Insights into the asymmetric heterogeneous catalysis in porous organic polymers: Constructing A TADDOL-Embedded chiral catalyst for studying the structure-activity relationship[ ]

Article abstract of DOI:10.1002/chem.201403002

Construction of porous organic polymers (POPs) as asymmetric catalysts remains as an important but challenging task. Herein, we exploit the "bottom-up" strategy to facilely synthesize an α,α, α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-based chiral porous polymer (TADDOL-CPP) for highly efficient asymmetric catalysis. Constructed through the covalent linkages among the three-dimensional rigid monomers, TADDOL-CPP possesses hierarchical porous structure, high Brunauer-Emmett-Teller (BET) surface area, together with abundant and uniformly-distributed chiral sites. In the presence of [Ti(OiPr)₄], TADDOL-CPP acts as a highly efficient and recyclable catalyst in the asymmetric addition of diethylzinc (Et₂Zn) to aromatic aldehydes. Based on the direct observation of the key intermediates, the reaction mechanism has been revealed by solid-state ¹³C magic-angle spinning (MAS) NMR spectroscopy. In combination with the catalytic testing results, characterization on the working catalyst provides further information for understanding the structure-activity relationship. We suggest that the catalytic activity of TADDOL-CPP is largely affected by the structural rigidity, cooperative catalysis, local chiral environment, and hierarchical porous framework. We expect that the information obtained herein will benefit to the designed synthesis of robust POP catalysts toward practical applications.

Full text of DOI:10.1002/chem.201403002

DOI: 10.1002/chem.201403002
Full Paper
&
Polymers |Very Important Paper|
Insights into the Asymmetric Heterogeneous Catalysis in Porous
Organic Polymers: Constructing A TADDOL-Embedded Chiral
Catalyst for Studying the Structure–Activity Relationship[**]
Wan-Kai An,[a] Man-Yi Han,[a] Chang-An Wang,[a] Si-Min Yu,[a] Yuan Zhang,[a] Shi Bai,[a] and
Wei Wang*[a, b]
Abstract: Construction of porous organic polymers (POPs)
as asymmetric catalysts remains as an important but chal-
lenging task. Herein, we exploit the “bottom-up” strategy to
facilely synthesize an a,a,a’,a’-tetraaryl-1,3-dioxolane-4,5-di-
methanol (TADDOL)-based chiral porous polymer (TADDOL-
CPP) for highly efficient asymmetric catalysis. Constructed
through the covalent linkages among the three-dimensional
rigid monomers, TADDOL-CPP possesses hierarchical porous
structure, high Brunauer–Emmett–Teller (BET) surface area,
together with abundant and uniformly-distributed chiral
sites. In the presence of [Ti(OiPr)4], TADDOL-CPP acts as
a highly efficient and recyclable catalyst in the asymmetric
addition of diethylzinc (Et2Zn) to aromatic aldehydes. Based
on the direct observation of the key intermediates, the reac-
tion mechanism has been revealed by solid-state 13C magic-
angle spinning (MAS) NMR spectroscopy. In combination
with the catalytic testing results, characterization on the
working catalyst provides further information for under-
standing the structure–activity relationship. We suggest that
the catalytic activity of TADDOL-CPP is largely affected by
the structural rigidity, cooperative catalysis, local chiral envi-
ronment, and hierarchical porous framework. We expect that
the information obtained herein will benefit to the designed
synthesis of robust POP catalysts toward practical applica-
tions.
the metal supports for heterogeneous catalysis.[17a–f] In 2010,
the first metal-free POP catalyst[18] was constructed by the
“bottom-up” approach,[24] through which the Trçger’s base was
directly embedded as the catalytic moiety into the material
network. This functional POP material was applied as an achiral
heterogeneous catalyst that showed comparable activity as
the homogeneous Trçger’s base. This application-oriented
“bottom-up” strategy has therefore opened up a new ap-
proach to connecting nanoporous organic polymers with het-
erogeneous catalysis. In comparison with the traditional “anch-
ored” heterogeneous catalysts,[25] the POP catalysts prepared
by this way possess easily accessible, highly concentrated, and
homogeneously distributed catalytic sites.[26] However, the
structure–property–activity relationship is largely unknown for
the POP catalysts because of the limited examples available so
far. In this work, we exploit the “bottom-up” strategy to con-
struct a TADDOL-functionalized chiral POP material (denoted
as TADDOL-CPP, Scheme 1) for highly efficient asymmetric cat-
alysis. We focus herein on the understanding of the catalytic
mechanism for the POP materials, especially of the relationship
between the chiral porous structure and the enantioselective
control of the TADDOL-CPP catalyst.
Introduction
Rooted in the structure–property–activity relationship, the ap-
plication-oriented strategy has been serving as a rational ap-
proach for the designed synthesis of functional materials.[1–11]
For example, porous organic polymers (POPs)[1–7,9–11] have re-
cently emerged as new and promising materials for potential
applications in gas storage/separation,[3–6,9–13] light-harvest-
ing,[14] and molecular recognition/sensors,[15] mainly due to
their porous structure and p-conjugation network. Particularly,
in view of the high porosity, enhanced stability, and tunable
property, the POP materials embedded with catalytic moieties
could possibly work as new candidates for heterogeneous cat-
alysts.[9,10,16–23] For example, POP materials were first applied as
[a] W.-K. An, Dr. M.-Y. Han, Dr. C.-A. Wang, Dr. S.-M. Yu, Dr. Y. Zhang,
Prof. Dr. S. Bai, Prof. Dr. W. Wang
State Key Laboratory of Applied Organic Chemistry
College of Chemistry and Chemical Engineering
Lanzhou University, Lanzhou
Gansu 730000 (P.R. China)
[b] Prof. Dr. W. Wang
Collaborative Innovation Center of
Chemical Science and Engineering
Tianjin 300071 (P.R. China)
Over the past 30 years, asymmetric catalysis has appeared as
one of the most significant frontiers in organic synthetic re-
search.[27] Remarkable progress has been made in the develop-
ment of efficient chiral catalysts for numerous enantioselective
reactions.[27,28] However, only a handful of homogeneous asym-
E-mail: wang_wei@lzu.edu.cn
[**] TADDOL=tetraaryl-1,3-dioxolane-4,5-dimethanol.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403002.
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porous catalyst for the asymmet-
ric addition reaction of Et2Zn to
aromatic aldehydes. In the pres-
ence of [Ti(OiPr)4], TADDOL-CPP
presents excellent enantioselec-
tivity control (up to 94% enan-
tiomeric excess (ee)) to a variety
of aldehyde substrates and
could be easily recovered and
reused for at least 11 iterative
cycles.
Along with the catalytic test-
ing results, the detailed charac-
terization on the working
TADDOL-CPP/Ti catalyst provid-
ed insightful information on the
structure–property–activity rela-
tionship. Specifically, the trans-
formation of 13C-labeled benzal-
dehyde reactant on the catalyst
was directly monitored by solid-
state 13C NMR spectroscopy. We
propose that the excellent cata-
lytic activity of chiral TADDOL-
CPP is attributed to the rigid
network, evenly dispersed dihy-
Scheme 1. “Bottom-up” construction of TADDOL-embedded chiral porous polymer (TADDOL-CPP) through a con-
cise three-step route. As shown in the X-ray single-crystal structure of the functional building block 4, the four
benzene rings are positioned as butterfly wings, which could offer the steric shielding for asymmetric catalysis. To
investigate the cooperative nature of the working catalyst for the asymmetric addition reaction of Et2Zn to aro-
matic aldehydes, the TADDOL-CPP was further treated with [Ti(OiPr)4] to afford the TADDOL-CPP/Ti (see the main
text for details). Reagents and conditions: a) Mg, I2, THF, under Ar, 808C, 7 h; b) K2CO3, CH3OH, RT, 2 h;
c) [Pd(PPh3)2Cl2], CuI, PPh3, DMF, Et3N, under Ar, 808C, 3 d; d) [Ti(OiPr)4], toluene, under Ar, RT, 16 h.
droxy
sites,
local
“chiral
metric reactions have successfully been transferred into indus-
trial applications.[28] One of the main challenges is that most of
the scaling-up processes suffer from the costly preparation of
the chiral catalysts/ligands and from the tedious separation of
the reaction products.[26] An effective solution to these vital
problems is therefore to prepare the heterogeneous chiral cat-
pocket”,[31] and hierarchical[32] porous structure. The informa-
tion disclosed herein should therefore shed light on the de-
signed synthesis of robust POP catalysts towards the industrial
applications.
alysts that can be easily recycled and reused.[26,29] In this con- Results and Discussion
text, the chiral and porous POP catalysts, if they can be con-
Designed synthesis and characterization of TADDOL-CPP
structed, meet these requirements and possess additional ad-
vantages by providing accessible catalytic sites and facilitating
the mass transport.
Derived from tartaric acid, TADDOLs and their derivatives have
been playing a key role in the asymmetric synthesis, racemic
mixture separation, supramolecular chemistry, and the prepara-
tion of chiral liquid crystals and NMR-shift reagents.[32] In partic-
ular, beneficial from the strong interactions such as those be-
tween the dihydroxy groups and various H-bond recep-
tors,[33,34] TADDOLs and their derivatives could act as efficient
catalysts or ligands to catalyze a variety of highly enantioselec-
tive reactions.[35–44] Because of the catalytic importance of the
TADDOL family, heterogenization onto various supports[34,45–50]
through the post-synthesis[34,45–48] or copolymerization strat-
egy[34,45,50] has been attempted. For example, targeting the re-
cyclable use of the TADDOL catalysts, Seebach and co-workers
have reported the successful immobilization of TADDOLs on
resin,[34] silica gel,[47] and dendrimers.[34,49] It should be noted
that the post-synthetic immobilization in general suffers from
the disadvantages[25] of tedious synthetic efforts, less and
uneven catalytic sites, and poor stability of the catalyst.
Very few chiral POPs have been reported to date.[20–23] To-
wards the potential applications of chiral POP catalysts, further
development is expected to meet the following criteria: 1) The
synthesis of chiral POP catalysts should be concise and based
on inexpensive and readily available chemicals; 2) The porous
frameworks are robust and embedded with highly accessible
catalytic sites; 3) The catalysts should possess excellent catalyt-
ic performance in the stereoselectivity together with the reac-
tion yield; 4) The catalysts are reusable and easily recyclable. In
addition, it would be highly desirable that the catalytic proper-
ties of the POP catalysts can be tuned upon the understanding
of the structure–property–activity relationship.
According to these criteria, we report herein the designed
synthesis, characterization, asymmetric catalysis, and mechanis-
tic study of a TADDOL-based chiral porous polymer, TADDOL-
CPP. As shown in Scheme 1, “bottom-up” incorporation of
chiral TADDOL moieties into the POP network was facilely ach-
ieved in three steps from the simple reagents. Moreover, the
resulting TADDOL-CPP material is an excellent heterogeneous
Compared with the immobilization strategy, the “bottom-
up” approach applied herein (Scheme 1) not only enables
a convenient construction of TADDOL-CPP porous network,
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but also guarantees the uniform distribution of catalytic
TADDOL sites. Moreover, to improve the BET surface area and
the pore volume of the POP material, three-dimensional rigid
monomers 4 and 5 were selected in our design as the func-
tional and structural building blocks, respectively. Starting from
the commercially available tartaric acid derivative (4R, 5R)-1,
the synthesis of tetraethynyl TADDOL derivative 4 could be
easily performed by using the Grignard reaction[38b,51] followed
by the deprotection of the trimethylsilyl (TMS) groups
(Scheme 1). The TADDOL-CPP catalyst was, therefore, easily
prepared with a yield of 97% through the Sonogashira–Hagi-
hara cross-coupling reaction of 4 and the structural monomer,
tetrakis(4-bromophenyl)methane 5, at 808C (see the Experi-
mental Section for details). The thermogravimetric analysis
(TGA) revealed that TADDOL-CPP was stable up to 2708C
under a nitrogen atmosphere (the Supporting Information, Fig-
ure S1). The powder X-ray diffraction (XRD) spectrum of
TADDOL-CPP displayed broad peaks (the Supporting Informa-
tion, Figure S2). Meanwhile, the scanning electron microscopy
(SEM) and transmission electron microscope (TEM) showed
that TADDOL-CPP consisted of platelet-like units (30–50 nm in
size) with rough surfaces (the Supporting Information, Figur-
es S4 and S5).
group, whereas those at d=78 and 108 ppm are assigned to
the carbon atoms on the 1,3-dioxolane ring. Meanwhile, the
signals at d=64 and 67 ppm are characteristic for the quater-
nary carbon atoms on the tetrakis(phenyl)methane moiet-
ies.[12,22,52] TADDOL-CPP network also showed the 13C NMR
spectroscopic signal of the internal alkyne group (CArÀCꢀCÀ
CAr) at d=89 ppm.[1,18,19] For the purpose of comparison, the
liquid 13C NMR spectrum of the monomer 4 is also shown (Fig-
ure 1a). It can be seen that the chemical shifts of the 13C NMR
spectroscopic signals for TADDOL-CPP (Figure 1b) are in
agreement with those observed for 4 (Figure 1a) in a liquid. In
addition, the FTIR spectrum of TADDOL-CPP (the Supporting
Information, Figure S3) showed a strong vibration peak at
3430 cmÀ1 (characteristic for the dihydroxyl groups in the
TADDOL moiety), together with a weak peak at 2200 cmÀ1 (cor-
responding to the ÀCꢀCÀ stretching). All these data provided
overwhelming evidence for the successful incorporation of
TADDOL moieties into the TADDOL-CPP network. Furthermore,
as calculated from the integration of the peak area at d=
26 ppm in the quantitative 13C high-power proton decoupling
(HPDEC) MAS NMR spectra (the Supporting Information, Fig-
ure S9), the TADDOL content in TADDOL-CPP was determined
as 0.93 mmolgÀ1 (see the Supporting Information for the calcu-
lation details). This value (theoretical value of 1.14 mmolgÀ1) is
much higher than those reported[34,45–48] for TADDOL-immobi-
lized catalysts. For example, in the controlled-pore glass (CPG)-
bound materials,[47] the highest TADDOL content is only
0.32 mmolgÀ1.
The covalent bonding in TADDOL-CPP was confirmed by
solid-state 13C cross-polarization magic-angle spinning (CP/
MAS) NMR spectroscopy (Figure 1). As shown in Figure 1b, the
13C NMR spectroscopic signals at d=122, 128, 130, and
145 ppm can be assigned to the carbon atoms on the phenyl
rings. The peak at d=26 ppm corresponds to the methyl
The nitrogen sorption measurements at 77 K verified the co-
existence of micropores (55% of total surface area) and meso-
pores (45% of total surface area) in TADDOL-CPP (the Support-
ing Information, Figure S7). Thus, constructed from the rigid
three-dimensional building blocks 4 and 5, TADDOL-CPP ex-
hibits the expected high Brunauer–Emmet–Teller (BET) surface
area (781 m2 gÀ1) and pore volume (0.43 cm3 gÀ1). Moreover,
the hierarchical porous structure may have a unique advant-
age: The micropores offer the confined space for a better ste-
reocontrol, whereas the mesopores facilitate the mass trans-
port of the reactants and products during the catalytic pro-
cess.[32] This issue will be discussed in detail later.
Catalytic performance of TADDOL-CPP
We then explored the catalytic activity of TADDOL-CPP. As it is
well known, the asymmetric addition of Et2Zn to aldehydes
provides a feasible approach to the synthesis of optically pure
secondary alcohols that are among the most important inter-
mediates in the pharmaceutical synthesis.[53] The research on
homogeneous systems has proposed that the dihydroxy
groups of TADDOLs[34] can easily coordinate with TiIV and the
obtained cooperative catalysts are essential for the asymmetric
addition of Et2Zn to aldehydes. Accordingly, we used TADDOL-
CPP as the asymmetric heterogeneous catalyst in the addition
reaction of Et2Zn to aldehydes. We found that, in the presence
of [Ti(OiPr)4], TADDOL-CPP presented excellent enantioselec-
tive control (84–94% ee) to a variety of aldehyde substrates.
Figure 1. The liquid 13C NMR spectrum (CDCl3, 100 MHz) of the chiral mono-
mer 4 (a), and the solid-state 13C CP/MAS NMR (100 MHz) spectra of
TADDOL-CPP (b), TADDOL-CPP/Ti (c), and the recycled TADDOL-CPP after
the 11th run (d). The asterisks denote the spinning sidebands. The 13C NMR
signal at d=21 ppm is due to the residual toluene.
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condition for the asymmetric addition of Et2Zn to aromatic al-
dehydes was then chosen to be 20 mol% of TADDOL-CPP
with 2.0 equiv of [Ti(OiPr)4] at a reaction temperature of
À308C. For the purpose of comparison, the chiral monomer 3
was also applied to catalyze the same reaction. The catalytic
results (Table 1, entry 13) showed that TADDOL-CPP possesses
the comparable activity (reaction in 48 h) as its homogeneous
counterpart 3 (reaction in 24 h).
Table 1. Optimization of the reaction conditions for the asymmetric addi-
tion of Et2Zn to benzaldehyde catalyzed by TADDOL-CPP in the presence
of [Ti(OiPr)4].[a]
Entry
Catalyst
[mol%]
[Ti(OiPr)4]
[equiv]
T
[8C]
Yield[b]
[%]
ee[c]
[%]
After establishing the optimal reaction condition, we next
examined the substrate scope for this reaction. As revealed in
Table 2, a wide range of aromatic aldehydes with either the
1
2
3
4
5
TADDOL-CPP (10)
TADDOL-CPP (20)
TADDOL-CPP (30)
TADDOL-CPP (20)
TADDOL-CPP (20)
TADDOL-CPP (20)
TADDOL-CPP (20)
–
1.7
1.7
1.7
1.7
1.7
2.0
2.3
–
2.0
–
–
1.8
2.0
À30
À30
À30
À40
À20
À30
À30
À30
À30
À30
À30
À30
À30
77
78
74
79
73
86
80
trace
58
18
21
81
93 (79[i])
88
91
90
91
89
91
91
–
0
0
36
90
96
6
7
Table 2. Asymmetric addition of Et2Zn to aromatic aldehydes catalyzed
by TADDOL-CPP in the presence of [Ti(OiPr)4].[a]
8[d]
9[e]
10[f]
11[g]
12[g]
13[h]
–
TADDOL-CPP (20)
TADDOL-CPP/Ti (20)
TADDOL-CPP/Ti (20)
3 (20)
Entry
Product
Yield[b]
[%]
ee[c]
[%]
[a] General conditions: Benzaldehyde (0.19 mmol), Et2Zn (0.57 mmol), an-
hydrous toluene (1.3 mL), 48 h. TADDOL-CPP (or 3) and [Ti(OiPr)4] served
as the cooperative catalyst. [b] Yield of the isolated product. [c] Deter-
mined by chiral HPLC (Daicel chiral OD-H column). The absolute configu-
ration of the product was determined according to the references.[35,54]
[d] The reaction without any catalyst. [e] [Ti(OiPr)4] alone was used as the
catalyst. [f] TADDOL-CPP alone was used as the heterogeneous catalyst.
[g] The isolated TADDOL-CPP/Ti was used as the heterogeneous catalyst.
[h] The homogeneous counterpart 3 and [Ti(OiPr)4] were used as the co-
operative catalyst. [i] Yield for the reaction catalyzed by 3 in 24 h.
1
2
86
95
91
88
3
4
5
90
92
96
92
91
84
Moreover, the control experiments verified the cooperative cat-
alysis contribution from both TADDOL-CPP and [Ti(OiPr)4].
We first examined the catalytic activity of TADDOL-CPP in
asymmetric addition of Et2Zn to benzaldehyde (Table 1). In the
presence of 10 mol% of TADDOL-CPP and 1.7 equiv of [Ti-
(OiPr)4], the reaction proceeded smoothly in toluene at À308C
(Table 1, entry 1), producing the desired chiral secondary alco-
hol in good yield (77%) and with a high ee value (88%). The ee
value could be further enhanced to 91% when the loading of
TADDOL-CPP was increased to 20 mol% (Table 1, entry 2). Fur-
ther increase of the TADDOL-CPP loading to 30 mol% resulted
in, however, a similar yield and ee value (Table 1, entry 3). In-
vestigation on the influence of the reaction temperature re-
vealed that À308C was appropriate for the reaction (Table 1,
entries 2, 4, and 5). As reported by Gau et al.,[55] an appropriate
increase in the amount of [Ti(OiPr)4] could reduce the side re-
actions. Consequently, an improved yield (86%, Table 1,
entry 6) was achieved by using 2.0 equiv of [Ti(OiPr)4] relative
to benzaldehyde. Importantly, control experiments further
showed that the reaction could not proceed in the absence of
the catalysts (Table 1, entry 8). Moreover, [Ti(OiPr)4] alone could
catalyze this addition reaction (58% yield) but with no enantio-
selectivity (Table 1, entry 9). These results demonstrated the co-
operativity of the catalysts: [Ti(OiPr)4] is necessary for binding
and activating the substrates, whereas TADDOL-CPP is respon-
sible for the enantioselective control. By recognizing the coop-
erative nature of the working catalysts, the optimal reaction
6
7
92
96
90
94
[a] General conditions: aromatic aldehydes (0.19 mmol), TADDOL-CPP
(0.038 mmol), [Ti(OiPr)4] (0.38 mmol), Et2Zn (0.57 mmol), anhydrous tolu-
ene (1.3 mL), 48 h. TADDOL-CPP and [Ti(OiPr)4] served as the cooperative
catalyst. [b] Yield of the isolated product. [c] Determined by chiral HPLC.
electron-withdrawing or electron-donating substituents on the
benzene ring are well applicable (Table 2, entries 1–7), produc-
ing the chiral secondary alcohols in excellent yields (86–96%)
and with high ee values (84–94%). The electronic feature and
the substituent position (meta or para) on the benzene ring
exhibited only a slight effect on the stereoselectivity of the re-
action products. Compared with benzaldehyde, the 2-naph-
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thaldehyde substrate showed even better results, producing
the corresponding product in 96% yield and with 94% ee
(Table 2, entry 7).
Catalytic mechanism of TADDOL-CPP
In accordance with those found[57] for the homogeneous sys-
tems, our results (Table 1, entries 6–12) have shown the clear
evidence for the cooperative catalysis of TADDOL-CPP and [Ti-
(OiPr)4]. To gain further insights into the reaction mechanism,
we prepared the cooperative TADDOL-CPP/Ti catalyst through
a post-treatment[34] of TADDOL-CPP with [Ti(OiPr)4] (Scheme 1).
The obtained TADDOL-CPP/Ti catalyst was then subject to
characterization. As shown in the 13C CP/MAS NMR spectrum
(Figure 1c), the increased signal at d=26 ppm and the new
signal at d=81 ppm originate from the carbon atoms of the
isopropoxy groups in TADDOL-CPP/Ti. The chemical shifts of
other 13C NMR signals for TADDOL-CPP/Ti (Figure 1c) remain
unchanged as those for TADDOL-CPP (Figure 1b). Compared
with TADDOL-CPP, TADDOL-CPP/Ti exhibits a slightly lower
thermal stability, as revealed by the TGA measurement (the
Supporting Information, Figure S1). The inductively coupled
plasma (ICP) analysis indicated that the Ti content in TADDOL-
CPP/Ti was 3.0%, which is in consistent with the calculated
value (3.8%). Energy-dispersive X-ray spectroscopic (EDX) anal-
ysis also afforded evidence for the existence of the titanium
species (the Supporting Information, Figure S6). As shown in
the SEM and TEM images (the Supporting Information, Fig-
ure S4 and S5), the morphology of TADDOL-CPP/Ti is similar
to that of TADDOL-CPP. In addition, the measured BET surface
area of TADDOL-CPP/Ti is 579 m2 gÀ1. All these information in-
dicated that the TiIV species has successfully been chelated
within the TADDOL-CPP polymeric network, and the porous
structure of TADDOL-CPP was well maintained during the
post-modification with [Ti(OiPr)4]. As expected, the TADDOL-
CPP/Ti catalyst showed excellent catalytic performance in the
enantiocontrol (Table 1, entries 9–12). These results once again
confirmed the cooperativity of TADDOL-CPP/Ti: [Ti(OiPr)4] for
the substrate activation and TADDOL-CPP for the enantioselec-
tive control.
Figure 2. The reaction mechanism proposed for the asymmetric addition of
Et2Zn to aromatic aldehydes (PhCHO as an example) catalyzed by TADDOL-
CPP/[Ti(OiPr)4]. The deactivation of catalyst could be caused by the formed
metallic oxides and the residual organic species occluded into the pores of
13
*
the working catalyst. The C chemical shifts of the marked ( ) atoms are in-
dicated.
or E can be further converted to the corresponding chiral sec-
ondary alcohols.
The proposed mechanism (Figure 2) was further verified by
our 13C NMR spectroscopic observation of the intermediates B
(or D), C, and E on TADDOL-CPP/Ti. For this purpose, the se-
lectively 13C-labeled Ph13CHO (see the Supporting Information
for its synthesis and characterization) was used as the sub-
strate, and the catalytic process was directly monitored with
solid-state 13C CP/MAS NMR spectroscopy. Compared with that
of the blank TADDOL-CPP/Ti catalyst (Figure 1c), the NMR
spectra (Figure 3) of the working TADDOL-CPP/Ti catalysts
showed a significant difference, demonstrating the transforma-
tion of 13C-labeled Ph13CHO. For clarity, the new signals are
We propose herein a possible reaction mechanism (Figure 2)
for the heterogeneous asymmetric addition catalyzed by
TADDOL-CPP/[Ti(OiPr)4] based on our observation and those
from the homogeneous systems.[57] Initially, the ethyl group of
Et2Zn and the isopropoxy group of TADDOL-CPP/Ti exchange
with each other[57a] to produce a primary intermediate A. The
benzaldehyde substrate can be fixed through the Ti···O=CÀ in-
teraction and activated upon the TiIV active sites of A, through
which the enantioselectivity can be controlled and the chiral
intermediate B is formed. The intermediate B can be converted
back to A or reacted further to D through the exchange reac-
tions. Meanwhile, the excess of [Ti(OiPr)4] will recover TADDOL-
CPP/Ti from B or D to produce E, and consequently, promote
the catalytic cycle.[57a] Thus, the reaction could proceed effi-
ciently in this TADDOL-based catalytic system. Finally, when
treated with the saturated NH4Cl solution, the intermediates C
marked as “ ” in Figure 3. In Figure 3a is shown the 13C CP/
!
MAS NMR spectrum recorded for the transformation of
Ph13CHO on TADDOL-CPP/Ti (reaction condition as in Table 1,
entry 12). The new signals at d=80 and 90 ppm are attributed
to the intermediates C and E, respectively. These assignments
have been supported by liquid 13C NMR data: We synthesized
the intermediates C and E, which indeed showed the liquid
13C NMR signals at d=82 and 88 ppm, respectively (the Sup-
porting Information, Figure S10). In addition, the supernatant
after the heterogeneous reaction showed the liquid 13C NMR
signals at d=82 and 88 ppm as well (the Supporting Informa-
tion, Figure S11). Furthermore, adsorption of C and E on
TADDOL-CPP resulted in the 13C CP/MAS NMR signals at d=80
and 90 ppm, respectively (the Supporting Information, Fig-
ure S12). All these data verified the existence of the intermedi-
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Table 3. Asymmetric addition of Et2Zn to aromatic aldehydes catalyzed
by TADDOL-CPP or 3 in the presence of [Ti(OiPr)4].[a]
Entry
1
Product
Yield[b]
[%]
ee[c]
[%]
96 (99[d]
84 (95[d]
)
)
94 (99[d]
)
)
2
3
74 (93[d]
91 (88[d]
)
65 (86[d]
)
[a] General conditions: aromatic aldehydes (0.19 mmol), TADDOL-CPP (or
3) (0.038 mmol), [Ti(OiPr)4] (0.38 mmol), Et2Zn (0.57 mmol), anhydrous tol-
uene (1.3 mL), 48 h. TADDOL-CPP (or 3), and [Ti(OiPr)4] served as the co-
operative catalyst. [b] Yield of the isolated product. [c] Determined by
chiral HPLC. [d] For the purpose of comparison, compound 3 and [Ti-
(OiPr)4] were used as the cooperative catalyst and the obtained results
are presented in parentheses.
Figure 3. Solid-state 13C CP/MAS NMR (100 MHz) spectra of the TADDOL-
CPP/Ti catalyst for the reaction of Et2Zn and Ph13CHO with (a) and without
(b) the adding of additional [Ti(OiPr)4]. The asterisks denote the spinning
13
sidebands. The C-labeled atoms are marked as ( ), and their 13C NMR
*
chemical shifts are indicated. Unmarked signals are due to the carbon atoms
on the blank TADDOL-CPP/Ti catalyst (see Figure 1c).
ates C and E on TADDOL-CPP/Ti catalyst, through which the
catalytic cycle in Figure 2 can be validated.
tries 1–3). These results imply that, in addition to the local
chiral environment, the nanopores (together with the pore
walls) of TADDOL-CPP should have further impacts on the
enantioselectivity. Therefore, only the aldehyde substrates with
suitable size that matches well with the microporous dimen-
sions of TADDOL-CPP could possibly achieve a higher ee
value. In this context, the large mesopores may mainly offer an
access to the catalytic sites and promote the mass transport
process. In fact, the hierarchical structures containing both mi-
cropores and mesopores have long been pursued in inorganic
zeolites as a key solution to improving the catalytic per-
formance.[32] The same concept has been applied therein: The
micropores in the hierarchical zeolites govern the shape-selec-
tive catalysis, whereas the mesopores (or macropores) improve
the site accessibility and molecular transport.
The additional signal at d=70 ppm in Figure 3a should orig-
inate from the surface species B (or D, their chemical shifts
cannot be distinguished). Without the addition of the excess
[Ti(OiPr)4] (reaction condition as in Table 1, entry 11), the signal
at d=70 ppm dominates the corresponding 13C CP/MAS NMR
spectrum (Figure 3b). The difference between Figure 3a and
3b accordingly highlights the role for the excess [Ti(OiPr)4]:
The surface species B and D can be further transformed upon
reaction with [Ti(OiPr)4], which promotes the catalytic cycle
shown in Figure 2. Besides, the signals at d=63 and 174 ppm
in Figure 3b are characteristics of 13C-benzyloxy and -benzoate
species, both of which come from the side reactions of
Ph13CHO.[58] These two signals are absent in Figure 3a, imply-
ing that the excess [Ti(OiPr)4] could suppress the side reaction-
s.[57a] It is worth mentioning that, by 13C liquid and solid-state
NMR spectroscopy, we have identified the key intermediates
formed in the reaction of diethylzinc to aromatic aldehydes.
This information has never been obtained before in any other
homogeneous or heterogeneous systems.
Recyclability and deactivation mechanism of TADDOL-CPP
Finally, we evaluated the stability and recyclability of TADDOL-
CPP. The recycling experiments were carried out with the
asymmetric addition of Et2Zn to benzaldehyde under the opti-
mal reaction conditions as in Table 1, entry 6. Compared with
JH-CPP,[22] an efficient heterogeneous organocatalyst for the
asymmetric Michael addition reaction, TADDOL-CPP showed
remarkable enhancement in the recyclability and catalytic sta-
bility. As shown in Figure 4, TADDOL-CPP can be reused for at
least 11 iterative runs without an obvious loss of activity (yield
from 86 to 77%; however, the ee value decreases from 91 to
76%). The 13C CP/MAS NMR spectrum recorded for the catalyst
used after the 11th run revealed that the spectral features of
The mechanism proposed in Figure 2, however, has not con-
sidered the contribution from the inherent pores of the
TADDOL-CPP catalyst. Additional control experiments showed
that the enantioselectivity of the reaction products was affect-
ed by the size of the polycyclic aromatic aldehydes: the larger
substrate gave the lower ee value (Table 3, entries 1–3). Com-
pared with TADDOL-CPP, the homogeneous counterpart 3
showed better enantioselectivity when catalyzing the same
bulky aldehydes (data shown in the parentheses, Table 3, en-
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ments for the diastereoselectivity and the reaction yield. For
this purpose, we first synthesized chiral TADDOL-CPP catalyst
through a concise three-step route (Scheme 1). The catalytic
reactions under different conditions and with different sub-
strates not only identified the cooperative nature of the work-
ing catalyst but also improved our understanding on the struc-
ture–activity relationship. The key information obtained is sum-
marized as follows.
Design principle
The first prerequisites for reaching an excellent performance in
asymmetric catalysis are rational design and concise synthesis
of the chiral catalyst itself. Similar for the homogeneous or im-
mobilized catalysts, the rational design for the chiral POP cata-
lysts should at least include the concerns of the binding
(active) site and the chiral environment: The binding site
would anchor the substrates upon activation and the chiral en-
vironment could adjust the orientation of substrates upon re-
action. Under the optimal reaction conditions, the cooperative
nature between binding site and chiral environment should
bring about the best enantiocontrol. In this study, the TiIV
center serves as a binding site and the TADDOL-CPP network
offers the chiral environment (Figure 2). The cooperative catal-
ysis has well been evidenced by the catalytic results (Table 1,
entries 6–12). In addition, the construction of permanent
porous structure is key to ensure the accessibility of the active
sites and facilitate the mass transport. To improve the BET sur-
face area and the pore volume of TADDOL-CPP, three-dimen-
sional rigid monomers 4 and 5 were selected as the functional
and structural monomers, respectively. The reproducibility for
synthesis of porous catalysts and for their catalytic activity
much relies on the rigidity of building blocks and on the pre-
cise control of the reaction conditions.
Figure 4. Evaluation of the recyclability of TADDOL-CPP in the asymmetric
addition of Et2Zn to benzaldehyde. All the recycling experiments reactions
(runs 2 to 11) were carried out for 48 h with benzaldehyde (0.19 mmol)
under identical condition as in Table 1, entry 6. The yield of the isolated
product is given for each run.
TADDOL-CPP were well maintained (Figure 1d), indicating that
the TADDOL-CPP network is robust for recycling and reuse.
Upon the repeated recycling, the micropores in TADDOL-CPP
may gradually capture the guest molecules (e.g., the residual
products, unreacted substrates, and so on). Indeed, the 13C CP/
MAS NMR spectrum recorded for the recycled TADDOL-CPP
after the 11th run showed small changes in the high-field
region (d=0 to 50 ppm, Figure 1d), implying the inclusion of
bulky organic species. Meanwhile, the increased Ti content
(4.4%) identified by the ICP analysis of TADDOL-CPP after the
11th run also suggested the formation of inorganic titanium
oxide species (TiO2). Indeed, liberation from the organic metal
species has been suggested as the origin for the formation of
metal oxides (Figure 2).[34,47] The BET surface area and the total
volume of the recycled TADDOL-CPP catalyst after the 6th run
were decreased to 421 m2 gÀ1 and 0.29 cm3 gÀ1, respectively
(the Supporting Information, Figure S8b). Further decrease of
the BET surface area to 148 m2 gÀ1 and of the total volume to
0.09 cm3 gÀ1 was found for the recycled TADDOL-CPP after the
11th run (the Supporting Information, Figure S8c). Gradual de-
crease in the enantioselectivity could therefore attribute to the
diminished BET surface area and the total volume. It emphasiz-
es again the importance of the porous structure for the cata-
lytic performance of TADDOL-CPP. Accordingly, instead of the
decomposition of TADDOL-CPP network, the residual bulky or-
ganic species and the metallic oxides (TiO2 or ZnO) occluded
within the pores should be the main reasons for the deactiva-
tion of the TADDOL-CPP catalyst.
Uniform distribution of the catalytic sites
Facilely constructed through the covalent bonding of rigid
monomers, the porous TADDOL-CPP is robust and uniformly
embedded with accessible dihydroxy groups. Lin and co-work-
ers recently reported the use of 1,1’-binaphthyl-embedded
cross-linked polymer/Ti (denoted as CCP/Ti) as a Lewis acid cat-
alyst to promote asymmetric addition of Et2Zn to aldehydes.[20]
The CCP/Ti catalyst could afford the alcohol products in quanti-
tative yields but with only modest ee values (55–81%). They
proposed that the low ee values could be attributed to the for-
mation of intermolecular [(OiPr)2Ti-(BINOL)2] (BINOL=1,1’-bi-2-
naphthol) binary complexes upon the further reaction of [Ti-
(OiPr)4].[20,56] Because the TADDOL moieties in TADDOL-CPP
were evenly separated by the bulky 3D structural units, the si-
multaneous interaction of [Ti(OiPr)4] with two TADDOL moiet-
ies to form the similar binary complexes could be prevented.
As a result, excellent ee values were obtained in our case.
Discussion on the structure–property–activity relationship
Exploration of the POP materials for heterogeneous catalysis is
a new research topic and, thus, very little information is avail-
able for the application-oriented synthesis of highly efficient
POP catalysts. Particularly, for the designed construction of
chiral POPs, an excellent enantioselective performance should
be considered as the first priority in addition to the require-
Chem. Eur. J. 2014, 20, 11019 – 11028
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Local “chiral pocket”
excellent asymmetric catalytic activity (up to 94% ee) in
asymmetric addition reaction of Et2Zn to aromatic alde-
hydes. Meanwhile, beneficial from the rigid and hierarchical
porous structure with abundant mesopores, TADDOL-CPP
could be easily recovered and reused for at least 11 itera-
tive cycles without a significant loss of its catalytic activity.
3) In an effort to offer further insights on the designed syn-
thesis of the robust POP catalysts, we studied the reaction
mechanism involved in the chiral POP catalysis. By using
solid-state 13C MAS NMR spectroscopy, we observed directly
the key intermediates formed upon the reaction of 13C-la-
beled benzaldehyde reactant on the catalyst. The porous
structure has ensured the formation of these intermediates
in a large amount so that the direct 13C NMR spectroscopic
observation is feasible. Meanwhile, we found the key pa-
rameters (such as the building blocks, cooperative catalysis,
local chiral environment, and hierarchical porous structure)
that affect the catalytic performance of TADDOL-CPP.
The unique structure in TADDOL-CPP offers an ideal chiral en-
vironment for enantiocontrol. We were able to obtain the
single crystals of monomer 4 (the Supporting Information). The
X-ray single-crystal structure of 4 (Scheme 1) shows that, the
four benzene rings are arranged like rigid butterfly wings,
which could offer the steric shielding. The bulky benzene rings
in the network of TADDOL-CPP has afforded the local “chiral
pocket”.[31] The best orientation for reaction substrates could
be reached within this “chiral pocket”, which ensures the high
stereoselectivity of the products. The importance of this “chiral
pocket” was also verified by the excellent performance of the
homogeneous catalyst 3 (Table 1, entry 13).
Hierarchical porous structure
For the porous catalytic systems, a key question to answer is
whether the catalysis being performed within the pores or on
the outer surface. It is quite clear in this study that the asym-
metric heterogeneous catalysis takes place within the
TADDOL-CPP nanopores as well. Firstly, TADDOL-CPP and its
homogeneous counterpart 3 showed comparable activity for
the smaller substrates but showed difference for the bulky
ones. Secondly, the partial blocking of the nanopores in the re-
cycled TADDOL-CPP catalyst resulted in the slight decrease of
the catalyst activity (Figure 4).
With the excellent activity and recyclability, the easily pre-
pared TADDOL-CPP catalyst may have further applications in
the industrial production of chiral secondary alcohols. More-
over, TADDOL-CPP may also be used as an efficient heteroge-
neous catalyst to promote various asymmetric reactions, such
as the Diels–Alder and Mukaiyama-aldol reactions. Besides, as
a good H-bond donor, TADDOL-CPP could also work as a new
candidate for the stationary phases of HPLC or GC for the
enantiomer separation.[34] Furthermore, we expect that the
mechanism-related information offered herein may shed new
light on the designed synthesis of robust POP catalysts.
Conclusion
Recent years have witnessed a rapid development in the new
research area of POP materials. Towards the practical applica-
tion of functional POPs in asymmetric heterogeneous catalysis,
we achieved herein a concise construction of a TADDOL-de-
rived chiral POP catalyst, TADDOL-CPP, and investigated its
structure–property–activity relationship in catalyzing the asym-
metric addition reaction of Et2Zn to aromatic aldehydes. The
main results obtained are summarized in the following:
Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (No. 21172103), the 111 project, the Innovative
Research Team in University (PCSIRT: IRT1138), and the Funda-
mental Research Funds for the Central Universities (lzujbky-
2013-ct02) is gratefully acknowledged. We thank Prof. Wei Yu
at Lanzhou University for the valuable comments.
1) For the first time,[23c] the TADDOL moiety was used as the
functional building block for the convenient construction
of the chiral POP catalyst. Through a concise “bottom-up”
strategy shown in Scheme 1, TADDOL-CPP can be reprodu-
cibly synthesized within three steps from readily available
building blocks. Due to the efficient covalent linkages be-
tween the rigid three-dimensional building blocks,
TADDOL-CPP possesses the porous structure, high BET sur-
face area, and enhanced stability. Meanwhile, the TADDOL
moieties are evenly distributed in the network.
Keywords: chirality
·
heterogeneous catalysis
·
NMR
spectroscopy · polymers · reaction mechanisms · structure–
activity relationships
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Received: April 8, 2014
Published online on July 25, 2014
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