Supermacrocyclic Assemblies by Hydrogen-Bond Codes of C7-Phenol Pyrazolo and Pyrrolo Derivatives of Adenine

Article abstract of DOI:10.1002/chem.201803429

Hydrogen bond (HB) mediated base pair motifs are versatile scaffolds of diverse supramolecular constructs. Here, we report that two new four- and six-membered supermacrocyclic assemblies with intriguing geometries could self-assemble from two new adenine derivatives, APN (1) and APC (2). The conversion of a conventional HB acceptor, N8 of 1, to a non-conventional HB donor, C8?H of 2, had a pronounced impact on the overall intricate HB network and self-assembly patterns, epitomizing the subtleties in design and exploitation of such base-pair motifs as promising tectons for building supramolecular architectures.

Full text of DOI:10.1002/chem.201803429

A Journal of
Accepted Article
Title: Supermacrocyclic assemblies by Hydrogen-Bond Codes of C7-
Phenol Pyrazolo and Pyrrolo Derivatives of Adenine
Authors: Yingying Chai, Xinglong Zhou, Changfu Li, Beibei Ma, Zhen
Shen, Ridong Huang, Hai Chen, Bojiang Chen, Weimin Li,
and Yang He
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To be cited as: Chem. Eur. J. 10.1002/chem.201803429
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Supermacrocyclic assemblies by Hydrogen-Bond Codes of C7-
Phenol Pyrazolo and Pyrrolo Derivatives of Adenine
Yingying Chai,[a,c,#] Xinglong Zhou,[b,#] Changfu Li,[a,c] Beibei Ma,[a] Zhen Shen,[a] Ridong Huang,[a] Hai
Chen,[a] Bojiang Chen,[a] Weimin Li*[a] and Yang He*[a]
Abstract: Hydrogen bond (HB) mediated base pair motifs are
versatile scaffolds of diverse supramolecular constructs. Here, we
report that two novel four and six-membered supermacrocyclic
assemblies with intriguing geometries can be self-assembled from
two new adenine derivatives, APN (1) and APC (2). The conversion
of a conventional HB acceptor, N8 of 1, to a non-conventional HB
donor, C8-H of 2, has a pronounced impact on the whole intricate
overall HB network and self-assembly patterns, epitomizing the
subtleties in design and exploitation of such base pair motifs as
promising tectons for building supramolecular architectures.
assembling patterns. Herein, the fine details and properties of
these supermacrocyclic assemblies and how subtle structural
parameter alter these novel supramolecular cycles through
different HB codes are described.
Macrocycles have been attractive entities in the physical,
chemical, material and biological sciences.1 Paralleling their
covalent counterparts, supramolecular macrocycles have been
drawing increasing interest for their innate adaptivity.2 HB
information-bearing nucleobases have been judiciously utilized
to build programmable supramolecular cyclic structures, from
trimeric to hexametric macrocycles.3-6 Importantly, the HB
pattern alone in these cases is insufficient to univocally govern
the outcome of the assembly, and the formation of these cyclic
arrays also depends on additional metal ion binding or steric
effects. Pure HB motifs based supermacryocyclic assemblies
were achieved by Lehn and Fenniri, et al, through the
construction of rosette structures via Janus-type GC base
derivatives.7,8 Inspired by these works, we designed and
synthesized a series of Janus-type nucleosides by merging all
four chemical letters of the genetic alphabet into the fused
pyrimido[4,5-d]pyrimidine heterocyclic system. However, our
attempt to build hexameric supermacrocyclic assemblies based
on six-membered Watson-Crick base pairing motif from the
bidentate J-AT series was unsuccessful.9-11
Figure 1. a): The ball-stick representations of conformers 1a and 2a. b): The
overlap graphs of 1a and 2a from side-views (up) and top-views (down).
This prompted us to investigate other adenine analogues in
the pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine
contexts.12 We have found two new adenine derivatives, hereby
refered to as APN (1, A for adenine, P for phenol, N for N8) and
APC (2, C for C8), bearing phenol and tert-butyl groups at C7
and N9 positions (Figure 1a), can form supramolecular ring
structures with different base pair motifs, sizes, shapes and
Due to steric hindrance from the tert-butyl group, two linear
synthetic routes were adopted. For 1, the key pyrazole precursor
8 was obtained following reported procedures.13 For 2, the
pyrrolopyrimidine nucleus 11 was obtained by cyclization from a
dichloropyrimidine precursor.14 The 7-phenol group was
introduced via Suzuki−Miyaura cross coupling with either
bromine or iodine derivatives (Scheme S1, S2). Suitable single
crystals for X-ray diffraction analysis were obtained from
MeOH/H2O (10:1) for 1, with a triclinic P-1 space group, and
from MeOH/CH2Cl2 (2:1) for 2, with a trigonal R-3 space group.
At the monomeric molecular level, a pair of conformational
enantiomers exists in the single crystals of both 1 and 2. Using
the torsion angle τ (C5-C7-C10-C11), we denote the conformers
as 1a (τ = 60.04)/1b (τ = -60.04), and 2a (τ = 51.72)/ 2b (τ = -
51.72) (Figure 1b, S1). Within the unit cell of 1, only two
inversion related conformational enantiomers are present. In
contrast, a total of 18 conformers of 2 are located within the unit
cell, leading to a much larger unit-cell and a high Z’=3. From the
overlap graphs, the molecular shapes of the corresponding
conformers of the two series are found to be almost the same
(Figure 1b, S1). The electron densities of the Watson-Crick
[a]
Y Chai, C Li, B Ma, Z Shen, R Huang, H Chen, B Chen, W Li and Y
He
Precision Medicine Research center, Department of Respiratory and
Critical Care Medicine, West China Hospital, Sichuan University,
Chengdu, Sichuan 610041, China
E-mail: heyangqx@scu.edu.cn (Yang He)
X Zhou
School of Chemical Engineering, Sichuan University
Chengdu, Sichuan, 610041, China
[b]
[c]
Y Chai, C Li
Institute for Nanobiomedical Technology and Membrane Biology,
Sichuan University
Chengdu, Sichuan, 610041, China
# These authors contributed equally to this study
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.2018xxxxx.
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edges (N1 and 6-NH2) and the N3 atoms on the adenine-
pyrimidine rings do not differ much between these two systems
and the electron density differences reside on the pyrazolo and
pyrrolo rings (ab initio 6-31G* level, Figure S2). The UV
absorption spectra are displayed in Figure S3.
group and the Watson-Crick edge (N1 and 6-NH2) of adjacent
molecules (motif IV), which also connects six conformers (-2a-
2b-)3 alternatingly into a second type of hexagonal barrel-like
supermacrocyclic assembly, barrel-2 (vide infra) (Figure S6).
Barrel-1 and -2 line up to form a continuous one dimensional
host channel structure along its own C3-axis (Figure 3).
Figure 3. The HB motifs III, IV and the six-membered macrocycles, barrel-1
and barrel-2, and the schematic representation of the 1D host channel
assembled by them.
Figure 2. a): The HB motifs I, II and the four-membered ring. b): The space-
filling views of four-membered ring and their cross-layered spatial arrangement.
c): The intermolecular interactions of the two neighboring crossed-layered
rings: HB between 6-NH2 and phenol-OH, upper-right and amino-aromatic
type π-π interactions, lower-right.
According to the space-filling representations displayed in
Figure 4, the top views of barrel-1 and -2 both display an
equilateral hexagonal exterior (18.28 Å) and a circular interior
with a diameter of 7.33 Å (Figure 3). It is worthwhile mentioning
that there are solvent guest molecules located in the interior, but
due to the lack of specific interactions between the host methyl
groups and the guests, X-ray structural analysis cannot
accurately locate the guest atoms. The PLATON/SQUEEZE tool
was applied to treat these non-commensurate disordered
solvent molecules. The high disorder of the solvent molecules
also accounts for the higher R1 and wR values of crystal 2,
compared to 1.
The side-views of barrel-1 and -2 are different: Barrel-1 is
connected via motif III and all the individual molecular
components are arranged in a fully-closed circular manner
(Figure 4a); Barrel-2 is connected via motif IV and its individual
molecular components are arranged in a zigzag manner, and so
At the single crystal level of 1, an adenine-adenine (A-A) base
pair connecting opposite conformational enantiomers via the
Watson-Crick edges (N1 and 6-NH2) is disclosed (motif I).
Meanwhile, another intermolecular HB motif (motif II, Figure 2a)
is also formed between the N3 and the phenol group of the
same conformational enantiomers. Together, a novel four-
membered adenine analog-based ring structure is formed by
these two HB motifs (Figure 2a). Considering these individual
four-membered rings separately, there are empty rectangular
holes (6.04
×
6.52 Å2, Figure S4) encircled by four
interconnected molecules, m1-m4 (Figure 2b). These rings form
ladder-like ribbons extending along the phenol-N3 direction, and
ladders on the same plane layers are in turn associated together
through the interdigital tert-butyl side-chains (Figure S5).
Considering the situation across different layers, the four-
membered rings in neighbouring layers are connected by
additional HBs and amino-aromatic type π-π interactions (Figure
2c). Thus, APN actually forms a closely packed crystal structure
with the four-membered rings embedded in interlinked ladder-
like ribbons (Figure S5).
barrel-2 appears as
a concave-convex circular structure,
reminiscent of the mortise-and-tenon-joint component (Figure
4b). Thus, each individual molecule of 2 is tethered to the
nearest four opposite conformational enantiomers (2a
surrounded by four 2bs, and vice versa, Figure S7) and
assembles into a continuous 1D host channel structure (Figure
4c).
These 1D host channels of 2 are associated side-by-side into
an overall honeycomb-like crystal structure, with one individual
hexagonal channel being surrounded by six nearest channels,
which are also arranged in a hexagonal manner with inter-center
distance 18.64 Å (Figure 4d). The assembly of these nearby
channels is longitudinally shifted along their C3-axis in relation to
the positions of the nearest barrel-1s (Figure S8). These host
For APC (2), the self-assembly patterns and the entire crystal
structure are drastically altered. Two distinct HB motifs are
formed (Figure 3): i) a C-H···N type HB motif is formed between
the C8-H and the N3 of adjacent molecules (motif III), which
connects six conformers (-2a-2b-)3 alternatingly into
a
supermacrocyclic hexagonal barrel-like structure, barrel-1 (vide
infra); ii) a bifurcate HB motif is formed between the phenol -OH
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channels are laterally associated through van der Waals
interactions between 6-NH2 group of one channel and one CH3
of the tert-butyl group in the nearest channel (Figure S7).
In the MeOH/CH2Cl2 (2:1) solvent system, concentration
dependent morphology transitions were observed (Figure S14).
At 0.5 mg/mL, 1 forms interwoven microbundles, while 2 forms a
membrane structure. At 1 mg/mL, both 1 and 2 formed
membrane structures. At 2 mg/mL, both compounds displayed
fused vesicular morphologies, and the fusion process of
individual spherical particles could be visualized by time-
elapsing experiments, and some of these spherical particles
contained holes, suggesting their concave interiors (Figure 5).17
In this solvent system the spatial orientations of adjacent
individual molecules in accordance with the base pair motifs I-IV,
for either compound 1 or 2, were revealed by 2D-NOESY
(Figure S16).
Figure 5. The supramolecular polymeric morphology formation process of
APN (1) and APC (2) indicated by time-elapsing experiments at 2mg/mL within
5 days.
Figure 4. a,b): The space-filling top and side views of barrel-1 and barrel-2
formed by 2. c): The side views of the 1D channel assembled by barrel-1 and
barrel-2. d): The stick-ball top views of the honeycomb-like structure formed by
2. e): The central projection of d) displaying the 1D channels. f): The top views
of d) indicating the empty interiors. g): The schematic representation of the 3D
honeycomb-like structure.
Upon quick evaporation of the solvents MeOH/CH2Cl2 (2:1),
crystalline powder solids of both compounds were obtained, and
they displayed distinct microcrystalline morphologies (Figure
S15). To investigate their properties and inner structures, the
powder samples of 1 and 2 were examined by DSC, TGA and
the VT-PXRD (Figure 6). For 1, except for the melting, the DSC
experiment indicate a phase transition might happen between
115 and 135˚C (Figure 6a, Table S1), and TGA measurement
Next, the supramolecular assemblies of both compounds in
solution were investigated. by variable temperature 1H NMR
(VT-NMR) 15 and ESI-MS 7b,16 techniques, two powerful methods
for the examination of intermolecular interactions and species in
solution state. For both 1 and 2, according to VT-NMR, the
formation of HBs between those functional groups, which
participate into the HB motifs in crystal state, was confirmed in
solution too (Figure S9). The DOSY-NMR measurements
indicated the aggregate formation for both compounds in DMSO
(Figure S10). The mass peaks of 1-mer to 4-mer of 1 and 2 in
MeOH were detectable by negative mode ESI-MS. Though the
molecular mass peaks of 5-mer to 6-mer of 2 were observable,
their corresponding isotopic patterns were covered by noise
signals due to their lower abundances (Figure S11, S12).
indicates
a sigmoid weight-loss curve (12%) within this
temperature range (Figure 6b). The powder crystal of 1 displays
a different PXRD spectrum from the computed spectra based on
its single crystal structure at temperature range of 25 to 115˚C.
Upon increasing the temperature to above 160˚C and up to
190˚C, the crystal form is then converted such that it resembles
the same pattern as the computed spectrum of the single crystal
of 1 (Figure 6c, S17). These findings indicate the powder solid of
1 adopts different crystal form from its single crystal obtained by
the slow crystallization process mentioned above.
The lower melting point of 2 and its much smaller ΔH of the
melting (9.38 kJ/mol) compared to that of 1 (27.24 kJ/mol)
indicates that the crystal lattice of 2 is constructed by a weaker
HB network (C-H···N type) (Figure 6d, Table S1). The DSC and
VT-PXRD experiments indicate that the powder crystalline solid
of 2 adopts the same crystal form as its single crystal state at
lower temperatures, and a phase transition happens at around
Since the single crystals of 1 and 2 were obtained from
different solvent systems, we then analyzed their properties
under the same solvent system. The morphologies of the
supramolecular polymeric assemblies of 1 and 2 in solution state
were revealed via SEM images. In MeOH/H2O (10:1) system, 1
forms a membrane-covered aggregate with spherical protrusions
and 2 forms a flat extending membrane aggregate (Figure S13).
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169˚C (Figure 6f). From the TGA measurement, a gradual linear
weight loss starting from around 50˚C is found (Figure 6e), with
a small inflexion between 165 and 175˚C (where a crystal phase
transition happens). The gradual release of inclusion solvent
molecules is due to the lack of specific interaction between the
guest molecules and the host tert-butyl interior (which is in
accordance with the findings for the single crystal state of 1), a
characteristic of non-commensurate inclusion solids.18
Keywords: nucleobase • pyrazolo[3,4-d]pyrimidine • pyrrolo[2,3-
d]pyrimidine • self-assembly • supermacrocyclic assembly
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In summary, two new adenine analogues, APN (1) and APC
(2), have been synthesized. Both compounds display intrinsic
capabilities to form intriguing supramolecular macrocyclic
structures, mediated by distinct HB base pair motifs. The
conversion of nitrogen at 8 position of 1 to C8-H of 2 has a
marked impact on their supramolecular structures and properties.
In powder crystalline state both compounds can act as inclusion
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with different release behaviours which induces phase change
phenomena in both cases. These new types of adenine
analogues may represent potential avenues of further
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Detailed experimental procedures and data for NMR, VT-NMR,
HR-MS, X-ray, SEM and UV spectroscopy can be found in the
Supporting Information.
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National Natural Science Foundations of China (21572144),
the Chengdu Science and Technology Program Projects (2017-
CY02-00025-GX) and Testing & Analytical Center, Nuclear
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Yingying Chai, Xinglong Zhou, Changfu
Li, Beibei Ma, Zhen Shen, Ridong
Huang, Hai Chen, Bojiang Chen,
Weimin Li* and Yang He*
Two novel adenine analogues can
form either four or six-membered
supermacrocyclic assemblies via
distinct hydrogen bonded base pairs
depending on their 8-positioned
atomic identities.
Page No. – Page No.
Supermacrocyclic assemblies by
Hydrogen-Bond Codes of C7-Phenol
Pyrazolo and Pyrrolo Derivatives of
Adenine
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