‘Frustrated’ hydrogen-bonded self-associated systems as templates towards DNA incorporated nanostructure formation

Article abstract of DOI:10.1080/10610278.2017.1351613

Herein, we present the synthesis of a thymine nucleobase-appended ‘frustrated’ monomer, which exhibits self-association in DMSO solutions through the formation of hydrogen bonds. This self-association process has been explored in both competitive DMSO solutions and the solid state, using a combination of NMR and single crystal X-ray diffraction techniques. The self-associative equilibria within the solution state are balanced in such a way that the hydrogen bond donating and accepting thymine residue present within the monomeric structure is free to coordinate further guest species such as the complimentary DNA base adenine. The adenine simulants, 2-aminopyridine and 2,6-diaminopyridine have been used to explore the potential of these self-associated structures towards the coordination of complimentary DNA base pairs.

Full text of DOI:10.1080/10610278.2017.1351613

Supramolecular Chemistry
ISSN: 1061-0278 (Print) 1029-0478 (Online) Journal homepage: http://www.tandfonline.com/loi/gsch20
‘Frustrated’ hydrogen-bonded self-associated
systems as templates towards DNA incorporated
nanostructure formation
Tamrin L. Gumbs, Lisa J. White, Neil J. Wells, Helena J. Shepherd & Jennifer R.
Hiscock
To cite this article: Tamrin L. Gumbs, Lisa J. White, Neil J. Wells, Helena J. Shepherd
& Jennifer R. Hiscock (2017): ‘Frustrated’ hydrogen-bonded self-associated systems as
templates towards DNA incorporated nanostructure formation, Supramolecular Chemistry, DOI:
10.1080/10610278.2017.1351613
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Date: 19 July 2017, At: 11:13

Supramolecular chemiStry, 2017
https://doi.org/10.1080/10610278.2017.1351613
‘Frustrated’ hydrogen-bonded self-associated systems as templates towards DNA
incorporated nanostructure formation
Tamrin L. Gumbsa, Lisa J. Whitea, Neil J. Wellsb, Helena J. Shepherda and Jennifer R. Hiscocka
aDr J. r. hiscock, School of physical Sciences, university of Kent, canterbury, uK; bSchool of chemistry, university of Southampton, Southampton,
uK
ABSTRACT
ARTICLE HISTORY
received 30 may 2017
accepted 3 July 2017
Herein, we present the synthesis of a thymine nucleobase-appended ‘frustrated’ monomer, which
exhibits self-association in DMSO solutions through the formation of hydrogen bonds. This self-
association process has been explored in both competitive DMSO solutions and the solid state,
using a combination of NMR and single crystal X-ray diffraction techniques. The self-associative
equilibria within the solution state are balanced in such a way that the hydrogen bond donating
and accepting thymine residue present within the monomeric structure is free to coordinate further
guest species such as the complimentary DNA base adenine.The adenine simulants, 2-aminopyridine
and 2,6-diaminopyridine have been used to explore the potential of these self-associated structures
towards the coordination of complimentary DNA base pairs.
KEYWORDS
Self-association; hydrogen
bonding; host–guest
chemistry
1. Introduction
have shown supramolecular frameworks synthesised
from pyrogallol[4] arene and 4,4′-bipyridine-type spacers
to be solvent stable; and Steed and co-workers (12) who
showed that hydrogen-bonded linkages could replace
covalent bonds in the design of supramolecular gelators.
Work, such as this showcases the importance of hydrogen
bond formation in the control self-association events, and
therefore, the fundamental need to understand how to
control these interactions at the molecular level.
Although the formation of hydrogen-bonded urea:an-
ion hydrogen-bonded complexes is well-known (13,
14), the self-associating properties of anion-spacer-urea
amphiphilic monomers were first probed in the solution
state by Faustino and co-workers (15). Members from this
Molecular self-association and resultant nanostructure
formation typically rely on supramolecular interactions,
such as hydrogen bonding, electrostatics and charge
transfer (1, 2). As a consequence, supramolecular princi-
ples are now being effectively used within the design of
novel self-associated systems, giving rise to controlled
aggregation events and stimulating a move towards pro-
grammable nanostructure (2–6), supramolecular organic
framework (7) and supramolecular gel design (8, 9). This
has included work by Zhao and co-workers (10) who have
shown the potential of hydrogen-bonded self-associated
amphiphiles towards the development of novel drug/
gene nanocarriers; Atwood and co-workers (11) who
CONTACT Jennifer r. hiscock
J.r.hiscock@Kent.ac.uk
the supplemental data for this article is available online at https://doi.org/10.1080/10610278.2017.1351613.
© 2017 informa uK limited, trading as taylor & Francis Group

2
T. L. GUMBS ET AL.
synthesised receptors 2 and 3, which contain the HBD
thymine and urea functionalities, respectively, to better
understand the roles of these functionalities within pos-
sible coordination events in the absence of the self-asso-
ciated species.
DNA has now moved beyond its traditional biological
function to be seen by many as an intelligent construction
material, producing two- and three dimensional networks
with an ever extending role in electronics, diagnostics,
medicine, materials science and synthetic biology (19).
More recently, the development of DNA-inspired supramo-
lecular chemistry (20) has included the use of DNA micelles
as nanoreactors (21) and the synthesis of dynamic DNA
nanotubes (22). The use of nucleobases in the construc-
tion of supramolecular assemblies and synthetic polymers
is also attracting attention (23). Examples of this include
work by Champness and co-workers, who have used thy-
mine-appended porphyrins to give a molecule which is
capable of square two-dimensional network assembly on
a planar graphite surface (24); and O’Reilly and co-workers
who have used a combination of block copolymer self-as-
sociation and complimentary nucleobase complexation
for controllable polymer formation (25).
Figure 1. General structure for the anionic component of the
sulphonate-urea amphiphilic salts.
class of compound were shown to exhibit similar critical
micelle concentrations to sodium decanoate (16); these
properties were attributed to intermolecular hydrogen
bonding interactions. In our preliminary studies (17, 18),
we extended this work using similar amphiphilic mono-
mers with the basic structure shown in Figure 1. These
systems are‘frustrated’in the sense that they cannot fulfil
all of their potential self-associative hydrogen bonding
modes, simultaneously as they contain a single hydrogen
bond donating (HBD) urea functionality but two hydrogen
bond accepting (HBA) sulphonate and urea groups. These
compounds can form tapes through both urea-anion and
urea-urea complex formation events in the solid state (17).
They may also form dimeric species with the stability of
these complexes maintained through intermolecular sul-
phonate-urea hydrogen-bonded complex formation. We
were able to show that a preference of any one of these
binding modes could be modulated through the alteration
of HBD acidity or the strength of counter cation coordi-
nation. Moving into the solution state (18), we were able
to go some way to controlling the hydrogen bonding
modes present in the self-associated structure through
the addition of competitive HBD and HBA species. As we
are now beginning to gain an understanding of the hydro-
gen bonding modes involved within these self-associated
species, we wish to utilise the nanostructures formed as
templates the controllable synthesis of ever more complex
nanostructure and material design.
Here, we present the first steps to achieving this, though
the synthesis of 1 which was synthesised as the tetrabu-
tylammonium (TBA) salt of the anion. This compound
contains the same basic urea-spacer-anion motif as our
previous ‘frustrated’ amphiphiles but we have extended
the functionality by appending the nucleobase thymine,
responsible for hydrogen-bonded duplex formation within
the DNA double helix. This increases the number of HBD
NH and HBA carbonyl functionalities present in our already
‘frustrated’ system. In this work, we show that the con-
trolled balance of these hydrogen-bonded complexation
events could lead to the ever more complex controlled
assembly of DNA incorporated nanostructures. In order
to investigate these systems more thoroughly, we also
2. Materials and methods
2.1. Synthesis
Compound 1 was synthesised from previously published
compound 4 (18). The nitro group of 4 was reduced
with hydrazine and Pd/C 10% in ethanol to give crude 5.
Thymine-1-acetic acid was then activated with carbon-
yldiimidazole (CDI) in DMF and crude 5 added. The ana-
lytically pure product was isolated through precipitation
of a white solid from the reaction mixture with the addi-
tion of DCM in a yield of 18%. Receptor 2 was prepared
through the reaction of thymine-1-acetic acid with CDI
in chloroform, followed by the addition of 4-nitroanaline.
The resultant solid was removed by filtration and washed
with methanol to give the product as a white solid in a
yield of 38%. Receptor 3 was obtained by reaction of butyl
isocyanate with 4-nitroanaline in pyridine. The resultant
solution was diluted with chloroform and washed with
dilute HCl and water. The organic phase was then dried
over magnesium sulphate and the product obtained as a
yellow solid in a yield of 47% through precipitation from
chloroform with hexane.
2.2. Single crystal X-ray diffraction
Single crystal diffraction data were collected using a Rigaku
Oxford Diffraction Supernova diffractometer, with Cu–Kα
radiation to a maximum resolution of 0.84 Å. The crystal
was kept at 100(1) K during data collection, using an Oxford

SUPRAMOLECULAR CHEMISTRY
3
Cryosystems 800-series Cryostream. Single crystals of 1 are
exceptionally prone to damage when removed from the
mother liquor, with complete amorphisation taking place
within seconds. After several attempts, a well diffracting
crystal was mounted on the diffractometer in the cold
stream. While, crystal decay is reduced at 100 K, diffraction
quality significantly decreased during data collection. The
low-angle data were collected first, followed by high-angle
data. Unfortunately the crystal quality was reduced to the
extent that little diffraction can be observed beyond 1 Å.
Subsequent attempts to recollect better quality high-an-
gle data before crystal degradation unsuccessful; however,
the unit cell of each crystal was found to be equivalent to
that reported here, for 1 in all cases.
3. Results and discussion
3.1. Solution state self-association
As DNA complexation typically occurs under highly com-
petitive aqueous conditions our complexation studies
were conducted in DMSO or DMSO-water mixtures. At the
present time, we have not moved into aqueous conditions
due to the inherent difficulties in the observation of NH
resonances via 1H NMR as a result of deuterium exchange
effects. The presence of hydrogen bond-mediated self-as-
1
sociation was determined by a H NMR dilution study in
DMSO-d6. As illustrated in Figure 2, dilution of the origi-
nal sample resulted in the up-field perturbation of those
signals corresponding to the urea NHs only with increas-
ing concentration of 1. No change in chemical shift for
those resonances corresponding the amide or thymine
NHs could be detected, demonstrating that out of the
four possible HBD NH groups only the urea functionality
is involved in the hydrogen-bonded self-association pro-
cess under these conditions. Further analysis of the 1H NMR
resonances corresponding to the methylene group also
showed no change in chemical shift during the course of
the dilution experiment, this is further evidence that the
thymine functionality is not involved in the self-association
process.
The dilution data obtained from the change in chem-
ical shift of the urea NH was fitted to both the dimerisa-
tion/equal K model (EK) (30, 31), where the association
constants for all self-associative effects are equal, and
the cooperative equal K model (coEK), where the first
association constant in the self-association process is
different to the subsequent association constants which
are all equal, using BindFit v0.5 (32, 33). These models
As a consequence of the general poor quality of the data,
interpretation of fine structural detail should be approached
with caution but, the network structure of anion and cation
can nevertheless be unambiguously identified.
The structure was solved with the ShelXT (26) structure
solution programme using Direct Methods and refined
with ShelXL (27) by Least Squares minimisation. Olex2
(28) was used as an interface to all ShelX programmes.
The unit cell contains two monomers of 1, five molecules
of DCM and further disordered solvent that could not be
modelled with discrete atomic positions. The PLATON
SQUEEZE (29) tool was used to remove the contribution
of disordered solvent to the calculated structure factors.
More details are provided in the cif. All non-hydrogen
atoms were refined using anisotropic displacement
parameters, and hydrogen atoms were placed at calcu-
lated positions. A significant number of restraints and
constrains were used to ensure a convergent refinement,
also detailed in the cif.
Figure 2. Graph illustrating the 1h Nmr down-field change in chemical shift of the Nh resonances with increasing concentration of 1 in
DmSo-d6 (298 K).

4
T. L. GUMBS ET AL.
Figure 4. 1h DoSy of 1 (55.56 mm) in DmSo-d6 conducted at
299.3 K.
Figure 3. (colour online) 1h roeSy of 1 (55.6 mm) in DmSo-d6.
assume one component, one-dimensional homogene-
ous aggregation (34). The association constants calculated
for the strength of self-associated complex formation
were shown to be <10 M−1 in both cases, implying that
the self-associative interaction is weak. A better fit was
obtained with the equal EK model than the coEK model,
which gives evidence for the former being the self-asso-
Figure 5. (colour online) Single crystal X-ray structure of 1,
illustrating dimerisation through urea-anion complexation.
residual solvent molecules, second anionic monomer and tBa
counter cations have been omitted for clarity.
1
ciative mode that exists within the solution state. A H
ROESY NMR study (Figure 3) also showed through space
interactions between the aryl urea NHs and the CH2 adja-
cent to the sulphonate functionality, revealing that these
two chemical groups are in close proximity within the
DMSO-d6 solution.
where kB is the Boltzmann constant, T is the temperature
and η is the viscosity of the solvent. However, this approxi-
mation of the hydrodynamic radius must be treated with
caution as it assumes that the diffusing entity is a sphere
and that the van der Waals volume of the molecular com-
plex is large compared to that of the solvent (36). This sys-
tem also exists in fast exchange, which can cause further
complications with data interpretation (37, 38). The TBA
counter cation was shown to have a hydrodynamic radius
of 0.59 and 0.55 nm and the self-associated anionic compo-
nent was shown to have a hydrodynamic radius of 0.90 and
0.81 nm, respectively at 55.56 and 5.56 mM concentrations.
An estimation for the size of the self-associated nano-
structures of 1 present in a DMSO-d6 solution, visible by
1H NMR was obtained through DOSY experiments (35).
As shown in Figure 4, the cationic and anionic compo-
nent of 1 have different diffusion constants, showing
that these two species are not strongly coordinated.
1
The H NMR DOSY experiments were performed with
two different concentrations of 1 (55.6 and 5.6 mM). The
translational diffusion coefficients (D) obtained from 1H
NMR DOSY experiments were then used to calculate
hydrodynamic radius (rH) of the self-associated species in
solution, through rearrangement of the Stokes–Einstein
equation:
3.2. Solid state self-association
The single crystal X-ray structure shown in Figure 5 of 1 was
obtained by the slow evaporation of DCM into a DMF solu-
tion of the salt. As described in the materials and methods
kBT
D =
(1)
6ꢀꢁrH

SUPRAMOLECULAR CHEMISTRY
5
section, the crystals obtained were found to be unstable
over time which resulted in a decrease in the quality of the
data collection. The molecular self-association of 1 can be
determined although the data collected do not allow us to
calculate hydrogen bond lengths or angles with certainty.
The unit cell contains two crystallographically distinct
monomers of 1, five molecules of DCM and further solvent
molecules that could not be resolved. Each of the anionic
components of 1 was found to dimerise with a symmetry
equivalent to itself (forming two crystallographically dis-
tinct dimers) through the formation of four inter-molec-
ular sulphonate-urea hydrogen bonds. The dimeric units
were calculated to be, approximately 1.9 nm by 1.5 nm by
0.8 nm in size. These values are in approximate agreement
with those calculated by DOSY NMR which have a hydro-
dynamic diameter of 1.6 nm (5.56 mM)–1.8 nm (55.56 mM).
Unlike in solution, within the solid state there is lim-
ited competition from HBD/HBA solvent molecules, and
as a consequence, weaker hydrogen bonds that may be
out competed in solution can be observed in the solid
state. Further analysis of the extended hydrogen-bonded
network showed that these dimeric units were able to
further self-associate, through the formation of urea oxy-
gen:thymine NH hydrogen bonds, to produce the helical
tetrameric units shown in Figure 6.
The tetrameric units formed by each of the two differ-
ent anionic substituents contained within the unit cell
are able to further independently self-associate through
the formation of thymine NH:amide O hydrogen bonds
to form an extended pseudo porous crystalline structure.
These pseudo pores are approximately 27 Å in diameter
and contain both the TBA and residual solvent molecules.
An extended pseudo porous network is produced by each
of the two anionic components within the unit cell. These
networks interlink perpendicular to one another to pro-
duce a three-dimensional chainmail motif, illustrated in
Figure 7.
Figure 6. extended single crystal X-ray structure of a single
anionic monomer of 1, showing tetramer formation through
amide Nh-urea o hydrogen bond formation between hydrogen-
bonded dimeric units.
Figure 7. (left) extended single crystal X-ray structure of a single
anionic monomer of 1, showing a pseudo porous molecular
extended strucure through thymine Nh-sulphonate hydrogen
bond formation between hydrogen-bonded tetrameric units.
(right) extended single crystal X-ray structure of both anionic
monomers showing interlinking ring systems.
In order to further probe these self-associated systems
towards the eventual coordination of a complimentary
base-paired single strand of DNA, as illustrated in Figure
8, 2-aminopyridine (compound 6) and 2,6-diamino
pyridine (compound 7) were used as adenine simu-
lants. These two simulants have a similar arrangement
of HBD and HBA functionalities to that of adenine, the
complimentary base pair of thymine. A series of 1H NMR
titration studies with 1 vs. these adenine simulants was
conducted in a DMSO-d6 0.5% water solution. Figure
9(a) and (b) show the results of these titration studies
and the association constants calculated for 1:1 complex
formation are given in Table 1. There was no significant
change in chemical shift observed with either the aryl
urea or amide NH resonances upon the addition of 6 to
1, showing no evidence of host–guest hydrogen-bonded
complex formation. The position of the alkyl urea NH res-
onance was obscured by overlapping signals within the
1H NMR spectra and so could not be observed. However,
a down-field change in chemical shift for the resonance
corresponding to the thymine NH was observed, indicat-
ing the presence of a thymine NH:6 hydrogen-bonded
3.3. Extended host–guest complexation within the
solution state
The combination of evidence obtained from 1H NMR DOSY,
1
1H NMR ROESY, H NMR dilution study and X-ray crystal
structure determination supports the self-association pro-
cess of compound 1 in DMSO favouring the formation of
urea-anion rather than urea-urea interactions, as shown
in Scheme 1. We further propose that the self-associated
solution state structure predominantly includes only
a small number of molecular anionic units. We can also
assume that the HBD/HBA thymine residue is free to coor-
dinate further guest species. For this reason, the images
presented within the Scheme 1 have been limited to the
self-assembly of two anionic units only.

6
T. L. GUMBS ET AL.
Scheme 1. (colour online) possible self-associative and guest coordination hydrogen-bonding modes for 1.
Figure 8. potential hydrogen-bonded coordination of the self-associated structures of 1 with a complimentary single stranded DNa.
1
complex. An analogous H titration experiment, with 7
again showed no discernible hydrogen-bonded complex
formation with either the amide or aryl urea NH groups,
but there was a significant change downfield in chem-
ical shift noted for the alkyl urea NH, which in this case
was not obscured by any other resonances. Again the
most significant down-field change in chemical shift was
noted with for the thymine NH. The association constants
calculated for each of these 1:1 complexation events
were <10 M−1, demonstrating weak binding. This is unsur-
prising when considering that in this instance, formation
of a neutral molecule complex is observed, theoretically
stabilised through as few as two hydrogen bonds in a
highly competitive solvent mixture. Nevertheless, this
does give an indication as to the type of hydrogen bond
complexation that may occur within any DNA incorpo-
rated nanostructure.
Due to the complex molecular structure and resultant
self-association processes of 1 which may influence any
observed host–guest complexation events, receptors 2
and 3 were produced which contain either the thymine
and amide or urea HBD moieties, respectively but do not
experience the self-association effects of 1 as the sul-
phonate functionality is not present in either receptor
structure. As a consequence, the individual complexation
events of 1 can be observed independently of the parent
system. A series of 1H NMR titrations with both receptors 2
and 3 were conducted in a DMSO-d6 0.5% water solution
with both adenine simulants andHSO−4. The results of these
titration studies are shown in Figure 10(a) and (b) for 2 and

SUPRAMOLECULAR CHEMISTRY
7
Figure 9. Graph illustrating the down-field change in chemical shift for those signals corresponding to the Nh resonances of the thymine
(X), alkyl urea (•), aryl urea (+) and amide (−) hydrogen bond donating residues, during a 1h Nmr titration of 1 at 298 K with the addition
of (a) 6 and (b) 7.
3, respectively.HSO−4 was used in this instance to establish
whether the spatial orientation of the HBD groups in rela-
tion to the sulphonate moiety of 1 was responsible for the
hydrogen bonding mode present or if it was more strongly
influenced simply by preferential complex formation. The
association constants calculated from this series of titra-
tions with 2 and 3 are given in Table 1. Interestingly the
thymine NH of 2 shows no interaction withHSO−4, but there
is evidence for hydrogen bond formation with the amide
NH. Under these conditions weak hydrogen-bonded com-
plexes were observed to form with both the DNA simulants
and thymine NH. These DNA simulants were also shown
to interact at the amide NH. The analogous set of experi-
ments conducted with 3 showed no significant change in
chemical shift upon the addition of 7, however, associa-
tion constants were calculated for the hydrogen-bonded

8
T. L. GUMBS ET AL.
Table 1. association constants calculated (m−1) for 1–3 with
DNa simulants (6 and 7), and HSO−4 (supplied as the tBa salt) in
a DmSo-d6 0.5% water solution at 298 K. these constants were
obtained from fitting of h Nmr titration data and refined to 1:1
host:guest models using Bindfit (32).
complexes formed upon the addition of both 6 (43 M−1)
and HSO−4 (27 M−1).
The weak 1:1 hydrogen-bonded complexes observed
for 2 (amide NH): 7 (28 M−1), 2 (amide NH):HSO4− (25 M−1)
and 3 (urea NH): 6 (43 M−1) were not observed to form
with 1, indicating that the self-association process affects
the type and presence of these hydrogen-bonded com-
plexation events. The absence of a 2 (thymine NH):HSO4−
and the presence of a 3 (urea NH):HSO−4 bonded complex
supports the formation of the urea-anion complex within
the self-association of 1 in the solution state.
1
1
2
3
Thymine Amide
Thymine Amide
Guest
NH
NH
Urea NH
NH
NH
Urea NH
6
7
<1
<1
Na
a
a
Na
a
4
Nh
5
1
a
a
28
25
43
a
27
HSO−4
Note: a – Failed to fit/change in chemical shift <0.1 ppm.
Figure 10. Graph illustrating the down-field change in chemical shift for those signals corresponding to the Nh resonances of the
hydrogen bond donating residues of (a) 2 and (b) 3 in the presence of various guest species.

SUPRAMOLECULAR CHEMISTRY
9
4. Conclusions
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We have synthesised a thymine-inspired monomer,
based on our previous ‘frustrated’ amphiphile design
which contains a combination of different HBD (urea,
thymine and amide) and HBA (carbonyl oxygen and sul-
phonate) groups. Proton NMR dilution studies suggest
that the anionic monomer self-associates through the
use of HBD urea groups in a DMSO solution. DOSY NMR
experiments indicate that the self-associated structures
have a concentration-dependent hydrodynamic radius
between 0.55 and 0.59 nm, meaning that only a few ani-
onic units are involved in the formation of the pre-domi-
nant self-associated structure. Although there are several
different types of hydrogen-bonded self-association
possible for 1, single crystal X-ray structure determina-
tion shows the formation of a sulphonate-urea dimer.
Single crystal X-ray diffraction analysis also showed that
hydrogen-bonded network of the anionic component
extended into a three dimensional interlinking pseudo
porous network.
The formation of the dimeric urea-anion hydro-
gen-bonded complex within solution state is also sup-
ported by the results of 1H NMR ROESY and a series of 1H
1
NMR titration experiments. The H NMR titration exper-
iments with the adenine simulant, 6, showing hydro-
gen-bonded complex formation with the thymine but not
the urea or amide NH groups, provides evidence that this
type of self-associated structure may be used to produce
a novel class of DNA-templated nanostructures. Receptors
2 and 3 have allowed the identification of contributions of
the different HBD groups separately and independently of
the self-associative process experienced by 1. These stud-
ies have confirmed the preferential interaction of HSO4−
towards the urea and amide NH functionalities over the
thymine group. Complexation of the DNA simulants to all
HBD functionalities of 2 and 3 suggest that any reversal
of this trend with 1 is due to preferential self-associative
complexation events.
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Acknowledgements
The authors would like to thank K. Howland for his assistance
with mass spectrometry during the project.
Disclosure statement
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No potential conflict of interest was reported by the authors.
Funding
This work was supported by the Army Research Office (US)
[grant number W911NF-16-1-0247]; the University of Kent
[Caldin Fellowship].

10
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