Helicity induction in charged poly(phenylacetylene)s bearing various acidic functional groups in water and its mechanism

Article abstract of DOI:10.1021/ma051617+

We investigated the helicity induction in a series of stereoregular cis-transoidal poly-(phenylacetylene)s bearing various acidic functional groups, such as a phosphonic acid and its monoethyl ester (poly-1-H and poly-2-H, respectively), a carboxylic acid

Full text of DOI:10.1021/ma051617+

Macromolecules 2005, 38, 8625-8633
8625
Helicity Induction in Charged Poly(phenylacetylene)s Bearing Various
Acidic Functional Groups in Water and Its Mechanism
Hisanari Onouchi, Takashi Hasegawa, Daisuke Kashiwagi, Hiroyuki Ishiguro,
Katsuhiro Maeda, and Eiji Yashima*
Department of Molecular Design and Engineering, Graduate School of Engineering,
Nagoya University, Chikusa-ku, Nagoya 464-8603, Japan
Received July 6, 2005
ABSTRACT: We investigated the helicity induction in a series of stereoregular cis-transoidal poly-
(phenylacetylene)s bearing various acidic functional groups, such as a phosphonic acid and its monoethyl
ester (poly-1-H and poly-2-H, respectively), a carboxylic acid (poly-3-H), and a sulfonic acid (poly-4-
H) as the pendants with optically active small molecules with opposite charges, such as amino acids and
amines in water. Poly-1-H, poly-2-H, and poly-4-H have a more acidic phosphonic or a sulfonic group
than the carboxy group of poly-3-H as the pendant, and they could form complexes with the 19 common
free L-amino acids as well as optically active amines. The complexes showed characteristic induced circular
dichroisms (ICDs) in the polymer backbone regions, due to the prevailing one-handed helix formations
on the polymers. On the other hand, poly-3-H, which was insoluble in water, but became soluble as the
sodium salt (poly-3-Na), exhibited ICDs in the presence of only several common free L-amino acids and
optically active amines. The interactions of these polyelectrolytes with selected optically active amino
acids and amines in water depending on the pH were studied in detail by means of CD spectroscopy
together with the potentiometric pH titrations, and the mechanism of the helicity induction in the
polyelectrolytes was discussed.
Chart 1. Structures of Poly(phenylacetylene)-Based
Polyelectrolytes
Introduction
Biological macromolecules, such as proteins and
nucleic acids, are typical polyelectrolytes with optical
activity, and they bind to a variety of biomolecules and
drugs with opposite charges through specific interac-
tions, such as electrostatic, directed hydrogen bonding,
and van der Waals interactions in water.1 To mimic such
specific interactions occurring in biological events, a
number of synthetic receptor molecules have been
prepared with great interest, but they usually show
chiral or molecular recognition abilities in organic
media. The rationale design of charged synthetic recep-
tors for biomolecular recognition through polar interac-
tions in water still remains very difficult.2 This is
because small electrolytes predominantly dissociate into
free ions in water by hydration, and therefore attractive
interactions including hydrogen bonding and electro-
static interactions cannot be anticipated in water.3
However, polyelectrolytes are completely different
from small electrolytes; that is, a portion of the coun-
terions are bound to polyelectrolytes of a sufficiently
high charge density, resulting in the lower ionic activity
of the counterions than that expected from small
electrolytes.4,5 Therefore, polyelectrolytes can efficiently
interact with small charged molecules even in water.
This effect is called counterion condensation.4 This
characteristic feature of polyelectrolytes may give an
important clue for the design of charged synthetic
receptors for biomolecular recognition in water.
an induced circular dichroism (ICD) in the UV-visible
region of the polymer backbone due to the predomi-
nantly one-handed helical structure. However, the
polymer was not highly sensitive to amino acids and
other biologically important chiral molecules.7
Recently, we found that a rationally designed poly-
electrolyte, cis-transoidal poly((4-phosphonophenyl)-
acetylene) (poly-1-H) (Chart 1), bioinspired by the
interaction motifs of nucleic acids, interacted with a
variety of biomolecules including free L-amino acids,
peptides, proteins, aminoglycosides, and carbohydrates,
and formed a one-handed helical conformation in water.8
The complexes formed supramolecular assemblies
through electrostatic and hydrogen bonding interac-
tions, and exhibited an ICD in the UV-visible region
of the polymer backbone in water. We anticipated that
other chromophoric polyelectrolytes bearing more acidic
functional groups as the pendants might be more
sensitive to the chirality of biomolecules, resulting in
more intense ICDs in their polymer backbone regions.
In this study, we systematically investigated the
helicity induction in a series of cis-transoidal poly-
(phenylacetylene)s bearing various acidic functional
groups as the pendants (poly-1-H, poly-2-H, poly-3-
H, and poly-4-H) (Chart 1) in the presence of optically
active amino acids and amines in water by means of
CD spectroscopy and potentiometric pH titrations in
In a series of our studies, we reported the helicity
induction in optically inactive poly((4-carboxyphenyl)-
acetylene) and its sodium salt (poly-3-H and poly-3-
Na, respectively) (Chart 1) with chiral amines in DMSO6
and some amino acids in water.7 The complexes showed
* To whom correspondence should be addressed. E-mail:
yashima@apchem.nagoya-u.ac.jp.
10.1021/ma051617+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/17/2005

8626 Onouchi et al.
Macromolecules, Vol. 38, No. 21, 2005
Figure 1. CD and absorption spectra of polymers with amino acids in water at 25 °C. Shown are the CD spectra of the poly-1-H
with D- and L-Trp at pH 4.5, poly-1-H with L-Ala at pH 4.3 (A), poly-2-H with D- and L-Trp at pH 3.8, poly-2-H with L-Ala at
pH 3.8 (B), poly-3-Na with D- and L-Trp at pH 7.9, poly-3-Na with L-Met at pH 7.7 (C), and poly-4-H with D- and L-Trp at pH
5.4, and poly-4-H with L-Ala at pH 2.3 (D). The concentration of polymers is 1.0 mg/mL and the molar ratio to polymers is 5 for
L-Trp, 10 for L-Ala and L-Met. The absorption spectra of polymers in the presence of L-Trp are also shown.
order to propose the mechanism of the helicity induction
in the polyelectrolytes in water. Poly-4-H was a new
poly(phenylacetylene)-based polyelectrolyte. Poly(ethyl
(4-ethynylphenyl)phosphonate) (poly-2-H) (Chart 1)
was already reported to form a predominantly one-
handed helix upon complexation with various chiral
amines in DMSO, and was more sensitive to the
chirality of amines than poly-1-H and poly-3-H,9 but
the helicity induction on poly-2-H in water has not yet
been reported. These results will contribute not only to
constructing novel helical polyelectrolytes as a sensitive
probe for the chirality assignments of chiral biomol-
ecules in water, but also to understanding the mecha-
nism of specific bimolecular interactions of biological
polymers with biomolecules and drugs in water.10
for poly-1-H, poly-2-H, and poly-4-H, while the
sodium salt of poly-3-H (poly-3-Na) exhibited ICDs
with only 8 of them (Gln, Ile, Leu, Met, Phe, Trp, Arg,
and Lys) (Table 1). The ICD magnitudes, in most cases,
increased with the decreasing temperature. The com-
plexes with L-Trp having a bulky aromatic side group
and basic amino acids, such as L-Lys and L-Arg, tend to
show more intense ICDs than those with other L-amino
acids. Concerning the relationship between the Cotton
effect signs of poly-1-H and the absolute configurations
of the L-amino acids, 12 neutral and 2 acidic L-amino
acids gave the same ICD signs, while the secondary
amino acid, L-Pro, and the three basic amino acids,
L-Arg, L-His, and L-Lys, gave the opposite ICD sign
(negative second Cotton) at 25 °C. In contrast, all of the
primary L-amino acids gave the same ICD sign (positive
second Cotton) for poly-2-H and poly-3-Na at 25 °C,
but the complexes of poly-2-H with L-Pro at 0 and 25
°C and poly-3-Na with L-Phe at 0 °C exhibited the
opposite ICD sign. On the other hand, there is no
general relation between the ICD signs and the absolute
configurations of the amino acids for poly-4-H. Among
the four different poly(phenylacetylene)s, poly-2-H
appeared to be the most sensitive to the chirality of the
L-amino acids and exhibited the more intense ICDs in
the presence of the L-amino acids, except for L-Asn,
L-Asp, L-Arg, and L-His. The CD titrations using some
amino acids showed that the ICD intensities increased
with the increasing concentration of the amino acids
(Supporting Information). Interestingly, the CD inten-
sity of the complex of poly-2-H with L-Trp reached an
almost constant value in the presence of ca. 1 equiv of
L-Trp at 25 °C (Figure S-2B in the Supporting Informa-
tion). Plots of the CD intensities of the second Cotton
(∆ꢀsecond) of poly-2-H as a function of the concentration
of L-Trp gave a saturated binding isotherm. The Hill
plot analyses of the data for the polymers with L-Trp
resulted in the apparent binding constants (Ks) of 137,
1310, 19.6, and 244 for poly-1-H, poly-2-H, poly-3-
Na, and poly-4-H, respectively.6k,12 The K value for the
complexation of L-Trp with poly-2-H was the highest
among these polymers, and more than 100 times greater
than those of L-Ala with these polymers (9.8, 11.8, and
3.3 for poly-1-H, poly-2-H, and poly-4-H, respectively;
see Figure S-1-S-4 in the Supporting Information).
Results and Discussion
Synthesis and Helicity Induction of Polyelec-
trolytes with Free Amino Acids and Chiral Amino
Alcohols. Cis-transoidal poly-1-H,8,9 poly-2-H,9 and
poly-3-H6,7 were prepared according to previously
reported methods. A novel cis-transoidal stereoregular
polymer, poly-4-H, was prepared by the polymerization
of the ammonium salt of the corresponding monomer
with a rhodium (Rh) complex in water in a method
similar to that previously reported,7,9 followed by acidi-
fication of the pendants with aqueous 2 N HCl. The
number-average molecular weight (Mn) and its distribu-
tion (Mw/Mn) were estimated to be 1.48 × 105 and 1.9
(poly-1-H), 1.9 × 104 and 3.5 (poly-2-H), 5.8 × 104 and
2.5 (poly-3-H), and 9.5 × 104 and 5.6 (poly-4-H),
respectively, as determined by size exclusion chroma-
tography (SEC) (see Experimental Section in the Sup-
porting Information). The 1H NMR spectra of these
polymers showed sharp singlets centered at around 5.8
ppm, due to the main chain protons, indicating that
these polymers possess a highly cis-transoidal, stereo-
regular structure.11
The typical CD and absorption spectra of the polymers
in the presence of free amino acids, L- and D-tryptophan
(Trp) ([Trp]/[polymer] ) 5) and L-alanine (L-Ala) or
L-methionine (L-Met) ([Ala or Met]/[polymer] ) 10) in
water at 25 °C are shown in Figure 1. The complexes
showed split-type similar ICDs in their patterns and the
ICDs with L- and D-Trp were mirror images of each
other. The assay of 19 common free L-amino acids (Ala,
Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met,
Phe, Pro, Ser, Thr, Tyr, Trp, and Val) produced ICDs
To obtain information regarding the interactions
between the polymers and amino acids in water, the
effects of the pH and salt concentration in solution on

Macromolecules, Vol. 38, No. 21, 2005
Helicity Induction Mechanism in Water 8627
Table 1. Signs and Difference in Exciton Coefficient of the Second Cotton (∆Esecond) for the Complexes of Poly-1-H,
Poly-2-H, Poly-3-Na, and Poly-4-H with Amino Acids in Watera
second Cotton [λ (nm) and ∆ꢀsecond (M-1 cm-1)]
poly-1-H
λ (∆ꢀ)
poly-2-H
λ (∆ꢀ)
poly-3-Na
λ (∆ꢀ)
poly-4-H
λ (∆ꢀ)
amino acid
L-Ala
N-Ac-L-Ala-OMe 3.6 c
pH
4.3 365 (+1.8) 365 (+8.0) 3.8 368 (+9.0) 368 (+14.1)
4.4 367 (+3.5) 368 (+6.1)
363 (+1.2) 3.8 367 (+0.8) 369 (+2.1)
4.2 364 (+4.0) 365 (+9.2) 3.7 368 (+9.0) 369 (+14.1)
25 °Cb
0 °C
pH
25 °C
0 °C
pH
25 °Cb
0 °C
pH
25 °C
0 °C
c
c
c
c
c
c
c
c
2.3 363 (-3.6) 367 (-4.3)
2.8 364 (+0.8) 365 (+2.2)
2.1 363 (+2.7) 363 (+5.3)
2.1 365 (-3.3) 363 (-4.0)
c
L-Asn
L-Cys
L-Gln
L-Ile
4.3 c
4.2 363 (-0.9) 365 (+1.8)b 3.8 368 (+1.7) 369 (+9.2) 7.5 388 (+0.1) 380 (+0.1) 2.0 363 (-1.0) 364 (+1.5)
4.3 364 (+3.3) 364 (+7.2) 3.9 367 (+9.9) 368 (+13.5) 7.5 381 (+0.3) 373 (+0.6) 2.0 367 (+6.9) 364 (+9.2)
4.2 364 (+3.3) 365 (+6.7) 3.9 367 (+12.2) 368 (+15.4) 7.8 372 (+0.3) 373 (+0.6) 1.9 363 (+3.1) 361 (+4.0)
4.4 364 (+2.2) 366 (+4.8) 3.8 368 (+9.0) 369 (+12.7) 7.7 375 (+0.5) 374 (+1.5)d 1.5 365 (+3.6) 365 (+5.6)
L-Leu
L-Met
L-Phe
L-Pro
4.4 368 (+0.8) 365 (+4.0) 3.8 368 (+6.6) 368 (+11.8) 7.6 c
383 (-0.4) 4.7 364 (-3.8) 364 (-6.1)
4.0 364 (-4.0) 365 (-7.1) 3.7 368 (-7.4) 369 (-11.6)
4.3 363 (+1.9) 365 (+6.0) 3.8 368 (+4.3) 369 (+11.1)
4.2 364 (+2.0) 365 (+5.5) 3.8 367 (+5.7) 369 (+11.5)
c
c
c
c
c
c
1.9 357 (-1.0) 363 (-2.4)
2.0 363 (-0.1) 364 (+0.5)
2.1 363 (+1.5) 364 (+2.6)
L-Ser
L-Thr
L-Trpe
L-Tyrf,g
L-Val
4.5 362 (+10.8) 364 (+13.3) 3.8 366 (+13.8) 366 (+14.4) 7.9 373 (+1.7) 372 (+3.9) 5.4 363 (-9.3) 363 (-11.0)
5.3 367 (+0.1) 367 (+1.1) 6.1 367 (+1.1) 368 (+4.3)
4.3 361 (+0.8) 365 (+3.6) 3.9 367 (+2.5) 368 (+8.2)
3.1 364 (+1.4) 366 (+7.4) 3.8 368 (+1.1) 369 (+7.0)
3.4 360 (+0.3) 365 (+3.3) 3.8 368 (+0.3) 368 (+4.6)
c
c
c
c
c
c
c
c
2.1 361 (-1.6) 361 (-2.1)
2.1 363 (+0.5) 365 (+1.8)
3.1 365 (+3.1) 365 (+8.4)
3.0 365 (+1.4) 365 (+3.7)
L-Aspe,h
L-Glue,h
L-Arg
L-Hise,h
L-Lys
3.6 365 (-6.5) 365 (-4.8) 3.2 368 (+1.9) 367 (+6.1) 6.9 371 (+2.7) 371 (+3.8) 4.2 363 (+7.4) 363 (+8.1)
3.6 364 (-3.0) 364 (-11.2) 3.1 368 (+3.6) 367 (+5.2) 2.1 362 (+6.9) 394 (+7.0)
3.7 365 (-3.0) 358 (+1.5) 3.3 367 (+14.1) 368 (+16.1) 6.9 371 (+2.3) 373 (+2.9) 2.5 365 (+7.5) 363 (+10.7)
c
c
a [polymer] ) 1.0 mg/mL, [amino acid]/[polymer] ) 10. b Taken from ref 8. c Not detected. d Taken from ref 7a. e [amino acid]/[polymer]
) 5. f [amino acid]/[polymer] ) 2. g [polymer] ) 0.1 mg/mL. h [polymer] ) 0.5 mg/mL.
Chart 2. Structures of Chiral Amino Alcohols
es of the ICD intensities on the pH and salt concentra-
tion are consistent with the ionic nature of the inter-
actions in water, which will be discussed later in detail.
These polymers also exhibited ICDs in the presence
of water-soluble amino alcohols (Chart 2) in water, and
these results are summarized in Table 2. All the
polyelectrolytes formed an induced helix with an excess
one-handedness upon complexation with these amino
alcohols. In particular, poly-2-H was highly sensitive
to the chirality of the amino alcohols and exhibited
relatively intense ICDs. Poly-3-Na responded to the
chirality of (S)-5 derived from the L-amino acid, L-Ala,
which exhibited no ICD for poly-3-Na in water (Table
1), indicating that the electrostatic repulsion between
the pendants of poly-3-Na and the carboxy group of the
amino acid prevents their effective interactions. In the
previous study, we reported that the amino alcohols (5-
10) of the same configuration gave the same Cotton
effect sign for poly-2-H in DMSO,9 but a similar
tendency could not be observed in water for poly-2-H
and the other polymers. The CD titrations using (S)-7,
which exhibited relatively intense ICDs upon the com-
plexation with these polymers, were also carried out in
order to estimate the Ks for the complexation of (S)-7
with the polymers. The Hill plot analyses of the data
resulted in the Ks of 174, 532, 115, and 986 for poly-
1-H, poly-2-H, poly-3-Na, and poly-4-H, respective-
ly.6k,12 Poly-4-H bearing strong sulfonic acid residues
showed the highest affinity to the amino alcohol (S)-7
among these polymers and the CD intensity reached an
Figure 2. pH dependence of ICD (second Cotton effect) during
the complexation of poly-1-H (b) and poly-2-H (O) with L-Leu
at 25 °C, poly-3-Na with L-Met at -10 °C (2), and poly-4-H
with L-Ile at 25 °C ([) in the absence of salt in water. The
concentration of polymers is 1.0 mg/mL and the molar ratio
of amino acids to polymers is 10. The pH was adjusted with
HCl and NaOH at room temperature.
the ICDs were investigated. The ICD magnitudes of
these polymers with L-amino acids were significantly
influenced by the solution pH, and showed maximum
values at around pH ) 4, 8, and 2 for poly-1-H and
poly-2-H, poly-3-Na, and poly-4-H, respectively (Fig-
ure 2). These pH-dependent ICD changes must be
correlated to the degrees of dissociation of the polymer’s
pendants and the amino acids, which will be discussed
later in detail. The ICD intensities were also strongly
influenced by the salt (NaCl) concentration and de-
creased with the increasing concentration (see Figure
S-5 in the Supporting Information). The presence of a
salt is expected to attenuate the electrostatic inter-
actions because of the charge-shielding effect of the
salt,1,4,5 so that the atropisomerization of the polymer
backbones might occur more occasionally, resulting in
the decreased ICD intensities. These strong dependenc-

8628 Onouchi et al.
Macromolecules, Vol. 38, No. 21, 2005
Table 2. Signs and Difference in Exciton Coefficient of the Second Cotton (∆Esecond) for the Complexes of Poly-1-H,
Poly-2-H, Poly-3-Na, and Poly-4-H with Amino Alcohols in Water at Room Temperaturea
second Cotton [λ (nm) and ∆ꢀsecond (M-1 cm-1)]
poly-1-H
λ (∆ꢀ)
poly-2-H
λ (∆ꢀ)
poly-3-Na
λ (∆ꢀ)
poly-4-H
λ (∆ꢀ)
amino alcohols
pH
pH
pH
pH
(S)-5
11.0
10.6
10.3
9.6
10.3
11.0
365 (+0.2)
360 (+0.4)
364 (-8.6)
367 (-0.9)
363 (-10.4)
363 (+0.6)
11.1
10.7
10.5
10.0
10.2
10.9
367 (-1.9)
367 (+6.7)
366 (-15.2)
367 (-2.2)
368 (-14.1)
368 (+2.6)
11.0
10.7
10.6
10.2
10.0
11.0
369 (-1.2)
369 (-0.6)
366 (-5.7)
366 (+0.9)
366 (-3.0)
363 (-2.0)
11.2
10.9
10.2
9.8
10.0
10.9
364 (-1.5)
359 (+0.2)
364 (+5.9)
363 (+1.6)
363 (-7.0)
361 (+0.5)
(S)-6
(S)-7
(R)-8
(1R,2S)-9
(S)-10
a [polymer] ) 1.0 mg/mL, [amino alcohol]/[polymer] ) 10.
Figure 3. Optimized structures of poly-1-H, poly-2-H, poly-3-H,6b and poly-4-H (20-mer). Shown are space-filling models in
side view (top) and top view (bottom): scale bar, 1.0 nm. The average dihedral angles of the double and single bonds (φ and Ψ,
respectively) from planarity are also shown.
plateau value in the presence of ca. 1 equiv of (S)-7
lated structures of the model polymers including the
previously reported poly-3-H structure are shown in
Figure 3. The average dihedral angles of the double and
single bonds (φ and Ψ, respectively) from planarity for
these model polymers are also shown in Figure 3. The
poly-1-H and poly-2-H adopt an approximately 7/3
helical conformation similar to that of poly-3-H,6b while
the model polymer of poly-4-H had a slightly loose
helical conformation compared with the other polymers.
Among the poly(phenylacetylene)s, poly-2-H has the
most bulky side groups, which may be closely correlated
to its high sensitivity to the chirality of the chiral
biomolecules in water as well as in DMSO. Because the
steric hindrance between the neighboring pendants of
poly-2-H may create a steeper internal-rotation energy
(Figure S-4C in the Supporting Information).
Molecular mechanics calculations with the Dreiding
force field13 were then carried out for the model poly-
mers (20-mer) of poly-1-H, poly-2-H, poly-3-H, and
poly-4-H in order to obtain information regarding the
conformations of the polymers used in this study. The
1H NMR studies revealed that these polymers possess
a highly cis-transoidal, stereoregular structure. There-
fore, we constructed cis-transoidal poly(phenylacety-
lene)s bearing a phosphonic acid and its monoethyl ester
(for poly-1-H and poly-2-H, respectively) and a sulfonic
acid residue (for poly-4-H) as model polymers for the
calculations according to the previously reported method
for a model polymer (20-mer) of poly-3-H.6b The calcu-

Macromolecules, Vol. 38, No. 21, 2005
Helicity Induction Mechanism in Water 8629
Figure 4. Possible structures for the poly-3-Na-L-amino acid (A) and poly-1-H or poly-2-H-L-amino acid complexes in water
(B).
for the polymer main chain,14 poly-2-H may be more
rigid with a longer persistent length than those of the
other poly(phenylacetylene)s.
L-amino acids, thus showing the same Cotton effect
signs. As mentioned above, the complexes of poly-1-H
with basic L-amino acids exhibited the opposite Cotton
effect signs as those with neutral and acidic L-amino
acids, whereas poly-2-H showed the same Cotton effect
signs in the presence of the primary L-amino acids in
water irrespective of the kinds of amino acid substitu-
ents (Table 1). The reason is not clear at present, but
the fact that poly-1-H has two acid OH groups with
different pKa values should be an important factor.
Mechanism of the Helicity Induction on Various
Polyelectrolytes Based on Poly(phenylacetylene)s
with Chiral Amines and Free L-Amino Acids in
Water. As described above, the electrostatic ionic
interactions between the acidic pendants of the chro-
mophoric poly(phenylacetylene)s and small electrolytes,
such as amino acids and amines with the opposite
charges in water appear to be the main driving force
for the helicity induction in the polymer backbones in
water because the ICD intensities are strongly depend-
ent on the pH and NaCl concentration of the solutions.
We then initially investigated the dissociation behaviors
of the four polyelectrolytes by potentiometric pH titra-
tions in 0.05 M aqueous NaCl. The titration experiments
were performed according to reported methods16 (the
detailed procedures are described in the Experimental
Section in the Supporting Information). On the basis of
the potentiometric titration results of the polymers with
NaOH and HCl, the relations between the degree of
dissociation of the polymers (R), the solution pH and the
apparent dissociation constant (pKa) of the polymers
defined by pH - log(R/(1 - R)) were obtained, and the
plots are depicted in Figure 5, parts A and B, respec-
tively. Apparently, poly-1-H showed a two-step dis-
sociation process because poly-1-H has the two acidic
OH groups with different pKa values; the first step
ended at around pH 6 and the second one started at
around pH 7.5. The second dissociation was much
steeper than the first one. In general, a plot of pKa vs R
shows a monotonic increase in its pKa with R if a
polyelectrolyte has no dramatic conformational change
depending on the pH, and the apparent acidity de-
creases with the progressive dissociation of the poly-
mer.4,16 In fact, strong polyacid polyelectrolytes, i.e.,
poly-1-H, poly-2-H, and poly-4-H, displayed almost
linear relationships between the pKa and R values, while
a weak polyacid, poly-3-H, showed a discontinuous
increase in the pKa vs the R value (Figure 5B). Similar
Previously, the interactions of poly-1-H,9 poly-2-H,9
and poly-3-H6b,6c,15 with optically active amines and
amino alcohols in DMSO (poly-1-H, poly-2-H, and
poly-3-H) or water (poly-3-H) were systematically
studied using NMR and CD spectroscopies, and rational
models were proposed to explain the relationships
between the Cotton effect signs of the polymers reflect-
ing the helix-sense and the absolute configurations of
the chiral primary amines and amino alcohols. On the
basis of these models together with the present ICD
results of poly-1-H, poly-2-H, and poly-3-Na with
L-amino acids in water, a possible mechanism for the
helicity induction during the complexation of poly-1-
H, poly-2-H, and poly-3-Na with L-amino acids in
water can be proposed as follows (Figure 4). In water,
L-amino acids may be favorably complexed with the
poly-3-Na to form ion pairs as shown in Figure 4A,
where the conformation of the ammonium group is
closer to being anti-staggered and the carboxylate group
is located outside and remote from poly-3-Na because
of electrostatic repulsion by the negatively charged
carboxylate groups in the polymer’s pendants. There-
fore, the predominant helix-sense may be determined
by the steric difference in the bulkiness of the substit-
uents of the amino acids (R) and the hydrogen (H) of
the neighboring monomer units. The presumed molec-
ular model of the poly-3-Na-L-amino acids complexes
suggests that the right-handed side monomer unit in
Figure 4A is favorably positioned on the front side, while
the left-handed side monomer unit is on backside, so
that the poly-3-Na backbone will possess a right-
handed helix. We noted that the pendant groups of the
poly-3-Na in Figure 4A appear to arrange in a left-
handed screw-sense from the side view, but the main
chain folds into a right-handed screw-sense.15
A similar model can be possible for the complexes of
poly-1-H and poly-2-H with L-amino acids (Figure 4B).
In addition to the steric difference in the R and H
substituents of the neighboring monomer units, the
steric repulsion between the R and the OH or OEt group
(R′) of the neighboring phosphonate monomer units
should be taken into consideration, resulting in a similar
right-handed helical conformation of the polymer back-
bone as poly-3-Na. Therefore, poly-1-H, poly-2-H, and
poly-3-Na take the same right-handed helix with

8630 Onouchi et al.
Macromolecules, Vol. 38, No. 21, 2005
dissociation of poly-2-H is suppressed and the ICD
intensity decreased even though the (S)-6 completely
ionized. These results clearly indicate that sufficiently
dissociated polymer pendants are favorable for interact-
ing with the positively charged chiral ammonium ions
in order to exhibit a strong ICD in water. A similar
tendency was observed for other polymers in the pres-
ence of chiral amines (Figure 6, parts A, C, and D). We
note that poly-4-H bearing strong sulfonic acid residues
exists as a dissociated form over a wide pH range even
at pH < 2, so that the polymer can complex with (S)-5
through electrostatic interactions under the basic, neu-
tral, and acidic conditions, resulting in the ICD at pH
∼ 1 (Figure 6D).
Next we focused on the interactions of the polymers
with an L-amino acid (L-Met) in water. Amino acids exist
as zwitterions in aqueous solution over a large pH
range, and the interaction between the negatively
charged polymers and amino acids was anticipated to
be complicated depending on the pH because a repulsive
ionic interaction between the negatively charged poly-
mers and amino acids should occur as well as an
attractive ionic interaction between the polyelectrolytes
and amino acids with opposite charges from each other.
Poly-2-H exhibited almost no ICD in the presence of
L-Met which exists as a negatively charged carboxylate
or a zwitterion form under the basic and neutral
conditions (6 < pH < 12) (Figure 6B). However, the ICD
intensity of poly-2-H sharply increased at pH < 6 and
reached a maximum value at around pH ) 3, where the
polymer partially protonates and the L-Met mainly
exists as the zwitterion, but transforms into the posi-
tively charged form at around pH ) 2.5. Under a more
acidic condition (pH < 3), poly-2-H could not suf-
ficiently dissociate in order to interact with the cationic
L-Met, so that the ICD intensity slightly decreased.
These ICD changes are quite different from those with
the chiral amine ((S)-6). These results indicate that the
interaction of poly-2-H with amino acids for the helicity
induction strongly depends on the ionization state of the
amino acids, and the anionic and zwitterionic amino
acids cannot efficiently interact with the completely
dissociated anionic poly-2-H because of the electrostatic
repulsion between the negatively charged pendants of
poly-2-H and the anionic carboxylates of the amino
acids. Once the poly-2-H partially protonates, an
attractive ionic interaction thus predominantly occurred
with the amino acids, resulting in the appearance of the
ICD. Poly-1-H and poly-4-H showed similar behaviors
in their pH-dependent ICD changes as poly-2-H, though
poly-1-H showed a weak, but apparent ICD at the weak
alkaline and neutral pH regions probably because poly-
1-H has the two acidic OH groups with different pKa
values. Poly-4-H also exhibited ICDs which gradually
increased with the decreasing pH, and reached a
maximum value at pH ca. 1; at around this pH, the
amino acid carboxylate protonates and exists in a
favorable cationic form for the complexation with the
anionic poly-4-H. On the other hand, the pH-dependent
ICD intensity changes of poly-3-Na with L-Met, as
depicted in Figure 6C, were similar to those with (S)-6;
the ICD intensities monotonically increased with an
increase in the amino acid or (S)-6 ammonium concen-
trations and showed a maximal response at pH 8, even
in the presence of the zwitterions of L-Met. The reason
for this is not clear at present, but electrostatic repulsion
between the carboxylate anions may be weaker than
Figure 5. (A) Normalized titration curves of poly-1-H (b,
R1; O, R2), poly-2-H (0), poly-3-H (2), and poly-4-H (1) in
0.05 M NaCl. The concentrations of the polymers are 4.75,
4.83, 4.65, and 4.13 mM for poly-1-H, poly-2-H, poly-3-H,
and poly-4-H, respectively. (B) Plots of pKa values of poly-
1-H (b, pKa1; O, pKa2), poly-2-H (0), poly-3-H (2), and poly-
4-H (1) against R in 0.05 M NaCl.
nonlinear changes in the potentiometric pH titration
curves were reported for isotactic poly(methacrylic
acid)17 and hydrophobically modified polyelectrolytes,18
and these nonlinear changes were considered to be due
to a conformational transition from a compact form to
an extended one including helix-coil transitions.17,18
Poly-4-H is a very strong polyacid and dissociates into
anions under acidic conditions at pH 2.5. The intrinsic
dissociation constant (pK0) can be obtained, in principle,
by back-extrapolation of the titration curve to R ) 0.
However, the pKa values are dependent on the salt and
polymer concentrations, and the extrapolation requires
a theoretically based curve fitting, and therefore, the
extrapolated values for pK0 may be ambiguous, in
particular, when the titration could not be possible at
low ionization regions. In the present study, the pK0
value could be obtained for the second dissociation of
poly-1-H (pK02) at ca. 9.4 by the linear extrapolation
of the titration curve in Figure 5B. The pK02 value was
greater than that of phenylphosphonic acid, a model
compound of poly-1-H (7.07). This result suggests that
it becomes more difficult for protons of acidic polyelec-
trolytes to dissociate against the attractive force from
the dissociated groups in the neighboring pendants.4
The reported pKa values of phenylphosphonic acid and
its monomethyl ester, benzoic acid, and phenylsulfonic
acid as model compounds of these polymers are 1.83 and
7.07 (pKa1 and pKa2, respectively)19 and 2.97,20 4.2,21 and
0.7,21 respectively.
We then investigated the relationships between the
ICD intensities of the polymers in the presence of chiral
amines ((S)-6 for poly-1-H, poly-2-H, and poly-3-Na
and (S)-5 for poly-4-H) and L-amino acid (L-Met) and
the ionic species of the polymers and the amines and
amino acid in water depending on the pH (Figure 6).
The CD spectra were measured in 0.05 M NaCl under
the same experimental conditions for the potentiometric
pH titrations, so that the pH-dependent CD intensity
changes were more or less different from those in Figure
2. In the case of poly-2-H with (S)-6 (Figure 6B), the
ICD intensity of poly-2-H increased with the increasing
ammonium ion concentration of (S)-6 at 7 < pH < 11,
and reached a maximum value when both the poly-2-H
and (S)-6 dissociated completely into the negative and
positive ions, respectively. However, at pH < 5, the

Macromolecules, Vol. 38, No. 21, 2005
Helicity Induction Mechanism in Water 8631
Figure 6. pH dependence of ICD intensities (the absolute value of the second Cotton effect) during the complexation with L-Met
(9) and (S)-6 ((S)-5 for poly-4-H) (0.05 M, [) and the degree of dissociation (b, R1; O, R2) of poly-1-H (A), poly-2-H (B), poly-
3-Na (C), and poly-4-H (D) (0.005 M) as a function of pH in 0.05 M NaCl solution at 25 °C. The red and blue solid lines and red
broken line illustrate the ionization ratios of the amino and carboxy groups of L-Met and amino group of ethanolamine as a model
compound of (S)-5 and (S)-6, respectively. The CD spectra of poly-1-H with (S)-6 in A were measured at 0 °C.
those between the carboxylate and phosphonate or
sulfonate anions.
the nonlinearities became stronger at 0 °C; even at 40%
ee of Trp gave rise to almost full ICDs as induced by
the pure L-Trp for poly-1-H, poly-2-H, and poly-4-H
at 0 °C. A similar positive, but weak nonlinear effect
was observed for poly-3-Na at 0 °C. As mentioned
above, the complexes of the polymers with L-Trp showed
stronger ICDs than those with other, less bulky L-amino
acids, such as L-Ala and L-Met (Figure 1 and Table 1),
and this strong helicity inducing ability of Trp might
be closely correlated with the chiral amplification
phenomena of these polymers with Trp. The chiral
amine (8) was not sensitive and exhibited a weak
nonlinear effect for poly-2-H at 0 °C (Figure S-6C in
the Supporting Information).
Chiral Amplification (Nonlinear Effect) in Wa-
ter. In our previous studies, we reported that the
complex formations of poly-1-H, poly-2-H, and poly-
3-H with partially resolved amines, such as 1-(1-
naphthyl)ethylamine, displayed a unique, positive non-
linear relationship (chiral amplification or “majority
rule”)6b,9,22 between the enantiomeric excess (ee) of
amines and the observed molar ellipticity of the Cotton
effects; that is, the ICD intensities of the polymers,
corresponding to the helical sense excesses, were out of
proportion to the ee’s of the amines, showing a convex
deviation from linearity through a wide range of ee
values of the chiral amines in DMSO.
Conclusions
The changes in the ICD intensities of the polymers
vs the ee values of amino acids, such as Ala for poly-
1-H, poly-2-H, and poly-4-H and Met for poly-3-Na
and a chiral amine, phenylglycinol (8), were then
measured in water (Figure S-6 in the Supporting
Information). The ICD intensities of poly-1-H, poly-3-
Na, and poly-4-H in the presence of Ala with different
ee values showed a linear effect at 25 °C and lower
temperatures, while a positive nonlinear effect was
observed for poly-2-H in water at 0 °C (see Figure S-6A
in the Supporting Information). The bulky, aromatic
amino acid such as Trp also showed nonlinear effects
for poly-1-H, poly-2-H, and poly-4-H even at 25 °C
(see Figure S-6B in the Supporting Information), and
In summary, we found that novel polyelectrolytes
based on chromophoric poly(phenylacetylene)s bearing
various acidic functional groups, such as a phosphonic
acid residue and its monoethyl ester, a carboxy acid, and
a sulfonic acid as the pendants, can interact with
L-amino acids and optically active amines in water, and
the mechanism of the helicity induction in these poly-
electrolytes in water was investigated by means of CD
spectroscopy together with the potentiometric pH titra-
tions. In particular, the polymer having the bulky
phosphonic acid monoethyl ester as the pendant is the
most sensitive induced helical polymer as a novel probe
for sensing the chirality of free amino acids and amines,

8632 Onouchi et al.
Macromolecules, Vol. 38, No. 21, 2005
without derivatization in water.23 The complexations
between the polyelectrolytes and small electrolytes are
highly dependent on the ionic species of the polymers
and biomolecules in water, which can be controlled by
changing the pH. The polyelectrolytes have optimum
pHs for their helicity induction with biomolecules in
water. Sufficiently dissociated anionic polyelectrolytes
interact with the positively charged ammonium groups
of amines through electrostatic attractive interactions
in water, whereas the electrostatic repulsions between
the anionic polyelectrolytes and the carboxylate groups
of amino acids disturb the effective complexation. The
counterion condensation effect, which is a characteristic
feature of polyelectrolytes, appears to play an important
role to generate the polar ionic interactions between the
synthetic receptors consisting of a polyelectrolyte and
oppositely charged small molecules even in water. These
findings will contribute to the development of more
sensitive and selective synthetic polyelectrolytes for the
detection of chirality of target biomolecules in water.
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Experimental Section
Full experimental details are available in the Supporting
Information.
Acknowledgment. We thank Prof. S. Kawaguchi
(Yamagata University) for valuable discussions. This
work was partially supported by a Grant-in-Aid for
Scientific Research from Japan Society for the Promo-
tion of Science. H.O. expresses thanks for a JSPS
Research Fellowship (No.05704) for Young Scientists.
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Supporting Information Available: Text giving the
experimental details, including reaction schemes, and figures
showing plots of the CD data and the Hill plots. This material
is available free of charge via the Internet at http://
pubs.acs.org.
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