Supramolecularly Regulated Ligands for Asymmetric Hydroformylations and Hydrogenations

Article abstract of DOI:10.1002/chem.201501441

Herein we report the use of polyether binders as regulation agents (RAs) to enhance the enantioselectivity of rhodium-catalyzed transformations. For reactions of diverse substrates mediated by rhodium complexes of the α,ω-bisphosphite-polyether ligands 1-5,a-d, the enantiomeric excess (ee) of hydroformylations was increased by up to 82 (substrate: vinyl benzoate, 96ee), and the ee value of hydrogenations was increased by up to 5 (substrate: N-(1-(naphthalene-1-yl)vinyl)acetamide, 78ee). The ligand design enabled the regulation of enantioselectivity by generation of an array of catalysts that simultaneously preserve the advantages of a privileged structure in asymmetric catalysis and offer geometrically close catalytic sites. The highest enantioselectivities in the hydroformylation of vinyl acetate with ligand 4b were achieved by using the Rb[B(3,5-(CF₃)₂C₆H₃)₄] (RbBArF) as the RA. The enantioselective hydrogenation of the substrates 10 required the rhodium catalysts derived from bisphosphites 3a or 4a, either alone or in combination with different RAs (sodium, cesium, or (R,R)-bis(1-phenylethyl)ammonium salts). This design approach was supported by results from computational studies.

Full text of DOI:10.1002/chem.201501441

DOI: 10.1002/chem.201501441
Full Paper
&
Asymmetric Catalysis
Supramolecularly Regulated Ligands for Asymmetric
Hydroformylations and Hydrogenations
[a, c]
[a]
[b]
[b]
Anton Vidal-Ferran,*
Laura Rovira
Ignasi Mon, Antonio Bauzµ, Antonio Frontera, and
[a]
Abstract: Herein we report the use of polyether binders as
regulation agents (RAs) to enhance the enantioselectivity of
rhodium-catalyzed transformations. For reactions of diverse
substrates mediated by rhodium complexes of the a,w-bi-
sphosphite-polyether ligands 1–5,a–d, the enantiomeric
excess (ee) of hydroformylations was increased by up to
the advantages of a privileged structure in asymmetric catal-
ysis and offer geometrically close catalytic sites. The highest
enantioselectivities in the hydroformylation of vinyl acetate
with ligand 4b were achieved by using the Rb[B(3,5-
(CF ) C H ) ] (RbBArF) as the RA. The enantioselective hydro-
3
2
6
3 4
genation of the substrates 10 required the rhodium catalysts
derived from bisphosphites 3a or 4a, either alone or in
combination with different RAs (sodium, cesium, or (R,R)-
bis(1-phenylethyl)ammonium salts). This design approach
was supported by results from computational studies.
8
2% (substrate: vinyl benzoate, 96% ee), and the ee value of
hydrogenations was increased by up to 5% (substrate: N-(1-
naphthalene-1-yl)vinyl)acetamide, 78% ee). The ligand
(
design enabled the regulation of enantioselectivity by gen-
eration of an array of catalysts that simultaneously preserve
[
5]
Introduction
catalysts with unprecedented ease, or even to introduce ster-
[
6]
eogenicity into the catalyst.
Asymmetric catalysis enables unique and selective pathways
for the conversion of simple compounds into enantiomerically
pure complex molecules, often with significant advantages
over non-catalytic methods. It has evolved greatly since the
early 1970s to now encompass nearly any transformation sub-
Within this context, regulation of a catalyst refers to modifi-
cation of its active site upon binding of an effector molecule
at a distinct site (known as the regulation site). Progress has
been made in regulating the size and shape of a chiral catalyst
[
7]
by using a regulation agent (RA). This agent has also been
used to change the first-sphere coordination geometry of the
[1]
ject to three-dimensional bias. A general enantioselective cat-
alyst for a given transformation does not exist. Structural
changes to the substrate(s) and/or reagent(s) often translate to
a loss of enantioselectivity. Several strategies have been de-
[
8]
active metal in asymmetric catalysis. However, there are only
scarce examples of fine modification of the active-site geome-
try that do not imply major alteration of the principal structur-
[2,3]
[9,10]
vised to overcome this limitation. Ligand tuning
in catalysis
al features of the asymmetric catalyst.
[
10]
has allowed the rapid development of efficient catalytic sys-
tems for a broad substrate scope in a given transformation.
Parallel chemistry and subsequent assessment of catalysts by
automated high-throughput screening techniques have also al-
lowed rapid identification of high-performing catalysts for
In a previous study, we demonstrated that conformation-
ally transformable a,w-bisphosphite 3b (Scheme 1) behaved as
a supramolecularly regulated ligand in asymmetric hydrofor-
mylations with moderate efficiency. To develop more efficient
catalysts and gain a better understanding of the regulation
mechanism, we describe a new set of enantiomerically pure
supramolecular catalysts that incorporate a wider range of reg-
ulation centers (the (poly)ether chains 1, 2, 4, and 5;
Scheme 1), new catalytic sites (those derived from the phos-
phite groups c and d; Scheme 1), and new RAs (alkali metal
and ammonium salts). A highly efficient supramolecular cata-
lyst for asymmetric hydroformylations was identified. Further-
more, computational studies were performed; the results of
which have elucidated the regulation mechanism. Lastly, the
catalytic activity of rhodium pre-catalysts of the aforemen-
tioned supramolecular ligands was also assessed in asymmetric
hydrogenations.
[4]
a broad substrate scope. Supramolecular interactions have
been used to construct the skeletons of the enantioselective
[
a] Prof. Dr. A. Vidal-Ferran, Dr. I. Mon, L. Rovira
Institute of Chemical Research of Catalonia (ICIQ)
Avgda. Pa ¨ı sos Catalans 16, 43007 Tarragona (Spain)
Fax: (+34)977920228
E-mail: avidal@iciq.cat
[
b] A. Bauzµ, Prof. Dr. A. Frontera
Departament de Química, Universitat de les Illes Balears (UIB)
Cra. de Valldemossa, km 7.5. Palma, 07122 Palma de Mallorca (Spain)
[
c] Prof. Dr. A. Vidal-Ferran
Catalan Institution for Research and Advanced Studies (ICREA)
Passeig Lluís Companys 23, 08010 Barcelona (Spain)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501441.
Chem. Eur. J. 2015, 21, 11417 – 11426
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Full Paper
Scheme 1. Supramolecularly regulated bisphosphite ligands with a distal regulation site.
Results and Discussion
The preparation of bisphosphite ligands is well documented,
[
13b]
and relies on an O-phosphorylation of the diol of interest.
Thus, compounds 1–5,a–d were synthesized this way (48 to
2% yield) from the corresponding diols and chlorophosphites
Design and synthesis of supramolecularly regulated bis-
phosphite ligands and RAs
9
With the aim of developing highly efficient catalysts for asym-
metric hydroformylations and hydrogenations and gaining in-
sight into the regulation mechanism, we have designed and
prepared an array of highly diverse bisphosphite ligands by
combining a linker group and a polyether chain for regulation
in the presence of NEt as a base. The synthetic protocols for
3
bisphosphite–polyether ligands 1–5,a–d, together with the
preparation methods for the required starting materials, metal
BArF salts, and compounds 6–I, 6–II, and 6–III, are detailed in
the Supporting Information.
(
see the fragments in orange and blue, respectively, in
Scheme 1) with stereogenic phosphite groups for catalysis (see
the fragments in green in Scheme 1).
Studies on binding of the ligands 1–5,a–d to the RAs
The resulting ligands exhibit several characteristics:
The design principle of the regulation mechanism proposed
herein is the binding of suitable RAs to the regulation site (a
polyether group). Metal cations bind to polyether groups
through ion–dipole interactions, as do ammonium salts
1
) The proposed regulation sites encompass polyether groups
of varying size, oxygen atom number, and spacer length
(
see the O(CH CH O) X(OCH CH ) O cores in Scheme 1), to
2 2 n 2 2 n
[
11]
offer a wide range of binding capacities to RAs of different
through hydrogen bonding.
It is generally accepted that
[
11,12]
size and types.
when the ionic radius of the positively charged species match-
es the length and shape of the polyether chain, the binding
2
3
) The binding groups comprised a structurally diverse array
of conformationally stable [1,1’-biaryl]-2,2’-diol-derived
phosphites (see structures a–d in Scheme 1).
[
11]
will be strong.
To begin studying supramolecular ligands with a distal regu-
lation site, we examined the binding of various RAs (alkali
metal and ammonium salts; Tables 1 and 2) to bisphosphites
3a, 3b, 4a, and 4b (see Figure 1). These compounds were
chosen as a structurally representative set of the ligands 1–
5,a–d on the basis of two considerations. Firstly, bisphosphites
3a and 3b have a large binding site, whereas 4a and 4b have
a small one, and secondly, bisphosphites 3b and 4b have
a substituent at the 3 and 3’ positions in the binaphthyl moiet-
ies, whereas 3a and 4a do not. NaBArF and CsBArF were
chosen as representative examples of salts with cationic spe-
) With regard to the RA, we considered that any polyether
binder might prove utile. However, from the myriad possi-
[
11]
bilities available, we focused on alkali metal and ammoni-
um salts (see Scheme 1). With the aim of facilitating higher
binding strength between the proposed RAs and the poly-
ether moiety, we considered salts with an adequate solubil-
ity profile in organic solvents and with a weakly coordinat-
À
ing anion. Thus, the [B(3,5-(CF ) C H ) ] anion (hereafter,
3
2
6
3 4
BArF) was deemed an attractive option, although other
anions also were assessed.
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binding constants were found for the ligands without substitu-
[
a]
Table 1. Binding constant data for complexation between ligands 3a,
b, 4a, or 4b and NaBArF or CsBArF.
ents in the 3 and 3’ positions of the bisphosphite groups (li-
3
6
À1
gands 3a and 4a; K>10 m ; entries 1 and 3 in Table 1) com-
pared with those of the 3,3’-disubstituted ones (ligands 3b
À1
Entry
Ligand
K value [m
]
NaBArF
CsBArF
4
À1
and 4b; K value ca. 10 m ; entries 2 and 4 in Table 1). NaBArF
showed its greatest binding affinity with the 3,3’-unsubstituted
ligand with the shorter polyether chain (ligand 4a, entry 3,
third column in Table 1), whereas CsBArF achieved its greatest
binding affinity with the analogous ligand with the longer
polyether chain (ligand 3a, entry 1, fourth column in Table 1).
The stoichiometry of the resulting complexes was deter-
[
b]
6
5
8
7
1
2
3
4
3a
4.5”10 (Æ3”10 )
1.5”10 (Æ1”10 )
3.0”10 (Æ4”10 )
5.6”10 (Æ4”10 )
1.2”10 (Æ7”10 )
5.2”10 (Æ3”10 )
8.7”10 (Æ2”10 )
1.4”10 (Æ6”10 )
[
c]
4
3
3
2 [d]
3b
4a
4b
[
b]
7
6
6
6
[
c]
3
2
4
2
[
a] Average value at 298 K of at least two independent measurements.
The mean absolute error (MAE=1/n S IK
ÀKI) is in parentheses. [b] Mea-
sured by UV/Vis spectrophotometry (CH Cl /THF, 99.8:0.2 v/v). [c] Mea-
sured by NMR spectroscopy ([D ]toluene/[D ]THF, 95:5 v/v). [d] This K
value was already reported but has been included here for compari-
son.
i
i
2
2
[
17]
8
8
mined by the method of continuous variations (for details,
see the Supporting Information). All the studied ligands were
capable of adapting to a 1:1 stoichiometry, independently of
the size of the host cavity or the cation. This adaptability
might be attributed to the high flexibility of the ligands 3a,
3b, 4a, and 4b.
[
10]
[
a]
Table 2. Binding constant data for complexation between ligands 3a,
[
b]
4
a, or 4b and ammonium salts 6–II or 6–III.
The binding constants of the enantiomerically pure ammoni-
um salts 6–II and 6–III to the bisphosphite ligands 3a, 4a, or
4b were determined at 298 K by using isothermal titration cal-
[
b]
[b]
Entry
Ligand
K values with 6–II
K values with 6–III
[
c]
[c]
[c]
[c]
DH
TDS
DH
TDS
[
18]
4
2
4
2
orimetry (ITC). The binding constants, together with DH and
DS (also determined by ITC), are summarized in Table 2. In all
1
2
3
3a
4a
4b
1.2”10 (Æ2”10 )
1.7”10 (Æ8”10 )
À7.9
À2.4
À7.0
À1.4
3
3
4
2
4
À1
9.4”10 (Æ1”10 )
1.3”10 (Æ8”10 )
cases, the binding constants were approximately 10 m . Anal-
ysis of the ITC data also revealed a 1:1 ratio between each
ligand (3a, 4a, or 4b) and each ammonium salt (6–II or 6–III).
Furthermore, all the complexation processes were exothermal
À7.3
À2.0
À7.2
À1.7
3
2
3
2
7.3”10 (Æ2”10 )
8.6”10 (Æ6”10 )
À7.8
À2.7
À8.2
À2.9
À1
[
[
a] Measured in CH
c] kcalmol
2
Cl at 298 K. [b] (in m ); see note [a] in Table 1.
2
(
DH<0) but entropically unfavorable (DS<0), as would be ex-
pected when a conformationally transformable host (ligand
a, 4a or 4b) loses conformational freedom upon complexa-
À1
.
3
tion.
Complexation studies of ligands 1–5,a–d towards pre-cata-
lysts for hydroformylations and hydrogenations
To elucidate the structure of catalytically relevant species, com-
plexation experiments (in the presence and absence of an RA)
were performed between representative bisphosphites and
2
standard catalyst precursors ([Rh(k O,O’-acac)(CO) ] (acac=ace-
2
tylacetonate) for hydroformylation and [Rh(cod) ][BArF] (cod=
2
1
,5-cyclooctadiene) for hydrogenation).
2
[
Rh(k O,O’–acac)(CO) ] and 4b were reacted at 408C in a typi-
2
cal solvent mixture for hydroformylations under 10 bar of 1:1
Figure 1. General structures for the complexes between a regulation agent
RA) and a bisphosphite (3a, 3b, 4a, or 4b).
(
CO/H . Interestingly, the addition of equimolar amounts of
2
2
[
Rh(k O,O’–acac)(CO) ] to a solution of 4b, followed by reac-
2
tion for 2 h, did not lead to the expected hydrido-dicarbonyl
+
2
cies that have a small and large ionic radius, respectively (Na
chelate [Rh(H)(CO) (k P,P’–4b)], but rather to the complex
2
+
[14]
2
1
[
0.98 Š] and Cs [1.67 Š]).
The binding of the bisphosphites 3a, 3b, 4a, or 4b to
[Rh(k O,O’–acac)(CO)(k P–4b)] (see Scheme 2), which was
formed upon displacement of a CO ligand by a phosphite
2
1
NaBArF or CsBArF was studied by using several spectroscopic
techniques. Addition of increasing amounts of the RA to a solu-
tion of the bisphosphite (dichloromethane or toluene, plus
a minimal amount of THF to ensure solubility of the RA
group. The complex [Rh(k O,O’–acac)(CO)(k P–4b)] evolved to
2
the expected chelate [Rh(H)(CO) (k P,P’–4b)] with time (16 h
total), even in the absence of a polyether chain binder.
2
Binding between RbBArF and the ligand 4b is strong ((1”
1
4
3
À1
throughout the titration) led to changes in the UV, H, or
10 Æ2”10 )m ; measured by NMR spectroscopy at 298 K in
3
1
[15]
P NMR spectra.
Association constants between the bisphosphites and RAs
were determined by multivariate factor analysis of titration
[D ]toluene/[D ]THF (99.8:0.2, v/v); data not shown in Table 1).
8
8
This high affinity translates into the efficient formation under
hydroformylation reaction conditions of the chelate
[16]
2
data, considering a 1:1 binding model (see Table 1). Higher
([Rh(H)(CO) (k P,P’–RbBArF·4b)]) after only 2 h (instead of the
2
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gands 1a and 2a) or a shorter one (ligand 4a) in AHF of vinyl
acetate 7a, a commonly used benchmark substrate in this
chemistry. The reaction conditions and results are summarized
in Scheme 3 and Table 3, respectively.
2
Scheme 2. Complexation of [Rh(k O,O’–acac)(CO)
2
] and 4b in the presence
Scheme 3. Asymmetric hydroformylation of vinyl acetate mediated by regu-
lable bisphosphite ligands.
or absence of RbBArF.
1
6 h required for the reaction without RA; see Scheme 2). This
behavior clearly demonstrates that binding of the RA to 4b
serves to bring the two terminal phosphorus groups closer to-
Table 3. AHF of vinyl acetate 7a using rhodium complexes of the bi-
sphosphite ligands 1a–4a
[a]
gether, thereby favoring the formation of chelate species.
[b]
[b]
Entry
Ligand
RA
Conv.
[%]
b/l ratio
ee [%],
2
[b]
[c]
Formation of the rhodium chelates [Rh(H)(CO) (k P,P’–4b)]
(config.)
2
2
and [Rh(H)(CO) (k P,P’–RbBArF·4b)] was proven by using stan-
2
1
2
3
4
5
6
7
1a
2a
3a
3a
3a
3a
4a
NaBArF
NaBArF
none
38
48
99
84
99
99
66
96:4
98:2
90:10
99:1
90:10
91:9
26, (S)
20, (S)
17, (S)
26, (S)
17, (S)
17, (S)
10, (S)
[15]
dard spectroscopic techniques. NMR spectroscopic analysis
indicated that the hydrido ligand has a preference for a cis ori-
entation relative to the P-ligating groups, which are coordinat-
ed in an equatorial–equatorial fashion to a trigonal-bipyramidal
NaBArF
NaBF
NaClO
NaBArF
4
4
[
19]
rhodium center. Other rhodium complexes with this type of
spatial orientation between the bisphosphite ligand and the
hydride have been reported as active hydroformylation cata-
97:3
[
a] The AHF were performed in a parallel autoclave. The reaction condi-
tions are the same as those shown in Scheme 3 (S/C ratio=200:1; [7a]=
0.26m; T=708C; t=5 h). [b] Conversion, and b/l ratio, were determined
by GC analysis (b-Dex 225). ee Values were determined by GC analysis on
a chiral stationary phase (b-Dex 225, for details, see the Supporting Infor-
mation). [c] The configuration of the branched product was assigned by
comparison with previously reported elution-order data (for details, see
the Supporting Information).
[
19b]
lysts.
Complexation studies similar to those described above were
performed for asymmetric hydrogenation, by using [Rh(cod)2]
[
BArF], the ligand 3a and the regulating agent NaBArF. Forma-
2
tion of the chelate [Rh(cod)(k P,P’–3a)][BArF] was unequivocal-
ly proven by using standard spectroscopic techniques after
treating stoichiometric amounts of 3a with the rhodium pre-
[
15]
cursor. When an analogous complexation experiment was
The results in Table 3 reveal that the ligands with a longer
polyether chain (1a and 2a) than those of ligands 3a or 4a
led to the lowest conversions (compare entries 1 and 2 with 4
or 7 in Table 3). Although correlating the enantioselectivity to
the RA is not trivial, there was an observable trend linking the
regioselectivity to the counterion used: with ligand 3a, the
BArF anion provided higher regioselectivities (b/l ratio=99:1)
than those of the BF or ClO analogues (b/l ratio for each=
performed by using a preformed complex of NaBArF and 3a
(
ratio [Rh]/3a/NaBArF=1:1:1.3), an analogous chelate was ob-
2
tained [Rh(cod)(k P,P’–NaBArF·3a)][BArF], according to the
spectral data obtained.
[15]
Thus, we concluded that suitable
rhodium chelates for asymmetric hydrogenation had been effi-
ciently and selectively formed.
4
4
ca., 90:10; compare entry 4 with entry 6 in Table 3). Thus, only
BArF salts were considered in subsequent optimization studies.
We then endeavored to optimize the enantioselectivity of
the AHF of vinyl acetate by tuning the reaction parameters
and the catalyst structure. Firstly, the reactions were run at
lower temperature (408C instead of 708C), on the basis of the
established premise that lowering the temperature in AHF
Asymmetric hydroformylation of alkenes catalyzed by rhodi-
um complexes of bisphosphite ligands 1–5,a–d
With the supramolecular ligands and binding parameters of
representative bisphosphite ligands (3a, 3b, 4a and 4b) in
hand, we then turned our attention to applications in asym-
metric catalysis. The ligands were tested in asymmetric hydro-
formylation (AHF), in which olefins are converted into enantio-
[
20]
offers higher enantioselectivity.
Secondly, a representative
[20]
merically enriched aldehydes in a single step. The only bis-
phosphite ligands that we had explored in the previously pub-
lished studies were 3a and 3b, whose polyether chains con-
set of alkali metal salts (NaBArF or CsBArF) was assessed as
RAs. Lastly, a diverse set of additional bisphosphite ligands was
explored: these combined the shortest polyether chains (either
3 or 4 in Scheme 1) with a phosphite moiety, either 3,3’-unsub-
stituted (fragment a) or 3,3’-disubstituted (groups b–d). This
set also included the bisphosphite ligand 5b, which is the
[10]
tain eight oxygen atoms. With the aim of developing more
efficient supramolecularly regulated ligands, we sought to
assess bisphosphites containing a longer polyether chain (li-
Chem. Eur. J. 2015, 21, 11417 – 11426
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same size as 3b, but lacks the four central oxygen atoms in
the polyether chain. We reasoned that, in terms of the regula-
tion mechanism presented in this paper, use of the new ligand
between the polyether chain of the ligand and the RA is cru-
cial for improving the stereodifferentiating ability of the cata-
lyst.
[
21]
5
b would entail much weaker supramolecular interactions
Further optimization studies were performed with the high-
est-performing ligand 4b (entry 6, Table 4). Of all the RA/ligand
combinations tested for AHF of vinyl acetate, RbBArF·4b gave
the best results: Full conversion, complete regioselectivity, and
99% ee towards the branched product (see entry 4, in Table 5).
and therefore, that AHF reactions with 5b should be consid-
ered to be a background experiment for the aforementioned
regulation mechanism. The reactions conditions and results are
summarized in Table 4.
Table 4. Catalytic studies on the hydroformylation of 7a using Rh com-
plexes of ligands 3a–d, 4a,b, or 5b and a set of RAs.
Table 5. Catalytic studies on the hydroformylation of 7a using Rh com-
plexes of the ligand 4b and a set of RAs.
[
a]
[a]
[
b]
[b]
[b]
[c]
Conv.
Entry
RA
Conv. [%], b/l ratio, ee [%] (config.)
[
b]
[b]
[
%], b/l ratio, ee
[
b]
[c]
1
2
3
4
5
6
7
none
18, 90:10, 35 (S)
[
%] (config.)
NaBArF
KBArF
RbBArF
CsBArF
6–II
87, >99:1, 74 (S)
>99, >99:1, 98 (S)
>99, >99/1, 99 (S)
>99, >99:1, 96 (S)
50, >99:1, 40 (S)
46, >99:1, 40 (S)
Entry
1
Ligand
RA=none
RA=NaBArF
RA=CsBArF
3a
69, 94:6,
12, >99:1,
21 (S)
46, 90:10,
29 (S)
[
d]
1
7 (S)
2
3
4
5
6
7
3b
3c
3d
4a
4b
5b
76, 99:1,
57, >99:1,
95, >99:1,
[
d]
[d]
[d]
2
8 (S)
55, 98:2,
5 (S)
22, >99:1,
6 (S)
33, 93:7,
5 (S)
18, 90:10,
5 (S)
44, 94:6,
2 (S)
23 (S)
90 (S)
6–III
79, >99:1,
86 (S)
13, >99:1,
19 (S)
61, 97:3,
12 (S)
87,> 99:1,
74 (S)
>99, >99:1,
80 (S)
>99, >99:1
86 (S)
9, >99:1,
54 (S)
>99, >99:1,
96 (S)
[
a]–[c] See notes [a], [b], and [c] in Table 3 and Table 4.
6
1
1
For all the assays summarized in Table 5, a substrate-to-catalyst
(S/C) ratio of 100:1 was used. However, the amount of rhodium
3
[22]
catalyst of RbBArF·4b was reduced to 0.1 mol%
000:1), with almost no consequent decrease in catalytic activi-
(S/C=
12,> 99:1,
22 (S)
74, >99:1,
21 (S)
1
2
ty (99% conv., b/l ratio: >99:1 and 97% ee for (S)-8a; data not
shown in Table 5). Interestingly, these results obtained with
RbBArF·4b rival those achieved with the highest performing
[
a] For the reaction conditions see note [a] in Table 3, with these excep-
tions: T=408C, t=5 h. [b, c] See notes [b] and [c] in Table 3. [d] These re-
sults have already been published but are included here for compari-
son.
[
10]
[
23]
Rh-mediated AHF catalyst reported for vinyl acetate. Further-
more, RbBArF·4b proved to be a much more efficient ligand in
terms of activity, regioselectivity, and enantioselectivity relative
to known ligands containing the same phosphite group but
When no RA was used (see the third column from the left in
Table 4), the AHF products were obtained in conversions from
[
24]
lacking a regulation site.
1
1
8 to 76%; b/l ratios from 90:10 to> 99:1; and ee values from
5 to 65% in favor of the product (S)-8a. The use of NaBArF or
Interestingly, the use of KBArF or CsBArF rather than RbBArF
also provided very high enantioselectivities (98 and 96% ee, re-
spectively; see entries 3 and 5 in Table 5). In contrast, when
the enantiomerically pure derivatives 6–II and 6–III were used
as RAs, the activity of the catalysts derived from 4b was worse
(entries 6 and 7 in Table 5).
CsBArF as RAs for ligands 1–5,a–d enabled better conversions
in most cases and, with few exceptions, higher b/l ratios and
greater enantiopurity of the product (see Table 4). Greater reg-
ulation effects in the ee values were achieved with the ligands
that contained a 3,3’-substituted-1,1’-[biaryl] moiety (the li-
gands 3b–d, and 4b; increase in the ee value of up to 61%;
Conversion curves for hydroformylation of 7a (vinyl acetate),
as catalyzed by rhodium complexes of RbBArF·4b, were re-
[
15]
9
6% ee; see entry 6 in Table 4) relative to those achieved with
corded from the gas-uptake profiles (see Figure 2), and then
used to calculate TOF values at approximately 50% conversion
(TOF ). Interestingly, the AHF of 7a without catalyst incuba-
the unsubstituted analogues (the ligands 3a and 4a; ee in-
crease of up to 39%; 54% ee; see entry 5 in Table 4). The opti-
mal phosphite group was structure b, as evidenced by the fact
that the ligand 3b (entry 2, Table 4) gave a higher ee value
than that of its analogues with the same polyether core and
different phosphite groups (ligands 3c and 3d; entries 3 and
1/2
tion, and without using a RA, under 10 bar of syngas (CO/H2
1:1) at 408C, took about 6 h to start (see the black curve in
Figure 2). This observation corroborates the complexation re-
sults discussed in the previous section (i.e., the hydroformyla-
tion-active hydrido-dicarbonyl complexes of 4b are not
formed immediately). However, when the same reaction was
4
, Table 4).
As previously mentioned, we reasoned that our proposed
2
regulation mechanism through supramolecular interactions at
performed under incubation conditions (by stirring [Rh(k O,O’–
[21]
the polyether chain would not be observed with 5b. Indeed,
the enantioselectivity of the reactions with 5b was the same
regardless of whether or not RAs were present (entry 7,
Table 4). This finding corroborates the premise that interaction
acac)(CO) ] and 4b for 16 h under syngas at 408C), the hydro-
2
formylation began as soon as the vinyl acetate was added to
[
25]
the reaction mixture (see the blue curve in Figure 2). Inter-
estingly, when the rhodium complexes of RbBArF·4b were
Chem. Eur. J. 2015, 21, 11417 – 11426
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[a]
Table 6. Studies on AHF of 7a–e using rhodium complexes of the
ligand 4b with or without RA (RbBArF).
[b]
[b]
[b]
[c]
Conv. [%], b/l ratio, ee [%] (config.)
Entry
Alkene
RA=none
RA=RbBArF
[
d]
1
2
3
4
5
7a
7b
7c
7d
7e
18, 90:10, 35 (S)
93, 96:4, 36 (S)
97, 98:2, 14 (S)
>99, 95:5, 12 (S)
>99, >99:1, 99 (S)
>99, >99:1, 99 (S)
99, >99:1, 96 (S)
57, 80:20, 5 (S)
[e]
[e]
[e]
[e]
>99, 59:41, 7 (S)
>99, 18:82, 25 (S)
[a, b, c] See notes [a], [b], and [c] in Table 3 and Table 4. [d] Although
these results appear in Table 4, they have been included for comparison.
1
[
e] Conv. and b/l product ratio were determined by using H NMR spec-
troscopy.
Figure 2. Conversion plotted against reaction time for the AHF of 7a medi-
ated by RbBArF·4b (S/C=1000:1).
see entry 4 in Table 6). In contrast, with RbBArF·4b the enan-
tioselectivity for the allylic alcohol 7e was 18% higher than
that without the RA (25% ee compared with 7% ee; see
entry 5 in Table 6), although the use of RbBArF did imply
worse regioselectivity (entry 5 in Table 6).
used, consumption of syngas was detected from the beginning
of the experiment: a clear indication that the catalytically
active complexes had quickly formed. In addition to an in-
crease in the ee value (entry 4 in Table 5), the RA provokes a re-
duction in the catalyst-activation time (compare the red and
black curves in Figure 2), brought about by the binding of the
RA (i.e., RbBArF helping to fold ligand 4b into the conforma-
tion required for bidentate coordination to the rhodium
center). Furthermore, the RA enhances turnover frequency:
Computational studies on the geometry of the complexes
[
Rh(H)(CO) (RA·4b)]
2
To gain insight into the structural and geometric contributions
I
of each component in the hydrido-dicarbonyl Rh complexes of
the highest-performing ligand 4b, either with or without RA,
À1
À1
[27]
TOF1/2 =177 h or 40 h in the presence or absence of
RbBArF, respectively.
computational studies at the DFT level of theory were per-
formed. Because these complexes have proven to be the cata-
[
28]
We then studied the catalytic activity of the highest per-
forming catalyst (rhodium complexes of RbBArF·4b) in the
AHF of diverse alkenes, comprising vinyl esters 7a–c, styrene
lyst resting-states in hydroformylations,
we reasoned that
studying their geometries would provide insight into the regu-
lation mechanism. We focused on three geometrical parame-
ters that could have a priori the greatest potential impact on
catalytic performance: PÀRhÀP bond angle (b), dihedral angle
(q) in the binaphthyl groups, and phosphorus–rhodium dis-
7
d and the allylic alcohol 7e (see Scheme 4 and Table 6).
When the AHF of the vinyl esters was catalyzed by a rhodium
complex of ligand 4b without RA, the enantioselectivity was
poor; however, when the RA/ligand combination RbBArF·4b
was used, the enantioselectivity, conversion, and regioselectivi-
ty of the process were much higher. For example, with
RbBArF·4b the enantioselectivity for 8c was 82% higher than
that achieved in the reaction in which no RA was used
tance (d ) (see Figure 3). The calculated values for these pa-
PÀRh
rameters are listed in Table 7.
For the PÀRhÀP bond angle (b) of the rhodium complexes
of 4b, the general trend observed is that the size of the ionic
radius in the RA cation (no RA to 2.7 Š) directly correlates to
the width of the bond angle (from 113 to 1218).
(
96% ee compared with 14% ee without the RA; see entry 3 in
Table 6). Furthermore, to the best of our knowledge, the ee
values achieved for 8b (99% ee) and 8c (96% ee) are the best
values ever reported. Unfortunately, the use of the RA led to
As for the PÀRh distance (d ) in these complexes, the
PÀRh
values calculated for the complex without RA was the same as
[26]
that for the complexes with the two largest cations in the RAs
+
+
+
+
lower regioselectivity and enantioselectivity for styrene (7d;
(Rb or Cs ); however, the values for the Na and K com-
plexes (smaller ionic radii) were smaller (smallest Dd
=
PÀRh
+
À0.02 Š for Na ). Lastly, the calculated values for the bi-
naphthyl dihedral angle (q) of the rhodium complexes of 4b
indicate that the RA forces the binaphthyl units to adopt a con-
formation with a lower dihedral angle (À57.98 for the complex
without RA vs. À58.48 (average value) for the complexes con-
taining an alkali metal cation).
+
Another significant difference between the Na complex
and the rest of complexes with the other cations is the interac-
tion of the alkali ion with the oxygen atoms of the regulation
+
site (RS). The size of Na is ideal to fit inside the cavity of the
Scheme 4. Asymmetric hydroformylation of the alkenes 7a–e.
RS and consequently the effect on the PÀRhÀP bond angle (b)
Chem. Eur. J. 2015, 21, 11417 – 11426
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Figure 4. Experimental ee values versus calculated PÀRhÀP bond angle
Figure 3. Selected geometrical parameters of the rhodium-derived supra-
molecular complexes. H-atoms have been omitted for clarity.
values.
tion to developing supramolecularly regulated catalysts for
asymmetric hydrogenation (AH). The rhodium complexes de-
rived from ligands 3a and 4a were evaluated as representative
pre-catalysts in the AH of six structurally diverse substrates
(10a–f; Scheme 5). Alkali metal (NaBArF, KBArF, RbBArF, or
CsBArF) or ammonium (6–I, 6–II, or 6–III) salts were used as
RAs. Ligands 3a and 4a were used throughout the entire
study because they provided higher enantioselectivities than
those obtained with the 3,3’-disubstituted [1,1’-biaryl]-2,2’-diol
2
Table 7. Calculated geometrical parameter values for [Rh(H)(CO) (alkali
+
2
metal·4b)] and [Rh(H)(CO) (4b)].
Entry
Cation and
ionic radius [Š]
PÀRhÀP angle
Dihedral
angle (q)
d
[Š]
PÀRh
[
a]
[b]
[c]
[d]
(b)
1
2
3
4
5
–
Na
K
Rb
–
113.2
115.8
122.1
121.5
121.5
À57.9
À58.7
À58.3
À58.5
À58.3
2.268
2.252
2.261
2.269
2.272
+
1.9
2.3
2.5
2.7
+
+
+
Cs
[
29]
analogues 3b and 4b. The results on AH are partially sum-
marized in Table 8, which shows all the results for the catalysts
that lack a RA, as well as the highest positive regulation effects
[
a] Extracted from ref. [14]. [b] b: the angle formed between the Rh and
the two P atoms. [c] q: the mean value of the two OCAr-CAr-CAr-CAr
O
angles in the two binaphthyl groups. [d] dPÀRh: the mean value of the two
PÀRh distances.
(
for the full set of results, see Table SI-1 in the Supporting Infor-
mation).
In almost all the reactions, conversion was complete and
enantioselectivity was very high (73 to 99% ee), with the
values being equal to or only slightly lower than the best
values reported in the literature for the highest performing li-
is very small (see Table 7). In larger cations, the final optimized
geometry of the complex is a compromise between increasing
the PÀRhÀP bond angle (and the dPÀRh distance) to enlarge the
size of the cavity and moving the cation outside the cavity
[
30]
gands in AHs. When no RA was used, the ee values ranged
[
31]
from 73 to 98% (see Table 8). Interestingly, ligands 3a and
4a gave very similar results, although slightly higher ee values
and positive regulation effects associated with the use of an
RA were obtained for ligand 3a, as detailed in the discussion
that follows.
(
see Figure 3), thus provoking larger geometrical changes.
Most interestingly, a plot of the enantiomeric excesses ob-
tained in the AHF of vinyl acetate against the PÀRhÀP bond
angle (b) revealed a maximum in the ee value around the
b value induced by the rubidium derivative (see Figure 4). On
the basis of these findings, we postulated that the significant
increase in enantiomeric excess provided by the RAs
for vinyl esters 7a–c might be result from adaptation
of the PÀRhÀP bond angle of the catalyst from
a non-ideal value to a value very close to that re-
quired for high enantioselectivity.
In the hydrogenations using ligand 3a and an RA the enan-
tioselectivities varied, but the conversions were all complete.
Asymmetric hydrogenation of alkenes catalyzed by
Rh-complexes of supramolecularly regulated bis-
phosphites
Encouraged by the performance of ligands with
a distal regulation site in AHF, we shifted our atten- Scheme 5. Asymmetric hydrogenation of alkenes 10a–f mediated by ligands 3a or 4a.
Chem. Eur. J. 2015, 21, 11417 – 11426
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high levels of enantioselectivity achieved for substrates 10a
and 10c with ligand 4a alone, by using a RA, were unsuccess-
Table 8. Catalytic studies on the AH of alkenes 10a–f mediated by bis-
phosphite ligands 3a or 4a, with or without RA.
[
a]
ful.
[
b]
[c]
[d]
Conv. [%], ee [%] (config.)
Appropriate combinations of [Rh(cod) ][BArF] and bisphos-
2
Entry
Ligand
Substrate
RA=none
Highest performing RA
phite ligands 3a or 4a, plus a regulation agent (NaBArF,
CsBArF, or 6–III), can provide an adaptive catalytic system spe-
cific to the substrate geometry: enantioselectivity in these hy-
drogenations can be maximized by the choice of whether or
not to use an RA (and if so, which one to use). These results
confirm the validity of our regulation design: easy generation
of an efficient catalytic system by combining a ligand and
a suitable RA.
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
4a
4a
4a
4a
4a
4a
10a
10b
10c
10d
10e
10 f
10a
10b
10c
10d
10e
10 f
99, 98, (R)
99, 94, (S)
99, 92, (S)
99, 95, (S)
99, 93, (S)
59, 94, (S)
99, 97, (R)
99, 94, (S)
99, 92, (S)
99, 90, (S)
99, 73, (R)
48, 93, (S)
99, 99, (R); with CsBArF
[e]
99, 97, (S); with CsBArF
[
f]
–
–
[
f]
99, 94, (S); with NaBArF
[
f]
–
–
[
f]
99, 96, (S); with 6–III
[
f]
–
1
0
99, 93, (S); with 6–III
99, 78, (R); with CsBArF
50, 95, (S); with 6–III
1
1
1
2
Conclusion
[
a] The reaction conditions used are those in Scheme 5, unless otherwise
We have reported an efficient synthesis of the new a,w-bis-
phosphite ligands 1–5,a–d, which incorporate a polyether
motif as regulation site. Rhodium complexes of these ligands,
either alone or in combination with various regulation agents
(RAs), have been assayed in asymmetric hydroformylation
stated. The values shown are the average values of at least two inde-
pendent runs. [b] Conversion, as determined by using H NMR spectros-
copy. [c] Enantioselectivity, as determined by GC or HPLC using chiral sta-
tionary phases. [d] Absolute configuration was assigned by comparison of
the specific rotation or the elution order in GC or HPLC (for details, see
the Supporting Information). [e] 2.0 equiv of RA relative to 3a was used.
1
(
AHF) and asymmetric hydrogenation (AH) of diverse sub-
9
5% ee was observed when 1.3 equiv of CsBArF were used. [f] None of
strates. Strong binding affinities between the ligands and the
alkali-metal BArF salts have been demonstrated by using NMR
spectroscopy and UV/Vis studies. The binding ability of the
studied bisphosphites towards enantiomerically pure ammoni-
um salts was also proven. Complexation studies between
the RAs provided any improvement in the ee values relative to the reac-
tions of the ligand alone.
2
When the standard amount of polyether binder (1.3 equiv of
CsBArF relative to the ligand) was used for the AH of substrate
these ligands, rhodium precursors (either [Rh(k O,O’–
acac)(CO) ] or [Rh(cod) ][BArF]), and alkali metal salts (RbBArF
2
2
1
0b, the ee value was slightly (1%) higher than that observed
and NaBArF) have demonstrated that 1:1:1 [Rh]/L/RA chelates
are formed, which are suitable enantiomerically pure pre-cata-
lysts for AHF and AH.
in the reaction in which no RA was used (95% ee, see footnote
e in Table 8). With a higher amount of CsBArF (2 equiv of RA
relative to the ligand), the ee value was 3% higher than that
observed when no RA was used (97% ee, entry 2, Table 8).
CsBArF had the same effect on the hydrogenation of itaconic
acid derivative 10a, as did NaBArF on the hydrogenation of 1-
The presence of substituents at the 3,3’ positions of the
[1,1’-biaryl]-2,2’-diol-derived phosphite moieties was beneficial
to catalytic activity in asymmetric hydroformylation. Further-
more, small amounts of polyether-binder RAs were shown to
regulate the activity of the AHF catalysts by biasing the distri-
bution of enantiomers, as evidenced by the fact the rhodium
complexes of a ligand and RA enabled up to 82% higher enan-
tioselectivity compared with those obtained in the reactions of
the corresponding complexes without RA. For example, rhodi-
um complexes of the bisphosphite ligand 4b that contained
a rubidium salt as the regulation agent gave much higher
enantioselectivity in the AHF of diversely substituted sub-
strates than those obtained in the AHF of the complexes with-
out RA. Computational studies suggest that the increase in
enantioselectivity provided by the RAs arise from adaptation of
the PÀRhÀP bond angle (b) to the particular requirements of
the substrate.
(
naphthyl)vinyl acetamide 10e (up to 1% higher ee than that
observed when no RA was used; Table 8, 99% ee in entry 1
and 94% ee in entry 5, respectively). However, attempts to en-
hance the positive regulation effect observed in the reaction
of the substrates 10a and 10e, by increasing the amount of
RA (up to 2.0 equiv relative to the ligand 3a), were not suc-
cessful.
For the substrates 10c, 10d, and 10 f, the rhodium complex
of 3a (without RA) afforded the corresponding products 11 c,
11 d, and 11 f with the highest enantioselectivity (from 92 to
9
5%; see entries 3, 4, and 6, respectively; Table 8); none of the
analogous complexes containing an RA provided any increase
in enantioselectivity.
In the AHs using ligand 4a, the rhodium complex of 4a
without RA) gave the product 11 b in 94% ee, whereas the
corresponding ligand containing the 6–III as RA gave a slightly
higher value (96% ee; see entry 8; Table 8). For the substrates
For asymmetric hydrogenation, the presence of substituents
at the 3,3’ positions of a [1,1’-biaryl]-2,2’-diol-derived phos-
phites was detrimental to catalytic activity. Moreover, for sub-
strates 10a–f, the best enantioselectivities were found when
the rhodium complexes of ligands 3a or 4a contained an RA
(either NaBArF, CsBArF, or 6–III). The regulation effects in the
AH were minor: the rhodium complexes of 3a or 4a without
RA gave very high enantioselectivities that could not be fur-
ther enhanced through use of an RA. We are currently design-
(
1
0d–f, the use of ligand 4a and CsBArF or 6–III as RAs gave
higher ee values than those obtained in the corresponding re-
action in the absence of an RA (see entries 10–12; Table 8): for
example, for substrate 10e, the ee increased up to 5%
(
78% ee). Unfortunately, attempts at enhancing the already
11424
Chem. Eur. J. 2015, 21, 11417 – 11426
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ing new supramolecularly regulated catalysts for other pivotal
enantioselective transformations.
Keywords: asymmetric catalysis
hydroformylation · hydrogenation · rhodium · supramolecular
·
enantioselectivity
·
chemistry
Experimental Section
[
[
[
1] For general references on this topic, see, for example: a) Comprehensive
Asymmetric Catalysis, Vols. I–III, 1st ed. (Eds.: E. N. Jacobsen, A. Pfaltz, H.
Yamamoto), Springer, Heidelberg, 1999; b) Comprehensive Chirality,
Vols. 1–9 (Eds.: E. M. Carreira, H. Yamamoto), Elsevier Science, Oxford,
2012.
2] See, for example: a) B. M. Trost, D. L. Van Vranken, C. Bingel, J. Am.
Chem. Soc. 1992, 114, 9327–9343; b) T. V. Rajanbabu, A. L. Casalnuovo,
T. A. Ayers, Adv. Catal. Processes 1997, 2, 1–41c) D. Popa, C. Puigjaner,
M. Gómez, J. Benet-Buchholz, A. Vidal-Ferran, M. A. Pericàs, Adv. Synth.
Catal. 2007, 349, 2265–2278.
General procedure for the Rh-mediated asymmetric hydro-
formylation
2
In a glovebox filled with nitrogen, [Rh(k O,O’–acac)(CO) ] (ca.
2
2
.3 mmol in 65 mL of toluene) was added to a stirred solution of
ligand 1–5 (ca. 2.7 mmol in 360 mL of toluene) and the BArF salt
ca. 3.6 mmol in 27 mL of THF) in a 2 mL vial. The substrate (ca.
30 mmol), dodecane (ca. 69 mmol), and additional toluene were
(
2
charged to provide the desired final solution of toluene/THF (97:3
v/v). The vial was then taken out of the glovebox and transferred
into an autoclave. The autoclave was purged three times with
3] a) H. Fernµndez-PØrez, M. A. Pericàs, A. Vidal-Ferran, Adv. Synth. Catal.
2008, 350, 1984–1990; b) H. Fernµndez-PØrez, S. M. A. Donald, I. J. Mun-
slow, J. Benet-Buchholz, F. Maseras, A. Vidal-Ferran, Chem. Eur. J. 2010,
16, 6495–6508.
syngas (1:1 H /CO at a pressure not higher than 10 bar) and finally,
2
the autoclave was pressurized with syngas to the desired pressure.
The reaction mixture was stirred at 408C for the required reaction
time. The reaction was cooled and the pressure was carefully re-
leased in a well-ventilated hood. Conversion and branched-to-
linear product ratio for the hydroformylation products of 7a–d
were determined by using GC analysis. Conversion and branch-to-
linear ratio for the hydroformylation products of 7e were deter-
[4] See, for example: D. Leung, S. O. Kang, E. V. Anslyn, Chem. Soc. Rev.
012, 41, 448–479.
2
[
5] For a summary on the use of supramolecular interactions in the con-
struction of (enantioselective) catalysts, see: a) M. Raynal, P. Ballester, A.
Vidal-Ferran, P. W. N. M. van Leeuwen, Chem. Soc. Rev. 2014, 43, 1660–
1733; b) M. Raynal, P. Ballester, A. Vidal-Ferran, P. W. N. M. van Leeuwen,
Chem. Soc. Rev. 2014, 43, 1734–1787.
[
6] See, for example: a) A. M. Costa, C. Jimeno, J. Gavenonis, P. J. Carroll,
P. J. Walsh, J. Am. Chem. Soc. 2002, 124, 6929–6941; b) R. Eelkema, B. L.
Feringa, J. Am. Chem. Soc. 2005, 127, 13480–13481; c) J. Etxebarria, H.
Degenbeck, A. S. Felten, S. Serres, N. Nieto, A. Vidal-Ferran, J. Org.
Chem. 2009, 74, 8794–8797; d) P. Dydio, C. Rubay, T. Gadzikwa, M. Lutz,
J. N. H. Reek, J. Am. Chem. Soc. 2011, 133, 17176–17179; e) H. Degen-
beck, A. S. Felten, J. Etxebarria, E. C. Escudero-Adan, J. Benet-Buchholz,
A. Vidal-Ferran, Cryst. Growth Des. 2012, 12, 2719–2723; f) H. Degen-
beck, A. S. Felten, E. C. Escudero-Adan, J. Benet-Buchholz, L. Di Bari, G.
Pescitelli, A. Vidal-Ferran, Inorg. Chem. 2012, 51, 8643–8645.
1
mined by using H NMR analysis. The enantiomeric excesses for
the hydroformylation products of 7a–e were determined by GC
using chiral stationary phases (for details, see the Supporting Infor-
mation). For a hydroformylation reaction with higher amounts of
substrate and a higher S/C ratio, see the Supporting Information.
General procedure for the Rh-mediated asymmetric hydro-
genation
[7] For example, see: a) N. C. Gianneschi, P. A. Bertin, S. T. Nguyen, C. A.
Mirkin, L. N. Zakharov, A. L. Rheingold, J. Am. Chem. Soc. 2003, 125,
In a glovebox filled with nitrogen, [Rh(cod) ]BArF (0.01 equiv in di-
2
1
0508–10509; b) N. C. Gianneschi, S.-H. Cho, S. B. T. Nguyen, C. A.
Mirkin, Angew. Chem. Int. Ed. 2004, 43, 5503–5507; Angew. Chem. 2004,
16, 5619–5623; c) D. Sud, T. B. Norsten, N. R. Branda, Angew. Chem. Int.
chloromethane) was added to a 2 mL vial equipped with a magnet-
ic bar and the substrate (ca. 15 mg, 1 equiv). A previously stirred
solution (10 min) of the ligand (0.012 equiv) and regulation agent
1
Ed. 2005, 44, 2019–2021; Angew. Chem. 2005, 117, 2055–2057; d) J.
Wang, B. L. Feringa, Science 2011, 331, 1429–1432.
(
0.0156 equiv) were then added to this solution. Additional di-
chloromethane was charged to provide the desired final concen-
tration of substrate (0.2m). The vial was then taken out of the glo-
vebox and transferred into an autoclave. The autoclave was
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2
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2
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pressure. The reaction mixture was stirred at room temperature for
He, F. Zhang, Q.-H. Fan, Chem. Asian J. 2010, 5, 2454–2458;
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1
8 h. The pressure was carefully released in a well-ventilated hood.
1
The conversion was determined by H NMR spectroscopy and
enantiomeric excesses were determined by GC or HPLC analysis
using chiral stationary phases (for details, see the Supporting Infor-
mation).
[10] I. Mon, D. A. Jose, A. Vidal-Ferran, Chem. Eur. J. 2013, 19, 2720–2725.
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Acknowledgements
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The authors thank MINECO (CTQ2014-60256-P, CTQ2014-
[
[
5
2
7393-C2-1-P and Severo Ochoa Excellence Accreditation 2014-
018 SEV-2013-0319) and the ICIQ Foundation for financial
15] See the Supporting Information for details.
support. Financial support from CELLEX Foundation through
the CELLEX-ICIQ high throughput experimentation platform is
gratefully acknowledged. L.R. thanks the ICIQ Foundation for
a stipend. Dr. H. Fernµndez-PØrez is acknowledged for his help
in the preparation of the manuscript.
[16] NMR titration data were analyzed by using HypNMR software (ver.
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2
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Chem. Eur. J. 2015, 21, 11417 – 11426
www.chemeurj.org
11425
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Software Associates) was used:c) H. Gampp, M. Maeder, C. J. Meyer,
A. D. Zuberbuehler, Talanta 1985, 32, 95–101; d) H. Gampp, M. Maeder,
C. J. Meyer, A. D. Zuberbuehler, Talanta 1986, 33, 943–951.
was used for all atoms. It employs effective core potentials for Rh (ECP-
28, as in D. Andrae, U. Haeussermann, M. Dolg, H. Stoll, H. Preuss,
Theor. Chim. Acta 1990, 77, 123–141). For the calculations, the BP86
functional with Grimme’s latest available correction for dispersion (D3,
as reported by S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys.
2010, 132, 154104/1–154104/19), was used.
[
17] See, for example: J. S. Renny, L. L. Tomasevich, E. H. Tallmadge, D. B.
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18] F. P. Schmidtchen, in Analytical Methods in Supramolecular Chemistry
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[
[
[28] See the following reference and those cited therein: S. H. Chikkali, J. I.
van der Vlugt, J. N. H. Reek, Coord. Chem. Rev. 2014, 262, 1–15.
[29] The presence of substituents at the 3,3’ positions of a [1,1’-biaryl]-2,2’-
diol-derived phosphites is detrimental to catalytic activity in AH: See,
for example: a) A. Korostylev, A. Monsees, C. Fischer, A. Borner, Tetrahe-
dron: Asymmetry 2004, 15, 1001–1005; b) L. Pignataro, S. Carboni, M.
Civera, R. Colombo, U. Piarulli, C. Gennari, Angew. Chem. Int. Ed. 2010,
49, 6633–6637; Angew. Chem. 2010, 122, 6783–6787. The AH of 10b
using ligands 3a or 4a gave the hydrogenated product in complete
conversion and 94% ee (entries 2 and 8, Table 8), whereas the ligands
3b or 4b mediated the AH in complete conversion, but with only 86
and 74% ee, respectively (for clarity, these results have not been in-
cluded in Table 8).
[30] For milestone ligands whose Rh complexes mediate the hydrogenation
of 10a–d in 99% ee see, for example: a) H. Fernµndez-PØrez, P. Etayo, A.
Panossian, A. Vidal-Ferran, Chem. Rev. 2011, 111, 2119–2176; b) J.-H. Xie,
S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011, 111, 1713–1760. For the highest
performing ligands in the Rh-mediated hydrogenation of 10e and 10 f,
see: c) T. Imamoto, K. Tamura, Z. Zhang, Y. Horiuchi, M. Sugiya, K. Yoshi-
da, A. Yanagisawa, I. D. Gridnev, J. Am. Chem. Soc. 2012, 134, 1754–
1769; d) L. Pignataro, M. Boghi, M. Civera, S. Carboni, U. Piarulli, C. Gen-
nari, Chem. Eur. J. 2012, 18, 1383–1400.
(
2
der Vlugt, J. N. H. Reek, J. Am. Chem. Soc. 2012, 134, 6607–6616.
20] R. Franke, D. Selent, A. Boerner, Chem. Rev. 2012, 112, 5675–5732.
21] Addition of increasing amounts of alkali metal BArF salts to a solution
of 5b did not induce any change in its spectra, which led us to con-
clude that weak binding was occurring.
[
[
[
22] The required catalyst amount was obtained from a substrate/RbBArF/
ligand 4b/[Rh] ratio=100:0.156:0.12:0.1 in a solution with a vinyl ace-
tate concentration of 1m. Under these conditions, the ligand and
À–3
RbBArF concentrations in the reaction mixture were 1.2”10
and
À–3
1
.56”10 m, respectively. The association constant between 4b and
4
À1
RbBArF in toluene/THF (97:3, v/v) was 1”10 m , which translates into
the formation of the RbBArF·4b complex to an extent of about 84%.
Addition of a six-fold excess of RbBArF relative to 4b at the working
concentration ensured the formation of the RbBArF·4b complex to an
extent of >98%. However, hydroformylation of 7a using a substrate/
RbBArF/ligand 4b/[Rh] ratio=100:0.72:0.12:0.1 did not offer any advan-
tages relative to the previously mentioned conditions.
[
[
[
[
[
23] G. W. Wong, C. R. Landis, Angew. Chem. Int. Ed. 2013, 52, 1564–1567;
Angew. Chem. 2013, 125, 1604–1607.
24] C. J. Cobley, R. D. J. Froese, J. Klosin, C. Qin, G. T. Whiteker, K. A. Abboud,
Organometallics 2007, 26, 2986–2999.
25] In the absence of RA, the b/l ratio and enantioselectivity were identical
with or without incubation time (b/l ratio=94:6; ee=37%).
26] X. Zhang, B. Cao, Y. Yan, S. Yu, B. Ji, X. Zhang, Chem. Eur. J. 2010, 16,
[31] These results corroborate a recent report that rhodium complexes of
phosphorus ligands with long chains between the two phosphorus
binding groups mediate AHs with high enantioselectivity. See, for ex-
ample: a) K. N. Gavrilov, O. G. Bondarev, A. I. Polosukhin, Russ. Chem.
Rev. 2004, 73, 671–699; b) G. Farkas, S. Balogh, J. Madarasz, A. Szoello-
sy, F. Darvas, L. Uerge, M. Gouygou, J. Bakos, Dalton Trans. 2012, 41,
9493–9502.
8
71–877.
27] The geometry of all the complexes included in this study was opti-
mized at the BP86-D3/def2-TZVPD level of theory within the program
TURBOMOLE ver. 6.4 (R. Ahlrichs, M. Baer, M. Haeser, H. Horn, C. Koel-
mel, Chem. Phys. Lett. 1989, 162, 165–169). The def2-TZVPD basis set
Received: April 14, 2015
Published online on June 26, 2015
Chem. Eur. J. 2015, 21, 11417 – 11426
www.chemeurj.org
11426
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim