Crystal structures of N6-modified-amino acid related nucleobase analogs (II): Hybrid adenine-β-alanine and adenine-GABA molecules

Article abstract of DOI:10.1039/c9nj02279a

In this manuscript we report the synthesis and X-ray characterization of four N⁶-amino acid/peptide-adenine-derivatives: N⁶-βAlaAde·1.5H₂O (1) and N⁶-GABAAde·2H₂O (2) and their corresponding protonated forms N⁶-βAlaAde·HCl (3) and N⁶-GABAAde·HCl (4). In (1) with a neutral adenine ring, the protonated carboxylate interacts with the N(7) and N(6)H of the neighbouring molecule. The hydrogen bond N9-H?N(3) and the hydrogen bonds between the water molecules are responsible for the planar and parallel disposition of the adenine rings. In (2), two different molecules are present in the crystal structure: (a) a cationic unit in which the N(7)H tautomeric adenine is protonated at N(3) and the carboxylic group interacts with N(6B)-H and N(7B) of the adjacent molecule; (b) an anionic unit, which presents the adenine ring in the N(9)H tautomeric form, where the carboxylate interacts with the N(7A)H and N(6A)H of the neighbouring adenine. In the hydrochloride form of N⁶-βAlaAde (compound 3) the amino acid chain with the carboxylic acid is almost orthogonal to the ring plane and exhibits protonation at N(3) of the adenine. On the other hand, in compound (4), the side chain is arranged parallel to the ring and anion (Cl^-)-π interactions are responsible for a parallel ordering of the final solid state architecture. We have studied the noncovalent interactions observed in the solid state architecture energetically using DFT calculations and rationalized the interactions using Molecular Electrostatic Potential surfaces and Bader's theory of "Atoms-in-Molecules". The main purpose of this study is to explore the competition between homodimer formation by the Hoogsteen site of the adeninium cation, and self-association of the carboxylic group or through the interaction of the carboxylic group with the adeninium cation by X-ray crystallography.

Full text of DOI:10.1039/c9nj02279a

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Vazquez-Lopez and J. J. Fiol, New J. Chem., 2019, DOI: 10.1039/C9NJ02279A.
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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Crystal structures of N6-modified-aminoacid related nucleobase
analogs (II): Hybrid Adenine-β-Alanine and Adenine-GABA
molecules
Angel García-Rasoa, Angel Terróna, Adela López-Zafra,a Andrés García-Viada,b Agostina Barta,a
Antonio Fronteraa,*, Julia Lorenzoc, Sergi Rodríguez-Caladoc, Ezequiel M. Vázquez-Lópezd and Juan
J. Fiola,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
In this manuscript we report the synthesis and X-ray characterization of four N6-aminoacid/peptide-adenine-derivatives:
N6-βAlaAde·1.5H2O (1) and N6-GABAAde·2H2O (2) and their corresponding protonated forms N6-βAlaAde·HCl (3) and N6-
GABAAde·HCl (4). In (1) with neutral adenine ring, the protonated carboxylate interacts with the N(7) and N(6)H of the
neighbour molecule. The hydrogen bond N9-H ···N(3) and the hydrogen bonds implying the water molecules are
responsible of the planar and parallel disposition of the adenine rings. In (2), two different molecules are present in the
crystal structure: a) A cationic unit in which the N(7)H tautomeric adenine is protonated at N(3) and the carboxylic group
interacts with N(6B)-H and N(7B) of the adjacent molecule; b) An anionic unit, that presents the adenine ring in N(9)H
tautomeric form, where the carboxylate interacts with the N(7A)H and N(6A)H of the neighbour adenine. In the
hydrochloride form of N6-βAlaAde (compound 3) the aminoacidic chain with the carboxylic acid is almost orthogonal to the
ring plane and exhibits protonation at N(3) of the adenine. On the other hand, in compound (4), the side chain is arranged
parallel to the ring and anion(Cl-)–π interactions are responsible of a parallel ordering of the final solid state architecture.
We have studied the noncovalent interactions observed in the solid state architecture energetically using DFT calculations
and rationalized the interactions using Molecular Electrostatic Potential surfaces and the Bader’s theory of “Atoms-in-
Molecules”. The main purpose of this manuscript is to explore the competition between homodimer formation by the
Hoogsteen site of the adeninium cation, self-association of the carboxylic group or through the interaction of the
carboxylic group with the adeninium cation by X-ray crystallography.
.
derivatives have been reported as protein kinase inhibitors.12
Furthermore, adenosine receptors participate in a variety of
pathophysiological processes (inflammation and cancer).13 In
fact, diverse antagonists have been already reported in the
literature.14 The biological activity of all these adenine
derivatives highly depends on the nature and position of the
substituents on the heterocyclic ring. The capacity to
synthesize new compounds, controlling their substitution
pattern, is a relevant topic for research, diversifying the
available adenine derivatives.
We and other have previously reported N6-substituted
adenines since they are interesting substrates due to their
cytokinin activity.15 Natural cytokinins (CK) are involved in
most aspects of plant growth. They are modified adenine
molecules with a side chain at the N6-position that exhibit
interesting biological properties including antiviral and
antitumoral activities.16 X-ray structural determination studies
of N6-modified-aminoacid/peptide nucleobase derivatives are
scarce and very little structural information is available.17 For
instance, Krasnov et al. have described the synthesis,
spectroscopic characterization and in vitro antimycobacterial
activity of N-(2-aminopurin-6-yl) and N-(purin-6-yl) derivatives
1. Introduction
The purine skeleton exists in a wide variety of molecules
either from natural1 or synthetic sources.2 Purine derivatives
have a number of applications and are common targets in the
synthesis of new therapeutic agents.3 For instance,
compounds containing the purine scaffold have been utilized
as interferon inducers4 and tested to treat chronic hepatitis C.5
Moreover, they are used as cytostatic antitumor agents6 and
Hsp90 inhibitors. In particular, they induce the degradation of
several Hsp90 client proteins associated to cancer.7
Adenine derivatives are promising therapeutic agents for the
treatment of osteoporosis,8 breast cancer,9 inhibitors of
cysteine protease cathepsin k10 and as potent
phosphodiesterase inhibitors.11 Several N-substituted adenine
a. Departament de Química, Universitat de les Illes Balears, Crta. de Valldemossa km
7.5, 07122 Palma (Baleares), Spain. E-mail: jfa950@uib.es; toni.frontera@uib.es
b. Facultad de Ciencias, Universidad Autónoma de Madrid
c. Instituto de Biotecnología y Biomedicina. Departamento de Bioquímica y Biologia
Molecular. Universidad Autónoma de Barcelona. Barcelona. Spain.
d. Instituto de Investigación Sanitaria Galicia Sur/
Universidade de Vigo. Departamento de Química Inorgánica, Facultade de
Química. Edificio Ciencias Experimentais. E-36310 Vigo. Galicia-Spain
CCDC deposition numbers 1913605-1913608 contain the supplementary
crystallographic data for compounds 1–4.
This journal is © The Royal Society of Chemistry 20xx
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with amino acids and peptides.17c Recently, we reported the ray diffraction were collected from DMSO/MeOH 1:1 solution
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synthesis and X-ray crystal structures of N6-aminoacid/peptide of the initial microcrystalline material. Anal. calcd for (1),
DOI: 10.1039/C9NJ02279A
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purines.
The packing of two hybrid adenine-glycine and C8H12N5O3.5 (234.21): C, 41.03; H, 5.16; N, 29.90. Found: C,
glycylglycine molecules was described and revealed that H- 40.50; H, 5.12; N, 29.95. FT-IR (cm-1): 1695m,sh, 1630s, 1604s,
bonding, anion- and lp- contacts were important in the 1469m, 1413s, 1385m, 1311m, 1253w, 1229m, 1172w,
1
packing of the solids. The supramolecular interactions of the 1034w, 963w, 906w, 793w, 675m, 636w, 537w. H NMR,
nucleobases in biological systems are of great importance δ(300 MHz); DMSO-d6: 12.88s,br [N+H], 8.19s [H8], 8.09s [H2],
since they determine the folding and assembly of these 7.55s,br [NH], 3.68s,br [HN-CH2-], 2.58t, (J = 7.2 Hz)[CH2-COO].
systems.19,20
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Herein, we report the synthesis, the lack of cytotoxicity‡ Synthesis of N6-GABAadenine·2H2O (2)
and X-ray crystal structures of two N6-aminoacid/peptide Yellow crystals of (2) were synthetized by the same method by
modified-adenine compounds, namely N6-βAlaAde·1.5H2O (1) using -aminobutyryc acid instead β-alanine. (60% yield). Anal.
and N6-GABAAde·2H2O (GABA = -aminobutyric acid) (2) and calcd for (2), C9H15N5O4 (257.1): C, 42.02; H, 5.88; N, 27.22.
their corresponding protonated forms N6-βAlaAde·HCl (3) and Found: C, 42.14; H, 5.85; N, 27.32. FT-IR (cm-1): 3380s,br,
N6-GABAAde·HCl (4) (see Scheme 1). We have analysed their 3286s, 1660s, 1628s, 1570sh, 1503m, 1468m, 1430m, 1402m,
X-ray solid state structure in detail. DFT calculations are used 1374m, 1321m, 1301m, 1244m, 1194m, 1139m, 977w, 781m,
1
to evaluate the formation energy of several supramolecular 706br,m, 629br,m, 543m. H NMR, δ(300 MHz); DMSO-d6:
assemblies, which are further characterized using the Bader’s 8.17s, 8.08s [H8,H2], 7.65s,br [NH], 3.49s,br [NH-CH2-], 2.28t,
theory of “atoms-in-molecules”.
(J = 7.2 Hz) [CH2-COO], 1.83 quintuplet (J = 7.2 Hz) [-CH2-].
Synthesis of N6-βAlaAde·HCl (3) and N6-GABAAde·HCl (4)
Light orange crystals of (3) and (4) were obtained by
treatment of (1) and (2) respectively in HCl 2M. The obtained
solution was refluxed during 2h. After two weeks of slow
evaporation, suitable monocrystals were obtained in each
case. Anal. calcd for (3), C8H10ClN5O4 (243.65): C, 39.44; H,
4.14; N, 28.74. Found: C, 39.45; H, 4.13; N, 29.15. FT-IR (cm-1):
3121s,sh, 1739s, 1652s, 1608m, 1510m, 1483m, 1444s,
1
1424m, 1393w, 1356m, 1290s, 1214s, 779m, 615m, 632w. H
Scheme 1. Representation of the N6-βAlaAde and N6-GABAAde compounds and the
atom-numbering scheme
NMR, δ(300 MHz); DMSO-d6: 9.50s,br, 8.60s [H8], 8.51s [H2],
3.78s,br [NH-CH2-], 2.68t (J = 6.9 Hz) [CH2-COO]. Anal. calcd for
(4), C9H12ClN5O2 (257.7): C, 41.95; H, 4.69; N, 27.18. Found: C,
41.68; H, 4.67; N, 27.05. FT-IR (cm-1): 3121s,sh, 1739s, 1652s,
1608m, 1510m, 1483m, 1444s, 1424m, 1393w, 1356m, 1290s,
2. Experimental
2.1. Materials and measurements
1
1214s, 779m, 615m, 632w. H NMR, δ(300 MHz); DMSO-d6:
9.91s,br, 8.61s [H8], 8.57s [H2], 3.63d,br [NH-CH2-], 2.38t (J =
7.2 Hz) [CH2-COO], 1.88 quintuplet (J = 7.2 Hz) [-CH2-].
All chemicals were obtained from commercial sources (Sigma-
Aldrich) and used without further purification. Elemental
analyses of C, H and N were carried out on a Carlo-Erba (1106
and 1108) and Microanalyzer Thermo Finnigan Flash 1112
apparatus. FT-IR spectra in the solid state (KBr pellets) were
measured in the 4000-400 cm-1 range on a Bruker Tensor 27
spectrometer. 1H NMR spectra were recorded at room
temperature on a Bruker AMX 300 (300MHz). Proton chemical
shifts in DMSO-d6 were referenced itself to DMSO-d6 [1H NMR
δ= 2.50 ppm]. The N6-βAlanine or GABA substituted adenines
were obtained according to the previously described method
by reaction of 6-chloropurine and βalanine or -aminobutyric
acid17,21 and further detailed below.
2.3. Crystallographic analyses
A summary of the key crystallographic information is given in
Table 1. Crystallographic data were collected at 100K on a
Bruker D8 Venture diffractometer Photon 100 CMOS using an
incoated high brilliance IμS microsource equipped with a
Incoated HeliosTM multilayer optics. Data reduction and cell
refinements were performed using the Bruker APEX3
program.22a Scaling and absorption corrections were carried
out using the SADABS program in all cases. The structures
were solved by direct methods using the program SHELXS.22b
All non-hydrogen atoms were refined with anisotropic thermal
parameters by full-matrix least-squares calculations on F2
using the program SHELXL.22b Hydrogen atoms were generally
inserted at calculated positions and refined as riders, except
those of the –NH and –CO2H groups and water molecule,
which were generally located using a Fourier difference map
and refined isotropically.
2.2. Preparation of the compounds
Synthesis of N6-βAlanyladenine·1.5H2O (1).
A mixture of βAlanine (10.6 mmol), 6-Chloropurine (5.3
mmol) and Na2CO3 (6 mmol) in 10 mL water were refluxed
during 3.5 h. The resulting green solution was cooled and the
pH adjusted to 3.5 using formic acid. An ochre-yellow-
microcrystalline product was obtained, washed with water
and air-dried (60% yield). Yellow monocrystals suitable for X-
2 | J. Name., 2012, 00, 1-3
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Table 1. Crystal data and structure refinement parameters for 1 to 4.
5
6
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8
Empirical formula
Formula Weight
Wavelength (Å)
Crystal system
Space group
C8H12N5O3.5 (1)
234.23
0.71073
Monoclinic
C 2/c
a = 28.836(2)
b = 10.5330(8)
c = 7.2981(5)
α=90
β=103.099(3)
=90
2159.0(3)
8/1.441
0.115
984
0.175 x 0.093
x 0.054
3.397 to 28.339°
-38≤h≤37,
-14≤k≤14,
-9≤l≤9
C9H15N5O4 (2)
257.26
0.71073
Monoclinic
P 21/c
a = 11.9730(14)
b = 12.7692(14)
c = 14.8340(18)
α=90
β=95.582(4)
=90
2257.2(5)
8/1.514
C8H10ClN5O2 (3)
243.66
0.71073
Monoclinic
P 21/n
a = 4.4965(3)
b = 18.9802(13)
c = 11.8656(7)
α=90
β=98.716(2)
=90
998.74(11)
4/1.620
0.376
C9H12ClN5O2 (4)
257.69
0.71073
Triclinic
P-1
9
a, b, c (Å)
a = 5.7390(3)
b = 9.8258(5)
c = 10.4109(5)
α=72.819(2)
β=85.079(2)
=85.218(2)
557.77(5)
2/1.534
0.341
268
0.189 x 0.085
x 0.083
2.174 to 28.318°
-7≤h≤7,
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α, β, γ (°)
Volume (Å3)
Z/Density(calc.) (Mg/m3)
Absorption coeff (mm-1)
F(000)
0.121
1088
504
0.298 x 0.273
x 0.193
2.761 to 28.333°
-5≤h≤5,
Crystal size (mm3)
0.298 x 0.067
x 0.032
2.629 to 28.401°
-15≤h≤16,
-17≤k≤17,
-19≤l≤15
θ range for data collect
Limiting indices
-25≤k≤25,
-15≤l≤15
99.7 %
-13≤k≤13,
-13≤l≤13
99.9 %
Completeness to θmax (%)
Max. and min. transmission
Data/restraints/parameters
Goodness-of-fit on F2
99.0 %
99.6%
0.7457 and 0.7228
2672/3/179
1.081
0.7457 and 0.6798
5616/0/362
1.023
0.7457 and 0.6685
2458/0/157
1.116
0.7457 and 0.7178
2780/0/170
1.090
Final R índices [I > 2σ(I)]
R1=0.086,
wR2=0.1359
R1=0.0855,
wR2=0.1018
0.788 and
-0.308
R1=0.0602,
wR2=0.1350
R1=0.1017,
wR2=0.1551
0.635 and
-0.398
R1=0.0307,
wR2=0.0750
R1=0.0334,
wR2=0.0763
0.401 and
-0.348
R1=0.0308,
wR2=0.0708
R1=0.0360,
wR2=0.0732
0.355 and
-0.265
R indices (all data)
Largest diff. peak
and hole (e.Å3)
CCDC
1913605
1913606
1913607
1913608
2.4. Theoretical methods.
and their protonated forms (3) and (4) are shown in Fig. 1.
The calculations of the non-covalent interactions were carried Selected hydrogen bonds are given in Table 2.
out using the Gaussian-0923 and the M06-2X/def2-TZVP level
of theory.24 To evaluate the interactions in the solid state, the
crystallographic coordinates have been used. This procedure
and level of theory have been successfully used to evaluate
similar interactions.25 The interaction energies have been
computed by calculating the difference between the energies
of isolated monomers and their assembly. The interaction
energies were calculated with correction for the basis set
superposition error (BSSE) by using the Boys–Bernardi
counterpoise technique.26 The Bader’s "Atoms in molecules"
theory (QTAIM) has been used to study the interactions
discussed herein by means of the AIMall calculation package.27
The molecular electrostatic potential surfaces have been
computed using the Gaussian-09 software.23
3. Results and discussion
3.1. Description of the crystal structures of 1–4
Single crystal X-ray analysis revealed that (1), (2) and (3)
crystallized in the monoclinic system with C2/c, P21/c and
P21/n space groups respectively, while (4) is triclinic (P-1). A
perspective view of N6-βAlaAde molecule (1), N6-GABAAde (2)
Fig. 1 X-ray structure of N6-βAlaAde·1.5H2O (1), N6-AdeGaba·2H2O (2), N6-βAlaAde·HCl
(3) and N6-GABAAde·HCl (4).
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A comparison of the asymmetric unit of N6-βAlaAde·1.5H2O (1) for the H-bonding geometric features) between the
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with N6-AdeGaba·2H2O (2) shows interesting changes: while Hoogsteen face of adenine and the carboxylic/carboxylate
DOI: 10.1039/C9NJ02279A
(1) is formed by neutral molecules with N(9)-H adenine groups of the side chains. In case of the anion (B), N7 acts as
tautomer, in (2) a pair of two different ionic molecules are H-bond acceptor (see green coloured supramolecular ring in
present: the carboxylate anionic form of the N(9)-H adenine Fig.3a) and the carboxylic group is protonated. On the
tautomer and protonated N(3) cationic form of the N(7)-H contrary, for the cation (A), the N7–H group acts as H-bond
adenine tautomer. The tautomerism of carboxylate salts of donor (see buff coloured supramolecular ring) and the
adenine and pharmaceutically relevant N6-substituted carboxylic group is deprotonated. The final 3D architecture is
adenines have been analysed in detail28 and the influence of generated by the stacking of these 2D layers as detailed in Fig.
hydrogen-bonding interactions and molecular recognition on 2b.
tautomeric and protonation equilibria has been also studied,
and some examples in which a non-canonical nucleobase
tautomer is stabilized by a properly positioned H-bond
acceptor have been reported in the literature.29
The crystal structure of (1) is dominated by a tandem of N(3)-
H(3)···N(9) interactions between coplanar adenine rings that
generate a self-assembled dimer (see Fig. 2a). Additional H-
bonding interactions through the Hoogsteen face involving
N(6)–H6 as donor and N(7) as acceptor and the COOH group of
neighbour coplanar molecules complete the connectivity into
the plane [O(1)–H···N(7) and O(2)···H6-N(6) H-bonds, see Fig
2a highlighted in pale green]. These 2D layers are connected
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by π-stacking interactions and reinforced by a network of
hydrogen bonds thus generating the final 3D structure (see
Fig. 2b).
Fig. 3 (a) 2D layer formed in compound (2) by means of H-bonding interactions. (b)
final 3D architecture.
Previous works have used adenines substituted with –(CH2)n–
COOH groups as minimalistic model systems to interpret
protein-nucleic acid interaction. Specifically, the presence of a
carboxyl group in adenine derivatives has been studied to
mimic adenine-aspartic/glutamic acid interaction.30 In
addition, it has been demonstrated that the hydrogen bonding
pattern of adeninium cation having incorporated –(CH2)2–
COOH at N9 position depends on the counterion. For instance,
the nitrate and chloride promote self-dimerization of
adeninium cation moiety through the Hoogsteen face. In
Fig. 2 X-ray solid state structure of compound (1). (a) Interactions into the plane (2D).
Distances in Å (b) 3D crystal packing.
contrast, the trifuoroacetate induces the cross-dimerization
between carboxylic group and the Hoogsteen face of
adeninium cation.30b
A characteristic fact of the asymmetric unit of (2) is the
presence of two different ionic species (organic salt). That is,
We have obtained the hydrochloride salts of compounds (1)
and
(2)
to
analyze
the
competition
between
the cationic A unit with the N(3) and COOH protonated and
the anionic B form with neutral ring and deprotonated
carboxylate group. A representation of the 2D interactions is
shown is Fig. 3 as well as the final 3D packing. The 2D layer
represented in Fig 3a is stabilized by a network of H-bonding
interactions. Curiously the protonated N(3)–H group does not
participates in this network because it is blocked by a water
molecule. In addition to the N(7)–H···N(9) adenine···adenine
H-bond that connects the counter-ions through the five
membered rings, the hydrogen bonding network is generated
by the formation of O–H···N and N–H···O contacts (see Table 2
homodimerization of the adeninium cation through the
Hoogsteen site, cross-dimerization where the carboxyl group
interacts with the Hoogsteen face of the adeninium cation and
finally, homodimerization of the carboxyl group.
Unexpectedly, compound (3) exhibits the N(3) atom of
adenine protonated instead of the more common N(1)
protonation site, see Fig. 1c. Moreover, the tautomeric form
of (3) is N(7)–H and, consequently, these cations occur as
dimers in the solid state crystal structure, hydrogen bonded
across a centre of symmetry, with an N(3)–H···N(9) distance of
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2.812(3) Å. It is possible that the occurrence of these dimers bonds (highlighted in buff colour, see Fig. 5a) Both types of
leads to the N(3) protonation instead of N(1). It is also worth supramolecular assemblies generate the formation of infinite
View Article Online
DOI: 10.1039/C9NJ02279A
mentioning that the Hoogsteen site of adeninium is blocked 1D tapes. These tapes stack generating 2D supramolecular
by a chloride anion that establishes a bifurcated H-bond with sheets (see Fig 5b) with partial ··· stacking between five
N(6)–H and N(7)–H groups. The H-bonded dimers stack in zig- membered rings (see Fig 5c). The chloride anions, in addition
zag columns along the c axis, with partial ··· stacking to the formation of several H-bonds connecting the adenine
between the imidazole and the six membered rings, as moieties, they establish Cl···π interactions, as indicated in Fig.
5
6
7
8
9
represented in Fig. 4b.
5c. The interaction is basically with the protonated N(1) atom
of the adeninium moiety (3.239 Å).
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Table 2. Selected hydrogen bonds [d(D-H) ≤ 1.02 Å and <(DHA) > 150°] for (1) to (4) [Å
and °]. See Scheme 1 for atom numbering.
(1)
D-H···A
d(D-H)
0.99(3)
0.88(2)
0.93(3)
0.99(3)
1.02(4)
d(H···A)
1.64(3)
1.95(2)
1.90(3)
1.96(3)
1.85(6)
d(D···A)
2.6185(17)
2.8173(17) 167.6(19)
2.8189(17)
2.8855(18)
2.782(4)
<(DHA)
170(2)
O(1)-H(1)···N(7)#1
N(6)-H(6)···O(2)#2
N(9)-H(9)···N(3)#4
O(1W)-H(1W2)···O(1) #1
O(2W)-H(2W2)···O(1W)
167(3)
155(2)
151(6)
#1 –x+½,y-½,-z+½; #2 -x+½,y+½,-z+½; #4 –x,-y+2,-z+1
(2)
D-H···A
d(D-H)
0.95
0.95
0.73(3)
0.88
1.02(3)
0.95
d(H···A)
2.36
2.57
2.02(3)
2.03
1.58(3)
2.63
2.05(4)
2.05(3)
1.92(4)
1.94(4)
1.94(4)
1.96(3)
1.93(3)
1.96(3)
2.07(3)
1.38(2)
d(D···A)
3.283(3)
3.400(3)
2.727(3)
2.897(2)
2.572(2)
3.508(3)
2.923(2)
2.867(3)
2.660(3)
2.756(3)
2.709(3)
2.750(2)
2.794(2)
2.755(2)
2.857(2)
2.552(2)
<(DHA)
163.0
146.2
164(3)
168.8
163(2)
154.5
C(32)-H(32)···O(1W)
C(2A)-H(2A)···N(1B)#1
N(3A)-H(3A)···O(1W)#2
N(6A)-H(6A)···O(1B)
N(7A)-H(7A)···O(2B)
C(8A)-H(8A)···O(3W) #2
N(6B)-H(6B)···O(2A)#4
N(9B)-H(9B)···N(9A)#5
0.88
0.84(3)
170.9
Fig. 4 (a) Detail of dimers in compound (3). (b) zig zag columns generated through -
stacking interactions.
165(2)
161(4)
172(3)
155(4)
164(3)
177(3)
175(3)
170(3)
165(2)
O(1W)-H(1W1)···O(3W)#6 0.77(4)
O(1W)-H(1W2)···O(2W)
O(3W)-H(3W1)···O(4W)
O(4W)-H(4W1)···O(2B)#5
O(4W)-H(4W2)···O(2A)#3
O(2W)-H(2W1)···O(1B)#4
O(2W)-H(2W2)···O(1A)#4
O(1A)-H(1A)···N7B#7
0.83(4)
0.82(4)
0.81(3)
0.86(3)
0.80(3)
0.79(3)
1.19(2)
#1 x+1,-y-½,z+½; #2 x+1,-y-3/2,z+½; #3 x-1,-y-½,z-½; #4 x,y-1,z;
#5 x-1,-y-3/2,z-½; #6 -x+1,y-½,-z-½; #7 x, 1+y, z
(3)
D-H···A
d(D-H)
d(H···A)
d(D···A)
<(DHA)
N(6)-H(6)···Cl(1)#5
O(2)-H(10)···Cl(1)
N(3)-H(3)···N(9)#6
N(7)-H(7)···Cl(1)#6
0.843(17) 2.426(18)
0.858(18) 2.168(18)
0.874(17) 1.973(17)
0.795(18) 2.432(18)
3.2626(12) 171.9(15)
3.0199(12) 172.1(15)
2.8125(15) 160.4(15)
3.1826(11) 157.9(15)
#5 x+½,-y+½,z+½; #6 -x+1,-y-½,-z+2
(4)
D-H···A
d(D-H)
d(H···A)
1.83(2)
d(D···A)
2.7290(15)
2.7734(14) 165.7(17)
2.9295(15) 162.2(18)
3.0306(11) 162.3(17)
<(DHA)
170(2)
O(1)-H(1)···N(7)#4
N(6)-H(5)···O(2) #4
N(9)-H(3)···N(3)#5
N(1)-H(4)···Cl(1)
0.90(2)
0.821(18) 1.970(18)
0.847(19) 2.112(19)
0.88(2)
2.18(2)
#4 -x-1,-y,-z; #5 –x+1, -y+1, -z-1
In case of hydrochloride (4) the expected N(1) is the
protonation site in the adenine ring and the tautomer is N(9)-
H (Fig 1c). Similarly to compound (3), it forms adenine
homodimers in the solid state via two symmetrically
equivalent N(9)–H···N3 H-bonds (highlighted in green, see Fig.
5a). Moreover, additional self-assembled dimers are formed
via two sets of [O(1)-H(1)···N(7) and N(6)-H(5)···O(2)] hydrogen
Fig. 5 (a) Detail of dimers in compound (4). (b) packing of dimer units through -
stacking interactions. (c) Detail of the anion–π/π–π/anion–π assembly
3.2 Theoretical Study
To gain an insight into the different modes of interaction
described above, we have performed a DFT at the M06-
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2x/def2-TZVP level of theory. The hydrogen bond energies spheres) also emerge upon complexation due to tVhieewfAortricmleaOtniloinne
were determined using two methodologies. First, we have of supramolecular rings. For the dimer DshOoI:w10n.10in39F/Cig9.N6J0b2,2t7h9Ae
used the common equation ΔE = E(A···B) – (EA + EB) [Eq. 1] where distribution also shows the existence of a weak C–H···O
E(A···B) is the energy (kcal/mol) of the H-bonded dimer and EA interaction between the H-atom of the alkyl chain and the O
and EB depict the energy of the individual monomers. atom of the carboxylic group. The interaction energy of this
Secondly, we have used the QTAIM and the value of the dimer is ΔE1 = –16.7 kcal/mol, which is larger in absolute value
kinetic G(rCP) contributions to the local energy density of than that obtained for the self–assembled dimer (see Fig. 6c,
electrons at the critical point (CP). We have computed the ΔE2 = –14.1 kcal/mol). We have also indicated in Fig. 6 the
energies for each individual H-bonding contacts according to individual energy of each H-bond, which was estimated using
the conventional approach by Vener et al.31 that was the QTAIM method by means of the kinetic energy G(r) values
specifically developed for HBs [Energy = 0.429 * G(r) at the at the bond CPs. For the self-assembled homodimer (see Fig.
bond CP]. The latter method is convenient to know the 6c), the agreement between the interaction energy computed
individual contribution of each contact and also to evaluate using Eq. 1 (–14.1 kcal/mol) or the QTAIM (–14.4 kcal/mol) is
the influence of the H-bonding in the presence of other excellent. For the dimer where the carboxylic group interacts
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interactions.
through the Hoogsteen face of adenine, the interaction energy
In Fig. 6a we show the molecular electrostatic potential using the QTAIM is slightly overestimated (–19.5 kcal/mol).
plotted onto the van der Waals surface for compound (1) as a The strongest H-bonds corresponds to the O–H···N(7) in
model of N6-carboxyalkyl substituted adenine. The MEP agreement with the shortest O···N distance observed
surface analysis is adequate to know the electron rich and experimentally and the acidity of the H-bond donor.
electron poor regions of the molecule. It can be observed that
the most positive region corresponds to the carboxylic acid
(+56 kcal/mol) followed by N9–H (+50 kcal/mol) and finally
N6–H (+36 kcal/mol). Moreover, the most negative parts
correspond to the N1 (–35 kcal/mol), followed by the O-atom
of the COOH group (–34 kcal/mol) and the N3 atom (–33
kcal/mol). The MEP is also negative at the N7 atom (–29
kcal/mol).
Fig. 6 (a) MEP surface of compound (1) at the M06-2X-def2-TZVP level of theory.
Isosurface 0.001 a.u. The energies at selected points of the surface are indicated. (b,c)
AIM distribution of bond and ring critical points (green and yellow spheres,
respectively) and bond paths obtained for two dimers of compound (1). The
interaction energies are indicated. The dissociation energy of the H-bond using the G(r)
Fig. 7 (a,b) AIM distribution of bond and ring critical points (green and yellow spheres,
respectively) and bond paths obtained for two dimers of compound (2). The
interaction energies are indicated. The dissociation energy of the H-bond using the G(r)
values at the bond CP are indicated in red (kcal/mol).
values at the bond CP are indicated in red (kcal/mol).
For compound (2) (organic salt) we have studied the energetic
In Fig. 6 we have also represented the distribution of bond
features of both dimers that govern the formation of the 2D
critical points (CP) and bond paths for the two dimers that are
responsible for the formation of the 2D layer in compound (1),
as aforementioned in Fig. 2a. The QTAIM analysis shows the
presence of appropriate bond CPs (3, –1) and bond path
between the N/O and H atoms for the intermolecular H-bonds
interactions in both dimers. Moreover, ring CPs (yellow
supramolecular sheet represented in Fig. 3a. The interaction
energies are very large due to the electrostatic attraction of
both counterions. In fact, the dimer represented in Fig 7a
exhibits a very large binding energy ΔE3 = –112.7 kcal/mol,
much larger than the dimer of Fig. 7b (ΔE4 = –55.8 kcal/mol)
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simply because the separation of the opposite charges is Moreover, the interaction energy is significant (ΔE8 = –17.2
View Article Online
smaller. In this case, it is very useful to use the individual kcal/mol) thus suggesting a relevant roleDiOnI:t1h0e.1c0r3y9s/Cta9lNpJa02c2k7in9Ag
energies obtained from the QTAIM analysis, because they are of (4). The distribution of bond CPs also shows a bond path
free from purely electrostatic effects. Interestingly, for the that connects the anion to one H-atom of the alkyl chain.
interaction where the carboxylate interacts with the adenine However, the contribution of this C–H···Cl interaction is very
(Fig. 7a), the QTAIM analysis shows the existence of an week (–0.8 kcal/mol).
ancillary C–H···O interaction in addition to the expected N–
H···O H-bonds, similarly to that described above for compound
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(1) (see Fig. 6a). This interaction is the weakest one (–1.9
kcal/mol), and the sum of the three interactions (–20.9
kcal/mol) is comparable to the interaction estimated for
compound (1) and also for the other dimer of compound (2) (–
19.9 kcal/mol) represented in Fig. 7b. These results show that
the binding energies for the interaction of either a carboxylic
or a carboxylate group with neutral or protonated adenine
through its Hoogsteen face are similar.
For compound (3), we have analysed the self-assembled dimer
shown in Fig. 8 and the interaction energy is ΔE5 = –12.1
kcal/mol, in excellent agreement with that computed using
the QTAIM (–12.8 kcal/mol). It is worthy to comment that the
binding energy of this dimer is smaller compared to the
equivalent dimer computed for neutral compound (1) (see Fig.
6c) in line with the longer H-bonds, likely provoked by the
protonation of the adenine rings.
Fig. 9 (a,b) AIM distribution of bond and ring critical points (green and yellow spheres,
respectively) and bond paths obtained for two self-assembled dimers of compound (4).
(c) AIM distribution of bond and ring critical points (green and yellow spheres,
respectively) and bond paths obtained for the anion–π complex of (4). The interaction
energies are indicated. The dissociation energy of the H-bond using the G(r) values at
the bond CP are indicated in red (kcal/mol).
4. Concluding remarks
We have synthesized and X-ray characterized several
derivatives of N6-akylcarboxy functionalized adenine and their
corresponding hydrochloride salts. We have studied and
rationalized the changes in the dimerization patterns of
Fig. 8 AIM distribution of bond and ring critical points (green and yellow spheres,
adeninium cation because of the competition between
respectively) and bond paths obtained for one self-assembled dimers of compound (3).
The interaction energy is indicated. The dissociation energy of the H-bond using the
G(r) values at the bond CP are indicated in red (kcal/mol).
homodimerization and cross-dimerization between the
carboxylic group and the Hoogsteen face of
adenine/adeninium cation. DFT studies and QTAIM analysis
revealed that the feasibility for self-dimerization through the
In compound (4), we have analysed two H-bonded self–
assembled dimers (see Fig. 9a,b) and the anion–π interaction
(see Fig. 9c). The interaction energy of the double N(7)–
H···N(3) self-assembled dimer (see Fig. 9a) is ΔE6 = –9.6
kcal/mol, also in excellent agreement with that computed
using the QTAIM method (–9.2 kcal/mol). This suggests that
the QTAIM is an excellent tool to predict the individual H-
bonding energies in adenine derivatives. The other self-
assembled dimer where two symmetrically equivalent
carboxylic···adenine interactions through the Hoogsteen face
are established is significantly more favoured (ΔE7 = –22.4
kcal/mol) due to the formation of four H-bonds. In general,
the H-bond energies are smaller for the hydrochloride salts
than for the neutral adenines. Finally, the QTAIM analysis of
the anion–π complex (see Fig. 9c) shows a bond CP and bond
path connecting the Cl anion to the N(1) atom of the adenine
ring, thus confirming the existence of the interaction.32
carboxylic
group
is
favoured
with
respect
to
homodimerization. The energetic study and evaluation of
individual contributions is useful in terms of mimicking
adenine-aspartic/glutamic acid interactions and for the
parametrisation of force fields.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
AF thanks the MINECO/AEI from Spain for a “Juan de la
Cierva” contract. We thank the MINECO/AEI from Spain for
financial support (project numbers CTQ2017-85821-R,
ENE2015-63969-C3-3-R, BIO2016-78057-R and SEV2015-0496,
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J. Stagg, Immunol. Cell Biol., 2017, 95, 333–339; (g) C. Cekic
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H-bonding networks and anion–π interactions in crystal structures of N -modified-aminoacid
adenine analogs are investigated using X-ray crystallography and DFT calculations.
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