Designing Structural Motifs for Clickamers: Exploiting the 1,2,3-Triazole Moiety to Generate Conformationally Restricted Molecular Architectures

Article abstract of DOI:10.1002/chem.201002491

Noncovalent interactions, especially hydrogen-bonding interactions as well as electrostatic forces, confined within one macromolecule are the key to designing foldamers that adopt well-defined conformations in solution. In the context of significant recent activities in the area of triazole-connected foldamers, so-called clickamers, we present a fundamental study that compares various model compounds that bear adjacent N-, O-, or F-heteroatom substituents. The interplay of attractive and repulsive interactions leads to rotational constraints around the single bonds attached to both the 1- and 4-positions of the 1,2,3-triazole moiety and should therefore be able to induce well-defined conformational preferences in higher oligomers and polymers, that is, foldamers. Various compounds were synthesized and characterized with regard to their preferred conformations in all three aggregation statesa-that is, in the gas phase, in solution as well as in the solid statea-by employing DFT calculations, NMR spectroscopic experiments, and X-ray crystallography, respectively. On the basis of the thus-obtained general understanding of the conformational behavior of the individual connection motifs, heterostructures were prepared from different motifs without affecting their distinct folding characteristics. Therefore, this work provides a kind of foldamer construction kit, which should enable the design of various clickamers with specific shape and incorporated functionality. A foldamer construction kit: Various heterostructures "clicked" together by structure-directing triazole moieties were investigated with regard to their conformational behavior. Different heteroatoms (X; see graphic) can be used to bias the conformation around the N(1)- and C(4)-connecting single bonds of the triazoles based on tunable noncovalent interactions.

Full text of DOI:10.1002/chem.201002491

FULL PAPER
DOI: 10.1002/chem.201002491
Designing Structural Motifs for Clickamers: Exploiting the 1,2,3-Triazole
Moiety to Generate Conformationally Restricted Molecular Architectures
Denise Zornik,[a] Robert M. Meudtner,[a] Tamer El Malah,[a] Christina M. Thiele,[b] and
Stefan Hecht*[a]
Abstract: Noncovalent interactions, es-
pecially hydrogen-bonding interactions
as well as electrostatic forces, confined
within one macromolecule are the key
to designing foldamers that adopt well-
defined conformations in solution. In
the context of significant recent activi-
ties in the area of triazole-connected
foldamers, so-called clickamers, we
present a fundamental study that com-
pares various model compounds that
bear adjacent N-, O-, or F-heteroatom
substituents. The interplay of attractive
and repulsive interactions leads to rota-
tional constraints around the single
bonds attached to both the 1- and 4-po-
sitions of the 1,2,3-triazole moiety and
should therefore be able to induce
well-defined conformational preferen-
ces in higher oligomers and polymers,
that is, foldamers. Various compounds
were synthesized and characterized
with regard to their preferred confor-
mations in all three aggregation
states—that is, in the gas phase, in solu-
tion as well as in the solid state—by
employing DFT calculations, NMR
spectroscopic experiments, and X-ray
crystallography, respectively. On the
basis of the thus-obtained general un-
derstanding of the conformational be-
havior of the individual connection
motifs, heterostructures were prepared
from different motifs without affecting
their distinct folding characteristics.
Therefore, this work provides a kind of
foldamer construction kit, which
should enable the design of various
clickamers with specific shape and in-
corporated functionality.
Keywords: click chemistry · confor-
mation analysis · foldamers · supra-
molecular chemistry · triazoles
Introduction
mers[3]—as well as covalent approaches—that is, dendrim-
ers[4] and foldamers[5]—and combinations of both have been
used.[6] This hierarchical bottom-up strategy to assemble
complex functional systems is, not surprisingly, mainly in-
spired by natureꢀs strategies, exemplified by protein struc-
ture formation. Here, the primary structure encoding a (het-
ero)sequence of monomer units is translated to a defined
secondary structure, which is further organized into tertiary
folds. Both of these levels of organization are caused by in-
tramolecular noncovalent interactions within a covalently
connected backbone, which in general is referred to as a fol-
damer.[5] Nature utilizes primarily peptides for this task;
however, for nonbiological materials. thermally and chemi-
cally more robust backbones are desired. Aromatic—as op-
posed to aliphatic—amide foldamers offer such enhanced
stability,[7] and several groups have successfully designed ex-
amples of these backbones.[8] In these systems, folding—in
most cases into a helical structure—is induced by geometri-
cal constraints rather than environmental effects.[9] These
constraints are generated by various stabilizing and destabi-
lizing interactions between adjacent aromatic monomers
units connected by the rigid and trans-configured amide
linkage.[8]
In recent years, a great deal of scientific effort has been de-
voted towards understanding general structure–function re-
lationships in synthetic macro- and supramolecules and also
exploiting this insight to improve their properties for future
applications. The key question in designing novel soft mate-
rials relates to the controlled spatial arrangement of func-
tional entities (most commonly monomer units) for which
noncovalent approaches—that is, self-assembly of small mol-
ecules[1] or block copolymers[2] and supramolecular poly-
[a] Dipl.-Chem. D. Zornik, Dr. R. M. Meudtner,
Dipl.-Chem. T. El Malah, Prof. Dr. S. Hecht
Department of Chemistry, Humboldt-Universitꢁt zu Berlin
Brook-Taylor-Strasse 2, 12489 Berlin (Germany)
Fax : (+49)30-2093-6940
E-mail: sh@chemie.hu-berlin.de
[b] Dr. C. M. Thiele
Clemens Schçpf Institut fꢂr Organische Chemie
Technische Universitꢁt Darmstadt
Petersenstrasse 22, 64287 Darmstadt (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem201002491.
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These interactions can generate conformationally biased
bent connections, which at a critical length lead either to a
folding into a three-dimensional helical structure or into a
two-dimensional zigzag linear tape structure (Figure 1). The
amide linkage is by far the most popular connection[10] of ar-
omatic monomer units in these foldamers. However, substi-
on C(5). We have investigated various types of heteroatom
substitution, that is, nitrogen, oxygen, and fluorine, known
to engage in considerably strong hydrogen-bonding-type in-
teractions. In addition to N-containing heteroaromatics—
that is, pyridines and benzimidazoles—ortho-alkoxy-substi-
tuted as well as ortho-fluorine-substituted phenyl moieties
have been explored (Scheme 1).
Based upon the relative orienta-
tion of the heteroatoms adja-
cent to the triazole ring, either
progressively kinked or zigzag
structures can be formed, there-
by resulting in helices and
Figure 1. Illustration of conformational preferences within rigid aromatic foldamers that lead to either 3D
helix or 2D linear tape formation (aromatic units shown in red, bent connections shown in blue).
linear strands, respectively.
Conformational
constraints
tution of the amide functionalities by the isosteric 1,2,3-tria-
based on H···N interactions:
zole moieties[11] offers both, a synthetic advantage due to
the orthogonal and high-yielding coupling chemistry as well
as new structural and electronic features that arise from the
triazole ring. By exploiting the highly efficient copper-cata-
lyzed “click” reaction not only to efficiently connect mono-
mer units but also to incorporate the triazole unit to induce
secondary structure formation, we have recently developed
the 2,6-bis(1-aryl-1,2,3-triazol-4-yl)pyridine (BTP) motif[12,13]
and investigated BTP-derived scaffolds for responsive fold-
ing in solution,[14] as ligands[15] and metallosupramolecular
gels,[16] as well as at the liquid–solid interface.[17] To apply
our strategy for the design of new backbones, we have en-
gaged in a detailed study of various 1,2,3-triazole-connected
(hetero)aromatic systems. Here, we report on the synthesis
of these new folding motifs and discuss the influence of dif-
ferent heteroatoms—that is, N-, O-, F-substitution—on the
conformational preference about both the N(1)-aryl of the
triazole as well as the C(4)-aryl bonds.
Our original design of clickamers[14] based on the BTP motif
offers conformational constraints only about the C(4)-tria-
zolyl–2-pyridyl bond, whereas the N(1)-triazolyl–phenyl
bond displays no preference for either the syn or the anti
conformation (Scheme 2, left). Hence, folding involves ri-
gidified kinked BTP moieties connected by flexible meta-
phenylene hinges.[14,16] To generate fully rigidified helices,
ortho-pyridyl moieties were introduced by means of click
chemistry that involved the corresponding 2-azidopyridines,
which should bias the conformation about the N(1)-triazol-
yl–2-pyridyl bond (Scheme 2, right).
2-Azidopyridine derivative 8a (Scheme 3) could success-
fully be synthesized from nitroxide 5. Although the com-
pound mostly exists as the tetrazole tautomer 8b,[18] the sub-
sequent click reaction with the previously described 2,6-bis-
AHCTUNGTREG(NNNU ethynyl)pyridine 9 was successful and gave the desired
product 10. Please note that the yields of the click reactions
given throughout this article are not optimized and do not
necessarily reflect inefficient reactions but rather trouble-
some purification of the target compounds, often caused by
their low solubility in combination with residual traces of
copper species. Presumably due to the less ordered tri(ethy-
lene glycol) groups, no single crystals of compound 10 could
be grown for detailed structural analysis and hence n-hexyl
side chains were introduced by a two-step saponification–
esterification sequence to yield 12. Indeed, single crystals
could be obtained by slow diffusion of petroleum ether into
a solution of 12 in acetone. The corresponding single crystal
structure (Figure 2) displays the expected horseshoelike,
planar anti–anti conformation of both linkages, that is, the
Results and Discussion
General design considerations: In our previous work,[12,14–17]
solely the BTP motif was used, which offers conformational
restriction only about the C(4)-aryl connection, readily ach-
ieved by means of a click reaction of bis(ortho-ethynyl)pyri-
dines with aromatic azides. Initial attempts to also bias the
N(1)-aryl connection failed because bis(ortho-azido)pyri-
dines could not be prepared. We therefore sought to incor-
porate other (hetero)aromatic units to bias conformation
about the N(1)- as well as C(4)-linkages. By assuming only
two possible flat conformations due to p conjugation—that
is, syn and anti (Scheme 1, top)—attractive interactions of
the incorporated heteroatoms with the triazole proton on
C(5) as well as the ortho protons with N(2) or N(3) are sup-
posed to favor the anti conformation. On the other hand,
the syn conformation should be strongly disfavored due to
repulsive interactions of the heteroatoms (X) with the N(2)
and N(3) atoms of the central triazole moiety and steric re-
pulsion between the ortho-protons and the triazole proton
À
N(1) C of the triazoles as well as the C(4)–C connectivities
of the triazoles. Due to deviations in bond lengths and dihe-
dral angles (Figure 2), the molecule possesses only little
symmetry yet can still be considered planar as the absolute
angle variations are rather small.
Unfortunately, available synthetic strategies could only be
applied to introduce one azide group in the ortho position
of the pyridine heterocycle. Both synthesis of the 2,6-bisazi-
dopyridine derivative as well as extension of the initially
prepared structure 12 at its termini by repeated introduction
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Structural Motifs for Clickamers
FULL PAPER
Scheme 1. Design of clickamer motifs that involve heteroatom substitution, which illustrates general conformational preferences and the resulting secon-
dary structure of the various investigated foldamer motifs discussed in this article.
Figure 2. Single-crystal structure of compound 12 with the average bond
¯
¯
lengths dCÀC =(1.463Æ0.045) ꢄ, and dCÀN =(1.435Æ0.015) ꢄ, and average
¯
dihedral angles #=(178.0Æ2.0)8, and f=(174.2Æ3.8)8 (average bond
lengths and angles of the eight molecules contained in one unit cell).
of the azide functionality failed. As a result, the rigid oligo/
poly(pyridine–triazole)s—although most likely giving rise to
a very stable helical structure—could not be accessed and
therefore alternative building blocks, which connected the
triazole moieties at their N(1) termini, were investigated.
Scheme 2. Foldamer motifs based on 2,6-diethynylpyridine: Partially re-
stricted conformation by oligomerization with 1,3-bisazidobenzene (left)
versus fully restricted conformation by oligomerization with 2,6-bisazido-
pyridines (right).
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S. Hecht et al.
Scheme 3. Synthesis of all-(pyridine–triazole) oligomer 12.
Subsequently, our interest was focused on 2-(1,2,3-triazol-
4-yl)benzimidazoles. In addition to its extended annelated
backbone, the benzimidazole ring offers both remote donat-
ing and accepting interaction sites, that is, N(1) and lone
pair N(3). The further increased outer bond angles of the
five-membered ring should enable the tuning of the dihedral
angles about the N(1)-triazolyl–2-benzimidazolyl bond and
the C(4)-triazolyl–2-benzimidazolyl bond, respectively. To
compare conformational preferences with the pyridine
motif, the benzimidazole derivatives 14 and 15 were reacted
by means of click chemistry to generate target compound
13. To obtain additional information about the influence of
electrostatic interactions between the NACTHNUTRGNE(NUG 2,3)-triazolyl and
À
À
H(1)-benzimidazolyl atoms, N H as well as N’ H were con-
secutively N-methylated to yield all four possible combina-
tions, that is, 13a–d (Scheme 4).
First assumptions of a preferred anti–anti conformation in
solution were supported by extensive NOESY experiments
of 13a–c in [D6]DMSO. As we did not attempt to observe a
heteronuclear NOE between the triazole C(5) and the ben-
zimidazole N(1) atoms in 13a–c due to the low abundance
of 15N, the actual conformation can only indirectly be infer-
red by the absence of a cross-peak between the triazole and
benzimidazole protons (see Figures S17–S19 in the Support-
ing Information), thereby suggesting their large spatial sepa-
ration and hence pointing to their relative anti relationship.
Crystal structures of 13b und 13d (Figure 3), obtained by
slowly evaporating the DMSO solvent at room temperature,
Scheme 4. Synthesis of benzimidazole–triazole–benzimidazole model
compounds 13a–d.
confirmed these findings as the anti–anti conformations
could clearly be identified for these two compounds. The
crystal structure of 13a, unfortunately, shines no light on its
conformation because the N(1) atoms in 13a cannot clearly
be assigned to either one side of the benzimidazole in the
obtained data set. Note that in solution the imidazole N(1)
atoms show tautomerism that could clearly be observed in
the corresponding NOESY-spectrum (see Figure S17). Im-
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Structural Motifs for Clickamers
FULL PAPER
amide connectivities. To see whether a triazole-derived aro-
matic foldamer strand would gain additional stabilization by
introducing ortho-alkoxy substituents, various alkylated re-
sorcinol derivatives were linked by means of the click reac-
tion. The required model compounds 21, 22, and 23 could
be obtained in good and very good yields from the respec-
tive azide and ethynyl precursors 16–20 (Scheme 5; see also
Figure S3 in the Supporting Information).
The connectivity in the meta-substituted, and therefore
kinked, derivatives 21 and 22 is different as the first one is
based on the diazide core 16, whereas the latter one is
formed from the diethynyl core 17. Related compounds 21
and 22 display considerably different chemical shifts in the
aromatic region of their NMR spectra (Figure 4, top). In
particular, the strong chemical-shift difference of the central
proton adjacent to the triazole moiety is remarkable, as the
corresponding signal, located at d=9.29 ppm (Hf) in 22, ex-
periences a significant upfield shift to d=8.06 ppm (Hb) in
21. This can be explained by the electron-donating meso-
meric (+M) effect of both adjacent N(1)-triazole atoms in
compound 21, thus causing a shielding of the central phenyl
proton relative to compound 22.
Figure 3. Molecular structures of benzimidazole–triazole–benzimidazole
model compounds 13a,b,d. Selected bond lengths [ꢄ] and dihedral
¯
¯
angles [8] in 13a (averaged): dCÀC =(1.441Æ0.023), dCÀN =(1.388Æ0.023);
¯
#=(176.6Æ0.1), f=(174.8Æ3.0) (average bond lengths and angles of the
two molecules contained in one unit cell); in 13b: dCÀC =1.470, dCÀ
=
N
1.418; #=175.2, f=160.9; and in 13d: dCÀN =1.436, dCÀN =1.418; #=
175.4, and f=177.7.
The NOESY spectrum of 21 (Figure 4) shows only cross-
peaks for the methylene protons to each other as well as to
their adjacent ortho-phenylene protons Ha and Hc. No cross-
peaks between the triazole protons HT and their adjacent
ortho-phenylene protons Hb and Hd, respectively, are ob-
served. This finding supports the assumption that the syn–
syn conformation is not adopted and hence suggests that the
preferred anti–anti conformation, in which these protons are
located at maximum distance, is populated. Also, in the
NOESY spectrum of 22 (Figure 4), no cross-peaks between
the triazole protons HT and their neighboring ortho-phenyl-
ene protons Hf and Hh are observed, and again the only
cross-peaks involve the methylene protons of the n-hexyl
side chains. Therefore, compound 22 also seems to adopt an
portantly, all three systems show a planar arrangement of
the respective aromatic units (Figure 3, side views). Whereas
13a and 13d are completely planar, the benzimidazole
À
moiety connected through the C N bond of 13b is twisted
by 19.18, which is probably induced by crystal packing.
Conformational constraints based on H···O interactions: An
alternative conformationally restricting element, which is
commonly used to bias the conformation of aromatic
amides, is based on ortho-alkoxy substitution. The resulting
interaction between neighboring hydrogen and O atoms
leads to a wide variety of foldamer structures reported over
the past years;[19–21] however, they are solely restricted to
Scheme 5. Synthesis of resorcinol–triazole–resorcinol model compounds 21–23 with R=C6H13 (21, 22) and CH3 (23), shown in their preferred anti–anti
conformations.
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S. Hecht et al.
1
Figure 4. NOESY spectra of 21 (top) and 22 (bottom) including H NMR
spectra. Apparent cross-peaks for methylene protons to adjacent ortho-
phenylene protons Ha as well as He are shown in black boxes. Expected
regions with absent cross-peaks between the triazole proton and the adja-
cent ortho-phenylene protons HT and Hb and Hd (for 21) and Hh and Hf
for (22), respectively, which confirm the preferred anti–anti conformation,
are marked with dashed lines.
anti–anti conformation in solution. Single crystals of 21
could be obtained by slowly evaporating the NMR spectro-
scopic solvent CDCl3 at room temperature, and the molecu-
lar structure reveals the expected anti–anti conformation
(Figure S5 in the Supporting Information). However, the
quality of the obtained structural data was limited with final
R indices above 10% (wR=14%), probably due to the poor
packing of the n-hexyl chains. Unfortunately, no single crys-
tals could be obtained in the case of compound 22.
When the meta-substituted aromatic core unit is displaced
by the para-substituted diacetylene 18, the resulting oligo-
mer structure was not kinked, but rather linear. In contrast
to compounds 21 and 22, the cross peaks between the tria-
zole proton HT and the adjacent ortho-phenylene proton Hk
in the NOESY spectrum of 23 (see Figure S22 in the Sup-
porting Information) are not completely absent. The intensi-
ty of these cross-peaks, however, is negligible (comparable
signal-to-noise ratio to the t1 streaks). Thus we believe that
23 also adopts the expected anti conformation. In this case,
methyl groups were introduced instead of hexyl chains to
grow high-quality crystals of 23. Structural analysis shows
that the molecule adopts the anti–anti conformation
(Figure 5). More importantly, the structure exhibits nearly
perfect planarity (dihedral angle of 0.28) in the core region
Figure 5. Single-crystal structure of compound 23 with Ci symmetry with
selected bond lengths dCÀC =1.531 ꢄ and dCÀN =1.530 ꢄ and selected di-
hedral angles #=0.28 and f=42.78 (middle: top view; bottom: side
view).
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Structural Motifs for Clickamers
FULL PAPER
À
that involves a triazol-4-yl connection, that is, along a C C
bond, whereas the terminal resorcinol units are significantly
twisted by 42.78 about the triazol-1-yl linkage, that is, the
À
the pyridine nor with the protons of the phenylene can be
observed (Figure S23 and S24 in the Supporting Informa-
tion). The structure analyses of both crystals, shown in
Figure 6, also reveals the backbone that adopts the pre-
ferred anti conformation not only at the pyridine-bridged
triazole connectivity, but also at the ortho-alkoxy-substituted
phenyl-triazole connection as well. Whereas the pyridine-tri-
C N bond. This points to the importance of connectivity in
this system. Whereas the attachment through the C(4) posi-
tion of the triazole as in 23 gives rise to the desired highly
planar anti arrangement, the alternative attachment through
the N(1) position of the triazole leads to a significantly
twisted anti conformation. This distortion is most likely
caused by steric repulsion, which furthermore also leads to
À
À
azole-connectivity through C C linkage shows nearly planar
conformation, the ortho-alkoxy-substituted phenylenes show
À
a perceivable twist for the C N linkage, as was already ob-
an elongation of the connecting N(1) C bond (dCÀN
=
served in compounds 21 and 23. When the dihedral angles
are taken into account, it is noteworthy that 24 shows some-
what comparable values of #=10.98 and f=55.28 to com-
pound 25 with #=6.48 and f=31.88, thereby indicating that
not only the choice of the structure-directing heteroatom di-
rectly influences the conformational design of the resulting
oligomer and polymer vice versa, but also the steric demand
of ortho-alkoxy substituent. On the contrary, the electronic
effects of the C(4) substituents of the pyridine seem to be
negligible due to similar torsions of the withdrawing nitro
and donating amine compound.
1.530 ꢄ).as compared to the parent nonsubstituted 1-phenyl-
1,2,3-triazoles (dCÀN =1.429 ꢄ as well as 1.443 ꢄ).[21,22]
The maximum benefit of these structural motifs would be
gained when different building blocks, which possess their
distinct conformational properties, could be combined in a
construction kit principle and any desired foldamer shape
could be afforded consequently. For this purpose, mixed sys-
tems that comprised a central BTP unit with terminal ortho-
alkoxy-substituted phenyl moieties were synthesized. Two
pyridine cores (Figure 6) were introduced to yield two
Conformational constraints based on H···F interactions:
With the knowledge that halogen substituents serve as po-
tential hydrogen-bond acceptors as well,[23] we further exam-
ined the structure-inducing influence of ortho-substituted
fluorobenzene on the triazole moiety to expand the variety
of structure-inducing substituents in our toolbox. Fluorine
as a strong proton acceptor asserted itself in that field,[24] al-
though its application has been quite limited up to now.
Therefore, we decided to prepare compounds 26 and 27
(Scheme 6), which again were functionalized with electron-
withdrawing and electron-donating in the C(4) position of
the pyridine to investigate their structural influences in solu-
tion. The ortho-fluorophenyl azide 30 was reacted with the
three different bisACTHNUTRGNEUNG(ethynyl)pyridines 9, 31, and 32 to afford
click products 26, 27, and 28, respectively. Whereas the tri-
glyme side chain in 26 and 27 provide solubility for confor-
mational characterization in solution, the methyl derivative
28 was prepared to obtain single crystals suitable for X-ray
crystallography.
Electron-donating and -accepting properties of the ob-
tained click products can be observed as expected by the
significant difference of the protons of the pyridine on C-
Figure 6. Structures and conformational preferences of mixed systems 24
and 25 for the anti–anti conformation in the solid that bears the struc-
ture-directing pyridine–triazole connection as well as the ortho-alkoxy-
phenylene connection with selected bond lengths [ꢄ] and dihedral angles
[8] of 24: dCÀC =1.466 and dCÀN =1.427 and #=10.9 and f=55.2; 25:
d
CÀC =1.471 and dCÀN =1.432 and #=6.4 and f=31.8.
AHCTUNGTREG(NNNU 3,5) upfield-shifted from d=8.78 ppm in 26 to d=7.79 ppm
model compounds with different substitution, as electron-
withdrawing nitro (24) and electron-donating amino func-
tionality (25), in the 4-position of the pyridine, yet both
bearing an ortho-alkoxy substituent. These compounds
could be easily synthesized in very good yields by adapting
a convergent procedure. To show that the structural consid-
erations proven for the structures above are also valid for
mixed structures, both compounds were studied in solution
by NOESY and in the solid state by crystal-structure analy-
sis, respectively. As expected, the conformation in solution
adopts the preferred anti–anti orientation as neither a cross-
in 27, yet are barely reflected by the triazole shifts from d=
8.75 ppm (26) to d=8.70 ppm (27). Indications for the an-
ticipated anti–anti conformation can already be extracted
from 1D proton spectra: the triazole protons are split by a
5
“through-space” J
N
26 and 27.[25] Additional evidence is provided from homo-
and heteronuclear NOE experiments since cross-peaks be-
tween the triazole proton and the ortho-phenyl proton are
again absent. As a big advantage of these systems, a spatial
proximity between the fluoro atoms and triazole protons
1
could directly be detected qualitatively in H-19F 2D hetero-
peak between the triazole proton with the C
G
nuclear NOESY (HOESY) experiments as evidenced by
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S. Hecht et al.
forces that contribute to the po-
tential
energy
diagram
(Figure 9) for the triazole-
phenyl rotamers. On the one
hand, repulsive forces increase
(dotted line in Figure 9), as the
triazole proton and the ortho-
phenyl proton on one side of
the molecule as well as the
phenyl ortho substituent and
the lone pair of the triazole
N(2) atom on the other side ex-
perience spatial proximity. This
steric repulsion will be reduced
by turning the dihedral angle in
the opposite direction, there-
fore placing the triazole and
ortho-phenyl protons in an anti
relationship. On the other
hand, while these steric repul-
sive forces are being reduced,
additional attractive forces arise
(solid line in Figure 9) to fur-
ther reduce the potential
Scheme 6. Synthesis of fluoro-substituted click compounds 26–28.
energy in the anti conforma-
tion.
cross-peaks between the triazole proton and the fluoro sub-
stituent of the benzene ring (Figure 7).
This effect originates from the electrostatic attraction (hy-
drogen bond) between the triazole nitrogen lone pairs and
the ortho-phenyl proton as well as the ortho-heteroatom and
the triazole proton in the anti conformation. Last but not
least, forcing the phenyl rings away from coplanarity results
in a loss of p conjugation (dashed line in Figure 9), thereby
leading to an increase of potential energy, which reaches its
maximum at the perpendicular orientation of two adjacent
aromatic systems, that is, the transition state for rotation.
For representative and comparable calculations, appropriate
model compounds were chosen that consisted of a central
triazole moiety connected on both its N(1) and C(4) posi-
tions to ortho-substituted phenyl rings with the investigated
heteroatom functionalities attached, which are essential for
rotational restriction (Scheme 7). After geometry optimiza-
tion using the B3LYP density functional with the TZVP
basis set, the backbone coordinates were restricted and only
These findings could analogously be supported by crystal-
structure analyses of 28, which was successfully crystallized
twice by slow evaporation of THF on the one hand and
CDCl3 on the other (Figure 8). Again, in this type of model
compound, the BTP core shows a well-established horse-
shoelike structure. Interestingly, the choice of solvent influ-
enced the conformational situation of the molecule in lattice
around the N(3) connection of the triazoles and the C(1)
connection of the phenylenes. Whereas crystals grown in
THF showed a twist of both ortho-fluoro-substituted phenyl
rings of 23.7 and 32.18 out of the molecular plane, crystals
grown from CDCl3 reveal this twist on only one side, which
is probably induced by cocrystallized solvent molecules in
the crystal package. Nevertheless, both structures adopt the
À
preferred anti–anti conformation on both the C N as well as
À
the C C connectivity, as was
expected by preliminary consid-
erations.
Computational studies: To eval-
uate and rationalize our experi-
mental findings, first DFT cal-
culations were carried out by
computing the rotational barri-
er between the syn–syn and
anti–anti conformations about
the triazole-phenyl linkage in
the gas phase. Theoretical con-
siderations reveal three major Scheme 7. Model compounds 13a, 13d, 33, 34, and 35 established for computational studies.
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Structural Motifs for Clickamers
FULL PAPER
Figure 8. Crystal structures of 28 are illustrated as on-top-view (left) and
in-plane-view (right) with selected bond lengths [ꢄ ] and dihedral angles
[8] crystallized from THF (top): dCÀ (#)=1.301, dCÀ (f)=1.224 and #=
C
N
4.1, f=32.1; and crystallized from CDCl3 (bottom): dCÀ (#)=1.638, dCÀ
C
C
(#’)=1.995, dCÀ (f)=1.696, dCÀN (f’)=1.372 and #=2.6, #’=5.0, f=
N
41.2 and f’=2.4.
Figure 7. a) Partial 1H-1H NOESY (500 MHz, 1 s mixing time) and
b) 1H-19F HOESY spectra (300 MHz, 200 ms mixing time; see the Sup-
porting Information) of compound 27, showing the absence of a 1H-1H
NOE between the triazole proton and the ortho-proton of the terminal
phenyl moiety and the presence of a 1H-19F HOE between the triazole
proton and the ortho-fluorine atoms. For compound 26, essentially identi-
cal results were obtained (data not shown).
Figure 9. Expected energetic contributions that result from repulsive
(dotted) and attractive interactions (solid) as well as the loss of aromatic-
ity (dashed). Z denotes the ortho-heteroatom substituent, X and Y are
either N(1) (related to f) or C(4) (related to #) of the triazole moiety
and vice versa.
the phenyl rings were subsequently twisted by incremental
steps of 108. Then, absolute energies were calculated and
plotted against the corresponding dihedral angles f and #,
Former DFT calculations on a 4-(2-pyridyl)-1,2,3-triazole
model system predicted a conformational preference along
À
À
À
which related to rotation about the N(1) C and C(4) C
bonds, respectively. This rather crude but less intense scan-
ning procedure was adapted to all five experimentally inves-
tigated motifs. The obtained results (Table 1) give insights
into the minimum conformations (#opt/fopt), their relative
thermodynamic stabilities (DH) as compared to an alterna-
tive conformation (local minimum), and the barrier of rota-
tion (DH°).
the C(4) C connection for the anti conformation of
6.4 kcalmolÀ1 over the syn conformer in the gas phase,[12]
which was slightly larger than the comparable conformation-
al preference of 2,2’-bipyridines (5.9 kcalmolÀ1).[26] Unfortu-
nately, these calculations provide no insight into the ener-
À
getics at the N(1) C connection. Therefore, the pyridine
motif was investigated again and relevant parameters calcu-
lated for both connectivities—that is, C(4) C and N(1) C—
at this time. Geometry optimization provided a completely
À
À
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1481

S. Hecht et al.
Table 1. Rotational parameters calculated by means of DFT (B3LYP, TZVP).
°
DH° [kcal
f°
d
(H X)
#
DH [kcal
#
DH° [kcal
#
d
(H X)
À
À
fopt
DH [kcal
falt
opt
[8][a]
alt
[8][c]
[b]
[d]
[b]
[d]
[8][a]
molÀ1
]
[8][c]
molÀ1
]
[8][e]
[ꢄ][f]
molÀ1
]
molÀ1
]
[8][e]
[ꢄ][f]
0
0
6.1
140
6.7
100
180
2.6
0
6.8
150
8.1
90
2.9
o.o.m.
o.o.m.
o.o.m. 11.0
o.o.m. 17.3
2.8
2.6
0
0
7.6
160
8.9
100
180
3.1
2.9
0
180
o.o.m.
o.o.m. 16.0
42
34
7.4
6.4
42
9.7
2.0
180
100
2.5
2.4
3
0
5.0
4.7
130
130
5.3
5.4
100
100
2.4
2.4
110
[a] Rotational angle in fully optimized geometry of most stable conformer. [b] Stabilization relative to alternative conformation (if existing, o.o.m. =
only one minimum). [c] Rotational angle in local minimum conformation. [d] Rotational barrier to alternative minimum or for full rotation. [e] Torsion
angle of conformation displaying the highest rotational barrier. [f] Distance between the nuclei of the triazole HC(5) and the respective adjacent heteroa-
tom X.
planar—that is, flat—structure with both torsion angles f
and # equal to 08. The barrier for rotation DG° was calcu-
formers for both compounds. These results nicely illustrate
that the linkage of two five-membered heteroaromatic rings
is suitable to achieve flat, coplanar geometries due to the re-
duction of steric repulsion between adjacent substituents.
Analogously to 13, the optimized geometry as well as the
rotational barriers were calculated for 1,4-bis(2-methoxy-
phenyl)-1H-1,2,3-triazole 34 as the model compound for
alkoxy-substituted molecules. The minimum structure dis-
lated to be 7.2 kcalmolÀ1 for the twist around the C N
À
À
bond, whereas the syn conformation at the C C linkage was
determined to be 8.1 kcalmolÀ1 higher in energy than the
anti conformation. These values for both connectivities are
larger than Lehn and co-workersꢀ 2,2’-bipyridine motif.[26]
Astonishingly high rotational barriers were calculated for
the benzimidazole motif. Due to the increased outer bond
angles associated with the five-membered triazole ring, the
dihedral angles about the N(1)–2-benzimidazolyl and the
C(4)–2-benzimidazolyl bonds should reduce the steric repul-
sion between adjacent substituents on both heteroaryl moi-
eties. Consequently, compound 13a and 13d were calculated
to be planar in their geometry-optimized states. The rota-
À
played a significant distortion about the N(1) C bond that
resulted in a dihedral angle f of 428, whereas the system re-
À
mained essentially coplanar at the C(4) C connection (#=
38). It should be noted that geometry optimization nicely re-
produces the structural data derived experimentally from
single-crystal-X-ray diffraction (f=42.78, #=0.28). A poten-
tial explanation for the deviation from coplanarity in the
tional barriers of 13a were calculated to be 11.0 kcalmolÀ1
for the N C connection related to f and 8.9 kcalmol for
the C C connection related to #, which is in agreement with
the shorter N C bond as evidenced by X-ray crystal-struc-
case of the N(1) C connection involves
a stabilizing
À
À1
À
HOMO–LUMO interaction, which can occur in the twisted
geometry only (Figure S16 in the Supporting Information).
Neglecting the presence of a shallow minimum in the case
À
À
À
ture analysis. Interestingly, introduction of the N-methyl
substituents in the benzimidazole moieties does not lead to
a destabilization of the anti–anti conformation, and instead
the N-methylated derivative 13d displays even higher rota-
tional barriers that amount to 17.3 and 16.0 kcalmolÀ1, re-
spectively. This effect seems to originate from the stabiliza-
tion of the anti–anti conformation due to attractive electro-
static interactions between two methyl protons each and the
neighboring N(2) and N(3) atoms relative to the significant
destabilization of the syn–syn conformation by enhanced
of the C(4) C connection (Figure S14), the global minima
(anti conformers) are slightly more stable in the case of the
À1
À
N(1) C connection (9.4 kcalmol ) as compared to the
À1
À
C(4) C connection (8.2 kcalmol ) with regard to their syn
counterparts (dihedral angles f and #=1808). As compared
to the benzimidazole motif, the rotational barriers in 34
amount to only one half; however, they are sufficiently high
enough to enable the use of ortho-alkoxy substitution as a
conformation-restricting motif. Similar results were obtained
for the calculation of the fluorine analogue 35. Ortho substi-
tution by fluorine also causes a phenyl twist of 348 for the
À
steric repulsion of the C(5) H and both adjacent methyl
À
À
groups. Compared to the BTP motif, it should be empha-
sized that the benzimidazole as the backbone entity shows
an extraordinarily strong stabilization of the anti–anti con-
N(1) C bond that relates to f, wheras the C(4) C connec-
tion was repeatedly predicted to be coplanar (#=08). The
relative stability of the anti conformers with regard to the
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Chem. Eur. J. 2011, 17, 1473 – 1484

Structural Motifs for Clickamers
FULL PAPER
syn conformations amounts to 6.4 kcalmolÀ1 in both cases,
that is, for torsion angles f as well as #. When comparing
these results with our H···N and H···O motifs, these values
represent the lowest rotational barriers yet they are still
higher than the barrier calculated for Lehn and co-workersꢀ
2,2’-bipyridine motif,[26] and therefore also an ortho-fluorine
substitution should be able to induce the desired conforma-
tional preferences. Taking into account all the calculated rel-
ative stabilities of the various conformers, useful energetic
considerations for foldamer design emerge (Figure 10). In
Conclusion
Conformationally preorganized motifs for triazole-based fol-
damers based on adjacent heteroatom substituents have ex-
perimentally and theoretically been investigated. Various
suitable model compounds were prepared and investigated
with regard to their preferred conformations in the gas
phase, in solution, and in the solid state by employing DFT
calculations, NMR spectroscopic experiments, and X-ray
crystallography, respectively. The results show that the intro-
duced N-, O-, and F-substituents induce rotational con-
straints around the single bonds attached to the 1- and 4-po-
sitions of the 1,2,3-triazole and hence the investigated motifs
should lead to well-defined conformational preferences in
higher oligomers and polymers, that is, “clickamers.” On the
basis of the thus-obtained general understanding of the con-
formational behavior of the individual connection motifs,
heterostructures composed of different motifs could be pre-
pared without affecting their distinct conformational charac-
teristics. These studies support the general concept of tria-
zole-based foldamers and, for the first time, provide rather
detailed information useful for designing new “clickamer”
backbones.
By using this toolbox and rationally introducing the right
heteroatom substituents in the correct positions, folded con-
formations with enhanced stability can be created while
maintaining synthetic accessibility by means of click chemis-
try.
Figure 10. Stabilization energies DH for the anti-conformation compared
Currently, ongoing work in our laboratories is focused on
clickamers derived from connecting aromatic ethers to
obtain elongated helical or linear tape structures and the in-
corporation of functional groups to induce self-assembly and
to provide response to external stimuli, in particular light.[28]
In the future, the concept of the preparation of new folda-
mer backbones by means of click chemistry should enable
the design of a wide variety of highly sophisticated function-
al yet nonbiological macromolecules by combining defined
secondary (and higher structures) with the facile incorpora-
tion of any desired functional entity. In addition to specific
efforts, this endeavor will greatly benefit from stronger theo-
retical involvements including the computation of larger
structures and their dynamics in solution.[29]
À
to the syn-conformation by rotating the dihedral angles f (C N bond)
À
and # (C C bond) from 0 to 1808.
each clickamer motif, there are two connectivities associated
with a preferred and a nonpreferred conformation, that is,
anti and syn conformations, respectively. As the triazole
moiety intrinsically always provides two connections, one
has to consider the superposition of these partial conforma-
tional equilibria, that is, four different conformations (anti–
anti vs. anti–syn vs. syn–anti vs. syn–syn).
To guide the design of global helical structures with en-
hanced stability, which geometrically arises from the anti–
anti conformation, its stabilization relative to all other possi-
ble conformations is the most important parameter to opti-
mize; and clearly, from the data provided in Figure 10, privi-
leged structure types can be derived. The basis of these
Experimental Section
priviACHTUNGTRENNUNGleged kinked or zigzag flat structures is the balancing of
Experimental details can be found in the Supporting Information.
stabilizing electrostatic (i.e., hydrogen-bonding) interactions
with the counteracting destabilizing steric repulsion that
arises from the close proximity of the adjacent substituents/
atoms. Note that hydrogen bonding occurs most likely
through space (distances see Table 1), although alternatively
through-bond interactions are also conceivable. Clearly
more elaborate computational work will be necessary to un-
ambiguously understand the basis for the observed confor-
mational preferences in the systems investigated herein.[27]
CCDC-759338 (12), 759332 (13a), 759331 (13b), 759330 (13c) and 759335
(23) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
The authors thank Dr. B. Ziemer (HU Berlin) for carrying out the
single-crystal X-ray structure analyses and Merck KgA (Darmstadt)—es-
Chem. Eur. J. 2011, 17, 1473 – 1484
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1483

S. Hecht et al.
pecially M. Schwarzkopf-Hofmann—for helpful discussions and granting
access to the DPX 300 NMR spectrometer for 1H-19F HOESY measure-
ments. Generous support by the German Research Foundation (DFG
through the SFB 765, Emmy Noether programme TH1115/3-1 to C.M.T)
and the Fonds der Chemischen Industrie is gratefully acknowledged.
Wacker Chemie AG, BASF AG, Bayer Industry Services, and Sasol Ger-
many are thanked for generous donations of chemicals.
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Received: August 28, 2010
Published online: December 10, 2010
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Chem. Eur. J. 2011, 17, 1473 – 1484