Synthesis of helical poly(phenylacetylene)s with amide linkage bearing l -phenylalanine and l -phenylglycine ethyl ester pendants and their applications as chiral stationary phases for HPLC

Article abstract of DOI:10.1021/ma4015802

Novel stereoregular helical poly(phenylacetylene) derivatives (PPA-Phe and PPA-Phg) with an amide linkage bearing l-phenylalanine and l-phenylglycine ethyl ester pendants were synthesized for use as chiral stationary phases (CSPs) in HPLC. The polymers showed different chiral recognition abilities depending on the coating solvents. Both PPA-Phe and PPA-Phg exhibited higher chiral recognitions when coated with CHCl₃ by having preferable conformations. Their chiral recognition abilities depended on their molecular weight and optical rotations which were influenced by the polymerization solvents and monomer concentration. PPA-Phe and PPA-Phg showed rather different chiral recognitions, indicating that the benzyl group of the former and the phenyl group of the latter also play important roles in the chiral recognition. A few racemates were completely separated on PPA-Phe or PPA-Phg with separation factors comparable or higher than those obtained on the popular polysaccharide-based CSPs.

Full text of DOI:10.1021/ma4015802

Article
pubs.acs.org/Macromolecules
Synthesis of Helical Poly(phenylacetylene)s with Amide Linkage
Bearing L‑Phenylalanine and L‑Phenylglycine Ethyl Ester Pendants
and Their Applications as Chiral Stationary Phases for HPLC
†
,‡,
†
†
†
†
§
Chunhong Zhang, * Hailun Wang, Qianqian Geng, Taotao Yang, Lijia Liu, Ryosuke Sakai,
∥
∥
†,⊥,
Toshifumi Satoh, Toyoji Kakuchi, and Yoshio Okamoto *
†Polymer Materials Research Center, College of Materials Science and Chemical Engineering, Harbin Engineering University,
Harbin 150001, China
‡
Key Laboratory of Superlight Materials and Surface Technology (College of Materials Science and Chemical Engineering,
Harbin Engineering University), Ministry of Education, Harbin 150001, China
§
Department of Materials Chemistry, Asahikawa National College of Technology, Asahikawa 071-8142, Japan
∥
Division of Biotechnology and Macromolecular Chemistry, Graduate School of Chemical Sciences and Engineering,
Faculty of Engineering, Hokkaido University, Sapporo 060-8628, Japan
⊥Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
*
S Supporting Information
ABSTRACT: Novel stereoregular helical poly(phenylacetylene)
derivatives (PPA-Phe and PPA-Phg) with an amide linkage
bearing L-phenylalanine and L-phenylglycine ethyl ester
pendants were synthesized for use as chiral stationary phases
(
CSPs) in HPLC. The polymers showed different chiral
recognition abilities depending on the coating solvents. Both
PPA-Phe and PPA-Phg exhibited higher chiral recognitions
when coated with CHCl by having preferable conformations.
3
Their chiral recognition abilities depended on their molecular
weight and optical rotations which were influenced by the
polymerization solvents and monomer concentration. PPA-Phe and PPA-Phg showed rather different chiral recognitions,
indicating that the benzyl group of the former and the phenyl group of the latter also play important roles in the chiral
recognition. A few racemates were completely separated on PPA-Phe or PPA-Phg with separation factors comparable or higher
than those obtained on the popular polysaccharide-based CSPs.
INTRODUCTION
structure, such as the one-handed helical poly(triphenylmethyl
methacrylate), have been commercialized. Several stereoregular
helical poly(phenylacetylene) derivatives bearing chiral pend-
ants, which are synthesized using a rhodium catalyst, have
proved to be prospective CSPs for the HPLC separation of
■
In recent years, considering the different pharmacokinetics,
physiological, toxicological, and metabolic activities of a pair of
enantiomers of chiral compounds, more and more scientists are
paying much more attention to the preparation and application
of the single-isomer forms of chiral pharmaceuticals, agro-
chemicals, and food additives, etc.
especially by high-performance liquid chromatography
HPLC), which can easily provide a pair of enantiomers with
a high enantiomeric excess, is recognized as a reliable tool to
20−25
enantiomers.
However, the effect of the chiral pendant
1
,2
groups and chiral recognition mechanism as CSPs are still not
well-known and have been attractive research areas.
Previously, we reported that the regular structure of the
poly(phenylacetylene) main chains is essential for the high
chiral recognition of poly(phenylacetylene)-based CSPs for
HPLC, and an amide linkage group between the poly-
Chiral separation,
(
3
−5
obtain pure enantiomers on analytical and industrial scales.
The chiral recognition ability of chiral stationary phases (CSPs)
is the key point of this separation technique. Although
polysaccharide derivatives with high chiral recognition abilities
have been widely developed as popular CSPs, optically active
synthetic polymers as CSPs have also attracted significant
(
phenylacetylene) main chains and chiral pendants showed a
higher chiral recognition than the urea or sulfonamide linkage
groups. We also reported that the coating solvents on silica gel
also played an important role in the chiral recognition because
6
−12
interest by researchers around the world.
Many optically
active synthetic polymers have been prepared and some of
them show chiral recognition abilities as CSPs for HPLC.
A few optically active synthetic polymers with a stereoregular
Received: July 28, 2013
Revised: October 11, 2013
Published: October 23, 2013
13−19
©
2013 American Chemical Society
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Scheme 1. Synthesis of Poly(phenylacetylene) Derivatives PPA-Phe and PPA-Phg
Table 1. Polymerization Results of PA-Phe and PA-Phg
a
b
c
c
[α]D20 /deg
d
polymer
monomer
yield /%
solvent
[monomer]/M
Mn
PDI
PPA-Phe-1a
PPA-Phe-1b
PPA-Phe-1c
PPA-Phe-2a
PPA-Phe-2b
PPA-Phe-2c
PPA-Phg-1a
PPA-Phg-1b
PPA-Phg-1c
PPA-Phg-2a
PPA-Phg-2b
PPA-Phg-2c
PA-Phe
PA-Phe
PA-Phe
PA-Phe
PA-Phe
PA-Phe
PA-Phg
PA-Phg
PA-Phg
PA-Phg
PA-Phg
PA-Phg
99.3
98.6
99.1
97.8
98.3
97.2
96.7
97.6
98.1
97.7
98.4
98.2
CHCl3
CHCl3
CHCl3
DMF
0.03
0.06
0.10
0.03
0.06
0.10
0.03
0.06
0.10
0.03
0.06
0.10
3.90 × 104
5.09 × 104
1.14 × 10
1.40 × 105
2.7
2.3
3.6
5.9
6.0
5.6
3.3
4.4
5.6
5.5
6.2
6.0
−714
−749
−754
−718
−707
−667
−573
−787
−805
−756
−738
−695
5
5
DMF
1.61 × 10
DMF
2.57 × 105
3
CHCl3
CHCl3
CHCl3
DMF
4.50 × 10
1.38 × 105
5
2.07 × 10
1.69 × 105
5
DMF
1.75 × 10
DMF
2.19 × 105
a
b
Polymerization condition: catalyst, Rh(nbd)BPh ; [Monomer]/[Rh(nbd)BPh ] = 45/1; temperature, 28 °C; time, 24 h. Hexane insoluble part,
determined via gravimetry. Determined by SEC in DMF containing LiCl (0.01 M) using polystyrene standards. In CHCl , specific rotations of the
monomers in CHCl : [α]D (PA-Pha) = +123°, [α]D (PA-Phg) = +58.5°.
4
4
c
d
3
20
20
3
different conformations of the helical poly(phenylacetylene)
derivatives were induced by changing the coating solvents.
purchased from Chengdu Xiya Chemistry Technology Co., Ltd.
Chengdu, China). 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methyl
2
5,26
(
morpholinium chloride (DMT-MM) (purity 98%) was purchased
from Sahn Chemical Technology Co., Ltd. (Shanghai, China).
Triphenylphosphine (purity 99%) was purchased from J&K Chemical
Co., Ltd. (Beijing, China). 4-Ethynylbenzoic acid was synthesized
In this study, we designed and synthesized novel stereoregular
one-handed helical poly(phenylacetylene) derivatives (PPA-
Phe and PPA-Phg) with an amide linkage bearing L-
phenylalanine and L-phenylglycine ethyl ester pendants in
order to develop effective CSPs for HPLC. The influence of the
molecular weight and optical activity of the polymers on the
chiral recognition abilities, and the influence of the structure of
the pendant groups on the chiral recognition abilities will be
mainly discussed.
27
+
according to a previously reported method. Rh (2,5-norbornadiene)
6
[
(η -C H )B(C H ) ] (Rh(nbd)BPh ) was prepared based on a
6 5 6 5 3 4
28
previous report. All solvents used in the reactions were of analytical
grade, carefully dried, and distilled before use. Silica gel with a mean
particle size of 37−56 μm for column chromatography was purchased
from Qingdao Haiyang Chemical Co., Ltd. (Qingdao, China). The
porous spherical silica gel with a mean particle size of 7 μm and a
mean pore diameter of 100 nm (Daiso gel SP-1000−7) for HPLC was
kindly supplied by Daiso Chemicals (Osaka, Japan), then silanized
with (3-aminopropyl)triethoxysilane in toluene at 80 °C before use.
All solvents used in the preparation of the chiral stationary phases were
of analytical grade. Hexane and 2-propanol used in chromatographic
EXPERIMENTAL SECTION
Materials. L-Phenylalanine (purity 99%) and L-phenylglycine
purity 98%) were purchased from Shanghai Jingchun Reagent Co.,
■
(
Ltd. (Shanghai, China). Hydrochloride in ethanol (30−40%) was
8
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experiments were of HPLC grade. The racemates were commercially
available or were prepared by the usual methods.
1
Instrumentation. The H NMR spectra (500 MHz) were
recorded using a Bruker AVANCE III-500 instrument at room
temperature. The number-average molecular weight (M ), the weight-
n
average molecular weight (M ), and the polydispersity (M /M ) of
w
w
n
the polymers were determined by size exclusion chromatography
SEC) calibrated with standard polystyrenes at 40 °C using a JASCO
(
SEC system (PU-980 Intelligent pump, CO-965 column oven, RI-930
Intelligent RI detector, and Shodex DEGAS KT-16) equipped with a
Shodex Asahipak GF-310 HQ column (linear, 7.6 mm ×300 mm; pore
size, 20 nm; bead size, 5 μm; exclusion limit, 4 × 104) and a Shodex
Asahipak GF-7 M HQ column (linear, 7.6 mm ×300 mm; pore size,
7
2
0 nm; bead size, 9 μm; exclusion limit, 4 × 10 ) in DMF containing
−1
lithium chloride (0.01 M) at the flow rate of 0.4 mL· min . The
optical rotation was measured in CHCl at room temperature using a
3
Perkin-Elmer Model 341 polarimeter. The circular dichroism (CD)
and ultraviolet visible (UV−vis) spectra were measured in a 1-mm
path length cell using a JASCO J-815 spectropolarimeter. All the
enantioseparation experiments were performed using a JASCO
PU-2089 high performance liquid chromatograph (HPLC) system
equipped with UV−vis (JASCO-UV-2070) and circular dichroism
(
JASCO-CD-2095) detectors. A solution of a racemate (3 mg/mL)
was injected into the chromatographic system through an intelligent
sampler (JASCO AS-2055). The thermogravimetric analyses (TGA)
were performed using a TGA Q 50 (TA) instrument.
Synthesis of L-Phenylalanine Ethyl Ester and L-Phenyl-
glycine Ethyl Ester. L-Phenylalanine ethyl ester and L-phenylglycine
ethyl ester were synthesized via the esterification reaction of the
corresponding L-amino acid in a hydrochloride ethanol solution. A
typical procedure is described as follows. L-Phenylalanine (8.00 g,
48.0 mmol) and hydrochloride in ethanol (1.50M, 160 mL) were
added to a 500 mL round-bottomed flask. The mixture was refluxed
with stirring for 15 h and turned yellow. It was then cooled to room
temperature, and extracted in a saturated NaHCO aqueous solution
3
and CH Cl . The organic layer was dried using MgSO and filtered.
1
2
2
4
Figure 1. H NMR spectra of (a) PPA-Phe-1a and (b) PPA-Phg-1a in
The filtrate was evaporated to remove the CH Cl2 to give the
2
DMSO-d at 80 °C.
6
L-phenylalanine ethyl ester as a brown-yellow liquid. Yield: 7.63g
1
(
5
−
1
82.2%). H NMR (500 MHz, CDCl , TMS, ppm): δ = 7.33−7.20 (m,
3
Table 2. Specific Rotations of PPA-Phe-1a and PPA-Phg-1a
in Different Solvents
H, Ar−H), 4.20−4.15 (q, 2H, −O−CH −), 3.77−3.74 (t, 1H,
2
CH−), 3.13−2.88 (d, 2HAr−CH −), 2.13 (s, 2H, −NH ), 1.27−
2
2
.23 (t, 3H, −CH ).
α]D20/deg
3
[
According to the above procedure, the L-phenylglycine ethyl ester
a
1
polymers
CHCl3
−714
−573
CH Cl2
DMF
acetone DMSO DMAc
was synthesized as a pale yellow liquid. Yield: 76.4%. H NMR (500
2
MHz, CDCl , TMS, ppm): δ = 7.39−7.28 (m, 5H, Ar−H), 4.59 (s,
PPA-Phe-1a
PPA-Phg-1a
−159
−381
+418
+259
+378
+271
+288
+261
+221
3
1
1
H, −CH−), 4.24−4.09 (q, 2H, −CH −), 1.86 (s, 2H, −NH ), 1.25−
2
2
+331
.19 (t, 3H, −CH ).
a
20
D
3
Specific rotations of the monomers in CHCl : [α]
123°, [α]D (PA-Phg) = +58.5°.
(PA-Phe) =
3
Synthesis of N-(4-Ethynylbenzoyl)-L-phenylalanine Ethyl
20
+
Ester (PA-Phe) and N-(4-Ethynylbenzoyl)-L-phenylglycine
Ethyl Ester (PA-Phg). The N-(4-ethynylbenzoyl)-L-phenylalanine
ethyl ester (PA-Phe) and N-(4-ethynylbenzoyl)-L-phenylglycine ethyl
ester (PA-Phg) were synthesized via the amidation reaction between
(
−CH −CH ). Anal. Calcd for C H O N (321): C, 74.77; H, 5.92;
N, 4.36. Found: C, 74.75; H, 5.95; N, 4.40.
According to the procedure, PA-Phg was synthesized as pale yellow
crystals. Yield: 7.28 g (75.5%). H NMR (500 MHz, CDCl , TMS,
2
3
20 19
3
4-ethynylbenzoic acid and L-phenylalanine ethyl ester or L-phenyl-
1
glycine ethyl ester. A typical procedure is described as follows. To
a solution of the 4-ethynylbenzoic acid (4.30 g, 29.4 mmol) and
DMT-MM (8.93 g, 32.3 mmol) in MeOH (150 mL) was added the
L-phenylalanine ethyl ester (5.68 g, 29.4 mmol). After stirring at room
temperature for 18 h, the reaction mixture was purified by column
chromatography on silica gel with hexane/ethyl acetate (3/1, v/v) to
3
ppm): δ = 7.80−7.75 (d, 2H, Ar−H), 7.57−7.54 (d, 2H, Ar−H),
7.45−7.43 (t, 2H, Ar−H), 7.40−7.36 (t, 1H, Ar−H), 7.36−7.32 (d,
2H, Ar−H), 7.17−1.15 (d, 1H, −NH−), 5.76−5.74 (d, 1H, NH−
CH−), 4.32−4.15 (mm, 2H, −O−CH −), 3.21 (s, 1H, CH), 1.26−
2
13
1.23 (t, 3H, −CH ). C NMR (125 MHz, CDCl , TMS, ppm): 171.0
3
3
1
give PA-Phe as pale yellow crystals. Yield: 7.36 g (78.0%). H NMR
(−CO−(ester)), 165.7 (−CO− (amino)), 136.6 (aromatic), 133.6
(aromatic), 132.3 (aromatic), 129.0 (aromatic), 128.6 (aromatic),
127.3 (aromatic), 127.1 (aromatic), 125.7 (aromatic), 82.7 (−C
CH), 79.7 (−CCH), 62.1(−CH −CH ), 56.9 (−CH−NH), 14.0
(
7
500 MHz, CDCl , TMS, ppm): δ = 7.68−7.66 (d, 2H, Ar−H), 7.54−
3
.52 (d, 2H, Ar−H), 7.30−7.26 (t, 1H, Ar−H), 7.26−7.23 (t, 2H, Ar−
H), 7.14−7.12 (d, 2H, Ar−H), 6.57−6.54 (d, 1H, −NH−), 5.07−5.02
2
3
(
2
q, 1H, NH−CH−), 4.24−4.19 (q, 2H, −O−CH −), 3.31−3.21(m,
(−CH −CH ). Anal. Calcd for C H O N (321): C, 74.27; H, 5.54;
2
2
3
19 17
3
13
H, Ar−CH −), 3.20 (s, 1H, CH), 1.30−1.26 (t, 3H, −CH ).
C
N, 4.56. Found: C, 74.62; H, 5.62; N, 4.56.
2
3
NMR (125 MHz, CDCl , TMS, ppm): δ = 171.5 (−CO−(ester)),
Polymerization. The polymerization of PA-Phe and PA-Phg was
carried out in dry CHCl or DMF using Rh(nbd)BPh as a catalyst
under a nitrogen atmosphere for 24 h at 28 °C with [monomer] =
0.03, 0.06, 0.10 M, and [monomer] /[Rh(nbd)BPh ] = 44.5. A
3
1
66.0 (−CO− (amino)), 153.8 (aromatic), 134.0 (aromatic), 132.3
aromatic), 129.4 (aromatic), 128.6 (aromatic), 127.2 (aromatic),
27.0 (aromatic), 125.7 (aromatic), 82.7 (−CCH), 79.6 (−C
CH), 61.7(−CH −CH ), 53.6 (−CH−NH), 37.9 (−CH −CH), 14.2
3
4
(
1
0
0
4 0
typical procedure is described as follows. PA-Phe (1.40 g, 4.36 mmol)
2
3
2
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Figure 2. CD (upper) and UV−vis (lower) spectra of (a) PPA-Phe-2c in variable solvents at 25 °C, (b) PPA-Phe-1a−c and PPA-Phe2a−c in
CHCl at 25 °C, and (c) PPA-Phe-1a in CHCl at different temperature (c = 1 mg/mL).
3
3
was weighed into a flask and dissolved in dry CHCl (132.8 mL)
6.73−7.65 (d, 2H, Ar−H), 5.72 (s, 1H, main chain), 5.58−5.54 (d, 1H,
NH−CH−), 4.05−3.94 (m, 2H, −O−CH −), 1.05−0.98 (t, 3H, −CH ).
3
before a solution of Rh(nbd)BPh (50.4 mg, 98 μmol) in dry CHCl3
4
2
3
(12.5 mL) was added. After stirring at room temperature for 24 h,
Preparation of Chiral Stationary Phases (CSPs). The poly-
(phenylacetylene) derivatives (PPA-Phe and PPA-Phg) (0.2 g each)
were first dissolved in a coating solvent (5 mL) and then coated on
aminopropyl silanized silica gel (0.8 g) according to a previous
triphenylphosphine (214.0 mg, 0.82 mmol) was added to the reaction
mixture. The solution was concentrated and then poured into a large
amount of hexane (1000 mL). The precipitates were purified by
reprecipitation using hexane and then dried under reduced pressure to
2
9
method. The polymer-coated silica gels were then packed in a
stainless-steel tube (25 cm ×0.20 cm i.d.) by a slurry method. The
plate numbers of the packed columns were 1600−3100 for benzene
using a hexane/2-propanol (95/5, v/v) mixture as the eluent at the
4
give PPA-Phe as a yellow solid (1.39 g, 99.3%). M = 3.90 × 10 ; M /
n
w
1
M = 2.7. H NMR (500 MHz, DMSO-d , TMS, ppm): δ = 8.15−8.04
n
6
(
d, 1H, −NH−), 7.50−7.35 (d, 2H, Ar−H), 7.22−7.00 (m, 5H, Ar−
H), 6.76−7.58 (d, 2H, Ar−H), 5.75 (s, 1H, main chain), 4.72−4.60 (q,
H, NH−CH−), 4.03−3.88 (q, 2H, −O−CH −), 3.16−3.01 (m, 2H,
flow rate of 0.1 mL/min at 25 °C. The dead time (t ) of the columns
0
1
was estimated using 1,3,5-tritert-butylbenzene as the nonretained
2
3
0
Ar−CH −), 1.04−0.88 (t, 3H, −CH ).
compound. The theoretical plate number (N) and t of each column
2
3
0
According to the above procedure, PA-Phg was polymerized to give
are summarized in Table S1 (see the Supporting Information). In
order to tell variability from column preparation, an assessment of
repeatability has been carried out. We repeated coating and packing
processes three times to prepare three columns on one polymer as a
1
PPA-Phg as a yellow solid. Yield = 96.7−98.4%. H NMR (500 MHz,
DMSO-d , TMS, ppm): δ = 8.45−8.32 (d, 1H, −NH−), 7.54−7.46 (d,
6
2
H, Ar−H), 7.37−7.32 (d, 2H, Ar−H), 7.26−7.17 (m, 3H, Ar−H),
8
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Figure 3. CD (upper) and UV−vis (lower) spectra of (a) PPA-Phg-1a in variable solvents at 25 °C, (b) PPA-Phg-1a−c and PPA-Phg-2a−c in
CHCl at 25 °C, and (c) PPA-Phg-1a in CHCl at different temperature (c = 1 mg/mL).
3
3
representative example, PPA-Phe-1a, which was synthesized in CHCl3
with monomer concentration of 0.03 M. The comparison of resolution
results on the three columns are summarized in Table S2 (see the
Supporting Information). Thus, it has been confirmed that the
inherent variability of α is quite small.
structures of the two monomers, the benzyl group is adjacent to
the chiral carbon atom of PA-Phe, while the phenyl group is
adjacent to the chiral carbon atom of PA-Phg. The acetylenyl
protons of PA-Phe and PA-Phg appeared at 3.20 and 3.21 ppm,
respectively.
To obtain the stereoregular polymers for chiral separation,
RESULTS AND DISCUSSION
■
the monomers were polymerized using Rh(nbd)BPh as a
4
Synthesis of Polymers PPA-Phe and PPA-Phg. The
monomers and polymers were synthesized via the route illustrated
in Scheme 1. The amidation reaction of 4-ethynylbenzoic acid with
the L-phenylalanine ethyl ester and L-phenylglycine ethyl ester
proceeded using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl
morpholinium chloride (DMT-MM) as a catalyst in good yields
to produce two novel monomers, N-(4-ethynylbenzoyl)-L-phenyl-
alanine ethyl ester (PA-Phe) and N-(4-ethynylbenzoyl)-L-phenyl-
glycine ethyl ester (PA-Phg), respectively. Comparing the
catalyst (Table 1). PPA-Phe-1a−c and PPA-Phg-1a−c were
synthesized in CHCl with the monomer concentrations of
3
0.03M, 0.06 M, and 0.10M, while PPA-Phe-2a−c and PPA-
Phg-2a−c were obtained in N,N-dimethylformamide (DMF)
with the monomer concentrations of 0.03M, 0.06 M, and
0.10 M. In all cases, the SEC profiles of the polymers were
monomodal with high molecular weights. As shown in Table 1,
the polymerization solvents and monomer concentration had
effects on the molecular weight of the resultant polymers. PPA-
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Figure 4. Structures of racemates.
a
Table 3. Influence of Coating Solvents on Resolution of Racemates on PPA-Phe-2c
CHCl3
CH Cl2
acetone
DMF
2
racemates
K ′
1
α
K ′
1
α
K ′
1
α
K ′
1
α
1
2
3
4
0.36
0.37
3.36
0.92
9.45
1.36
1.37
0.48
∼1(+)
0.53
0.77
3.44
0.97
10.13
1.04
1.52
0.57
1.00
0.23
0.31
2.64
0.67
7.97
0.87
0.88
0.28
1.00
0.35
0.37
3.36
0.90
9.97
1.46
1.18
0.35
1.00
1.00
1.00
1.00
1.00
3.50(+)
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
∼1(−)
1.33(+)
∼1(+)
b
5
6
7
8
∼1(+)
∼1(+)
∼1(+)
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
Phe-1a−c and PPA-Phg-1a−c synthesized in CHCl showed
These results also suggest that the polymer main chains possess
a helical conformation with a preferred screw sense. As well as
PPA-Phe, the optical rotations of PPA-Phgs were also
influenced by the polymerization solvents and monomer
3
lower molecular weights than PPA-Phe-2a−c and PPA-Phg-
2a−c synthesized in DMF. In addition, the molecular weight of the
polymers increased with the increasing monomer concentration in
both solvents. All of the obtained polymers were soluble in CHCl3,
CH Cl , acetone, DMF, N,N-dimethylacetamide (DMAc), and
concentration. PPA-Phg-1a−c synthesized in CHCl exhibited
3
higher optical rotations than those obtained in DMF. In CHCl ,
2
2
3
dimethyl sulfoxide (DMSO), but only partially soluble in
tetrahydrofuran (THF), and insoluble in hexane and 2-propanol.
Figure 1 depicts the assigned H NMR spectra of PPA-Phe-1a and
the optical rotations of the obtained polymers increased with
the increasing concentration of PA-Phg, whereas the optical
rotations of PPA-Phg-2a−c synthesized in DMF slightly
decreased with the increasing concentration of PA-Phg.
In addition, the optical rotations of PPA-Phe-1a and PPA-
Phg-1a were also determined in various solvents (Table 2).
The [α] D20 values of PPA-Phe-1a and PPA-Phg-1a were
negative in CH Cl2 and CHCl , while these values were
positive in polar solvents, such as acetone, DMF, DMAc, and
DMSO. The observed significant solvent dependence of the
optical activity suggests that the polymers possess dynamic
helical structure highly dependent on solvent.
1
PPA-Phg-1a in DMSO-d at 80 °C as representative examples.
6
1
The H NMR spectra showed the characteristic signals due to the
main chain proton at 5.75 and 5.72 ppm, respectively, indicating the
stereoregular cis-configuration in the polyacetylene main chain.
Chiroptical Properties of PPA-Phe and PPA-Phg. As
shown in Table 1, a series of PPA-Phes showed high
2
3
2
0
levorotatory optical rotations ([α]D = −754° to −667°) in
CHCl3, though the optical rotation of the corresponding
monomer (PA-Phe) was +123° in the same solvent. These
opposite optical rotations of the polymers in CHCl suggest
To confirm the helical structure of PPA-Phe and PPA-Phg,
their chiroptical properties were investigated by CD spectros-
copy (Figures 2 and 3). Figure 2a shows the solvent
dependence on the chiroptical properties of PPA-Phe-2c as a
representative example for a series of PPA-Phes. PPA-Phe-2c
showed distinct Cotton effects due to the absorption of the
helical poly(phenylacetylene) backbone in acetone, DMF,
3
that a new structure, most likely a secondary helical structure, is
formed after the polymerization. Moreover, the polymerization
solvents and monomer concentration had influences on the
optical rotations of the resultant polymers. PPA-Phe-1a−c
synthesized in CHCl exhibited higher optical rotations, and
3
the optical rotations increased with the increasing concen-
tration of PA-Phe. In contrast, PPA-Phe-2a−c synthesized in
DMF showed lower optical rotations, and the optical rotations
slightly decreased with the increasing concentration of PA-Phe.
Table 1 also shows the optical rotations of a series of PPA-
DMSO, DMAc, and CHCl in the range from 300 to 500 nm,
3
indicating that PPA-Phe-2c main chain definitely possesses a
2
1,31
predominantly one-handed helical conformation.
Similar to
the [α]D20 values, the chain helicity of the PPA-Phes changed with
the solvents. The polymer induced the same split-type Cotton
effects in acetone, DMF, DMSO, and DMAc, i.e., the first positive
Cotton effect at 375 nm and the second negative Cotton effect at
Phgs in CHCl . Compared to the optical rotation of PA-Phg
3
(
[α]D20 = +58°), high levorotatory optical activities ([α]D
20
=
−805° to −573°) of the PPA-Phgs were obtained in CHCl3.
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20 nm. The CD profiles in CHCl were nearly mirror images of
Article
3
3
those found in acetone, DMF, DMSO, and DMAc, showing the
first negative Cotton effect at 370 nm and the second positive
Cotton effect at 312 nm. In addition, weak Cotton effects and a
3
2
UV−vis absorption were exhibited in CH Cl . These results
2
2
suggested that PPA-Phe-2c has a dynamic helical conformation in
these solvents. Figure 2(b) shows the CD and UV−vis spectra of
PPA-Phe-1a−c and PPA-Phe-2a−c in CHCl at 25 °C. These
3
polymers showed the consistent CD and UV−vis profiles in
CHCl in the range from 300 to 500 nm with similar CD
3
intensities. Figure 2(c) shows the influence of temperature on the
chiroptical property of PPA-Phe-1a in CHCl . PPA-Phe-1a
3
showed the consistent CD and UV−vis profiles in CHCl at the
3
temperatures of −10 to +40 °C. The CD intensities of PPA-Phe-
1
a in CHCl slightly decreased when the temperature was
3
progressively increased from −10 to +40 °C. This suggests that the
rigid and one-handed helical conformation of PPA-Phe-1a is
probably stabilized by intramolecular hydrogen bonds so that the
CD intensity is almost unchanging even when the solution is
33,34
heated to 40 °C.
The chiroptical properties of a series of PPA-Phgs are similar
to those of the PPA-Phes. As shown in Figure 3a, PPA-Phg-1a,
as a representative example for a series of PPA-Phgs, exhibited
intense CD signals at 300 nm-500 nm with high molar ellipticities
in CHCl , while its monomer is completely CD-inactive in this
3
wavelength range. Thus, the observed Cotton effects must be
associated with the polymer backbone, unambiguously indicating
that the polymer takes a helical structure with a predominant
20
one-handed screw sense. Similar to the [α]D values, the chain
helicity of PPA-Phgs changed with the solvents. The polymer
induced the same split-type Cotton effects in acetone, DMF,
DMSO, and DMAc, showing the first positive Cotton effect at
380 nm and the second negative Cotton effect at 322 nm. The CD
profiles in CHCl and CH Cl were nearly mirror images of those
3
2
2
found in acetone, DMF, DMSO, and DMAc, showing the first
negative Cotton effect at 372 nm and the second positive Cotton
effect at 315 nm. As shown in Figure 3b, the CD and UV−vis
profiles of PPA-Phg-1a−c and PPA-Phg-2a−c are quite similar,
and from Figure 3c, the existence of the stable one-handed helical
conformation of PPA-Phg-1a at the temperatures of −10 to
+40 °C was confirmed.
Chiral Recognition of PPA-Phe. Because a series of PPA-
Phes not only have a chirality at pendants, but also possess a
one-handed helical conformation at the main chains, they are
expected to show a chiral recognition. Their chiral recognition
abilities were evaluated as CSPs in HPLC using the eight tested
racemates shown in Figure 4.
As PPA-Phes showed different optical rotations and Cotton
effects in CHCl , CH Cl , acetone, and DMF, these solvents
3
2
2
were selected as the solvent for coating the PPA-Phes on the
silica gel. The influences of the coating solvents on the
resolution of the racemates on PPA-Phe-2c were evaluated by
HPLC as a representative example of a series of PPA-Phes, and
these results are summarized in Table 3. PPA-Phe-2c showed
different chiral recognition abilities under the same chromato-
25
graphic conditions when different coating solvents were used.
The retention factor, k ′ [=(t − t )/t ], for the first eluted
1
1
0
0
enantiomer in Table 3 is the factor indicating the interaction
strength between a CSP and the corresponding enantiomer,
and can be obtained from its elution time t and the dead time
1
t . The k ′ values varied with the coating solvents of PPA-Phe-
0
1
2c. The separation factor α, which is directly correlated to the
chiral recognition ability of a CSP, is an important factor for
8
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Article
Figure 5. Chromatograms for the resolution of (a) trans-stilbene oxide (2) on PPA-Phe-2c and (b) 1-(9-anthyl)-2,2,2-trifluoroethanol (5) on PPA-
Phe-1a with hexane/2-propanol (95/5) as eluent.
a
Table 5. Influence of Coating Solvents on Resolution of Racemates on PPA-Phg-1a
CHCl3
CH2Cl2
Acetone
racemates
K ′
1
α
K ′
1
α
K ′
1
α
1
2
3
4
5
6
7
8
0.56
0.37
5.18
1.32
20.13
1.99
2.34
0.55
1.50(+)
1.24(−)
1.00
0.52
0.68
5.39
1.25
19.88
0.79
2.25
0.49
1.00
0.54
0.64
6.03
1.33
22.82
0.49
2.31
0.47
1.00
1.00
1.00
1.00
1.00
∼1(+)
1.57(+)
∼1(+)
1.00
∼1(−)
1.00
1.00
b
b
1.49(+)
1.00
1.22(+)
1.00
1.00
1.00
∼1(−)
1.00
a
Column: 25 cm ×0.20 cm i.d. Eluent: hexane/2-propanol (95/5, v/v). Flow rate: 0.1 mL/min. The signs in parentheses represent the optical
b
rotation of the first-eluted enantiomer. Flow rate: 0.5 mL/min.
evaluating a CSP. If α is equal to 1.00, this means no chiral
recognition, and the higher α value, the better the chiral
recognition ability of a CSP. Although PPA-Phe-2c coated with
CH Cl , acetone or DMF exhibited a very low chiral
recognition for 6 racemates, it showed a clear enantioselectivity
of trans-stilbene oxide (2) and 1-(9-anthyl)-2,2,2-trifluoroetha-
and separation factor did not show a clear dependence on the
molecular weight and optical rotations. PPA-Phe-1a−c, which
were synthesized in CHCl , showed a higher chiral recognition
3
for 2 with the increasing molecular weight. One the other hand,
their chiral recognition for 5 decreased with the increasing
molecular weight and the highest separation factor was 1.55,
which is comparable to those obtained on the very popular
polysaccharide-based CSPs, Chiracel OD (α = 2.59) and
2
2
nol (5) when coated with CHCl . The coating solvent
3
dependence of PPA-Phe-2c is probably due to the variation
in its conformation on the silica surface induced by the coating
solvents. A higher chiral recognition was obtained when PPA-
11,29
Chiralpak AD (α = 1.39).
PPA-Phe-2a−c, which were synthesized in DMF, exhibited a
Phe-2c was coated with CHCl in which the polymer exhibited
higher chiral recognition for 2 than PPA-Phe-1a−c synthesized
3
a negative [α]D20 value and showed the first negative Cotton
effect at 370 nm and the second positive Cotton effect at
in CHCl . In addition, a higher chiral recognition of α = 3.50
3
for 2 was achieved by the higher molecular weight polymer
PPA-Phe-2c. This high α value is higher than those obtained
312 nm. This conformation is preferable in order to attain a
11,29
higher chiral recognition. The PPA-Phe-2c in acetone or DMF
on Chiralcel OD (α = 1.68) and Chiralpak AD (α = 2.81).
showed nearly mirror images of that found in CHCl , and
Figure 5 shows the chromatograms of the resolution of 2 on
PPA-Phe-2c and 5 on PPA-Phe-1a, whose enantiomers were
completely separated. These results indicated that the chiral
recognition abilities of the helical PPA-Phes are sensitive to the
polymer structures such as molecular weight and stereo-
regularity. Their chiral recognition abilities were maintained for
at least half a year, implying the good conformational stability
of the PPA-Phes series.
3
exhibited very low chiral recognition abilities. In addition, the
PPA-Phe-2c with a weak Cotton effects below 320 nm in
CH Cl also exhibited very low chiral recognition abilities.
2
2
As already mentioned, the polymerization conditions, such as
the polymerization solvents and monomer concentration, have
effects on the molecular weight and chiroptical properties of the
resultant polymers. In this study, the influences of these factors
on the chiral recognition abilities of the PPA-Phes were
investigated for some racemates, and the results are
summarized in Table 4. Most of the PPA-Phes recognized
the enantiomers of racemates 2 and 5, but the retention factor
Chiral Recognition of PPA-Phg. To elucidate the role of
the chiral pendants on the chiral recognition of the helical
poly(phenylacetylene) derivatives, another new monomer PA-
Phg was synthesized and polymerized in CHCl and DMF with
3
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Macromolecules
Article
different monomer concentrations using Rh(nbd)BPh as the
4
catalyst to obtain a series of helical PPA-Phgs. The difference
between the chemical structures of PPA-Phg and PPA-Phe is
the group adjacent to the chiral carbon atom at the pendants;
PPA-Phg has a phenyl group and PPA-Phe has a benzyl group.
The chiral recognition abilities of a series of PPA-Phgs were
also evaluated as CSPs for HPLC. Similar to the PPA-Phes, a
series of PPA-Phgs also showed different optical rotations and
Cotton effects in CHCl , CH Cl , acetone, and DMF (see
3
2
2
Table 2 and Figure 3, respectively). CHCl , CH Cl , and
3
2
2
acetone were selected as the coating solvents to prepare the
PPA-Phg CSPs. The influences of the coating solvents on
the resolution of the racemates on PPA-Phg-1a as a
representative example were evaluated by HPLC, and the results
are summarized in Table 5. As shown in Table 5, the retention
factor k ′ and separation factor α varied depending on the coating
1
solvents of PPA-Phg-1a on silica gel. The PPA-Phg-1a coated
with CHCl showed a higher chiral recognition than that coated
3
20
D
with CH Cl and acetone. The high negative [α]
value and the
2
2
stronger first negative Cotton effect at 372 nm and second positive
Cotton effect at 315 nm in CHCl suggested that the polymer has
3
a higher one-handedness in this solvent, which seems to be related
to the higher chiral recognition.
Table 6 shows the resolution results of the racemates on a
series of PPA-Phgs under the same chromatographic conditions.
̈
Most of the PPA-Phgs showed a chiral recognition for the Troger
base (1) in addition to 2 and 5, which were well resolved on the
PPA-Phes. In addition, the retention factor of racemate 5 on the
PPA-Phgs was much greater than that on PPA-Phes, indicating
the stronger interaction between the PPA-Phgs and racemate 5.
These results imply that the absence of the −CH − group
2
between the chiral carbon atom and phenyl group at the pendants
improved the chiral recognition for racemate 1 and increased the
interaction with racemate 5. This means that the group adjacent to
the chiral carbon atom at the pendants also plays an important role
in the chiral recognition.
CONCLUSION
■
A series of novel dynamic helical poly(phenylacetylene)
derivatives, PPA-Phe and PPA-Phg, with an amide linkage
bearing L-phenylalanine and L-phenylglycine ethyl ester
pendants, respectively, were synthesized to evaluate their chiral
recognition as CSPs in HPLC using 8 racemates. The polymers
changed their conformation in different solvents, which resulted
in different chiral recognition abilities depending on the coating
solvents on silica gel. Both PPA-Phe and PPA-Phg showed
higher chiral recognitions when CHCl was used as the coating
3
solvent In this solvent, the polymers showed a high negative
.
[
α]D20 value and high first negative Cotton effect at 370−372 nm
with the second positive Cotton effect at 312−315 nm. The chiral
recognition abilities of the helical PPA-Phe and PPA-Phg
probably depended on their molecular weight and optical
rotations. The phenyl and benzyl groups adjacent to the chiral
carbon atom at the pendants also play an important role in the
chiral recognition. A few racemates were completely separated on
PPA-Phe or PPA-Phg with high separation factors comparable or
even higher than those obtained on the very popular CSPs derived
from the phenylcarbamate derivatives of cellulose and amylose.
ASSOCIATED CONTENT
Supporting Information
Theoretical plate number (N) and dead time (t ) of each
■
*
S
0
column and comparison of resolution results on the three
8
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Macromolecules
Article
columns. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) Naito, Y.; Tang, Z.; Iida, H.; Miyabe, T.; Yashima, E. Chem. Lett.
2
(
012, 41, 809−811.
25) Zhang, C.; Liu, F.; Li, Y.; Shen, X.; Xu, X.; Sakai, R.; Satoh, T.;
Kakuchi, T.; Okamoto, Y. J. Polym. Sci., Part A: Polym. Chem. 2013, 51,
2271−2278.
AUTHOR INFORMATION
■
Corresponding Authors
E-mail: (C.Z.) zhangchunhong97@163.com.
E-mail: (Y.O.) okamoto@apchem.nagoya-u.ac.jp.
(26) Zhang, C.; Wang, H.; Liu, F.; Shen, X.; Liu, L.; Sakai, R.; Satoh,
T.; Kakuchi, T.; Okamoto, Y. ACTA Polym. Sin. 2013, No. 6, 811−
*
8
16.
*
(27) Yashima, E.; Matsushima, T.; Okamoto, Y. J. Am. Chem. Soc.
Notes
1
997, 119, 6345−6359.
The authors declare no competing financial interest.
(28) Kishimoto, Y.; Itou, M.; Miyatake, T.; Ikariya, T.; Noyori, R.
Macromolecules 1995, 28, 6662−6666.
(
29) Okamoto, Y.; Kawashima, M.; Hatada, K. J. Chromatogr. 1986,
ACKNOWLEDGMENTS
■
3
(
63, 173−186.
This work was supported by the National Science Foundation
of China (Grant No. 51373044 and 21204014), the Natural
Science Foundation of Heilongjiang Province (Grant No.
B201013), the Scientific Research Foundation for the Returned
Overseas Chinese Scholars, State Education Ministry (Grant
No. 20111568), the Special Fund for Scientific and
Technological Innovative Talents in Harbin City (Grant No.
30) Okamoto, Y.; Aburatani, R.; Fukumoto, T.; Hatada, K. Chem.
Lett. 1987, 1857−1860.
(31) Sakai, R.; Barasa, B. E.; Sakai, N.; Sato, S.; Satoh, T.; Kakuchi, T.
Macromolecules 2012, 45, 8221−8227.
(32) The significant hypsochromic effect observed in CH Cl is
2 2
considered to be based on the shortened conjugation length on the
polymer main chain. A similar phenomenon was also observed in some
poly(phenylacetylene)s with amide or urea groups.
molecular structures, a hydrogen-bonding interaction is suggested to
play important role in this phenomenon.
2
1,35,36
Given these
2
012RFLXG001), and the Fundamental Research Funds for
the Central Universities, China (Grant No. HEUCFT1009,
HEUCF201310009, HEUCF201310003, HEUCF1227). This
work was also partially supported by Daicel Corporation
(33) Aoki, T.; Kaneko, T.; Maruyama, N.; Sumi, A.; Takahashi, M.;
Sato, T.; Teraguchi, M. J. Am. Chem. Soc. 2003, 125, 6346−6347.
(34) Sato, T.; Aoki, T.; Teraguchi, M.; Kaneko, T.; Kim, S.-Y.
Polymer 2004, 45, 8109−8114.
(
Tokyo, Japan). The authors are grateful for the support.
(35) Kakuchi, R.; Nagata, S.; Sakai, R.; Otsuka, I.; Nakade, H.; Satoh,
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