Z-Formamidoximes in molecular folding and macrocycles

Article abstract of DOI:10.1039/c1ob06378b

The formamidoxime configurational Z isomer coupled with the pyridylbiscarboxamide conformational codon were used to fold planar, curved structures. When embedded into macrocycles, this folded motif promotes dimerization through π-π stacking and hydrogen-b

Full text of DOI:10.1039/c1ob06378b

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Z-Formamidoximes in molecular folding and macrocycles†‡
Weiwen Zhao, Ruiyao Wang and Anne Petitjean*
Received 12th August 2011, Accepted 9th September 2011
DOI: 10.1039/c1ob06378b
The formamidoxime configurational Z isomer coupled
with the pyridylbiscarboxamide conformational codon were
used to fold planar, curved structures. When embedded
into macrocycles, this folded motif promotes dimerization
through p–p stacking and hydrogen-bonding and the forma-
tion of tubules akin to molecular channels in the solid state.
assembly of the Z-Formamidoxime-Pyridyl-biscarboxamide-Z-
Formamidoxime (FPF) triad, where the amide hydrogen atoms
were anticipated to organize the three consecutive units into a
U-shape overall segment (Scheme 1).
Solution-state studies
1
In solution, the H NMR signals of the three molecules reflect
Inspired by the importance of molecular folding in nature and its
consequences on biological functions1 and pathologies,2 chemists
have been very active at creating new folding motifs coding for
particular structures (‘folding codons’).3 As in peptide secondary
structures, hydrogen-bonding has played a significant role in
these developments.4 Surprisingly, despite their significance in
biological targeting,5 self-assembly,6 and coordination chemistry,7
amidines and formamidines have found few applications in molec-
ular folding, although they offer very rich H-bonding patterns
and conformational/configurational control.8 More specifically,
formamidines derived from alkoxyamines (‘formamidoximes’,
Scheme 1) have, to our knowledge, never been applied to molecular
folding prior to our work. This is quite intriguing, as their Z-
isomer has been consistently characterized in the solid state
as locked in a 5-membered H-bonded ring.9 In the present
communication is reported the first instance of folded structures
based on Z-formamidoxime subunits that are conjugated to the
well-known pyridylbiscarboxamide4a,10 and form planar segments
prone to dimerization through p–p stacking. Molecular folding
based on this conjugate motif is illustrated on an open-structure
(ZZ-open) as well as 18-atom and 54-atom macrocycles (ZZ-M
similar electronic environments. The pyridyl 3Py(A) protons (see
Scheme 1 for numbering) are deshielded by the proximity of the
carboxyl oxygen (d(3Py(A)) ~8.5 ppm), while the formamidine Hf
proton appears as a sharp doublet with a large, trans, coupling
constant (3J = 10 Hz) to the NH proton at a chemical shift
which is typical for Z-N-acylformamidoxime motifs (d(Hf) ~7.8
ppm), and very different from their E counterpart.11b The NH
group coupled to Hf appears as a doublet with the same large
coupling constant, and at a chemical shift consistent with H-
bonding to both the pyridine nitrogen and the formamidoxime
oxygen11 (d(NH) ~9.7 ppm in pyridylbisaryl-carboxamides with
H-bonding to the central pyridine nitrogen only10a). Based on
chemical shifts, it appears as though the intramolecular H-bond
is stronger in the more rigid ZZ-M (Fig. 1, middle spectrum).
1
and Tri(ZZ-M)) respectively, Scheme 1) and was studied by H
NMR spectroscopy and crystallography.
The syntheses of ZZ-open, ZZ-M and Tri(ZZ-M) are described
in the supporting information‡ (and will be discussed in a separate
publication specifically examining the strategies of condensation
and cyclization involving formamidoximes).11 The present article
focuses on the folding, molecular structure and resulting self-
Fig. 1 1H NMR of ZZ-open (300 MHz), ZZ-M (500 MHz), and
Tri(ZZ-M) (500 MHz), from bottom to top, in CDCl3, 25 ◦C (see Scheme
1 for molecule formula and proton numbering).
Interestingly, chemical shifts in ZZ-M are about the same in
CDCl3 and in CD3OD (except for the NH signal which disappears
in CD3OD).‡ In particular Hf remains at 7.9 ppm suggesting that
the Z-configuration of the C N double bond is retained in a
competing H-bonding solvent.§
Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, ON
K7L3N6, Canada. E-mail: anne.petitjean@chem.queensu.ca
† This article is part of an Organic & Biomolecular Chemistry web theme
issue on Foldamer Chemistry.
‡ Electronic supplementary information (ESI) available: Synthetic pro-
cedures and characterizations of formamidoxime macrocycles and open
structure. Stacked plot for 1H NMR spectra of ZZ-open, ZZ-M
and Tri(ZZ-M). CCDC reference numbers 828090 (monoformami-
doxime PyFBn), 837812 (ZZ-M) and 837813 (Tri(ZZ-M)). For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob06378b
Solid-state studies
X-ray diffraction analysis of ZZ-M crystals grown by slow diffu-
sion of diethyl ether into a dichloromethane solution confirmed
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Scheme 1 Open and macrocyclic structures with proton numbering. Highlighted in red are the Z-formamidoxime subunits.
the anticipated planar U-shape organized by the H-bond relay
through the NH group within the FPF triad (Fig. 2).
Bond lengths for the pyridine N ◊ ◊ ◊ H(N) in ZZ-M are
longer than in known pyridyldicarboxamide-based open-ended
intramolecularly H-bonded, and offer an opening akin to a mouth
(Fig. 2a,b). Highlighting the propensity for the FPF motif to stack,
two such dimers further dimerize in an antiparallel manner to form
a quartet channel (Fig. 2c).
foldamers (2.38–2.40 A vs. 2.20–2.22 A10a). However, such effect
may mostly reflect steric constrains associated with macrocycliza-
tion, as observed before.12 Indeed, in a mono pyridylamide-Z-
formamidoxime diad, the pyridine N ◊ ◊ ◊ H(N) H-bond is shorter
A similar behaviour is observed in the solid state for Tri(ZZ-M).
Due to its sheer size, the 54-atom macrocycle is a very intriguing
member of the FPF family, full of information about local folding,
overall compaction (Fig. 3) and self-assembly in the solid state
(Fig. 4 and 5). Although the molecular structure of Tri(ZZ-
M) may be expected to adopt a 3-fold symmetry based on its
˚
˚
(2.238 A).11b,‡ Similarly, H-bonds within the formamidoxime units
˚
of the ZZ-M macrocycle are slightly longer than in the model diad
1
˚
˚
(2.29–2.35 A vs. 2.243 A).
chemical formula (Scheme 1) and symmetrical H NMR (Fig.
ZZ-M macrocycles dimerize in the solid state through a
combination of p–p stacking of their planar FPF segments
and water mediated H-bonding involving the nitrogen atoms of
the extra pyridine rings (noted B in Scheme 1) which are not
1), its crystal structure differentiates one curved FPF motif (1-
loop unit, Fig. 3) from the other two which stack on top of one
another (stacked 2-loop unit, Fig. 3). Such a stacking effect within
a bispyridylcarboxamide-derived macrocycle has precedent.12h
Fig. 2 Crystal structure of ZZ-M; a) side view of the water-mediated dimer, b) focused on the pyridine–water–pyridine H-bonded mouth; c) self-assembly
˚
into a dimer of dimers by p–p stacking. Selected bond distances (A): N1 ◊ ◊ ◊ H6A: 2.406, N1 ◊ ◊ ◊ H2B: 2.397, H6A ◊ ◊ ◊ O3: 2.294, H2B ◊ ◊ ◊ O2: 2.325,
N7 ◊ ◊ ◊ H8C: 2.386, N7 ◊ ◊ ◊ H12B: 2.381, H8C ◊ ◊ ◊ O6: 2.351, H12B ◊ ◊ ◊ O7: 2.344, O1W ◊ ◊ ◊ N4: 2.893, O1W ◊ ◊ ◊ N10: 2.976.¶
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Fig. 3 Crystal structure of Tri(ZZ-M); a) molecular structure seen from the side showing the stacked 2-loop unit, b) view highlighting the folding mode
of the pyridylmethylene hinges; c) molecular structure seen from the top and simplified cartoonꢀ
equivalent FPF motifs (Fig. 1) and CH2 groups electronically
similar to the flexible ZZ-open analog in CDCl3.‡
The planar curved segments of Tri(ZZ-M) and its 2-loop/1-
loop structural pattern (Fig. 3c) allow its self-assembly in the solid
state into a very interesting tubular network. Indeed, infinite 1 D
tubules result from the stacking of alternating 1-loop and 2-loop
units (Fig. 4).
Simultaneously, while the 1-loop subunit of one Tri(ZZ-M)
molecule is included in a 1 D tubule in one direction, its
corresponding 2-loop fragment is involved in another stack in a
perpendicular direction. In other words, each Tri(ZZ-M) molecule
is involved in two 1 D tubules growing in perpendicular directions
(Fig. 5). The overall result is a self-assembled structure into
a compact, crosslinked network of orthogonal linear tubules
(Fig. 5).
Fig. 4 Self-assembly of Tri(ZZ-M) into alternating 2-loop/1-loop tubu-
lar stacks in the solid state.
Within each of the three planar loop structures, the same H-
bonded relay is observed as in the ZZ-M macrocycle, however
˚
with shorter N ◊ ◊ ◊ H(N) distances, ranging from 2.29 to 2.36 A.
Within the formamidoxime as well, the length of the (N)H ◊ ◊ ◊ O
˚
H-bond is decreased in Tri(ZZ-M) (2.17–2.26 A) compared to
ZZ-M, probably due to the larger flexibility of Tri(ZZ-M) and its
resulting ability to adjust its structure to optimize interactions.
When analyzing the folding pattern within Tri(ZZ-M), it is
interesting to note that the two stacked FPF units are not only
held through p–p interactions as in ZZ-M, but also through two
mutual H-bonds between the benzyl-like protons and pyridine
nitrogen atoms of two bridging pyridyl-methylene segments ((C)–
˚
H ◊ ◊ ◊ N(Py) 2.42 and 2.48 A; highlighted in black in Fig. 3a,b).
As in ZZ-M where they bind a water molecule, the pyridine units
constituting the hinge between the rigid segments therefore play
a significant role in the self-organization of these species. These
interactions are, however, probably only expressed in the solid
Fig. 5 Cartoon representation of the Tri(ZZ-M) network of tubules
extending in two orthogonal directions in the crystal.
1
state, as the H NMR signature of Tri(Z-MM) points to three
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In conclusion, the conjugation of the pyridylbiscarboxamide
conformational codon with the Z-formamidoxime configurational
isomer (FPF triad) allows the folding of a curved, planar motif
through a relay of H-bonds. In the present article, this new triad
was applied to the folding of an open-ended structure (ZZ-open)
and two macrocycles (ZZ-M and Tri(ZZ-M)). The curved FPF
motif is planar and prone to p–p stacking, as exemplified in the
solid-state structures of ZZ-M and Tri(ZZ-M). In both cases,
extensive p–p stacking interactions are expressed to form tubular
structures. In this context, the 3 D structure of Tri(Z-MM) crystals
is particularly striking. Because each molecule is involved in two
orthogonal infinite stacks, the solid is composed of a compact,
crosslinked infinite network of tubular substructures. Although
the cavity defined by the curved FPF motif is probably too small
to offer guest inclusion, its organization into uncapped tubules
is inspiring in the perspective of gas storage. Several enlarged
analogs of the pyridyl-biscarboxamide codon have been used
to expand the cavity of folded helices.4a They may similarly be
used in conjunction with the formamidoxime subunit in order to
expand the cavity of the tubular channels reported herein, and
allow significant gas/guest loading, while the orthogonal self-
assembled tubules (assuming they are maintained) should promote
fast exchange in and out of the crystal.
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Acknowledgements
The authors would like to thank Dr. F. Sauriol for assistance
with NMR experiments, and Queen’s University, the National
Science and Engineering Research Council of Canada, the Cana-
dian Foundation for Innovation and the Ontario Ministry of
Research and Innovation (Early Researcher Award) for financial
support.
Notes and references
§ This observation is consistent with what we observed at room temperature
in DMSO-d6 on open structures such as ZZ-open.
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¶ These crystals were grown in the presence of the dimethylammonium
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˚
ꢀ Selected bond distances for Tri(ZZ-M) (A): N16 ◊ ◊ ◊ H15B: 2.364,
H15B ◊ ◊ ◊ O9: 2.209, N16 ◊ ◊ ◊ H17A: 2.306, H17A ◊ ◊ ◊ O12: 2.169,
N4 ◊ ◊ ◊ H5A: 2.293, H5A ◊ ◊ ◊ O4: 2.196, N4 ◊ ◊ ◊ H3B: 2.295, H3B ◊ ◊ ◊ O1:
2.220, N10 ◊ ◊ ◊ H11B: 2.339, H11B ◊ ◊ ◊ O8: 2.242, N10 ◊ ◊ ◊ H11A: 2.326,
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