Insight into the role of fluorinated dendrimers in ruthenium(II) catalyst for asymmetric transfer hydrogenation: The stabilizing effects from experimental and DFT approach

Article abstract of DOI:10.1016/j.molcata.2014.02.030

A series of fluorinated dendritic chiral ligands have been designed and synthesized. These fluorinated dendrimers are capable of forming a well-defined semi-rigid structure, which was revealed to play a vital role in the ruthenium(II) bifunctional catalys

Full text of DOI:10.1016/j.molcata.2014.02.030

Journal of Molecular Catalysis A: Chemical 387 (2014) 92–102
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Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Insight into the role of fluorinated dendrimers in ruthenium(II)
catalyst for asymmetric transfer hydrogenation: The stabilizing
effects from experimental and DFT approach
Wei-Wei Wanga,∗, Zhi-Ming Lib,∗, Ling Sub, Quan-Rui Wangb, Ying-Li Wua
a Department of Pathophysiology, Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of the
Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai 200025, PR China
b Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of fluorinated dendritic chiral ligands have been designed and synthesized. These fluorinated
dendrimers are capable of forming a well-defined semi-rigid structure, which was revealed to play a
vital role in the ruthenium(II) bifunctional catalyst for asymmetric transfer hydrogenation of prochiral
ketone substrates. In contrast to the classical non-fluorinated dendrimer carrier, both NMR and DFT study
exhibit that the introduction of fluorine atoms leads to considerable intramolecular weak interactions
such as ␲–␲ stacking and hydrogen bonding interactions, which make the dendritic backbone exist
with a semi-rigid structure in the catalyst. This influences the performance of the catalytic center in
terms of the stability and reusability. This concept was employed as a strategy to design a new Ru(II)-
complex catalyst Ru-G-2ꢀ-F, which demonstrated obviously improved recycling ability up to fifteen times.
Significantly enhanced activity, high enantioselectivity and outstanding recycling ability have also been
achieved even at high reaction temperature with Ru-G-2-F.
Received 17 December 2013
Received in revised form 20 February 2014
Accepted 25 February 2014
Available online 5 March 2014
Keywords:
Asymmetric transfer hydrogenation
Supported catalysis
Fluorinated dendrimer
Density functional calculations
© 2014 Elsevier B.V. All rights reserved.
1. Introduction
In recent years, continuous efforts have been made to develop
new catalytic systems for the ATH reactions with the archetypal cat-
Asymmetric transfer hydrogenation (ATH) reactions catalyzed
by chiral transition-metal complexes provide a fundamental tool
for the preparation of optically active organic compounds [1].
Since the pioneer work by Noyori, Ikariya and Hashiguchi reported
in the mid-1990s [2], the phosphine-free Ru catalysts bearing
N-sulfonated 1,2-diamines as chiral ligands, which coupled with 2-
propanol [2a] or HCO2H-NEt3 azeotropic mixture [2b] and HCO2Na
[3] as hydrogen source, have evolved to a class of effective cata-
lysts for asymmetric transfer hydrogenation of prochiral ketones.
Noyori first proposed that both an amidoruthenium complex
with a square-planer geometry and a coordinatively saturated
hydrido(amine)ruthenium complex are involved in the catalytic
cycle as shown in Scheme 1a [4]. Since the postulate of these
bifunctional ruthenium based-molecular catalysts with cooperat-
ing amine/amido ligands has been proposed, the theoretical study
also evoked many chemists’ interest [5].
alyst to improve the efficiency in terms of activity [6], selectivity [7],
substrate scope [8] and practicability [9–11]. To address the latter
issue, supported catalysts [10,11] have inherently operational and
economical advantages: facilitating the separation from reaction
mixtures, easy recovery and reuse of the expensive but always toxic
chiral transition-metal catalysts. Amongst them, dendritic catalysts
have received special attention since they have the potential to
combine both the advantages of homogeneous and heterogeneous
catalysts in a single system [12]. However, in terms of catalyst activ-
ity and reusability, dendritic catalysts [11] cannot outperform other
types of catalysts immobilized on inorganic materials, such as silica
[10b,d,f]. Compared to inorganic materials, the normal dendrimer
[13] is now viewed as a “flexible” carrier [11,14] in supported cat-
alysts. Herein we reveal a “semi-rigid” fluorinated dendrimer [15]
as a functional carrier [16] in ruthenium(II) catalyst for asymmetric
transfer hydrogenation reactions.
As a part of our own program of studies, we have recently
developed a fluorinated dendritic chiral mono-N-tosylated 1,2-
diphenylethylenediamine ruthenium complex (Ru-G-2-F, see
Scheme 1b) for the asymmetric transfer hydrogenation of ketones
in aqueous medium [17]. Compared to other dendritic catalysts
∗
Corresponding authors. Tel.: +86 21 63846590; fax: +86 2164154900.
E-mail addresses: weiweiwang@shsmu.edu.cn (W.-W. Wang),
zmli@fudan.edu.cn (Z.-M. Li).
http://dx.doi.org/10.1016/j.molcata.2014.02.030
1381-1169/© 2014 Elsevier B.V. All rights reserved.

W.-W. Wang et al. / Journal of Molecular Catalysis A: Chemical 387 (2014) 92–102
93
O
Ar
R
a)
b)
F
F
F
Ar
O
F
F
Cl
R
Ru
H
NH2
Ph
H
F
Ru
Ru
TsN
Ph
NH2
O
H
TsN
Ph
TsN
Ph
NH
O
O
O
F
F
O
Ph
F
catalyst
Ph
F
O
The possible transition state
amine hydrido complex
O
Base
F
F
F
O
F
O2S
N
F
Ru
Ph
Ph
F
Ru
TsN
Ph
NH
Ph
OH
Cl
N
H2
2[H]
Ar
R
Ru-G-2-F
amido complex
Scheme 1. (a) Concerted hydrogen transfer mechanism for ATH of ketones catalyzed by Ru–TsDPEN catalyst. (b) Structure of fluorinated dendritic chiral mono-N-tosylated
1,2-diphenylethylenediamine ruthenium complex Ru-H-G-2-F.
[11], this new well-defined catalyst leads to reactions with high
activity and excellent recycling ability up to twenty-six times.
Although we have shown that Ru-G-2-F complex was highly
stabilized and efficient with performances far surpassing those
obtained from other types of dendritic and immobilized catalysts
[10,12], little is known about the nature of the active sites and in
particular what the real role of the fluorinated dendrimers play in
affecting the activity and the stability of the Ru catalytic sites.
In the present work, detailed experiments combined with
theoretical computation have been carried out to unravel the char-
acteristic of fluorinated dendrimers and their role on the high
activity and stability of our catalyst. First, a series of catalysts were
synthesized, and the catalytic activities and reusabilities were eval-
uated including those at high temperatures [6i]. We were pleasingly
to disclose that Ru-G-2-F exhibited unprecedented recycling ability
up to twenty-three times even at 80 ◦C with enhanced activity and
unaltered enantioselectivity. A novel stabilization pattern of the
catalyst is proposed: the existence of fluorine atoms [15g] leads to
considerable intramolecular weak interactions such as ␲–␲ stack-
ing [15g,18] and hydrogen bonding [15g,19] interactions, which
make the dendritic segment occur as a relatively rigid status in the
catalyst and hence assists the performance of the catalytic center.
IonSpec 4.7 Tesla FTMS. GC–MS spectra were recorded on PE 680-
SQ8T (GC analysis: HP-5ms 30 m × 0.25 m × 0.25 ␮m, T = 50–280 ◦C,
1.0 mL/min). IR spectra were obtained on an Avatar 360 FT-IR
spectrometer. Optical rotations were measured on an Autopol IV
automatic polarimeter. Enantiomeric excesses were determined on
GC analysis and HPLC analysis. The reactions were monitored by
thin layer chromatography coated with silica gel. All solvents were
purified and dried by standard procedures and kept over a suitable
drying agent prior to use. Unless otherwise noted, all reagents were
purchased from commercial sources and were used without further
purification.
2.2. General procedure for the transfer hydrogenation reactions
Synthesis of pre-catalyst Ru-G-n-F (n = 1, 2, 2ꢀ, 3): [RuCl2(p-
cymene)]2 (3.0 mg, 0.005 mmol), ligand G-n-F (n = 1, 2, 2ꢀ, 3)
(0.011 mmol) and Et3N (2.0 mg, 0.02 mmol) was dissolved in 1 mL
of CH2Cl2. After the solution was stirred at 35 ◦C for 10 h, the sol-
vent was removed to provide Ru-G-n-F (n = 1, 2, 2ꢀ, 3) as a crude
solid. The crude product Ru-G-n-F (n = 1, 2, 2ꢀ, 3) was used directly
in the following asymmetric transfer hydrogenation reactions as
the catalyst.
Reduction of ketones using catalyst Ru-G-n-F (n = 1, 2, 2ꢀ, 3): The
catalyst Ru-G-n-F (n = 1, 2, 2ꢀ, 3) (0.01 mmol), CH2Cl2 (0.5 mL),
ketone (1.0 mmol) and TBAI (tetrabutylammonium iodide, 185 mg,
0.5 mmol) were added in 5 M liquor of HCO2Na (6 mL), and the mix-
ture was stirred at the corresponding temperature (10 ◦C, 40 ◦C,
60 ◦C, 80 ◦C) under nitrogen for a certain period of time. After
the reaction was completed (monitored by TLC), the reaction
mixture was extracted with ethyl acetate (20 mL). The organic
phase was dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The product was purified by flash chromatogra-
phy.
2. Experimental
2.1. Generals
The 1H NMR, 13C NMR and 19F NMR spectra were acquired in
CDCl3 as solvent on a Bruker DMX 500 or a JEOL ECA-400 spec-
trometer. The chemical shifts (ı) are expressed in ppm (parts per
million) relative to TMS (CF3COOH, for 19F NMR). Spin-spin cou-
pling constants (J) were measured directly from the spectra and
were given in Hz. Exact mass spectra (HR-MS) were recorded on

94
W.-W. Wang et al. / Journal of Molecular Catalysis A: Chemical 387 (2014) 92–102
Br
F
F
F
F
F
F
O
O
COOMe
OH
ORf
ORf
ORf
ORf
O
a
b
c
F
F
MeO
39%
82%
HO
Cl
HO
Br
( 2 steps )
ORf
1
2
O
O
O
d
ORf
ORf
F
71%
MeO
F
Rf =
3
F
RfO
HOOC
ORf
ORf
ORf
F
e
HO
52%
ORf
1
4
Scheme 2. Preparation of the second-generation fluorinated dendrimer 3 and first-generation fluorinated dendrimer 4. Reagents and conditions: (a) Bromopentafluoroben-
zene, NaH, DMF.(b) LiAlH4, THF. (c) PPh3, CCl4, acetonitrile. (d) Methyl 3,5-dihydroxybenzoate, K2CO3, TBAI, acetone. (e) Jones reagent, acetone.
2.3. Recovery and reuse of the catalyst
result persuaded us to develop an alternative route for accessing
larger fluorinated dendrimer.
[RuCl2(p-cymene)]2 (3.0 mg, 0.005 mmol), ligand G-n-F (n = 1, 2,
2ꢀ, 3) (0.011 mmol) and Et3N (2.0 mg, 0.020 mmol) was dissolved
in 0.5 mL of CH2Cl2. After the solution was stirred at 35 ◦C for
10 h, the mixture of ketone (1.0 mmol) and TBAI (tetrabutylammo-
nium iodide, 185 mg, 0.5 mmol) in 5 M liquor of HCO2Na (6 mL) was
added. The mixture was stirred at the corresponding temperature
(40 ◦C and 80 ◦C) under nitrogen for a certain period of time. After
the reaction was completed (monitored by TLC), hexane (20 mL)
were added to the reaction mixture and the catalyst began to pre-
cipitate from solution. The organic phase was removed by using a
syringe, and washed with saturated brine (20 mL) and then dried
(Na2SO4). The solvent was removed, and the product was purified
by flash chromatography on silica gel to afford pure alcohol product.
For the next run of the reduction to be conducted, 1 equiv.
HCO2H (0.1 mL, 10 M) was added to adjust the pH value. The
new reduction was started by feeding another portion of ketone
(1.0 mmol) in 0.5 mL of CH2Cl2. The solution was allowed to react
and the same workup procedure was used as mentioned above.
Subsequent runs were performed in the same manner as the sec-
ond.
As illustrated in Scheme 3, the intermediate 5 was prepared from
halogenide 2 and 3,5-dihydroxylbenzyl alcohol with an accept-
able yield, which was adopted by Ueda et al. [20]. It is worthy
of comment that the halogenation conversion of alcohol 5 to
halogenide 6 could be greatly promoted by addition of TBAI (tetra-
butylammonium iodide). Finally, treatment of halogenide 6 with
3,5-dihydroxylbenzyl methyl ester under basic condition afforded
dendrimer 7.
The fluorinated dendrimer 4 and 7 were converted to their acid
derivatives by saponification respectively. Finally, the fluorinated
dendritic chiral ligands G-1-F and G-3-F were obtained by coupling
the acid groups of the corresponding fluorinated dendrimers with
the modified chiral ligand 8 [21] under the conditions of EDC/DMAP
and consecutive deprotection of the Boci-group (Scheme 4).
3.2. Catalyst application and recovery study
With the fluorinated dendritic chiral ligands in hand, their per-
formance was evaluated for use as ruthenium complex in the
asymmetric transfer hydrogenation reactions of ketones. Accord-
ing to our previously established procedure [17], the reaction was
performed under aqueous reaction conditions using HCO2Na as a
hydrogen source. The pre-catalyst was generated by reaction of the
ligands with [RuCl2(p-cymene)]2 in CH2Cl2 at 35 ◦C for 1 h with
Et3N as a base.
3. Results and discussion
3.1. Synthesis of the fluorinated dendritic chiral ligands
The transfer hydrogenation of acetophenone in aqueous media
was employed as the benchmark reaction (Table 1). All the three
catalysts displayed high catalytic activity and good enantioselectiv-
ity. Compared to Ru-G-2-F (entry 2, [17]), an enhanced reactivity
was observed for Ru-G-1-F (entry 1), but Ru-G-3-F (entry 3) was
less active with much longer reaction time due to its bigger den-
dritic backbone. This may be explained by the steric hindrance
and the semi surrounding structure of the dendrimer [6i], which
counterbalance the activity of the real catalysts [11a,d].
Considering the structure of G-2-F [17], fluorinated dendritic
chiral ligands G-1-F and G-3-F were designed and synthesized. As
shown in Scheme 2, the second-generation fluorinated dendrimer
3 was obtained in a four-step sequence according to our previously
reported method [17]. The first-generation fluorinated dendrimer
4 was prepared by oxidation of the benzyl alcohol 1 with Jones
reagent.
However, the attempt to synthesize the third-generation fluo-
rinated dendrimer 7 was proved to be unsuccessful. We found that
the reduction of dendrimer 3 to alcohol analog 5 was very slug-
gish by using a diversity of reducing reagents including LiAlH4. This
One of the most important motivations to design the fluorinated
dendritic catalysts was to facilitate catalyst/product separation
and recover the catalyst. Thus, the reusability of the catalysts was

W.-W. Wang et al. / Journal of Molecular Catalysis A: Chemical 387 (2014) 92–102
95
ORf
ORf
O
O
O
O
a
b
ORf
ORf
ORf
ORf
2
46%
55%
HO
Cl
5
6
ORf
O
ORf
OMe
O
c
O
O
F
63%
F
Rf =
O
RfO
ORf
O
F
O
F
ORf
ORf
ORf
RfO
ORf
ORf
7
Scheme 3. Preparation of third generation fluorinated dendrimer 7. Reagents and conditions: (a) 3,5-Dihydroxylbenzyl alcohol, K2CO3, NMP. (b) PPh3, CCl4, TBAI, acetonitrile.
(d) Methyl 3,5-dihydroxybenzoate, K2CO3, TBAI, acetone.
F
F
F
O
F
F
F
O
O
O
O
S
O
F
F
H
N
O
a, b, c
G-3-F
24% ( 3 steps )
OH
Ph
Ph
F
F
7
O
O
NHBoc
(S, S)-8
F
F
F
O
O2S
NH
b, c
G-1-F
71% ( 2 steps )
n
4
F
Ph
Ph
F
G-1-F (n=0)
G-2-F (n=1)
G-3-F (n=2)
F
NH2
Scheme 4. Synthesis of fluorinated dendritic chiral ligands G-1-F and G-3-F. Reagents and conditions: (a) NaOH, H2O. (b) (S,S)-8, EDC, DMAP, CH2Cl2. (c) TFA, CH2Cl2.
investigated at 40 ◦C with an S/C ratio of 100/1. After completion of
Table 1
the reaction, hexane was added to precipitate the catalyst. For the
next run to be conducted, 1 equiv. of HCO2H was added to adjust
the pH.
Asymmetric transfer hydrogenation of acetophenone catalyzed by Ru-G-n-F (n = 1,
O
OH
G-n-F (n=1, 2, 2', 3)
[RuCl2(cymene)2]2
In our previously reported results [17], Ru-G-2-F behaved excel-
lently and can be reused more than twenty-six runs with no
significant decline both in selectivity and activity (Fig. 1b). Com-
pared to Ru-G-2-F, Ru-G-1-F almost lost the recycling ability just
as unmodified Ru-TsDPEN (Fig. 1a). Ru-G-3-F was evidently infe-
rior, which can be reused only nine runs (Fig. 1c). However, this
result still outperforms other types of dendritic catalysts. [11] And
this reveals that the structure of the fluorinated dendrimer plays
an important role in the stability of the catalyst, and the second
generation fluorinated dendrimer is the most suitable carrier for
ATH catalyst.
2, 3).a
Entry
.
Ligand
T (◦C)
t (h)
Conv. (%)b
ee (%)c
1
2
3
G-1-F
G-2-F
G-3-F
40
40
40
3
4
7
>99
>99
>99
97 (S)
97 (S)
94 (S)
a
The reactions were carried out in 5 M liquor of HCO2Na (6 mL) and CH2Cl2
(0.5 mL) with TBAI (0.5 equiv.) under a nitrogen atmosphere, S/C = 100. The con-
figuration of the ligands was assigned as S,S.
b
Yield of isolated product after flash chromatography.
Determined by GC analysis using a CHIRALSIL-DEX-CB capillary column and
c
HPLC analysis using a Daicel Chiralcel OB-H column. The configuration of the alcohol
was assigned as S.
3.3. NMR and computation study
To get deep insight in the nature of our dendrimer ruthe-
nium catalyst and in particular the role of the ancillary dendrimer

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W.-W. Wang et al. / Journal of Molecular Catalysis A: Chemical 387 (2014) 92–102
fragment on the catalyst, the NMR and computational study were
performed with our catalyst and the corresponding fluorinated
dendrimer. As described above, Ru-G-2-F is the most efficient
catalyst in our work, we therefore selected Ru-G-2-F and the
second-generation fluorinated dendrimer 3 as the research model.
In the NMR spectra of the dendrimer 3 at 25 ◦C (Fig. 2c), there
are two peaks corresponding to the benzyl protons: a main peak
(ı = 5.092) and a tiny peak (ı = 5.117) beside it. This abnormal phe-
nomenon is also discernible in the 1H NMR spectra of G-2-F (Fig. 3a)
and Ru-G-2-F (Fig. 3b). Moreover, in the NMR spectra of G-2-F, the
area of the down-field peak increased apparently compared with
that of the dendrimer. The ratio of the two peak areas in lower field
to that in upper field in G-2-F is about 1:2, larger than that in the
dendrimer. In Ru-G-2-F, the ratio is further increased to 1:1. An
NMR spectrum represents the statistical result from the thermo-
dynamic and kinetic effect. Thus we assume that there should be a
thermodynamic stable conformer corresponding to the tiny peak,
and the conversion barrier between other conformers and this con-
former is substantial. So we first set out to locate the most stable
conformer of dendrimer 3.
On the basis that MM [22] force field can give reasonable con-
formations and energetics compared to the ab initio results, we
first carried out a Monte Carlo [23] conformational search for
fluorinated dendrimer 3 using MM force field with the Hyper-
chem program [24]. Totally, 5000 structures were optimized during
the conformational search, and conformations within 12 kcal/mol
with respect to the most stable conformation were accumulated.
To ensure that all the conformers in the low-energy area were
obtained, another conformational search starting with the lowest
energy conformer that had been found in the first run was carried
out and the same result was obtained. On the basis of the confor-
mational search results, 30 lowest energy conformers (within about
4.0 kcal/mol relative to the global minimum) were optimized with
PM6 method, in which the 10 lowest energy conformers (within
about 2.3 kcal/mol relative to the global minimum) were optimized
with the M062X/6-31G(d) [25] method of computation using the
GAUSSIAN09 programm [26].
Our computation results indicate that the introduction of flu-
orine atoms confers certain scaffold rigidity. The most stable
conformer of the 10 lowest energy conformers features a very
rigid structure via intramolecular hydrogen bonding (C–H· · ·F and
C–H· · ·O hydrogen bonds) and ␲–␲ stacking interactions between
aromatic rings including fluorinated phenyl rings (see Figure S1
and Table S1). This hydrogen bond influence is unique compared to
other non-fluorinated dendrimers [13]. Computations reveal that
there is a three-center hydrogen bond in this conformer, which
exists between F, O atoms of a fluorinated phenyl and an H atom
of the phenyl ring connected directly with the benzyl carbon, the
´
˚
distances of H· · ·O and H· · ·F are 2.21 and 2.58 A, respectively (see
Figure S1). Moreover, there is an interesting sandwich structure
due to the ␲–␲ stacking interactions [27] between the three fluo-
rinated phenyl rings (see Figure S1). Thus the rotations about the
single bond are constrained. On the other hand, the shortest dis-
tance between the two aromatic rings connected directly with the
´
˚
two methylene carbons is only about 3.22 A, while similar situ-
ations can not be found in other 9 stable conformers (Fig. 2b).
The short distances and the strong ␲–␲ stacking interactions in
the most stable conformer enhance the induced magnetic field of
Fig. 1. Graph of conversion, ee vs. run numbers for the reduction of acetophenone with Ru-G-1-F (a), Ru-G-2-F [17] (b) and Ru-G-3-F (c) in water at 40 ◦C.

W.-W. Wang et al. / Journal of Molecular Catalysis A: Chemical 387 (2014) 92–102
97
Fig. 2. (a) Molecular structure of the fluorinated dendrimer 3. (b) Optimized structure of the global minimum of fluorinated dendrimer 3. (c) 1H NMR spectra of benzyl
protons of 3, 25 ◦C. (d) 80 ◦C. (e) 150 ◦C.
Fig. 3. 1H NMR spectra of benzyl protons of (a) G-2-F, (b) Ru-G-2-F.

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W.-W. Wang et al. / Journal of Molecular Catalysis A: Chemical 387 (2014) 92–102
the phenyl ␲ electrons, and consequently reinforce the deshield-
ing of aryl protons and benzyl protons as well [28]. The tiny peak
(ı = 5.117) beside the main peak (ı = 5.092) is attributed to the ben-
zyl protons in the most stable conformer. Since one can only get
the average environment of the protons in the NMR time-scale, the
main peak at upper-field is attributed to the benzyl protons in other
conformers of the dendrimer, in which the hydrogen bonding and
␲–␲ stacking interactions are less significant.
Similarly, computational study from the same strategy as Ru-
G-2-F, is performed with the hydride intermediate Ru-H-G-2-F
(Fig. 4). To our satisfaction the calculation results demonstrate the
existence of a similar rigid structure in Ru-H-G-2-F [4,5]. The ꢀG
between Ru-H-G-2-F-A and Ru-H-G-2-F-B is 17.1 kcal/mol, larger
than that of Ru-G-2-F (ꢀG = 16.8 kcal/mol). This value verified that
Ru-H-G-2-F-A is more stabilized as compared to Ru-H-G-2-F-B
when Ru-G-2-F is converted to Ru-H-G-2-F. Besides, it is worth
noting that there is a three-center hydrogen-bond in the hydride
intermediate, which is between one of the F atoms in the den-
drimer part, an H atom on NH2, and an H atom on the phenyl
ring connected directly with CHNH2 (Fig. 4). The distance between
´
of N–H· · ·F is 158.2o. These data means that this hydrogen bond
is relatively strong. Moreover, the hydrogen atom is one member
in the six-membered ring in the transition structure (Scheme 1a).
Thus, the higher stability of our catalyst may result from this strong
hydrogen bond to a large extent: the rigid fluorinated dendrimer
part participates in the catalytic cycle via this hydrogen bonding
and stabilizes the amine hydrido complex intermediate. This con-
cept has been proved in Xiao’s work [5b], in which the solvent
water forms a hydrogen bond to the ketone oxygen in the transi-
tion state of hydrogen transfer. Thus, the dendrimer size may play
an important role in affecting the catalyst efficiency (See Figure
S6).
From the above discussion, we can come to the following
conclusions: first, due to the stable rigid conformation of the
fluorinated-dendrimer catalyst, it is easy to precipitate out the
catalyst from the reaction system, similar to the inorganic car-
rier supported catalyst. Second, for the hydrido(amine)ruthenium
complex intermediate Ru-H-G-2-F (Fig. 1b), the hydrogen atom in
the hydrogen bond N–H· · ·F is one member of the six-membered
ring in the catalytic transition structure, which stabilizes the
hydride intermediate and thus elongate the catalytic lifetime and
rendering much better recycling performance than other types
of supported catalyst such as the inorganic carrier supported
ones.
In the case of G-2-F and Ru-G-2-F, we assumed that the introduc-
tion of polar group such as amino group, more aromatic rings and
rigid Ru segment can enhance the rigid character of G-2-F and Ru-G-
2-F for more hydrogen bonding and ␲–␲ stacking interactions, and
consequently stabilize the most stable conformers to more extent.
To test this assumption, we set about to explore the ligand G-2-F
and the ruthenium catalyst Ru-G-2-F, based on the crystal structure
of the ligand and ruthenium catalyst [4a]. Considering the compu-
tation cost, the dendrimer moiety was constrained to the structure
of the lowest energy conformer of the original dendrimer (labeled
with A), and the potential energy profiles were scanned along the
three bonds of the ester unit between the dendrimer skeleton and
the chiral diamine part (see Figure S2 and Figure S3). The struc-
ture of the ligand and the catalyst with the lowest energy in the
scanned potential energy profiles were then located. Finally, the
structures were optimized with the M062X method using 6-31G(d)
basis set for the main group atoms and the SDD basis set for Ru
atom [29]. To our gladness, the computation results agree well with
our assumption: the conformer of G-2-F-A and Ru-G-2-F-A with
the lowest energy are also rigid and the rotation of the dendrimer
part turns to be more constrained, which are from more hydrogen
bonding, ␲–␲ stacking interactions as well as the rigid Ru-based
fragment. For instance, in G-2-F, one of the hydrogen of NH2 and
one hydrogen of phenyl ring connected directly with CHNH2, can
form a three-center hydrogen bond with one F atom of dendrimer
part (see Figure S4) [30].
Following the same strategy, the second stable dendrimer (see
Table S1–S2) was used to build the structure of G-2-F and Ru-
G-2-F (labeled with B). The computation results exhibit that the
most stable conformer of G-2-F-A and Ru-G-2-F-A can be more
stabilized than G-2-F-B and Ru-G-2-F-B (see Figure S5 and Table
S2). The difference between the free energies of G-2-F-A and G-
2-F-B is 5.2 kcal/mol, obviously larger than that of the dendrimers
(ꢀG = 4.7 kcal/mol). These data predict that G-2-F content with the
most stable dendrimer conformer structure is increased. For Ru-G-
2-F, the ꢀG of A and B is enlarged to 16.8 kcal/mol, suggesting that
the rigid structure of Ru-G-2-F-A is more stabilized than Ru-G-2-F-
B, and the rigid character of Ru-G-2-F becomes more pronounced.
Considering the computation cost, the interconversion transi-
tion state and barriers between conformers are not located. But on
the basis of the previous computational results, we can deduce that
hydrogen bonding and ␲–␲ stacking interactions contribute a lot to
the barrier. On the other hand, variable-temperature NMR experi-
ment can give us some clues about the barrier. In order to prove
our prediction, the 1H NMR experiments at 25, 80, 150 ◦C were
performed. We can reasonably envision that, with the increase of
the temperature, the remote intramolecular interactions such as
␲–␲ stacking and hydrogen bonding will decrease thus the tiny
peak area declines. The experimental clearly verified our predic-
tion. Though the tiny peak area at 80 ◦C does not change much as
compared with that at 25 ◦C (Fig. 2d), it did disappear completely
at 150 ◦C (Fig. 2e), indicating that the energy barrier separating
the most stable conformer and other conformers is sizable but the
molecules at 150 ◦C can surmount it freely. In view of the NMR
experiments, we can also predict that 80 ◦C is a safe tempera-
ture for the catalyst, and the catalytic reaction temperature can be
increased to 80 ◦C, which is advantageous for performing the AHT
reactions.
˚
the F atom and the H atom on NH2 is 2.13 A, and the bond angle
3.4. Design, synthesis and application of new catalyst
In order to prove our mechanistic assumption, a new chiral
ligand G-2ꢀ-F was designed and prepared. As shown in Scheme 5,
compound 9 was readily assembled from halogenide 2, then the
chiral ligand G-2ꢀ-F was prepared according to our previously
established method. The structure of compound 9, which con-
tains half size of the second generation fluorinated dendrimer 3,
is asymmetric in the structure, different from the common den-
drimer molecules. The corresponding catalyst Ru-G-2ꢀ-F contains
only two fluorinated phenyl rings as in Ru-G-1-F, but has the
same distance between the terminus of the fluorinated carrier part
and the Ru catalytic sites as in Ru-G-2-F. Based on our theoreti-
cal computation results, the F atoms in catalyst Ru-G-2ꢀ-F (in the
end of carrier part) can influence the performance of the Ru cat-
alytic sites in the hydrido(amine) intermediate as in Ru-G-2-F, thus
extend the lifetime and enhance the recycling ability of the cata-
lyst.
The experimental results of Ru-G-2ꢀ-F verified our assumption.
The asymmetric transfer hydrogenation of acetophenone in aque-
ous media afforded 99% conversion and 96% ee in 2 h at 40 ◦C. As
expected, the recycling of the Ru-G-2ꢀ-F at 40 ◦C proved to be quite
satisfactory. As shown in Fig. 5, the catalyst can be reused more than
fifteen times. Even in the 15th run, the reaction also afforded 91%
conversion and 95% ee in 18 h. This result outperforms Ru-G-1-F (5
runs) and even Ru-G-3-F (9 runs).

W.-W. Wang et al. / Journal of Molecular Catalysis A: Chemical 387 (2014) 92–102
99
Fig. 4. Molecular structure (left) and optimized structure (right) of the lowest energy conformer in the scanned potential energy profiles of Ru-H-G-2-F.
COOMe
O
O
O
F
O
a
b, c, d
O
F
2
76%
45% ( 3 steps )
F
F
O
F
F
F
F
O2S
O
F
F
NH
F
F
Ph
Ph
O
F
F
NH2
F
F
9
G-2'-F
Scheme 5. Synthesis of chiral ligands G-2ꢀ-F. Reagents and conditions: (a) Methyl 3,5-dihydroxybenzoate, K2CO3, TBAI, acetone. (b) NaOH, H2O. (c) (S,S)-8, EDC, DMAP, CH2Cl2.
(d) TFA, CH2Cl2.
3.5. Catalyst application at high reaction temperature
Although we have shown that Ru-G-2-F complex provides high
enantioselectivity and outstanding recycling ability, the improve-
ment in activity nearly remained unchanged as compared to the
unmodified system. As mentioned above, the conversion barrier
from the most stable conformer to other conformers is compara-
ble and the temperature of 80 ◦C is a possible safe temperature to
promote the transfer hydrogen reaction without significant change
in the catalyst conformation (See Figure S7), thus accelerating the
reaction rate. A series of temperature gradients (10 ◦C, 60 ◦C, 80 ◦C)
were investigated with Ru-G-2-F and the results are summarized
in Table 2. Faster rates were obtained at higher temperatures with-
out prominent loss in enantioselectivity (entry 1 vs. 2). At 80 ◦C, the
reaction time was reduced to 25 min in 96% ee (entry 3). The cata-
lyst also performed quit well to afford equal enantioselectivity at a
lower catalyst dosage of S/C = 1000, yet a longer reaction time was
required (entry 5).
Encouraged by these results, we extended this protocol to
a set of substituted acetophenones 11–15 and uniformly high
Fig. 5. Graph of conversion, ee vs. run numbers for the reduction of acetophenone
enantioselectivities were obtained (entries 5–9). All of the tested
ketones were successfully reduced within a few minutes with more
than 99% conversion at 80 ◦C. Compared to the low temperature
with Ru-G-2ꢀ-F in water at 40 ◦C.

100
W.-W. Wang et al. / Journal of Molecular Catalysis A: Chemical 387 (2014) 92–102
Table 2
Asymmetric transfer hydrogenation of ketones catalyzed by Ru-G-n-F (n = 1, 2ꢀ, 2, 3).a
O
O
O
O
O
O
R1
R2
S
OEt
OEt
R
G-2-F
[RuCl2(cymene)2]2
14
15
10 R = H
11 R = p-Cl
OH
R2
12 R = p-CH3
13 R = p-OCH3
R1
.
Entry
Ketone
Ligand
Tmep. (◦C)
Time (h)
Conv. (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
10
10
10
10d
12
12
13
14
15
G-2-F
G-2-F
G-2-F
G-2ꢀ-F
G-2-F
G-2-F
G-2-F
G-2-F
G-2-F
G-2-F
10
60
80
80
80
80
80
80
80
80
8
>99
>99
>99
>99
97
>99
>99
>99
>99
>99
98 (S)
95 (S)
96 (S)
94 (S)
96 (S)
94 (S)
96 (S)
95 (S)
94 (S)e
96 (S)e
1.5
0.4
0.5
5
0.2
1.1
0.9
0.2
0.3
10
a
The reactions were carried out in 5 M liquor of HCO2Na (6 mL) and CH2Cl2 (0.5 mL) with TBAI (0.5 equiv.) under a nitrogen atmosphere, S/C = 100. The configuration of
the ligands was assigned to be S,S.
b
Isolated yield by flash chromatography.
c
Determined by GC analysis using a CHIRALSIL-DEX-CB capillary column and HPLC analysis using a Daicel Chiralcel OB-H column. The configuration of the alcohol was
assigned as S.
d
The reaction with S/C = 1000.
e
Determined by HPLC analysis using a Daicel Chiralcel OD column. The configuration of the alcohol was assigned as S.
conditions [17], the deterioration of enantiomeric purity of the
products was generally less than 1%. The reduction of ␤-ketoester
14 led to a >99% conversion in 94% ee in only 10 minutes (entry
8). In comparison, the same reaction performed at 40 ◦C was slug-
gish with only 92% ee [17]. Particularly noteworthy is that the
thiophene substrate 15 was also successfully reduced in 99% yield
and 96% ee within only 20 minutes, leading to the corresponding
(S)-␤-hydroxy carboxylic ester, which serves as the key synthetic
intermediate for the antidepressant drug duloxetine [21,31].
Next, Ru-G-2-F was applied to investigate the catalyst reusabil-
ity at 80 ◦C. To our delight, the catalyst can be reused more than
twenty-three times with no significant decline both in selectiv-
ity and activity (Fig. 6a). As shown in Fig. 6, during the initial
recycling period (runs 1–10), excellent conversion and enantio-
selectivity were obtained with no extension of the reaction time.
The ee values remained almost unchanged until the last run (23rd
run, 82% conversion and 93% ee, in 180 minutes). No appreciable
ruthenium leaching into the product was observed as proved by an
ICP analysis [32]. These excellent experimental results with high
enantioselectivity and efficiency can be maintained at 80 ◦C.
Finally, we also attempted to use Ru-G-2ꢀ-F at high temperature.
Although Ru-G-2ꢀ-F was proved to work well at 80 ◦C (Table 2, entry
Fig. 6. Graph of conversion, ee vs. run numbers for the reduction of acetophenone with (a) Ru-G-2-F and (b) Ru-G-2ꢀ-F in water at 80 ◦C.

W.-W. Wang et al. / Journal of Molecular Catalysis A: Chemical 387 (2014) 92–102
101
4), the recycling ability of the catalyst was considerably dissatisfac-
tory in comparison to that of Ru-G-2-F. The catalyst could only be
reused for no more than six times (Fig. 6b). We hypothesized that
this is due to the imperfect ␲–␲ stacking interactions of the carrier
part moiety with less number of aromatic rings.
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In conclusion, we have demonstrated that the fluorinated den-
drimer plays a vital role in the catalyst system, which has a
well-defined semi-rigid structure. Both of the theoretical analy-
ses and experimental examination revealed that introduction of an
appropriate fluorinated dendrimer can influences the performance
of the Ru catalytic sites in the hydrido(amine)ruthenium complex
intermediate, thus extend the lifetime and enhance the recycling
performance of the catalyst. This strategy has been employed for
designing and realization of a novel Ru(II)-complex catalyst Ru-
G-2ꢀ-F, which exhibits obviously improved recycling ability up to
fifteen times. Significantly enhanced activity, high enantioselectiv-
ity and outstanding recycling ability have been achieved at high
reaction temperature with Ru-G-2-F. We believe that the fluori-
nated dendrited ligands offer a conceptually new prototype for the
design of related bifunctional catalysts with cooperating amine-
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Financial support from the National Natural Science Foundation
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[32] The residual ruthenium (in 10 ml 10% liquor of HNO3) was determined by
ICP (P-4010). No leaching of Ru could be found until the limit of detection
(0.02 ppm).