Folding-induced folding: The assembly of aromatic amide and 1,2,3-triazole hybrid helices

Article abstract of DOI:10.1002/chem.201304161

Folding-induced folding for the construction of artificial hybrid helices from two different kinds of aromatic sequences is described. Linear compounds 1a, 1b, and 2, containing one aromatic amide trimer or pentamer and one or two aromatic 1,2,3-triazole tetramers, have been designed and synthesized. The trimeric and pentameric amide segments are driven by intramolecluar N-HF hydrogen bonding to adopt a folded or helical conformation, whereas the triazole segment is intrinsically disordered. In organic solvents of low polarity, the amide foldamer segment induces the attached triazole segment(s) to fold through intramolecular stacking, leading to the formation of hybrid helices. The helical conformation of these hybrid sequences has been confirmed by 1H and 19F NMR spectroscopy, UV/Vis spectroscopy, circular dichroism (CD) experiments, and theoretical calculations. It was found that the amide pentamer exhibits a stronger ability to induce the folding of the attached triazole segment(s) compared with that of the shorter trimer. Enantiomers (R)-3 and (S)-3, which contain an R-or S-(1-naphthyl)ethylamino group at the end of a tetraamide segment, have also been synthesized. CD experiments showed that introduction of a chiral group caused the whole framework to produce a strong helicity bias. Densityfunctional-theory calculations on (S)-3 suggested that this compound exists as a right-handed (P) helix.

Full text of DOI:10.1002/chem.201304161

DOI: 10.1002/chem.201304161
Full Paper
&
Foldamers
Folding-Induced Folding: The Assembly of Aromatic Amide and
1,2,3-Triazole Hybrid Helices
Chun-Fang Wu,[a] Zhi-Ming Li,[b] Xiao-Na Xu,[a] Zhi-Xiong Zhao,[a] Xin Zhao,*[a]
Ren-Xiao Wang,[a] and Zhan-Ting Li*[a, b]
1
Abstract: Folding-induced folding for the construction of ar-
tificial hybrid helices from two different kinds of aromatic se-
quences is described. Linear compounds 1a, 1b, and 2, con-
taining one aromatic amide trimer or pentamer and one or
two aromatic 1,2,3-triazole tetramers, have been designed
and synthesized. The trimeric and pentameric amide seg-
ments are driven by intramolecluar NÀH···F hydrogen bond-
ing to adopt a folded or helical conformation, whereas the
triazole segment is intrinsically disordered. In organic sol-
vents of low polarity, the amide foldamer segment induces
the attached triazole segment(s) to fold through intramolec-
ular stacking, leading to the formation of hybrid helices. The
helical conformation of these hybrid sequences has been
confirmed by H and 19F NMR spectroscopy, UV/Vis spectros-
copy, circular dichroism (CD) experiments, and theoretical
calculations. It was found that the amide pentamer exhibits
a stronger ability to induce the folding of the attached tria-
zole segment(s) compared with that of the shorter trimer.
Enantiomers (R)-3 and (S)-3, which contain an R- or
S-(1-naphthyl)ethylamino group at the end of a tetraamide
segment, have also been synthesized. CD experiments
showed that introduction of a chiral group caused the
whole framework to produce a strong helicity bias. Density-
functional-theory calculations on (S)-3 suggested that this
compound exists as a right-handed (P) helix.
Introduction
molecules in life, it would be of value to design synthetic sys-
tems that can mimic their advanced structures and functions.
Recently, there has been much interest in creating foldamers
that can mimic the ability of biomacromolecules, particularly
peptides and proteins, to fold into well-defined conforma-
tions.[6–23] Currently, a variety of secondary-structure sequences
consisting of repeat units is being developed. Examples of su-
persecondary, tertiary, and quaternary structures, containing
two or more segments possessing a secondary structure, have
also been reported.[24–30] Many of these synthetic systems have
applications in molecular recognition,[8–10,19–23] catalysis,[31–33]
design of functional materials,[34] and bioactive molecules.[35,36]
The properties of both natural and synthetic systems are close-
ly related to their sequences and structures. Therefore, the de-
velopment of efficient strategies to construct new compact
backbones could provide the opportunity to further extend
the functions and applications of synthetic systems. The choice
of noncovalently tunable molecular units that can be used to
construct repeat sequences is limited; however, a promising
strategy is to construct hybrid frameworks by combining differ-
ent types of repeat unit into one entity. To realize this, the co-
valently connected units would need to be able to produce
specific noncovalent interactions, such that the whole mole-
cule can self-assemble into a defined compact structure.
The complicated functions of proteins rely on their three-di-
mensional (3D) structures, which consist of different local sec-
ondary structures such as a-helices, b-sheets, and b-turns. In
most cases, these secondary structures are stabilized by intra-
molecular hydrogen-bonding, aromatic-stacking, and hydro-
phobic interactions.[1] However, these secondary structures
may also be induced through binding to ordered structures or
higher-grade partners.[2] In this manner, nature has developed
molecular chaperones,[3] which are proteins that can assist in-
trinsically disordered proteins to fold. Moreover, many biomac-
romolecules, such as glycoproteins[4] and nucleoproteins,[5] are
composed of two or more sequences of discrete repeating
units. These different segments interact with each other and
cause the molecule to produce well-defined 3D ordered struc-
tures and functions. Given the importance of these biomacro-
[a] Dr. C.-F. Wu, Dr. X.-N. Xu, Dr. Z.-X. Zhao, Prof. Dr. X. Zhao,
Prof. Dr. R.-X. Wang, Prof. Dr. Z.-T. Li
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
Fax: (+86)21-64166128
E-mail: ztli@mail.sioc.ac.cn
xzhao@mail.sioc.ac.cn
Aromatic amide foldamers that result from hydrogen bond-
ing represent a large family of synthetic secondary structur-
es.[23b] Although intramolecular NÀH···N and NÀH···O hydrogen
bonds are typically used to encourage folded conforma-
tions,[13a,23b] we found that NÀH···F hydrogen bonds are also
[b] Dr. Z.-M. Li, Prof. Dr. Z.-T. Li
Department of Chemistry, Fudan University
220 Handan Road, Shanghai 200433 (China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304161.
Chem. Eur. J. 2014, 20, 1418 – 1426
1418
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
tramolecular CÀH···O hydrogen bonding.[46,47] The backbone of
these oligomers is conformationally disordered, but the CÀ
H···ClÀ hydrogen-bonding-induced helical conformations have
a diameter comparable to that of the NÀH···F hydrogen
bonded amide foldamers. Thus, we envisioned that an intrinsi-
cally folded aromatic oligoamide might induce one or two co-
valently connected and intrinsically disordered triazole oligo-
mers to fold by means of strong intramolecular stacking, lead-
ing to the formation of new hybrid helices. Huc and Tanatani
and co-workers have reported that folded 8-amino-2-quinoline-
carboxylic acid oligomers could induce attached amide oligo-
mers to fold, resulting in hybrid helices.[48] Herein, we report
the design and synthesis of hybrid oligomers 1a, 1b, 2, (R)-3,
and (S)-3. We demonstrate that, depending on the media,
these hybrid backbones can form compact helical conforma-
tions through folding of the intrinsically disordered triazole
segment(s). These helical conformations are induced by the in-
trinsically folded state of the amide segment. We also show
that the chiral group, introduced at the end of the amide unit
of (R)-3 and (S)-3, is able to induce the whole hybrid backbone
to produce a strong helicity bias.
Results and Discussion
Design and synthesis
Hybrid oligomers 1a, 1b, 2, (R)-3, and (S)-3 have been de-
signed to investigate the possibility of folding-induced folding.
For each sequence, a triazole tetramer was used as the intrinsi-
cally disordered segment. Previous studies have shown that
a folded tetramer, with the H atoms of the triazole rings orien-
tated inward, could form one turn.[41–43] Compounds 1a and
1b contain an amide trimer and pentamer, respectively. It has
already been reported that a pentamer of this series is long
enough to form one turn,[33] maximizing homo- or heterogene-
ous stacking. Thus, a comparison of the folding propensity of
the triazole segment of 1a and 1b could demonstrate the abil-
ity of the folded amide segment to template the folding of the
attached triazole segment. Compound 2 contains two triazole
segments and was designed to explore the possibility that one
folded segment can induce two intrinsically disordered seg-
ments to fold. Enantiomers (R)-3 and (S)-3 were prepared to
test whether chiral transfer occurs through folding-induced
folding. Compounds 4a, 4b, (R)-4c, (S)-4c, and 5 were used as
controls. All of the compounds used in this study are soluble
in common organic solvents owing to the presence of aliphatic
1
chains and have been characterized by using H and 13C NMR
spectroscopy and high-resolution mass spectrometry.
strong enough to encourage aromatic oligoamides to form
folded conformations.[37] Because fluorine atoms do not pro-
duce as much steric hindrance as the widely used alkoxyl
groups, NÀH···F hydrogen-bonded amide foldamers possess
a high degree of planarity and consequently, a high stacking
propensity.[38–40] In recent years, a series of alternating 1,2,3-tria-
zole and benzene or pyridine oligomers have also been dem-
onstrated to form helical conformations, driven by intermolec-
ular CÀH···ClÀ hydrogen bonding,[41–44] hydrophobicity,[45] or in-
1H NMR spectroscopy
It is well established that p–p stacking reduces the resolution
of 1H NMR spectra of aromatic molecules. However, 1H NMR
spectroscopy has been used to characterize the folded confor-
mation of linear aromatic sequences.[49] The H NMR spectra of
1
control compounds 4a and 5 in CDCl3 (Figures S82 and S91,
see the Supporting Information) and in C6D6 (Figure 1a, b) dis-
Chem. Eur. J. 2014, 20, 1418 – 1426
www.chemeurj.org
1419
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
a rapid reduction of the spectral resolution on addition of C6D6
(Figure S93, see the Supporting Information). When the per-
centage of C6D6 was increased to approximately 40%, the
spectrum only displayed broad unresolved signals. Further in-
creasing the amount of C6D6 caused the signals to disappear
almost completely. Diluting the solution did not improve the
resolution of the spectrum (Figure S95, see the Supporting In-
formation), excluding the possibility that the low resolution
was caused by intermolecular stacking. A similar result was
1
also observed in [D8]toluene (Figure 1 f), whereas the H NMR
spectra of control compounds 4a and 5 gave rise to sharp sig-
nals, even in pure C6D6. Thus, it is reasonable to propose that
the low resolution of the spectra of 1a, in the binary solvent
mixture or in pure C6D6, was caused by the strong intramolecu-
lar stacking of the two different aromatic segments, leading to
the formation of a relatively stable hybrid helix (Figure 2a,
B).[50] In principle, the triazole segment could adopt two folded
patterns, depending on whether the five H atoms of the tria-
zole rings are facing inward or outward. The first pattern could
produce a folded entity with a diameter comparable to that of
the folded amide oligomers,[41–43] whereas the diameter of the
second folded pattern is substantially larger than that of the
amide foldamers.[47] Thus, the first folded pattern is required to
favor intramolecular stacking with the attached amide seg-
ment. The spectrum of 1a in less-polar [D8]toluene did not ex-
hibit any signals, suggesting the formation of a more stable
hybrid helix.
1
Figure 1. Partial H NMR spectra (400 MHz) of a) 4a and b) 5 in C6D6, and 1a
in c) [D6]DMSO, d) CDCl3, e) C6D6, and f) [D8]toluene at 258C. The concentra-
tion was 2.0 mm for all samples.
played high-resolution signals. The 1H NMR spectra of 1a in
different solvents are also shown in Figure 1. In highly polar
1
[D6]DMSO, the H NMR spectrum exhibited sharp signals, indi-
cating flexible conformation of the backbone (Figure 1c). In
CDCl3, the spectral resolution was good (Figure 1d), but was
not as high as that in [D6]DMSO, and the resolution was not in-
creased upon dilution (Figure S95, see the Supporting Informa-
tion). The folded conformation of the amide segment has been
well established in chloroform.[37,38] Therefore, these observa-
tions indicate that the conformation of the triazole segment
was dominantly flexible in chloroform (Figure 2a, A), but weak
intramolecular stacking between the amide and triazole seg-
ments also occurred, leading to the formation of a less-stable
hybrid helix (Figure 2a, B). The spectra in a CDCl3/C6D6 mixture
were further recorded with 10% increments of C6D6, revealing
The formation of the hybrid helix of 1a in binary CDCl3/C6D6
mixtures or pure C6D6 or [D8]toluene may be attributed to sev-
eral factors. Firstly, compared with that in CDCl3 or in solvents
of higher polarity, the folded conformation of the amide seg-
ment in lower polarity media was more compact, increasing
the ability to induce the folding of the attached triazole seg-
ment through intramolecular stacking. Secondly, the solvopho-
bicity is increased in C6D6 or [D8]toluene, forcing the triazole
segment to fold so that the amount of surface area exposed
to the solvent is reduced. Thirdly, the intramolecular stacking
between the two connected aromatic segments minimized the
surface area of the backbone exposed to the solvent. Finally, in
the folded state, the interior region of the amide segment was
electronegative because all of the fluorine atoms were directed
inward, whereas the external region of the triazole segment
was electronegative because the N atoms of the triazole rings
were directed outward. As a result, the stacking might be fur-
ther promoted by intramolecular electrostatic interactions,
which become stronger in solvents of low polarity. In highly
polar [D6]DMSO, the folding-induced folding process should
not occur, although the amide trimer might exist in a less-
stable folded state (Figure 2a, A) owing to the high stability of
the intramolecular NÀH···F hydrogen bonding.[51]
1
The H NMR spectra of 1b in different solvents are provided
in Figure 3. In contrast to the 1H NMR spectrum of control
compound 4b (Figure 3a), which gave rise to a set of sharp
signals, the spectrum of 1b in CDCl3 (Figure 3c) was of low
resolution. In C6D6, the signals became even broader (Fig-
ure 3b). In contrast, the spectrum in polar [D6]acetone dis-
played one set of resolved signals (Figure S94, see the Sup-
Figure 2. Schematic representation of the solvent-dependent folding-in-
duced folding process of compounds a) 1a and 1b, b) 2, and c) (S)-3.
Chem. Eur. J. 2014, 20, 1418 – 1426
www.chemeurj.org
1420
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
gen bonded aromatic amide pentamers or longer heptamers
with the same backbone, in CDCl3, exhibit a set of sharp sig-
nals in the downfield area.[37a,38] This result suggests that the
central folded amide segment of 2 was able to induce the two
attached triazole segments to fold, producing a longer hybrid
helix through stacking (Figure 2b, B). Upon cooling the solu-
tion of 2 in CDCl3, from 40 to À508C, the resolution of the
1H NMR spectra gradually decreased. These results were similar
to those for 1b, again reflecting the dynamic nature of the hel-
ical conformation. Adding [D6]DMSO to the solution remarka-
bly suppressed this process and, in the binary solvent contain-
ing 10% [D6]DMSO, the spectrum gave rise to a set of resolved
signals, indicating the high flexibility of the two triazole seg-
ments. Given the stability of NÀH···F hydrogen bonding, the
folded state of the amide segment should be maintained in
this binary medium and the whole backbone produced the
unique flexible-folded-flexible conformation (Figure 2b, A).
When the content of [D6]DMSO was increased to 90% (Fig-
ure S94, see the Supporting Information), the spectrum afford-
ed a set of sharp signals, implying the loss of intramolecular
stacking between the two different aromatic segments.
Enantiomers (R)-3 and (S)-3 consist of a tetraamide segment
1
attached to a triazole tetramer and a chiral group. The H NMR
1
Figure 3. Partial H NMR spectra (400 MHz) of a) 4b in CDCl3; 1b in b) C6D6,
spectrum in CDCl3 exhibited unresolved broad signals, but the
spectrum in [D6]DMSO displayed one set of sharp signals.
These results are very similar to those observed for 1b and 2.
In contrast, control compounds (S)-4c and (R)-4c afforded
a spectrum with high resolution in both solvents. Thus, we
propose that, in CDCl3, the folded tetraamide segment of (R)-3
and (S)-3 was able to induce the attached triazole segment to
fold through intramolecular stacking (Figure 2c). The spectrum
of (R)-3 and (S)-3 did not display any signals with good resolu-
tion in the downfield area, therefore, we propose that in
chloroform or less-polar solvents, the naphthalene unit of (R)-3
and (S)-3 also underwent strong intramolecular stacking to
afford chiral helices (Figure 3c, B and C), even though this unit
is connected by an sp3 carbon atom to the aromatic backbone.
Circular dichroism experiments showed that the chiral carbon
atom in (R)-3 and (S)-3 could induce the new hybrid helices to
produce a helicity bias (see below).
c) CDCl3, and d) [D6]DMSO; 2 in e) CDCl3 and f) CDCl3/[D6]DMSO (1:9 v/v) at
258C. The concentration was 2.0 mm for all samples.
porting Information). Adding [D6]DMSO to the solution of
CDCl3 caused the spectral resolution to improve (Figure S94,
see the Supporting Information). Just 4% of [D6]DMSO resulted
in the formation of a set of resolved signals in the downfield
area. With the addition of more [D6]DMSO, the spectral resolu-
tion was further increased. In pure [D6]DMSO, the spectrum
displayed sharp signals (Figure 3d). Again, the resolution of
the spectra in CDCl3 was independent of concentration (Fig-
ure S96, see the Supporting Information). Furthermore, cooling
the CDCl3 solution from 40 to À508C reduced the resolution of
the spectra (Figure S98, see the Supporting Information), re-
flecting the dynamic feature of the helical conformation, which
could not be frozen at low temperature. Therefore, the above
observations suggest that, in CDCl3, 1b undergoes the folding-
induced folding process (Figure 2a, B), demonstrating that the
longer folded pentaamide was more powerful than the shorter
triamide (1a) in inducing the folding of the attached triazole
segment. This is not unexpected because the pentamer could
produce a one-turn helix, providing the maximum area for
stacking with the attached triazole segment. The very broad
spectrum in C6D6 reflects the formation of a more compact
hybrid helix. In [D6]DMSO, the triazole segment prefers to exist
in disordered states as observed for 1a.
19F NMR spectroscopy
The 19F NMR spectra of compounds 1a, 1b, 2, and (R)-3 and
control compounds 4a, 4b, and (R)-4c in CDCl3 are shown in
Figure 4. As expected, the spectra of the control compounds
displayed sharp signals. The signals in the spectrum of 1a
were slightly broadened compared to those of control com-
pound 4a. This broadening became more obvious for 1b and
(R)-3, and remarkably, the spectrum of compound 2 did not
display any observable signals. Compared with the correspond-
ing signals of the control compounds, the signals of 1a, 1b,
and (R)-3 are all shifted downfield (Dd=0.2–4.7 ppm, Figure 4).
For compounds 1b and (R)-3 this shift was larger than that for
Encouraged by the above observations, we synthesized
compound 2, in which two triazole segments are attached to
1
a folded amide pentamer. The H NMR spectrum of 2 in CDCl3
exhibited very broad signals that were independent of concen-
tration (Figure S97, see the Supporting Information). The reso-
lution of this spectrum was lower than that of the shorter com-
1
1a. These results were in accordance with the above H NMR
spectroscopy investigations, supporting the proposal that
weak stacking interactions occur between the triazole and
1
pound, 1b. The H NMR spectra of the reported FÀH···N hydro-
Chem. Eur. J. 2014, 20, 1418 – 1426
www.chemeurj.org
1421
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
copy investigations revealed that the hybrid oligomers can un-
dergo intramolecular folding-induced folding, which depends
heavily on the polarity of the media. To get more insight into
this unique conformational modulation, solvent titration ex-
periments were performed in mixtures of chloroform and n-
hexane.
UV/Vis dilution experiments showed that for 1a, 1b, 2, and
(R)-3 and for control compounds 4a, 4b, (R)-4c, and 5, the ab-
sorption properties obeyed the Beer–Lambert law in chloro-
form, n-hexane, or a 1:1 (v/v) mixture of these solvents, when
the concentration was ꢀ5.0ꢁ10À6 m. Titration experiments
were then carried out at 5.0ꢁ10À6 m or a lower concentration
to avoid intermolecular stacking (Figure 5). It was found that
increasing the percentage of n-hexane caused a pronounced
hypochromic effect for the four hybrid sequences and also
caused a considerable blue shift (up to 15 nm) in the maxi-
mum absorbance. However, the trend for each compound was
substantially different. For 1a, the hypochromic effect followed
an S curve (Figure 5a). That is, it was initially “dull” and
became more intense after the percentage of n-hexane was in-
creased to approximately 30%. This observation supports the
proposal that, at the early stage, the triazole segment exists
Figure 4. Partial 19F NMR spectrum of a) 4a, b) 1a, c) 4b, d) 1b, e) 2, f) (R)-
4c, and g) (R)-3 in CDCl3 and h) 2 in [D6]DMSO/CDCl3 (9:1 v/v) at 258C. The
concentration was 2.0 mm for all samples. The data (ppm) indicated are the
difference between the chemical shifts of the two related signals. Chemical
shifts were referenced to PhCF3 (d=À62.7 ppm).
amide segments of 1a, thus leading to the formation of a less-
stable hybrid helix. This stacking interaction was stronger, and
the resulting hybrid helices were more stable, for 1b, 2, and
1
(R)-3. The downfield shifting of the H NMR signals of 1b and
(R)-3 can be rationalized by considering that the folded triazole
segment imposes an important shielding effect on the fluorine
atoms. In [D6]DMSO, the spectra of both the control com-
pounds and the target compounds displayed sharp signals
and no downfield shifting was observed for the hybrid sequen-
ces, indicating that intramolecular stacking of the two different
segments did not occur and that the backbones adopted flexi-
ble conformations. The fact that the 19F NMR spectrum of 2 in
CDCl3 did not display any observable signals is also consistent
1
with the above H NMR spectroscopy experiments, supporting
the formation of a three-segment hybrid helix, which might be
facilitated by two factors. Firstly, compound 2 can produce
two intramolecular stacking interactions that can promote
each other by strengthening the co-planarity of the central
amide segment. Secondly, the two-layer stacking of 2 more ef-
ficiently reduces the amount of surface area exposed to the
solvent, also promoting the formation of the hybrid helix.
UV/Vis spectroscopy
The UV/Vis absorption of linear conjugated molecules is sensi-
tive to conformational change caused by solvophobicity. Sol-
vent titration experiments have been demonstrated as
a robust method to investigate the folding of oligomeric aro-
Figure 5. UV/Vis spectra of a) 1a (5.0ꢁ10À6 m) and b) 2 (2.5ꢁ10À6 m) in
binary chloroform and n-hexane mixtures at 258C. F represents the relative
volume content of n-hexane. Inset: The absorbance at 280 nm versus F.
1
matic backbones.[10b,45,52] The above H and 19F NMR spectros-
Chem. Eur. J. 2014, 20, 1418 – 1426
www.chemeurj.org
1422
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
mainly in the flexible state. On increasing the amount of n-
hexane, the folding and stacking of the attached amide seg-
ment were intensified, leading to the formation of the hybrid
helix and, consequently, enhanced hypochromism. The hypo-
chromism was reduced when the percentage of n-hexane was
increased to about 80%, implying that the hybrid helix was
close to the maximum stability. Further increasing the n-
hexane percentage affected the absorbance because of the re-
sulting change in the polarity of the medium. Compounds 1b
(Figure S100, see the Supporting Information), 2 (Figure 5b),
and (R)-3 (Figure S101, see the Supporting Information)
showed a continuous and smooth hypochromism. On increas-
ing the amount of n-hexane, the curve tended to flatten, sug-
gesting that the triazole segment might be approaching fold-
ing saturation.
The UV/Vis spectra of 1:1 mixtures of 4a, 4b, and (R)-4c
with 5, at 5.0ꢁ10À6 m in a mixture of chloroform and n-hexane,
were also recorded. For all of the mixtures, before the content
of n-hexane was increased to approximately 70% (F=0.7, F
represents the relative volume content of n-hexane), no impor-
tant hypochromic effect was observed. On increasing the n-
hexane content further, the absorbance of the four mixtures
showed a notable hypochromic effect. However, similar hypo-
chromism was not observed at lower concentration (1.0ꢁ
10À6 m). At 5.0ꢁ10À6 m, solutions of pure 4a, 4b, (R)-4c, or 5
did not exhibit similar hypochromism in chloroform, n-hexane,
or a 1:1 mixture of these solvents. Thus, the hypochromic be-
havior of the four mixtures, observed at high n-hexane con-
tent, can be reasonably attributed to intermolecular heteroge-
neous stacking. Compared with this weak intermolecular stack-
ing, intramolecular stacking of the amide and triazole seg-
ments of the hybrid sequences was substantially stronger and
could occur in chloroform, which is usually considered as a sol-
vent that weakens aromatic stacking,[10b,50] or in a mixture of
chloroform with benzene or n-hexane.
Figure 6. CD spectra of a) enantiomers (R)-3 and (S)-3 and b) (R)-4c in
chloroform/n-hexane mixtures at 258C (Inset: CD intensity at 295 nm versus
F). The concentration was 0.3 mm for all samples.
the whole backbone, a result of the enhancement of the intra-
molecular stacking of the two aromatic segments on decreas-
ing the polarity of the medium (Figure 2c, B and C). This obser-
vation was consistent with the above UV/Vis experiments of
(R)-3 in the same solvent system (Figure S101, see the Support-
ing Information). The CD spectra of (R)-3 in chloroform/n-
hexane (F=0.3) were also recorded at different temperatures.
Within the studied temperature range (30 to À168C), the CD
signal gradually intensified on lowering the temperature (Fig-
ure S102, see the Supporting Information), suggesting that the
chiral helical conformation becomes more compact at lower
temperature. Similar signal enhancement was also observed in
a mixture of chloroform with cyclohexane or toluene (Figur-
es S103 and S104, see the Supporting Information). Notably,
on increasing the amount of the two less-polar solvents to
about 50–60%, the CD signal intensity ceased to increase, im-
plying that compacting of the hybrid helices had reached its
maximum. As expected, compound (S)-3 gave rise to a positive
Cotton effect, which was also intensified on increasing the
amount of n-hexane (Figure 6a). For compounds (R)-3, (S)-3,
and (R)-4c, in highly polar DMF, no CD signal was observed, in-
dicating that any intramolecular stacking was very weak and
that the backbones adopted a flexible conformation. These re-
Circular dichroism (CD) spectroscopy
The CD spectra of compounds (R)-3, (S)-3, and (R)-4c in
a binary chloroform/n-hexane mixture are shown in Figure 6.
In pure chloroform, (R)-3 and (R)-4c both exhibited a negative
Cotton effect. Similar signals were not observed for the shorter
chiral analogues (compounds (R)-36–38 in the Supporting In-
formation) of (R)-4c. The maximum CD signal for both chiral
molecules was reached at around 295 nm. However, the signal
for (R)-3 was substantially stronger than that for (R)-4c. The CD
signal of (R)-3 could be attributed to the helicity bias of the
folded backbone, induced by the attached chiral center by in-
tramolecular stacking of the two aromatic segments.[53]
In the binary chloroform/n-hexane mixture, increasing the
amount of n-hexane (up to F=0.5) remarkably enhanced the
signal of (R)-3. Further increasing the amount of n-hexane
caused the solution to become turbid, implying that precipita-
tion of (R)-3 occurred. Similar signal enhancement was not ob-
served for (R)-4c, which instead exhibited a stable CD signal,
even when F was increased to 0.7. Thus, the signal enhance-
ment observed for (R)-3 reflects the enhanced helicity bias of
Chem. Eur. J. 2014, 20, 1418 – 1426
www.chemeurj.org
1423
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
sults are consistent with the above H and 19F NMR and UV/Vis
experiments.
Density functional theory (DFT) calculations
To further understand the conformational change of the new
hybrid sequences, M062X DFT calculations were performed in
chloroform (for calculation method and details, see the Sup-
porting Information) with Gaussian 09 package using the 6-
31G (d,p) basis set for compounds 1b, 2, and (S)-3 in chloro-
form. To simplify the calculations, we first carried out Monte
Carlo conformational searches for the aromatic amide segment
of these compounds, with the side chains being omitted, to
obtain the energy minimum folded conformation. The back-
bones were then constructed by attaching one (for 1b and (S)-
3) or two (for 2) randomly arranged flexible triazole segments
to the corresponding folded aromatic amide segment. These
partially compact sequences were, again, subjected to confor-
mational searches. In total, 5000 structures were accumulated
and the ten lowest-energy conformers were further optimized.
The representative conformers are shown in Figure 7.
For all three compounds (1b, 2, and (S)-3), the fully helical
conformer, in which the amide and triazole segments are
stacked intramolecularly, was the lowest-energy conformer. As
expected, the two different folded segments in these conform-
ers were comparable in diameter and thus were well matched
for stacking. Both folded segments formed one turn, maximiz-
ing the stacking ability. The distance between the stacking aro-
matic units was in the range of 3.4–3.5 ꢂ,[54] which is typical for
this kind of noncovalent interaction. For 1b, there were several
different low-energy conformers, in which the amide segment
folded and the triazole segment was flexible. The free energies
of these conformers were similar, and the conformer with the
lowest energy (Figure 7a) was 17.6 kcalmolÀ1 higher in energy
than the fully folded conformer (Figure 7b). For compound 2,
the free energy of the conformers (Figure 7d, e) with either
one or none of the triazole segments stacking with the central
amide segment is either 29.6 or 57.1 kcalmolÀ1 higher than
that of the fully folded conformer (Figure 7c), respectively. The
second value is approximately double that of the first one, in-
dicating that stabilization, caused by the intramolecular stack-
ing between the two different kinds of aromatic segments, in-
creases as the stacking aromatic units are increased. In princi-
ple, the fully folded (S)-3 results in two helical diastereoiso-
mers,[55] that is, the right-handed conformer (S)-P and the left-
handed conformer (S)-M (Figure 2c, B and C). DFT calculations
revealed that the P conformer (Figure 7 f) was 9.8 kcalmolÀ1
lower in free energy than the M conformer (Figure 7 g), sug-
gesting that (S)-3 exists mainly as the P diastereoisomeric con-
former. These calculations also revealed that for conformers of
(S)-3 with the triazole segment being disordered the energies
were generally higher than the corresponding fully folded con-
formers. For the (S)-P series, the energy of the conformer that
has a folded amide segment and a flexible triazole segment
(Figure 7 h) was at least 12.5 kcalmolÀ1 higher than that of the
fully folded conformer (Figure 7 f).
Figure 7. The optimized conformers of hybrid oligomers that have a folded
amide segment and one or two folded or disordered triazole segments, cal-
culated in chloroform with Gaussian 09 package using the 6-31G(d) basis
set. For 1b: the triazole segment was a) disordered and b) folded; For 2:
c) the two triazole segments were folded, d) one triazole was folded and an-
other was disordered, and e) both triazole segments were disordered; For
(S)-3: f) the triazole segment was folded with P helicity, g) the triazole seg-
ment was folded with M helicity, and h) the triazole segment was disordered
with P helicity.
Conclusion
We have demonstrated that attaching intrinsically disordered
aromatic triazole tetramers to hydrogen-bonding-induced
folded aromatic oligoamides can lead to folding of the triazole
segment(s) through intramolecular stacking between the two
different kinds of aromatic segments. In a broad sense, this
Chem. Eur. J. 2014, 20, 1418 – 1426
www.chemeurj.org
1424
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[14] a) B. Gong, Acc. Chem. Res. 2008, 41, 1376–1386; b) K. Yamato, M. Kline,
B. Gong, Chem. Commun. 2012, 48, 12142–12158.
[15] G. Licini, L. J. Prins, P. Scrimin, Eur. J. Org. Chem. 2005, 969–977.
[16] a) X. Li, D. Yang, Chem. Commun. 2006, 3367–3379; b) X. Li, Y.-D. Wu, D.
Yang, Acc. Chem. Res. 2008, 41, 1428–1438.
[17] Y. Zhao, Curr. Opin. Colloid Interface Sci. 2007, 12, 92–97.
[18] Y.-D. Wu, W. Han, D.-P. Wang, Y. Gao, Y.-W. Zhao, Acc. Chem. Res. 2008,
41, 1418–1427.
[19] I. Saraogi, A. D. Hamilton, Chem. Soc. Rev. 2009, 38, 1726–1743.
[20] H. Juwarker, J.-m. Suk, K.-S. Jeong, Chem. Soc. Rev. 2009, 38, 3316–
3325.
[21] a) Q. Gan, Y. Wang, H. Jiang, Curr. Org. Chem. 2011, 15, 1293–1301;
b) Q. Gan, Y. Ferrand, C. Bao, B. Kauffmann, A. Grꢃlard, H. Jiang, I. Huc,
Science 2011, 331, 1172–1175; c) C. Bao, Q. Gan, B. Kauffmann, H. Jiang,
I. Huc, Chem. Eur. J. 2009, 15, 11530–11536.
[22] A. Roy, P. Prabhakaran, P. K. Baruah, G. J. Sanjayan, Chem. Commun.
2011, 47, 11593–11611.
[23] a) Z.-T. Li, J.-L. Hou, C. Li, Acc. Chem. Res. 2008, 41, 1343–1353; b) D.-W.
Zhang, X. Zhao, J.-L. Hou, Z.-T. Li, Chem. Rev. 2012, 112, 5271–5316;
c) X. Zhao, Z.-T. Li, Chem. Commun. 2010, 46, 1601–1616.
[24] a) T. L. Raguse, J. R. Lai, P. R. Le Plae, S. H. Gellman, Org. Lett. 2001, 3,
3963–3966; b) M. W. Giuliano, W. S. Horne, S. H. Gellman, J. Am. Chem.
Soc. 2009, 131, 9860–9861; c) J. L. Price, E. B. Hadley, J. D. Steinkruger,
S. H. Gellman, Angew. Chem. 2010, 122, 378–381; Angew. Chem. Int. Ed.
2010, 49, 368–371.
folding-induced folding process may be considered as a special
binding behavior and, thus, to some extent, resembles the
binding-induced folding phenomenon that commonly occurs
for natural peptides and proteins. The process is highly depen-
dent on the polarity of the solvents. In solvents of high polari-
ty, the folded conformation of the aromatic amide segment is
less stable and, therefore, cannot efficiently induce the folding
of the triazole segment. In less-polar solvents, the stable
folded state serves well as a compact platform, which, togeth-
er with the enhanced solvophobic interaction, is able to
induce the folding of the attached triazole segment(s). This
templating can be very efficient and a chiral center, attached
to the end of the folded amide segment, could induce the
whole hybrid framework to produce a strong helicity bias.
The successful induction of the folded conformation of one
and two intrinsically disordered aromatic triazole oligomer(s)
by an attached folded aromatic amide segment raises several
issues that we believe are worthy of further study: 1) Is this in-
ducing process a general behavior for aromatic hybrid sequen-
ces? 2) Can a short folded segment serve as a “seed” to induce
one or two attached polymeric backbones to fold and to fur-
ther transfer and amplify the chirality to the whole polymeric
backbone? A systematic exploration of these possibilities may
lead to the development of functional helices or polymeric
tubes that are potentially useful for advanced recognition, en-
capsulation, or transport.
[25] T. S. Burkoth, E. Beausoleil, S. Kaur, D. Tang, F. E. Cohen, R. N. Zucker-
mann, Chem. Biol. 2002, 9, 647–654.
[26] a) V. Maurizot, C. Dolain, Y. Leydet, J.-M. Lꢃger, P. Guionneau, I. Huc, J.
Am. Chem. Soc. 2004, 126, 10049–10052; b) N. Delsuc, M. Hutin, V. E.
Campbell, B. Kauffmann, J. R. Nitschke, I. Huc, Chem. Eur. J. 2008, 14,
7140–7143; c) N. Delsuc, S. Massip, J.-M. Lꢃger, B. Kauffmann, I. Huc, J.
Am. Chem. Soc. 2011, 133, 3165–3172.
[27] E. J. Petersson, A. Schepartz, J. Am. Chem. Soc. 2008, 130, 821–823.
[28] O. Khakshoor, B. Demeler, J. S. Nowick, J. Am. Chem. Soc. 2007, 129,
5558–5569.
[29] a) H.-Y. Hu, J.-F. Xiang, Y. Yang, C.-F. Chen, Org. Lett. 2008, 10, 69–72;
b) H.-Y. Hu, J.-F. Xiang, C.-F. Chen, Org. Biomol. Chem. 2009, 7, 2534–
2539.
[30] T. A. Martinek, F. Fꢄlçp, Chem. Soc. Rev. 2012, 41, 687–702.
[31] a) C. Dolain, C. Zhan, J.-M. Lꢃger, L. Daniels, I. Huc, J. Am. Chem. Soc.
2005, 127, 2400–2401; b) H.-P. Yi, J. Wu, K.-L. Ding, X.-K. Jiang, Z.-T. Li, J.
Org. Chem. 2007, 72, 870–877; c) R. A. Smaldone, J. S. Moore, Chem.
Eur. J. 2008, 14, 2650–2657; d) K. Srinivas, B. Kauffmann, C. Dolain, J.-M.
Lꢃger, L. Ghosꢃz, I. Huc, J. Am. Chem. Soc. 2008, 130, 13210–13211;
e) M. M. Mꢄller, M. A. Windsor, W. C. Pomerantz, S. H. Gellman, D. Hilvert,
Angew. Chem. 2009, 121, 940–943; Angew. Chem. Int. Ed. 2009, 48,
922–925; f) H. Cho, Z. Zhong, Y. Zhao, Tetrahedron 2009, 65, 7311–
7316; g) G. Maayan, M. D. Ward, K. Kirshenbaum, Proc. Natl. Acad. Sci.
USA 2009, 106, 13679–13684; h) R. R. Araghi, B. Koksch, Chem.
Commun. 2011, 47, 3544–3546.
Acknowledgements
We are grateful to the Ministry of Science and Technology
(2013CB834501), the Ministry of Education (IRT1117), and the
National Natural Science Foundation of China (21272042,
21102019), and to the Science and Technology Commission of
Shanghai Municipality (13M1400200) for financial support.
Keywords: foldamers · helices · hydrogen bonding · stacking ·
triazoles
[1] D. L. Nelson, M. M. Cox, Lehninger’s Principles of Biochemistry, 5th ed.,
W. H. Freeman & Company, New York, 2008.
[32] a) H. Jiang, J.-M. Lꢃger, P. Guionneau, I. Huc, Org. Lett. 2004, 6, 2985–
2988; b) L. Yuan, W. Feng, K. Yamato, A. R. Sanford, D. Xu, H. Guo, B.
Gong, J. Am. Chem. Soc. 2004, 126, 11120–11121; c) J. Zhu, X.-Z. Wang,
Y.-Q. Chen, X.-K. Jiang, X.-Z. Chen, Z.-T. Li, J. Org. Chem. 2004, 69, 6221–
6227; d) F. Li, Q. Gan, L. Xue, Z.-m. Wang, H. Jiang, Tetrahedron Lett.
2009, 50, 2367–2369.
[33] a) B. Qin, X. Chen, X. Fang, Y. Shu, Y. K. Yip, Y. Yan, S. Pan, W. Q. Ong, C.
Ren, H. Su, H. Zeng, Org. Lett. 2008, 10, 5127–5130; b) B. Qin, W. Q.
Ong, R. Ye, Z. Du, X. Chen, Y. Yan, K. Zhang, H. Su, H. Zeng, Chem.
Commun. 2011, 47, 5419–5421; c) C. Ren, V. Maurizot, H. Zhao, J. Shen,
F. Zhou, W. Q. Ong, Z. Du, K. Zhang, H. Su, H. Zeng, J. Am. Chem. Soc.
2011, 133, 13930–13933; d) H. Fu, Y. Liu, H. Zeng, Chem. Commun.
2013, 49, 4127–4144; e) W. Q. Ong, H. Zeng, J. Inclusion Phenom. Mac-
rocyclic Chem. 2013, 76, 1–11; f) H. Zhao, W. Q. Ong, F. Zhou, X. Fang, X.
Chen, S. F. Y. Li, H. Su, N.-J. Cho, H. Zeng, Chem. Sci. 2012, 3, 2042–
2046.
[2] V. N. Uversky, J. Mol. Biol. 2012, 418, 267–267.
[3] Y.-J. Chen, M. Inouye, Curr. Opin. Struct. Biol. 2008, 18, 765–770.
[4] J. Montreuil, J. F. G. Vliegenthart, H. Schachter, Glycoproteins, Elsevier,
Amsterdam, 1995.
[5] J. A. Speir, J. E. Johnson, Curr. Opin. Struct. Biol. 2012, 22, 65–71.
[6] S. Hecht, I. Huc, Foldamers: Structure, Properties and Applications, Wiley-
VCH, Weinheim, 2007.
[7] D. Seebach, J. L. Matthews, Chem. Commun. 1997, 2015–2022.
[8] a) S. H. Gellman, Acc. Chem. Res. 1998, 31, 173–180; b) W. S. Horne, S. H.
Gellman, Acc. Chem. Res. 2008, 41, 1399–1408.
[9] J. S. Nowick, Acc. Chem. Res. 2008, 41, 1319–1330.
[10] a) D. J. Hill, M. J. Mio, R. B. Prince, T. S. Hughes, J. S. Moore, Chem. Rev.
2001, 101, 3893–4011; b) M. T. Stone, J. M. Heemstra, J. S. Moore, Acc.
Chem. Res. 2006, 39, 11–20.
[11] M. S. Cubberley, B. L. Iverson, Curr. Opin. Chem. Biol. 2001, 5, 650–653.
[12] a) R. P. Cheng, S. H. Gellman, W. F. DeGrado, Chem. Rev. 2001, 101,
3219–3232; b) C. M. Goodman, S. Choi, S. Shandler, W. F. DeGrado, Nat.
Chem. Biol. 2007, 3, 252–262.
[13] a) I. Huc, Eur. J. Org. Chem. 2004, 17–29; b) G. Guichard, I. Huc, Chem.
Commun. 2011, 47, 5933–5941.
[34] a) Z.-M. Shi, J. Huang, Z. Ma, Z. Guan, Z.-T. Li, Macromolecules 2010, 43,
6185–6192; b) K.-D. Zhang, X. Zhao, G.-T. Wang, Y. Liu, Y. Zhang, H.-J.
Lu, X.-K. Jiang, Z.-T. Li, Angew. Chem. 2011, 123, 10040–10044; Angew.
Chem. Int. Ed. 2011, 50, 9866–9870.
Chem. Eur. J. 2014, 20, 1418 – 1426
www.chemeurj.org
1425
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[35] a) H. Yin, A. D. Hamilton, Angew. Chem. 2005, 117, 4200–4235; Angew.
Chem. Int. Ed. 2005, 44, 4130–4163; b) C. G. Cummings, A. D. Hamilton,
Curr. Opin. Chem. Biol. 2010, 14, 341–346; c) M. J. Adler, A. G. Jamieson,
A. D. Hamilton, Curr. Top. Microbiol. Immunol. 2011, 348, 1–23; d) A. D.
Bautista, C. J. Craig, E. A. Harker, A. Schepartz, Curr. Opin. Chem. Biol.
2007, 11, 685–692; e) G. N. Tew, R. W. Scott, M. L. Klein, W. F. DeGrado,
Acc. Chem. Res. 2010, 43, 30–39; f) V. Azzarito, K. Long, N. S. Murphy,
A. J. Wilson, Nat. Chem. 2013, 5, 161–173.
[36] a) J. D. Sadowsky, M. A. Schmitt, H.-S. Lee, N. Umezawa, S. Wang, Y.
Tomita, S. H. Gellman, J. Am. Chem. Soc. 2005, 127, 11966–11968;
b) W. S. Horne, L. M. Johnson, T. J. Ketas, P. J. Klasse, M. Lu, J. P. Moore,
S. H. Gellman, Proc. Natl. Acad. Sci. USA 2009, 106, 14751–14756; c) L.
Delauriꢅre, Z. Dong, K. Laxmi-Reddy, F. Godde, J.-J. Toulmꢃ, I. Huc,
Angew. Chem. 2012, 124, 488–492; Angew. Chem. Int. Ed. 2012, 51,
473–477.
[37] a) C. Li, S.-F. Ren, J.-L. Hou, H.-P. Yi, S.-Z. Zhu, X.-K. Jiang, Z.-T. Li, Angew.
Chem. 2005, 117, 5871–5875; Angew. Chem. Int. Ed. 2005, 44, 5725–
5729; b) Y.-Y. Zhu, J. Wu, C. Li, J. Zhu, J.-L. Hou, C.-Z. Li, X.-K. Jiang, Z.-T.
Li, Cryst. Growth Des. 2007, 7, 1490–1496.
[38] a) C. Li, Y.-Y. Zhu, H.-P. Yi, C.-Z. Li, X.-K. Jiang, Z.-T. Li, Y.-H. Yu, Chem. Eur.
J. 2007, 13, 9990–9998; b) Y.-Y. Zhu, C. Li, G.-Y. Li, X.-K. Jiang, Z.-T. Li, J.
Org. Chem. 2008, 73, 1745–1751; c) L. Wang, Z.-Y. Xiao, J.-L. Hou, G.-T.
Wang, X.-K. Jiang, Z.-T. Li, Tetrahedron 2009, 65, 10544–10551.
[39] Q. Gan, C. Bao, B. Kauffmann, A. Grelard, J. Xiang, S. Liu, I. Huc, H. Jiang,
Angew. Chem. 2008, 120, 1739–1742; Angew. Chem. Int. Ed. 2008, 47,
1715–1718.
[42] a) H. Juwarker, J. M. Lenhardt, D. M. Pham, S. L. Craig, Angew. Chem.
2008, 120, 3800–3803; Angew. Chem. Int. Ed. 2008, 47, 3740–3743;
b) H. Juwarker, J. M. Lenhardt, J. C. Castillo, E. Zhao, S. Krishnamurthy,
R. M. Jamiolkowski, K.-H. Kim, S. L. Craig, J. Org. Chem. 2009, 74, 8924–
8934.
[43] R. M. Meudtner, S. Hecht, Angew. Chem. 2008, 120, 5004–5008; Angew.
Chem. Int. Ed. 2008, 47, 4926–4930.
[44] a) Y. Wang, F. Bie, H. Jiang, Org. Lett. 2010, 12, 3630–3633; b) Y. Wang, J.
Xiang, H. Jiang, Chem. Eur. J. 2011, 17, 613–619.
[45] Y. Wang, F. Li, Y. Han, F. Wang, H. Jiang, Chem. Eur. J. 2009, 15, 9424–
9433.
[46] D. Zornik, R. M. Meudtner, T. El Malah, C. M. Thiele, S. Hecht, Chem. Eur.
J. 2011, 17, 1473–1484.
[47] L.-Y. You, S.-G. Chen, X. Zhao, Y. Liu, W.-X. Lan, Y. Zhang, H.-J. Lu, C.-Y.
Cao, Z.-T. Li, Angew. Chem. 2012, 124, 1689–1693; Angew. Chem. Int. Ed.
2012, 51, 1657–1661.
[48] a) D. Sꢆnchez-Garcꢇa, B. Kauffmann, T. Kawanami, H. Ihara, M. Takafuji,
M.-H. Delville, I. Huc, J. Am. Chem. Soc. 2009, 131, 8642–8648; b) M.
Kudo, V. Maurizot, B. Kauffmann, A. Tanatani, I. Huc, J. Am. Chem. Soc.
2013, 135, 9628–9631.
[49] J. C. Nelson, J. G. Saven, J. S. Moore, P. G. Wolynes, Science 1997, 277,
1793–1796.
[50] C. R. Martinez, B. L. Iverson, Chem. Sci. 2012, 3, 2191–2201.
[51] J. F. Galan, J. Brown, J. L. Wildin, Z. Liu, D. Liu, G. Moyna, V. Pophristic, J.
Phys. Chem. B 2009, 113, 12809–12815.
[52] J.-L. Hou, X.-B. Shao, G.-J. Chen, Y.-X. Zhou, X.-K. Jiang, Z.-T. Li, J. Am.
Chem. Soc. 2004, 126, 12386–12394.
[40] a) C. Ren, S. Xu, J. Xu, H. Chen, H. Zeng, Org. Lett. 2011, 13, 3840–3843;
b) C. Ren, F. Zhou, B. Qin, R. Ye, S. Shen, H. Su, H. Zeng, Angew. Chem.
2011, 123, 10800–10803; Angew. Chem. Int. Ed. 2011, 50, 10612–10615.
[41] a) Y. Hua, A. H. Flood, Chem. Soc. Rev. 2010, 39, 1262–1271; b) K. P.
McDonald, Y. Hua, A. H. Flood, Top. Heterocycl. Chem. 2010, 24, 341–
366; c) S. Lee, A. H. Flood, Top. Heterocycl. Chem. 2012, 28, 85–107; d) Y.
Li, A. H. Flood, J. Am. Chem. Soc. 2008, 130, 12111–12122; e) Y. Hua,
A. H. Flood, J. Am. Chem. Soc. 2010, 132, 12838–12840; f) K. P. McDo-
nald, R. O. Ramabhadran, S. Lee, K. Raghavachari, A. H. Flood, Org. Lett.
2011, 13, 6260–6263.
[53] M. T. Stone, J. M. Fox, J. S. Moore, Org. Lett. 2004, 6, 3317–3320.
[54] a) R. Podeszwa, R. Bukowski, K. Szalewicz, J. Phys. Chem. A 2006, 110,
10345–10354; b) J. G. Hill, J. A. Platts, H.-J. Werner, Phys. Chem. Chem.
Phys. 2006, 8, 4072–4078.
[55] C. Dolain, H. Jiang, J.-M. Lꢃger, P. Guionneau, I. Huc, J. Am. Chem. Soc.
2005, 127, 12943–12591.
Received: October 24, 2013
Published online on January 2, 2014
Chem. Eur. J. 2014, 20, 1418 – 1426
www.chemeurj.org
1426
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim