A novel poly(N-isopropyl-acrylamine-co-l-proline) catalyst for aldol reaction: Synthesis, catalytic performance and recyclability

Article abstract of DOI:10.1039/c4ra05951d

A novel homogeneous copolymer catalyst was synthesized via single step radical copolymerization and developed for the aldol reaction. It was demonstrated that the catalyst possessed excellent activity and stereoselectivity. The secondary structure of the

Full text of DOI:10.1039/c4ra05951d

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A novel poly(N-isopropyl-acrylamine-co-L-proline)
catalyst for aldol reaction: synthesis, catalytic
performance and recyclability†
Cite this: RSC Adv., 2014, 4, 50412
b
bc
ab
Yubing Liu,ab Qing Tong,ab Liya Ge,de Yu Zhang, Lin Hua
Received 19th June 2014
Accepted 24th September 2014
*
*
and Yining Fan
DOI: 10.1039/c4ra05951d
www.rsc.org/advances
A novel homogeneous copolymer catalyst was synthesized via single emerged as a promising strategy due to the high catalytic
step radical copolymerization and developed for the aldol reaction. It activity and low cost. In homogeneous polymer-supported
was demonstrated that the catalyst possessed excellent activity and L-proline, the polymer skeleton can act as a natural part of the
stereoselectivity. The secondary structure of the copolymer catalyst catalytic system and the amphipathic polymer provides a
was evaluated by circular dichroism. Furthermore, the catalyst was favourable catalytic microenvironment, like a pseudo-enzyme
readily recovered without loss of conversion and stereoselectivity system.8
even after ten cycles.
Herein, a novel homogeneous polymer-supported L-proline
copolymer catalyst, poly(N-isopropyl-acrylamine-co-L-proline),
which combines the merit of homogeneous and heterogeneous
processes, is synthesized by radical copolymerization. The
catalytic reaction carries out homogeneously and the catalyst
can be easily recovered by precipitation (Fig. 1). The secondary
structure of copolymer catalyst is also evaluated to elucidate the
relationship between secondary structure and selectivities in
this study.
The synthesis of polymer-supported L-proline follows the
outline shown in Scheme 1. In contrast to traditional post-
modication scheme, radical copolymerization has many
advantages, including high and controllable catalyst loading,
and less synthetic steps. With the presence of azodiisobutyr-
onitrile (AIBN) as radical initiator, the copolymerization of
N-isopropylacrylamide (NIPAM) with O-acryloyl-trans-4-hydroxy-
L-proline hydrochloride is carried out in N,N-dimethylforma-
mide (DMF) at 70 ꢀC for 8 h with a single synthetic step
L-Proline has been widely used as an organocatalyst for the
construction of asymmetric carbon–carbon bonds, since
2000.1,2 Although L-proline and its derivatives are highly effec-
tive and metal-free, used in many reactions such as aldol reac-
tions, Mannich reactions, Diels–Alder reactions and others,2–5
there are two main issues that must be considered. The rst one
is the relative low activity of catalysts, which need further
improve by choosing the appropriate functional groups or
adjusting the structure of catalysts. The second one is the
difficulty associated with recycling and reusing of the organo-
catalysts. To counterbalance these points, recent research
efforts have been dedicated to immobilizing and recycling of
L-proline and its derivatives.6,7 Among those immobilization
methods, heterogeneous materials supported L-proline has
generally reduced the catalytic activity and stereoselectivities,
whereas homogeneous polymer-supported L-proline has
aKey Laboratory of Mesoscopic Chemistry of MOE, School of Chemistry and Chemical
Engineering, Nanjing University, Nanjing 210093, Jiangsu Province, China. E-mail:
ynfan@nju.edu.cn; Fax: +86 25 83317761; Tel: +86 25 83594620
bNanjing University-Yangzhou Institute of Chemistry and Chemical Engineering,
Yizheng 211400, Jiangsu Province, China
cLinovus Technology Pte Ltd, 8 Chang Charn Road, Link (THM) Building #02-11,
Singapore 159637, Singapore. E-mail: hualin@linovus.com
dResidues and Resource Reclamation Centre, Nanyang Environment and Water
Research Institute, Nanyang Technological University, 1 Cleantech Loop, Clean Tech
One, Singapore 637141, Singapore
eNatural Sciences and Science Education Academic Group, Nanyang Technological
University, 1 Nanyang Walk, Singapore 637616, Singapore
Fig. 1 (A) The copolymer catalyst, (B) the catalytic reaction carried out
homogeneously, (C) the catalyst precipitated out of solution after
reaction.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra05951d
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moderate stereoselectivities were observed (Table 1, entry 1–5),
which could probably due to that the hydrophobic part of the
copolymer backbone played an important role in the stereo-
control.14,15 Compared with the heterogeneous catalyst system,
the homogeneous catalyst system exhibited better catalytic
performance with high conversion (98–99%) and moderate to
high stereoselectivities (anti/syn ¼ 37–99/63–1, 48–99% ee)
(Table 1, entry 6–10). Notably, the best result with respect to
conversion, diastereo- and enantioselectivities (98–99%
conversion, anti/syn ¼ 96–99/4–1, 97% ee) were achieved in
DMF/H2O and DMSO/H2O (Table 1, entry 9 and 10). However,
both conversion and stereoselectivities decreased obviously as
the content of water was increased, and enantioselectivities
decreased slightly as the amount of water was reduced (Table 1,
entry 11 and 12). This result provides evidence that appropriate
amount of water could accelerate reactions and improve ster-
eoselectivities, but the excess water resulted in low yields.16–19
For comparison, the aldol addition was performed under the
same conditions with monomer O-acryloyl-trans-4-hydroxy-L-
proline hydrochloride and poly(N-isopropylacrylamide) (PNI-
PAM) (Table 1, entry 13–17). Obviously, PNIPAM had no activity
in the aldol reaction and the monomer exhibited less stereo-
selectivities (anti/syn ¼ 40–83/60–17, 73–88% ee) compared with
the copolymer catalyst. Thus, the polymeric system is favorable
to aldol reaction. The hydrophobic/hydrophilic balance of
copolymer catalyst and the water are helpful to form hydrogen
bonds, an ideal reaction microenvironment which oen
Scheme 1 Polymer-supported L-proline by copolymerization.
(Scheme 1). The proline compositions in the copolymers
possessed different loading amounts were determined by 1H
NMR spectroscopy (Fig. S1†). Although the catalyst loading was
8.6 mol% lower than 10 mol% feed ratio, it was interesting to
nd the good linear relationship of feed ratio from 5 mol% to 20
mol% against catalyst loading (Fig. S5†). Therefore, it suggested
that the catalyst loading could be adjusted by radical
copolymerization.
A model reaction, the asymmetric aldol addition of p-nitro-
benzaldehyde to cyclohexanone, was chosen to evaluate the
copolymer catalyst (Table 1).9–11 The aldol addition was typically
carried out in polar aprotic solvents, dimethylformamide (DMF)
or dimethyl sulfoxide (DMSO), which had proven to be the
optimal media for the reaction.12,13 Thus, the reaction could be
performed heterogeneously in H2O, tetrahydrofuran (THF),
CHCl3, CH3CN and CH3COOCH2CH3, and homogeneously in
CH3OH, DMF, DMSO, DMF/H2O and DMSO/H2O. Although the
heterogeneous catalyst system gave low conversion, the
Table 1 The model aldol reaction catalyzed bycopolymer catalyst, monomer and PNIPAMa
Entry
Catalyst
Solvent
Conversionb [mol%]
anti : synb
eec [%]
1
2
3
4
5
6
7
8
III
III
III
III
III
III
III
III
III
III
III
III
II
H2O
THF
CHCl3
CH3CN
CH3COOCH2CH3
CH3OH
DMF
63
19
60
48
17
95
99
99
99
98
46
97
74
62
97
99
0
86 : 14
99 : 1
99 : 1
83 : 17
80 : 20
99 : 1
37 : 63
74 : 26
99 : 1
96 : 4
58 : 42
97 : 3
83 : 17
75 : 25
57 : 43
40 : 60
—
79
94
90
70
85
97
99
48
97
97
73
81
65
82
88
73
—
DMSO
9
DMSO/H2O (3 : 1 v/v)
DMF/H2O (3 : 1 v/v)
DMF/H2O (1 : 3 v/v)
DMF/H2O (10 : 1 v/v)
H2O
10
11
12
13
14
15
16
17
II
II
II
CH3OH
DMF/H2O (3 : 1 v/v)
DMSO/H2O (3 : 1 v/v)
DMF/H2O (3 : 1 v/v)
PNIPAM
a
Reaction conditions: p-nitrobenzaldehyde (0.0756 g, 0.50 mmol), cyclohexanone (2.0 mL), 0.5 g, 8.6 mol% loading of copolymer catalyst, 24 h, rt.
b
Determined by 1H NMR. c Determined by chiral HPLC.
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positively inuences activity and stereoselectivities of the con- high conversion (99%) and moderate stereoselectivity (88%
gurated catalyst.8,17,18,20
anti, 72% ee) were obtained. However, only 33% conversion and
It is noteworthy that all the catalytic reaction data was 84% ee were obtained when acetone was used as substrate.
obtained without treating with triethylamine (Et3N) to cause The circular dichroism (CD) and UV-vis spectroscopy of the
free amino acid polymer, which is different from the previous copolymer catalyst and monomer have been investigated (Fig. 2,
reports.21,22 Not only did it shorten the synthetic route, but also S6 and S7†). CD is a technique commonly used for probing the
inuenced the catalytic activity and stereoselectivities. It was secondary structure and chiroptical properties of proteins,
also evident that the role of the HCl as acid additive was dual, polymers and other compounds.24–26 The CD spectra of the
orienting the substrate and facilitating the formation of copolymer catalyst are signicantly different from the monomer
enamine. The same phenomenon had been observed in aldol both in H2O or MeOH. In H2O, the molecular ellipticities are as
reaction with Brønsted acid as additive to improve the activity follows: [q]l
¼ ꢁ8.03 ꢂ 104 (212 nm), +2.21 ꢂ 104 (204 nm).
(max)
and stereoselectivity.11,23
Clearly, the copolymer catalyst exhibits CD signals with negative
A series of aldehydes and ketones were also employed to Cotton effects, which is similar to polyprolineIIhelix confor-
explore the scope of the copolymer catalyst under the optimized mation,27 while the monomer possess CD signal with positive
reaction conditions (Table 2). Reaction between aldehydes with Cotton effects, suggesting the noticeable secondary structure
an electron-withdrawing group and cyclohexanone gave the differences between them. In CH3OH, the copolymer catalyst
corresponding products in high conversion (>94%) and ster- not only exhibits negative CD signal at 219 nm, but also has
eoselectivities (diastereoselectivity > 96%, ee > 91%) (entry 1–4). positive CD signal at 205 nm, while the CD signal monomer has
Electron-withdrawing groups (–NO2, –Cl, –Br) at the aromatic no signicant change compared with it in H2O (Fig. S6†). These
portion were well tolerated, however, the electron-donating results suggest that secondary structure is related to the
substituted aldehydes (–CH3 or –OCH3 substituted) resulted in conformation of copolymer catalyst in solutions and there is a
low conversions, moderate diastereo-selectivities and high dramatic change of monomer and copolymer catalyst in
enantioselectivities (entry 5 and 6). In fact, as previously secondary structure. Therefore, it is not difficult to explain that
reported, the aldehydes with electron-withdrawing groups copolymer catalyst can increase the stereoselectivities and the
showed much higher reactivity and enantioselectivity than solvents affect the stereoselectivities (Table 1, entry 1, 6, 9, 10
those with electron-donating groups.11,20,21 Moreover, the and 13–16).25 The change of structure induced the change of
expected products in excellent conversion (99%) and enantio- stereoselectivities. In other words, the secondary structure of
selectivity (97%) were observed when p-pyridinecarbox- copolymer catalyst provides an advantage in improving the
aldehyde, a heteroaromatic aldehyde, was used as the acceptor stereoselectivities and the appropriate solvent is also favorable
(entry 7). Finally, other aldol donors, such as acetone and toward increasing the stereoselectivities.
cyclopentanone, reacted with p-nitrobenzaldehyde (entry 8 and
In order to further investigate the activity of copolymer
9). In the cases of cyclic ketones (cyclohexanone and cyclo- catalyst, we turned attention to the kinetics for aldol reaction in
pentanone), the catalyst exhibited better catalytic performance polymer catalytic system (Fig. 3). Gratifyingly, we found that the
than acetone.11,18,20 When cyclopentanone was used as donor, stereoselectivities was preserved at high level (diaster-
eoselectivity > 95%, ee > 95%) aer 5 h reaction. It was found
that the stereoselectivities did not change over time. But
importantly, at the initial stage, the conversion was very low
(conversion < 10%); and aer 5 h, with the subsequent increase
in reaction time, the conversion increased from 56% to 99%.
Table 2 Asymmetric aldol reaction in DMF/H2O with copolymer
catalyst
Obviously, there was a jump in conversion between 4 and 5 h. It
Entry
n
R
Conversiona [mol%]
anti : syna
eeb [%]
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
3
0
2
o-NO2Ph
m-NO2Ph
p-ClPh
97
94
99
99
58
7
99
33
99
97 : 3
99 : 1
96 : 4
99 : 1
56 : 44
53 : 47
81 : 19
99c
96
91
99
94
95
94
97
84
72
p-BrPh
p-MePh
p-MeOPh
p-Pyridyl
p-NO2Ph
p-NO2Ph
88 : 12
Fig. 2 CD spectra of copolymer catalyst (1.0 ꢂ 10ꢁ5 mol Lꢁ1) and
monomer (1.0 ꢂ 10ꢁ5 mol Lꢁ1) in H2O.
a
Determined by 1H NMR. b Determined by chiral HPLC. c Selectivity to
4-hydroxy-4-(4-nitrophenyl)-butan-2-one.
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Fig. 3 The catalytic activity of the copolymer catalyst against time.
Fig. 4 Recyclability of the copolymer catalyst.
was probably that the catalytic rate is associated with mass
transfering the polymer catalytic system. Aer the polymer had
dissolved, the viscosity of catalytic system increased distinctly,
and thus, the reactants transfer rate decreased. It was univer-
sally accepted that the viscosity is inversely related to the mass
transfer rate, which can well explain the low conversion at the
beginning of reaction and abrupt change. This diffusion
controlled process has been widely found in polymer catalytic
system.28 The limiting factors arise from mass transfer have
always been and will continue to be one of the challenges to
overcome for polymer catalytic system.29
As the catalyst is homogeneously mixed on a molecular scale
within the reaction mixtures, recycling of the homogeneous
catalysts is a problem that must be appropriately settled to
date.21,30–32 In present work, we therefore investigated the recy-
cling potential of copolymer catalyst using diethyl ether (Et2O)
or saturated brine as the precipitants. The catalyst was readily
precipitated out of reaction mixture by addition of Et2O. Then,
the precipitated catalyst was isolated, washed, dried and reused
in the following recycle experiments.
As Fig. 3 shown, the copolymer catalyst had excellent recy-
clability. Even in the tenth run, there was no loss in conversion
(>96%) and stereoselectivities (anti/syn ¼ 99/1, 99% ee).
In addition, we also successfully recovered the copolymer
catalyst by precipitation using saturated brine, which is a green
recycling method. At the end of aldol reaction, the mixture was
added saturated brine to form three phases: aqueous phase,
organic phase and solid phase. The polymer was successfully
isolated by centrifugation. The separated organic phase was
dried over MgSO4 and concentrated under vacuum. The
aqueous phase was reused directly in the next recycling (Scheme
S1†). Under these conditions, the catalyst was used in 7 cycles
without losing signicant stereoselectivities (>95%), but the
conversion was decreased from 99% to nearly 80% aer 2 cycles
(Fig. 4). Predicated on these data, the inuence of salt on the
conversion and stereoselectivity couldn't escape notice. Gal-
lardo and co-workers suggested that the addition of salts
promoted an appreciable increase of stereoselectivity at the
expense of the conversion.15 On the other hand, the reduction in
copolymer solubility was related to the adsorption of salt on
copolymer. Thus, due to the adsorption and subsequent
adsorption saturation, the conversion was decreased signi-
cantly and subsequently retained at around 80%.
In summary, a novel homogeneous copolymer catalyst was
synthesized by the simple radical copolymerization of the
L-proline derivative with N-isopropylacrylamide. This copolymer
catalyst offers several advantages, including single synthetic
step, high catalytic activity and recyclability. It was demon-
strated that the copolymer catalyst exhibited excellent catalytic
properties, resulting in higher conversion (98–99%) and ster-
eoselectivities (anti/syn ¼ 96–99/4–1, 97% ee) in the model aldol
reaction compared to unsupported L-proline derivative mono-
mer. The CD spectra of the copolymer catalyst are apparently
different from the corresponding monomer, which, from the
point of secondary structure, suggested the supported catalyst
by copolymerization beneted promoting the catalytic activity.
Regarding to the affect of the solvent, two main issues have
been raised: (1) the solubility of copolymer catalyst, and (2) the
different secondary structure of copolymer catalyst in different
solvents. The copolymer catalyst can be recovered and reused
with the conversion keeping above 96% and high stereo-
selectivities (anti/syn ¼ 99/1, 99% ee), even aer ten cycles,
allowing efficient recycle of the copolymer catalyst. Neverthe-
less, a more detailed study will be carried out on the relation-
ship between secondary structure of copolymer catalyst and
catalytic activity.
This work was nancially supported by the Key Science &
Technology Specic Projects of Yangzhou, Jiangsu Province of
China (YZ20122029).
Notes and references
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