Radical polymerization of styrene derivatives bearing N-free amino acid side chains, synergic effect of chirality, and hydrogen bonding for stereoselective polymerization

Article abstract of DOI:10.1002/pola.24274

Radical polymerization of styrene derivatives having a series of amino acid, alanine, glycine, leucine, valine, Boc-leucine, and Boc-valine, in the side chain bound at the C-terminal was conducted to regulate the stereoinduction system in the propagation

Full text of DOI:10.1002/pola.24274

Radical Polymerization of Styrene Derivatives Bearing N-Free Amino Acid
Side Chains, Synergic Effect of Chirality, and Hydrogen Bonding for
Stereoselective Polymerization
KOUKI MATSUBARA, ATSUMI KURIMARU, MIYUKI YAMANAKA, TETSUYA HIRASHIMA, YOSHIE ONISHI, EIJI MURAKAMI,
EMI KAWACHI, YUJI KOGA, SETSUKO ANDO
Department of Chemistry, Faculty of Science, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka, Japan
Received 15 December 2009; accepted 23 July 2010
DOI: 10.1002/pola.24274
Published online 5 October 2010 in Wiley Online Library (wileyonlinelibrary.com).
ABSTRACT: Radical polymerization of styrene derivatives having
a series of amino acid, alanine, glycine, leucine, valine, Boc-
leucine, and Boc-valine, in the side chain bound at the C-termi-
nal was conducted to regulate the stereoinduction system in
the propagation step. Isotacticity increased in the polymer
main chain, especially in the polymerization of monomers
bearing N-free L-leucyl and L-valyl esters in THF or DMF at
50 ꢀC, by the synergic stereoregulation with chirality control
and hydrogen bonding between the radical polymer terminal
C
V
and the monomer.
2010 Wiley Periodicals, Inc. J Polym Sci
Part A: Polym Chem 48: 5593–5602, 2010
KEYWORDS: amino acid-bound polyolefine; isotactic; NMR;
polystyrene; radical polymerization; stereoinduced polymers
INTRODUCTION Induction of chirality into the backbone of
polyolefins synthesized by free radical polymerization has
been a challenging target for a long time and many chemists
have tried to solve it.1,2 Until now, using monomers having chi-
ral auxiliaries3–6 is one of the efficient methods for stereospe-
cific or stereoregulated radical polymerization. Moreover, chi-
ral bioactive substituents in polymer side chains, such as
amino acids, peptides, and sugars, can also play important
roles as functional bioactive groups in part.7–14 However, it is
still unclear how stereoselection is regulated by such chiral
auxiliaries. Porter et al. reported that a penultimate group of
the growing radical terminal effects on stereocontrol of chiral-
monomer addition,15 whereas a recent study discussed that
radical chain end can control the stereochemistry.16 Using
monomers bearing chiral amino acid, North and coworkers
reported that the specific rotation of copolymers varied in a
nonlinear manner with the proportion of chiral amino acid,
indicating the capability of chiral induction.17 Although steric
hindrance between the hindered group in acrylates and the
growing radical terminal was regarded as the important regu-
lating factor in the chirality induction system, hydrogen bond-
ing, which is a characteristic interaction with amino acid deriv-
atives, has rarely been focused as an important factor. Quite
recently, Bag et al. reported importance of hydrogen-bonding
interaction between monomer and growing polymer terminal
in the radical polymerization of L-leucine-substituted acrylam-
ide, though chirality induction mechanism was not clear.18
mer side chain and the growing polymer terminal is
expected to induce stereocontrol in the polymer main chain
to some extent, because stereoregulation might be conducted
if the chiral monomer accesses to the prochiral radical termi-
nal with selecting a suitable route (path A in Fig. 1) via for-
mation of intermolecular hydrogen-bonding interaction,
other than paths B–D, in which the synergic stereocontrol
system does not work appropriately. Analogous chiral induc-
tion system was performed for polymerization of amino-acid
substituted isocyanides.19
In our preliminary study exploring synthetic polymers with
the ammonium residues exhibiting antibiotic activity adsorb-
ing on the bacterial cell walls, we reported an efficient prep-
arative method for a styrene derivative bearing N-free alanyl
ester.20 The designed structure of the polymers is different
from the amino-acid bound N-acrylamides or N-methacryla-
mides reported previously7–14 in the following two points:
(1) the amino group in amino acid is free, and (2) not acry-
late but styrene derivatives were used as monomers. Stereo-
selective radical polymerization of styrene and its derivatives
has rarely been reported until now. Here, we report AIBN-
initiated radical polymerization of the styrene derivatives
bearing (L)-alanine, glycine, (L)-leucine, (rac)-leucine, (L)-va-
ꢀ
line, Boc-(L)-leucine, and Boc-(L)-valine at 50 C to form new
polystyrene derivatives bearing amino acid in the side chain.
As a result, we can observe significant increase of 13C signals
due to the m diads or the mm triads showing isotacticity
in the polystyrenes, which were made from the polymers
bearing (L)-leucine and (L)-valine, whereas, interestingly,
We noticed that the synergic effect of chirality and intermo-
lecular hydrogen bonding between amino acid in the mono-
Correspondence to: K. Matsubara (E-mail: kmatsuba@fukuoka-u.ac.jp)
C
V
Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 48, 5593–5602 (2010) 2010 Wiley Periodicals, Inc.
RADICAL POLYMERIZATION OF STYRENE DERIVATIVES, MATSUBARA ET AL.
5593

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
DMF (150 mL) containing 1% water (1.5 mL) were added and
ꢀ
stirred at 60 C for 6 h. Complete consumption of the starting
materials was confirmed by means of 1H NMR measurement of
the crude mixture in CDCl3. After removal of the solvent under
reduced pressure, water (80 mL) was added and extracted
with ethyl acetate (50 mL ꢂ 3). Most of the cases, additional
purification was not necessary. If further purification of the
resulting mixture is required (containing a small amount of 4-
(chloromethyl)styrene and DMF), washing with petroleum
ether gave a white solid, 1a (4.29 g, 3.28 mmol, 78% yield).
1a: Anal. C17H23NO4: Calcd. C 66.86, H 7.59, N 4.59; Found C,
FIGURE 1 Supposed routes of the styrene derivatives for the
1
66.91; H, 7.47; N, 4.69. H NMR (CDCl3): d ¼ 7.41 (d, J ¼ 8.0
polymer terminal.
Hz, 2H, Ph), 7.31 (d, J ¼ 8.0 Hz, 2H, Ph), 6.71 (dd, J ¼ 10.8 Hz,
1H, ACH¼¼), 5.78 (t, J ¼ 17.6 Hz, 1H, ¼¼CH2), 5.28 (d, J ¼ 6.40
Hz, 1H, ¼¼CH2), 5.17 (AB pattern, 2H, CH2), 5.10 (t, J ¼ 21.6
Hz, 1H, NH), 4.35 (quint, J ¼ 6.80 Hz, 1H, CH), 1.40 (d, J ¼
monomers with glycine, (rac)-leucine, Boc-leucine, and Boc-
valine or those which were polymerized at 80 ꢀC were not
much suitable for stereoselective polymerization. This shows
that the synergic interaction of chirality and hydrogen bond-
ing is one of the appropriate ways to achieve the stereoselec-
tive radical polymerization.
t
16.4 Hz, 3H, CH3), 1.44 (s, 9H, Bu). 13C NMR (CDCl3): d ¼
172.9, 154.9, 137.5, 136.1, 134.7, 128.3, 126.2, 114.3, 79.8,
66.7, 49.3, 28.4, 18.7. IR: 3384 (s, NH), 1719 cmꢁ1 (vs, C¼¼O).
1b (coupled with Boc-glycine at 90 ꢀC for 50 min, yield
75%): ESI-MS Calcd. (C16H21NO4) 314.1362 (M þ Naþ);
Found 314.1351. 1H NMR (CDCl3): d ¼ 7.40 (d, J ¼ 8.0 Hz,
2H, Ph), 7.31 (d, J ¼ 8.0 Hz, 2H, Ph), 6.71 (dd, J ¼ 10.8, 17.6
Hz, 1H, ACH¼¼), 5.76 (t, J ¼ 17.6 Hz, 1H, ¼¼CH2), 5.27 (d, J ¼
10.8 Hz, 1H, ¼¼CH2), 5.16 (s, 2H, CH2), 5.01 (br, 1H, NH),
EXPERIMENTAL
Materials
AIBN and 4-(chloromethyl)styrene were used as purchased
from Aldrich. Boc-(L)-alanine and the other Boc-protected
amino acids were used as purchased from Watanabe Chemi-
cal. THF or DMF for radical polymerization was dried over
sodium benzophenone ketyl or calcium hydride and distilled
just before use. Other solvents were used as purchased.
t
3.95 (d, J ¼ 5.2 Hz, 1H, CH), 1.45 (s, 9H, Bu). 13C NMR
(CDCl3): d ¼ 170.3, 155.7, 137.8, 136.2, 134.6, 128.6, 126.4,
114.5, 80.0, 66.8, 42.5, 28.3. IR: 3375 (s, NH), 1748 cmꢁ1
(sh, C¼¼O), 1700 cmꢁ1 (vs, C¼¼O).
1c [coupled with Boc-leucine at 45 ꢀC for 24 h, yields 89%
Techniques
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a VARIAN Mercury Y plus 400 MHz spectrome-
ter at room temperature in CDCl3, D2O, or CD3OD. IR spectra
were recorded in cmꢁ1 on a PERKIN ELMER Spectrum One
spectrometer equipped with a universal diamond ATR. Size
exclusion chromatography analysis of the polymers was car-
ried out using a JASCO HPLC system equipped with a RI-
2031Plus differential refractometer and an UV-2075Plus UV-
VIS detector (254 nm) using two Shodex KF-804LþKF-804L
columns at 40 ꢀC. THF was used as an eluent (1.0 mL
minꢁ1). Calibration was carried out using standard samples
of polystyrene. The optical rotations were measuredꢀwith a
JASCO DIP-140 digital polarimeter in methanol at 25 C. The
concentration was at 1 g dLꢁ1. The path length was 0.1 cm,
and the light source was sodium D line. The circular dichro-
ism (CD) spectra were recorded on a JASCO J-600 spectropo-
larimeter at 25 ꢀC over the range of 195–260 nm using a
quartz cell of 0.1 cm path length at a sample concentration
of 1 ꢂ 10ꢁ3 M. Electrospray ionization time-of-flight mass
spectrometry (ESI-TOF MS) was carried out on a JEOL JMS-
T100 mass spectrometer. The sample solutions in methanol
were directly infused using methanol as solvent stream.
(for
L form) and 90% (for racemate)]: ESI-MS Calcd.
(C20H29NO4) 370.1989 (M þ Naþ); Found 370.1930. H NMR
(CDCl3): d ¼ 7.40 (d, J ¼ 8.0 Hz, 2H, Ph), 7.30 (d, J ¼ 8.0 Hz,
2H, Ph), 6.71 (dd, J ¼ 10.8, 17.6 Hz, 1H, ACH¼¼), 5.76 (t, J ¼
17.6 Hz, 1H, ¼¼CH2), 5.27 (d, J ¼ 10.8 Hz, 1H, ¼¼CH2), 5.14
(AB pattern, 2H, CH2), 4.88 (d, J ¼ 8.4 Hz, 1H, NH), 4.35 (br,
1
t
1H, CH), 1.75–1.55 (m, 3H, CH3), 1.43 (s, 9H, Bu), 0.92 (d, J
¼ 6.4 Hz, 3H, CH3), 0.92 (d, J ¼ 6.4 Hz, 3H, CH3). 13C NMR
(CDCl3): d ¼ 173.4, 155.4, 137.6, 136.3, 134.9, 128.4, 126.3,
114.4, 79.8, 66.6, 52.2, 41.7, 28.3, 24.7, 22.8, 21.9. IR: 3370
(s, NH), 1710 cmꢁ1 (vs, C¼¼O).
1d (coupled with Boc-valine at 60 ꢀC for 6 h, yield 90%): ESI-
MS Calcd. (C19H27NO4) 356.1832 (M þ Naþ); Found 356.1648.
1H NMR (CDCl3): d ¼ 7.40 (d, J ¼ 8.4 Hz, 2H, Ph), 7.31 (d, J ¼
8.4 Hz, 2H, Ph), 6.71 (dd, J ¼ 10.8, 17.6 Hz, 1H, ACH¼¼), 5.76
(t, J ¼ 17.6 Hz, 1H, ¼¼CH2), 5.27 (d, J ¼ 10.8 Hz, 1H, ¼¼CH2),
5.15 (AB pattern, 2H, CH2), 5.02 (d, J ¼ 9.2 Hz, 1H, NH), 4.27
(dd, J ¼ 9.2, 4.4 Hz, 1H, CH), 2.14 (sept, J ¼ 5.2 Hz, 1H, CH),
1.44 (s, 9H, tBu), 0.93 (d, J ¼ 6.8 Hz, 3H, CH3), 0.85 (d, J ¼ 7.2
Hz, 3H, CH3). 13C NMR (CDCl3): d ¼ 172.0, 155.5, 137.5, 136.1,
134.7, 128.4, 126.1, 114.2, 79.64, 66.3, 58.4, 31.1, 28.1, 18.8,
17.3. IR: 3380 (s, NH), 1710 cmꢁ1 (vs, C¼¼O).
Preparation of Boc-Amino Acid Styrenes, 1a–1d
In a typical example, to a 50-mL round-bottom flask, Boc-(L)-
alanine (3.78 g, 20.0 mmol), 4-(chloromethyl)styrene (3.05
mL, 20.0 mmol), sodium carbonate (1.05 g, 10.0 mmol), and
Preparation of 2a–2d
In a typical example, to a 200-mL flask, 1a (1.97g, 6.45
mmol) and a toluene solution of trifluoroacetic acid (TFA,
5594
WILEYONLINELIBRARY.COM/JOURNAL/JPOLA

ARTICLE
25%, 130 mL) were added and stirred at room temperature
for 1 h. The solution was concentrated with N2 gas bubbling
and then evaporated under reduced pressure. The resulting
yellow oil was dissolved in a small amount of water, and
aqueous sodium hydrocarbonate (4%) was added to the
solution at 0 ꢀC to raise its pH up to 7–8. After extraction
with ethyl acetate (50 mL ꢂ 3) and salting out from aqueous
solution, the ethyl acetate solution was dried over anhydride
sodium sulfate and evaporation of the solvent gave a pale
yellow solid, 2a (1.05 g, 5.16 mmol, 80% yield). The product
was not able to purified further using column chromatogra-
phy with neutralized silica, because of hydrolysis of the ester,
forming alanine and 4-vinylbenzylalcohol.
temperature, polymers were precipitated, and the solution
was washed with THF (ca. 20 mL) and was dried under
reduced pressure to form a pale yellow precipitate, 3a
(0.894 g, 85% yield).
3a: 1H NMR (CD3OD): d ¼ 7.07 (Ph), 6.48 (Ph), 5.14
(ACH2AOA), 4.10 (NH2ACHACO), 1.51 (CH3), 1.8–1.1
(ACHACH2A). 13C NMR (D2O containing HCOOH): d ¼
170.7, 145, 132, 128, 68.1, 49.0, 40, 15.3. IR: 3423 (brw,
NH), 1655 cmꢁ1 (vs, C¼¼O).
1
3b (yield: 78%): H NMR (CD3OD): d ¼ 7.03 (Ph), 6.43 (Ph),
5.16
(ACH2AOA),
3.91
(NH2ACH2ACO),
2.0–1.1
(ACHACH2A). IR: 3365 (brw, NH), 1748 cmꢁ1 (vs, C¼¼O).
The 13C NMR spectrum for 3b could not be obtained
because of low solubility of 3b in common solvents.
2a: ESI-MS Calcd. (C12H15NO2) 206.1176 (M þ Hþ); Found
206.1130. 1H NMR (CDCl3): d ¼ 7.37 (d, J ¼ 8.41 Hz, 2H,
Ar), 7.25 (d, J ¼ 8.41 Hz, 2H, Ar), 6.68 (dd, J ¼ 11.2, 17.6
Hz, 1H, ACH¼¼), 5.74 (d, J ¼ 17.6 Hz, 1H, CH¼¼), 5.27 (d, J ¼
11.2 Hz, 1H, CH¼¼), 5.13 (AB pattern, 2H, CH2), 4.04 (q, J ¼
21.6 Hz, 1H, CH), 1.56 (d, J ¼ 7.21 Hz, 3H, CH3). 13C NMR
(CDCl3): d ¼ 173.3, 140.7, 138.8, 137.0, 131.6, 129.2, 117.8,
70.9, 51.5, 17.8. IR: 1749 (vs, C¼¼O), 1611 cmꢁ1 (s, HNH).
2b (yield: 88%): ESI-MS Calcd. (C11H13NO2) 192.1019 (M þ
Hþ); Found 192.1013. 1H NMR (CD3OD): d ¼ 7.45 (d, J ¼
8.00 Hz, 2H, Ph), 7.38 (d, J ¼ 8.40 Hz, 2H, Ph), 6.74 (dd, J ¼
10.8, 17.6 Hz, 1H, ACH¼¼), 5.80 (d, J ¼ 17.6 Hz, 1H, CH¼¼),
5.27 (s, 2H, CH2A), 5.26 (d, J ¼ 10.8 Hz, 1H, CH), 3.87 (s,
2H, CH). 13C NMR (CD3OD): d ¼ 168.5, 139.4, 137.5, 135.9,
130.0, 127.4, 114.8, 68.6, 41.1. IR: 1751 (vs, C¼¼O), 1602
cmꢁ1 (s, HNH).
3c (yield: 92% for L form) and 3i (yield: 69% for race-
mate)): 1H NMR (CD3OD): d ¼ 7.06 (Ph), 6.44 (Ph), 5.18
(ACH2AOA), 4.06 (NH2ACHACO), 1.71 (CH2CH(CH3)2), 2.3–
1.1 (ACHACH2A), 0.90 (CH(CH3)2). 13C NMR (CD3OD): d ¼
170.1, 134, 130, 129, 68.9, 59.3, 41–42, 31.1, 26.5, 18.7,
18.3. IR: 3365 (brw, NH), 1733 cmꢁ1 (vs, C¼¼O).
1
3d (yield: 82%): H NMR (CD3OD): d ¼ 7.06 (Ph), 6.40 (Ph),
5.17 (ACH2AOA), 3.96 (NH2ACHACO), 2.25 (CH(CH3)2),
1.8–1.2 (ACHACH2A), 0.90 (CH(CH3)2). IR: 3379 (brw, NH),
1728 cmꢁ1 (vs, C¼¼O). The 13C NMR spectrum for 3d could
not be obtained because of low solubility of 3d in common
solvents.
Radical Polymerization of 1c and 1d
In a typical example, to a 10 mL ampoule, a solution of
monomer 1d (2.00 g, 5.99 mmol) in THF (2.0 mL) and AIBN
(9.0 mg, 59.9 lmol) was added and degassed. The ampule
was sealed under reduced pressure and stirred at 50 ꢀC for
24 h. The solution was added dropwise into stirring hexane
(30 mL) to form a pale yellow precipitate, 3f (1.64 g, 82%
yield).
2c [yields: 73% (for L form) and 85% (for racemate)]: ESI-
MS Calcd. (C15H21NO2) 270.1464 (M
þ
Naþ); Found
270.1527. 1H NMR (CDCl3): d ¼ 7.38 (d, J ¼ 8.40 Hz, 2H,
Ph), 7.26 (d, J ¼ 8.0 Hz, 2H, Ph), 6.69 (dd, J ¼ 10.8, 17.6 Hz,
1H, ACH¼¼), 5.75 (d, J ¼ 17.6 Hz, 1H, CH¼¼), 5.27 (d, J ¼
10.8 Hz, 1H, CH¼¼), 5.14 (AB pattern, 2H, CH2), 3.98 (t, J ¼
6.8 Hz, 1H, CH), 1.76 (m, 3H, CH2, CH), 0.92–0.90 (m, 6H,
CH3). 13C NMR (CDCl3): d ¼ 171.5, 138.1, 136.3, 134.3,
128.8, 126.6, 114.7, 67.7, 51.9, 40.6, 28.5, 24.5, 22.3. IR:
3375 (s, NH), 1731 cmꢁ1 (vs, C¼¼O).
3e (from 1c, 1.72 g, 86% yield): 1H NMR (CDCl3): d ¼ 7.09
(Ph), 6.84 (Ph), 6.56–6.44 (Ph), 5.11 (ACH2AOA), 4.23
(NH2ACHACO),
1.68
(CH), 1.57 (CH), 1.68–1.30
(ACH2ACHA), 1.42 (C(CH3)3), 0.89 (CH3). 13C NMR
(CD3OD): d ¼ 173.6, 155.6, 145.2, 133.2, 127.8, 77.8, 66.6,
52.3, 46.3, 41.7, 40.3, 28.5, 24.9, 23.1, 22.0. IR: 3364 (brw,
NH), 1709 cmꢁ1 (vs, C¼¼O).
2d (yield: 96%): ESI-MS Calcd. (C14H19NO2) 234.1494 (M þ
Hþ); Found 234.1489. 1H NMR (CDCl3): d ¼ 7.37 (d, J ¼
8.00 Hz, 2H, Ph), 7.28 (d, J ¼ 8.0 Hz, 2H, Ph), 6.68 (dd, J ¼
10.8, 17.6 Hz, 1H, ACH¼¼), 5.75 (d, J ¼ 17.6 Hz, 1H, CH¼¼),
5.27 (d, J ¼ 10.8 Hz, 1H, CH¼¼), 5.21 (d, J ¼ 12 Hz, 1H, gem-
CH), 5.11 (d, J ¼ 12 Hz, 1H, gem-CH), 3.87 (m, 1H, CH), 2.31
(m, 1H, CH), 1.00 (d, J ¼ 6.8 Hz, 6H, CH3). 13C NMR (CDCl3):
d ¼ 169.1, 138.2, 136.3, 134.0, 129.1, 126.6, 114.8, 68.0,
58.5, 30.0, 17.9, 17.7. IR: 3321 (s, NH), 1733 cmꢁ1 (vs,
C¼¼O).
3f: 1H NMR (CDCl3): d ¼ 7.11 (Ph), 6.54–6.70 (Ph), 5.12
(ACH2AOA), 4.10 (NH2ACHACO), 2.09 (CH), 1.43–1.29
(ACHACH2A), 1.43 (C(CH3)3), 0.89 (CH3). 13C NMR (CDCl3):
d ¼ 172.4, 155.8, 145.0, 133.1, 128.0, 79.8, 66.7, 58.6, 46.2,
40.3, 31.5, 28.5, 19.2, 17.7. IR: 3374 (brw, NH), 1709 cmꢁ1
(vs, C¼¼O).
Hydrolysis of 3a–3i
Radical Polymerization of 2a–2d
To a 50-mL round-bottom flask, a solution of polymer 3a
(0.105 mg) in methanol (10 mL) was added and a 40% solu-
tion of sodium hydroxide (1.25 mL) was added dropwise. Af-
ter stirring for 1 h, addition of excess amount of water gave
white precipitate, which was filtered (4a: 53% yield).
(C9H10O)n: Calcd. C, 80.56; H, 7.51; Found C, 78.78; H, 7.53.
In a typical example, to a 10-mL ampule was added a solu-
tion of monomer 2a (1.05 g, 5.11 mmol) in THF (1.0 mL)
and AIBN (8.0 mg, 51.1 lmol). The ampule was degassed,
sealed under reduced pressure, and stirred at 50 ꢀC for 24
h. The solution became viscous and after cooling to room
RADICAL POLYMERIZATION OF STYRENE DERIVATIVES, MATSUBARA ET AL.
5595

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
SCHEME 1 Synthesis of 1a–1d
and 2a–2d.
The nitrogen content ratio in the polymer was 0.60%, sug-
gesting that amino acid barely remained. The carbon content
ratio was a little smaller than the theoretical one, because
some amount of water may persistently remained in the
polymer. 1H NMR (CD3OD): d ¼ 7.06 (br, 2H, Ar), 6.54 (br,
2H, Ar), 4.54 (br, 2H, CH2), 1.80 (br, 1H, CH), 1.5 (br, 2H,
CH2). IR: 3309 cmꢁ1 (brs, OH). The other polymers also
showed the same spectra after hydrolysis.
and 2 were characterized on the basis of NMR, IR, and ESI-
Mass spectra and were confirmed on the basis of elemental
analysis. The NMR spectra for these monomers bearing chi-
ral amino acid showed characteristic AB patterns around d 5
assigned as the diastereotopic benzyl methylene protons
(Fig. 2), except for the monomer having achiral glycine in
the side chain. Further, a set of three signals assigned as the
vinyl protons appeared at 5–7 ppm. Deprotection of the N-
Boc group was confirmed by the disappearance of a sharp,
singlet 1H resonance because of the methyl protons in the
tert-butyl group around d 1.4 ppm (Fig. 2).
Acetylation of 4a–4i
To a 100-mL round-bottom flask, poly(4-hydroxymethylstyr-
ene) 4c (131.5 mg) and acetic anhydride (20 mL) were
added and refluxed for 18ꢀh. The addition of water (20 mL)
followed by stirring at 90 C at 1 h gave a white precipitate,
which was filtered (5c: 159.6 mg, 92% yield).
IR resonances of the amino-acid substituted styrene mono-
mers with or without N-Boc group in the side chain gave sig-
nificant information about intermolecular hydrogen-bonding
interaction between secondary Boc-amide or primary amine
NAH moiety and carbonyl groups in the amino acid side
chains. As shown in Figure 3, a single band at 3370 cmꢁ1
for the Boc-protected monomers (e.g., 1c) was out of the
range assigned as secondary amide NAH absorbance with
hydrogen bonding (3330–3060 cmꢁ1; Fig. 3). In contrast,
two bands for the deprotected monomers (e.g., 2c) at 3375
and 3305 (sh) cmꢁ1 were in the range of the primary amine
NAH absorbance with hydrogen bonding (3400–3250 cmꢁ1).
The results showed that hydrogen-bonding interaction may
be efficient for the amino-acid bound monomers after re-
moval of the Boc group, whereas Boc protection of amino
acid in the side chain disturbs hydrogen bonding between
amide NAH and carbonyl groups.
1H NMR (CDCl3): d ¼ 7.04 (br, 2H, Ar), 6.47 (br, 2H, Ar),
5.00 (br, 2H, Ar-CH2A), 2.09 (s, 3H, COCH3), 1.69 (br, 1H, a-
CH), 1.32 (br, 2H, b-CH2). 13C NMR (CDCl3): d ¼ 170.8 (CO),
144.8 (4o-Ph), 133.3 (4o-Ph), 128.0 (Ph), 127.7 (Ph), 66.0
(Ar-CH2A), 46.0, 43.6, 42.6, 42.2 (br, a-CH), 40.2 (b-CH2),
21.0 (CH3). IR: 1732 cmꢁ1 (vs, C¼¼O).
RESULTS AND DISCUSSION
Preparation of a Series of Amino Acid-Bound Styrene
To prepare the amino acid-substituted styrene, in this study,
a simple coupling method was used using inexpensive 4-
(chloromethyl)styrene and N-tert-butoxycarbonyloxy(Boc)-
protected amino acids in DMF containing a small amount of
water with Na2CO3 to form benzyl esters, N-Boc-protected
styrene derivatives of alanine (1a: 78%), glycine (1b: 75%),
leucine [1c: 89% (for L form) and 90% (for racemate)], and
valine (1d: 90%) (Scheme 1).21 The N-Boc group, which is
easily deprotected by acids, is more favored than the other
types of protecting groups, because undesirable hydrolysis of
benzyl ester does not proceed under acidic condition. As a
result, monomers (2a–2d) without the Boc group were suc-
cessfully obtained in high yields [2a (alanyl ester): 80%, 2b
(glycyl ester): 88%, 2c (leucyl ester): 73% (for L form) and
85% (for racemate), 2d (valyl ester): 96%] after treatment
of 1a–1d with 25% TFA in toluene. More acidic conditions
using aqueous solution of some carboxylic acids, which are
generally used for deprotection of the Boc group in peptide
synthesis,22 resulted in hydrolysis of the benzyl ester to
some extent in addition to the deprotection. Compounds 1
Radical Polymerization
Free radical polymerization of monomers, 2a–2d, 1c, and
1d, was conducted (Scheme 2) in degassed THF with AIBN,
which initiated the polymerization at 50 ꢀC under reduced
pressure to form the polystyrene derivatives, 3a–3d from
2a–2d and 3e and 3f from 1c and 1d, efficiently (Table 1,
entries 1–6). Particularly, the (L)-valine-substituted monomer
ꢀ
2d was also polymerized at higher temperature, 80 C, form-
ing a polymer 3g (entry 7). DMF was also used instead of
THF as a solvent for the polymerization of 2d to form a poly-
mer 3h (entry 8). In addition to use achiral glycine-substi-
tuted styrene 2b, racemic amino acid-substituted styrene, a
DL-leucine derivative (rac)-2c, was also polymerized to form
polymer 3i to evaluate necessity of chirality in the monomer
side chain for stereoselective polymerization (Table 1, entry
5596
WILEYONLINELIBRARY.COM/JOURNAL/JPOLA

ARTICLE
FIGURE 2 Representative exam-
ples of the 1H NMR spectra (in
CDCl3, 400 MHz) for (a) 1c and
(b) 2c.
9 and Scheme 3). The polystyrene derivatives, 3a–3d and
3g–3i, bearing no Boc groups could be dissolved in metha-
nol, DMSO, or DMF, but were only swelled in toluene, THF,
or chloroform, suggesting that intramolecular strong hydro-
gen bonding between amine and carbonyl moieties in the
side chains prevents dissolution in nonpolar solvents. In con-
trast, the Boc-protected polymers 3e and 3f were soluble
even in nonpolar solvents. Thus, in the polymerization of
2a–2d in THF resulted in production of the swelled poly-
mers, which were precipitated in hexane, yielding polymers
3a–3d and 3g–3i, whereas the other Boc-substituted poly-
mers 3e and 3f were precipitated in methanol after polymer-
ization. Because of the poor solubility in THF, molecular
weight of these amino acid-bound polystyrenes could not be
determined by SEC analysis. The 1H NMR analysis of these
polymers in CD3OD (for 3a–3d and 3g–3i) or CDCl3 (for 3e
and 3f) demonstrated the disappearance of the characteristic
set of the three signals due to the vinyl protons of the mono-
mers and appearance of broadened characteristic signals
around d 6–7 and 1–2 ppm, assigned as phenylene and alkyl
chain groups, respectively, in 4-substituted polystyrene as
shown in Figure 4.
to form corresponding polymers 4a–4i and 5a–5i in good
yields (Scheme 2 and Table 1). The absence of amino acid
groups in these polymers was confirmed on the basis of the
NMR and IR spectra. Elemental analysis data of the
Hydrolysis and Acetylation
To evaluate the tacticity of the polymers from responsible
NMR spectra, we removed amino acid side chain. As shown
in Scheme 2, polymers 3a–3i were hydrolyzed with NaOH in
methanol and water (1 mol Lꢁ1) solution at room tempera-
ture to remove amino acid in the side chains and then acety-
lated with acetic anhydride under reflux condition for 18 h
FIGURE 3 Representative examples of IR spectra (solid state)
for 1c and 2c in the region of NAH stretching (3100–3600
cmꢁ1). Small bands at 3084 cmꢁ1 in the both spectra were
assigned as sp2 CAH stretching.
RADICAL POLYMERIZATION OF STYRENE DERIVATIVES, MATSUBARA ET AL.
5597

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
SCHEME 2 Radical polymeriza-
tion of 1a, 1d, and 2a–2d to form
3a–3h, which were hydrolyzed
and acetylated to form 4a–4h
and 5a–5h.
hydrolyzed polymer 4 also supported the disappearance of
amino acid. The ratio of nitrogen content in the hydrolyzed
polymer 4 was 0.60%, suggesting that a little amount of
amino acid remained. The ratio of carbon content was
78.78%, which was a little smaller than the theoretical one,
because some amount of water may persistently remained in
the polymer. Detailed spectroscopic analysis of polymers 4a–
4i was difficult, because these polymers were not dissolved
in nonpolar solvents and slightly soluble in polar solvents,
such as methanol and DMF. IR spectra for 4a–4i in the solid
state showed broad absorbance around 3309 cmꢁ1 assigna-
ble to OH stretching band. In contrast, acetylated polymers
5a–5i were easily dissolved in THF and chloroform, so that
the molecular weight of acetylated polymers was finally
determined as 3.2–27 kg molꢁ1 by means of the SEC analysis
using polystyrene as a calibrating standard as shown in Ta-
1
ble 1. The H and 13C resonances due to the methyl protons
and carbon (Hg and Ci in Fig. 5) in the acetyl group for 5a–
5i appeared at d 2.09 and 21.0, showing that the polymers
4a–4i were completely acetylated. Existence of the carbonyl
group in 5a–5i was confirmed by the 13C NMR resonance, in
which the corresponding signal was observed at d 170.8 and
the IR resonance due to the carbonyl stretching band at
1732 cmꢁ1
.
Stereochemistry
Unfortunately, we could not measure specific rotations of the
soluble acetylated polymers because of some coloration
TABLE 1 Synthetic and Analytical Results in Polymers 3–5
3a
4a
5a
b
Mn
Yield (kg
Product (%)
molꢁ1
Temperature Time
Yield
Solvent Product (%)
Yield
Product (%)
Mw/
Entry Monomer (ꢀC)
(h)
)
Mn mm:mr:rr (m:r)c
1
2
3
4
5
6
7
8
9
a
2a (L-Ala) 50
2b (Gly) 50
24
48
48
48
48
48
24
24
24
THF
THF
THF
THF
THF
THF
THF
DMF
THF
3a
3b
3c
3d
3e
3f
85
69
4a
4b
4c
4d
4e
4f
52
54
5a
5b
5c
5d
5e
5f
80
89
92
88
80
85
67
90
47
6.7
3.8
4.2
3.4
8:35:57 (26:74)
6:41:53 (26:74)
2c (L-Leu) 50
2d (L-Val) 50
92
58
3.2
2.3 18:31:51 (34:66)
3.1 13:44:43 (35:65)
2.3 10:30:60 (25:75)
100
86
57
7.4
1c (Boc)
1d (Boc)
50
50
100
64
10.3
11.6
3.7
82
d
1.8
1.9
9:42:49 (30:70)
9:38:53 (28:72)
2d (L-Val) 80
2d (L-Val) 50
3g
3h
3i
–
4g
4h
4i
56
5g
5h
5i
100
69
61
26.6
13.8
2.2 10:45:45 (33:67)
1.4 10:32:58 (26:74)
rac-2c
50
34
The compounds 3, 4, and 5 are polystyrene with amino acid side
styrene analog in the literature.17 The ratios between mr and rr include
chain, poly(4-hydroxymethyl-styrene) after hydrolysis, and poly(4-acety-
loxymethyl-styrene) after acetylation, respectively.
some error (about 5%) because of large overlap of these signals.
d
The yield could not be determined because the product and the
b
Molecular weight was determined by means of size-exclusion chroma-
monomer could not be separated because of these high solubility in
various organic solvents, such as methanol, THF, and hexane.
tography (SEC) in THF, calibrated with polystyrene standard.
c
The ratios of the tacticity were determined by
a curve-fitting pro-
gram23 using the 13C NMR spectra, according to those of a similar poly-
5598
WILEYONLINELIBRARY.COM/JOURNAL/JPOLA

ARTICLE
SCHEME 3 Polymer synthesis using
a
monomer containing a racemic isomer of
leucine, rac-2c.
FIGURE 4 Representative exam-
ple of the 1H NMR spectrum (in
CD3OD, 400 MHz) for 3c.
FIGURE 5 (a) 1H and (b) 13C NMR spectra
(in CDCl3) for acetylated polymer 5.
RADICAL POLYMERIZATION OF STYRENE DERIVATIVES, MATSUBARA ET AL.
5599

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
mr and rr include some error (about 5%) because of large
overlap of these signals. Only in the case of 5a from alanine-
containing polystyrene, unknown signal was contaminated at
d 144.4. Remarkably, we found significant increase of the
low-field signal due to the mm triad of the aromatic carbon
up to 13–20% in the polymers 5c and 5d at d 145-6, which
were synthesized from the polymers having (L)-leucine and
(L)-valine. In contrast, the mm contents of the other poly-
mers, 5a, 5b, 5e, 5f, 5g, and 5i, were under 10% and did
not broadly differ from each other. The solvent, DMF, was
also effective for the stereoselective polymerization in part,
probably because the hydrogen-bonding interaction with
DMF might link the CO and NH groups between the mono-
mer side chain and the growing polymer terminal during
propagation step to form 3h.
Increase of isotacticity in 5c and 5d demonstrated that ster-
eochemistry was successfully controlled to some extent in
FIGURE 6 Partial 13C NMR spectra for 5a–5i around d 144–146
in the aromatic ipso-carbon region.
during acetylation and also could not observe the crystallin-
ity in 5a–5i by powder X-ray diffraction studies, probably
attributed to the inappropriate polymer side-chain length of
the acetyloxymethylphenyl group for the formation of crys-
tals. Thus, we observed the 13C NMR spectra for 5a–5i (Fig.
6) to determine the tacticity of these polymers. The tacticity
of the 13C resonance was assigned according to that for a
similar polymer, poly(4-methoxymethyl-styrene).23 As shown
in Figure 6, the shape of the signals around d 144–146 ppm
assigned as a quaternary phenylene carbon adjacent to the
main-chain carbon in the 13C NMR spectra for 5a–5i shows
increase and decrease of the mm triad contents, which dem-
onstrated an isotactic sequence of three monomer unit in
the polymer main chain. Curve fitting simulation was con-
ducted using an NMR analyzing program, 1D NMR ver. 3. 7.
16.24 Gaussian distributions were applied and optimized by
the least-squares method. Representative examples are
shown in Figure 7. Five or four resonances were found in
the overlapped signals: the lowest-field signal at d 145.8 was
assigned as the mm triad, and the highest ones at d 144.9
were assigned as the rr triads, of which these integrated
ratios in the curve-fitting simulation roughly agreed with the
known values of polystyrene (Table 1). The ratios between
FIGURE 7 Examples of curve-fitting experimental results using
13C NMR spectra for 5c (leucine) and 5b (glycine) around d
144–146 in the aromatic ipso-carbon region, indicating that the
lowest field signal assigned as mm triad for 5c increased in
comparison with that for 5b.
5600
WILEYONLINELIBRARY.COM/JOURNAL/JPOLA

ARTICLE
ꢀ
perature (50 C). It is a significant result, demonstrating that
our hypothesis can be actualized in free radical polymeriza-
tion of styrene derivatives.
CONCLUSIONS
In summary, stereoselective radical polymerization of styrene
derivatives having N-free amino acids in the side chain
bound at the C-terminal was conducted successfully to form
chirality-induced polystyrenes by the synergic stereoregula-
tion with chirality and hydrogen-bonding interaction
between the polymer radical terminal and the monomer.
Remarkably, this synergic control works even at high tem-
perature (50 ꢀC). The stereoselectivity may increase when
the polymerization is conducted at low temperature and the
steric hindrance of the amino acid residues increased. We
are now researching clarification of the detailed mechanism
in stereoregulation and applications of these polymers.
FIGURE 8 One of the models in the stereoselection of free radi-
cal carbon with monomer. One-dimensional hydrogen-bonding
network exists in the main chain, and similar mode of hydro-
gen bonding between the side chains of monomer and poly-
mer a-end.
the polymerization of the styrene derivatives containing chi-
ral amino acids, expectedly. Moreover, the synergic effect of
chirality and intermolecular hydrogen-bonding interaction
between the amino acid-containing monomer and the poly-
mer a-end was indicated from the tacticity of the polymers
5a–5i. Critical differences in the monomer structures and
polymerization conditions of the poorly controlled polymers,
5a, 5b, 5e, 5f, 5g, and 5i from those of the more isotactic
polymers, 5c, 5d, and 5h, were (1) using amino acid without
chirality, glycine or (rac)-leucine, (2) presence of the Boc-am-
REFERENCES AND NOTES
1 (a) Matsumoto, A. In Handbook of Radical Polymerization;
Matyjaszewski, K.; Davis, T. P., Eds.; Wiley: New York, 2002;
Chapter 13; pp 691–773; (b) Nakano, T.; Okamoto, Y. Chem Rev
2001, 101, 4013–4038; (c) Nakano, T.; Okamoto, Y. Macromol
Rapid Commun 2000, 21, 603–612; (d) Furusho, Y.; Yashima, E.
J Polym Sci Part A: Polym Chem 2009, 47, 5195–5207.
2 Satoh, K.; Kamigaito, M. Chem Rev 2009, 109, 5120–5156.
3 (a) Tsuji, M.; Sakai, R.; Satoh, T.; Kaga, H.; Kakuchi, T. Macro-
molecules 2002, 35, 8255–8257; (b) Doiuchi, T.; Dodoh, T.;
Yamaguchi, H. Makromol Chem 1990, 191, 1253–1260; (c)
Bando, Y.; Minoura, Y. Eur Polym J 1979, 15, 999–1006; (d)
Bando, Y.; Yamaguchi, H.; Minoura, Y. Eur Polym J 1979, 15,
497–501.
ꢀ
ide moiety, and (3) at higher temperature, 80 C, for unsuc-
cessful stereoselective polymerization. The above factor (1)
may affect stereoselection with chirality, whereas (2) and (3)
may affect that with hydrogen bonding as expected in Figure
1. Figure 8 shows one of the models in the stereoselection of
free radical carbon in the growing terminal with monomer.
Polymer side chains containing amino acid may make strong
one-dimensional hydrogen-bonding network using carbonyl
and amine moiety. When vinyl carbon in the monomer
makes an approach to the radical carbon, hydrogen-bonding
interaction between the side chains of monomer and the
polymer a-end, before the radical addition, may restrict the
way to two of the four approaches as shown in Figure 1. In
addition, chiral alkyl group in the monomer side chain may
select one of the two approaches, the faces of the sp2 radical
carbon (Fig. 8). Chirality of (L)-alanine in 2a may be insuffi-
cient to control the stereoselection. The N-Boc protection at
the amino group in the styrene derivatives 1c and 1d also
had difficulty in stereoselective polymerization due to weak
hydrogen-bonding interaction, as indicated in the IR resonan-
ces for the monomers 1a–1d (Fig. 3), probably because
steric hindrance of the Boc substituent disturbed the hydro-
gen bonding to some extent. In other words, both chirality
and hydrogen-bonding interaction of chiral amino acid in the
monomer with those in the radical terminal play the crucial
roles in controlling the tacticity. In comparison with earlier
cases, in which only the chirality or hydrogen-bonding inter-
actions could control the tacticity in radical polymerization
4 Porter, N. A.; Allen, T. R.; Breyer, R. A. J Am Chem Soc 1992,
114, 7676–7683.
5 Suenaga, J.; Sutherlin, D. M.; Stille, J. K. Macromolecules
1984, 17, 2913–2916.
6 (a) Okamoto, Y.; Nishikawa, M.; Nakano, T.; Yashima, E.;
Hatada, K. Macromolecules 1995, 28, 5135–5138; (b) Wu, J.;
Nakano, T.; Okamoto, Y. J Polym Sci Part A: Polym Chem
1999, 37, 2645–2648; (c) Vera, F.; Almuzara, C.; Orera, I.; Bar-
bera´, J.; Oriol, L.; Serrano, J. L.; Sierra, T. J Polym Sci Part A:
Polym Chem 2008, 46, 5528–5541; (d) Zhi, J.; Guan, Y.; Cui, J.;
Liu, A.; Zhu, Z.; Wan, X.; Zhou, Q. J Polym Sci Part A: Polym
Chem 2009, 47, 2408–2421.
7 Klok, H.-A.; Schlaad, H. In Peptide Hybrid Polymers, Vol.202,
Advances in Polymer Science; Springer: Heidelberg, 2006.
8 Sanda, F.; Endo, T. Macromol Chem Phys 1999, 200,
2651–2661.
9 (a) Nishihara, K.; Suzuoka, A.; Satoka, N. J Polym Sci Part A:
Polym Chem 1973, 11, 2315–2327; (b) Nishihara, K.; Satoka, N.
J Polym Sci Part A: Polym Chem 1973, 11, 3171–3179.
10 (a) Sanda, F.; Ogawa, F.; Endo, T. Polymer 1998, 39,
5543–5547; (b) Sanda, F.; Nakamura, M.; Endo, T. Macromole-
cules 1994, 27, 7928–7929; (c) Sanda, F.; Nakamura, M.; Endo,
3
ꢀ
under 0 C, this synergic control works even at higher tem-
RADICAL POLYMERIZATION OF STYRENE DERIVATIVES, MATSUBARA ET AL.
5601

JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY DOI 10.1002/POLA
T. J Polym Sci Part A: Polym Chem 1998, 36, 2681–2690; (d)
Sanda, F.; Nakamura, M.; Endo, T. Macromolecules 1996, 29,
8064–8068; (e) Murata, H.; Sanda, F.; Endo, T. Macromolecules
1996, 29, 5535–5538; (f) Sanda, F.; Abe, T.; Endo, T. J Polym
Sci Part A: Polym Chem 1996, 34, 1969–1975; (g) Sanda, F.;
Nakamura, M.; Endo, T. Chem Lett 1997,175–176; (h) Skey, J.;
O’reilly, R. K. J Polym Sci Part A: Polym Chem 2008, 46,
3690–3702.
17 (a) Bush, S. M.; North, M. Polymer 1996, 37, 4649–4652; (b)
Birchall, A. C.; Bush, S. M.; North, M. Polymer 2001, 42,
375–389, and references cited therein.
18 Bag, D. S.; Dutta, D.; Shami, T. C.; Rao, K. U. B. J Polym Sci
Part A: Polym Chem 2009, 47, 2228–2242.
19 (a) Cornelissen, J. J. L. M.; Graswinckel, W. S.; Adams, P. J.
H. M.; Nachtegaal, G. H.; Kentgens, A. P. M.; Sommerdijk, N.
A. J. M.; Nolte, R. J. M. J Polym Sci Part A: Polym Chem 2001,
39, 4255–4264; (b) Yashima, E.; Maeda, K.; Iida, H.; Furusho, Y.;
Nagai, K. Chem Rev 2009, 109, 6102–6211, and references cited
therein.
11 Sanda, F.; Kurokawa, T.; Endo, T. Polym
J 1999, 31,
353–358.
12 Bentolila, A.; Vlodavsky, I.; Ishai-Michaeli, R.; Kovalchuk, O.;
Haloun, C.; Domb, A. J. J Med Chem 2000, 43, 2591–2600.
20 Matsubara, K.; Ando, S.; Yamanaka, M.; Murakami, E.;
13 (a) Morcellet, M.; Loucheux, C.; Daoust, H. Macromolecules
1982, 15, 890–894; (b) Lekchiri, A.; Morcellet, J.; Morcellet, M.
Macromolecules 1987, 20, 49–53; (c) Methenitis, C.; Morcellet,
J.; Pneumatikakis, G.; Morcellet, M. Macromolecules 1994, 27,
1455–1460, and references cited therein.
Onishi, Y. Fukuoka Daigaku Rigakushuhou 2005, 35, 25–31.
21 Especially in the coupling reaction of 4-(chloromethyl)styr-
ene with Boc-alanine, the solvent DMF needs adding more
than 1 wt % of water, because DMF in high quality could not
dissolve the inorganic base, Na2CO3.
14 Wang, J.; Xu, W.; Cheng, Z.; Zhu, X.; Zhang, Z.; Zhu, J.;
22 Fujii, M.; Yajima, H. J Chem Soc Perkin Trans 1 1981,
Zhang, W.
7690–7701.
J Polym Sci Part A: Polym Chem 2008, 46,
831–841, and references cited therein.
23 Monthe´ard, J. P.; Boinon, B.; Ainad-Tabet, D.; Pham, Q. T.
15 (a) Wu, W.-X.; McPhail, A. T.; Porter, N. A. J Org Chem
1994, 59, 1302–1308; (b) Porter, N. A.; Carter, R. L.; Mero, C. L.
Tetrahedron 1996, 52, 4181–4198.
Polym Bull 1986, 16, 59–66.
24 Nakamura, H. FT-NMR Data Processing Using a Computer;
16 Tanaka, H.; Niwa, M. Polymer 2008, 49, 3693–3701.
Sankyo Shuppan: Tokyo, 2000.
5602
WILEYONLINELIBRARY.COM/JOURNAL/JPOLA