Structural Tuning and Conformational Stability of Aromatic Oligoamide Foldamers

Article abstract of DOI:10.1002/chem.201703985

A series of aromatic oligoamide foldamers with two or three pyridine-2,6-dicarboxamide units as their main folding motifs and varying aromatic building blocks as linkers have been synthetized to study the effects of the structural variation on the folding properties and conformational stability. Crystallographic studies showed that in the solid state the central linker unit either elongates the helices and more open S-shaped conformations, compresses the helices to more compact conformations, or acts as a rigid spacer separating the pyridine-2,6-dicarboxamide units, which for their part add the predictability of the conformational properties. Multidimensional NMR studies showed that, even in solution, foldamers show conformational stability and folded conformations comparable to the solid-state structures.

Full text of DOI:10.1002/chem.201703985

DOI: 10.1002/chem.201703985
Full Paper
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Supramolecular Chemistry
Structural Tuning and Conformational Stability of Aromatic
Oligoamide Foldamers
Riia Annala,[a] Aku Suhonen,[a] Heikki Laakkonen,[a] Perttu Permi,[a, b] and Maija Nissinen*[a]
Abstract: A series of aromatic oligoamide foldamers with
two or three pyridine-2,6-dicarboxamide units as their main
folding motifs and varying aromatic building blocks as link-
ers have been synthetized to study the effects of the struc-
tural variation on the folding properties and conformational
stability. Crystallographic studies showed that in the solid
state the central linker unit either elongates the helices and
more open S-shaped conformations, compresses the helices
to more compact conformations, or acts as a rigid spacer
separating the pyridine-2,6-dicarboxamide units, which for
their part add the predictability of the conformational prop-
erties. Multidimensional NMR studies showed that, even in
solution, foldamers show conformational stability and folded
conformations comparable to the solid-state structures.
in solution.[5] In the solid state, on the other hand, the require-
ment of the closest packing and possibility of small-molecule
inclusion either in the interstice between the foldamers or
inside the fold, may alter the folding and conformational prop-
erties.[6,7] The properties of aromatic foldamers, such as the
flexibility,[8] water solubility[9] and overall conformation[10] as
well as diameter[11] and chirality[12] of the helix, have been
tuned by the addition of different types of monomers. The
most common trend has been the addition of aliphatic mono-
mers to make heterogeneous foldamers[13,14] but also foldam-
ers with different aromatic sequences have been made to
create, for example, foldamer capsules[15] and selective recep-
tors.[16] The pyridine-2,6-dicarboxamide unit is one of the struc-
tural motifs used as a turn unit to impose helical conforma-
tions on oligomers.[17] Our previous studies with a series of aro-
matic oligoamides (4–5 aromatic rings) with a pyridine-2,6-di-
carboxamide center have shown that this type of short folda-
mer reliably adopt two, almost equally stabile folded
conformers with only small variances in their hydrogen bond-
ing and structural features.[18–20] Which conformer, denoted as
@ or S according to their overall shape (Scheme 1),[21] prevails
depends on the chemical structure of the foldamer as well as
environment, such as crystallization conditions and solvent.
The conformers and folding of these molecules are based on
intramolecular hydrogen bonding between the amide groups
and the pyridine-2,6-dicarboxamide unit, which forms a suita-
ble niche for multiple interactions, whereas aromatic interac-
tions seem to play a minor role in the folding preferences of
the oligoamides. Interestingly, the @ conformer with three in-
tramolecular hydrogen bonds forming to a single carbonyl
oxygen, resembles closely an oxyanion hole motif found in the
active sites of certain enzymes.[22] Artificial, nonpeptidic models
for oxyanion holes are not common, as only a few examples of
amide and ester carbonyl motifs as acceptors for multiple hy-
drogen bonds have been described.[23] Thus, aromatic
Introduction
During the last decades our understanding about biological
processes, such as the catalytic activity and selectivity of en-
zymes, has greatly increased. This understanding has brought
numerous new opportunities for chemists to learn from and
adapt towards chemical applications. Synthetic biomimetic
oligomers known as foldamers aim to combine the advantages
of biological polymers to the favourable properties of synthetic
oligomers, such as endurance of varying temperatures, pH and
salt concentrations, and possibility to function in organic sol-
vents.[1,2] Their structural rigidity obtained by, for example, re-
peating aromatic moieties connected by amide or urea bonds
allows a smaller size and a simpler design of the molecules
and adds predictability and stability to their folding and secon-
dary structures, which is the basis for potential applications of
foldamers.[3]
A number of different types of aromatic oligoamides have
been studied both in solution and in the solid state giving an
indication of how structural features and interactions affect the
folding and conformational properties.[4] In solution, the fold-
ing properties are greatly affected by competitive interactions
with solvent, thus diminishing the predictability of the folding
[a] R. Annala, Dr. A. Suhonen, H. Laakkonen, Prof. Dr. P. Permi,
Prof. Dr. M. Nissinen
Department of Chemistry, Nanoscience Center
University of Jyvaskyla, P.O. Box 35
40014 University of Jyvaskyla (Finland)
E-mail: maija.nissinen@jyu.fi
[b] Prof. Dr. P. Permi
Department of Chemistry and Department of Biological
and Environmental Sciences, Nanoscience Center
University of Jyvaskyla, P.O. Box 35
40014 University of Jyvaskyla (Finland)
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under https://doi.org/10.1002/
chem.201703985.
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oxyanion hole motif were studied in the solid state by X-ray
crystallography and compared with the solution-state informa-
tion obtained by multidimensional NMR spectroscopy. In fol-
damers 1–3, two pyridine-2,6-dicarboxamide units are separat-
ed by 1–3 ortho-substituted phenyl rings and 0–2 amide
bonds, whereas in foldamers 4 and 5, either a third pyridine-
2,6-dicarboxamide center or its phenyl analogue are used as a
spacer. The ortho-substituted phenyl rings of foldamers 1–3,
especially three consequent rings, act as a linear type of
spacer, whereas meta-substituted centers of 4 and 5 automati-
cally cause a different type of overall fold, which in the case of
the pyridine-2,6-dicarboxamide center of 5 leads to a helical
fold stabilized by intramolecular hydrogen bonding to pyri-
dine.
Solid-state conformations
The crystallization studies of the foldamers resulted in 17 dif-
ferent crystal structures. All of the crystal structures obtained
for 1–5 were solvates, which indicates that folded molecules
cannot pack very efficiently due to their complex and awkward
shape. In the structures of foldamers 1–3 and 5 at least one of
the pyridine-2,6-carboxamide units adopts the predicted
folded @ conformation (Scheme 1; Table 1; Table S3 in the Sup-
Table 1. 17 solvate structures of the foldamers 1–5 and the conforma-
tions of the pyridine centers
Structure
Center P1
@
Center P2
@
Notes
1-DMA-H2O
1-MeCN-H2O
1-DMF-H2O
1-MeOH
1-DMSO
1-DCM
2-MeCN
2-EtOAc
2-DCM
2-DMSO
3-DMA
3-DMSO
4-EtOAc
5-Ac
isomorphous
Scheme 1. Chemical structures of the foldamers 1–5 including notifications
of benzene and pyridine rings and numbering of C=O and NH groups. The
spacer groups are circled with dotted lines. A schematic presentation of two
observed folding patterns around the pyridine-2,6-dicarboxamide center
(bottom row).
@
@
@
S
@
@
@
@
S
@
isomorphous
@
@
@
@
S
S
S
@
@
S
oligoamide foldamers possess great potential as structural and
functional mimics of enzyme catalysts.
trans
cis
In our current study, we show that the oxyanion hole motif
and the folding patterns are preserved, when the size of the
foldamer increases and the number of pyridine-2,6-dicarboxa-
mide units is doubled or tripled (Scheme 1). The spacer unit
separating the pyridine-2,6-dicarboxamide units affects the
overall folding of the foldamer by preventing certain geome-
tries and/or inducing helicity or compact conformations by
participating in intramolecular hydrogen bonding. This indi-
cates that conformational adaptability of foldamers can be
controlled with suitable spacers without losing the essential
folding motifs and potential binding sites, such as oxyanion
hole motif.
@
@
isomorphous
5-DCM
5-DMF
5-CHCl3
S
@
porting Information) by 2–3 hydrogen bonds from the adja-
cent C=O group to NH groups next to the pyridine ring, thus
retaining the desired oxyanion hole motif. Foldamer 4 is the
only exception to this as both pyridine-2,6-dicarboxamide cen-
ters are in a more open S conformation.
Results and Discussion
Foldamer 1
A series of five oligoamide foldamers (7–9 aromatic rings) were
synthetized by applying the procedures described in our previ-
ous papers[18–20] (see the Supporting Information for details).
The conformational features and the stability of the fold and
Altogether six single-crystal structures of the foldamer 1 were
obtained (see the Supporting Information for crystallization de-
tails), but only two variations of overall conformation were
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set R44(20)) and further to chains formed by these pairs
(NH1···Ow, graph sets C22(13) and R44(20); Figure 1). The pairing is
enhanced by p–p stacking between the pyridine centers P1 of
the adjacent molecules. The solvent (DMA, MeCN, or DMF) is
hydrogen bonded to the outer groove of the fold (NH6···Sol-
vent; D(2) motif). The difference of the crystal structures of iso-
morphous structures and 1-DMF-H2O comes from the efficien-
cy of packing. In 1-DMA-H2O and 1-MeCN-H2O there is p–p
stacking between the end phenyl rings (D), which is prevented
in the 1-DMF-H2O structure by the inclusion of one extra sol-
vent molecule between the rings (see the Supporting Informa-
tion, Figure S2). In 1-DMSO solvate the intermolecular hydro-
gen bonds orient to two DMSO molecules, which fill the inter-
stice between the foldamers. The foldamers still pack into
layers: the grooves of the folds assemble parallel to each other
and interact through p–p interactions (see the Supporting In-
formation, Figure S2).
In 1-DCM and 1-MeOH solvates there are direct hydrogen
bonds between the foldamers as two intermolecular hydrogen
bonds between NH1 and C=O2 groups (R44(14) motif) connect
the foldamers into pairs. In case of the more open @/S confor-
mation of the 1-DCM structure, this leads to a niche for a dis-
ordered solvent molecule inside the pair of the awkwardly
shaped molecules (Figure 1). In 1-MeOH solvate, the pairs are
further connected to chains through solvent-mediated hydro-
gen bonds from MeOH to NH6 of one foldamer and C=O4 of
the next pair (see the Supporting Information, Figure S2).
Foldamer 2
Figure 1. Conformations and schematic presentations of folding of 1-DMA-
H2O (top left) and 1-DCM (top right). Crystal packing of 1-DMA-H2O (middle)
and 1-DCM structures (below) showing the inclusion of solvents and inter-
molecular hydrogen-bonding motifs (turquoise lines and graph set notifica-
tions). Nonbonding hydrogen atoms and disorder have been omitted for
clarity and solvents are shown with with a space fill model.
Four different single-crystal structures of foldamer 2 were ob-
tained from acetonitrile, ethyl acetate, dichloromethane, and
DMSO solutions. Two of these structures, the MeCN and the
EtOAc solvates (2-MeCN and 2-EtOAc), are isomorphous and
the differences between all four structures are minor. In all
four structures, the P2 pyridine-2,6-dicarboxamide center
adopts an @-fold, whereas the P1 center is in S-fold (Figure 2
and Figure S3 in the Supporting Information). The overall con-
formation is a compact, almost helical structure in which two
pyridines have parallel displaced p-interactions with each
other and the end of the S-fold surrounds the helical part. The
similarities are facilitated by the unsymmetrical linker unit, in
which the C=O4 group prefers to form the S-fold by hydrogen
bonds to the NH groups of the pyridine-2,6-dicarboxamide
unit P1 (graph set motifs S(6) and S(12)). The outmost NH1 fin-
ishes the S-fold by a hydrogen bond to the O2 (S(7) motif; 2-
DCM) or to O5 of the pyridine-2,6-dicarboxamide center P2
(S(20) motif; other solvates), which leads to a slight difference
in the orientation of the outmost phenyl ring. The @ folds
around the pyridine center P2 in isomorphous 2-MeCN and 2-
EtOAc structures and in 2-DCM solvate are based on typical
three hydrogen bonds between the outmost C=O group (O7)
and NH groups of the P2 unit (S(7) and S(13) motifs) and to
the next NH group (NH4) in the linker (S(16) motif). In 2-DMSO,
however, the third hydrogen bond is missing as the amide
NH4 is hydrogen bonded to solvent (D(2) motif).
observed. The isomorphous structures of 1-DMA-H2O and 1-
MeCN-H2O adopt an overall tight helical conformation with
both pyridine centers in an @ fold (@/@; Figure 1). The confor-
mations of 1-DMSO, 1-MeOH, and 1-DMF-H2O solvates are also
similar with both pyridine centers in @ fold (see the Support-
ing Information, Figure S1, for an overlay of all @/@ structures).
In these structures either one (1-MeOH) or both (1-DMA-H2O,
1-MeCN-H2O, 1-DMF-H2O, and 1-DMSO) of the outmost phenyl
rings have a CH–p interaction with the spacer phenyl ring. 1-
DCM solvate has a less folded structure, as one of the pyridine-
2,6-dicarboxamide centers adopts an open S fold, whereas the
other one is in an @ fold (@/S; Figure 1). The outmost phenyl
ring of the @ folded part of the molecule interacts with the
spacer phenyl ring by a CH–p interaction (3.041 ꢁ) like in the
other structures.
The crystal packing in all structures of foldamer 1 is based
on intermolecular hydrogen bonding. In isomorphous
@/@-structures (1-DMA-H2O and 1-MeCN-H2O) and in the 1-
DMF-H2O structure, two water molecules connect two foldam-
ers into pairs by bifurcated hydrogen bonds (OHw···O=C; graph
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Figure 2. Conformations of 2-MeCN (top left) and an overlay presentation of
the structures of 2-DMSO (orange) and 2-DCM (green; top right). The crystal
packing of 2-DCM (middle) and 2-DMSO (bottom). Solvents are shown with
a space-filling model and hydrogen bonds with turquoise bonds. Nonbond-
ing hydrogen atoms and disorder have been omitted for clarity.
Figure 3. Solid-state conformations and crystal packing of 3-DMA (top left
and middle) and 3-DMSO (top right and bottom) showing the trans and cis
orientations of pyridine-2,6-dicarboxamide centers in respect to a spacer
unit. Non-bonding hydrogen atoms and disorder have been omitted for
clarity and the solvents are shown with a space-fill model.
Also in the case of foldamer 2, the crystal packing is based
on the pairing of molecules through direct intermolecular hy-
drogen bonding (NH7···O6; R22(14) motif; Figure 2). The solvents
are located inside the cleft formed by two hydrogen-bonded
pairs of foldamers (DCM) or interstice in the crystal lattice
(EtOAc and MeCN) (see the Supporting Information, Figure S4).
The exception to pairwise hydrogen bonding is the DMSO sol-
vate, as DMSO disrupts this pattern and the intermolecular hy-
drogen bonds to two DMSO molecules (from NH7 and NH4 to
O10A and O30A; D(2) motifs).
the crystal structures are indeed distinctly different (Figure 3).
In 3-DMSO solvate the pyridine-2,6-dicarboxamide units of the
molecule turn on the same side of the spacer (cis) giving a fol-
damer a bowl-like overall conformation with a solvent accessi-
ble cavity occupied by a disordered DMSO which is hydrogen-
bonded to NH4. The foldamer molecules are connected in a
head-to-tail manner into continuous chains (NH8···O6; C(11)
motif and NH1···O4; C(16) motif; Figure 3). In 3-DMA solvate,
the pyridine-2,6-dicarboxamide units are oriented on the differ-
ent sides of the linker group (trans), which leaves the center of
the foldamer open for interaction with solvents and enables
the packing into ladder-like chains through direct intermolecu-
lar hydrogen bonding (O3···HN8) on one side and via solvent-
mediated hydrogen bonds on the other side (NH1···Os···HN5;
Figure 3). Two DMA molecules are nested in between the di-
rectly hydrogen-bonded foldamer pair and have intermolecular
hydrogen bonds to the NH4 of the foldamers (NH4···Os). The
conformational difference between the two solvates may be
caused by the efficiency of packing, as nearly planar DMA ena-
bles denser packing than DMSO, as well as the hydrogen-
bonding preferences in each case.
Foldamer 3
Two single-crystal structures of the foldamer 3 were obtained
from crystallizations in DMA and DMSO solution. Both struc-
tures have two @-folded pyridine-2,6-dicarboxamide units with
typical hydrogen-bonding patterns (S(7) and S(13) motifs), but
the foldamer 3 does not have an overall helical conformation
because the linker group constituting of three ortho-substitut-
ed phenyl rings is fairly rigid, thus separating the ends of the
foldamer as independent folds, which can orient differently in
respect to the spacer unit. The two conformers observed in
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Foldamer 4
hydrogen bonds (NH8···O7) and these pairs are further con-
nected to the chains of pairs through hydrogen bonds
(NH1···O6) which connects each foldamer to three other fol-
damers; to one with two hydrogen bonds, to two with one hy-
drogen bond.
The only crystal structure of foldamer 4 was obtained from
ethyl acetate. The conformation is symmetrical with two S
folds oriented on the opposite sides of the central phenyl ring.
The meta-substituted spacer of foldamer 4 is not as planar and
rigid as the ortho-substituted analogue of the foldamer 3,
which might be a reason for the preference of S folds. The
conformation is stabilized to a compact entity by an additional
In 5-CHCl3 solvate, however, the overall conformation is less
folded and bowl-like, as pyridine-2,6-dicarboxamide center P1
adopts an S fold. The bowl-shaped molecule is occupied by
the ends of the neighboring foldamers and solvents. The mu-
intramolecular hydrogen bond from the outmost carbonyl C= tually included assembly is further strengthened by intermolec-
O (O1 and O8) to the central NH groups (NH5 and NH4, re-
ular hydrogen bonds between a pair of foldamers occupying
each other’s cavities (H8N···O7; R22(14) motif). The hydrogen-
bonded pairs pack together in a 2D plane by p-stacking from
the sides of the bowls. The gaps between the 2D planes are
filled with disordered solvents.
spectively). The packing of 4-EtOAc (Figure 4) is based on
Structural comparison of the compounds
The solid-state structures of a series of foldamers 1–5 show
that the hydrogen bonding and the folding patterns of the
pyridine-2,6-dicarboxamide units are reliably the same as ob-
served with shorter oligoamide foldamers with only one pyri-
dine-2,6-dicarboxamide unit.[18–20] The role of the spacer unit
for the overall conformation becomes evident, when compar-
ing foldamers 1–3. In foldamer 3 the rigidity of the spacer sep-
arates the pyridine centers to act like individual folding centers
and hinders the formation of S folds in the solid state. The po-
sition of individual centers with respect to relatively long,
linear, and rigid spacers may be either cis or trans, which indu-
ces either a Z-shaped or bowl-shaped overall conformation, re-
spectively. Both these conformations have an intrinsic niche or
cavity for binding small guests, which is seen as solvent inclu-
sion. In foldamers 1 and 2 the spacer is shorter and such indi-
vidual behaviour of pyridine-2,6-dicarboxamide units is not
possible. In foldamer 1 the short phenyl spacer plays only a
minor role in conformational preferences and four different
crystal forms with two distinctly different overall conformers
are hence likely caused by packing effects. The foldamer 2, on
the other hand, has an unsymmetrical spacer which exclusively
favors the @/S conformation in the solid state and the differen-
ces in overall conformations of different crystal structures are
only minor (Figure 2).
Figure 4. Conformation and crystal packing of 4-EtOAc. The conformation of
the foldamer 4 is very compactly folded and the solvents fill the interstice
between the chains of foldamers. Nonbonding hydrogen atoms and solvent
disorder have been omitted for clarity. Solvents are shown with a space-fill
model and hydrogen bonds with turquoise.
continuous chains formed by an intermolecular hydrogen
bond from O3 and O6 to NH4 and NH5 of the neighboring fol-
damers. Two disordered EtOAc molecules fill the interstice be-
tween the chains.
Changing the substitution positions of the central phenyl
ring from ortho to meta in foldamer 4 increases the flexibility
of the molecule which changes both the overall conformation
and behaviour of pyridine-2,6-dicarboxamide units. The more
flexible linker part enables the formation and stabilization of S-
folds by additional intramolecular hydrogen bonds. The overall
conformation, however, is relatively compact. It is not possible
to make any definite conclusions about the conformational
stability and prevalence as only one crystal structure of folda-
mer 4 was obtained.
Introducing a third pyridine-2,6-dicarboxamide unit as a
spacer in foldamer 5 changes the intramolecular hydrogen
bonding significantly, which is seen as a reduction of number
of hydrogen bonds from three to two in @-folded conforma-
tions of pyridine centers P1 and P2 (Figure 5). The foldamer 5
Foldamer 5
Four single-crystal structures of the foldamer 5 were obtained,
three of which (5-Ac, 5-DCM and 5-DMF) are isomorphous and
nearly helical structures with the outmost pyridine-2,6-dicar-
boxamide units adopting an @ fold. In this case, the fold is sta-
bilized by only two hydrogen bonds (S(7) and S(13) motifs) as
additional hydrogen bonds are prevented because of hydro-
gen bonds to the pyridine-2,6-dicarboxamide center P3 at the
spacer unit. This center facilitates a significantly helical-type of
folding by forming a third center for intramolecular hydrogen
bonds. The helical folding of the foldamer leaves several hy-
drogen-bonding groups exposed at the outer surface of the
fold, which enables the formation of a complex intermolecular
hydrogen-bond network. The foldamers form pairs with two
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foldamer 1 and 5 both have helical solvate structures and one
more open structure. The difference between the two confor-
mations observed is probably due to solvent interactions and
packing.
Solution-state studies
Solution-state studies were performed for foldamers 1–5 to
compare their solution-state conformations with their solid
state structures and to see, if the solid state motifs are ob-
served in solution. To this end, a suite of 2D of homo- and het-
eronuclear correlation experiments was employed in addition
1
to 1D H and 13C NMR experiments to yield a complete reso-
nance assignment to all foldamers (see the Supporting Infor-
mation for details). 2D NOESY spectra were measured to
obtain through-space internuclear connectivities for conforma-
tional analysis. [D6]DMSO was used as the solvent in all sam-
ples. The 2D NOESY spectra show that the foldamers adopt
folded conformations in the solution and in the case of fol-
damers 3–5, the data is fairly consistent with conformations
seen in the crystal structures.
In the case of foldamer 1, the correlations show that the
compound has a folded structure, but the correlations fit both
solid-state conformations equally well (see the Supporting In-
formation, Table S3, for a detailed list of correlations). Two of
the correlations, however, support the conclusion that the fol-
damer is folded also in solution (Figure 7a). The correlation a
shows an interaction between the hydrogen atoms of aromatic
ring A or D and the amide NH3 or 4. This correlation is possible
in both @/@- and S/@-conformations although based on the
crystal structures 1-DMSO and 1-DCM the correlation is stron-
ger in the @/@-conformation. Another observation supporting
the conclusion about a folded conformation is the correlation
b, which is an interaction between the hydrogen atoms of aro-
matic ring B or C and pyridine ring P2 or P1. This correlation is
also possible in both @/@- and S/@-conformations.
Figure 5. Conformations and packing of 5-Ac (top left and middle) and 5-
CHCl3 (top right and bottom). Aromatic hydrogen atoms have been re-
moved for clarity.
The solution-state conformation of foldamer 2 is likely to de-
viate from the one observed in the solid state. The correlations
of the one half of the foldamer match the solid-state confor-
mation, while the other end does not correspond to any of
the interactions seen in the crystal structures. The deviating
correlations a–e are all located at the pyridine center adopting
the S-conformation in the crystal structure (Figure 7b; left side
of the molecule, red lines). If the solution-state conformation
corresponded to the crystal structures, the correlation a
should be found between NH1 and hydrogen atoms on the
opposite side of the aromatic ring S2 (para position to NH4
and NH5). Instead, the correlation is seen between NH1 and S2
hydrogen atoms next to the amide groups. The same differ-
ence is observed with the correlation c (NH2) with respect to
the orientation of ring S2. Correlation b between NH2 and aro-
matic ring A hydrogen atoms is not possible in the crystalline-
state conformation, which indicates a different orientation to-
wards the end of the molecule compared with the crystal
structures. Correlation d between NH2 and aromatic ring D hy-
drogen atoms and correlation e between the NH3 and aromat-
ic ring A hydrogen atoms further confirm the tighter and more
Figure 6. Comparison of the different conformations of foldamer 1 (green)
and foldamer 5 (orange): a) Comparison between the helical structures of 1-
DMA-H2O and 5-Ac. b) Comparison between the open structures of 1-DCM
and 5-CHCl3.
can be seen as an extended version of foldamer 1 and they
indeed share similar types of conformations (Figure 6). The
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3-DMSO. The correlation f, however, differs from the distances
of the crystal structures. This can be explained by permanent
hydrogen bonding to solvent DMSO in the crystal structure.
Another minor difference between the solution and solid-state
structures is the stronger correlation a between NH1 and NH3
in solution. The NMR spectra also show some peaks, which
could be identified as an additional solution-state conforma-
tion. No clear NOE correlations, however, that could be used to
determine the features of this conformation were identified.
The characterization of the solution-state conformation of
foldamer 4 was difficult because of many overlapping interac-
tions and the presence of a second minor conformation in so-
lution. Correlations a–d from NH2/7 and NH3/6 protons to aro-
matic hydrogen atoms still indicate a folded conformation (Fig-
ure 7d, Table S4 in the Supporting Information). Due to over-
lapping peaks of S2 and P1/P2 hydrogen atoms and S2 and A/
D hydrogen atoms, however, it is not possible to unambigu-
ously determine the conformations or how well they corre-
spond to the solid-state structure.
NOESY spectra of foldamer 5 show several correlations that
confirm
a folded solution-state conformation (Figure 7e,
Table S4 in the Supporting Information). Most of these correla-
tions (b–f) are in agreement with both conformations observed
in the crystal structures, while two correlations (g=P1–S2 and
h=P3–D) narrow the conformation to resemble the @/@ struc-
ture, which is also more prevalent in the solid state. Correlation
a, however, does not correspond to any of the interactions
seen in the crystal structures. This suggests that although the
solution-state conformation resembles the helical @/@ confor-
mation, it is still slightly different with respect to the orienta-
tion of the end of the molecule in the solid state. Alternatively,
fast conformational exchange on the NMR timescale may take
place between different structures.
Figure 7. Selected NOE correlations of foldamers 1–5 shown in relation to
relevant crystal structures. In symmetric foldamers only one set of correla-
tions is shown. Correlations are marked with green if they are seen in the
crystal structure and with red if they are not seen in the crystal structure.
Conclusion
Foldamers 1–5 with two or three pyridine-2,6-dicarboxamide
centers and varying linker groups as their structural compo-
nents show reliable folding patterns and stability of the de-
sired oxyanion hole motif with respect to pyridine-2,6-dicar-
boxamide centers both in solution and in the solid state. Addi-
tionally, the number of pyridine-2,6-dicarboxamide centers can
be multiplied without losing the essential structural features.
The overall conformation of the foldamer varies depending on
the linker unit. Foldamer 1 and foldamer 5, which is an extend-
ed version of 1, have similar ubiquitous helical conformations
(@/@), but also an alternative, more open structure in the solid
state (@/S), probably caused by solvent effects during the crys-
tallization. In the case of foldamer 1, no conclusive information
about the solution conformation could be obtained, whereas
in the case of foldamer 5, the prevalent conformation in solu-
tion appears to be @/@. The unsymmetrical linker unit of folda-
mer 2 directs the foldamers to have similar compact helical
conformations in the solid state, whereas NOESY spectra indi-
cate a more folded @/@ type of conformer in solution. The
flexibility of the meta-substituted linker group in foldamer 4
folded orientation of the molecule end in solution. Correlations
f–i (f=NH4—D; g=NH5—S1; h=NH5—D; i=NH6—S1) corre-
spond well to the @-folded pyridine-2,6-dicarboxamide center
of the crystal structures (Figure 7b; the right side of the mole-
cule, green lines). These results indicate that the conformation
of foldamer 2 in solution is probably @/@ instead of @/S that
is exclusively seen in all crystal structures.
The NOE correlations a—f of foldamer 3 agree well with the
@ folds of the crystal structures (Figure 7c, Table S4). Addition-
ally, a strong correlation (g) between the aromatic hydrogen
atoms of rings B and S2 suggests that the structure resembles
the crystal structure 3-DMSO in which the pyridine centers are
in cis orientation with respect to the spacer. Given that DMSO
was used as a solvent both in the solution and solid-state stud-
ies, the observed similarities between the crystal structure and
the NMR data are somewhat expected. Based on the roughly
similar correlations of symmetrically equivalent bonds (see the
Supporting Information, Table S4), the conformation is nearly
symmetrical in solution as in the solid-state structure of
enables
a
compact S-shaped folded conformation with
Chem. Eur. J. 2017, 23, 1 – 11
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Table 2. Crystal data and data collection parameters. The data of the isomorphous structures and the data of the structures 1-DMF-H2O and 1-MeOH are
presented in the Supporting Information.
1-DMA-H2O
1-DMSO
1-DCM
2-MeCN
2-DCM
formula
M [gmolÀ1
C46H34N8O6·C4H9NO·H2O
899.95
C46H34N8O6·2(C2H6OS)
951.07
C46H34N8O6·CH2Cl2
879.74
C53H39N9O7·1.5(C2H3N)
975.51
C53H39N9O7·CH2Cl2
998.86
]
crystal system
space group
V [ꢁ]
V [ꢁ]
V [ꢁ]
triclinic
¯
P1
monoclinic
P21/c
16.1850(4)
20.8963(3)
15.4316(4)
90
117.981(3)
90
4609.0(2)
4
monoclinic
P21/c
21.4224(4)
8.59628(14)
23.4432(5)
90
98.435(2)
90
4270.44(14)
4
triclinic
¯
P1
triclinic
¯
P<1
11.7500(4)
12.2120(6)
17.0988(6)
105.575(4)
99.439(3)
100.534(4)
2263.99(17)
2
9.6033(3)
14.7566(6)
18.3628(10)
66.954(4)
83.106(4)
82.514(3)
2367.33(19)
2
11.7016(3)
12.8693(3)
17.0721(5)
70.042(2)
86.966(2)
76.8250(10)
2352.04(11)
2
a [8]
b [8]
g [8]
V [ꢁ3]
Z
1calcd [gcm3]
1.320
0.092
944
1.371
1.587
1992
1.368
0.213
1824
1.369
0.761
1018
1.410
0.205
1036
m [mmÀ1
F(000)
]
crystal size/[mm]
2qmax [8]
T [K]
0.18ꢂ0.10ꢂ0.10
58.412
173
0.22ꢂ0.10ꢂ0.02
148.778
123
0.26ꢂ0.08ꢂ0.08
50.698
173
0.28ꢂ0.12ꢂ0.02
153.886
123
0.32ꢂ0.14ꢂ0.14
57.28
173
radiation
MoKa
CuKa
MoKa
CuKa
MoKa
l [ꢁ]
0.7107
mirror
multiscan
CrysAlisPro
ShelXle
30246
10756
650
0.0269
1.5418
mirror
multiscan
CrysAlisPro
ShelXle
27685
9190
635
0.0331
0.7107
mirror
multiscan
CrysAlisPro
ShelXle
13910
7760
614
0.0236
1.5418
mirror
multiscan
CrysAlisPro
ShelXle
15013
9464
683
0.0265
0.71073
graphite
multiscan
Denzo-SMN 1997
SHELXL-97
23446
12030
670
0.0449
monochromation
absorption correction
abs. cor. program
refinement programs
meas. reflns
indep. reflns
parameters
Rint
R1 [I>2s(I)]
wR2 [I>2s(I)]
GooF on F2
d. peak/ hole/[eꢁÀ3
0.0487
0.1071
1.033
0.217, À0.242
0.0379
0.0956
1.032
0.499, À0.375
0.0495
0.1006
1.020
0.487, À0.468
0.0430
0.1065
1.037
0.255, À0.407
0.0648
0.1454
1.070
0.463, À0.732
]
3-DMA
3-DMSO
4-EtOAc
5-Ac
5-CHCl3
formula
C60H44N10O8·2(C4H9NO)
1207.29
triclinic
C60H44N10O8· C2H6OS
1111.18
triclinic
0.5C60H44N10O8· 0.5(C4H8O2)
1121.15
monoclinic
C2/c
30.8937(6)
8.3612(2)
22.6973(4)
90
108.423(2)
90
5562.4(2)
4
C59H43N11O8· 0.16(C3H6O)
1043.57
triclinic
C59H43N11O8· CHCl3
1153.41
triclinic
M [gmolÀ1
]
crystal system
space group
V [ꢁ]
V [ꢁ]
V [ꢁ]
¯
P1
¯
P1
¯
P1
¯
P1
13.4719(11)
16.0247(8)
16.1687(13)
115.068(6)
104.451(7)
93.334(5)
3007.8(4)
2
9.4954(3)
14.7041(5)
20.5624(5)
80.211(2)
77.542(2)
75.175(3)
2689.91(15)
2
11.8122(4)
12.4913(4)
18.8041(6)
91.549(3)
108.190(3)
102.989(3)
2554.26(14)
2
13.0605(2)
13.21636(19)
22.8823(3)
79.6980(12)
82.4084(12)
63.0169(16)
3357.19(10)
2
a [8]
b [8]
g [8]
V [ꢁ3]
Z
1calcd [gcm-3]
1.333
0.749
1268
1.372
1.119
1160
1.339
0.093
2344
1.357
0.764
1086
1.108
1.647
1192
m [mmÀ1
F(000)
]
crystal size [mm]
2qmax [8]
T [K]
0.227ꢂ0.145ꢂ0.44
152.686
123
0.216ꢂ0.176ꢂ0.100
154.112
123
0.360ꢂ0.222ꢂ0.134
28.950
123
0.20ꢂ0.10ꢂ0.08
153.988
123
0.343ꢂ0.168ꢂ0.138
153.984
123
radiation
CuKa
CuKa
MoKa
CuKa
CuKa
l [ꢁ]
monochromation
1.5418
mirror
1.5418
mirror
0.71073
mirror
1.5418
mirror
1.5418
mirror
absorption correction
abs. cor. program
refinement programs
meas. reflns
indep. reflns
parameters
analytical
CrysAlisPro
ShelXle
17709
11797
877
analytical
CrysAlisPro
ShelXle
20331
11025
810
multiscan
CrysAlisPro
ShelXle
18883
6458
477
multiscan
CrysAlisPro
ShelXle
40504
10625
765
analytical
CrysAlisPro
ShelXle
69781
14337
791
Rint
0.0306
0.0249
0.0138
0.0266
0.0305
R1 [I>2s(I)]
0.0513
0.0491
0.0435
0.394
0.0751
wR2 [I>2s(I)]
GooF
d. peak/ hole/[eꢁÀ3
0.1323
1.047
0.322, À0.348
0.1311
1.019
1.021, À0.314
0.1149
1.062
0.514, À0.230
0.1007
1.025
0.260, À0.257
21.63
1.045
0.489, À0.509
]
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ideal position, and included in the structure factor calculations.
SQUEEZE was used on structure 5-CHCl3 to remove severely disor-
dered CHCl3 molecules that could not be modelled. Details of the
crystal data and the refinement are presented in the Supporting In-
formation. Graph set symbols[25] for hydrogen bonding were as-
signed and used to compare the hydrogen bonding between the
different crystal structures. CCDC 1555244, 1555245, 1555246,
1555247, 1555248, 1555249, 1555250, 1555251, 1555252, 1555253,
1555254, 1555255, 1555256, 1555257, 1555258, 1555259 and
1555260 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
additional intramolecular hydrogen bonds in contrast to the
rigid ortho substituted spacer of foldamer 3 which enables the
@-folded pyridine-2,6-dicarboxamide units to orient in either
trans or cis in relation to the center. The flexibility of foldamer
4 was also seen in solution, as no conclusive conformational
information could be obtained and a possibility of alternative
conformers was observed in the NMR spectra.
Our future studies will orient toward utilizing extended fol-
damers as anion hosts utilizing their conformational predicta-
bility, and on the other hand, conformational adaptability with-
out losing the binding-site structure, which creates a suitable
binding site for, for example, halogen anions.[24] Additionally,
anion binding capacity together with the resemblance to oxy-
anion hole motifs of enzymes provides an excellent basis for
future studies as enzyme-mimicking organocatalysts.
Acknowledgements
The financial support of Academy of Finland (proj. no. 257246
and 288235) is gratefully acknowledged. We thank B.Sc. Annii-
na Aho, M.Sc. Minna Kortelainen and M.Sc. Jussi Ollikka for the
help in the synthesis, Spec. Lab. Technician Elina Hautakangas
for the elemental analysis and Spec. Lab. Technician Esa
Haapaniemi for the part of the NMR measurements.
Experimental Section
Materials and methods
The synthesis and characterization details of foldamers 1–5 are pre-
sented in the Supporting Information. All starting materials were
commercially available and used as such unless otherwise noted.
Analytical grade solvents and Millipore water were used for crystal-
lizations and slurries. NMR spectra were measured with a Bruker
Avance DPX250 MHz, Bruker Avance DRX 500 MHz, or with Bruker
Avance III HD 800 MHz spectrometer and the chemical shifts were
calibrated to the residual proton and carbon resonance of the deu-
terated solvent. Melting points were measured in an open capillary
using a Stuart SMP30 melting-point apparatus and are uncorrect-
ed. ESI-TOF mass spectra were measured with a LCT Micromass
spectrometer.
Conflict of interest
The authors declare no conflict of interest.
Keywords: foldamers
·
hydrogen bonding
·
molecular
folding · NMR spectroscopy · X-ray crystallography
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General procedure for crystallization
5–50 mg of foldamers were dissolved in 0.1–6 mL of solvent. Heat-
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Manuscript received: August 24, 2017
Accepted manuscript online: October 2, 2017
Version of record online: && &&, 0000
[21] S-Conformation is based on the hydrogen bonds between C=O and
pyridine-2,6-dicarboxamide NHs similar to the @ conformer, but the
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FULL PAPER
Predictability and persistence of fold-
ing: Aromatic oligoamide foldamers
fold into helices and more open, folded
conformations depending on the identi-
ty of the central linker and solvent con-
ditions (see figure). Pyridine-2,6-dicar-
boxamide units add the predictability of
the conformation and lead to good per-
sistence and comparability of conforma-
tion in solution and in the solid state.
&
Supramolecular Chemistry
R. Annala, A. Suhonen, H. Laakkonen,
P. Permi, M. Nissinen*
&& – &&
Structural Tuning and Conformational
Stability of Aromatic Oligoamide
Foldamers
Chem. Eur. J. 2017, 23, 1 – 11
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