Application of supramolecular bidentate hybrid ligands in asymmetric hydroformylation

Article abstract of DOI:10.1002/chem.201202044

In this study we report a novel class of supramolecular bidentate hybrid ligands in which the two inequivalent phosphorus units and pyridine moieties are covalently attached to a chiral scaffold and the supramolecular interactions are used as a second handle to control the coordination sphere around the transition-metal centre. The coordination chemistry of these ligands was investigated under hydroformylation conditions by high-pressure NMR and IR spectroscopy, revealing the formation of a single active species in which the phosphane ligand is in the axial position and the phosphoramidite adopts the equatorial position. These ligands were applied in the asymmetric Rh-catalysed hydroformylation of styrene and para-substituted analogues. In these hydroformylation reactions, modification of the electronic and steric properties of the zinc(II)-templates appear to have a significant influence on the activity and selectivity of the catalysis. In particular, zinc(II)-templates bearing more electron-withdrawing substituents led to an increase in enantioselectivity.

Full text of DOI:10.1002/chem.201202044

FULL PAPER
DOI: 10.1002/chem.201202044
Application of Supramolecular Bidentate Hybrid Ligands in Asymmetric
Hydroformylation
Rosalba Bellini and Joost N. H. Reek*[a]
Abstract: In this study we report a
novel class of supramolecular bidentate
hybrid ligands in which the two inequi-
valent phosphorus units and pyridine
moieties are covalently attached to a
chiral scaffold and the supramolecular
pressure NMR and IR spectroscopy,
revealing the formation of a single
active species in which the phosphane
ligand is in the axial position and the
phosphoramidite adopts the equatorial
position. These ligands were applied in
the asymmetric Rh-catalysed hydrofor-
mylation of styrene and para-substitut-
ed analogues. In these hydroformyla-
tion reactions, modification of the elec-
tronic and steric properties of the
zinc(II)-templates appear to have a sig-
nificant influence on the activity and
selectivity of the catalysis. In particular,
zinc(II)-templates bearing more elec-
tron-withdrawing substituents led to an
increase in enantioselectivity.
interactions are used as
a second
handle to control the coordination
sphere around the transition-metal
centre. The coordination chemistry of
these ligands was investigated under
hydroformylation conditions by high-
Keywords: hydroformylation
· li-
gand design · IR spectroscopy ·
NMR spectroscopy · supramolecu-
lar chemistry
Introduction
been examined, excellent results were reported only for a
small number of ligands. Most of these ligands are bidentate
and rely on relatively p-acidic phosphorus atoms such as
phosphite, phosphoramidites, phospholanes and diazaphos-
pholanes to achieve good reaction rates. Bidentate phos-
phite ligands such as (2R,4R)-Chiraphite[3] exhibit good
enantioselectivity in the reaction of styrene. (S,S)-Kelli-
phite[4] is more efficient in the stereocontrol of HF of allyl
cyanide and vinyl acetate. Wills and co-workers reported the
first phospholane-type ligand, (S,S)-Esphos,[5] which was ef-
fective for the AHF of vinyl acetate. Landis, Klosin and co-
workers introduced the diazaphospholane ligands, which dis-
played effective control over regio- and enantioselectivities
in the AHF of styrene, vinyl acetate and allyl cyanide
(Figure 1).[6] The most successful class of ligands for Rh-cat-
alysed AHF are hybrid ligands containing a phosphane and
either a phosphite or a phosphoramidite. In this field a
major breakthrough was achieved with (R,S)-Binaphos, de-
veloped by Takaya, Nozaki and co-workers in 1993
(Figure 2, I).[7] This catalyst turned out to be extremely ver-
satile, giving ee values up to 95% for a wide range of sub-
strates. More recently, Zhang, Yang and co-workers report-
ed a phosphoramidite analogue of Binaphos, (R,S)-YanPhos,
which significantly improved the enantioselectivity over
(R,S)-Binaphos in AHF of styrenes and vinyl acetate
(Figure 2, II).[8] Other successful examples of hybrid biden-
tate ligands are depicted in Figure 2 and were developed by
the groups of van Leeuwen (III),[9] Claver (IV),[10] Pizzano
and Peruzzini (V),[11] Clarke (VI),[12] Schmalz (VII),[13] and
Reek (VIII and IX).[14]
Asymmetric hydroformylation (AHF) is a powerful and effi-
cient homogeneous catalytic process that transforms alkenes
and syngas (H2/CO) into chiral aldehydes in a single step
with 100% atom efficiency.[1] The chiral aldehydes are
highly valuable products that can be used as important pre-
cursors for a variety of pharmaceutical and fine chemical in-
termediates.[2] Although the reaction is extremely attractive
for both industry and academia, AHF has not been fre-
quently used in organic synthesis. One important reason lies
in the difficulty of controlling both the regio- and enantiose-
lectivity at moderately high temperature while still obtaining
reasonable reaction rates. This is usually a highly challeng-
ing task because higher temperatures are required to obtain
sufficient reaction rates, but this often is associated with a
decrease in regio- and enantioselectivity. The most efficient
way to control these selectivities, besides altering reaction
parameters such as pressure and temperature, is by employ-
ing chiral ligands that are able to steer the reaction towards
the desired product. Therefore, in the field of Rh-catalysed
AHF, significant efforts have been directed towards the
design and development of new chiral ligands. Over the past
three decades, although a large variety of chiral ligands have
[a] R. Bellini, Prof. Dr. J. N. H. Reek
Vanꢀt Hoff Institute for Molecular Science
University of Amsterdam
Science Park 904, Amsterdam 1098 XH (The Netherlands)
Fax : (+31)205255604
An alternative way to generate bidentate hybrid ligands
involves the self-assembly of monodentate units to bidentate
ligands employing noncovalent interactions such as hydro-
E-mail: j.n.h.reek@uva.nl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202044.
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gands was obtained by self-assembly of two different mono-
dentate building blocks on a rigid bis-zinc(II)-salphen
building block (Figure 3, A).[16] In the AHF of styrene this
assembly gave ee values up to 72%. An alternative ap-
proach involves combing different monodentate ligand
building blocks equipped with complementary binding
sites to form hybrid bidentate ligands. Through the prepa-
ration of 40 building blocks, a ligand library of 400 ligands
was created (Supraphos). The application of a part of this
library of chelating hybrid ligands in AHF of styrene gave
ee values up to 76% (Figure 3, B).[17]
Further development of this concept led us to search
for alternative strategies to form supramolecular bidentate
hybrid ligands. In this contribution we introduce a new
class of supramolecular bidentate ligands in which the two
inequivalent phosphorus units and the pyridine moieties
are covalently attached to a chiral scaffold and the supra-
molecular interactions are used as an additional handle to
increase the steric bulk and eventually encapsulate the
transition-metal centre (Figure 4). The supramolecular as-
sembly is formed in situ by selective interactions between
the nitrogen donor atoms and
Figure 1. Representative examples of chiral bidentate ligands successfully
used in AHF of alkenes.
the zinc(II) template, which will
result in the encapsulation of
the transition-metal centre that
is used for catalysis. In addition,
we demonstrate that we can in-
fluence the ligand properties by
using electronically and sterical-
ly different zinc(II) templates.
In asymmetric hydroformyla-
tion of styrene and p-styrene
derivatives, the different supra-
molecular ligands change dra-
matically key reaction features
such as activity and selectivity,
which illustrates the high versa-
tility of these new systems.
Ligand synthesis: The novel bi-
dentate phosphane–phosphor-
amidite ligands (S)-1a–c were
prepared according to the pro-
cedure depicted in Scheme 1.
The synthetic procedure started
with the conversion of N-meth-
ylaniline (1) into the corre-
sponding lithium carbamate
Figure 2. Representative examples of chiral bidentate hybrid ligands for AHF of alkenes.
compound, followed by o-lithia-
tion with tBuLi and treatment
gen bonds, ionic interactions or dynamic metal-ligand coor-
dination.[15] Our group has reported examples of supramo-
lecular bidentate ligands based on coordinative bonding be-
tween phosphane or phosphite ligands functionalised with
pyridine moieties and zinc(II)-templates. Successful exam-
ples of these assemblies in AHF are reported in Figure 3.
Formation of chelating supramolecular hybrid bidentate li-
with Ph2PCl and subsequent hydrolysis to give compound
2.[18] Phosphane 2 was transformed into 3 by reaction with
PCl3 at low temperature and under basic conditions. Quanti-
tative yields were achieved and the phosphorodichloride
compound was used in the next step without any further pu-
rification. Compounds (S)-6a–c were prepared starting from
the reduction of the commercially available (S)-binol in the
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Hybrid Ligands in Asymmetric Hydroformylation
FULL PAPER
presence of Pd/C.[19] The diol 4
was selectively brominated at
the 3,3’-positions to give prod-
uct 5.[20] Suzuki coupling of 5
with the appropriate boronic
acids provided compounds 6a–
c. Condensation of 3 with diols
6a–c produced the hybrid li-
gands 7a–c in good yields, up to
86% after flash column chro-
matography. All new com-
pounds were fully characterised
by 1H, 13C and 31P NMR spec-
troscopy and by high-resolution
mass spectrometry.
Figure 3. Formation of hybrid bidentate ligands by self-assembly of complementary units.
Coordination studies
UV/Vis titration: First, the coordination behaviour of ligands
(S)-7a and (S)-7b towards zinc(II)-porphyrin 8 was investi-
gated by using UV/Vis titration (Scheme 2). In the UV/Vis
spectrum of 8, a typical shift for the Q-bands of the porphyr-
in upon addition of 7a or 7b was observed and the binding
constants were determined by fitting the titration curve
using a mathematical model. Identical and independent
binding constants were obtained for ligand 7a (K1(7a–8)
2(7a–8) =5.3ꢂ103 mÀ1) as well as for ligand 7b (K1(7b–8) =K2(7b–
8) =8.3ꢂ103 mÀ1).
=
K
It is known that the binding of zinc(II) templates occurs
selectively through the nitrogen donors and, therefore, the
phosphorus is available for coordination to the catalytically
Figure 4. Supramolecular bidentate hybrid ligands.
Scheme 1. Synthesis of chiral bidentate hybrid ligands (S)-7a–c.
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R. Bellini and J. N. H. Reek
the HP 1H NMR spectrum at
high field
a single hydride
signal was detected. One of the
hydride couplings was very
large, which indicates that one
of the phosphorus atoms is in a
trans position to the hydride,
implying formation of an eq–ap
complex. The absence of the
large coupling in the 1H-
{31P} NMR spectrum confirmed
the trans relationship between
one of the phosphorus atoms
and the hydride. The 1H-{31P}
NMR spectrum displayed
a
doublet at d=À10.1 ppm indi-
Scheme 2. Assembly of ligand (S)-7a on meso-phenyl zinc(II)-porphyrin 8.
cative of the coupling of a hy-
active transition-metal centre. Hence, we next investigated
the coordination of these bidentate hybrid ligands to the
rhodium metal centre under hydroformylation conditions.
The formation of the rhodium complexes for the ligands
7a(8)2, 7b(8)2 and (S)-7a–c were fully characterised by high-
pressure (HP) NMR and HP IR spectroscopy.
High-pressure NMR experiments: Rhodium complexes were
prepared for the HP NMR experiments by adding 1 equiva-
lent of bidentate ligand to the metal precursor [Rh-
ACHTUNGTRENNUNG(acac)(CO)2] in [D8]toluene at 5 bar of syngas (H2/CO, 1:1)
pressure. According to these NMR experiments, displace-
ment of the two carbon monoxide ligands by the bidentate
Figure 5. Structures of equatorial–equatorial conformer A (eq–eq), and
equatorial–apical conformers (eq–ap) B and C of the hydridobiscarbonyl
rhodium complexes.
À
P
ligand (PPh
N) resulted in the Àformation of the square
À
P
P
(acac) PPh
N]. After an incubation
À
P
planar complex [Rh
time of 16 h at room temperature under these hydroformy-
lation conditions, the expected hydridobiscarbonyl rhodium
Table 1. 1H and 31P high pressure NMR data for the [RhH(CO)2PPh
PP–N] complexes in [D8]toluene.[a]
–
À
complex [RhH(CO)2PPh
N] was formed. For unsymmetri-
P
À
P
cal bidentate ligands, three different isomers can be formed,
the eq–eq isomer, with both phosphorus donor atoms in
equatorial position, and the two eq–ap isomers, in which
either the phosphane or the phosphoramidite occupies the
apical position, trans to the hydride (Figure 5).
Hydride
Ligand dHÀRh JRhÀH dP
Phosphane
Phosphoramidite
Ph
Ph
Ph
Ph PN
P
PN
PN
PN
JP
JP
JP
dP
JP
JP
Rh
H
Rh
H
[b]
7a(8)2 À10.1 11.0 30.5 89.1
7a
À8.9 12.0 31.3 90.2
120.3 62.5
117.2 64.0
115.0 63.5
118.1 61.7
116.1 62.3
166.2 234.2
–
166.1 233.0 14.0
165.3 229.8 20.1
165.5 232.0 15.0
164.6 228.1 19.0
7b(8)2 À10.0 11.6 30.3 90.0
7b
7c
À8.8 11.2 31.5 93.0
Stable rhodium complexes were obtained for all the li-
gands, and in none of the experiments hydrolysis or oxida-
tion of the ligands was observed. The chemical shifts of the
phosphorus and hydride signals, as well as the coupling con-
stants of the various complexes, measured under hydrofor-
mylation conditions, are shown in Table 1.
À8.8 11.0 31.9 93.1
[a] Hydridobiscarbonyl rhodium complexes were generated in situ from
[Rh(acac)(CO)2] and the corresponding ligand after incubation at room
AHCTUNGTRENNUNG
temperature for 16 h under 5 bar H2/CO in [D8]toluene. [b] Value not de-
tected due to small coupling constant.
Ligand 7a(8)2 in the presence of the rhodium precursor
gives rise to the formation of the square planar complex
1
dride with rhodium. The 2D H-31P NMR spectrum supports
1
[Rh
A
the correlation of the single hydride signal in the H NMR
spectroscopic analysis with two double of doublets centred,
respectively, at d=46.5 and 146.0 ppm. After exposing [Rh-
spectrum with the two doublet of doublets in the 31P NMR
spectrum, providing further evidence for the formation
A
of
the
hydridobiscarbonyl
rhodium
complex
appeared in the HP 31P NMR spectrum, indicating conver-
sion of the square planar precursor complex into the trigo-
nal bipyramidal hydrido complex [Rh(H)(CO)27a(8)2]. In
[Rh(H)(CO)27a(8)2]. In addition, in the 2D 1H-31P NMR
spectrum, the cross peaks between the hydride signals and
the doublet of doublets corresponding to the phosphane
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Hybrid Ligands in Asymmetric Hydroformylation
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ligand are more intense than the signal correlated to the
phosphoramidite ligand, giving a clear indication that in the
eq–ap complex the phosphane occupies the axial position,
trans to the hydride and the phosphoramidite the equatorial
position (Scheme 3, A). This is substantiated by the much
larger coupling of the phosphane with the hydride than with
the phosphoramidite.
catalyst at concentrations identical to those used in catalysis
experiments. We investigated the formation of the hydrido-
biscarbonyl complexes with ligands 7a(8)2, 7a and 7c. The
complexes were formed within 20 h at 408C and 20 bar H2/
CO in dichloromethane. In line with our HP NMR studies,
only one set of carbonyl signals (symmetric and antisymmet-
ric stretching modes) were observed in all cases, correspond-
ing to the eq–ap isomer. The
Rh-H vibration was not ob-
served in the spectra, possibly
because of overlap with one of
the carbonyl signals.
In the [Rh(H)(CO)27a] com-
plex two peaks were detected
in the carbonyl stretching
region (2007.7 and 1958.6 cmÀ1).
In the presence of template 8
the [Rh(H)(CO)27a(8)2] com-
plex is formed in which the two
absorption bands are shifted to
slightly higher wavenumbers
(2011.1 and 1963.4 cmÀ1; see the
Supporting Information). In
line with our previous findings
Scheme 3. Structures of the eq–ap isomers A and B of the [Rh(H)(CO)27a(8)2] complex.
using monodentate ligand ana-
logues,[21] coordination of the
Similar results were obtained from the HP NMR investi-
gations on the supramolecular ligand 7b(8)2 and ligands (S)-
7a–c, with formation in all cases of a single eq–ap hydrido-
biscarbonyl rhodium complex (Table 1). In these experi-
ments the association of the zinc(II)-porphyrin 8 to ligands
7a and 7b does not change the ligand coordination mode, in
contrast to what was observed for the monodentate ana-
logue ligands.[21]
pyridyl leads to lower electron density on the rhodium, as
indicated by the shift to higher wavenumbers. This implies a
decrease of back-bonding to the CO molecules and, hence,
faster CO dissociation and possibly an increase in the reac-
tion rates. The IR spectrum corresponding to complex
[Rh(H)(CO)27c] also shows only one set of carbonyl signals
(2005.1 and 1956.1 cmÀ1) corresponding to the eq–ap com-
plex (see the Supporting Information).
In the initial coordination studies on the [Rh(H)(CO)2-
ACHTUNGTRENNUNG(R,S)-Binaphos] complex, Nozaki and co-workers interpret-
In all of the spectra, the carbonyl signals at higher wave-
numbers have much lower intensity, suggesting possible dis-
tortion of the trigonal bipyramidal geometry in the Rh-hy-
drido complex. To obtain evidence for the formation of such
a distorted structure, we carried out DFT calculations of
complex [Rh(H)(CO)27c]. Indeed, the calculated structure
ed the HP NMR experiments as resulting from a single spe-
cies with eq–ap coordination in which the phosphite ligand
was trans to the hydride.[7b] Further investigation by Jꢃkel,
Nozaki and co-workers demonstrated that, at low tempera-
ture, both eq–ap conformers are present.[7c] At room temper-
ature these isomers are in rapid equilibrium and the spectra
represent the average of these complexes. On the basis of
of complex [Rh(H)(CO)27c] reveal a distorted trigonal bi-
Ph
À
pyramidal complex geometry (H-Rh P , Angle=172.878).
À
However, only a slight difference in the calculated Rh CO
and C O bond lengths were observed (see the Supporting
1
À
these studies we decided to perform low-temperature HP H
and
31P NMR
spectroscopic
analysis
of
the
Information).
[Rh(H)(CO)27a(8)2] complex to investigate the formation of
the two eq–ap isomers. Upon lowering the temperature
Asymmetric hydroformylation: The catalytic potential of the
new bidentate ligands (S)-7a–c was evaluated in the Rh-cat-
alysed asymmetric hydroformylation of styrene and para-
substituted styrene derivatives. Ligands (S)-7a–b were ap-
plied in the presence and absence of template 8 to evaluate
whether the effect of the supramolecular assemblies could
possibly enhance the activity and selectivity of this catalytic
transformation. We studied the performance of these ligands
using styrene as a benchmark substrate under 20 bar of H2/
CO (1:1) at 258C (Table 4, entry 2). The supramolecular
ligand 7a(8)2 gave higher conversion and slightly higher
1
from 25 to À908C, the signals in both H and 31P NMR spec-
tra broaden but no new signals appeared. These experiments
establish the exclusive formation of a single hydridobiscar-
bonyl rhodium active complex, in which the phosphane is
mainly located trans to the hydride and the phosphoramidite
is in the equatorial position (see the Supporting Informa-
tion).
High-pressure IR experiments: In situ HP IR spectroscopy
studies were then performed to study the formation of the
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R. Bellini and J. N. H. Reek
Table 2. Asymmetric hydroformylation of styrene using ligand (S)-7a–c
and template 8.[a]
Entry
Ligand
Conv. [%][b]
b/l[c]
ee [%][d]
1
2
3
4
5
6
7a(8)2
7a
7b(8)2
7b
7c
7c+8
52
5
56
3
18
18
91:9
95:5
97:3
99:1
97:3
97:3
59 (S)
51 (S)
20 (R)
52 (S)
51 (S)
50 (S)
Figure 6. Zinc(II) and ruthenium(II) building blocks used in this study.
Table 3. Asymmetric hydroformylation of styrene; template screening.[a]
[a] Reagents and conditions: [RhACTHNUTRGNE(UNG acac)(CO)2]=1 mm in toluene, ligand/
rhodium=3, styrene/rhodium=200, 258C, 20 bar, 84 h. [b] Percentage
conversion calculated on the basis of GC analysis. [c] Ratio of branched
to linear aldehyde. [d] Enantiomeric ratio determined by chiral GC anal-
ysis (Supelco BETA DEX 225).
Entry
Ligand
Template
Conv. [%][b]
b/l[c]
ee [%][d]
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7a
7a
7b
7b
7b
7b
7b
8
9
52
10
10
10
9
91:9
97:3
98:2
96:4
99:1
96:4
97:3
94:6
95:5
98:2
98:2
59 (S)
64 (S)
40 (S)
43 (S)
72 (S)
45 (S)
26 (R)
9 (R)
10
11
12
13
9
10
11
12
13
enantioselectivity compared with the nontemplated ana-
logue 7a (Table 2, entries 1 and 2). Ligand 7b(8)2 also gave
higher conversion, albeit with lower and opposite enantiose-
lectivity than ligand 7b (Table 2, entries 3 and 4). Ligand 7c,
which was used as control because it lacks the pyridyl group,
showed moderate conversion (Table 2, entry 5) and similar
levels of enantioselection to that obtained with ligand 7a. In
the presence of template 8, ligand 7c displayed the same ac-
tivity and selectivity, indicating that the zinc template does
not directly affect the catalytic outcome of the reaction
(Table 2, entry 6). In light of these preliminary results, in
which only improvements in activity and small effects in se-
lectivity were obtained in the presence of template 8, we de-
cided to investigate a small series of electronically and steri-
cally different porphyrins. It is known that changing the sub-
stituents on the porphyrins alters the electron density on the
pyridine moiety.[22] Therefore, an effect in the electron densi-
ty on the phosphorus atom can also be expected, which, in
turn, might influence the catalysis outcome.
7
11
11
10
8
9
10
11
10 (R)
40 (R)
8 (R)
8
[a] Reagents and conditions: [RhACTHNUTRGNE(UNG acac)(CO)2]=1 mm in toluene, ligand/
rhodium=3, styrene/rhodium=200, 258C, 20 bar, 84 h. [b] Percentage
conversion calculated on the basis of GC analysis. [c] Ratio of branched
to linear aldehyde. [d] Enantiomeric ratio determined by chiral GC anal-
ysis (Supelco BETA DEX 225).
tries 5 and 10), albeit with lower conversion than with tem-
plate 8 (Table 3, entry 1 vs. entries 5 and 10). Rutheniu-
m(II)-porphyrins bind pyridines with higher binding con-
stants[24] and the exchange between free and bonded species
is slow on the NMR time-scale. These properties may be im-
portant for the development of more selective catalysts.
Similar results were reported for the assembly of tris-3-pyri-
dylphoshine with ruthenium(II)-porphyrin 12, in which the
hydroformylation of 1-octene delivers higher selectivity but
lower activity compared with the assembly based on
zinc(II)-porphyrin (8).[25] Changes in the steric bulk of tem-
plate 12, using, for example, template 13, leads to similar ac-
tivity and regioselectivity, but lower enantioselectivity
(Table 3, entries 6 and 11). This is can be explained by a
match/mismatch effect due to the presence of multiple ster-
eocentres. Because the other diastereomer was not availa-
ble, we have not further studied this effect.
By using these new supramolecular bidentate systems we
are able to fine-tune the properties of the ligands and thus
influence the catalytic outcome of the reaction, by just
changing the properties of the supramolecular templates.
This is in contrast to our earlier findings employing mono-
dentate analogues of ligands 7a–b,[21] in which the catalytic
properties of the supramolecular catalysts were not influ-
enced by the properties of zinc templates, but instead were
Variation of electronic properties of ligands 7a–b: In these
studies we investigated the influence of different templates
on the electronic and steric properties of ligands 7a–b.
Upon variation of the steric and electronic properties of the
porphyrin building blocks[23] (Figure 6), a series of new su-
pramolecular ligands based on (S)-7a–b were evaluated in
Rh-catalysed asymmetric hydroformylation of styrene
(Table 3).
As is clear from the results presented in Table 3, the elec-
tronic properties of porphyrin templates have a distinct
effect on the catalysis outcome. In particular, the assemblies
of more electron-withdrawing zinc(II)-porphyrins on ligand
7a leads to an increase in enantioselectivity up to 64%
(Table 3, entries 1–5). A similar trend was obtained with su-
pramolecular catalysts formed by ligand 7b but with lower
enantioselectivity (Table 3, entries 7–10). Interestingly, the
highest enantioselectivity was obtained with the catalyst as-
semblies based on ruthenium(II) template 12 (Table 3, en-
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Hybrid Ligands in Asymmetric Hydroformylation
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Table 5. Asymmetric hydroformylation of styrene derivatives using
associated with the change in the coordination mode of the
ligand.
ligand (S)-7b and template 12.[a]
Entry
R
Template
Conv. [%][b]
b/l[c]
ee [%][d]
Asymmetric hydroformylation of para-substituted styrenes:
Having established 12 as the best template, we investigated
the substrate scope, studying the performance of supramo-
lecular ligands 7a(12)2 and 7b(12)2 as well as the control
ligand 7a–c in the AHF of para-substituted styrenes.
The catalytic results obtained by employing the supramo-
lecular ligand 7a(12)2 displayed a branched isomer selectivi-
ty that increases with more electron-withdrawing substrates
(Table 4, entries 1 and 3 vs. entry 5). A similar trend in re-
gioselectivity was observed for the nontemplated ligand 7a
(Table 4, entries 2, 4 and 6). Interestingly, higher enantiose-
lectivities were obtained with the supramolecular assemblies
(Table 4, entries 1, 3 and 5) with ee values up to 82% com-
pared with the nontemplated ligand. The nontemplated
ligand gives, however, slightly higher conversions (Table 4,
entries 2, 4 and 6).
1
2
3
4
5
6
OCH3
OCH3
CH3
CH3
Cl
12
–
12
–
12
–
9
18
13
16
13
12
92:8
92:8
99:1
98:2
99:1
99:1
37 (R)
60 (S)
32 (R)
69 (S)
17 (R)
30 (S)
Cl
[a] Reagents and conditions: [RhACTHNUTRGNE(UNG acac)(CO)2]=1 mm in toluene, ligand/
rhodium=3, p-styrene/rhodium=200, 258C, 20 bar, 84 h. [b] Percentage
conversion calculated on the basis of GC analysis. [c] Ratio of branched
to linear aldehyde. [d] Enantiomeric ratio determined by chiral GC anal-
ysis (Supelco BETA DEX 225).
Table 6. Asymmetric hydroformylation of styrene derivatives using
ligand (S)-7c.[a]
Entry
R
Conv. [%][b]
b/l[c]
ee [%][d]
1
2
3
OCH3
CH3
Cl
15
10
25
93:7
93:7
94:6
26 (S)
38 (S)
30 (S)
[a] Reagents and conditions: [RhACTHNUTRGNE(UNG acac)(CO)2]=1 mm in toluene, ligand/
Table 4. Asymmetric hydroformylation of styrene derivatives using
ligand (S)-7a and template 12.[a]
rhodium=3, p-styrene/rhodium=200, 258C, 20 bar, 84 h. [b] Percentage
conversion calculated on the basis of GC analysis. [c] Ratio of branched
to linear aldehyde. [d] Enantiomeric ratio determined by chiral GC anal-
ysis (Supelco BETA DEX 225).
Interestingly, a correlation between enantioselectivity and
the Hammett constants[26] (substrate s value) was observed
for the supramolecular ligands 7a(12)2 and 7b(12)2. Plotting
the ee values against the Hammett constants of the sub-
strates (p-methoxystyrene À0.27, p-methylstyrene À0.17,
styrene 0, p-chlorostyrene +0.23), a decrease of ee was ob-
tained when s increased (Figure 7). On the other hand, no
Entry
R
Template
Conv. [%][b]
b/l[c]
ee [%][d]
1
2
3
4
5
6
OCH3
OCH3
CH3
CH3
Cl
12
–
12
–
12
–
10
21
16
22
12
18
90:10
91:9
95:5
92:8
99:1
99:1
82 (S)
18 (S)
80 (S)
15 (S)
66 (S)
13 (S)
Cl
[a] Reagents and conditions: [RhACTHNUTRGNE(UNG acac)(CO)2]=1 mm in toluene, ligand/
rhodium=3, p-styrene/rhodium=200, 258C, 20 bar, 84 h. [b] Percentage
conversion calculated on the basis of GC analysis. [c] Ratio of branched
to linear aldehyde. [d] Enantiomeric ratio determined by chiral GC anal-
ysis (Supelco BETA DEX 225).
Interestingly, for ligand 7b, which is similar to ligand 7a,
but with a m-pyridyl group instead of a p-pyridyl, we found
the reverse effect. Supramolecular bidentate ligand 7b(12)2
displayed lower selectivity compared with the nontemplated
analogue 7b (Table 5, entries 1, 3 and 5 vs. entries 2, 4 and
6). Surprisingly, supramolecular ligand 7b(12)2 induced op-
posite enantioselectivity, with preferred formation of the R
enantiomer (Table 5, entries 1, 3, and 5). It should be noted
that all ligands have the same absolute configuration of the
8H-Binol moiety. Marginal changes in regioselectivity were
obtained with more electron-withdrawing substrates.
Control experiments using ligand 7c, which has phenyl
groups instead of pyridyls, show that the catalyst-induced re-
gioselectivity was independent of the electronic nature of
the substrate. The enantioselectivity is slightly higher than
that induced by 7a, and much lower than that of supramo-
lecular ligand 7a(12)2 (Table 6, entries 1–3).
Figure 7. Plot of the ee values versus Hammett constants s for ligands
7a(12)2 and 7b(12)2.
clear correlation between enantioselectivity and substrate
electronics was observed for ligands 7a–c (Figure 8). In a
recent publication, our group has reported on phosphane–
phosphite ligands in the AHF of electronically different styr-
ene derivatives.[27] A trend between the electronic properties
of the substrate and the orientation of the phenyl groups of
P-ligands was observed, with the conclusion that aryl–aryl
(p–p) interactions between substrate and ligands might take
Chem. Eur. J. 2012, 00, 0 – 0
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R. Bellini and J. N. H. Reek
This could be related to the presence of multiple active iso-
mers of the supramolecular catalyst, which have different se-
lectivities. Incubation of the catalyst at 408C for 18 h and
then reaction at lower temperature (258C) did not result in
higher conversion (Table 7, entry 17).
Conclusion
We report here the synthesis of a new class of supramolecu-
lar hybrid bidentate ligands and their application in AHF re-
actions. We investigated the coordination behaviour of these
ligands with zinc(II) template 8 as well as to rhodium com-
plexes under catalytically relevant conditions by using high
pressure NMR and IR spectroscopy. These studies revealed
the formation of a single rhodium bis-carbonyl hydrido com-
plex in which the phosphane ligand resides on the axial posi-
tion and the phosphoramidite ligand in the equatorial posi-
tion. In the rhodium-catalysed asymmetric hydroformylation
of styrene, modification of steric and electronic functionali-
ties on the zinc(II) and ruthenium(II) templates have been
shown to have a significant influence on the activity and se-
lectivity of the reaction. A notable improvement in enantio-
selectivity was obtained with the supramolecular ligand
7a(12)2 and ligands based on 7a with zinc(II) templates
functionalised with electron-withdrawing groups. Applica-
tion of 7a(12)2 in the AHF of styrene and para-substituted
styrene derivatives thereof shows higher enantiocontrol
compared to the nontemplated analogue ligands. This work
demonstrates the potential of the supramolecular strategy in
tailoring key catalyst properties such as activity and selectiv-
ity by using sterically and electronically different templates.
Figure 8. Plot of the ee values versus Hammett constants s for ligands
7a–c.
place, hence, influencing the selectivity of the reaction. This
may indeed also occur in our system, in which the substrate
and the phenyl groups of the porphyrin could interact
through weak interactions, and therefore influence the enan-
tioselectivity.
Next, we decided to perform the catalysis at higher tem-
perature (408C) with the aim of increasing the conversion of
ligands 7a(12)2, 7b(12)2, 7a and 7b. As shown in Table 7, all
the ligands provided catalysts that gave full conversion at
Table 7. Asymmetric hydroformylation of styrene derivatives.[a]
Entry
R
Ligand
Conv. [%][b]
b/l[c]
ee [%][d]
ee [%][e]
1
2
3
4
5
6
7
8
OCH3
OCH3
CH3
CH3
H
H
Cl
Cl
OCH3
OCH3
CH3
CH3
H
H
Cl
Cl
H
7a(12)2
7a
7a(12)2
7a
7a(12)2
7a
7a(12)2
7a
7b(12)2
7b
7b(12)2
7b
7b(12)2
7b
7b(12)2
7b
99
87
98
89
95
>99
99
>99
99
95:5
95:5
96:4
96:4
92:8
99:1
97:3
98:2
94:6
93:7
99:1
99:1
94:6
94:6
96:4
97:3
99:1
51 (S)
10 (S)
42 (S)
15 (S)
12 (S)
32 (S)
2 (S)
11 (S)
11 (R)
18 (S)
16 (R)
23 (S)
12 (R)
18 (S)
3 (R)
82 (S)
18 (S)
80 (S)
15 (S)
59 (S)
51 (S)
66 (S)
13 (S)
37 (R)
60 (S)
32 (R)
69 (S)
20 (R)
52 (S)
17 (R)
30 (S)
9
10
11
12
13
14
15
16
17[f]
99
Experimental Section
>99
>99
>99
>99
>99
>99
14
Unless stated otherwise, reactions were carried out under an atmosphere
of argon using standard Schlenk techniques. THF was distilled from
sodium benzophenone ketyl; CH2Cl2 was distilled from CaH2 and toluene
was distilled from sodium under nitrogen. With the exception of the com-
pounds given below, all reagents were purchased from commercial suppli-
ers and used without further purification.
7 (S)
69 (S)
7a(12)2
NMR spectra (1H, 31P and 13C) were measured with a Bruker DRX
400 MHz or Inova 500 MHz spectrometer; CDCl3 was used as a solvent,
if not further specified. High-resolution mass spectra were recorded with
a JEOL JMS SX/SX102A four sector mass spectrometer; for FAB-MS, 3-
nitrobenzyl alcohol was used as matrix. UV/Vis spectroscopy experiments
were performed with a Cary UV/Vis System. Gas chromatographic anal-
yses were performed with a Shimadzu GC-17A apparatus (split/splitless
injector, J&W Scientific, DB-1J&W 30 m column, film thickness 3.0 mm,
carrier gas 70 kPa He, FID Detector). Chiral GC separations were con-
ducted with an Interscience HR GC apparatus with a Supelco b-dex 225
(0.25 mmꢂ30 m) capillary column.
[a] Reagents and conditions: [RhACTHNUTRGNE(UNG acac)(CO)2]=1 mm in toluene, ligand/
rhodium=3, p-styrene/rhodium=200, 408C, 20 bar, 84 h. [b] Percentage
conversion calculated on the basis of GC analysis. [c] Ratio of branched
to linear aldehyde. [d] Enantiomeric ratio determined by chiral GC anal-
ysis (Supelco BETA DEX 225). [e] ee at 258C. [f] Incubation at 408C
and catalysis reaction at 258C.
408C but at the expense of regio- and enantioselectivity.
With supramolecular ligand 7a(12)2, a similar trend in enan-
tioselectivity as was observed at 258C, with a decrease in ee
when the substrate s value increases (Table 7, entries 1, 3, 5
and 7). Generally, the enantioselectivity is lower at higher
temperature, but, remarkably, this is more pronounced in
some reactions involving the supramolecular ligands. For ex-
ample, the ee becomes even lower than the corresponding
nontemplate analogue (Table 7, entry 5 vs. 6, entry 7 vs. 8).
The following compounds were synthesised according to published proce-
dures: 2-(diphenylphosphino)-N-methylaniline (2),[18] (S)-5,6,7,8,5,6,7,8-
octahydro-(1,1’-binaphtalene)-2,2’-diol
(4),[19]
(S)-3,3’-dibromo-
5,6,7,8,5’,6’,7’,8’-octahydro-(1,1’-binaphtalene)-2,2’-diol (5),[20] zinc(II)-por-
phyrins 8–11.[22] Zinc(II)-porphyrin 13 was kindly donated by the group
of A. Berkessel, Institute of Organic Chemistry, University of Kçln, Ger-
many. Details of the synthesis used to obtain (S)-6a–c were reported in a
previous publication.[21]
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Hybrid Ligands in Asymmetric Hydroformylation
FULL PAPER
Synthesis of 1,1-dichloro-N-(2-(diphenylphosphino)phenyl)-N-methyl-
phosphinamine (3): In a flame-dried Schlenk, distilled PCl3 (0.22 mL,
2.6 mmol) was added dropwise at 08C to a solution of 2-(diphenylphos-
phino)-N-methylaniline (500 mg, 1.7 mmol), and Et3N (0.24 mL,
1.7 mmol) in toluene (8.5 mL). The pale-yellow slurry was allowed to
warm to RT and then heated to 758C for 16 h. The reaction mixture was
cooled to RT and the formation of product was monitored by 31P NMR
spectroscopic analysis. The solvent and the residual PCl3 was removed in
vacuum and the resulting solid was used for the next step without any
further purification.
20 bar. After the catalytic reaction, the pressure was reduced to 1.0 bar
and a few drops of tri-n-butyl-phosphite were added to each reaction
vessel to prevent any further reaction. The reaction mixtures were not fil-
tered over basic alumina to remove catalyst residues because filtration
may cause retention of the aldehydes and thus influence the results of
the GC analysis. The mixtures were diluted with CH2Cl2 for GC analysis.
Chiral GC data for hydroformylation products: The ee values were calcu-
lated by chiral GC analysis (Supelco BETA DEX 225). Initial tempera-
ture=1008C for 5 min, then 48CminÀ1 to 1608C.
Styrene tR =4.35 min, tR (S)=11.55 min and tR (R)=11.78 min.
p-Me-Styrene tR =6.96 min, tR (S)=14.42 min and tR (R)=14.55 min.
p-OMe-Styrene tR =13.76 min, tR (S)=18.92 min and tR (R)=18.98 min.
p-Cl-Styrene tR =9.55 min, tR (S)=18.34 min and tR (R)=18.47 min.
General procedure for the preparation of ligands (S)-7a–c: In a flame-
dried Schlenk flask, compound (S)-6a–c (1.2 mmol), DMAP (10 mol%)
and pyridine (0.1 mL, 1.3 mmol) were dissolved in anhydrous THF
(4 mL). The resulting solution was cooled to 08C and phosphorodichlori-
dite 3 (467 mg, 1.2 mmol) in THF (2 mL) was added. The reaction mix-
ture was stirred overnight and warmed to RT. The resulting pale-yellow
solution was evaporated to dryness, and the resulting residue was purified
by flash column chromatography (silica gel; hexanes/CH2Cl2, 1:1 to hex-
anes/CH2Cl2/Et3N, 1:1:0.2).
Ligand (S)-7a: Yield: 85%; white foam; 1H NMR (400 MHz, CDCl3):
d=8.7 (d, J=5.7 Hz, 4H), 8.5 (d, J=5.7 Hz, 2H), 7.7 (m, 7H), 7.0 (m,
7H), 6.8 (s, 2H), 2.9 (m, 4H), 2.7 (m, 2H), 2.4 (m, 2H), 1.7 (m, 8H),
1.6 ppm (s, 3H); 13C NMR (101 MHz): d=150.0 (CH), 149.6 (CH), 148.5
(C), 146.2 (C), 145.4 (C), 138.9 (C), 138.6 (C), 135.1 (CH), 134.5 (C),
133.7 (C), 133.7 (CH), 133.6 (CH), 133.4 (CH), 133.2 (CH), 130.4 (CH),
130.2 (C), 129.9 (CH), 129.4 (C), 129.0 (CH), 128.9 (CH), 128.7(CH),
128.6(CH), 128.5(CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.1 (CH),
127.9 (C), 126.9 (CH), 124.9 (CH), 124.5 (CH), 35.6 (CH3), 29.2 (CH2),
29.1 (CH2), 28.0 (CH2), 27.7 (CH2) 22.7 (CH2), 22.7 (CH2), 22.6 (CH2),
22.5 ppm (CH2); 31P NMR (162 MHz): d=139.5 (d, J=55 Hz),
À14.5 ppm (d, J=55 Hz); HRMS (FAB+): m/z calcd for C49H43N3O2P2:
768.2909 [M+H+]; found: 768.2906.
Ligand (S)-7b: Yield: 86%; white foam; 1H NMR (400 MHz, CDCl3):
d=8.9 (s, 1H), 8.8 (s, 1H), 8.6 (m, 1H), 8.2 (m, 1H), 8.1 (m, 2H), 7.3 (m,
2H), 7.1 (m, 6H), 6.9 (m, 8H), 6.7 (m, 2H), 2.9 (m, 4H), 2.7 (m, 2H), 2.4
(m, 2H), 1.7 (m, 8H), 1.6 ppm (s, 3H); 13C NMR (101 MHz): d=150.3
(CH), 150.0 (CH), 148.3 (C), 147.9 (CH), 147.8 (CH), 145.7 (C), 138.2
(C), 137.8 (C), 137.9 (CH), 137.4 (CH), 134.8 (CH), 134.6 (C), 134.4 (C),
134.0 (CH), 133.8 (CH), 133.6 (C), 133.5 (C), 133.4 (CH), 133.2 (CH),
130.7 (CH), 130.3 (C), 129.9 (CH), 129.6 (C), 128.9 (C), 128.2 (CH),
128.1 (CH), 128.0 (CH), 127.9 (CH), 127.8 (CH), 126.6 (CH), 123.4
(CH), 123.2 (CH), 35.6 (CH3), 29.2 (CH2), 29.2 (CH2), 28.0 (CH2), 27.7
(CH2) 22.8 (CH2), 22.7 (CH2), 22.6 (CH2), 22.5 ppm (CH2); 31P NMR
(162 MHz): d=138.5 (d, J=57 Hz), À14.5 ppm (d, J=57 Hz); HRMS
(FAB+): m/z calcd for C49H43N3O2P2: 768.2909 [M+H+]; found:
768.2906.
Ligand (S)-7c: Yield: 80%; white foam; 1H NMR (400 MHz, CDCl3):
d=7.7 (m, 4H), 7.4 (m, 4H), 7.3 (m, 2H), 7.2 (m, 6H), 7.1 (m, 4H), 6.9
(m, 4H), 6.8 (m, 2H), 2.9 (m, 4H), 2.7 (m, 2H), 2.4 (m, 2H), 1.8 (m,
8H), 1.6 ppm (s, 3H); 13C NMR (101 MHz): d=138.8 (C), 137.9 (C),
137.0 (C), 134.5 (CH), 134.1 (CH), 133.8 (CH), 133.7 (C), 133.6 (CH),
133.5 (CH), 132.9 (C), 130.8 (CH), 130.7 (C), 130.2 (CH), 130.0 (CH),
129.6 (CH), 128.4 (CH), 128.2 (CH), 128.1 (CH), 128.0 (CH), 127.9
(CH), 127.8 (CH), 126.8 (CH), 126.6 (CH), 30.3 (CH3), 29.3 (CH2), 29.2
Preparation of the hydride complexes for high-pressure NMR spectrosco-
py: A solution of ligand (S)-7a–c (1 equiv), template 8 (2 equiv), and
[RhACHTNUGTRENUNG(acac)CO2] in [D8]toluene (20 mm) was stirred at 408C for 3 h. After
this time, the mixture was transferred into a 5 mm HP NMR tube, pres-
surized with 5 bar syngas H2/CO 1:1 (5 bar) at RT for 16 h and the high-
pressure NMR spectra were recorded.
Preparation of the hydride complexes for high-pressure IR spectroscopy:
High-pressure IR experiments were performed with an SS-316 50 mL au-
toclave equipped with IRTRAN windows (ZnS, transparent above
700 cmÀ1, ø=10 mm, optical path length=0.4 mm), a mechanical stirrer,
temperature controller, and a pressure device. In a typical experiment,
the high-pressure IR autoclave was filled with (S)-7a–c (0.03 mmol), tem-
plate 8 (0.06 mmol) and CH2Cl2 (13 mL). The autoclave was purged
three times with 15 bar H2/CO (1:1) and pressurized to 20 bar. The anti-
chamber was charged with a solution of [RhACTHNUTRGNEN(UG acac)CO2] (0.01 mmol) in
CH2Cl2 (1 mL) and pressurized to 30 bar. The HP-IR autoclave was
placed into a Nicolet 510 FTIR spectrometer and the temperature was
set to 408C. When the desired temperature was reached, the antichamber
was opened and the catalyst precursor was injected into the solution. A
series of IR spectra was recorded for 16 h while the samples were stirred.
Acknowledgements
Pawel Dydio is kindly acknowledged for performing the DFT calcula-
tions. This work was financially supported by the National Research
School Combination Chemistry (NRSC-C).
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(CH2), 27.9ACHTUNGTRENNUNG(CH2), 27.7 (CH2) 23.0 (CH2), 22.9 (CH2), 22.8 (CH2),
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(150 mL) charged with an insert that was suitable for 14 reaction vessels
(equipped with Teflon mini stirring bar) for performing parallel reactions.
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to use. Before starting the catalysis, the charged autoclave was purged
three times with 10 bar syngas (H2/CO=1:1) and then pressurized to
Chem. Eur. J. 2012, 00, 0 – 0
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Received: June 8, 2012
Published online: && &&, 0000
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www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Hybrid Ligands in Asymmetric Hydroformylation
FULL PAPER
Supramolecular bidentate ligands: A
new class of supramolecular hybrid
bidentate phosphane–phosphoramidite
ligands is presented (see scheme). The
coordination behaviour of these
ligands was studied under hydroformy-
lation conditions, showing formation of
a single active species, the
Ligand Design
R. Bellini, J. N. H. Reek* . . . &&&& — &&&&
Application of Supramolecular Biden-
tate Hybrid Ligands in Asymmetric
Hydroformylation
[RhH(CO)2(phosphane–phosphorami-
dite)] complex, in which the phosphor-
amidite occupies the equatorial posi-
tion and the phosphane occupies the
apical position. In the asymmetric
hydroformylation of styrene and para-
substituted analogues an influence of
electronically different zinc(II)-tem-
plates on the activity and selectivity of
the reaction is observed.
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!