Remarkable effects of terminal groups and solvents on helical folding of o -phenylene oligomers

Article abstract of DOI:10.1021/ja303117z

Although o-phenylene oligomers (OP_nR) made of dimethoxyphenylene units are thought to be intrinsically dynamic due to π-electronic repulsion, we show that they fold into a regular helical geometry in CH₃CN when they carry terminal groups such as CH₃, CH₂OH, Br, CO₂Bn, and NO₂. We evaluated their helical inversion kinetics via optical resolution of long-chain oligomers (e.g. 16- and 24-mers) by chiral HPLC. OP₂₄Br at 298 K shows a half-life for the optical activity of 5.5 h in CH₃OH/water (7/3 v/v) and requires 34 h for complete racemization. The perfectly folded helical conformers of OP _nR, unlike their imperfectly folded ones, are devoid of extended π-conjugation and show a cyclic voltammogram featuring reversible multistep oxidation waves.

Full text of DOI:10.1021/ja303117z

Communication
pubs.acs.org/JACS
Remarkable Effects of Terminal Groups and Solvents on Helical
Folding of o-Phenylene Oligomers
Shinji Ando,† Eisuke Ohta,† Atsuko Kosaka,† Daisuke Hashizume,† Hiroyuki Koshino,†
Takanori Fukushima,†,*,‡ and Takuzo Aida*,†,§
†RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
‡Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan
§School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
S
* Supporting Information
a
Scheme 1. General Synthesis of OPnR
ABSTRACT: Although o-phenylene oligomers (OPnR)
made of dimethoxyphenylene units are thought to be
intrinsically dynamic due to π-electronic repulsion, we
show that they fold into a regular helical geometry in
CH3CN when they carry terminal groups such as CH3,
CH2OH, Br, CO2Bn, and NO2. We evaluated their helical
inversion kinetics via optical resolution of long-chain
oligomers (e.g. 16- and 24-mers) by chiral HPLC. OP24Br
at 298 K shows a half-life for the optical activity of 5.5 h in
CH3OH/water (7/3 v/v) and requires 34 h for complete
racemization. The perfectly folded helical conformers of
OPnR, unlike their imperfectly folded ones, are devoid of
extended π-conjugation and show a cyclic voltammogram
featuring reversible multistep oxidation waves.
a
R = H, n = 6−24; R = Br, n = 4−24; R = CH3 and CH2OH, n = 10; R
= CO2Bn, n = 4−10. Reagents and conditions: (a) NBS, DMF, 0→
25°C; (b) 3,4-dimethoxyphenylboronic acid, Pd(OAc)2, SPhos,
K3PO4, THF, water, 60°C; (c) t-BuLi, THF, −78°C; (d) CO2,
−78→25°C; (e) BnBr, Cs2CO3, DMSO, 100°C; (f) LiAlH4, THF,
60°C; (g) Et3SiH, BF3OEt2, CH2Cl2, 0→25°C. SPhos = 2-
dicyclohexylphosphino-2′,6′-dimethoxybiphenyl. For OPnBr (n = 4,
8) and OPnH (n = 16, 24), see ref 3.
If the π-electronically repulsive character indeed hampers the
perfect folding of OPnR, this potentially interesting helical motif
would not be usable for many applications. We investigated in
detail the conformation of OPnR carrying different terminal
groups (R = H, CH3, CH2OH, Br, CO2Bn, and NO2) in
varying solvents and observed that all the oligomers except
OPnH fold into a stable helical conformation only in a limited
solvent such as CH3CN. This finding precluded investigating
the helical inversion kinetics of long oligomers but also unveiled
that the perfectly folded helical conformers, unlike their
imperfectly folded ones,2a are devoid of extended π-conjugation
and well behaved in electrochemistry.
As shown in Scheme 1, a series of OPnR (Figure 1a) with
different chain lengths (n = 4−24) and termini were
synthesized (see Supporting Information). OP6H and OP10H
were prepared from OP4Br and OP8Br,3 respectively, by
Pd(OAc)2/SPhos-catalyzed Suzuki−Miyaura coupling with 3,4-
dimethoxyphenylboronic acid in THF. The H-terminated
oligomers thus obtained were subjected to bromination with
N-bromosuccinimide (NBS) in DMF, affording OP6Br and
OP10Br. Longer H-terminated oligomers such as OP16H and
OP24H3 were successfully converted into OP16Br and OP24Br,
respectively. OPnCO2Bn (n = 4−10) with ester termini were
synthesized from OPnBr (n = 4−10) by terminal lithiation in
THF with t-BuLi, followed by carboxylation with CO2 and
ecause of the lack of readily accessible synthetic methods,
Boligomeric o-phenylenes, unlike their m- and p-connected
analogues, have scarcely been investigated until recently.1 Due
to a heavily angled aromatic connection, oligomeric o-
phenylenes are considered to adopt a helical conformation.
Simpkins et al. reported in 1998 that an o-phenylene hexamer
in the crystalline state folds into a regular 31-helical geometry.1d
This beautiful crystal structure gave us a preconceived notion
that 31-helical geometry is also preferred in solution. Recent
conformational studies by Hartley et al. on o-phenylene
oligomers in solution indicated that, regardless of the type of
solvent, they are considerably dynamic and hardly fold into a
regular helical geometry.2 We recently developed terminally
functionalized o-phenylene oligomers OPnR from 1,2-dime-
thoxybenzene and discovered that an octamer featuring nitro
groups at both termini (OP8NO2) undergoes chiral symmetry
breaking upon crystallization, affording optically pure crystals,
each having either a right- or left-handed 31-helical conformer.3
Using its optical activity as a probe, we investigated the stability
of this helically folded conformer in solution. Consistent with
Hartley’s reports,2 the optical activity disappeared very quickly
when the chiral crystal was dissolved in organic solvents. We
thought this dynamic nature might stem from π-electronically
repulsive character of the closely packed phenylene units in
cofacial orientation.4 One-electron oxidation of the helical
conformer of OP8NO2 resulted in a remarkable elongation of
the optical activity in solution.3
Received: April 11, 2012
Published: June 18, 2012
© 2012 American Chemical Society
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Figure 1. (a) Molecular structures of o-phenylene oligomers OPnR (R
= H, CH3, CH2OH, Br, CO2Bn, and NO2). (b) ORTEP drawings of
the crystal structure of OP6CO2Bn at 90 K, showing 50% probability
thermal ellipsoids. H atoms omitted for clarity.
esterification with benzyl bromide (BnBr) in DMSO containing
Cs2CO3. OP10CH2OH was obtained from the corresponding
carboxylated compound by reduction with LiAlH4 and
converted into OP10CH3 by reduction using Et3SiH/BF3OEt2.
All these oligomers were unambiguously characterized by NMR
spectroscopy and high-resolution mass spectrometry. Short-
chain oligomers OP4CO2Bn and OP6CO2Bn were crystallo-
graphically defined, both adopting perfect 31-helical conforma-
tion in the crystalline state (Figures 1b and S1).
1
Figure 2. H NMR (500 MHz) spectra at 273 K of OPnR.
diastereotopically into two sets of doublets at 4.48 and 4.79
ppm. In CD3CN, OP10CO2Bn and shorter-chain OPnCO2Bn (n
= 4, 6, and 8) showed well-defined NMR features (Figures S2
and S21−S30) characteristic of a perfect 31-helical conforma-
tion. The same holds true for the conformational behaviors of
OPnR carrying bromo (R = Br; n = 8, 10, 16, and 24), nitro (R
= NO2; n = 8), and hydroxymethyl groups (R = CH2OH; n =
10) in CD3CN (Figures 2e,f, S4−S7, S9, S10, and S34−S37).
In sharp contrast, as also Hartley reported,2a−d H-terminated
OPnH (n = 6, 10, 16, and 24) had very complicated H NMR
features even in CD3CN (Figures 2a,b and S11). We thought
that OPnR might require polar terminal groups for perfect
helical folding, but OP10CH3 showed in CD3CN a simple H
NMR spectrum (Figures 2c,d and S12a) analogous to those of
OP10R with polar terminal groups. Thus we conclude that a
steric factor at the termini is critical in the perfect folding of
OPnR. It is interesting to note that no steric effect of the
terminal functionalities emerges in other solvents (e.g. CDCl3
and DMF; Figure S12b,c).
2
1
Consistent with Hartley’s reports, the H NMR spectral
profiles of OPnCO2Bn (n = 6−10) were very complicated in a
variety of solvents, e.g. CDCl3, toluene-d8, DMSO-d6, and
DMF-d7 (Figures 2h, S3, and S8). However, in CD3CN solvent,
the NMR spectra were exceptionally simple. OP10CO2Bn
1
afforded one set of well-defined H NMR signals characteristic
of C2 symmetry (Figures 2g and S2d), indicating OP10CO2Bn
adopts a regular 31-helical geometry. Taking full advantage of
2D NMR techniques (HSQC, HMBC, and NOESY spectra;
Figures S31−S33), all the signals in Figures 2g and S2d were
unambiguously assigned. Ten singlet signals at 3.3−3.7 ppm are
due to methoxy protons. Certain aromatic protons at 5.1−5.7
ppm originate from the internal phenylene units that are
upfield-shifted considerably due to a ring-current effect. Strong
NOEs were observed for four sets of proximal aromatic protons
in folded OP10CO2Bn with 31-helical geometry (Figure S13);
the methylene protons in the benzyl ester termini split
1
1
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Figure 3. (a) 1H NMR (500 MHz) spectra (4.6−5.2 ppm) of
OP4CO2Bn in CD3CN at 233−313 K. Minor signals due to imperfect
helical conformation are asterisked. (b) Coalescence temperatures (red
circles) and free-energy changes of activation (blue squares) for helical
inversion of OPnCO2Bn (n = 4−8) in CD3CN.
Using the diastereotopically split signals in the terminal
benzyl ester groups as a probe, we investigated kinetic and
thermodynamic aspects of the helical inversion of OPnCO2Bn
(n = 4−8). For example, tetramer OP4CO2Bn at 293 K
displayed the corresponding signals at 4.94 and 5.03 ppm in
CD3CN (Figures 3a and S14). Upon cooling to 233 K, each of
these signals split into two major doublets and four minor
signals with an integral ratio of 1:0.22 (Figure 3a). Using 2D
NMR techniques (Figures S21−S23), all the signals observed at
233 K were unambiguously assigned. There are major and
minor conformers in the system: the major one (C2-symmetric)
adopts a perfectly folded helical conformation, while the minor
one (C1-symmetric) adopts an imperfect helical conformation
with one terminal phenylene unit flipping out. These
conformers are thermally interconvertible. In fact, upon
heating, the corresponding signals coalesced at 273 K, and
the resultant major doublets coalesced at 313 K (Figure 3a) as a
consequence of the helical inversion. Using the Gutowsky
equation,5 the rate constant for the helical inversion at the
coalescence temperature (313 K) was kc = 244 s−1. Using the
Eyring equations, the free-energy change of activation for the
helical inversion was ΔG⧧ = 62.5 kJ mol−1. For the hexamer
and octamer (OPnCO2Bn, n = 6 and 8; Figures S15−S17) in
CD3CN, we also obtained coalescence temperatures (Tc) and
ΔG⧧ values for the helical inversion (Figure 3b and Table S1).
Both increased monotonically as the number of the repeating
phenylene units in OPnCO2Bn increased (Figure 3b). This
trend is reasonable, provided the helical inversion occurs in a
stepwise manner from the terminal phenylene units.
These observations prompted us to investigate whether
longer-chain oligomers fold into a regular helical geometry in
CH3CN. We attempted direct chiral HPLC separation6 of the
right- and left-handed helical conformers of OP16Br and OP24Br
along with shorter-chain OP8Br and OP10Br. By optimizing the
HPLC conditions, we successfully separated their enantiomers.
When OP16Br in CH3CN was charged into a chiral column and
eluted using a mixture of CH3OH and water (7/3 v/v), a poor
solvent for OP16Br, two well-separated elution peaks developed
with positive and negative signs at 290 nm in a circular
dichroism (CD) detector (Figure 4c). The fractions corre-
sponding to these two peaks displayed mirror-image CD
spectra with intensity maxima at 265, 290, and 320 nm (Figure
4e). Longer-chain OP24Br showed analogous HPLC (Figure
4d) and CD features (Figure 4g). Consistent with the
difference in number of the repeating phenylene units, the
molar CD (Δε) of OP24Br was 1.5 times larger than that of
OP16Br. In both cases, the observed CD spectra gradually
Figure 4. (a−d) Chiral HPLC profiles at 298 K of OPnBr. Samples,
saturated CH3CN solutions (5 μL); column, CHIRALPAK IA 25 ×
0.46 (i.d.) cm; eluent, CH3OH/water (7/3 v/v);7 flow rate, 0.8 mL
min−1. CD spectra of (e) OP16Br and (g) OP24Br measured at the first
(red) and second (blue) peak tops of their chromatograms and (f,h)
their spectral decay profiles at 265 nm.
became less intense with time, indicating helical inversion.
Based on time-dependent CD intensity changes (Figure 4f,h),
we evaluated their helical inversion kinetics in terms of the half-
life (t1/2) of the CD intensity at 265 nm and decay rate
constants (kinv). As expected from the chain length-dependent
dynamic natures of OPnCO2Bn (n = 4−8; Figure 3b), OP24Br
showed longer t1/2 (5.5 h) and smaller kinv (1.75 × 10−5 s−1)
than OP16Br (2.5 h and 3.92 × 10−5 s−1) in CH3OH/water (7/
3 v/v) at 298 K (see Supporting Information). Notably, OP24Br
required 34 h for complete loss of optical activity. In contrast,
shorter-chain OP10Br was only partially optically resolved in
chiral HPLC (Figure 4b), and OP8Br did not show any optical
resolution (Figure 4a), indicating their helical inversion events
are too fast.
Perfect helical folding of OPnR was found to be accompanied
by a change in the balance between “through-bond” and
“through-space” electronic interactions of the repeating phenyl-
ene units. The absorption maximum of OPnBr in CH2Cl2
(Figure 5, blue) shifted toward a longer wavelength region as n
increased from 10 to 24; such chain-length dependence was not
observed when OPnBr was allowed to fold into a perfect helical
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ASSOCIATED CONTENT
* Supporting Information
Synthesis and characterization of selected OPnR. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
fukushima@res.titech.ac.jp; aida@macro.t.u-tokyo.ac.jp
■
Notes
The authors declare no competing financial interest.
Figure 5. Electronic absorption spectra at 298 K of OPnBr in CH3CN
(red) and CH2Cl2 (blue).
ACKNOWLEDGMENTS
■
This work was supported by KAKENHI (21350108 for T.F.
and 23750223 for S.A.). We thank Prof. S. Hiraoka (The
University of Tokyo) for helpful discussion.
REFERENCES
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phenylene oligomers are devoid of extended π-conjugation.
Also noteworthy, as exemplified by OP10CO2Bn in Figure 6,
OPnCO2Bn and OPnBr with n = 8 and 10 in CH3CN clearly
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voltammetry (CV) profiles (Figures 6a and S18); in CH2Cl2
their CV profiles showed a lower electrochemical reversibility
(Figures 6b and S19).8 For reference, short-chain OP4CO2Bn
and H-terminated OP10H, which are incapable of folding into a
perfect helical conformation, showed poor electrochemical
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helical conformation in CH3CN, where a steric rather than
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regular helical geometry. Taking advantage of optical resolution
by chiral HPLC, we reveal that long-chain oligomers such as
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OP24Br undergo a very slow helical inversion at 298 K, t1/2
=
5.5 h. Interestingly, perfect helical folding of OPnR is
accompanied by changes in electrochemical properties. These
achievements cast aside any concen that o-phenylene oligomers
are too dynamic2,3 and allow them to be categorized as a
unique class of well-behaved, fully characterized foldamers9
with many potential applications.
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