Coordination studies on supramolecular chiral ligands and application in asymmetric hydroformylation

Article abstract of DOI:10.1002/chem.201200225

In this study we introduce a series of monodentate pyridine-based ligands for which the phosphorus coordination mode to rhodium can be controlled by the binding of Zn^II-templates to the pyridyl group. A series of monodentate phosphoroamidite and phosphite ligands have been prepared and studied under hydroformylation conditions by in situ high-pressure NMR and IR techniques. These studies reveal the exclusive formation of rhodium hydride complexes in which the phosphorus atom of the ligand resides in an axial position, trans to the hydride, but only after addition of Zn ^II-template. In the absence of these templates the usual mono-coordinated rhodium hydrido complexes are formed, with the phosphorus ligated in the equatorial plane, cis to the hydride. The catalytic performance of these complexes is evaluated in asymmetric hydroformylation of unfunctionalised internal alkenes in which the supramolecular change is reflected in higher activity and selectivity.

Full text of DOI:10.1002/chem.201200225

FULL PAPER
DOI: 10.1002/chem.201200225
Coordination Studies on Supramolecular Chiral Ligands and Application in
Asymmetric Hydroformylation
Rosalba Bellini and Joost N. H. Reek*[a]
Dedicated to Professor Dr. Piet van Leeuwen on the occasion of his 70th birthday
Abstract: In this study we introduce
a series of monodentate pyridine-based
ligands for which the phosphorus coor-
dination mode to rhodium can be con-
trolled by the binding of ZnII-templates
to the pyridyl group. A series of mono-
dentate phosphoroamidite and phos-
phite ligands have been prepared and
studied under hydroformylation condi-
tions by in situ high-pressure NMR and
IR techniques. These studies reveal the
exclusive formation of rhodium hy-
dride complexes in which the phospho-
rus atom of the ligand resides in an
axial position, trans to the hydride, but
only after addition of ZnII-template. In
the absence of these templates the
usual mono-coordinated rhodium hy-
drido complexes are formed, with the
phosphorus ligated in the equatorial
plane, cis to the hydride. The catalytic
performance of these complexes is
evaluated in asymmetric hydroformyla-
tion of unfunctionalised internal al-
kenes in which the supramolecular
change is reflected in higher activity
and selectivity.
Keywords: alkenes · coordination
modes · hydroformylation · molecu-
lar recognition
chemistry
· supramolecular
Introduction
The influence of ligands on the structure and performance
of catalytically active metal complexes has been intensely
studied in coordination and organometallic chemistry.[1]
A
tremendous amount of research has been devoted to ligand
design to control coordination chemistry, which is leading to
new approaches in catalyst development. In modern coordi-
nation chemistry the use of highly advanced in situ spectro-
scopic techniques (high-pressure (HP) spectroscopy, for ex-
ample, HP NMR and HP IR) has enabled scientists to ob-
serve the formation of active species and the resting state
under relevant reaction conditions.[2,3] These spectroscopic
techniques have been widely used as tools for the identifica-
tion of catalytic intermediates and resting states, particularly
for the development of phosphine-based rhodium complexes
for hydroformylation reactions.[3]
The active species in this reaction has been determined to
be trigonal bipyramidal complexes in which the hydride
ligand resides on the axial position and the phosphorus li-
gands are either coordinated in the equatorial–equatorial
(eq–eq) or in the equatorial–axial (eq–ax) mode (Figure 1).
Figure 1. Different coordination modes of triphenylphosphine rhodium
catalyst.
For bidentate ligands, van Leeuwen and co-workers evalu-
ated the effect of the natural bite angle on the selectivity
and activity in the rhodium-catalysed hydroformylation re-
action using a series of diphosphine ligands based on a xan-
thene-type backbone.[4] These studies showed that bidentate
phosphorus ligands with wide bite angles predominantly
promote the formation of the eq–eq rhodium complex. In
addition, these complexes are highly selective in the rhodi-
um-catalysed hydroformylation of 1-octene, yielding the
linear aldehyde product.[4] Coordination behaviour of biden-
tate ligands also appears to be crucial for asymmetric hydro-
formylation. Most significant advances in the field of asym-
metric hydroformylation have been obtained with catalytic
systems that are based on hybrid phosphine–phosphite or
phosphine–phosphoroamidite ligands.[5] A historically impor-
tant breakthrough was reported by Takaya and Nozaki who
described the use of Binaphos rhodium complexes to gener-
ate enantiomeric excesses of up to 95% for a large variety
of substrates.[6] The reason for the exceptionally high enan-
tioselectivity was attributed to the exclusive formation of
a single active species in which the ligand preferentially co-
ordinates to the transition metal centre in an eq–ax fash-
ion.[6]
[a] R. Bellini, Prof. Dr. J. N. H. Reek
Vanꢀt Hoff Institute for Molecular Sciences
University of Amsterdam
Science Park 904, 1098 XH, Amsterdam (The Netherlands)
Fax : (+31)205255604
E-mail: j.n.h.reek@uva.nl
Homepage: http//www.science.uva.nl/research/imc/Homkat/
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200225.
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Monodentate ligands have
rarely been applied in asym-
metric hydroformylation reac-
tions because low selectivities
are anticipated due to lower
control
modes.
over
However,
coordination
break-
throughs in this area would be
interesting because these mono-
dentate ligands have a simple
structure and, hence, their syn-
thesis is generally much less
elaborate. This makes them po-
tentially cheaper and the prepa-
ration of large ligand libraries is
easier, which is crucial for com-
binatorial approaches to find
new active and selective cata-
lysts.[7] The application of very
bulky monodentate phosphite
(p-accepting) ligands have been
studied with the aim of generat-
ing highly active rather than
enantioselective catalysts. It has
been demonstrated that these
do indeed form very active hy-
droformylation catalysts, even
Figure 2. General structure of the shift of pyridine-based monodentate ligands upon addition of ZnII-template
to a rhodium complex.
for the less reactive internal alkenes, albeit with significant
ised internal alkenes. We report our investigations into the
origin of this shift in ligand coordination on a rhodium hy-
droformylation complex, and evaluate possible steric and
electronic effects induced by ZnII-templates by evaluating
a series of ligand-template building blocks (Figure 2). Con-
sistent control of the ligand coordination in a rhodium hy-
droformylation catalyst from the cis to trans position after
addition of the ZnII-template is observed, and in the asym-
metric hydroformylation of internal alkenes this trans com-
plex displayed higher activity, higher enantioselectivity, as
well as an increase in regioselectivity compared with the
analogous cis catalyst.
isomerisation.[8]
Spectroscopic experiments on such systems indicate that
only one bulky phosphite ligand coordinates to the metal
centre in the equatorial plane, cis to the hydride. Along the
same lines, Breit and co-workers have reported the use of
bulky phosphabenzenes in hydroformylation catalysis.[9] In
situ HP NMR and IR analyses indicated that the active and
selective catalyst was a monophosphabenzene rhodium com-
plex in which the ligand is located in the equatorial plane.
Recently, we have introduced a ligand-template approach
for the supramolecular encapsulation of transition-metal
complexes.[10] Ligand-template tris-3-pyridyl phosphine coor-
dinate ZnII-porphyrins exclusively through the nitrogen
donor atom, whereas the phosphorus atom coordinates to
the catalytically active rhodium. The rhodium complex
formed under hydroformylation conditions has only one
phosphorus atom coordinated in the equatorial position, and
this catalytic system displayed unprecedented regioselectivi-
ty in the hydroformylation of unfunctionalised terminal and
internal alkenes. In this contribution, we report the use of
chiral pyridyl-phosphoramidite and phosphite ligands that,
in the presence of ZnII-building blocks, show remarkable
supramolecular control on the coordination mode of the
rhodium hydroformylation complex.[11] The coordination of
the phosphorus to rhodium changes from equatorial to axial
in the presence of a supramolecular template. The supra-
molecular change is reflected in higher activity and enantio-
selectivity when these complexes were applied to the very
challenging asymmetric hydroformylation of unfunctional-
Results and Discussion
Ligand Synthesis: The ligands were synthesised starting
from commercially available (S)-2,2’-binaphthol, which was
reduced in the presence of Pd/C. The diol 2 obtained was se-
lectively brominated in the 3,3’-position at low temperature
(À308C) to give compound 3. Suzuki coupling of 3 with the
appropriate boronic acid provided intermediates 4a and 4b,
which were treated with PACHTNUGTRNEUG(N NMe2)3 and 4-(N,N-dimethylami-
no)pyridine (DMAP) in toluene at reflux to give ligands
(S)-1a and (S)-1b in good yield (Scheme 1).
Following the second route depicted in Scheme 2, ligands
(S)-1c–h were synthesised. The ligands were prepared in
a two-step fashion starting from diol 4a, which, after reac-
tion with PCl3, gave phosphorochloridite 5. Condensation of
a range of nucleophiles with 5 afforded the corresponding
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Asymmetric Hydroformylation
FULL PAPER
ligand (S)-1a towards ZnII-tetraphenylporphyrin 6 was in-
vestigated by NMR and UV/Vis spectroscopy. The UV/Vis
titration experiments revealed binding constants of K1 =
1.8ꢂ103 mÀ1 and K2 =1.7ꢂ103 mÀ1, related to the first and
second association of porphyrin to (S)-1a (Scheme 3). The
similarity between these constants indicates that the binding
events are independent and that no cooperativity is present
as previously observed in the case of tris-3-pyridyl phosphi-
ne.[10b] A job-plot analysis indicated the formation of a 1:2
complex between the phosphoroamidite ligand 1a and the
template 17 (see Figure 4 below).[13] The binding of this
building block through the nitrogen donor atom is very se-
lective, implying that the phosphorus atom of the ligand is
available for coordination to the transition-metal centre.
Scheme 1. Synthesis of phosphoroamidite ligands.
In situ high-pressure NMR and
IR analyses: The coordination
behaviour of (S)-1a to rhodium
under catalytically relevant con-
ditions was studied using high-
pressure (HP) NMR and IR
spectroscopy. Rhodium com-
plexes were prepared in situ by
using [RhACHTUNTGRNE(NUG acac)CO2] as the
metal precursor in [D8]toluene
under 5 bar syngas (H2/CO, 1:1)
(Scheme 4). The complex based
on bulky ligand (S)-1a is mono-
ligated [Rh(H)(CO)31a], with
the phosphorus ligand in the
equatorial position; a hydride signal centred at d=
Scheme 2. General synthesis of the pyridine-based monodentate ligands.
phosphite and phosphoroamidite ligands 1c–h in good
yield.[12,13] All new compounds were fully characterised by
1H NMR, 31P NMR and 13C NMR spectroscopy and by mass
spectroscopic analysis.
À11.01 ppm is observed with a small PH coupling consistent
with the cis-[Rh(H)(CO)31a] complex. Interestingly, in the
presence of two equivalents of porphyrin 6, the HP
1H NMR spectrum revealed new signals in the hydride
region; a double doublet centred at d=À10.3 ppm with
Coordination studies: The assembly of ligand (S)-1a and
ZnII-tetraphenylporphyrin 6: The coordination behaviour of
a large phosphorus coupling [JACTHNUGRTNENUG(P,H)=180 Hz and JACHTUNGTRNE(NUGN Rh,H)=
Scheme 3. Assembly of ligand (S)-1a on ZnII-tetraphenylporphyrin 6.
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J. N. H. Reek and R. Bellini
1
ligand (S)-1a. The HP H NMR
and 31P NMR spectra showed
formation of a rhodium com-
plex in which the phosphoroa-
midite ligand was located trans
to the hydride, indicating that
the size of the template is not
responsible for the switching of
ligand coordination.[13]
To probe the electronic influ-
ence of the ZnII-template in
changing the electron density
on the pyridine moiety and
therefore on the phosphorus
donor atom, we performed IR
Scheme 4. Structures of cis-[Rh(H)(CO)31a] and trans-[Rh(H)(CO)31a(6)2] derived from the high-pressure
1H NMR spectra.
6.1 Hz] indicating the formation of the trans-
[Rh(H)(CO)31a(6)2] complex. Further experiments such as
studies using several ZnII-templates (Figure 3). ZnII-tem-
plates containing more electron-withdrawing substituents
will increase the electron-withdrawing capacity of the pyri-
dine ring, which should result in a lower basicity of the
1
1
HP H-{31P}-NMR and 2D H-31P NMR spectroscopic stud-
ies confirmed the formation of the rhodium complex in
which the supramolecular monodentate ligand is coordinat-
ed trans to the hydride.[13]
phosphorus atom. Ligand (S)-1a and [Rh
mixed in a 1:1 ratio to form [Rh
ACHTUNGTRENNUNG
ACHUTNGREN(NUG 1a)COACHTUGNTRENNNUG
The formation of complexes cis-[Rh(H)(CO)31a] and
trans-[Rh(H)(CO)31a(6)2] were investigated under actual
hydroformylation conditions by IR spectroscopy, using reac-
tion conditions and concentrations identical to those applied
subsequently, two equivalents of ZnII-template were added.
The IR spectra of these rhodium complexes show that the
addition of the ZnII-template shifts the stretching of the car-
bonyl (nCO =1999.6 cmÀ1) of [Rh
ACTHUNTGRNENUG(1a)COCAHUTNGTREN(NUNG acac)] to higher
in catalysis.[13] In the presence of [Rh
N
wavenumbers. This indicates a lower electron density on the
rhodium, which implies decreased back-bonding from the
metal to the carbonyl ligand, and hence higher CO stretch-
(S)-1a, the tris-carbonyl rhodium hydride complex cis-
[Rh(H)(CO)31a] was obtained, as shown by the three peaks
in the carbonyl region of the IR spectrum at 2054, 2000 and
1982 cmÀ1. The rhodium complex formed in the presence of
(S)-1a and two equivalents of porphyrin 6 shows three ab-
sorption bands that are shifted to higher wavenumbers
(2055, 2022 and 1998 cmÀ1).[13] These higher wavenumbers
indicate weaker p-back-donation to the CO molecules in
the trans-[Rh(H)(CO)31a(6)2] complex and, hence, CO dis-
sociation from this assembly should be faster. If CO dissoci-
ation is involved in the rate determining step, as is common-
ly observed for phosphine-based catalysis, this could lead to
an increase in reaction rates.
To determine whether this unusual coordination mode is
more general, we also investigated the coordination proper-
ties of ligands (S)-1c–h by HP NMR analysis. Rhodium
complexes were prepared in situ by using [RhACTHNUTRGENUG(N acac)(CO)2]
in [D8]toluene under 5 bar syngas (H2/CO, 1:1), and fully
1
1
characterised by HP H NMR, HP 31P NMR, HP H-{31P}-
NMR and HP 2D H-31P NMR analyses, confirming the for-
1
mation of the rhodium complexes.[13] In line with our previ-
ous observations, all these new ligands showed a switching
in coordination mode upon addition of the supramolecular
template. This supramolecular control over ligand coordina-
tion therefore appears to be rather general.
Influence of steric and electronic properties on the trans
rhodium-complex: To determine whether this unusual tem-
plate effect is due to the steric bulk of the ZnII-templates,
we carried out HP NMR experiments using the much small-
er template triethylborane (BEt3) in combination with
Figure 3. IR spectra of ligand (S)-1a acquired in the presence of different
ZnII-salphens.
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Asymmetric Hydroformylation
FULL PAPER
ing frequencies are observed. More electron-withdrawing
substituents on the ZnII-templates gives higher nCO-band fre-
quency, which shows that the electronic properties of the
phosphoroamidite ligands can indeed be influenced by the
ZnII-templates.[13]
ence of template 6, and thus with complex
[Rh(H)(CO)31a(6)2], an increase in both conversion (56%)
and enantioselectivity (45%) was observed (Table 1,
entry 6). This indicates that the change in coordination
mode improves the catalyst performance in this challenging
reaction both in terms of activity and selectivity. Control ex-
periments using ligand (S)-1b (Table 1, entries 3 and 4),
which lacks the pyridyl group, shows that these complexes
give rise to low activity and the product 8a is produced in
low enantiomeric excess, regardless of the presence of ZnII-
porphyrin 6. Further indications of the absence of any ef-
fects of the ZnII-template in the presence of ligand (S)-1b
were obtained by IR studies and high-pressure NMR experi-
ments.[13] No changes in the spectra were observed upon ad-
dition of the ZnII-template to the rhodium catalyst binding
ligand (S)-1b. This demonstrates that template 6 does not
interfere directly with the rhodium-catalysed hydroformyla-
tion.
Application of the supramolecular ligands in asymmetric hy-
droformylation: Catalyst performances of cis- and trans-
complexes based on ligands (S)-1a–h and template 6 (ZnII-
tetraphenylporphyrin) as well as some control ligands such
as PPh3, (R,S)-Binaphos and (S)-1b were investigated in the
asymmetric hydroformylation (AHF) of trans-2-octene 7a
(Scheme 5).[14,15]
Having established that the supramolecular ligand (S)-
1a(6)2 performed better in terms of activity and selectivity,
we explored the use of different phosphite and phosphoroa-
midite pyridyl-based ligands (S)-1c–h and their assemblies
with template 6 in the same reaction. The results show a sim-
ilar trend; an increase in activity and selectivity was ob-
served in the presence of templated ligands (Table 1, en-
tries 8, 10, 12, 14, 16 and 18). In general, the use of bulky
phosphite ligands led to higher conversions, especially when
employing catalysts based on supramolecular ligands 1d(6)2,
1 f(6)2 and 1g(6)2 (Table 1, entries 10, 14 and 16). Interest-
ingly, increasing the steric bulk at the phosphorus atom led
to an increase in regioselectivity for the inner aldehyde 8a
(Table 1, entries 8, 10, 12, 14, 16 and 18). With the current
set of ligands it was possible to tune the 8a/8b ratio between
0.7 and 2.3, which is quite an achievement considering the
symmetry of the substrate.
Scheme 5. Hydroformylation of trans-2-octene.
As expected, the rhodium catalyst derived from triphenyl-
phosphine gave only low conversions and a significant
amount of isomerisation (Table 1, entry 1). The rhodium cat-
alyst based on (R,S)-Binaphos (Table 1, entry 2) gave useful
conversion (55%) but no significant enantiomeric excess.
Complex [Rh(H)(CO)31a] yielded the product with an
enantiomeric excess of 25%, albeit with relatively low con-
version (12%; Table 1, entry 5). Interestingly, in the pres-
Table 1. Results of the asymmetric hydroformylation of trans-2-octene.[a]
Entry
Ligand
Conv.
[%][b]
Iso.
8a/8b[b,d]
8a ee
[%][c]
[%][e,f]
In further studies we explored a small series of boron-
and zinc-based templates (Figure 4) in combination with
ligand (S)-1a, aiming to further fine-tune the properties of
the supramolecular ligands. Remarkably, the properties of
the template had very little effect on the catalyst properties;
in all cases the enantiomeric excess increased from 25%,
observed for the catalyst based on the parent ligand, to 35–
42% for the various templated ligands (Table 2, entries 1 vs.
2–8). Because we even observed this increase in enantiomer-
ic excess for the smallest boron-based templates 11 and 12
(Table 2, entries 2 and 3), we conclude that the dominant
effect on enantioselectivity is associated with the change in
coordination mode of the ligand, switching from equatorial
to axial upon templation. In terms of regioselectivity (8a/8b
ratio) and conversion also only small effects were noted
upon changing the template.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
PPh3
6
55
12
11
12
56
13
37
15
98
12
72
91
99
85
97
32
25
5
4
4
4
4
0
4
2
5
1
1
0
1
2
0
0
3
0
0.8
0.7
0.7
0.6
0.7
1.0
0.9
1.9
0.9
2.1
0.8
2.0
0.9
1.4
0.8
1.2
1.1
2.3
0
0
A
(S)-1b
(S)-1b, 6 (2 equiv)
(S)-1a
(S)-1a(6)2
(S)-1c
(S)-1c(6)2
(S)-1d
(S)-1d(6)2
(S)-1e
(S)-1e(6)2
(S)-1 f
(S)-1 f(6)2
(S)-1g
(S)-1g(6)2
(S)-1h
11 (R)
10 (R)
25 (R)
45 (R)
8 (R)
30 (R)
8 (R)
19 (R)
4 (R)
13 (R)
8 (R)
24 (R)
4 (R)
20 (R)
20 (R)
45 (R)
(S)-1h(6)2
[a] Reagents and conditions: [Rh]=1 mm in toluene, ligand/rhodium=9,
trans-2-octene/rhodium=200, 258C, 20 bar, 84 h. [b] Percentage conver-
sion determined by GC analysis. [c] Percentage of alkene isomerisation
product. [d] Ratio of the products 8a and 8b. [e] Enantiomeric excess of
product 8a. [f] The absolute configuration was determined by comparing
the GC traces with those of the enantiopure aldehydes (R)-8a and (S)-
8a.[11]
Influence of reaction conditions: Syngas pressure: The influ-
ence of syngas pressure was investigated by performing
a series of experiments at 10, 20, 30 and 40 bar (H2/CO=
1:1),
using
trans-[Rh(H)(CO)31a(6)2]
and
cis-
[Rh(H)(CO)31a] complexes and trans-2-octene as substrate
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J. N. H. Reek and R. Bellini
Figure 4. Boron- and zinc-based building blocks.
Table 2. Asymmetric hydroformylation of trans-2-octene; screening of
boron and zinc-templates in combination with ligand (S)-1a.[a]
Table 3. Results of the asymmetric hydroformylation of trans-2-octene.[a]
Entry
Ligand
H2/CO
T
[8C]
Conv.
[%][b]
Iso.
8a/8b[d]
8a ee
Entry
Ligand
Conv.
[%][b]
Iso.
8a/8b[b,d]
8a ee
[%][c]
[%][e,f]
[%][c]
[%][e,f]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1a(6)2
1a
1a(6)2
1a
1a(6)2
1a
1a(6)2
1a
1a(6)2
1a
1a(6)2
1a
1a(6)2
1a
5:5
5:5
25
25
25
25
25
25
25
25
25
25
25
25
50
50
50
50
28
58
38
54
30
49
27
43
31
47
15
15
>99
>99
>99
>99
5.0
1.0
4.1
0.5
2.1
0
0.7
0.9
0.7
1.0
0.7
1.0
0.7
1.0
0.7
1.0
0.7
1.0
0.7
1.0
0.7
0.9
28 (R)
41 (R)
26 (R)
43 (R)
28 (R)
43 (R)
27 (R)
43 (R)
26 (R)
48 (R)
24 (R)
45 (R)
14 (R)
27 (R)
15 (R)
25 (R)
1
2
3
4
5
6
7
8
(S)-1a
12
30
30
43
52
52
51
53
4
0.7
0.9
0.8
0.9
1.0
1.0
1.1
1.1
25 (R)
35 (R)
41 (R)
37 (R)
41 (R)
41 (R)
42 (R)
35 (R)
(S)-1a(11)2
(S)-1a(12)2
(S)-1a(13)2
(S)-1a(14)2
(S)-1a(15)2
(S)-1a(16)2
(S)-1a(17)2
0.6
1.0
0.6
0.6
0.6
0.7
0
10:10
10:10
15:15
15:15
20:20
20:20
20:10
20:10
10:20
10:20
10:20
10:20
10:10
10:10
2.1
0
3.2
1.2
1.1
0.5
2
0
1
0
[a] Reagents and conditions: [Rh]=1 mm in toluene, ligand/rhodium=9,
trans-2-octene/rhodium=200, 258C, 20 bar, 84 h. [b] Percentage conver-
sion determined by GC analysis. [c] Percentage of alkene isomerisation
product. [d] Ratio of the products 8a and 8b. [e] Enantiomeric excess of
product 8a. [f] The absolute configuration was determined by comparing
the GC traces with those of the enantiopure aldehydes (R)-8a and (S)-
8a.[11]
1a(6)2
[a] Reagents and conditions: [Rh]=1 mm in toluene, ligand/rhodium=5,
trans-2-octene/rhodium=200, 258C, 20 bar, 84 h. [b] Percentage conver-
sion determined by GC analysis. [c] Percentage of alkene isomerisation
product. [d] Ratio of the products 8a and 8b. [e] Enantiomeric excess of
product 8a. [f] The absolute configuration was determined by comparing
the GC traces with those of the enantiopure aldehydes (R)-8a and (S)-
8a.[11]
(Table 2). Under all pressure conditions, complex trans-
[Rh(H)(CO)31a(6)2] displayed higher activity and selectivity
than cis-[Rh(H)(CO)31a] (Table 3, entries 1–8). As expected
for rhodium complexes that follow type I kinetics[3] (nega-
tive order in CO), an increase in pressure results in a drop
in conversion and a decrease in isomerisation. No changes
in enantioselectivity were observed with any of the catalysts
using different reaction pressures. The optimal pressure for
the application of trans-[Rh(H)(CO)31a(6)2] was 20 bar;
under these conditions, the isomerisation side reaction was
slow and the conversion was good (Table 3, entry 4).
We examined the effect of CO and H2 partial pressures
and found that varying the hydrogen pressure had little
effect on either activity or selectivity, which is typical for
type I kinetics (Table 3, entries 9 and 10). Hydroformylation
with higher ratios of CO pressure led to a decrease in con-
version but did not affect the chemo- or enantioselectivity
(Table 3, entries 11 and 12). Increasing the reaction temper-
ature to 508C under these pressure conditions resulted in
full conversion but also lower enantioselectivity (Table 3,
entry 13 and 14). Increasing the reaction temperature to
508C under standard pressure conditions of 20 bar also led
to higher conversions, a slight increase in isomerisation and
lower enantiomeric excess (Table 3, entries 15 and 16).
The remaining catalytic reactions were conducted under
the conditions that gave the optimum compromise between
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Asymmetric Hydroformylation
FULL PAPER
enantioselectivities and reaction rates: a total pressure of
20 bar of syngas, a temperature of 258C and a ratio of CO/
H2 of 1:1.
above it was clear that the dominant effect in the change of
selectivity is the change in coordination mode. These experi-
ments together suggest that the formation of the rhodium-
hydride complex in which the phosphorus is trans to the hy-
dride already occurs if one the two templates is coordinated
to the ligand. High-pressure NMR experiments with the
complex based on a 1:1 ratio of template 6 to ligand (S)-1a
indeed confirm the quantitative formation of the trans-
[Rh(H)(CO)31a-(6)] complex under these conditions.[13] The
enantiomeric excess slightly increased between a ratio of 1:1
and 1:2, but no further changes in the catalysis were ob-
served upon addition of more than two equivalents of tem-
plate 6.
Influence of the ligand/rhodium ratio: We next studied the
effect of the supramolecular monodentate ligand (S)-1a(6)2/
rhodium ratio. Usually, an excess of ligand is required to
prevent ligand-free rhodium complexes being formed.
Ligand/rhodium ratios from 1:1 to 9:1 were explored. At
low ligand concentrations, low selectivity and high conver-
sion was observed (Table 4, entry 1), indicating the forma-
Table 4. Results of the asymmetric hydroformylation of trans-2-octene
by using different ratios of ligand (S)-1a(6)2 to rhodium.[a]
Asymmetric hydroformylation of trans-2-alkenes: To see if
the unusual template effect is more general, we investigated
the AHF of a series of trans-2-alkenes. In Table 5 we report
Entry
1a(6)2/Rh
Conv.
[%][b]
Iso.
8a/8b[d]
8a ee
[%][c]
[%][e,f]
1
2
3
4
5
6
1
2
3
5
7
91
36
39
40
40
42
11
3
1
1
1
0.6
1.0
1.1
1.1
1.1
1.1
0
44 (R)
47 (R)
46 (R)
45 (R)
46 (R)
Table 5. Results of the asymmetric hydrofomylation of internal alkenes
by using ligand (S)-1a and template 6.[a]
Entry Alkene
Template Conv. Iso.
[%][b] [%][c]
10a/10b[d] 10a ee
10
1
[%][e]
[a] Reagents and conditions: [Rh]=1 mm in toluene, trans-2-octene/rho-
dium=200, 258C, 20 bar, 84 h. [b] Percentage conversion determined by
GC analysis. [c] Percentage of alkene isomerisation product. [d] Ratio of
the products 8a and 8b. [e] Enantiomeric excess of product 8a. [f] The
absolute configuration was determined by comparing the GC traces with
those of the enantiopure aldehydes (R)-8a and (S)-8a.[11]
1
2
3
4
5
6
(E)-2-hexene
–
6
–
6
–
6
23
65
22
43
40
52
2
0.7
0.9
0.7
1.0
0.7
1.0
21
46
26
44
23
47
(E)-2-hexene
(E)-2-heptene
(E)-2-heptene
(E)-2-nonene
(E)-2-nonene
1
[a] Reagents and conditions: [Rh]=1 mm in toluene, ligand/rhodium=3,
trans-2-octene/rhodium=200, 258C, 20 bar, 84 h. [b] Percentage conver-
sion determined by GC analysis. [c] Percentage of alkene isomerisation
product. [d] Ratio of the products 10a and 10b. [e] Enantiomeric excess
of product 10a. For detailed conditions see the Supporting Information.
tion of rhodium hydride tris-carbonyl species, which is
known to be highly reactive under these conditions.[3] In-
creasing the ligand concentration provided a catalyst system
that displayed higher enantioselectivity (Table 4, entries 2–
6). Increasing the ligand/metal ratio to more than 2:1 (at
these concentrations) did not produce any significant
changes in selectivity of the catalyst, showing that a small
excess of ligand is sufficient to transform all the rhodium
into the ligated, catalytically active species.
the results obtained using catalytic complexes cis-
[Rh(H)(CO)31a] and trans-[Rh(H)(CO)31a(6)2] in the pres-
ence of trans-2-alkenes. As observed for trans-2-octene,
these substrates are also produced with higher enantioselec-
tivity when the templated ligand 1a(6)2 is used (Table 5, en-
tries 2, 4 and 6) compared with the nontemplated analogue
(Table 5, entries 1, 3 and 5). Ligands (S)-1c–h were also ap-
plied in the AHF of these substrates, and these experiments
also show higher enantio- and regioselectivity when the tem-
plated ligands were employed (see the Supporting Informa-
tion for details).
Influence of the ZnII-template/ligand ratio: To obtain more
insight into the templated ligand effect, we studied the for-
mation of the rhodium complexes using different ratios of
template 6 to ligand (S)-1a. In Figure 5 the enantioselectivi-
ty obtained as a function of the 6/1a ratio is displayed. Inter-
estingly, a major increase in enantioselectivity was already
observed using a 6/1a ratio of 1:1. From the experiments
Complexes
cis-[Rh(H)(CO)31a]
and
trans-
[Rh(H)(CO)31a(6)2] were also tested in the asymmetric hy-
droformylation of a small series of cis-2-alkenes. Although,
higher conversions were achieved with the supramolecular
system, the enantioselectivities were not always higher for
the templated complex.[13]
Conclusion
Figure 5. Enantioselectivity of 8a formed in the rhodium-catalysed asym-
metric hydroformylation of trans-2-octene by using (S)-1a in the pres-
ence of various amounts of ZnII-template 6.
Our results demonstrate that for monodentate pyridine-con-
taining phosphoroamidite and phosphite ligands, the coordi-
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J. N. H. Reek and R. Bellini
warm to RT and stirred overnight at this temperature. The precipitate
formed was filtered through a pad of Celite and the solvent was evapo-
rated in vacuum to obtain (S)-1c, (S)-1d, (S)-1e, (S)-1 f, (S)-1g, and (S)-
1h.
Ligand (S)-1c: Yield: 51% (0.23 mmol); white foam; 1H NMR
(400 MHz, [D8]toluene): d=8.66 (m, 4H), 8.44 (m, 4H), 7.06 (s, 1H),
7.01 (s, 1H), 2.68 (m, 4H), 2.29 (m, 2H), 2.13 (m, 1H), 1.62 (m, 8H),
1.34 (m, 2H), 0.74 (d, J=6.7 Hz, 3H), 0.51 ppm (d, J=6.7 Hz, 3H);
13C NMR (400 MHz): d=149.4 (CH), 146.3 (C), 145.3 (C), 143.9 (C),
139.1 (C), 138.4 (C), 134.6 (C), 133.6 (CH), 124.2 (CH), 69.3 (CH), 28.8
(CH2), 27.6 (CH2), 23.7 (CH3), 23.1 (CH3), 22.8 (CH2), 0.82 ppm (CH);
31P NMR (400 MHz): d=145.4 ppm. HRMS (FAB+): m/z calcd for
C33H34N2O3P: 537.2306 [M+H]+; found: 537.2307.
Ligand (S)-1d: Yield: 56% (0.25 mmol); white foam; 1H NMR
(400 MHz, CDCl3): d=8.65 (m, 2H), 8.57 (m, 2H), 7.57 (m, 2H), 7.51
(m, 2H), 7.22 (m, 2H), 7.06 (m, 1H), 6.98 (m, 2H), 6.22 (m, 2H), 2.92
(m, 4H), 2.77 (m, 2H), 2.47 (m, 2H), 1.90 ppm (m, 8H); 13C NMR
(400 MHz): d=149.3 (CH), 148.9 (C), 139.7 (C), 138.9 (C), 137.8 (C),
135.7 (C), 135.0 (C), 129.5 (CH), 129.0 (CH), 124.7 (CH), 124.4 (CH),
124.1 (CH), 119.0 (CH), 118.9 (CH), 115.3 (CH), 29.3 (CH2), 29.23
(CH2), 22.4 ppm (CH2); 31P NMR (400 MHz): d=140.8 ppm. HRMS
(FAB+): m/z calcd for C36H32N2O3P: 571.2154 [M+H]+; found: 571.2151.
Ligand (S)-1e: Yield: 77% (0.34 mmol); white foam; 1H NMR
(400 MHz, CDCl3): d=8.63 (m, 2H), 8.52 (m, 2H), 7.59 (m, 1H), 7.51
(m, 2H), 7.40 (m, 3H), 7.25 (m, 3H), 6.98 (m, 1H), 6.61 (s, 1H), 6,54 (s,
1H), 6,52 (s, 1H), 2.70 (m, 4H), 2.39 (m, 2H), 2.16 (m, 2H), 1.66 ppm
(m, 8H); 13C NMR (400 MHz): d=154.4 (C), 149.3 (CH), 148.7 (C),
146.6 (C), 139.7 (C), 135.7 (C), 133.6 (C), 130.4 (C), 129.9 (CH), 129.1
(CH), 129.2 (C), 128.2 (CH), 127.5 (CH), 126.8 (CH), 124.7 (CH), 123.2
(CH), 119.8 (CH), 118.3 (CH), 115.1 (CH), 109.4 (CH), 29.3 (CH2), 28.0
(CH2), 22.6 (CH2), 22.4 ppm (CH2); 31P NMR (400 MHz): d=135.5 ppm.
HRMS (FAB+): m/z calcd for C40H33N2O3P: 621.2229 [M+H]+; found:
621.2217.
Ligand (S)-1 f: Yield: 86% (0.38 mmol); white foam; 1H NMR
(400 MHz, CDCl3): d=8.60 (d, J=5.6 Hz, 2H), 8.55 (d, J=5.6 Hz, 2H),
7.60 (d, J=5.5 Hz, 2H), 7.49 (d, J=5.5 Hz, 2H), 7.21 (s, 1H), 7.18 (s,
1H), 6.81 (s, 1H), 6.65 (s, 1H), 2.93 (m, 4H), 2.74 (m, 2H), 2.45 (m, 2H),
2.17 (s, 3H), 1.90 (m, 8H), 1.64 ppm (s, 6H); 13C NMR (400 MHz): d=
135.4 (C), 134.5 (C), 133.8 (C), 130.2 (CH), 130.2 (CH), 129.7 (C), 129.4
(C), 129.3 (CH), 129.2 (CH), 124.9 (CH), 124.5 (CH), 29.7 (CH2), 29.1
(CH2), 27.8 (CH2), 22.5 (CH2), 22.4 (CH3), 16.6 (CH3), 15.8 ppm (CH3);
31P NMR (400 MHz): d=139.8 ppm. HRMS (FAB+): m/z calcd for
C39H37N2O3P: 613.2542 [M+H]+; found: 513.2544.
Ligand (S)-1g: Yield: 43% (0.19 mmol); white foam; 1H NMR
(400 MHz, [D8]toluene): d=8.64 (m, 4H), 8.53 (m, 2H), 8.40 (m, 2H),
8.22 (m, 2H), 7.69 (m, 2H), 7.45 (m, 4H), 6.48 (s, 1H), 6.37 (s, 1H), 2.71
(m, 4H), 2.59 (m, 2H), 2.46 (m, 2H), 1.66 ppm (m, 8H); 13C NMR
(400 MHz): d=155.4 (C), 149.7 (CH), 145.6 (C), 136.2 (C), 135.2 (C),
134.6 (C), 130.3 (CH), 128.7 (CH), 127.9 (CH), 126.8(CH), 125.4 (CH),
124.2 (CH), 122.6 (CH), 122.4 (CH), 122.3 (CH), 105.5 (CH), 29.3 (CH2),
29.0 (CH2), 22.5 (CH2), 22.3 ppm (CH2); 31P NMR (400 MHz): d=
140.0 ppm. HRMS (FAB+): m/z calcd for C44H35N2O3P: 671.2385
[M+H]+; found: 671.2474.
Ligand (S)-1h: Yield: 53% (0.23 mmol); white foam; 1H NMR
(400 MHz, CDCl3): d=8.68 (m, 4H), 7.63 (m, 2H), 7.56 (m, 2H), 8.02
(m, 2H), 7.27–7.20 (m, 5H), 6.91 (m, 2H), 2.92 (m, 4H), 2.74 (m, 2H),
2.38 (m, 2H), 1.88 (m, 8H), 1.81 (s, 3H), 1.72 (s, 3H), 1.28 ppm (s, 3H);
13C NMR (400 MHz): d=149.6 (CH), 149.4 (C), 148.1 (C), 145.3 (C),
139.0 (C), 134.0 (C), 129.6 (CH), 128.3 (CH), 127.3 (CH), 126.9 (CH),
124.5 (CH), 124.0 (CH), 29.4 (CH2), 27.9 (CH2), 22.4 (CH2), 0.89 ppm
(CH3); 31P NMR (400 MHz): d=138.2 ppm. HRMS (FAB+): m/z calcd
for C38H36N3O2P: 598.2623 [M+H]+; found: 598.2620.
nation mode to rhodium can be controlled in a unique
supramolecular fashion. In situ high-pressure NMR and IR
studies under hydroformylation conditions show for the first
time the formation of rhodium-hydride complexes in which
the phosphorus donor atom of the ligand is trans to the hy-
dride, but only after coordination of ZnII-templates (or
Boron based) to the pyridyl moieties of the ligand. In the
absence of these ZnII-templates, typical monoligated rhodi-
um-hydrido complexes are formed with the ligand in the
equatorial plane, in cis orientation to the hydride. The
origin of this shift in ligand coordination is not steric in
nature, because the size of the template does not influence
this shift in coordination mode. Moreover, the size of the
template also does not affect the catalytic outcome; in all
cases, a similar increase in conversion and enantioselectivity
compared to the cis rhodium complex was observed. In-
stead, electronic effects induced by the ZnII-templates on
the phosphorus donor atom are most likely responsible, as
supported by IR spectroscopic studies. These newly devel-
oped phosphite and phosphoroamidite ligands proved to be
effective ligands in rhodium-catalysed asymmetric hydrofor-
mylation of generally unreactive internal unfuctionalised al-
kenes leading to high conversion and moderate enantiose-
lectivity. The results also reveal that the presence of sterical-
ly bulky groups on the phosphorus moiety significantly im-
proved the regioselectivity of this challenging reaction. Fur-
ther studies are focussed on extending this concept to other
reactions, and further improving the enantio- and regioselec-
tivity of this reaction.
Experimental Section
General methods: Unless stated otherwise, reactions were carried out
under an atmosphere of argon using standard Schlenk techniques. NMR
spectra (1H, 31P and 13C) were measured with a Bruker DRX 400 MHz or
an Inova 500 MHz; CDCl3 was used as solvent, if not further specified.
High-resolution mass spectra were recorded with a JEOL JMS SX/
SX102 A four-sector mass spectrometer; for FAB-MS, 3-nitrobenzyl alco-
hol was used as matrix. UV/Vis spectroscopy experiments were per-
formed with a Cary UV/Vis System. Gas chromatographic analyses were
run with a Shimadzu GC-17 A apparatus (split/splitless injector, J&W
Scientific, DB-1 J&W 30 m column, film thickness 3.0 mm, carrier gas
70 kPa He, FID Detector). Chiral GC separations were conducted with
an Interscience HR GC apparatus with a Supelco b-dex 225 capillary
column. Details of the synthesis of (S)-1a and (S)-1b were reported in
previous work.[8]
Preparation of ligands (S)-5: In a flame-dried Schlenk flask (S)-4a
(200 mg, 0.44 mmol), pyridine (0.034 mL, 0.44 mmol) and DMAP
(10 mol%) were suspended in anhydrous toluene (4.4 mL, 0.1m). The so-
lution was cooled to 08C and distilled PCl3 (0.080 mL, 0.88 mmol) was
added dropwise over 10 min. The mixture was allowed to warm to RT
and then heated to reflux overnight. The reaction mixture was cooled to
RT and the formation of product was checked by 31P NMR analysis. The
solvent and the residual PCl3 were removed in vacuum and the resulting
solid was used for the next step without any further purification.
General procedure for the rhodium-catalysed hydroformylation: A typi-
cal experiment was carried out in a stainless steel autoclave (150 mL)
charged with an insert suitable for 14 reaction vessels (equipped with
Teflon mini stirring bars) for performing parallel reactions. Each vial was
charged with ZnII-template (10 mmol, 10 equiv), ligand (5 mmol, 5 equiv),
General procedure for the preparation of ligands (S)-1c–h: In a flame-
dried Schlenk flask, nucleophile (0.44 mmol) and pyridine (0.040 mL,
0.48 mmol) were dissolved in anhydrous toluene (1 mL). The solution
was added dropwise to a cooled (08C) mixture of (S)-5 (225.7 mg,
0.44 mmol) in anhydrous toluene (5 mL). The mixture was allowed to
[RhACTHNUGTRNE(UNG acac)CO2] (1 mmol), substrate (0.03 mL, 20 mmol) and toluene
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Asymmetric Hydroformylation
FULL PAPER
(1 mL). The substrate was filtered over basic alumina to remove possible
peroxide impurities. Toluene was distilled from sodium prior to use.
Before starting the catalysis, the charged autoclave was purged three
times with 10 bar of syngas (H2/CO=1:1) and then pressurised to 20 bar.
After the catalytic reaction, the autoclave was cooled to 08C, the pres-
sure 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 reac-
tion mixtures were not filtered over basic alumina to remove catalyst res-
idues because filtration may cause retention of the aldehydes and thus in-
fluence the results of the GC analysis. The mixtures were diluted with
CH2Cl2 for GC analysis. The absolute configuration was determined by
comparing the chiral GC traces of the reaction mixture to the enantio-
pure aldehydes (S)-2-ethylheptanal and (R)-2-ethylheptanal obtained by
known methods.[11]
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Reek, Chem. Commun. 2010, 46, 1244–1246; f) X. Zhang, B. Cao,
Y. Yan, S. Yu, B. Ji, X. Zhang, Chem. Eur. J. 2010, 16, 871–877;
g) T. Robert, Z. Abiri, J. Wassenaar, A. J. Sandee, S. Romanski,
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29, 478–483; h) J. Wassenaar, B. de Bruin, J. N. H. Reek, Organome-
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Preparation of the hydride complexes for high-pressure NMR analysis:
A solution of pyridine-based ligand (1 equiv), ZnII-template (2 equiv)
and [RhACHTUNGTRENNUNG(acac)CO2] in [D8]toluene (20 mm) was stirred at 408C for 3 h.
The mixture was then transferred to a 5 mm HP NMR tube, pressurised
with 5 bar of syngas (H2/CO, 1:1) at 408C for 24 h and the high-pressure
NMR spectra were recorded.
Preparation of the hydride complexes for high-pressure IR analysis:
High-pressure IR experiments were performed in an SS-316 50 mL auto-
clave 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)-1a (33 mg,
0.063 mmol), ZnII-tetraphenylporphyrin 6 (85 mg, 0.126 mmol) and di-
chloromethane (13 mL). The autoclave was purged three times with
15 bar of H2/CO (1:1) and pressurised to 20 bar. The antichamber was
[9] B. Breit, R. Winde, T. Mackewitz, R. Paciello, K. Harms, Chem.
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40, 4271–4274; b) V. F. Slagt, P. C. J. Kamer, P. W. N. M. van Leeu-
wen, J. N. H. Reek, J. Am. Chem. Soc. 2004, 126, 1526–1536; c) M.
Kuil, T. Solter, P. W. N. M. van Leeuwen, J. N. H. Reek, J. Am.
Chem. Soc. 2006, 128, 11344–11345; d) A. W. Kleij, M. Kuil, D. M.
Tooke, A. L. Spek, J. N. H. Reek, Inorg. Chem. 2005, 44, 7696–7698;
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charged with a solution of [RhACTHNUTRGNE(UNG acac)CO2] (2.7 mg, 0.01 mmol) in di-
chloromethane (2 mL) and pressurised to 30 bar. The HP-IR autoclave
was placed into a Nicolet 510 FTIR spectrometer and the temperature
was set to 408C. When the desire temperature was reached, the anti-
chamber was opened and the catalyst precursor was injected into the so-
lution. The series of IR spectra was recorded for 24 h, during which time
the samples were stirred.
[11] For a preliminary communication, see: R. Bellini, S. H. Chikkali, G.
Berthon-Gelloz, J. N. H. Reek, Angew. Chem. 2011, 123, 7480–7483;
Angew. Chem. Int. Ed. 2011, 50, 7342–7345.
Acknowledgements
We thank Dr. S. H. Chikkali and Dr. G. Berthon-Gelloz for valuable dis-
cussions and suggestions. This work was financially supported by the Na-
tional Research School Combination Chemistry (NRSCC) and by the
European Union, Marie-Curie ITN RevCat.
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ˇ
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Received: January 20, 2012
Published online: && &&, 2012
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!

J. N. H. Reek and R. Bellini
Asymmetric Hydroformylation
R. Bellini, J. N. H. Reek* . . . &&&& — &&&&
Coordination Studies on Supramolec-
ular Chiral Ligands and Application in
Asymmetric Hydroformylation
A guiding hand: The coordination
mode of monodentate phosphoroami-
dite and phosphite ligands in a rhodium
hydroformylation complex can be
switched from equatorial to axial
mode by a unique supramolecular
pseudo encapsulation (see scheme).
The supramolecular axial complex dis-
plays higher activity and selectivity in
the challenging asymmetric hydrofor-
mylation of internal alkenes.
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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!