . Monitoring the reaction progress by gas uptake for
4
complex [Rh(3)(6)(cod)]BF (red path) has a lower overall
experiments with different initial substrate concentrations
reveals a positive order dependency of the reaction rate in
the range 0.1 M-0.2 M on the substrate concentration. Also,
experiments carried out at different pressures of hydrogen
revealed a positive dependency of the TOF on the hydrogen
concentration.
4
energy barrier than the pathway provided by complex
[
Rh(1)(6)(cod)]BF (blue line). The difference between the
4
energy of the catalyst−substrate complex and the energy of the
hydride migration transition state (Figure 10) is lowered by
−
1
2
.25 kcal mol . The decrease in the overall energy barrier is
attributed to the enhanced strength of the hydrogen bond
provided by the strong hydrogen bond donor properties of the
phosphine oxide groups. Apparently, this hydrogen bond
stabilization is stronger in the transition state (D) than in the
substrate precomplex (C).
In order to evaluate the importance of the H-bond effect in
the reaction mechanism of the catalyst [Rh(3)(6)(cod)]BF4,
we removed the hydrogen-bond interactions in structures C
and E and the transition state D by replacing the hydroxyl
group on the substrate by a hydrogen (Figure 11). The SCF
energies of the structures were plotted on the same energy
profile, taking the energy of the diasteromers as a reference. As
can be seen in Figure 11, the hydrogen bond interaction is
more pronounced at the step of hydride migration than at the
Complex [Rh(1)(6)(cod)]BF ) was demonstrated previ-
4
ously to follow Michaelis−Menten (MM) kinetics in which the
substrate reversibly associates to the catalyst before the rate-
determining migration step. The kinetic data obtained for the
hydrogenation of substrate G by the complex [Rh(3)(6)-
(
cod)]BF also nicely fitted to the MM kinetic model (eq 1),
4
providing the parameters given in Table 4.
Vmax[S]
+ [S] +
V = KMM
KMM
[P]
Ki
(1)
The higher value of KMM measured for complex [Rh(3)-
6)(cod)]BF in comparison to [Rh(1)(6)(cod)]BF suggests
(
4
4
that binding of the substrate is weaker and that, under catalytic
F
DOI: 10.1021/acs.organomet.9b00484
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Organometallics
Article
−
1
2
kcal mol , in comparison to the hydride migration step D′
not featuring hydrogen bonds between the catalyst and the
substrate. Most likely, the structure of the complex during the
hydride migration step is favorable for hydrogen bond
formation.
CONCLUSION
■
Through rational design, on the basis of mechanistic
considerations, a second-generation catalyst based on supra-
molecular bidentate ligands was synthesized and evaluated in
the rhodium-catalyzed asymmetric hydrogenation of several
functionalized substrates. In this second generation of catalysts,
supramolecular complexes [Rh(3)(6)(cod)]BF and [Rh(5)-
4
(
6)(cod)]BF are very efficient in the asymmetric hydro-
4
genation of substrates F and G, both bearing a hydroxyl group,
leading to almost perfect enantioselectivity (up to 99.9% ee). A
mechanistic study demonstrates that two hydrogen bond
interactions between the catalyst and the substrate are involved
in the stabilization of a catalyst−substrate complex inter-
mediate. Kinetic studies show that the reaction is faster when it
is catalyzed by the phosphine oxide based catalysts Rh[(3)-
Figure 9. Energy profiles of the unsaturated pathways for the urea-
based supramolecular catalyst [Rh(1)(6)(cod)]BF (blue path) and
4
the phosphine oxide-based supramolecular catalyst [Rh(3)(6)(cod)]-
BF (red path).
4
(
6)(cod)]BF and [Rh(5)(6)(cod)]BF , suggesting hydrogen
4
4
bond stabilization of the rate-determining transition state.
Computational studies of the reaction mechanism of the
hydrogenation reaction mediated by the complex [Rh(3)(6)-
(
[
cod)]BF and comparison with the first-generation catalyst
4
Rh(1)(6)(cod)]BF indeed reveal that the supramolecular
4
interactions between the substrate and the catalyst in the
complex [Rh(3)(6)(cod)]BF stabilizes the transition state of
4
the hydride migration step to a larger extent than for the
substrate complex. This results in an overall lower energy
barrier, and thus this catalyst displays a higher activity. The
development of catalysts by rational approaches is based on
longstanding established parameters such as steric effects,
electronic effects, and bite angle effects. The flourishing
number of supramolecular strategies implies that noncovalent
interactions should also be taken into account in the design of
a catalyst. This work highlights the potential of fine-tuning
supramolecular interactions as a new tool to improve catalyst
performance.
Figure 10. Optimized structure of the hydride migration transition
−
1
⧧
−1
state D (ΔG2 = +18.64 kcal mol /A, υ = −616.9i cm ). All
98 K
hydrogen atoms are omitted for clarity except the proton of the alkene
and the hydrogen atoms involved in hydrogen bonds. Hydrogen
bonds are drawn in orange. The black dotted line represents the
hydride insertion to form the alkyl hydride species.
EXPERIMENTAL SECTION
■
Representative Procedures for the Synthesis of Ligands.
Synthesis of (3-Iodobenzyl)diphenylphosphine Oxide (3-int). To a
suspension of NaH (60% in mineral oil) (179 mg, 4.5 mmol) in
freshly distilled THF (35 mL) at 0 °C was added diphenylphosphine
oxide (606 mg, 3 mmol) under nitrogen. The mixture was stirred for
1
0 min. 3-Iodobenzyl bromide (3.3 mmol) was then added, and the
mixture was stirred at room temperature for 6 h. Water was added (10
mL) to quench the reaction, the organic layer was extracted with ethyl
acetate (40 mL) three times and dried over Na SO , and the volatile
2
4
materials were removed under reduced pressure. The crude product
was purified by flash chromatography on silica gel (ethyl acetate/
dichloromethane, 2/8) to give the product as a white solid. The yield
was 58%.
Synthesis of (3-(Diphenylphosphanyl)benzyl)diphenylphosphine
Oxide (3). (3-Iodobenzyl)diphenylphosphine oxide (1.75 mmol, 730
mg), diphenylphosphine (317 μL, 1.82 mmol), trimethylamine (485
μL), and palladium(II) acetate (2 mg) were dissolved in acetonitrile
(25 mL) under nitrogen, brought to reflux, and continued to reflux
overnight. The next day, volatiles were evaporated under reduced
pressure, and to the residue were added dry dichloromethane (30
mL) and degassed water (15 mL). The water phase was washed with
dichloromethane, the combined organic layers were dried over
Na SO and filtered, and the solvent was removed under vacuum. The
Figure 11. Relative SCF energies of the intermediates C, E, and D
with and without hydrogen bond interactions between the catalyst
and the substrate. C and C′ are set to zero.
early steps. The intramolecular hydrogen bonds are responsible
for the stabilization of the transition state D by approximately
2
4
G
DOI: 10.1021/acs.organomet.9b00484
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Article
crude product was purified by flash chromatography on silica gel
(4) Tang, W.; Zhang, X. New Chiral Phosphorus Ligands for
Enantioselective Hydrogenation. Chem. Rev. 2003, 103 (8), 3029−
3070.
(
100% ethyl acetate) to give the product as a white solid. The yield
was 85%.
Representative Procedure for the Synthesis of Complexes:
(5) Jak
̈
el, C.; Paciello, R. High-Throughput and Parallel Screening
Synthesis of [Rh(3)(6)(cod)]BF . Ligand 3 (0.025 mmol, 1 equiv)
4
Methods in Asymmetric Hydrogenation. Chem. Rev. 2006, 106 (7),
and ligand 6 (0.025 mmol, 1 equiv) were placed in a dry-flamed
Schlenk flask under an argon atmosphere. CD Cl (0.3 mL) was
2
912−2942.
2
2
(6) Chiba, M.; Takahashi, H.; Takahashi, H.; Morimoto, T.; Achiwa,
dropped on them, leading to a transparent solution. The commercially
available [Rh(cod) ]BF salt (0.025 mmol, 1 equiv) was placed in
K. Synthesis and Application of a Novel Bisphosphine Ligand,
2
4
(
−)-DIOCP, as an Unsymmetrized Diop to Prove the General Utility
of New Designing Concept. Tetrahedron Lett. 1987, 28 (32), 3675−
678.
7) Takahashi, H.; Morimoto, T.; Achiwa, K. Highly Effective
another flame-dried Schlenk flask under an argon atmosphere and was
dissolved with 0.25 mL of CD Cl . The solution of the metal salt was
2
2
3
added dropwise to the solution of ligands, and the medium was stirred
for 30 min at room temperature. The solution was transferred to an
NMR tube under an argon atmosphere.
Representative Procedure for the Catalysis Experiments.
The hydrogenation experiments were carried out in a stainless steel
autoclave (150 or 250 mL) charged with an insert suitable for 8 or 15
reaction vessels (including Teflon mini stirring bars) for conducting
parallel reactions. The reaction vessels were prepared in a glovebox
(
Catalytic Asymmetric Hydrogenations of α-Keto Esters and an α-
Keto Acetal with New Neutral Chiral Pyrrolidinebisphosphine-
Rhodium Complexes. Chem. Lett. 1987, 16 (5), 855−858.
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Hydroboration Reactions. J. Am. Chem. Soc. 1994, 116 (9), 4062−
under an N atmosphere. Except where noted, in a typical experiment,
2
4
(
066.
the reaction vessels were charged with 200 μL of a 1 mM solution of
9) Holz, J.; Heller, D.; Sturmer, R.; Borner, A. Synthesis of the First
̈
̈
catalyst and 0.1 mmol of substrate in 0.8 mL of CH Cl . Before the
2
2
Water-Soluble Chiral Tetrahydroxy Diphosphine Rh(I) Catalyst for
Enantioselective Hydrogenation. Tetrahedron Lett. 1999, 40 (39),
7059−7062.
catalytic reactions were started, the charged autoclave was purged
three times with 5 bar of dihydrogen and then pressurized at 5−40
bar of H . The reaction mixtures were stirred at 25 °C for 16 h. After
2
catalysis the pressure was released,the conversion was determined by
(10) Yoon, T. P.; Jacobsen, E. N. Privileged Chiral Catalysts. Science
2003, 299 (5613), 1691−1693.
1
H NMR, and the enantiomeric purity was determined by chiral GC
or HPLC.
(11) Imamoto, T.; Tamura, K.; Zhang, Z.; Horiuchi, Y.; Sugiya, M.;
Yoshida, K.; Yanagisawa, A.; Gridnev, I. D. Rigid P-Chiral Phosphine
Ligands with Tert-Butylmethylphosphino Groups for Rhodium-
Catalyzed Asymmetric Hydrogenation of Functionalized Alkenes. J.
Am. Chem. Soc. 2012, 134, 1754−1769.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications Web site at DOI: xxx The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.organomet.9b00484.
(
12) Teichert, J. F.; Feringa, B. L. Phosphoramidites : Privileged
Ligands in Asymmetric Catalysis. Angew. Chem., Int. Ed. 2010, 49,
486−2528.
13) Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. A New
2
(
General considerations, details of syntheses, catalysis,
kinetics, influence of the substrate concentration,
influence of the temperature, and DFT calculations
Principle in Combinatorial Asymmetric Transition-Metal Catalysis:
Mixtures of Chiral Monodentate P Ligands. Angew. Chem., Int. Ed.
2
(
003, 42 (7), 790−793.
14) Reetz, M. T.; Mehler, G. Mixtures of Chiral and Achiral
(
PDF)
Cartesian coordinates for the calculated structures
XYZ)
Monodentate Ligands in Asymmetric Rh-Catalyzed Olefin Hydro-
genation: Reversal of Enantioselectivity. Tetrahedron Lett. 2003, 44
(
(
24), 4593−4596.
(
15) Reetz, M. T.; Bondarev, O. Mixtures of Chiral Phosphorous
AUTHOR INFORMATION
Corresponding Author
E-mail for J.N.H.R.: j.n.h.reek@uva.nl.
acid Diesters and Achiral P Ligands in the Enantio- and
Diastereoselective Hydrogenation of Ketimines. Angew. Chem., Int.
Ed. 2007, 46 (24), 4523−4526.
■
*
(16) Reetz, M. T.; Guo, H. Mixtures of Monodentate P-Ligands as a
ORCID
Means to Control the Diastereoselectivity in Rh-Catalyzed Hydro-
genation of Chiral Alkenes. Beilstein J. Org. Chem. 2005, 1, 2−7.
(17) Reetz, M. T.; Fu, Y.; Meiswinkel, A. Nonlinear Effects in Rh-
Catalyzed Asymmetric Olefin Hydrogenation Using Mixtures of
Chiral Monodentate P Ligands. Angew. Chem., Int. Ed. 2006, 45 (9),
Bas de Bruin: 0000-0002-3482-7669
Joost N. H. Reek: 0000-0001-5024-508X
Notes
The authors declare no competing financial interest.
1
(
412−1415.
18) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.;
ACKNOWLEDGMENTS
■
de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Highly
Enantioselective Rhodium-Catalyzed Hydrogenation with Monoden-
tate Ligands. J. Am. Chem. Soc. 2000, 122 (46), 11539−11540.
Support for this work was generously provided by NWO, the
dutch national science foundation. The work is part of the
research priority sustainable chemistry from the University of
Amsterdam.
(19) Pena, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. Highly
̃
Enantioselective Rhodium-Catalyzed Hydrogenation of β-Dehydroa-
mino Acid Derivatives Using Monodentate Phosphoramidites. J. Am.
Chem. Soc. 2002, 124 (49), 14552−14553.
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I
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