Towards a Molecular Understanding of Cation-Anion Interactions and Self-aggregation of Adeninate Salts in DMSO by NMR and UV Spectroscopy and Crystallography

Article abstract of DOI:10.1002/cphc.202100098

Rare anionic forms of nucleic acids play a significant biological role and lead to spontaneous mutations and replication and translational errors. There is a lack of information surrounding the stability and reactivity of these forms. Ion pairs of mono-sodium and -potassium salts of adenine exist in DMSO solution with possible cation coordination sites at the N1, N7 and N9 atoms of the purine ring. At increasing concentrations π-π stacked dimers are the predominant species of aggregates followed by higher order aggregation governed by coordination to metal cations in which the type of counter ion present has a central role in the aggregate formation.

Full text of DOI:10.1002/cphc.202100098

Articles
ChemPhysChem
doi.org/10.1002/cphc.202100098
Towards a Molecular Understanding of Cation-Anion
Interactions and Self-aggregation of Adeninate Salts in
DMSO by NMR and UV Spectroscopy and Crystallography
[b]
[b]
[a, b]
Dominique M. S. Buyens, Lynne A. Pilcher, and Emil Roduner*
Rare anionic forms of nucleic acids play a significant biological
role and lead to spontaneous mutations and replication and
translational errors. There is a lack of information surrounding
the stability and reactivity of these forms. Ion pairs of mono-
sodium and -potassium salts of adenine exist in DMSO solution
with possible cation coordination sites at the N1, N7 and N9
atoms of the purine ring. At increasing concentrations π-π
stacked dimers are the predominant species of aggregates
followed by higher order aggregation governed by coordina-
tion to metal cations in which the type of counter ion present
has a central role in the aggregate formation.
[
17,18]
1
. Introduction
by nucleic acid repeat sequences show ion dependency
which further highlights the role and importance of monovalent
metal ions in DNA structure.
The multi-site coordination and ability of nucleobases to
interact non-covalently has rendered them desirable ligands in
the synthesis of stable bio-metal-organic frameworks that can
Non-covalent interactions governing the aggregation of iso-
lated purine bases, such as hydrogen bonding and π-π stacking,
have been investigated in order to gain greater understanding
of their role in structure, function and stability since Watson
and Crick (1953) proposed the structure of DNA. It is well
known that adenine is involved in Watson-Crick (WC) along
with reversed WC, Hoogsteen (HG) and reversed HG type
hydrogen bonding with thymine and uracil in DNA and RNA,
respectively. The self-
adenine derivatives with other nucleobases
acids
The binding of alkali metal ions such as Na and K to
nucleobases influences the structural integrity of DNA and play
a role in synthesis, replication, recognition and cleavage of DNA
[19–22]
have structural flexibility.
Metal complexes of adenine can
[
1]
have mono- or bidentate coordination through different
combinations of N3, N7 and N9 nitrogen atoms and its
deprotonated form (adeninate anion) can be di, tri- or
tetradentate, have varying coordinate combinations through
the N1, N3, N7 and N9 atoms (see reference within the review
and reference ) and bridging through the N3, N7 and N9
[2]
[3]
[4]
[5–7]
and hetero-association of adenine and
[
8,9]
[20]
and carboxylic
[10–12]
[23]
has been extensively investigated.
+
+
[24]
atoms.
The presence of disfavored tautomeric and anionic forms of
nucleic acids can form WC-like mispairs (i.e. guanine-thymine,
adenine-cytosine and guanine-uracil) that are involved in
[13,14]
and RNA.
Binding of metal ions can interfere with hydrogen
[25–28]
bonding and stacking interactions between base pairs and
mutations and replication and translational errors.
These
[
15]
compromise the structural stability of DNA. Experimentally,
the affinity for alkali metals increase in the order guanine>
cytosine>adenine>thymine>uracil, following the trend of
forms of nucleic acids are also believed to play a role in nucleic
acid catalysis and RNA-ligand recognition. The anion forms,
such as adeninate anion, features in investigations surrounding
[29]
[30]
[
13,16]
[31,32]
proton affinity in nucleobases.
The preferred binding sites
the photostability of nucleic acids in DNA
and is also used
of metal ions are the N7 in adenine, the N7 and O6 atoms in
guanine, the N3 and O2 atoms in cytosine and the O4 in
thymine and uracil. The three dimensional folding adopted
in the synthesis of N9-substituted adenines, which have
[33]
important biological roles such as anti-asthmatic and anti-
[13]
[34]
inflammatory activity, activity against diseases such as multi-
[35]
ple sclerosis and autoimmune disease.
There is a lack of information surrounding anionic forms of
[
a] Prof. Dr. E. Roduner
Institute of Physical Chemistry
University of Stuttgart
[
26,36]
nucleobases and is a topic being addressed currently.
Studies involving the chemical properties of the free adeninate
anion and its interactions with monovalent alkali metals are
limited. In this paper the ion-pair formation of the adeninate
70569 Stuttgart, Germany
E-mail: e.roduner@ipc.uni-stuttgart.de
b] D. M. S. Buyens, Prof. Dr. L. A. Pilcher, Prof. Dr. E. Roduner
Department of Chemistry
[
+
anion with the biologically important monovalent metals, Na
University of Pretoria
Pretoria 0002, Republic of South Africa
+
(Na-Ade) and K (K-Ade), and the self-aggregation of these
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cphc.202100098
ionic complexes in DMSO are investigated using NMR and UV
spectroscopy as well as XRD of crystal structures. In addition,
we have studied the influence of the 15-crown-5 (15C5) and 18-
crown-6 (18C6) ether on the spectroscopic and crystal struc-
tures of Na-Ade and K-Ade. To this end we show that ion-pair
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2021 The Authors. ChemPhysChem published by Wiley-VCH GmbH.
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formation exists between the adeninate anion and the counter
ions even at extremely dilute concentrations and that self-
aggregation of these complexes is highly influenced by the
counter ion present. Furthermore, there is a possibility of
complex formation between K-Ade and the 18-crown-6 ether.
2. Results and Discussion
2
.1. Ion Pairing
The use of organic solvents such as DMSO, DMF, methanol etc.,
has an effect on the non-covalent interactions (such as hydro-
gen bonding, pi-pi stacking and cation binding) of nucleic
[37]
acids and therefore on the interactions of nucleobases as
well. However, many thermodynamic properties of nucleobases
are reported in organic solvents or co-solvents of water and
organic solvents in order to enhance the chemical property
[38]
being studied or to understand the effect of solvent. It is
important to note that often nucleobase derivatives are used in
[39]
aqueous media due to the low solubility of free nucleobases.
In order to gain an understanding of the interactions
between adenine and the counter ion, the experiments are
conducted in a solvent which allowed for the solubility of
adenine and the adeninate salt and allows for potential ion-
pairing. DMSO, which acts as a hydrogen bond acceptor only,
will not form hydrogen bonds at nitrogen sites of adenine
rendering these sites available for metal ion coordination.
Moreover, further studies conducted of the regio-selectivity of
the adeninate salt (publication in preparation) require the use
of DMSO and hence, to maintain a common solvent, DMSO is
used to perform these studies.
Figure 1. Concentration dependent UV absorption profile of a) Na-Ade and
b) K-Ade in DMSO for the concentration range (0.05 – blue, 0.075 – red, 0.15
–
green, 0.10 – pink, 0.20 – orange, in mM) and in the presence of a large
excess of 15C5 (126 eq) and 18C6 (117 eq) ether, respectively (dashed black
lines).
Table 1. The λmax and (shoulder) bands in the UV absorption spectrum of
Na- and K-Ade, Na-Ade(15C5) and K-Ade(18C6) in DMSO/H O and DMSO.
2
Solvent
λmax [nm]
The UV studies performed showed a significant dependence
on the counter ion present indicating that ion pairs exist
DMSO/H
DMSO/H
DMSO+NaH
DMSO+KH
2
O+NaH
O+KH
246, 250, 264!265 (278, 287)
248, 250, 264!269 (278, 287)
251, 254, 269 (278, 287)
251, 253, 272 (278, 287)
245, 262
+
+
between the adeninate anion and the Na /K counter ion. The
normalized UV absorption profiles of Na-Ade and K-Ade in
anhydrous DMSO are shown in Figure 1 (UV absorbance
spectra, Figure S21). The λmax and shoulder bands observed are
reported in Table 1]. The blueshift of the λmax from K-Ade
2
DMSO/H
2
O + NaH+15C5
DMSO/H
2
O+KH+18C6
245, 262
(
272 nm) to Na-Ade (269 nm) in DMSO is associated with the
+
larger stabilization of the ground state of the anion by the Na
counter ion which has a stronger cationic field strength due to
its smaller ionic radius compared to K .
262 to 265 nm and K-Ade shift from 264 to 269 nm, accom-
panied by the increase in shoulder band intensity at 278 and
287 nm, which are attributed to the presence of the cationic
+
[40,41]
[
42]
Water molecules should facilitate the dissociation of the
counter ion from the adeninate ion pair. Studying the system
and anionic species.
These shoulder bands decrease in
intensity as the concentration of Na- and K-Ade decreases as
the presence of water molecules assists the dissociation of ion-
pairs. In DMSO, the concentration-dependent redshift of the
band around 265 nm for Na- and K-Ade is absent and the band
intensity at 278 and 287 nm is larger in magnitude than in
with a small amount of water present (5.2% v/v H O) provides
2
insight into i) how the Na- and K-Ade complexes respond to
interactions with water and ii) how the M-Ade concentration
dependent characteristics of the bands change (normalized UV
absorption profiles in DMSO/H O, Figure S22). The blueshift
DMSO/H O, indicating the ion-pairs are the predominate
2
2
from DMSO to DMSO/H O for both ionic complexes is due to
species.
2
+
+
the hydrogen bonding of water stabilizing the ground state of
the anion. Conversely, the solvation of the adeninate anion by
polar solvents stabilizes the π* orbital, resulting in a redshift of
the λmax with increasing polarity and hydrogen-acceptor proper-
The UV spectroscopy study of Na and K ion complexation
to the adeninate anion is conducted alongside the studies in
the presence of 15C5 and 18C6 (Figure 1, dashed), respectively,
in order to confirm the presence of ion-pairs. In the presence of
the large excess of 15C5 and 18C6, the shoulder profile is
absent and the λmax blueshifts to 262 nm for both Na- and K-
[42]
ties of the solvent.
A M-Ade concentration dependent
redshift is observed in DMSO/H O, having the Na-Ade shift from
2
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Ade as the free adeninate anion is formed, thus confirming that
ion-pairs exist in the absence of the crown ethers. Narrow finger
Ade provide insight into the potential coordination sites in
solution. The crystallographic information is given in Table S3
and selected geometric parameters of the crystal structure of
Na-Ade are given in Table S4. The crystal system for both the
Na-Ade and K-Ade display a zigzag packing morphology (Fig-
ure S16a and S17a) along the a axis in which there is a T-shape
edge to face arrangement. Along the c axis, the next row of
units is inverted along the b axis, cancelling the dipole moment
of the units and lowering the energy. In both the Na- and K-
like bands around the 245–250 nm region in the DMSO/H O
2
spectra are ascribed to DMSO-water-metal counter ion com-
plexes as they also appear in the cation-DMSO solutions in the
absence of the adeninate anion (SI Figure S23). In the Na-Ade
DMSO/H O UV spectra, a broad band lying below 235 nm is
2
observed and is largely suppressed in DMSO and in the
presence of 15C5 and is attributed to the population of higher
1
lying bright ππ* state(s) of the adeninate anion by the
Ade crystal structures, two DMSO-d solvent molecules per Na-
6
[
32]
excitation at 220 nm.
Ade/K-Ade are trapped within the channels formed by four Na-
Ade and K-Ade (Figure S16b and S17b) units packed edge to
face to form a rectangular cage. The DMSO-d molecules occur
6
+
+
2
.2. Coordination Sites of Na and K with Adeninate Anion
in groups of two, oriented in the opposite direction to each
other minimizing the steric hindrance between the methyl
groups and increases contact between the O atom and the
The addition of base, NaH/KH, to adenine in DMSO-d results in
deprotonation, shielding all the purine protons in NMR relative
to the peaks of adenine as electron density is gained in the
6
+
+
cation. The crystal packing shows that each Na /K counter ion
is coordinated to three adeninate anion molecules via the N1,
N7 and N9 atoms of three purine rings (Figure 2a, Figure S18
for K-Ade). Conversely, one adeninate anion is coordinated to
+
purine ring, Table 2. The Na counter ion, with the larger
charge/radius ratio, has stronger ion and ion-induced dipole
interactions with the adeninate anion, and this is reflected in
the larger deshielding of the C2-H and C8-H protons relative to
K-Ade (Δδ of 0.11 and 0.17 ppm at dilute and 0.18 and 0.24 at
saturated concentrations). The larger shielding of the C8-H is
ascribed to the ring current effect (Figure S5).
The gained negative charge from deprotonation of adenine
is shared on all five nitrogen atoms of the purine ring which in
turn shields the neighboring carbons in the C NMR spectra,
hence the deshielding of carbons indicates which neighboring
nitrogen atoms are involved in the ionic bond. In Table 2, the
C NMR chemical shifts for the imidazole ring carbons i.e. C4,
C5 and C8, are deshielded relative to adenine, highlighting the
membered ring’s involvement in the ionic bond. Moreover,
the C4 and C8 are the most deshielded, suggesting the N9 as
the site of coordination. The deshielding of the H and C NMR
chemical shifts of K-Ade(18C6) suggests that the 18C6 ether
+
+
three Na or K counter ions via the N1, N7 and N9 atoms. This
in agreement with previous research showing that the coordi-
nation sites of the adeninate anion are predominantly N1, N9
[24]
and N7.
The crystal structure of K-Ade(18C6), Figure 2b, provides
further information, showing the N3 and N9 atoms acting as a
+
chelate in coordination with one K counter ion, having the ion
1
3
positioned almost equally between the N3- and the N9-atom.
+
The K ion is simultaneously interacting with one 18C6 ether
molecule and one adeninate anion. The adeninate anion
molecules form zigzag ribbons along the a axis (Figure S19).
13
+
The K and 18C6 coordination is slightly perched, with a d
+
5
value of 0.924(8) Å (distance of K from the centroid of the
18C6). A herringbone packing morphology of the K-Ade(18C6)
units along the a axis is observed wherein a hydrogen-bonded
network exists in which the adeninate anion molecules are
linked via a mixed WC and HG type hydrogen bonding. From
the same set of crystals, a second morphology is obtained, SI
Figure S20, in which there is positional disorder in the system.
Note that no DMSO solvent is included in the crystals in the
presence of crown ether.
1
13
+
does not remove the K counter ion from K-Ade.
1
3
From C NMR spectroscopy, the site of coordination of the
counter ion with the adeninate anion cannot be determined
with certainty. The crystal structures obtained of Na-Ade and K-
From the above, the N3 and N9 atoms are the most likely
preferred sites of coordination in solution as the positively
charged counter ion will interact with two lone pairs on either
nitrogen atom. The size dependency of the counter ion for the
1
13
Table 2. H and C NMR chemical shifts (ppm) of adenine, Na-Ade, K-Ade
6
and K-Ade(18C6) in DMSO-d as solvent.
1
H NMR chemical shifts
C2-H
C8-H
NH
2
+
N3–N9 coordination will favor that of the K ion as it is larger in
[
a]
Adenine
8.11
7.90
7.72
7.81
8.09
7.66
7.42
7.50
7.08
5.94
size and more suitable for the bridging between the two atoms.
[
b]
Na-Ade
+
The Na ion can chelate or coordinate via either the N9 or the
[
c]
K-Ade
K-Ade(18C6)
[
d]
N3 site. No direct evidence for cation-π interactions have been
observed and the effect of the presence of the different counter
1
3
C NMR chemical shifts
1
3
ions on the C NMR chemical shifts is too large to be due to
C2
C4
C5
C6
C8
only electrostatic interactions between the π system and the
counter ion. The difference between the C chemical shifts of
[
a]
Adenine
152.4
146.9
147.9
147.5
150.6
157.7
160.7
161.2
118.2
119.7
121.7
121.8
155.6
154.3
155.0
154.0
139.2
149.4
150.5
151.1
13
[
b]
Na-Ade
[
c]
K-Ade
K-Ade(18C6)
K-Ade and Na-Ade range from 0.9–3.0 ppm for the imidazole
[
d]
+
+
ring whereas the difference between K and Na in a cation-π
[
43]
[
a] Adenine at 73.2 mM [b] Na-Ade at 52.2 mM, [c] K-Ade at 84.8 mM [d] K-
Ade(18C6) at 78.7 mM
interaction with benzene is predicted to be 0.13 ppm. It has
been shown that compounds containing heteroatoms, such as
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+
Figure 2. Molecular structure of a) Na-Ade and the Na coordination obtained from single crystal XRD of Na-Ade and b) K-Ade(18C6) and the hydrogen
+
bonding (red lines) and interaction with the K ion at the N3 and N9 atoms (black lines). The numberings of specified atoms and dihedral angles for
geometric parameters in Table S4, are shown.
imidazole, pyridine, aniline and imidazole have the cation
interact with the heteroatom in preference to the aromatic
system, with the cation-π binding being significantly low for
[44]
imidazole.
1
2
.3. Concentration and H NMR temperature coefficient of
Na-Ade, K-Ade, Na-Ade(15C5) and K-Ade(18C6)
Depending on the solvent used, hydrogen bonded (chloroform
as a solvent) or stacked dimers (solvents such as water or
DMSO) occur upon increasing concentrations of adenine,
[
45]
leading to the deshielding of the NH protons or shielding of
2
[46]
the purine protons, respectively. The competing H···O inter-
action between the amino group of adenine with water has a
larger interaction energy than H···N, promoting the formation of
[
7,39]
stacked dimers over hydrogen bonded dimers.
DMSO should
have a similar effect due to the partial negative oxygen
1
available for hydrogen bonding. Concentration dependent H
NMR studies were performed to investigate the ion-dependent
self-aggregation of the ionic complexes (Figure S6a and b). To
gain further knowledge of the influence of the cation and the
1
effect of the potential complexation of the K-Ade with 18C6, H
NMR studies in the presence of 2.4 equivalents of 15C5 ether
for Na-Ade (Na-Ade(15C5)) and 18C6 ether for K-Ade (K-Ade
(18C6)), Figure S6c and d, were performed. A graphical
representation of the shifts on a common axis is given in
1
Figure S7. The change in H NMR chemical shifts with the
change in concentration (Δδ=δ -δ , where δ is the chemical
0
n
0
shift of the reference point at the lowest concentration and δn
of higher concentration) of the ionic complexes as well as the
Figure 3. Change in chemical shift of purine protons with the change in
concentration for a) Na-Ade and K-Ade, b) Na-Ade(15C5) and K-Ade(18C6),
NH – squares, C8-H – circles and C2-H – triangles, and c) the CH protons of
2 2
the 15C5 and 18C6 ether in the presence of Na-Ade and K-Ade, respectively.
CH of the 15C5 and 18C6 are shown in Figure 3.
2
Temperature dependent studies were conducted over the
range of concentrations used in order to investigate how
increasing the temperature of the solution affects the inter-
All in DMSO-d at 320 K. Region 1 (highlighted in blue and green for Na-Ade
and K-Ade, respectively) and region 2 indicates concentration dependent
change in chemical shift.
6
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actions between molecules as the distance between them is
increased. Refer to Figure S9 for the change in δ with temper-
ature (300 K–380 K). The change in chemical shift of a proton
with the change in temperature gives the temperature
coefficient (Δδ/ΔT) which is used to monitor hydrogen bonding
molecules will experience a large negative temperature de-
pendence of the chemical shift as the hydrogen bonds with the
solvent are broken. The reduction in temperature coefficient
with increasing concentration indicates hydrogen bond forma-
tion shielding protons from hydrogen bonding with solvent
molecules, which in turn results in a decreased dependence of
[45,46]
and π-π stacking between molecules.
Dissociation of hydro-
[45]
gen bonds leads to shielding of the involved protons and
therefore a negative Δδ/ΔT value. Protons exposed to solvent
the proton chemical shift with temperature. For molecules in
solution, as the dissociation energy of hydrogen bonds
increases, the dependence of the chemical shift on temperature
decreases as a larger amount of energy is needed to distort the
[47]
bond. The effect of temperature on stacked dimers can also
[46]
be studied using Δδ/ΔT. Dissociation of dimers involved in π-
π stacking results in the deshielding of purine protons and
[
46]
hence a positive temperature coefficient (Δδ/ΔT>0).
The
change in the temperature coefficient with concentration is
shown for the purine protons of Na-Ade and K-Ade, Figure 4a,
and for the CH protons of the 15C5 and 18C6 ether, Figure 4b.
2
Refer to Figure S10 for the temperature coefficient of Na-Ade
(15C5) and K-Ade(18C6).
2
.4. Aggregation by π-π Stacking and In-Plane Dimerization
Two concentration dependent regions with opposite change in
chemical shift are observed in Figure 3a, indicated as region 1
and region 2. Region 1 showed shielding of both purine
protons, which indicates π-π stacking of the ionic complexes
and is attributed to the ring current effect experienced by the
neighboring molecule in π-π stacked dimers. The observed
changes in region 1 are not explained by ion-pairing which
would have caused deshielding of purine protons. Highlighting
1
3
the gain and loss of electron density in the C NMR chemical
shifts of Na- and K-Ade relative to adenine, Figure 5a, it is clear
that the purine ring is partially positive in the imidazole ring
and negative in the pyrimidine ring. In the presence of
competitive hydrogen bonding with DMSO solvent molecules,
the dimerization between two M-Ade molecules would be
driven by π-π stacking due to stabilizing electrostatic inter-
actions between the oppositely charged sections of the purine
1
Figure 4. The change in temperature coefficients with concentration of H
chemical shifts of a) Na-Ade and K-Ade and b) CH
the 18-crown-6 ether in DMSO-d . NH (squares), C8-H (circles) and C2-H
triangles). The shading relates to the regions defined in Figure 3.
2
of 15-crown-5 ether and
6
2
(
Figure 5. Cation induced change in atomic electron density in Na-Ade and K-Ade relative to adenine, based on the NMR chemical shifts in Table 2. Two
shades of blue indicate shifts towards more positive, red towards more negative charge. b) Suggested structures of π-π stacked, c) proposed shift of the M
ion from in-plane coordination to an out-of-plane coordination in the π-π stacked dimer of M-Ade. Hydrogen bonding indicated by red lines.
+
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ring, having the 5 membered ring of one molecule stack with
the 6 membered ring of the neighboring molecule. This can
occur via either antiparallel face to face or antiparallel displaced
stacking, Figure 5b. Anti-parallel stacking has been suggested
competitive complexing molecule, such as the adeninate anion,
+
and hence the K will not complex to the 18C6 ether alone.
+
The formation of an adeninate-K -18C6 complex is likely to
disfavor aggregation via π-π stacking. Thus, in region 1 of
Figure 3b, monomers of K-Ade(18C6) complex are likely the
predominant species. This would potentially allow for the NH2
[48]
for deprotonated purines.
These stacked dimers can be
further enhanced by hydrogen bonding of the NH group with
2
+
the N3 and N9 atom on the neighboring ring and additional
stabilization can occur if the counter ion moves from in-plane
to out-of-plane coordination (Figure 5c) allowing for a bridging
interaction with both adeninate anion molecules, coordinating
peak of K-Ade(18C6) to become visible since K would not be
in the vicinity of the NH group such as in the proposed π-π
2
stacked dimers. The increased shielding of the purine protons
with concentration in region 1 (Figure 3b) can be linked to the
gain of electron density in the purine ring as the 18C6 ether
+
to the N3, N9 and N7 atoms. The larger sized K counter ion
+
could bridge between two neighboring molecules more readily
complexes with the K of K-Ade, reducing the level of
+
+
than the smaller, more tightly bound Na counter ion. In
interaction between the adeninate anion and K . In-plane
aqueous media, the self-association of nucleotide bases is
driven by π-π stacking in which the association constants for
nucleobases involved are in the order of purine-purine>
purine-pyrimidine>pyrimidine-pyrimidine. Therefore, at low
concentrations, with competitive hydrogen bonding to DMSO
solvent molecules, π-π stacking of the adenine salts is highly
mixed WC-HG hydrogen bonded dimers such as those observed
in the XRD crystal structure of K-Ade(18C6) might occur in
region 2 (Figure 2b). Evidence of abstraction of the K from the
+
[49]
18C6 in Figure 3c region 2, CH protons become shielded as
2
electron density is regained, suggests influence of the aggre-
+
gate formation on the interaction between K and 18C6 ether,
likely to be the dominant form of aggregation.
resulting in partial release, Scheme 1. Upon increasing the
temperature and shifting the equilibrium towards the monomer
form, the 18C6 would engage in tighter binding once again as
suggested by the increased temperature coefficient in Figure 4b
1
The absence of the NH peak at all concentrations in the H
2
+
NMR of K-Ade indicates that the interaction of K with the
adeninate anion is different from that of Na . Thus, an
alternative protonation state or proton exchange regime of the
+
+
showing increased interaction between the K ions and the
NH group of K-Ade, either with the hydrogen bonded DMSO or
18C6. The absence of the NH peak at higher concentrations
2
2
neighboring adeninate molecules, could provide an explanation
could be a result of imine formation involving significant
dynamics of chemical shifts. From the crystal structure of K-Ade
(18C6), the hydrogen bond lengths between the NH···N7 and
NH···N1 differ between the linked molecules, having the latter
differ quite significantly, 2.262 vs 2.160 Å, which could arise
from imine formation.
1
as to why the protons are not observed in the H NMR spectra.
+
The nuclear electric quadrupole moment of K is smaller than
+
that of Na , so its coupling with the hydrogen atoms is unlikely
the reason for an additional relaxation. If the π-π stacked dimer
does indeed occur, this phenomenon could be supported as
+
the K counter ion would be closer in the vicinity of the
hydrogen atoms or shared or in a dynamic equilibrium between
two adeninate anions.
2.5. Higher Order Aggregates
The addition of 15C5 ether to Na-Ade did not result in a
1
large difference in H NMR chemical shifts concluding that it did
Apart from providing insight into the site of coordination
between the counter ion and the adeninate anion, the crystal
structures provide an interesting comparison and perhaps even
some guidance for the aggregate structures of Na- and K-Ade
+
not completely interact with the Na from Na-Ade. The ability
of the solvent to solvate the cation will influence the association
constant for the M -crown formation. The Na (15C5) com-
+
[50]
+
+
plex is a perched complex allowing for the Na to interact with
[
51]
solvent molecules.
Therefore, in the presence of DMSO
solvent molecules and the highly competing adeninate anion,
+
complexation between Na and 15C5 ether will be significantly
lowered.
The addition of 18C6 to K-Ade resulted in a reduced
concentration dependence in region 1, Figure 3b, and at the
1
very dilute concentrations of region 1, the H NMR peak of the
NH2 protons became visible (Figure S4 insert). The 18C6
+
complexed with the K forming a new complex whereby the
+
K
ion is simultaneously interacting with the 18C6 and the
adeninate anion. The crystal structure of K-Ade(18C6) reveals
the feasibility of such an interaction and is supported by the
+
1
13
lack of evidence for removal of the K in the H and C NMR
spectra (the UV data on the other hand, was obtained in dilute
solutions with >100-fold excess of the crown to allow for
+
removal of the counter ion). The K (18C6) complex is destabi-
Scheme 1. Hydrogen bonded aggregates of K-Ade(18C6). Hydrogen bonding
shown by red dashed line
lized by the presence of the DMSO solvent molecules or any
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in solution. The Na- and K-Ade complexes in the crystal
structures do not show in-plane adeninate-adeninate anion
mixed WC-HG hydrogen bonded aggregates as observed in K-
Ade(18C6), nor are π-π stacked aggregates evident. Instead, the
Na- and K-Ade complexes are linked via the counter ions.
solvent, this effect would reduce with increased concentration,
which is what is observed with the reduced temperature
coefficient of K-Ade. The proposed aggregate formation is one
+
whereby one K-Ade coordinates via the N7 to the K of the
neighboring K-Ade molecule which then has another neighbor-
ing molecule coordinate via the N1. This type of aggregation
will begin to shield the counter ion from the solvent, reducing
the solvent electric field effect.
Hydrogen bonds occur between the NH of one molecule with
2
an N3 and N7 of two neighboring molecules. This could suggest
that higher order aggregate formation in region 2 of Figure 3a
are governed by the complexation of M-Ade molecules via the
counter ions present, Scheme 2, through the coordination of N1
or N7 to the counter ion of the neighboring M-Ade molecule.
Aggregation of this type could result in the migration of the
counter ion between the N3 or N9 position allowing the N9 or
N3, respectively, to be available for hydrogen bonding.
Dissociation of these aggregates with increased temperature
The above proposed aggregate formations do not rule out
the π-π stacking believed to occur at the lower concentrations
of region 1 as the complexation of the ionic complexes in
higher order aggregates in region 2 can disrupt the aggregation
in region 1. Adenine has been reported to form trimers and
[8]
higher order aggregates upon self-association. Dimer forma-
tion has been observed for adenine, adenosine and adenosine
monophosphate at concentrations lower than 5 mM, followed
by higher order aggregation at concentrations >5 mM ascribed
would result in shielding of the NH protons involved in the
2
hydrogen bond with the N3/N9 of the neighboring molecule,
and i.e. shielding of the C8-H and deshielding of the C2-H as
the counter ion moves back from the N9 into the N3N9
coordination site, as observed with the temperature coefficient
in Figure 4a. It has been suggested that the C8-H could be
[54]
to the polymerization of dimers. This provides confidence
that dimer formation can occur at low concentrations (region
1), followed by the formation of higher order aggregates with
increasing concentration (region 2).
[52]
involved in hydrogen bonding with DMSO, therefore, this
effect has not been ruled out as additional influence on the
chemical shift.
2.6. Thermodynamics of Self-Aggregation
The concentration dependent change in the temperature
coefficient in Figure 4a for K-Ade showed both purine protons
undergo deshielding in region 2 and decreases with increasing
concentration. This effect is ascribed to the temperature
dependent solvent electric field effect as no explanation can be
provided considering the disruption of hydrogen bonds. The
cation has a peripheral solvation shell of DMSO solvent
molecules which orient their dipoles towards the cation,
Scheme 2. The positive charge on the cation would be partially
reduced as an inflow of electron density from the partially
negative O atom of DMSO will occur, weakening the ionic bond
with the adeninate anion. An increase in temperature results in
Two processes are possible for a single adeninate anion, the
first is the ion-pairing between the adeninate anion and the
+
+
counter ion Na /K and the second is the self-aggregation of
the ion pairs. It is assumed here that i) the self-complexation
between free adeninate anions is negligible and ii) a significant
amount of ion-pairing already exists. The concentration de-
pendence of the chemical shifts observed in Figure 3 for Na-/K-
Ade, Na-Ade(15C5) and K-Ade(18C6), is ascribed to self-
aggregation and can occur via monomeric metal-adeninate (M-
Ade) addition, i.e. monomer!dimer!trimer etc. The isodesmic
1
and trimer models were used to fit the normalized H NMR data
[53]
the disorder of these arranged DMSO molecules, strengthen-
of region 2 (refer to Table S1 in SI for K vlaues). In addition, the
+
ing the ionic bond between K and the adeninate anion,
thermodynamic data for the 1:1 complexation between 15C5
+
leading to deshielding of both purine protons. If the higher
order aggregates in region 2 shield the cations from the
ether with the Na were obtained (Table S2). This was not
+
possible for the complexation between 18C6 ether with K .
The van’t Hoff plot for the self–aggregation of Na-Ade, Na-
Ade(15C5) and K-Ade and for the 1:1 complexation between
+
1
5C5 ether and Na is shown in Figure S15. The thermody-
namic data are given in Table 3.
The equilibrium constants of aggregation are small and
À 1
dominated by enthalpic interactions in the order of À 5 kJmol ,
which compares with a weak water-amide N···H hydrogen bond
and is smaller than that of the self-aggregation of 9-
[
55,56]
ethyladenine
which has an enthalpy of formation of
À 1
À 16.7 kJmol associated with more than one hydrogen bond.
Cyclic dimer formation (two hydrogen bonds involved in the
dimer) is largely preferred over linear dimers (one hydrogen
[5]
bond). Considering the above proposed ion-assisted aggre-
gate formation, only one hydrogen bond is involved between
two M-Ade molecules and it can therefore be expected that the
enthalpy of formation will be about half. The gain in enthalpy is
in part compensated by negative entropies of association of
Scheme 2. M-Ade aggregate formation via the N1 and/or the N7
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1
13
system was observed in the H and C NMR study. It is
proposed that the addition of 18-crown-6 ether results in
complex formation with the K-Ade, as indicated also by the
crystal structure of K-Ade(18C6).
Table 3. Aggregation constants and thermodynamic parameters for the
a
[a]
[b]
self-aggregation of Na-Ade , Na-Ade(15C5) and K-Ade and the associa-
[c]
+
tion constant for the 1:1 complexation between C15C and Na in DMSO-
as solvent at 305 K
d
6
À 1
[d]
[e]
[d]
Complex
K
agg [M
]
ΔH
ΔS
ΔG
1
In the concentration dependent H NMR studies, two
Na-Ade
Na-Ade(15C5)
2.4�0.3
À 4.7�0.2
À 5.2�0.5
À 8.0�0.5
À 8.3�1.6
À 2.2
À 2.7
regions with opposite chemical shift are observed which
indicate two aggregation steps. The first aggregation is ascribed
to dimer formation via π-π stacking as suggested by the
shielding of the purine protons by the ring current of the
neighboring stacked molecule. At higher concentrations, the
dimer formation is followed by higher order aggregate
formation of the Na- and K-Ade. The counter ion plays a role in
the self-aggregation allowing for coordination to the counter
ion of the neighboring Na-/K-Ade ion pairs. The size of the
counter ion influences how the aggregates are arranged or
propagated though space, revealing a clear difference between
the Na-Ade and K-Ade forms. The assembly of the Na- and K-
Ade complexes in the crystal structures does not show WC or
HG type arrangement of hydrogen bonded aggregates. The
possibility of weak hydrogen bond formation involving the NH2
is indicated by the small enthalpy of formation of about
3.0�0.5
À 2
K (M
)
K-Ade
0.59�0.03
À 4.5�0.3
À 19�1
+1.4
À 1
K
1
(M
)
Na-Ade(15C5)
28�3
À 23�2
À 50�5
À 8.4
[
a] Isodesmic model, [b] Trimer model, [c] 1:1 Guest-host model, [d]
À 1
À 1 À 1
kJmol , [e] Jmol
K
À 1 À 1
about À 8 Jmol K , which is much less than the value of
À 1 À 1
À 145 Jmol
K
that should typically be expected for the loss
of translational entropy of a Na-Ade unit due to conformational
[57]
order. Much of it must be compensated by a large gain in
entropy of liberated solvent molecules during aggregation of
[58]
Na-Ade and the gain in vibrational entropy from the formed
weak hydrogen bond which would result in loose NH vibration.
In addition, if the π-π stacked dimer, which would have more
order, is dissociated upon larger aggregate formation, this
would also increase the entropy. The equilibrium of the K-Ade
aggregate is slightly disfavored as seen by the slight positive
ΔG.
À 1
À 5 kJmol . The small decrease in entropy of about
À 1 À 1
À 8 Jmol
K
with aggregate formation indicates that there is
a gain in entropy due to either the liberation of solvent
molecules, rearrangement of dimer aggregates and/or there is a
gain in vibrational entropy from the formation of weak hydro-
gen bonds.
À 1
The change in enthalpy (ΔH=À 23 kJmol ) for the 1:1
+
complexation between Na and 15C5 ether is slightly larger
Theoretical studies have been conducted to investigate the
proposed sites of coordination between the counter ions and
the adeninate molecule (publication in progress). Current
studies are underway to confirm the modes of aggregation,
with this research providing a good starting point. Although
these studies have been conducted in a non-aqueous environ-
ment, they provide insight into how the existence of the
potential deprotonated adenine base can interact in the alkali
metal ions present, having the dielectric constant of DMSO fall
in between that within the DNA double helix and inside the
[59]
[60]
than that previously reported in DMF and DMSO (ΔH=
À 1
À 20 and À 15 kJmol , respectively) and is attributed to the use
of anhydrous DMSO-d . The presence of water significantly
6
+
[60]
reduces the binding of Na to 15C5 ether.
3. Conclusions
Disfavored tautomeric and anionic forms of nucleobases which
have gained attention recently surround their involvement in
mutations, replication, and translational errors as well as nucleic
acid catalysis and RNA-ligand recognition. However, there is a
lack of information surrounding the anionic forms of nucleo-
bases such as the adeninate anion. In this paper, the ion-pairing
and self-aggregation ability of the adeninate anion in DMSO are
investigated using NMR and UV spectroscopy and crystallo-
graphic methods. An understanding of the variability of
chemical shifts is needed in context of ongoing kinetic experi-
ments by NMR.
[37]
cellular environment.
The counter ion present plays an essential role in directing
aggregate formation, adding new insight into how the
adeninate anion interacts with neighboring molecules, and
hence provides information regarding the reactivity of the
systems as well as insight for the association of adenine with
alkali metal counter ions which can provide stability for these
forms.
The large ion-dependent difference in the UV absorbance Acknowledgements
λmax from 272 nm for K-Ade to 269 nm for Na-Ade shows that
+
+
ion-pairs exist between the adeninate anion and Na and K
The authors acknowledge the National Research Foundation for
the funding of the research and Scarce Skills Doctoral Scholarships
awarded (grant number 97879 to DMS B); the crystallographer at
the University of Pretoria, Dr Frikkie Malan, for performing the
XRD analyses; the NMR spectroscopy personal, Dr Mamoalosi
Selepe, for accommodating extended use of the instrument; as
well as Dr Shankara Radhakrishnan for allowing use of her UV
counter ions in DMSO at very dilute concentrations. The crystal
structures obtained from the ionic complexes have the ion
coordinate at the N1, N9 and N7 atoms of the purine ring. It is
proposed that a chelating N3–N9 coordination is highly likely to
exist in solution. The counter ions are not successfully removed
by the addition of 15-crown-5 and 18-crown-6 ether from the
Na- and K-Ade as no gain of electron density in the purine
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instrument. Open access funding enabled and organized by
Projekt DEAL.
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Manuscript received: February 9, 2021
Revised manuscript received: March 24, 2021
Accepted manuscript online: June 21, 2021
Version of record online: ■■■, ■■■■
1
7644–17648.
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ARTICLES
Adeninate-metal ion pairs exist in
DMSO solution whereby the metal
ion coordinates via the N3, N7 or N9
nitrogen atom or chelated between
the N3–N9 atoms of the purine ring.
The monovalent metal ion governs
higher order aggregate formation in
which the identity of the metal ion
plays a role in structural arrange-
ment. These results provide insight
into the reactivity and stabilization of
anionic adenine in the presence of
important biological ions.
D. M. S. Buyens, Prof. Dr. L. A. Pilcher,
Prof. Dr. E. Roduner*
1
– 10
Towards a Molecular Understanding
of Cation-Anion Interactions and
Self-aggregation of Adeninate Salts
in DMSO by NMR and UV Spectro-
scopy and Crystallography