Enantioselective hydroformylation by a Rh-catalyst entrapped in a supramolecular metallocage

Article abstract of DOI:10.1021/ja512637k

Regio- and enantioselective hydroformylation of styrenes is attained upon embedding a chiral Rh complex in a nonchiral supramolecular cage formed from coordination-driven self-assembly of macrocyclic dipalladium complexes and tetracarboxylate zinc porphyrins. The resulting supramolecular catalyst converts styrene derivatives into aldehyde products with much higher chiral induction in comparison to the nonencapsulated Rh catalyst. Spectroscopic analysis shows that encapsulation does not change the electronic properties of the catalyst nor its first coordination sphere. Instead, enhanced enantioselectivity is rationalized by the modification of the second coordination sphere occurring upon catalyst inclusion inside the cage, being one of the few examples in achieving an enantioselective outcome via indirect through-space control of the chirality around the catalyst center. This effect resembles those taking place in enzymatic sites, where structural constraints imposed by the enzyme cavity can impart stereoselectivities that cannot be attained in bulk. These results are a showcase for the future development of asymmetric catalysis by using size-tunable supramolecular capsules.

Full text of DOI:10.1021/ja512637k

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Article
Enantioselective hydroformylation by a Rh-
catalyst entrapped in a supramolecular metallocage
Cristina García-Simón, Rafael Gramage-Doria, Saeed Raoufmoghaddam,
Teodor Parella, Miquel Costas, Xavi Ribas, and Joost N. H. Reek
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja512637k • Publication Date (Web): 29 Jan 2015
Downloaded from http://pubs.acs.org on February 3, 2015
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Enantioselective hydroformylation by a Rhꢀcatalyst
entrapped in a supramolecular metallocage
a
b
b
c
Cristina GarcíaꢀSimón, Rafael GramageꢀDoria, Saeed Raoufmoghaddam, Teodor Parella,
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a
a
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Miquel Costas, * Xavi Ribas, * Joost N. H. Reek *
a) Grup de Química Bioinorgànica i Supramolecular (QBIS). Institut de Química
Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona.
Campus Montilivi, E17071 Girona, Catalonia (Spain) xavi.ribas@udg.edu,
miquel.costas@udg.edu
b) Servei de RMN, Facultat de Ciències, Universitat Autònoma de Barcelona, Campus
UAB, Bellaterra Eꢀ08193, Catalonia, Spain.
c) Homogeneous and Supramolecular Catalysis Group, Van’t Hoff Institute for Molecular
Science (HIMS), University of Amsterdam (UvA), Science Park 904, 1098 XH
Amsterdam (The Netherlands) J.N.H.Reek@uva.nl
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Abstract
Regio and enantioselective hydroformylation of styrenes is described upon embedding a chiral
Rh complex in a nonꢀchiral supramolecular cage formed from coordinationꢀdriven selfꢀ
assembly of macrocyclic dipalladium complexes and tetracarboxylate zinc porphyrins. The
supramolecular catalyst that results converts styrene derivatives into aldehyde products with
much higher chiral induction in comparison to the nonꢀencapsulated Rh catalyst. Spectroscopic
analysis shows that encapsulation does not change the electronic properties of the catalyst, nor
changes its first coordination environment. Instead, enhanced enantioselectivity is rationalized
by the modification of the second coordination sphere occurring upon catalyst inclusion inside
the cage, being one of the few examples in achieving enantioselective outcome via indirect
throughꢀspace control of the chirality around the catalyst center. This effect resembles those
taking place in enzymatic sites, where structural constrains imposed by the enzyme cavity can
impart stereoselectivities that cannot be attained in bulk. These results are a showcase for the
future development of asymmetric catalysis by using sizeꢀtunable supramolecular capsules.
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Introduction
Reactions taking place at enzyme active sites generally exhibit high rates and exquisite
selectivities that differ from those occurring in bulk solution. This is best exemplified in
asymmetric catalysis. Weak interactions with aminoacid residues precisely modulate the relative
1
orientation of reagents and in some cases assist in their activation. The orientation of the
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reagents and substrates are controlled by the special environment around the active site leading
to highly selective transformations. As such, structural constrains and weak interactions
conspire in decreasing activation barriers of precise reactions to furnish rapid, chemo, regio and
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ꢀ14
stereoselective transformations.
In analogy to the spatial constrains imposed by enzyme
1
5ꢀ21
active sites metal based catalysts have been included in molecular nanovessels,
with the aim
to modulate their activity and selectivity via the second coordination sphere. High chemo and
regio selectivities have been obtained in selected cases, but the number of stereoselective
2
ꢀ3, 22ꢀ27,28
transformations carried out in molecular cages remains scarce.
Furthermore, a common
limitation of this kind of supramolecular catalysts is that selectivity is most often built at the
expenses of decreasing reaction rates.
O
O
N
N
O
O
O
O
Zn
Zn
N
N
5
,10,15,20ꢀ tetrakis(4ꢀcarboxyphenyl)ꢀporphyrin Zn(II)
(Znꢀ2)
O
O
N
Pd
N
N
Pd
Pd
N
N
N
Pd
Pdꢀ1b
4·(BArF)8
Scheme 1. Schematic representation of the building blocks used in the synthesis of tetragonalꢀprismatic
nanocapsule 4·(BArF)
8
.
A template ligand approach to form encapsulated ligands and their metal complexes were
previously described, and demonstrated that regioselectivity in hydroformylation reactions can
29ꢀ32
be controlled by the second coordination sphere.
Generally this strategy results in exclusive
monoligated rhodium complexes that are very reactive. For asymmetric hydroformylation some
10,12
of us recently extended the approach to chiral phosphoramidite,
but the monoligated
complexes generally resulted in low to moderate enantioselectivity. By using bisꢀzinc(II)salphen
building blocks, the ligandꢀtemplate approach resulted in the formation of bisꢀligated rhodium
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complexes, embedded in a wellꢀdefined cavity. Although the enantioselectivity induced by this
complex was high, the activity was rather low, especially at room temperature.
Here we use a different strategy that consists of encapsulating the monoꢀphosphoramiditeꢀ
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0ꢀ14
Rh(I) catalysts
in a tetragonal cage that was previously prepared by metal directed selfꢀ
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assembly. The resulting monoligated catalyst confined within the cavity of the capsule, is
especially active in hydroformylation of styrene and derivatives, and provides good levels of
steroselectivity. Chiral induction is greatly enhanced in comparison to the nonꢀencapsulated
analogue. These observations provide compelling evidence that steroselectivity provided by
these catalysts is based in controlling the second coordination sphere by reason of the structural
constrains imposed by the cage.
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Results and discussion
Hostꢀguest experiments. Some of us have previously described the synthesis of the
tetragonal prismatic nanocage 4·(BArF)
8
, which shows high affinity for fullerenes from C60 to
84. This property has been used in the selective separation of C60 from mixtures of fullerenes.
Cage 4·(BArF) is based on two opposing Znꢀporphyrin building blocks, linked by four bridging
macrocyclic walls that assemble the cage structure through Pdꢀcarboxylate coordination bonds
Scheme 1).
33
C
8
(
II
Scheme 2. Zn ꢀtemplate (ZnꢀTPP) and monoꢀphosphoramidite ligands (α, β, γ, δ) used in this study.
Structure of hostꢀguest α⊂4·(BArF)
TPP)
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cage structure and ligandꢀtemplate systems α(ZnꢀTPP)
2
and β(Znꢀ
2
.
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We envisioned that cage 4·(BArF)
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would be able to accommodate pyridineꢀbased ligands
8ꢀ14, 34
due to the wellꢀknown ability of Znꢀporphyrins to interact with pyridine moieties.
We first
sought to prove this by using 4,4’ꢀbipyridine (4,4’ꢀbpy) as guest since we have shown that the
Zn···Zn porphyrin distance of 4·(BArF) can vary from ∼11ꢀ14 Å (Scheme 2), owing to the
structural flexibility of Pdꢀcarboxylate bonds.
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As anticipated, UVꢀvis titration experiments unambiguously indicated an interaction
between the nanocapsule and 4,4’ꢀbpy. High resolution mass spectrometry (HRꢀMS) analysis as
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well as H NMR experiments of the hostꢀguest compound indicated the formation of 4,4’ꢀ
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bpy⊂4·(BArF) adduct in a 1:1 stoichiometry (see Experimental Section and Figures S1ꢀ4 in
the Supporting Information).
The geometry of the 4,4’ꢀbpy⊂4·(BArF)
8
adduct was fully characterized by means of 1D
1
and 2D NMR spectroscopy (see Figures S5ꢀ8). At room temperature, the HꢀNMR spectrum
exhibited some moderate upfield shifts in the signals corresponding to some of the aromatic
protons of the cage. Additionally, an isolated strongly upfield shifted doublet signal centered at
1
13
4
.91 ppm corresponding to the 4,4’ꢀbpy was observed (see Figure S5a). 2D COSY and Hꢀ C
1
13
HSQC spectra confirmed that the 4,4’ꢀbpy signals (resonate at 4.91/120.4 and 2.23/142.2 H/ C
ppm) experience a strong upfield chemical shift effect upon encapsulation, due to the
anisotropic ring currents from the porphyrin moieties. The stronger effect on proton a is a
consequence of its very close proximity to the aromatic rings from the porphyrin (see Figure
1
a). The 4,4’ꢀbpy nitrogen chemical shift was also expected to be a good indicator of the
35ꢀ36
encapsulation, since it will also be altered by the porphyrin rings electron density.
Therefore
1
15
Hꢀ N HMBC spectra of free and encapsulated 4,4’ꢀbpy were recorded. A chemical shift from
19.5 ppm (4,4’ꢀbpy) to 274.6 ppm (4,4’ꢀbpy⊂4·(BArF) ) further confirmed the coordination
of the N atoms from the bpy to the Zn(II)ꢀporphyrins (see Figure S7ꢀ8). DOSYꢀ2D NMR
3
8
8
experiments also supported the formation of the 4,4’ꢀbpy⊂4·(BArF) 1:1 hostꢀguest adduct (see
Section 1.4 in the Supplementary Information and Figure S9).
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Figure 1. a) HꢀNMR and NꢀNMR assignment of free and encapsulated 4,4’ꢀbpy (experiments were
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performed in CD
3
CN at 298 K). b) HꢀNMR assignment of free and encapsulated ligand α (experiments
CN at 298 K and 243 K respectively). See the corresponding spectra in the
were performed in CD
3
supplementary information.
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The next step was the inclusion of phosphoramidite (S)ꢀα within 4·(BArF) cage with the
aim of preparing in situ the encapsulated Rhꢀcatalysts to be then employed in asymmetric
hydroformylation reactions. We envisioned that the Npyr···Npyr distance in α (∼11 Å) might be
suitable to fit inside 4·(BArF)
does not have a suitably orientation to bind with both pyridyl groups simultaneously to the
porphyrin units of the cage. The UVꢀVis titration between capsule 4·(BArF) and ligand α,
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, whereas ligand β (containing pyridine groups in para position)
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displayed a bathochromic shift of the Soret band from the porphyrins, exhibiting two isosbestic
points, suggesting the formation of a 1:1 hostꢀguest adduct (see Figure 2aꢀb). The 1:1
interaction was further confirmed by Job’s Plot analysis (see Figure 2c). From the UVꢀVis data
6
–1
a binding constant of (3.6 ± 0.2)·10 M was obtained. This high binding constant can be
3
–1
illustratively compared to that observed for α(ZnꢀTPP)
that α is indeed bound in a ditopic fashion within α⊂4·(BArF)
phosphoramidite ligand is located in the middle of the supramolecular cage. HRMS experiments
also supported the formation of α⊂4·(BArF) (see Figure S10). As anticipated, ligand β is not
encapsulated within nanocapsule 4·(BArF) , as shown by UVꢀvis studies (see Figure S11).
2 a
(K ca. 10 M ), strongly suggesting
1
0
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.
As a consequence, the
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[
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λ (nm)
Figure 2. a) UVꢀVis monitoring of the titration of 4·(BArF)
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nanocapsule with ligand α, at a fixed total
in Toluene/CH CN (9/1). b) Absorbance variation
at the Soret band versus different concentrations of the ligand. c) Job’s plot showing a 1:1 stochiometry
ꢀ
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concentration (4.32·10 M) of nanocapsule 4·(BArF)
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for the hostꢀguest complex of the nanocage 4·(BArF) and ligand α.
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The HꢀNMR characterization of α⊂4·(BArF)
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displayed similar trends than the analogous
1
ones corresponding to 4,4’ꢀbpy⊂4·(BArF)
8
(see Figures S12ꢀ17). The HꢀNMR spectrum of the
8
α⊂4·(BArF) adduct in acetonitrile at 298 K exhibited some line broadening effects for all
ꢀ
BArF signals whereas smaller and very broad signals were observed for the encapsulated ligand
(
between 5ꢀ6.5 ppm) and the capsule. The broad signals might evidence some complex dynamic
process and loss of symmetry of the hostꢀguest adduct in comparison with the highly symmetric
structure of empty 4·(BArF) . In addition, a broad upfield shifted signal was observed at ꢀ0.3
8
ppm. In order to try to simplify the spectrum, it was recorded at 243 K. In the latter spectrum
the signals became sharper and suitable to be studied by 2D NMR methods. 2D COSY, NOESY
and HSQC spectra recorded at 243 K allowed us to identify and assign most of the signals
1
belonging to encapsulated ligand α (see Figure 1b). Compared to the free ligand, all H signals
corresponding to confined α appeared doubled at 243 K, confirming that the ligand is not
symmetric when bound to the nanocage. Moreover, very pronounced upfield effects are
observed for all pyridine aromatic protons from ligand α (resonating around 1ꢀ2 ppm), in strong
agreement with the trends observed for the model 4,4’ꢀbpy substrate. The three spin proton
systems belonging to the pyridine rings of α (protons labeled as 1,1’,2,2’,3,3’,5,5’,8,8’ see
Figures 1b and S15), were quickly assigned from the evident COSY and NOE crossꢀpeaks, and
13
their C chemical shifts assigned by HSQC. Protons 8 and 8’ which appeared as two separated
singlets at 5.30 and 5.27 ppm were assigned by the NOE enhancement with the aromatic proton
resonating at 1.50/1.16 ppm, respectively. The Nꢀmethyl signals were assigned to the signal at ꢀ
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Figure S16).
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Interestingly, the PꢀNMR exhibited a singlet at ≈ 137.0 ppm, similar to the free ligand α,
indicating that the phosphorus is not coordinated to any of the metals of 4·(BArF) , and
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therefore remains available for coordination to the rhodiumꢀmetal center that is used for
catalysis (see Figure S18).
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In conclusion, the sum of the spectroscopic data led to the conclusion that α is
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encapsulated and is strongly bound to 4·(BArF) . Furthermore, this binding did not involve the
phosphine atom, which remains available for binding the Rh ion.
Preparation of the encapsulated catalyst. The Rh(I) catalyst was formed inꢀsitu by
6
addition of 1 eq of [Rh(acac)(CO)
α⊂4·(BArF)
NMR spectroscopy (see Figures S19ꢀ20). The carbonyl vibration of the CO ligand was detected
2
] to a deuterated toluene/acetonitrile (5/2 v/v) solution of
8
(Scheme 3). Key features of the rhodium complex have been identified by IR and
–1
31
by IR spectroscopy (
ν
= 1995 cm ) (see Figure S21). The PꢀNMR displays a typical doublet
1
centered at δ = 147 ppm, with a phosphorus rhodium coupling ( JPꢀRh= 260 Hz) suggesting the
10
formation of monoligated species (see Scheme 3).
Under catalytic conditions (5 bar of H /CO 1:1), the rhodium acac precursor was converted
2
into the typical hydride species, in this case the [transꢀRh(H)(CO) α⊂4·(BArF) ] was observed.
3
8
1
High Pressure (HP) H NMR spectrum of [Rh(H)(CO) ꢀα⊂4·(BArF) ] shows signals
3
8
corresponding to the catalystꢀcapsule adduct (Fig. S22), thus indicating its stability under the
catalytic conditions. Moreover, a double doublet centered at ꢀ11.7 ppm is observed, indicating
formation of the hydride at a monoligated rhodium complex (Scheme 3). The large phosphorus
coupling (JHꢀP= 175.5 Hz) shows that the phosphorus donor atom is located trans to the hydride,
1
0ꢀ11
1
31
similar to that observed for [transꢀRh(H)(CO) ꢀβ(ZnꢀTPP) ].
The Hꢀ{ P}ꢀNMR spectrum
3
2
displays a single peak at ꢀ11.9 ppm, confirming that the large coupling is between the
phosphorus and the hydride (see Figure S22ꢀS23).
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N
N
O
OC
H
OC
O
Rh
O
Rh CO
CO
NMe2
H :CO
2
O
P
P
O
NMe2
O
–
Hacac
N
N
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[
Rh(acac)(CO)ꢀα⊂4·(BArF)8]
[transꢀRh(H)(CO) ꢀα⊂4·(BArF) ]
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1HꢀNMR
31PꢀNMR
1Hꢀ{31P}ꢀNMR
Scheme 3. NMR and High Pressure NMR spectra of [Rh(acac)(CO)ꢀα⊂4·(BArF)
Rh(H)(CO) ꢀα⊂4·(BArF) ].
8
] and [transꢀ
3
8
Application of the encapsulated catalyst in asymmetric hydroformylation catalysis.
Once the encapsulated Rh catalyst was thoroughly characterized, we focused on the
investigation of its catalytic performance in the asymmetric hydroformylation (AHF) of
3
7ꢀ41
styrene.
α⊂4·(BArF)
solubility, catalyst loading was kept low at 2·10 mol%. As common practice, a fiveꢀfold
excess of ligand⊂capsule (α⊂4·(BArF) ) was used in all the experiments in order to avoid the
To clearly study the effect of encapsulation, catalytic activities of [Rh(acac)(CO)ꢀ
8
] were compared with that of the Rhꢀcomplex of α(ZnꢀTPP) . Due to limited
2
ꢀ4
8
formation of ligandꢀfree rhodium species, an active and nonselective catalyst that could
compromise the selectivity. Reactions were performed at room temperature, and the turnover
numbers and ee’s are reported in Tables 1ꢀ4.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8
Table 1. Asymmetric hydroformylation of styrene using Rhꢀcatalysts based on α⊂4·(BArF) cage
[
a]
structure and ligandꢀtemplate system α(ZnꢀTPP)2.
O
H2/CO
O
[
Rh(acac)(CO)2]
Ligand
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
b
l
[
d]
[e]
Entry
Ligand
b/l
ee (%)
Conv (%)
TON
1
α⊂4·(BArF)8
99/1
74 (R)
14
<1
6
797
<1
[f]
[f]
2
3
4
5
6
7
8
9
1
1
1
1
ꢀ
n.d.
n.d.
α
99/1
99/1
99/1
99/1
99/1
<1
9(R)
<1
342
363
300
α(ZnTPP)
4·(BArF)
2
7
6
8
[
[
[
b]
c]
c]
α⊂4·(BArF)8
α⊂4·(BArF)8
65 (R)
70 (R)
32
7
1600
339
<1
[f]
[f]
ꢀ
n.d.
n.d.
<1
4
[c]
[c]
α
99/1
99/1
99/1
99/1
99/1
99/1
8 (R)
16 (R)
79 (R)
7 (R)
197
215
308
136
104
41
0
1
2
3
α(ZnTPP)
2
4
γ⊂4·(BArF)
8
6
γ
3
δ⊂4·(BArF)
8
77 (R)
6 (R)
2
14
δ
1
a] Reagents and conditions: [Rh]= 33 µM in toluene/MeCN (4/1), ligand⊂capsule/[Rh(acac)(CO)
2
]=5,
alkene/rhodium=5000, rt, 20 bar, 96 h. Rh Complex: Rh(acac)(CO) . [b] The catalytically active
2
species is generated under 20 bar of syngas, 16h, 40ºC. Then the styrene was added and the reaction
was performed at rt, 20 bar, 96h. [c] [Rh]= 33 µM in toluene/MeCN (2/3), rt, 20 bar, 96 h. [d] Ratio of
branched and linear aldehyde. [e] Enantiomeric ratio determined by chiral GC analysis (Supelco BETA
DEX 225). [f] n.d.= nonꢀdetected.
Much to our delight, encapsulated Rh catalyst [Rh(H)(CO)
turnover number (Table 1, entries 1, 6 and 7) than the nonꢀencapsulated analogue (entries 3 and
) and also than the catalyst based on assembly α(ZnTPP) (entries 4 and 10). As previously
3
ꢀα⊂4·(BArF)
8
] gave a higher
9
2
observed, when the reaction is carried out with rhodium complex α in absence of zinc(II)
porphyrins, very low conversion is observed, likely due the presence of free pyridyl groups that
compete with the substrate for coordination at the rhodium center. The effect of encapsulation
on the selectivity of the reaction was remarkable; when assembly α(ZnꢀTPP)
2
was used as
ligand, a modest 9% ee was observed, whereas complete encapsulation of the ligand by using
α⊂4·(BArF)
8
resulted in 74% ee (Table 1, entries 1ꢀ4). The encapsulated catalyst gives among
6
the highest chemo and stereoselectivities for a monoligated rhodium complex reported so far.
Using an incubation period at 40 ºC before initiating the reaction resulted in a higher TON, at
the expense of the selectivity (TON from 797 to 1600, ee from 74 to 65%; see entries 1 and 6).
Further optimization by changing the toluene/acetonitrile ratio did not improve the results
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(
8
Table 1, entries 7ꢀ10). Remarkably, a control experiment in which capsule 4·(BArF) , along
with the Rh complex, were used as catalyst provided racemic aldehyde (Table 1, entry 5).
1
Moreover, HꢀNMR experiments were performed in order to see if the nanocapsule still
maintains its structure under the high pressure reaction conditions employed in catalytic
experiments. Effectively, the cage remains unaltered even after heating a solution of 4·(BArF)
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
at 60 ºC under 5 bar of syngas during 2h (see Figure S24). No precipitate appeared on the NMR
tube, strongly suggesting that the capsule is not destroyed under these conditions since the
capsule’s building blocks are not soluble in DCM. Cage decomposition would have led to the
appearance of a precipitate. As a complementary experiment, the reaction crude obtained in one
8 3
of the catalytic experiments was dried and redissolved in a tolueneꢀd /CD CN mixture to record
1
the HꢀNMR. The spectrum showed that the integrity of the ligandꢀcage adduct was still
maintained after the catalysis (Fig. S25).
In order to fine tune the supramolecular assemblies and optimize the activity and the
selectivity of the catalytic transformation, the Rhꢀcatalyzed AHF of styrene was further studied
using ligands γ (R=Et) and δ (R= iPr) in the presence and the absence of cage 4·(BArF)
Scheme 1 and Table 1, entries 11ꢀ14). Replacing ligand α for γ leads to a slight increase in the
8
(
ee (from 74% to 79%) but at the expense of the activity (TON decreases from 797 to 308).
When using ligand δ again a small increase in the ee was observed (from 74% to 77%) but the
8
activity was drastically lower in comparison with ligand α⊂4·(BArF) (TON from 797 to 104).
These results reveal that small modifications to the ligand building block allow optimization of
the selectivity and activity of the supramolecular catalysts which opens the door to future
8
catalyst optimization. So far, α⊂4·(BArF) affords the best compromise in ee and TON of this
new class of encapsulated catalysts for the AHF of styrene.
Preliminary molecular modelling studies were performed (see Figures S26ꢀ29) to shine
light on the effect of encapsulation in the performance of the Rh catalyst. For the nonꢀ
encapsulated catalysts (Rh(H)(CO) ꢀα), calculations show that there is a wide space for
3
coordination of the styrene molecule in four orientations to the two available coordination sites
that can lead to subsequent selectivity determining hydride migration, which constitutes the key
step that ends up determining the enantioselectivity. Since the substrate can approach the
catalyst with multiple orientations, the overall stereoselectivity that results when reactions are
performed in absence of the cage is poor. In contrast, when the catalyst is docked into the
nanocapsule, the cage walls prevent most of the coordination modes of styrene to the Rh center,
effectively blocking some of the reaction pathways (Figures S28ꢀ29).
Given the promising results obtained in the AHF of styrene, the substrate scope of
α⊂4·(BArF)
8
was evaluated using different paraꢀRꢀsubstituted styrene derivates (R = H, Cl,
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CH
3
, OCH
3
, tBu). The results obtained for these substrates were similar to the ones obtained for
styrene (Table 2); in all cases, the best activities were obtained when ligand α was encapsulated
in cage α⊂4·(BArF) . The conversion (TON) and the regioselectivity depended to some extend
on the substituent on the styrene. The selectivity towards the branched aldehyde was maintained
when R = tBu (Table 2, entry 17), whereas for R = CH and OCH the b/l ratio was slightly
lower (91/9, Table 2, entries 9, 13). For 4ꢀClꢀstyrene the selectivity decrease even down to b/l =
0:20 (Table 2, entry 5). In all cases, substrates bearing substituents at position 4 showed a
decrease in ee. Nevertheless, comparison of these results with those of the α(ZnꢀTPP) rhodium
catalyst consistently showed the benefits of catalyst encapsulation in cage 4·(BArF) . In general,
ee’s are below 12% for α(ZnꢀTPP) (Table 2, entries 4, 8, 12, 16), but over 58% for the
8
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
2
8
2
encapsulated catalyst. For the most bulky substrate, when R = tBu, the effect is less pronounced
as the ee improves from moderate 31% to 48% (Table 2, entries 17 and 20).
Table 2. Asymmetric hydroformylation of styrene derivatives using Rhꢀcatalysts based on α⊂4·(BArF)
cage structure and ligandꢀtemplate system α(ZnꢀTPP) .
2
8
[
a]
[
b]
[c]
Conv (%)
Entry
R
Cat.
b/l
ee (%)
TON
1
2
3
4
5
6
7
8
9
H
H
H
α⊂4·(BArF)8
99/1
74 (R)
n.d.
<1
14
<1
6
797
<1
342
363
761
<1
180
577
1564
<1
140
482
1125
180
168
340
1042
107
180
361
[
d]
[d]
ꢀ
n.d.
99/1
99/1
α
H
α(ZnꢀTPP)2
9(R)
58(R)
7
Cl
α⊂4·(BArF)8
80/20
14
<1
4
12
31
<1
3
10
22
4
[
d]
[d]
Cl
Cl
Cl
ꢀ
n.d.
n.d.
α
91/9
91/9
91/1
<1
α(ZnꢀTPP)2
11 (R)
61(R)
CH3
CH3
CH
CH
α⊂4·(BArF)8
[d]
[d]
10
11
12
13
14
15
ꢀ
n.d.
n.d.
3
α
91/9
91/9
91/9
99/1
99/1
97/3
99/1
99/1
99/1
97/3
<1
12(R)
69(R)
<1
<1.
<1
3
α(ZnꢀTPP)
2
OCH3
OCH3
OCH
OCH
α⊂4·(BArF)8
ꢀ
3
α
3
7
16
17
18
3
α(ZnꢀTPP)
2
t
Bu
α⊂4·(BArF)8
48(R)
<1
<1
21
2
4
t
Bu
Bu
Bu
ꢀ
t
1
2
9
0
α
t
α(ZnꢀTPP)
2
31(R)
7
[
a] Reagents and conditions: [Rh]= 33 µM in toluene/MeCN (4/1), ligand⊂capsule /[Rh(acac)(CO)
2
]=5,
alkene/rhodium=5000, rt, 20 bar, 96 h. Rh Complex: Rh(acac)(CO) . [b] Ratio of branched and linear
aldehyde. [c] Enantiomeric ratio determined by chiral GC analysis (Supelco BETA DEX 225). [d] n.d.=
nonꢀdetected
2
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9
The substrate scope was further extended to orthoꢀ, metaꢀ and paraꢀsubstituted
methoxystyrene derivatives to investigate the effect of steric interactions in more detail. Higher
TON and ee values were obtained for pꢀmethoxystyrene when α⊂4·(BArF)
catalyst (see Table 3, entry 1), compared to the complex based on α(ZnꢀTPP)
4). In contrast, for oꢀmethoxystyrene the caged catalyst gave much lower TON than the complex
based on α(ZnꢀTPP) (Table 3, entry 9 vs 12). Since orthoꢀ and paraꢀmethoxystyrene can be
considered to have electronically equivalent olefinic sites, the sharp difference is fully attributed
to structural discrimination imposed by cage 4·(BArF) . For mꢀmethoxystyrene the encapsulated
catalyst gave rise to a higher TON (519) than the control reaction performed with α(ZnꢀTPP)
8
was used as
2
(Table 3, entry
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
8
2
template, and the product was formed with 56 % ee (Table 3, entry 5). Most importantly, for pꢀ
and mꢀmethoxystyrene the selectivity obtained for the caged catalyst was much higher than that
2
found for the catalyst based on α(ZnꢀTPP) (Table 3, entries 4, 8), which again clearly
substantiates the importance of the catalyst confinement in the AHF of styrene.
Table 3. Asymmetric hydroformylation of pꢀ, mꢀ and oꢀmethoxystyrene using Rhꢀcatalysts based on
[
a]
8 2
α⊂4·(BArF) cage structure and ligandꢀtemplate system α(ZnꢀTPP) .
[
c]
[d]
Entry
Ligand
b/l
ee (%)
Conv (%)
TON
paraꢀmethoxystyrene
1
2
3
4
α⊂4·(BArF)8
91/9
99/1
99/1
97/3
69(R)
<1
<1
22
4
3
1125
180
168
340
ꢀ
α
α(ZnꢀTPP)
2
<1
7
metaꢀmethoxystyrene
5
6
7
8
α⊂4·(BArF)8
99/1
n.d.
99/1
99/1
56
n.d. .
<1
10
<1
2
519
<1
113
180
[
d]
[d]
ꢀ
α
α(ZnꢀTPP)2
<1
4
orthoꢀmethoxystyrene
99/1
47
9
α⊂4·(BArF)8
2
<1
2
127
<1
109
245
[d]
[d]
10
11
12
ꢀ
n.d.
99/1
99/1
n.d. .
<1
<1
α
α(ZnꢀTPP)
2
5
[
a] Reagents and conditions: [Rh]= 0.033 mM in toluene/MeCN (4/1),
ligand⊂capsule/[Rh(acac)(CO)
Rh(acac)(CO) . [b] Ratio of branched and linear aldehyde. [c] Enantiomeric ratio
determined by chiral GC analysis (Supelco BETA DEX 225). [d] n.d.= nonꢀdetected.
2
]=5, alkene/rhodium=5000, rt, 20 bar, 96 h. Rh Complex:
2
Finally, we carried out AHF catalysis of styrene at variable concentrations of α⊂4·(BArF)
and α(ZnꢀTPP) . We reasoned that the relative high association constant of the ligand in the
cage (i.e. stability constant of α⊂4·(BArF) compared to α(ZnꢀTPP) ) should translate to a
8
2
8
2
higher concentration window in which these supramolecular catalysts can be operated. As such,
we performed experiments at four catalyst concentrations ranging from 147 to 1 ꢀM (see Table
4
8
). Upon lowering the concentration of Rhꢀα⊂4·(BArF) the TON is lower as expected because
of the typical positive order of the catalyst concentration on the reaction rate. Most indicative
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1
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
for the stability of the assembly is the selectivity. The selectivity induced by the encapsulated
catalysts remains high (71 ± 3% ee) even at concentrations of 6 µM, indicating that under these
conditions the catalysis is still dominated by the encapsulated catalyst (see Figure S30). In
2
contrast, when Rhꢀα(ZnꢀTPP) catalyst was used at 6 µM the product was formed in racemic
form, and also the TON was similar to the control experiment where no porphyrins were
present. These results are in agreement with a significantly more robust nature of catalyst
α⊂4·(BArF) compared to α(ZnꢀTPP) .
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
2
[a]
Table 4. Asymmetric hydroformylation of styrene at different Rhꢀcatalyst concentrations.
[b]
[c]
Entry
Cat.
[Rh] (µM) b/l
ee (%) Conv (%) TON
1
2
3
4
5
6
7
8
9
α⊂4·(BArF)8
98/2
96/4
98/2
97/3
97/3
91/9
97/3
97/3
99/1
ꢀ
71
<1
3
15
68
<1
3
97
64
90
92
79
20
88
49
14
0
193
128
180
183
158
39
176
99
29
0
ꢀ
α
1
47
α(ZnꢀTPP)
2
α⊂4·(BArF)8
ꢀ
α
3
3
α(ZnꢀTPP)
2
16
74
α⊂4·(BArF)8
[d]
1
1
0
1
ꢀ
α
n.d
6
99/1
99/1
ꢀ
<1
<1
17
15
0
33
31
0
12
α(ZnꢀTPP)
2
[
d]
13
14
15
16
α⊂4·(BArF)8
n.d
n.d
n.d
n.d
[d]
ꢀ
α
ꢀ
ꢀ
ꢀ
0
0
0
0
0
0
1
[
d]
d]
[
α(ZnꢀTPP)
2
[
2
a] Reagents and conditions: toluene/MeCN (4/1), ligand⊂capsule/[Rh(acac)(CO) ]=5, alkene/rhodium=200,
rt, 20 bar, 96 h. Rh Complex: Rh(acac)(CO) . [b] Ratio of branched and linear aldehyde. [c] Enantiomeric ratio
2
determined by chiral GC analysis (Supelco BETA DEX 225).[d] n.d.= nonꢀdetected.
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Conclusion
In summary, this work describes the encapsulation of a monoligated chiral rhodium complex
in a selfꢀassembled molecular cage. The encapsulated Rhꢀα⊂4·(BArF) catalyst exhibits among
8
the highest selectivities in the asymmetric hydroformylation of styrenes for monoligated
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
rhodium catalysts. Most significantly, stereoselectivity observed in the hydroformylation of
styrenes upon encapsulation of the catalyst are substantially improved with regard to analogous
reactions performed with the catalyst operating in bulk solution. Therefore, the cage can be
considered as a second coordination sphere of the catalyst, and its role may be understood as
reminiscent of enzymatic active sites. On the basis of these observations, we envision that the
use of the second coordination sphere tuning strategy over the selectivity of catalytic events may
8
be more broadly applicable. The sizeꢀtunability of cage 4·(BArF) , the high affinity for
pyridineꢀcontaining ligands and the possibility to modify the apertures of the cage provide
strong fundaments for the future development of these cage structures for asymmetric catalysis.
Experimental Section
Materials. Unless indicated otherwise, reagents and solvents used were commercially available
reagent quality and reactions were carried out under an atmosphere of nitrogen using standard
14
10
33
8
Schlenk techniques. Ligands α , β and molecular cage 4·(BArF)
were synthesized
following previously reported procedures.
1
31
13
Physical Methods. NMR spectra ( H, P and C) were measured on a Bruker DRX 400 MHz,
Bruker AVANCE 500 MHz, Bruker AVANCE 600 MHz and Varian Inova 500 MHz; CDCl
CD CN or Tolueneꢀd were used as solvents, if not further indicated. High resolution mass
3
,
3
8
spectra (HRMS) were obtained on a Bruker MicroTOFꢀQꢀII, using acetonitrile as the mobile
phase. UVꢀVis spectroscopy was performed on an Agilent 8452 UVꢀvis spectrophotometer with
1
cm quartz cell. Gas chromatographic analyses were runed on a Shimadzu GCꢀ17A apparatus
(split/splitless injector, J&W 30 m column, film thickness 3.0 µm, carrier gas 70kPa He, FID
Detector). Chiral GC separations were conducted on the Iterscience HR GC with a Supelco βꢀ
dex 225 capillary column. IR experiments were performed at r.t. into a Nicolet 510 FTIR
spectrometer. Molecular Modeling calculations were performed using PM3ꢀSpartan molecular
modeling program.
Synthesis of ligands γ and δ. In a flame dried Schlenk 200 mg (0.44 mmol) d, pyridine (0.068
mL, 0.88 mmol) and DMAP (10 mol%) were suspended in dry toluene (4.4 mL, 0.1 M). The
3
solution was cooled to 0 °C and distilled PCl (0.080 mL, 0.88 mmol) was added dropwise over
10 min. The mixture was warmed up to room temperature and then refluxed overnight. The
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reaction mixture was cooled to room temperature and the formation of product was checked by
31
3
P‐NMR. The solvent and the residual PCl were removed in vacuum. The resulting solid was
used for the next step without any further purification.
In a flame dried Schlenk the dialkylamine (0.44 mmol) and pyridine (0.040 mL, 0.48 mmol)
were dissolved in dry toluene (1 mL). The solution was added drop wise to a cooled (0 °C)
mixture of e (225.7 mg, 0.44 mmol) in dry toluene (5 mL). The mixture was warmed up to room
temperature and stirred overnight at room temperature. The precipitate formed was filtered over
a pad of Celite under argon, and then solvent was evaporated in vacuum to obtain α, γ, δ.
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See reaction scheme (including aꢀe representations) in the supporting information. See also
Figures S31ꢀ32.
1
Ligand γ: Yield: 81 % (white foam); H NMR (400 MHz, CDCl
3
): δ = 8.85 (m, 2H) 8.54 (dd,
2
2
1
H), 7.96 (dt, 1H), 7.90 (dt, 1H), 7.28 (m, 2H), 7.16 (s, 1H), 7.14 (s, 1H), 2.90 (m, 4H), 2.54 (m,
1
3
H), 2.35 (m, 4H), 1.87 (m, 8H), 0.51ꢀ0.59 (t, 6H); C NMR: 150.2, 149.1, 147.2, 138.0, 136.2,
31
30.2, 129.1, 128.4, 122.5, 122.1, 34.2, 30.2, 29.1, 28.3, 27.8, 23.1, 22.2; P NMR: δ= 140.85
ppm.
1
Ligand δ: Yield: 52 % (white foam); H NMR (400 MHz, Toluene): δ = 8.99ꢀ9.07 (dd, 2H) 8.43
(
(
d, 2H), 7.84 (dt, 1H), 7.73 (dt, 1H), 7.01 (m, 2H), 6.97 (s, 1H), 6.71 (s, 1H), 2.68 (m, 6H), 2.44
1
3
m, 2H), 1.79 (m, 2H), 1.59 (m, 8H), 0.87 (4*d, 12H); C NMR: 153.2, 152.7,150.2, 14.1,
1
1
39.2, 138.0, 135.2, 130.2, 129.1, 128.6, 122.1, 47.5, 46.6, 35.6, 34.2, 31.1, 28.3, 12.8, 12.1,
31
1.2; P NMR: δ= 139.89 ppm.
33
8 8
Preparation of 4,4’ꢀbpy⊂4·(BArF) . 4.0 mg of 4·(BArF) nanocapsule (0.33 µmols, 1 equiv.)
3
were dissolved in 100 µl of CH CN. Then 1 equiv. of 4,4’ꢀBpy dissolved in 400 µl of toluene
was added. The mixture was stirred at room temperature for 5 minutes. After the reaction time,
the mixture was filtered through cotton and recrystallized by diethyl ether diffusion.
1
Quantitative yield obtained. HꢀNMR (400 MHz, CD
3
CN) δ ppm: 8.59 (s, 16H, pyrrole ring),
8
.58 (dd, 8 H, aromꢀporph), 8.34 (dd, J=8 Hz, 8H, aromꢀporph), 8.28 (d, J= 8.5 Hz, 32 H, aromꢀ
clip), 8.13 (m, 32 H aromꢀclip + 8H aromꢀporph), 7.99 (dd, J=8 Hz, 8H, aromꢀporph), 7.67 (m,
9
6 H, NaBARF)*, 4.95 (m, 4 H, bpy) 4.04 (d, J=13 Hz, 16 H, ꢀCH
.60 (s, 48 H, NꢀCH ), 3.37 (m, 16 H, ꢀCH ꢀ), 3.14 (d, J=13 Hz, 16 H, ꢀCH
6 H, ꢀCH ꢀ), 2.38 (dd, J=13.5, 16 H, ꢀCH ꢀ), 1.59 (s, 24 H, NꢀCH ). HRMS (m/z): calcd.
186.923 and found 2186.910 ({4,4’ꢀbpy⊂4·(BArF)
2
ꢀ), 3.73 (m, 16H, ꢀCH
2
ꢀ),
3
3
2
2
ꢀ), 2.48 (dd, J=13.5,
1
2
2
3
4
+
2
4
} ); calcd. 1577.118 and found 1577.115
5
+
6+
({4,4’ꢀbpy⊂4·(BArF)
3
2
} ), calcd. 1170.251 and found 1170.255 ({4,4’ꢀbpy⊂4·(BArF) } );
7+
calcd. 879.634 and found 879.637 ({4,4’ꢀbpy⊂4·(BArF)} ); calcd. 661.796 and found 661.799
8
+
(
{4,4’ꢀbpy⊂4·(BArF)} ).
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Preparation of α⊂4·(BArF)
8 8
. 9 mg of 4·(BArF) nanocapsule (0.33 µmols, 1 equiv.) were
dissolved in 300 µl of CH CN. Then 1 equiv. of α dissolved in 1200 µl toluene was added. The
3
mixture was stirred at room temperature for 5 minutes. After the reaction time, the mixture is
filtered through cotton and recrystallized by diethyl ether diffusion. Quantitative yield obtained.
4
+
HRMS (m/z): calcd. 2278.453 and found 2278.452 ({α⊂4·(BArF)
4
} ); calcd. 1650.120 and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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+
6+
found 1650.151 ({α⊂4·(BArF)
3
2
} ), calcd. 1231.231 and found 1231.283 ({α⊂4·(BArF) } );
7+
calcd. 931.942 and found 931.945 ({α⊂4·(BArF)} ); calcd. 707.621 and found 707.693
8+
({α⊂4·(BArF)} ).
Preparation of the transꢀ[Rh(H)(CO)
3
8
ꢀα⊂4·(BArF) complex for the high pressure NMR
experiment. To 16 mg of 4·(BarF)
8
(0.0013 µmol), 1 eq the phosphoramidite ligand (α, β, γ or
δ), 1 eq Rh(acac)(CO) were added in a 7/3 (v/v) mixture of d ꢀToluene/CD CN (1.2 ml). The
2
8
3
mixture was transferred into a 5 mm HPꢀNMR tube, pressurized with 5 bar of syngas H
2 2
/CO
1
:1, and left at 40ºC for 16 h. After this time the High pressure NMR spectra was recorded.
DiffusionꢀOrdered NMR spectroscopy experiments. DiffusionꢀOrdered NMR experiment
(DOSY NMR) allows the determination of the translational selfꢀdiffusion coefficients (D) for
these species in acetonitrile solution. Making use of the StokesꢀEinstein equation (SEq.1), the
42
hydrodynamic radii (r ) for the diffused species can be calculated from the D value.
h
k ∙ T
D =
(SEq.1)
6
∙ π ∙ η ∙ rꢀ
where k is the Boltzmann constant, T is the temperature, and η is the viscosity of the solvent (η
CH CN) = 0.35 mPa s).
(
3
General procedure for UVꢀVis titrations. Hostꢀguest interactions in solution were studied by
ꢀ7
UVꢀVis spectroscopy. Solutions of nanocapsule 4·(BArF)
8
(4.32·10 M) and of the different
ꢀ5
substrates tested (1.39·10 M) were prepared using CH
3
CN/Tol (1/9) as solvent. An increasing
number of substrate equivalents were added to the nanocapsule solution (2ml, in a 1cm cuvette
cell). The host concentration was kept constant. The stoichiometry of the complexes was studied
using the method of Continuous Variations, by adding different ratios of guest solution, in order
to add an increasing number of substrate equivalents.
Hydroformylation Catalysis Unless indicated otherwise, the hydroformylation experiments
were carried out in a stainless stell autoclave charged with an inset suitable for 8 reaction
vessels (equiped with teflon mini stirring bars) for performing parallel reactions. Each vial was
charged with phosphoramidite ligands (α, β, γ, δ, 0.083 µmols), the template ZnꢀTPP (0.166
µmols) or nanocapsule 4·(BArF) (0.083 µmols), [Rh(acac)CO ] (0.016 µmols), the substrate
8
2
(83 µmols) and a mixture of toluene/acetonitrile (v/v, 4/1). The substrates were filtrated
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through basic alumina to remove possible peroxide immpurities.The solvents were destilled
from sodium previous to use. Before starting the catalysis, the charged autoclave was purged
2
three times with 10 bar of syngas (H /CO=1/1) and then pressurized to 20 bar. After the
catalytic reaction, the autoclave was cooled to r.t. if the reaction was carried out at high
temperature, the pressure was reduced to 1.0 bar and a few drops of triꢀbutylꢀposphite were
added in each reaction vessel to prevent any further reaction. The reaction mixtures were not
filtered over basic alumina to remove the catalyst residues, because filtration may cause
0
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2 2
retention of the aldehydes influencing the GC results. The mixtures were diluted with CH Cl
for GC analysis. The enantiomeric excess was analyzedby GC (Supelco βꢀdex 225 capillary
column). The absolute configuration was determined by comparing the chiral GC traces of the
reaction mixture with the comercially abailable enantiopure aldehydes.
Associated content.
Supporting information. DOSY 2D experiments of 4,4’ꢀbpy⊂4·(BArF) All 1D and 2D NMR
8
.
spectra. HRMS results. UVꢀVis experiments. Chiral GC data for hydroformylation products
information and chromatograms (Figures S33ꢀ37). This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgments.
We would like to acknowledge the European Research Council (ERCꢀ2011ꢀStGꢀ277801 to XR,
ERCꢀ2009ꢀStGꢀ239910 to MC and ERCꢀ2013ꢀAdGꢀ339782ꢀNAT_CAT to JNHR), the Spanish
MINECO (ConsoliderꢀIngenio CSD2010ꢀ00065, INNPLANTA project INPꢀ2011ꢀ0059ꢀPCTꢀ
420000ꢀACT1, CTQ2012ꢀ32436) and the Catalan DIUE of the Generalitat de Catalunya
(
2009SGR637 and PhD grant to CGS). XR and MC also thank ICREAꢀAcadèmia awards.
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