Thermodynamic and kinetic stabilities of complementary double helices utilizing amidinium-carboxylate salt bridges

Article abstract of DOI:10.1021/ja303701d

A series of dimer strands consisting of m-terphenyl backbones bearing complementary chiral or achiral amidines and achiral carboxylic acid residues connected by various types of linkers, such as diacetylene, Pt(II)-acetylide, and p-diethynylbenzene linkag

Full text of DOI:10.1021/ja303701d

Article
pubs.acs.org/JACS
Thermodynamic and Kinetic Stabilities of Complementary Double
Helices Utilizing Amidinium−Carboxylate Salt Bridges
Hidekazu Yamada, Zong-Quan Wu, Yoshio Furusho,† and Eiji Yashima*
Department of Molecular Design and Engineering, Graduate School of Engineering, Nagoya University, Chikusa-ku, Nagoya
464-8603, Japan
S
* Supporting Information
ABSTRACT: A series of dimer strands consisting of m-
terphenyl backbones bearing complementary chiral or achiral
amidines and achiral carboxylic acid residues connected by
various types of linkers, such as diacetylene, Pt(II)-acetylide,
and p-diethynylbenzene linkages, were synthesized by a
modular strategy, and their chiroptical properties on the
complementary double helix formations were investigated by
absorption, circular dichroism (CD), and 1H NMR spectroscopies. The thermodynamic and kinetic stabilities of the
complementary double helices assisted by amidinium−carboxylate salt bridges are highly dependent on their linkages, and the
thermodynamic analyses of the dimer duplexes revealed that the association constants increased in the order: Pt(II)-acetylide
linker < p-diethynylbenzene linker < diacetylene linker, which is in agreement with the reverse order of their bulkiness. The
substituents on the amidine groups were also found to affect the stabilities on the duplexes and the association constants
increased in the order: isopropyl < (R)-1-phenylethyl < cyclohexyl. In addition, the introduction of electron-donating and/or
electron-withdrawing substituents at the phenyl groups of the p-diethynylbenzene linkers connecting the amidine and carboxylic
acid units, respectively, tends to stabilize the complementary double helices, especially in polar solvents, such as DMSO, due to
the attractive charge-transfer interactions between the aromatic linkers, although the salt bridge formation is hampered in DMSO.
Furthermore, the kinetic analyses of the chain exchange reactions for the duplexes bearing diacetylene and p-diethynylbenzene
linkages showed that these were slow processes with negative ΔS⧧ values, meaning that the chain exchange reactions proceed via
direct exchange pathways. In contrast, those for the duplexes bearing Pt(II)-acetylide linkages were fast processes supported by
positive ΔS⧧ values, suggesting that the chain exchange reactions proceed via dissociation−exchange ones. The helix-inversion
1
kinetics investigated for the racemic dimer duplexes composed of achiral amidines based on variable-temperature H NMR
measurements indicated that the barriers for the helix-inversion increased in the order: Pt(II)-acetylide linker, p-
diethynylbenzene linker < diacetylene linker.
A novel class of metal-free double-stranded helices has
recently been reported by Lehn, Huc, and co-workers based on
aromatic oligoamides that fold into double helices primarily
through interstrand aromatic interactions along with hydrogen
bondings.8 Although such a hydrogen-bonding-driven self-
assembly is a readily available and versatile approach to
construct supramolecular duplexes, it remains difficult and
challenging to design double helices on the basis of interstrand
hydrogen-bonding, since most duplexes assembled via hydro-
gen-bonding interactions result in zipper or ladder structures.14
The oligoresorcinols, types of m-phenylene oligomers, with
specific chain lengths have also been found to self-assemble into
well-defined double-stranded helical structures in water through
interstrand aromatic interactions.9 These double helices are
unique and promising for further research and development of
double helices with specific functions, but most of the double
helices reported to date lack the important key feature of DNA,
that is, the complementarity of the strands.8e,11d,15
INTRODUCTION
■
Since the discovery of the α-helix in proteins1 and double helix
in DNA,2 amazing strides have been made in molecular biology,
and their sophisticated functions have been elucidated at a
molecular level.3 The discoveries of these biological helices with
remarkable functions have also significantly stimulated chemists
to challenge making artificial single- and double-stranded helical
polymers and oligomers (foldamers), aiming mainly at
mimicking such biological helical structures in the early stages
and even now.4 The one-handed helicity is specific to the DNA
double helix and protein’s α-helix because of the homochirality
of their components, which is critical and of key importance for
their remarkable functions. Currently, a number of synthetic
polymers4a,b,5 and oligomers4c,6 with a controlled helical
conformation have been reported, also for their applications
in the development of unique chiral materials for separating
enantiomers and asymmetric catalysis.4a,5q However, a limited
number of structural motifs7−11 are still available for
constructing double helices except for the DNA analogues
(peptide nucleic acids, PNA)12 and the helicates,7a−d,13 the
metal coordination-driven helical assemblies.
Received: April 17, 2012
Published: May 8, 2012
© 2012 American Chemical Society
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Figure 1. Modular strategy to construct a series of amidine dimers joined by various linkers (top), intertwined complementary double helix
formation between chiral amidine and achiral carboxylic acid dimers (middle), and the crystal structure of the diacetylene-linked double helix (A:
(R)-1a·2a) (bottom).
Recently, we developed a modular strategy to construct a
series of rationally designed complementary double helices
bound through amidinium−carboxylate salt bridges16 that have
a high stability and well-defined directionality (Figure 1).17 The
double helical structure relies on the crescent-shaped m-
terphenyl-based, rigid π-conjugated backbones joined by
diacetylene linkages, which prevent the duplex formation
from taking any conformations other than the double helices.
In addition, the helix-sense is readily controlled by the chirality
introduced on the amidine groups. Duplex A composed of an
achiral carboxylic acid dimer and an optically active (R)-1-
phenylethyl amidine-bound dimer was found to adopt a right-
handed double-helical structure as evidenced by an X-ray
crystallographic analysis (A in Figure 1).16a
complementary double helical oligomers16b,e,k and poly-
mers16c,h linked by the trans-Pt(II) acetylide16b,c,e,k,18 residues
and p-diethynylbenzene units16h as the linker moieties based on
the modular strategy that allows the one-step construction of
amidine dimers and carboxylic acid dimers joined by the
different linkers starting from the identical amidine ((R)-7a-H)
and carboxylic acid monomers (8a-H, Scheme 1) by the Glaser-
type coupling, Cu(I)-catalyzed reaction, and Sonogashira
reaction, respectively (Figure 1), and the resulting comple-
mentary double helices (B and C in Figure 1, respectively, for
dimers) also possess a helix-sense bias induced by the chiral
amidine groups.
In the present study, we synthesized a series of chiral and
achiral amidine and achiral carboxylic acid dimeric strands
bearing three kinds of linker units, i.e., diacetylene, trans-Pt(II)-
acetylide, and p-diethynylbenzene linkages, by the modular
By taking advantage of this complementary amidine/
carboxylic acid system, we have synthesized a series of
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Scheme 1. Synthesis of Diacetylene-Linked Amidine and Carboxylic Acid Dimers
strategy (Chart 1), and investigated the effects of the linkages
and the substituents on the amidine residues and those at the
phenyl groups of the p-diethynylbenzene linkers on their
complementary double helix formations by measuring the
Novel achiral amidine dimers (1b and 1c) joined by
diacetylene linkers were synthesized by the palladium-catalyzed
Glaser-type homocoupling of the corresponding monoethynyl
amidine monomers (7b-H and 7c-H) in 43 and 39% yield,
respectively (Scheme 1) according to the methods reported for
the synthesis of the analogous chiral amidine dimers ((R)- and
(S)-1a)16a and achiral carboxylic acid dimers (2a and 2b).16a,g
The four chiral amidine dimers ((R)- and (S)-3a and -3b)
and two achiral carboxylic acid dimers (4a and 4b) bearing
Pt(II)-acetylide linkers with triethylphosphine (PEt3) or
triphenylphosphine (PPh3) ligands were synthesized by the
Cu(I)-catalyzed reaction of the corresponding monoethynyl
amidine monomers ((R)- and (S)-7a-H) and carboxylic acid
monomer (8a-H) with PtCl2(PEt3)2 or PtCl2(PPh3)2,
respectively, in the presence of diethylamine according to our
previously reported methods (Scheme 2).16b,k In the same way,
a novel achiral cyclohexyl-bound amidine Pt(II)-acetylide-
linked dimer with PEt3 ligands (3c) was prepared from 7c-
H16l in moderate yield (62%).
1
absorption, circular dichroism (CD), and H NMR spectros-
copies. The thermodynamic and kinetic stabilities of the
complementary double helices stabilized by the amidinium−
carboxylate salt bridges were also investigated in detail by
determining the association constants for the double helix
formation, the rates for the chain exchanges of the chiral double
helices, and the helix-inversion barriers for racemic double
helices composed of achiral amidines. The present results will
not only contribute to a basic understanding of the principles
underlying the formation of synthetic and biological double
helices, but also provide a clue to developing rationally
designed novel double helices with specific structures and
functions. Although single-stranded helical foldamers, such as
oligo(m-phenylene ethynylene)s, have been comprehensively
investigated,4c there has been no report on the thermodynamics
and kinetics of the double helix formation except for the
seminal example of aromatic oligoamide-based double
helices.6t,8
The novel chiral ((S)-5a and (R)-5b and -5c) and achiral
amidine dimers (5d) and achiral carboxylic acid dimers (6a−
6e) linked through p-diethynylbenzene units with electron-
donating (2,5-dimethoxy) and/or electron-withdrawing
(2,3,5,6-tetrafluoro, 2-nitro, or 2,5-dinitro) substituents at the
phenyl groups were prepared from the corresponding
monoethynyl amidine monomers ((R)- and (S)-7a-H and 7c-
H) and carboxylic acid monomer (8a-H) with p-diiodobenzene
derivatives (9a−9e), respectively, by the palladium-catalyzed
Sonogashira reaction in similar to the synthesis of (R)-5a and
6f,16h giving the desired dimers in moderate yields (Scheme 3).
All the monomers and dimers were purified by column
RESULTS AND DISCUSSION
■
Synthesis. The chiral/achiral amidine and carboxylic acid
dimers joined by a variety of linkers (A, B, and C in Figure
1)16a,b,h,k were synthesized in a stepwise manner based on the
modular approach by the Glaser-type coupling (Scheme 1), the
Cu(I)-catalyzed reaction (Scheme 2), and the Sonogashira
reaction (Scheme 3), respectively, starting from the mono-
ethynyl amidine monomers ((R)- and (S)-7a-H, 7b-H, and 7c-
H) and carboxylic acid monomers (8a-H and 8b-H) with m-
terphenyl groups as versatile building blocks, which had been
prepared by the monodesilylation of the corresponding amidine
monomers ((R)- and (S)-7a, 7b, and 7c) and carboxylic acid
monomers (8a and 8b) using tetra-n-butylammonium fluoride
(TBAF) according to previously reported methods (Scheme
1).16a,e,h,l The monoethynyl carboxylic acid monomer bearing a
1-octynyl chain at the 5′-position of the m-terphenyl group
(8b), which was introduced as a solubility enhancer for their
oligomers and polymers,16g,h,j,k was also employed in this study.
1
chromatography and characterized and identified by H and
13C or 31P NMR spectroscopies, elemental analyses, and/or
mass measurements (see the Supporting Information [SI]).
Complementary Double-Helix Formation. The chiral
and achiral amidine dimers used in this study readily formed
double helices with their complementary carboxylic acid dimers
by mixing in a 1:1 molar ratio through salt bridge formations, as
1
confirmed by the H NMR and electron-spray ionization mass
1
(ESI-MS) spectroscopies. Figure 2 shows the typical H NMR
spectra of the duplexes linked by diacetylene ((R)-1a·2a)
(a),16a Pt(II)-acetylide with PEt3 ligands ((R)-3a·4a) (b),16k
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Chart 1. Structures of Chiral and Achiral Amidine and Achiral Carboxylic Acid Dimers Linked by a Variety of Linkers (A−C)
and Amidine and Carboxylic Acid Monomers (D)
and p-diethynylbenzene ((R)-5a·6a) (c) linkages and a chiral
amidine dimer strand ((R)-5a) (d) measured in CDCl3 at 25
two broadened doublets and singlet-like signals, respectively,
indicating the salt-bridge formation as well as the molecular
motion of the duplex that is slightly restricted probably due to
the steric repulsion of the bulky phosphine ligands. Other
racemic and optically active duplexes showed a similar tendency
with clear salt-bridged N−H protons in the low magnetic fields
(12−14 ppm) (Table S1 [SI]).
Figure 3A displays the typical CD spectra of the
enantiomeric double helices with different linkers, but the
same chiral amidine residues, (R)- and (S)-1a·2a,16a -3a·4a,16k
and -5a·6a in CHCl3 at 25 °C, which showed intense mirror
image CD signals below ∼370 nm, although their absorption
and CD spectral patterns were different from each other,
reflecting the difference in their linker structures, whereas the
corresponding (R)- and (S)-amidine dimer strands (1a, 3a, and
5a) exhibited very weak CDs in the same regions (Figure S1,
°C. As previously reported,16a,k the H NMR spectra of the
1
amidine dimer strands were complicated because of the E−Z
isomerization of the CN double bonds of the amidine
residues,16a,b,d,e,g−i,k whereas the duplexes showed sets of clear
signals including the salt-bridged N−H protons (c′ and c”) that
appeared as two sharp doublets in the low magnetic fields (13−
14 ppm) except for (R)-3a·4a (Figure 2 and Table S1 [SI]),
and the methine (a′ and b′) and/or methyl protons (d′ and e′)
of the amidine groups also gave two sets of signals; the
nonequivalency of these signals support the double helical
structures of the duplexes, since the monomer duplexes showed
a one-doublet signal for the NH-protons (Table S1 [SI]). In
contrast, the N−H protons in the duplex (R)-3a·4a (Figure
2b)16k as well as (R)-3b·4b (Table S1 [SI])16b were observed as
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Scheme 2. Synthesis of trans-Pt(II)-Acetylide-Linked Amidine and Carboxylic Acid Dimers
Scheme 3. Synthesis of p-Diethynylbenzene-Linked Amidine and Carboxylic Acid Dimers
SI).16a,k The significant enhancements of the Cotton effect
intensities were observed in the linker chromophore regions of
the diacetylene (∼300−370 nm) for 1a·2a, the trans-Pt(II)-
acetylide (∼300−380 nm) for 3a·4a, and the p-diethynylben-
zene (∼300−370 nm) for 5a·6a, suggesting that 1a·2a, 3a·4a,
and 5a·6a appear to adopt an excess single-handed double
helical structure. The Cotton effect signs of these duplexes with
the same configuration at the amidine residues were roughly
comparable to each other, suggesting that these dimers most
probably take a double-helical structure with the same
handedness when complexed with their complementary
strands, i.e., the (R)-phenylethyl groups on the amidine
residues may bias and induce the same right-handed double
helices independent of the linker structures as evidenced by the
X-ray crystallographic analysis result of the (R)-1a·2a (Figures
1 and S2A [SI]).16a Various attempts to obtain crystals of
double-helical dimers of 3a·4a and 5a·6a suitable for an X-ray
analysis produced only amorphous solids. Therefore, the energy
minimized structures of the duplexes of (R)-3a·4a and (R)-
5a·6a were constructed using the molecular mechanics (MM)
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1
Figure 2. Partial H NMR (500 MHz, 0.1 mM) spectra of (a) (R)-1a·2a, (b) (R)-3a·4a, (c) (R)-5a·6a, and (d) (R)-5a in CDCl3 at 25 °C. The
asterisks denote the signals derived from PEt3 ligands.
Figure 3. CD and absorption spectra (solid lines) of (R)-1a·2a, (R)-3a·4a, and (R)-5a·6a (0.1 mM) in CHCl3 (A) and DMSO (B) at 25 °C. CD
spectra (dashed lines) of (S)-1a·2a, (S)-3a·4a, and (S)-5a·6a (0.1 mM) in CHCl3 are also shown in A. (C) CD and absorption spectra of (R)-3a·4a
and (R)-3b·4b (0.1 mM) in CHCl3 at 25 °C. (D) CD and absorption spectra of (R)-5a·6a, (R)-5b·6c, (R)-5c·6b, (R)-5c·6d, and (R)-5c·6e (0.1
mM) in CHCl3 at 25 °C.
calculations based on analogous crystal structures.16a,b,e,h The
calculated structure of (R)-3a·4a revealed a right-handed
double-stranded helical structure (Figure S2B [SI]), in which
the two Pt atoms at the linker moieties were located at a slightly
long distance of 6.1 Å, due to the steric repulsion of the bulky
phosphine ligands as in the case for an analogous dimeric
double helix with the PPh3 ligands (7.7 Å).16b In contrast, the
calculated structure of (R)-5a·6a (Figure S2C [SI]) has the two
aromatic rings of the p-diethynylbenzene moieties overlapping
to each other with a distance of about 3.5 Å that is close to that
between the diacetylene linkers of each strand observed in the
X-ray structure of (R)-1a·2a (3.8 Å, Figures 1 and S2A [SI]).
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Figure 4. (A) CD and absorption spectral changes of (R)-7a (c = 2.48 × 10−6 M) upon the addition of 8a in CHCl3 at 25 °C. (B) Plots of the CD
intensity at 288 nm vs [8a]. The curve in the plots was obtained by the curve-fitting method, giving the association constant of (R)-7a·8a (K(R)‑7a·8a
)
to be (2.82 0.33) × 106 M−1. (C) Plots of the CD intensity at 295 nm of (R)-7a·8a (c = 1.00 × 10−6 M) upon the addition of 7b in CHCl3 at 25
°C vs [7b]. (D) Plots of the CD intensity at 295 nm of (R)-7a·8a (c = 1.00 × 10−6 M) upon the addition of 7c in CHCl3 at 25 °C vs [7c]. The
curves in C and D represent the curve-fittings according to the eq 4 in the SI. The relative association constants (Krel) of 7b·8a to (R)-7a·8a and
7c·8a to (R)-7a·8a were then estimated to be 0.474 0.017 and 4.47 0.15, respectively, resulting in the K7b·8a and K7c·8a values to be (1.34 0.20)
× 106 and (1.26 0.19) × 107 M−1, respectively.
It should be noted that (R)-1a·2a and (R)-5a·6a exhibited
intense Cotton effects even in DMSO in which the salt bridge
formation is hampered, although the intensities were reduced
to 67% and 28% of those in CHCl3, respectively, whereas (R)-
3a·4a showed a very weak CD similar to that of the amidine
strand (R)-3a, indicating that the (R)-3a·4a duplex underwent
dissociation into the (R)-3a and 4a single strands in DMSO
(Figure 3B). These remarkable solvent effects on the CD
spectra closely relate to their stabilities of the duplexes in
solution, being ascribed to the differences in their association
constants depending on the linker structures (see below).
The Cotton effect signs and pattern of (R)-3b·4b with the
more bulky PPh3 ligands in the Pt(II)-acetylide linker
chromophore region were almost similar to those of (R)-
3a·4a, indicating that the bulkiness of the phosphine ligands
hardly influences the helical sense, although the CD intensities
of (R)-3b·4b were slightly weaker than those of (R)-3a·4a, and
the absorption maximum shifted to a longer wavelength by ∼27
nm in the absorption spectrum (Figure 3C).
regions also changed, while maintaining their Cotton effect
signs when compared to those of the nonsubstituted duplex
((R)-5a·6a) (Figure 3D), indicating a charge-transfer complex-
ation between the p-phenylene residues that may enhance the
stability of their double helix formations with the same helix
sense bias (see also Figure 6 and the text below).
Thermodynamic Stabilities of Monomeric and Di-
meric Duplexes: Effect of Linkers. The effects of the linker
moieties and the substituents on the amidine residues and those
of the phenyl groups of the p-diethynylbenzene linkers on the
stabilities of the complementary double helices were then
investigated in terms of the association constants (Ka) by CD
titrations combined with competition CD titrations. These
results are summarized in Table 1.
First, the association constant of the monomeric duplex (R)-
7a·8a was estimated by the direct CD titration of the amidine
monomer (R)-7a with the carboxylic acid monomer 8a in a
similar way previously reported (Figure 4A).16h The CD
intensity at the first Cotton effect increased with the increasing
concentration of 8a accompanied by a synchronous increase in
its absorption intensity. The Ka for (R)-7a·8a was then
calculated to be (2.82 0.33) × 106 M−1 in CHCl3 at 25 °C
from the nonlinear least-squares curve fitting of the CD
intensity (CD288) at 288 nm (Figure 4B). The introduction of a
The introduction of either electron-donating or electron-
withdrawing substituents at the p-phenylene linkers of the
duplexes ((R)-5b·6c, (R)-5c·6b, (R)-5c·6d, and (R)-5c·6e)
gave rise to a considerable red-shift in their absorption spectra,
and their CD spectral patterns in the linker chromophore
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1-octynyl chain on the carboxylic acid unit did not significantly
affect the association constant; the Ka for (R)-7a·8b was (3.47
0.50) × 106 M−1 (Figure S3 [SI]). In the same way, the Ka
values of the Pt(II)-acetylide-linked duplexes bearing PPh3
ligands ((R)-3b·4b) and PEt3 ligands ((R)-3a·4a)16k in
value of 1b·2a in CHCl3 at 25 °C ((2.66 0.93) × 1012 M−1)
using the K(R)‑3b·2a as the base value (Figure S8 and the SI). The
Ka values for the other duplexes in CHCl3 at 25 °C were also
estimated in a similar fashion by the competition CD titrations
(Figures S9−S16, SI) and the results are summarized in Table
1.
CHCl3 at 25 °C were estimated to be (1.08
0.14) × 107
(Figure S4, SI) and (5.1 2.2) × 108 M−1, respectively, by the
direct CD titration experiments.
On the basis of the association constant measurement results,
the effects of the linker structures on the stabilities of the
double helix formations were clearly revealed; the Ka values of
(R)-1a·2a (6.43 × 1013 M−1), (R)-3a·4a (5.10 × 108 M−1), and
(R)-5a·6a (2.99 × 1012 M−1) in CHCl3 at 25 °C increased in
the following order: Pt(II)-acetylide linker < p-diethynylben-
zene linker < diacetylene linker, which is in agreement with the
reverse order of the bulkiness at the linkers. This tendency was
also supported by the facts that the Ka values of the
heteroduplexes formed between the Pt(II)-acetylide linked
amidine dimer with PPh3 ligands ((R)-3b) and the diacetylene-
linked (2a) or p-diethynylbenzene-linked (6a) carboxylic acid
dimer significantly decreased as compared to those of the
corresponding homoduplexes, 1a·2a and 5a·6a, respectively
(Table 1). A further comparison of the Ka values between (R)-
3a·4a with PEt3 ligands (5.10 × 108 M−1) and (R)-3b·4b with
PPh3 ligands (1.08 × 107 M−1) indicated that the bulkiness of
the phosphine ligands at the Pt(II)-acetylide linkers destabilizes
the double helical structure due to the steric repulsion caused
by the more bulky PPh3 ligands, as anticipated from their MM-
calculated structures (Figure S2B, SI).16b
Effect of Substituents on Amidine Residues. By
comparison of the observed Ka values for the duplexes between
the carboxylic acid (8a) and amidine monomers (7a−7c) and
the diacetylene-linked carboxylic acid (2a) and amidine dimers
(1a−1c), the effect of the substituents on the amidine residues
(isopropyl (i-Pr), (R)-1-phenylethyl, and cyclohexyl (c-Hex)
groups) on the stabilities of the duplex formations were clearly
revealed; the Ka values increased in the following order: i-Pr <
(R)-1-phenylethyl < c-Hex for both of the monomers and
dimers (Table 1). This order may not be consistent with the
bulkiness nor basicity of the substituents on the amidine
residues.19 Although the reason is not presently clear, an
interesting trend was observed when the Ka values of the
monomeric and dimeric duplexes were compared in terms of
K2mer/(K1mer)2, in which the K2mer and K1mer are the association
constants for the dimers and monomers bearing the same
In order to investigate the effects of the substituents on the
amidine residues on the duplex formation of the monomers, the
competition CD titration experiments were employed to
estimate the Ka value ((1.34
0.20) × 106 M−1) between
the isopropyl amidine-bound monomer 7b and the carboxylic
acid monomer 8a in the presence of (R)-7a, while the Ka value
of (R)-7a·8a was known as described above (Figures 4C and S5
and also the SI). In a similar fashion, the Ka value between the
cyclohexyl amidine-bound 7c and the carboxylic acid monomer
8a was estimated to be (1.26 0.19) × 107 M−1 (Figures 4D
and S6 [SI]), which is 4.5 times greater than that of (R)-7a·8a.
The competition CD titration experiments were also
employed to estimate the Ka values for the duplexes linked
through the diacetylene and p-diethynylbenzene units, such as
1a·2a and 5a·6a, respectively, because their association
constants were too high to be determined by the direct CD
titration experiments even at concentrations as low as 10−7
M
(i.e., the detection limit for our spectrophotometer using a 10-
cm quartz cell.) Therefore, the Ka value for the duplex
formation between (R)-3b and 2b was first estimated as the
base value by the competition CD titration experiments using
the achiral carboxylic acid monomer 8b (Figure 5A). The linker
substituents on the amidine residues, respectively; the K2mer
/
(K1mer)2 values were 1.48 for c-Hex, 2.00 for i-Pr, and 8.09 for
(R)-1-phenylethyl. In all cases, the K2mer values were higher
than those of the (K1mer)2 ones because of the synergistic
effects. However, a noticeable synergistic gain was observed in
the duplex bearing the chiral (R)-1-phenylethyl substituents on
the amidine residues compared to those with the other achiral
substituents. This remarkable synergy effect observed in the
(R)-1a·2a duplex may arise from the strong helical sense bias of
the chiral amidine substituents that are able to offer no choice
other than to form a right-handed double helical conformatio-
n,16a while the achiral amidine substituents of 1b·2a and 1c·2a
most likely produce interconvertible right- and left-handed
helical conformations as supported by their variable-temper-
ature 1H NMR measurement results (see below). These
differences in the possible helical conformations may more or
less affect the thermodynamic stabilities of the duplexes.
Effect of Substituents on Phenylene Linkers. The
introduction of either electron-donating (2,5-dimethoxy) or
electron-withdrawing (2,3,5,6-tetrafluoro, 2-nitro or 2,5-dini-
Figure 5. (A) CD and absorption spectral changes of duplex (R)-
3b·2b (c = 1.01 × 10−4 M) upon the addition of 8b in CHCl3 at 25 °C.
(B) Plots of the Krel (based on the CD intensities at 353 nm) vs [8b].
For more detailed calculation procedures, see eqs 5−8 in the SI.
structures of (R)-3b and 2b, in particular, their lengths were
considerably different from each other, resulting in the
formation of a heteroduplex with a smaller Ka suitable for the
measurements. The CD intensity of the (R)-3b·2b duplex
decreased with the increasing concentration of 8b, resulting in
the formation of the ternary complex (R)-3b·(8b)2. Based on
the changes in the CD intensities, the relative Ka value (Krel) of
(R)-3b·(8b)2 to (R)-3b·2b can be approximately given by
K(R)‑7a·8b2/K(R)‑3b·2b (13.3 0.4), leading to the K(R)‑3b·2b value
of (9.05 2.88) × 1011 M−1 at 25 °C (Figure 5B) (for more
detailed procedures, see the SI). Similarly, the Ka value of the
duplex (R)-3b·2a in CHCl3 was calculated to be (4.14 1.29)
× 1011 M−1 at 25 °C (Figure S7, SI). The competition CD
titration experiments were further performed to estimate the Ka
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tro) substituents at the p-phenylene linkers of the duplexes
((R)-5b·6c, (R)-5c·6b, (R)-5c·6d, and (R)-5c·6e) was found to
stabilize the complementary double helix formations due to the
charge-transfer interaction between the p-phenylene residues as
compared to the nonsubstituted duplex ((R)-5a·6a); the Ka
values increased from 2.99 × 1012 M−1 ((R)-5a·6a) to 1.12 ×
1013 M−1 ((R)-5c·6b) and 4.82 × 1012 M−1 ((R)-5c·6e) in
CHCl3 at 25 °C (Table 1). Such charge-transfer interactions
between the 2,5-dimethoxybenzene-linked amidine dimer ((R)-
5c) and 2,5-dinitrobenzene-linked carboxylic acid dimer (6e)
were supported by a visible color change in the (R)-5c·6e
solution upon mixing the colorless solution of (R)-5c and the
orange-yellow solution of 6e in CHCl3 (Figure 6C), and this
color change was accompanied by a change in their absorption
spectra, suggesting a charge-transfer complexation (Figure 6B).
Figure 7. (A) Partial 1H NMR (500 MHz, DMSO-d6, 0.10 mM)
spectra of 6b and (R)-5c at 25 °C and the duplex (R)-5c·6b at various
temperatures. The peaks of 6b, (R)-5c, and (R)-5c·6b were denoted
by green-, blue-, and red-filled circles, respectively. (B) CD and
absorption spectra (0.1 mM) of (R)-5c and (R)-5c·6b and absorption
spectrum (0.1 mM) of 6b in DMSO at 25 °C. CD and absorption
spectra (0.1 mM) of (R)-5c·6b in CDCl3 at 25 °C are also shown.
Temperature-dependent CD and absorption spectral changes (0.1
mM) of (R)-5a·6a (C) and (R)-5c·6b (D) in DMSO.
Figure 6. (A) CD and absorption spectra (0.1 mM) of (R)-5c, 6e, and
(R)-5c·6e in CDCl3 at 25 °C. (B) Partial absorption spectra (0.1 mM)
of (R)-5c, 6e, and (R)-5c·6e in CDCl3 at 25 °C. (C) Photographs of
the solutions of (R)-5c, 6e, and (R)-5c·6e in CDCl3 at 25 °C.
As observed in CHCl3, the attractive charge-transfer
interactions between the aromatic linkers bearing either
electron-donating or electron-withdrawing substituents also
enhanced the stabilities of the duplexes in DMSO-d6, and the
Ka values were estimated to be 2.4 × 104 M−1 for (R)-5b·6c, 6.6
× 104 M−1 for (R)-5c·6b, 1.5 × 104 M−1 for (R)-5c·6d, and 2.9
× 104 M−1 for (R)-5c·6e (Table 1); these values were
significantly higher than that of the nonsubstituted (R)-5a·6a
(6.5 × 103 M−1) and comparable to that of the diacetylene-
linked dimer (R)-1a·2a (3.8 × 104 M−1). More importantly, the
Ka value of (R)-5c·6b was much higher than that of (R)-5a·6a
by a factor of ∼10 in DMSO-d6, whereas in CHCl3, it was ∼3.7
times. The charge-transfer interaction might efficiently
contribute to stabilizing the duplex formation in DMSO-d6,
in which the salt bridges are diminished, while the salt bridge
formation is extremely strong in CHCl3 and determines the
overall stability of the duplexes in CHCl3. It should be noted
that (R)-5c·6b even exhibited intense Cotton effects in DMSO,
although the intensities were reduced to 78% of those in CHCl3
(Figure 7B), which is still higher than that of the diacetylene-
linked (R)-1a·2a (67%).
As described above, the double helical conformations of the
complementary duplexes are destabilized in DMSO because the
salt bridge formations are hampered in DMSO. In fact, the CD
intensity of the (R)-5a·6a duplex in DMSO was reduced to
28% of that in CHCl3 (see Figure 3A,B). We then further
investigated the effect of the substituents introduced at the p-
phenylene linkers on the stabilities of the duplex formations in
DMSO by estimating their Ka values along with measuring their
CDs in DMSO. The Ka values of a series of substituted p-
phenylene-linked duplexes were directly estimated from their
1H NMR spectra. As a typical example, Figure 7A shows the 1H
NMR spectra of the TMS proton resonance region of a 1:1
mixture of (R)-5c and 6b in DMSO-d6 at 25 °C, showing four
peaks being assignable to the single (R)-5c and 6b strands and
their duplex. Based on the integral ratio, the Ka value was
estimated to be 6.6 × 104 M−1 at 25 °C. In the same manner,
the Ka values of the other duplexes including the diacetylene-
linked duplex ((R)-1a·2a) and the Pt(II)-acetylide linked
duplex ((R)-3a·4a) in DMSO-d6 were also estimated (Table 1).
The obtained Ka values in DMSO-d6 at 25 °C were found to
increase in the order: (R)-3a·4a (∼0 M−1) < (R)-5a·6a (6.5 ×
103 M−1) < (R)-1a·2a (3.8 × 104 M−1) as anticipated from that
in CHCl3.
The variable-temperature CD measurements in DMSO more
clearly demonstrated the contribution of the charge-transfer
interactions to the stabilities of the duplexes (Figure 7C,D).
Upon heating, the CD intensities of (R)-5a·6a rapidly
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decreased and reached a constant value at around 70 °C, whose
spectral pattern was identical to that of the (R)-5a, indicating
the dissociation of the duplex (R)-5a·6a into (R)-5a and 6a
strands at that temperature (Figure 7C). In contrast, those of
(R)-5c·6b were gradually decreased with the increasing
temperature accompanied by a significant increase in the
absorbance in the longer wavelength regions (hyperchromic
effect), suggesting the dissociation of the (R)-5c·6b at around
80−85 °C (Figure 7D); a similar tendency was observed in the
data (Figure 8B and Table 2). The negative ΔS⧧ value for the
intermolecular chain exchange as well as the high Ka value for
the duplex 1a·2a indicated that the chain exchange reaction
most likely proceeds via a direct exchange pathway (Figure 9A)
that involves ternary complexation of (R)-1a·2a·(S)-1a,
followed by dissociation of the (R)-1a strand.
The k values and the activation parameters (ΔH⧧ and ΔS⧧)
of the chain exchange processes for the Pt(II)-acetylide linked
duplexes 3a·4a and 3b·4b and the p-diethynylbenzene linked
duplex 5a·6a were then estimated in a similar fashion (Figures
S17−S19, SI) and the results are summarized in Table 2. As a
consequence, the chain exchange rates (k) increased in the
order: diacetylene linker < p-diethynylbenzene linker <
Pt(II)(PEt3)2-acetylide linker < Pt(II)(PPh3)2-acetylide linker.
Again, this order is in agreement with the order of the
bulkiness. Judging from the smaller, but negative ΔS⧧ for the
duplex 5a·6a, the chain exchange appears to proceed via a
direct exchange one as well as the duplex 1a·2a (Figure 9A). In
sharp contrast, the ΔS⧧ values for the Pt(II)-acetylide linked
duplexes 3a·4a and 3b·4b were positive, 81.1 and 53.5 J mol−1
K−1, respectively (Table 2), suggesting that the chain exchange
reactions take place not via a direct exchange pathway, but via a
dissociation−exchange one (Figure 9B).
1
variable-temperature H NMR spectra of (R)-5c·6b in DMSO-
d6 (Figure 7A). Consequently, the charge-transfer interactions
were found to effectively contribute to stabilizing comple-
mentary double helices linked through the p-diethynylbenzene
units, especially in polar solvents such as DMSO.
Kinetic Studies of Chain Exchange Reactions of Chiral
Duplex. With the aim of elucidating the mechanism of the
chain exchange process between the (R)-1a strand in the (R)-
1a·2a double helix and its enantiomeric (S)-1a strand in
CDCl3, the kinetics of the chain exchange reaction were
investigated using CD spectroscopies. Upon mixing of the
equimolar amounts of (R)-1a·2a and (S)-1a in CDCl3,20 the
chain exchange slowly took place to form the corresponding
racemic double helices. Figure 8A shows the changes in the CD
Helix-Inversion Kinetics and Barriers of Double
1
Helices. The temperature-dependent H NMR measurements
of four racemic dimer duplexes carrying achiral amidine
residues (Table 3) in CDCl3 or CD2Cl2 were performed in
order to observe their helix-inversion processes and to estimate
their helix-inversion barriers under slow exchange conditions.
In contrast to the optically active dimer duplexes, the
diacetylene linked racemic duplex 1c·2b showed a rather
sharp doublet due to the N−H proton resonances for the salt
bridges at 12.22 ppm at 25 °C (Figure 10B), whereas the salt-
bridged N−H protons (c′ and c”) of the optically active dimer
duplexes appeared as two sets of nonequivalent doublets
(“outer” and “inner” N−H protons, respectively) (see Figure
2a−c) that originated from the stable preferred-handed double
helical structures. These results suggest that the rate of helix
inversion of the racemic duplex 1c·2b was too fast at 25 °C for
the present NMR time scale to distinguish the nonequivalent
N−H protons due to the right- and left-handed double helical
states of the duplex via rotation along the C−C bond between
the amidine and m-terphenyl groups as shown in Figure 10A
(bottom).
Figure 8. (A) Time-dependent CD intensity changes of (R)-1a·2a
(0.1 mM) at 354 nm upon mixing an equimolar of (S)-1a in CDCl3 at
various temperatures (25−45 °C). (B) Eyring plot for the chain
exchange rates estimated at 25 to 45 °C, where the thermodynamic
parameters (ΔH⧧, ΔS⧧, and ΔG298⧧) were estimated according to the
following equation, ln k/T = −ΔH⧧/R·(1/T) + ln kB/h + ΔS⧧/R. The
curves in A were obtained by the curve-fittings according to the eq 12
in the SI.
Upon cooling to a low temperature, the salt-bridged N−H
proton resonances of 1c·2b became broadened and coalesced at
−26 °C (Figure S20, SI). The N−H signal finally appeared as
two sets of nonequivalent signals (12.279 and 12.156 ppm) at
−60 °C as observed for (R)-1a·2a. The coalescence temper-
ature (Tc = −26 °C) along with the chemical shift difference
between the signals at −60 °C (Δν = 61.5 Hz) made it possible
to estimate the free energy of activation (ΔG⧧) for the helix-
inversion of the duplex 1c·2b to be 50.0 kJ mol−1 at 25 °C,
which corresponds to the lifetime of the one-handed helical
state (τ) of 9.37 × 10−5 s at 25 °C. The Tc, ΔG⧧, and τ values
for the helix-inversion of the other racemic double helices
1b·2a, 3c·4a, and 5d·6a were also attempted to be estimated in
a similar fashion (Figures S21−S23, SI) and the results are
summarized in Table 3. The salt-bridged N−H proton
resonances of the diacetylene-linked 1b·2a carrying isopropyl
groups on the amidine residues also split into two sets of signals
at low temperatures with a coalescence temperature of −47 °C
(Figure S21, SI), giving a slightly lower ΔG⧧ value than that of
intensities of the (R)-1a·2a/(S)-1a mixture at 354 nm (the first
negative Cotton effect) in CDCl3 at various temperatures from
25 to 45 °C vs time. The CD intensity of the mixture gradually
decreased with time and reached an equilibrium within 15 h at
25 °C and no detectable CD change was observed for 1 h
thereafter, resulting from a very slow chain exchange process.
The chain exchange process was analyzed according to eq 12 in
the SI, and the reaction rate (k) for the (R)-1a·2a/(S)-1a
mixture was then calculated based on the nonlinear least-
squares curve fitting of the CD changes to be k = 0.48 M−1 s−1
at 25 °C, which corresponds to the half-life time (τ) of 2 h at 25
°C. In the same way, the k values of the (R)-1a·2a/(S)-1a
mixture at various temperatures were estimated, showing a
gradual increase in the k values with the increasing temperature.
The activation parameters (ΔH⧧ and ΔS⧧) of the chain
exchange process were then estimated to be 50.8 kJ mol−1 and
−80.6 J mol−1 K−1, respectively, based on the Eyring plot of the
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Table 2. Rates of Chain Exchange Reactions in CDCl3
duplex
X
k(M−1 s−1) at 25 °C
t1/2 at 25 °C
ΔG⧧298(kJ/mol)
ΔH⧧ (kJ/mol)
ΔS⧧ (J/mol·K)
la·2a
none
0.48
57
2 h
74.8
63.1
58.2
68.4
50.8
87.2
74.2
58.7
−80.6
81.1
3a·4a
3b·4b
5a·6a
trans-Pt(PEt3)2
trans-Pt(PPh3)2
1,4-C6H4
61 s
9 s
379
6.4
53.5
9.1 min
−32.5
broadened upon cooling accompanied by a significant upfield
shift, but a clear coalescence point due to helix-inversion could
not be observed at −80 °C in CD2Cl2. This unexpected high
upfield shift of the N−H protons of 3c·4a that was not
observed for the diacetylene-linked dimers (Figures S20 and
S21, SI) and broadening of the NH proton resonances of 3c·4a
may be related to a slow chain exchange between each strand
via a dissociation−exchange pathway (see Figure 9 and Table
2), and its coalescence temperature due to helix-inversion could
be presumed to be lower than −80 °C. Similar broad NH
proton resonances were also observed for the p-diethynylben-
zene linked duplex 5d·6a at temperatures from 25 to −80 °C,
indicating that the helix-inversion rate of racemic dimers was
significantly influenced by the linker structures and the barriers
for the helix-inversion increased in the following order: Pt(II)-
acetylide linker, p-diethynylbenzene linker < diacetylene linker.
Figure 9. Schematic illustration of possible mechanisms (routes A and
B) of the chain exchange between the (R)-duplex and (S)-strand.
the 1c·2b duplex. These results indicate that the substituents on
the amidine groups do not significantly affect the helix-
inversion barrier for the diacetylene-linked dimers.
In contrast, the Pt(II)-acetylide linked duplex 3c·4a and the
p-diethynylbenzene linked duplex 5d·6a did not show such a
coalescence temperature due to helix-inversion even at −80 °C.
The N−H protons of the Pt(II)-acetylide linked duplex 3c·4a
appeared as one broad doublet at 25 °C, which gradually
CONCLUSIONS
■
In conclusion, we have successfully synthesized a series of
optically active and achiral amidine dimers and their
complementary achiral carboxylic acid dimers joined by
different linkers, such as diacetylene, Pt(II)-acetylide, and p-
diethynylbenzene linkages, using a modular strategy. We have
Table 3. Rates of Helix-Inversion
a
b
duplex
X
R1
solvent
TC (°C)
G⧧298(kJ/mol)
τ298 (s)
lb·2a
lc·2b
3c·4a
5d·6a
none
none
i-Pr
CDC13
CDC13
CD2C12
CD2C12
−47
−26
45.8
50.0
−
1.71 × 10−5
c-Hex
c-Hex
c-Hex
9.37 × 10−5
c
trans-Pt(PEt3)2
<−80
−
−
c
1,4-C6H4
<−80
−
a
b
c
Coalescence temperature. Life time of the one-handed helical state at 25 °C. Coalescence temperature was not observed.
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Figure 10. (A) Helix-inversion of duplex 1c·2b. (B) Variable-temperature 1H NMR spectra of 1c·2b (500 MHz, CDCl3, 2.0 mM) from −60 to 25
°C (those from −28 to −23 °C to estimate Tc, see Figure S20B, SI).
found that the thermodynamic and kinetic stabilities of the
complementary double helix formations assisted by the
amidinium−carboxylate salt bridges have a remarkable depend-
ence on the linker structures, and are also affected by the
substituents on the amidine groups. The thermodynamic
analyses of the chiral dimer duplexes revealed that the
association constants increase in the following order: Pt(II)-
acetylide linker < p-diethynylbenzene linker < diacetylene
linker, which is in agreement with the reverse order of the
bulkiness. The substituents on the amidine groups were also
found to affect the stabilities upon duplex formation, and the
association constants of the duplexes increased in the following
order: i-Pr < (R)-1-phenylethyl < c-Hex. During the formation
of the p-diethynylbenzene-linked double helices, the charge-
transfer interactions were found to contribute to stabilizing the
double helices, especially in polar solvents such as DMSO, in
which the salt bridge formation is significantly hampered. The
kinetic analyses of the chain exchange reactions revealed a
different mechanism that depends on the linker structures; i.e.,
the dissociation−exchange pathways are predominant for the
Pt(II)-acetylide linked duplexes, while a direct chain exchange
takes place for the diacetylene-linked and p-diethynylbenzene-
linked duplexes. The present systematic studies on the
mechanistic, thermodynamic, and kinetic stabilities of the
complementary double helix formations assisted by amidi-
nium−carboxylate salt bridges provide a clue not only for the
development of novel double helices with specific functions,
but also a possible strategy for template synthesis and an
artificial replication system based on the complementary double
helix formation.16j Studies along this line are currently ongoing
in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
yashima@apchem.nagoya-u.ac.jp
■
Present Address
†Molecular Engineering Institute, Kinki University, Kayano-
mori, Iizuka, Fukuoka 820-8555, Japan.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by Grants-in-Aid for Scientific
Research (S) from the Japan Society for the Promotion of
Science (JSPS) (E.Y.) and for Scientific Research on Innovative
Areas, “Emergence in Chemistry” (20111010) from the MEXT
(Y.F.). H.Y. expresses his thanks for a JSPS Research
Fellowship for Young Scientists (No. 2728). We thank Drs.
Takeshi Maeda and Kazuhiro Miwa for their help in the
synthesis of the amidine and carboxylic acid dimers.
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