Experimental and theoretical study of thymine and cytosine derivatives: The crucial role of weak noncovalent interactions

Article abstract of DOI:10.1039/c2ce25580d

In this paper we report the synthesis of N¹-hexylthymine (1), N¹-hexylcytosine (2), N¹-hexylcytosine hydrobromide (3) and [(N¹-hexylcytosinium)·(N¹-hexylcytosine)] ₂·[Cl₂Hg(μ-Cl)

Full text of DOI:10.1039/c2ce25580d

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PAPER
Experimental and theoretical study of thymine and cytosine derivatives: the
crucial role of weak noncovalent interactions{
a
a
a
a
Miquel Barcel o´ -Oliver,* Beatriz A. Baquero, Antonio Bauz a´ , Angel Garc ´ı a-Raso, Angel Terr o´ n,
a
b
Ignasi Mata, Elies Molins and Antonio Frontera*
b
a
Received 26th January 2012, Accepted 25th June 2012
DOI: 10.1039/c2ce25580d
1
In this paper we report the synthesis of N -hexylthymine (1), N -hexylcytosine (2), N -hexylcytosine
1
1
1
hydrobromide (3) and [(N -hexylcytosinium)?(N -hexylcytosine)] ?[Cl Hg(m-Cl) HgCl ] (4) (the
1
2
2
2
2
1
hemiprotonated form of the N -hexylcytosine forming a CHC pair with carbonyl-amino symmetric
+
3
and N –N recognitions) and X-ray characterization of compounds 1, 3 and 4. In the solid state, N -
3
1
1
hexylthymine 1 follows exactly the same behaviour as N -hexyluracil. In addition to strong hydrogen
bonding interactions, various weak forces, i.e. C–H/p, carbonyl–carbonyl (CLO…CLO) and anion–p
interactions (between the bromide and N of cytosine in 3), play a key role in stabilizing the 3D
1
architectures of the compounds. The theoretical calculations allow estimation of the strength of these
contacts and how they influence each other.
1
5
Introduction
ribosomal frame-shifting RNA pseudoknot. In addition, the
anion2p interaction has been observed in several biological
systems. For instance, it participates in the inhibition of the
The field of crystal engineering is nowadays viewed as a
comprehensive discipline, which is developed by scientists with
different interests. One of those is the construction of fascinating
topological architectures, and another one deals with modeling,
synthesis, evaluation and utilization of crystalline solids having
16
enzyme urate oxidase by cyanide or the enzymatic chlorination
17
of tryptophan by PrnA flavin-dependent halogenase. There are
18
several excellent reviews that describe different aspects of the
anion2p interaction.
1
,2
desired functions.
Unfortunately, the principle of designed
Moreover, finding new models for the study of nucleic acids
which mimic both the reactivity and the solubility conditions of
the biological models is of great importance. The use of simple
acyclic nucleosides as the methyl derivatives of the nucleobases
permits an enormous increase in the solubility of the molecules in
water, but maybe they are not the best examples to understand
the behaviour of the real bases. In this context, we have recently
communicated that the combination of a uracil ring with a long
aliphatic chain leads to a very interesting solid state architecture
synthesis of functional materials has not been achieved, mainly
because the delicate nature of competing weak forces makes it
difficult to succeed in a previously designed crystal engineering
3
experiment. Crystal structure prediction, which is an arduous
task, needs a precise understanding and complete control over
the complicated interplay of weak noncovalent interactions
responsible for crystal packing, since they are operating
3
–5
simultaneously.
Several noncovalent interactions are very commonly used by
chemists to construct supramolecular assemblies, such as
1
9
that resembles a lipid bilayer. The hydrogen bond donor/
acceptor capability of the nucleobase is responsible for the
formation of the 2D-hydrogen bonding network that nicely
stacks with another 2D layer by means of p–p interactions.
Hydrophobic interactions between the aliphatic chains are
responsible for the final architecture (see Fig. 1). Interestingly,
the prepared compounds, although insoluble in water, present
increased solubility in methanol and methanolic solutions, which
could perhaps model the cytoplasm dielectric constant.
6
hydrogen-bonding, p–p stacking, cation–p and C–H
,7
8
9
…
10
p
contacts. Moreover, lone pair (l.p.)–p and anion–p interac-
1
1
1
2
tions have been increasingly reported in the literature. For
instance, Egli and co-workers have reported two important cases
1
of l.p.–p interactions in biomacromolecules, i.e., the stabiliza-
3
1
tion of the structure of Z-DNA and the induction of the
4
a
Departament de Qu ´ı mica, Universitat de les Illes Balears, Ctra.
Valldemossa km 7.5, E-07122 Palma de Mallorca, Baleares, Spain.
E-mail: miquel.barcelo@uib.es; toni.frontera@uib.es
Institut de Ci e` ncia dels Materials (ICMAB-CSIC), campus de la
We have recently shown that these uracil derivatives form very
interesting quartets, with the same geometric parameters as those
found in RNA strands, stabilized by the presence of a silver
b
Universitat Aut o` noma, E-08193 Cerdanyola del Vall e´ s, Barcelona, Spain
Electronic supplementary information (ESI) available: Experimental
2
0
{
atom.
procedures for the preparation of 1–4, X-ray crystal data and
computational details. CCDC reference numbers 864483–864485 for
compounds 1, 3 and 4. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2ce25580d
Our recent findings bring us to study the effect of the long
aliphatic chains on the structure of cytosine and thymine.
Therefore, in this paper we report the synthesis and X-ray
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1
Fig. 1 Crystal packing of N -hexyluracil.
1
geometry of characterization of the related N -hexylthymine (1),
finding a similar structure as is described below. Furthermore,
we report the synthesis and solid state structures of the
protonated (hydrobromide, 3) and hemiprotonated (4) forms
Scheme 1 The four possible cytosine–cytosine base pairs. Among the
3
3
two hemiprotonated forms, the carbonyl-amino symmetric, N –N will be
preferred if the whole molecule does not restrict the geometry, due to the
presence of a third hydrogen bond interaction, mimicking a guanine–
cytosine interaction.
1
of N -hexylcytosine (2). In the former compound, an interesting
anion–p interaction is observed. In the latter compound, one
1
protonated N -hexylcytosine and one neutral N -hexylcytosine
1
+
moiety form an asymmetric base pair (CHC ) comprising three
hydrogen bonds.
˚
.71073 A) and graphite monochromator. Cell parameters were
0
2
The pKa reported for cytosine in water is 4.4, therefore the
1
determined from a set of 25 reflections in the range 4.6u , h ,
6.6u. Data collection was performed at room temperature with
v/2h scans. Measured intensities were corrected for Lorentz and
3
apparently easy protonation in N may induce the formation of
1
different pairing patterns. While neutral cytosine only forms one
kind of cytosine–cytosine pair, three possibilities are envisaged in
protonated cytosine that are drawn in Scheme 1. The results
presented herein will help to shed light to this topic, which is still
25
polarization with XCAD4. Numerical absorption correction
by Gaussian quadrature was applied.
Solving for structure factor phases was performed by direct
26
2
2
an object of study and discussion in the literature.
methods using SHELXS97 for compounds 3 and 4 and
27
SIR97 for compound 1 and the full-matrix least-squares
Finally, the different noncovalent interactions observed in the
solid state have been studied using high level ab initio
calculations (RI-MP2/auc-cc-pVDZ), focusing our attention on
the energy associated with each interaction. In compound 1,
where the interactions are dominated by dispersion, the standard
MP2 method overestimates the interaction. Therefore, we have
used the spin-component scaled SCS-RI-MP2 method, which
dramatically improves the accuracy, and provides energies
2
refinement on F , by SHELXL97. The structures were checked
26
28
for higher symmetry with the aid of the program PLATON.
Non-H atoms were refined anisotropically and H-atoms were
introduced in calculated positions and refined riding on their
parent atoms.
The hexyl aliphatic chains in all the compounds are disordered
over several different positions:
2
3
similar to the ones computed using the CCSD(T) method.
In compound 4, the occupancy for atoms from C9 to C12 and
C69 to C72, as well as their corresponding relatives C99 to C129
and C699 to C729, is 50%. Atoms from C29 to C32 present a
partial occupancy of 70% while their corresponding relatives
from C299 to C329 present 30% occupancy.
Crystal data collection and refinement
Suitable crystals of 1 and 4 were selected for X-ray single crystal
diffraction experiments, covered with oil (Infineum V8512,
formerly known as Paratone N) and mounted at the tip of a
nylon CryoLoop on an Oxford Diffraction Xcalibur system with
a Ruby detector, using graphite monochromated Mo-Ka
In compound 3, the aliphatic chain (from C7 to C12) is
disordered over three positions (C7–C12, 50% occupancy; C79–
C129 and C799–C1299, 25% occupancy for each).
1
˚
radiation (l = 0.7107 A). Crystallographic data were collected
In compound 1, the aliphatic chains on the N -thymine
2
4
at 183(2) K. The program suite CRYSALISPro was used for
data collection, semi-empirical absorption correction and data
reduction.
moieties are disordered over two positions. Occupancy for atoms
from C10 to C12 is 70% while their corresponding relatives (C109
to C129) present 30% occupancy. Atoms from C30 to C32
present a partial occupancy of 75% while their corresponding
relatives form C309 to C329 present 25% occupancy.
X-ray single-crystal data for 3 were measured on an Enraf-
Nonius CAD4 diffractometer with a Mo-Ka sealed tube (l =
5
778 | CrystEngComm, 2012, 14, 5777–5784
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Table 1 Crystal data and structure refinement parameters for compounds 1, 3 and 4
1
3
4
Empirical formula
Formula weight
Crystal system
Space group
C
11 18
H
210.27
N
2
O
2
C
276.18
Triclinic
¯
P1
10
H
18BrN
3
O
C
40 6 2 12 4
H70Cl Hg N O
1396.96
Monoclinic
P2 /c
Orthorhombic
Pbca
1
˚
a/A
11.6964(8)
17.7522(4)
22.7940(12)
90
90
90
4732.9(4)
16
1.180
0.082
1824
6.685(1)
8.004(3)
12.907(6)
89.62(5)
84.50(3)
81.14(3)
679.2(4)
2
7.4416(2)
28.1838(11)
25.9487(6)
90
91.616(3)
90
5440.1(3)
4
1.706
5.981
2752
0.41 6 0.10 6 0.06
2.68 to 26.37
27 ¡ h ¡ 9
235 ¡ k ¡ 32
232 ¡ l ¡ 24
32624
˚
b/A
˚
c/A
a/u
b/u
c/u
3
˚
Volume/A
Z
Density calc./Mg m
Absorption coefficient/mm
F(000)
Crystal size/mm
Theta range for data collection/u
Index ranges
23
1.350
3.009
284
2
1
0.42 6 0.19 6 0.12
2.46 to 25.68
214 ¡ h ¡ 14
0.50 6 0.12 6 0.06
1.59 to 26.00
28 ¡ h ¡ 8
29 ¡ k ¡ 9
0 ¡ l ¡ 15
2
2
16777
21 ¡ k ¡ 21
26 ¡ l ¡ 27
Reflections collected
2785
Independent reflections
Completeness to h max (%)
Max. and min. transmission
Data/restraints/parameters
4483 [R(int) = 0.0234]
99.9
0.9903 and 0.9665
4483/138/313
1.050
2661 [R(int) = 0.0332]
99.8
0.8375 and 0.3444
2661/417/229
1.016
11114 [R(int) = 0.0319]
99.9
0.7155 and 0.1930
11114/289/671
0.972
2
Goodness-of-fit on F
R
R
1
, wR
, wR
2
[I . 2s(I)]
(all data)
0.0599/0.1795
0.1085/0.1982
0.337 and 20.218
0.0547/0.1126
0.1309/0.1344
0.401 and 20.404
0.0520/0.1555
0.0896/0.1652
2.399 and 21.164
1
2
23
˚
Largest diff. peak and hole/e A
1
(
HMDS) for silylation. The second step is the alkylation of N
using 1-bromohexane and the subsequent desilylation in reflux-
ing methanol. Curiously, the reaction on thymine yields the
neutral compound 1 and the reaction on cytosine yields the
hydrobromide salt 3. Compound 2 and 4 were obtained from 3
by reaction with K CO and mercuric chloride, respectively. See
2
3
supplementary material for details regarding the synthesis, and
methods.{
Crystal Structure Description of 1.
Compound 1 crystallizes in the orthorhombic Pbca space group
3
with the asymmetric unit formed by a 4-carbonil-N symmetric
2
thymine–thymine base pair, as can be seen in Fig. 2. The base
2
Scheme 2 Synthetic route to compounds 1–4.
2
Publication material was generated with WinGX, ORTEP-3
9
3
for windows and Mercury.
0
31
Crystal data collection and refinement parameters are shown
in Table 1.
Results and discussion
Synthesis of the compounds.
We have synthesized compounds 1–4 by means of the general
procedure shown in Scheme 2. Compounds 1 and 3 were easily
obtained from either thymine or cytosine in two steps. The first
step consists of the synthesis of the O,O9-bistrimethylsilyloxy (or
N,O-bistrimethylsilyloxy) derivative using hexamethyldisilazane
Fig. 2 50% probability ORTEP representation for compound 1 (the
lower occupancy positions for the aliphatic chains have been omitted for
clarity). The two molecules are related by hydrogen bonds [distances:
…
N3 O24, 2.8123(6) A and N23 O4, 2.8350(6) A; angles: N3–H3–O24,
˚
…
˚
176.7u and N23–H23–O4, 173.8u] forming a thymine–thymine pair.
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1
-hexylcytosine. Unfortunately, all attempts to obtain suitable
crystals for X-ray crystallography of 1-hexylcytosine have been
unsuccessful. The noncovalent interactions that are responsible
for the formation of the stacked 2D H-bonded layers in
compound 1 will be further studied in more detail below.
Crystal Structure Description of 3
¯
Compound 3 crystallizes in the triclinic space group P1 with the
1
asymmetric unit consisting of one molecule of N -hexylcytosine
hydrobromide (the ORTEP representation can be seen in Fig. 5).
The cytosinium moiety is surrounded by three different
bromide atoms lying approximately in the same plane and
…
interacts with them by means of several N–H Br hydrogen
bonds. Each bromide also interacts with three different
cytosinium moieties, forming a planar ribbon (Fig. 6) reinforced
…
by C–H O hydrogen bonds between adjacent cytosinium rings.
This ribbon is placed in a whole stepped 2D layer thanks to
hydrophobic interactions between the aliphatic chains. The
presence of the bromide in the structure avoids the formation of
cytosine–cytosine pair interactions as described in Scheme 1. The
bromide is to some extend out of the plane caused by hydrogen
bonding interactions with two adjacent aliphatic chains
Fig. 3 Symmetry equivalence coloring for compound 1 forming a plane
normal to the c direction (aliphatic chains have been reduced for clarity).
The central base pair is forming hydrogen bonds with four other base
…
˚
pairs all around [distances and angles: O22 C6, 3.2511(8) A and
…
˚
1
62.14(4)u (light blue); O2 C26, 3.2103(8) A and 161.96(4)u (pink);
… …
˚ ˚
[
d(C(7)H Br), 3.262 A; d(C(10)H Br), 3.060 A]. In addition,
O2 C27, 3.4947(9) A and 142.80(5)u (pink); O4…C8, 3.5501(8) A and
45.44(5)u (orange)].
…
˚
˚
an interesting anion–p interactions are observed between the
1
bromide and a cytosinium ring (directed to the N atom). A more
1
detailed description of the solid state architecture of 3 is included
in the supplementary material.{
pair is surrounded by four additional pairs, forming a recogni-
tion plane (normal to the c axis of the crystal) with all the
aliphatic chains placed at the same side.
Crystal Structure Description of 4.
The non-standard hydrogen bonding interactions that extend
the H-bond network to form the 2D layer are depicted in Fig. 3.
First, the O2 of one molecule forms an intermolecular bifurcated
H-bond, one hydrogen atom belongs to the thymine ring and the
other one to the aliphatic chain (pink lines). Second, the O22 is
linked by a H-bond to C6 (blue line) and, finally, the O4 forms
1
Crystallographic analysis indicates that the reaction between N -
hexylcytosine and mercuric chloride yields an outer sphere complex
1
1
salt with formula [(N -hexylcytosinium)?(N -hexylcytosine)]
2
?
[Cl Hg(m-Cl) HgCl ]. The asymmetric unit contains two hemi-
2
2
2
+
protonated cytosine pairs (CHC ) and the anionic Hg
22
2 6
Cl
…
an O H–C bond with the aliphatic chain (orange line).
moiety (see Fig. 7).
2
+
An important aspect of this structure is that the 3D
architecture, which resembles a lipid bi-layer (see Fig. 4), is very
similar to that previously reported for 1-hexyluracil (see Fig. 1).
This result confirms that the combination of a pyrimidine base
and a long aliphatic chain leads to a well-defined 3D arrange-
ment combining hydrophobic and hydrophilic layers. It would
be nice to confirm the robustness of this arrangement using
In the bimetallic mercury moiety each Hg is bounded to two
bridging and two terminal chlorine atoms that form a distorted
tetrahedron around each metallic centre. This is quite a common
anionic moiety and even longer polymeric chains have been
described.
+
Concerning the hemiprotonated cytosine pairs (CHC ), very
few examples of this recognition pattern have been previously
Fig. 5 ORTEP representation (50% probability) for compound 3 (the
lower occupancy positions for the aliphatic chain have been omitted for
clarity).
1
Fig. 4 Crystal packing of N -hexylthymine.
5
780 | CrystEngComm, 2012, 14, 5777–5784
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Fig. 8 Symmetry equivalence coloring for compound 4 showing the
2
2
ribbon formed by alternation of Hg
2
Cl
6
anions (depicted in green) and
+
…
+
stacked CHC CHC cations (frontal and zenithal views).
Fig. 6 In compound 3, a planar ribbon is formed thanks to hydrogen
bonds between the cytosinium rings and bromides [distances and angles:
…
Br19 N4, 3.385(4) A and 165.7(3)u (black); Br1…N3, 3.239(3) A and
˚
˚
hydrophobic interactions between aliphatic chains forming a 2D
layer (Fig. 8). To pile the subsequent layers, chlorine atoms are
in close contact with upper and lower rings.
˚
…
1
61.1(2)u (black); Br1…N4, 3.529(4) A and 144.2(3)u (green); Br199 N4,
˚
…
˚
3
.434(5) A and 114.0(3)u (green); O2 C5, 3.123(5) A and 125.9(3)u
…
˚
(violet); O2 C6, 3.191(5) A and 122.2(3)u (violet)].
Theoretical analysis of the noncovalent interactions
In this part of the manuscript we study the energetic features of
some complexes observed in the solid state. In compound 1 we
have focused our attention in the noncovalent interactions that
govern the formation of the stacked 2D-layers. At first sight it
seems that this assembly should be governed by p–p stacking
interactions. However a closer look reveals that the thymine
rings of one 2D-layer are not located over the thymine rings of
the adjacent layer. In contrast, an absolute lack of overlapping is
observed, see Fig. 9.
We have computationally analyzed a fragment of compound
1
where two crucial interactions are established. They are
responsible for the aggregation of the 2D layers to generate the
final 3D architecture. These interactions are C–H/p and
…
carbonyl carbonyl interactions, which are indicated in the
theoretical model used to study this assembly (see Fig. 10). Both
Fig. 7 ORTEP representation (50% probability) for compound 4 (the
lower occupancy positions for the aliphatic chains have been omitted for
clarity).
3
reported in the literature. Among them, just in JETHAS and
2
3
ODICOU01 the authors define and describe a related cytosine–
3
cytosinium pair.
+
Two CHC units are stacked in the crystal structure as will be
discussed further on. This stacking is reinforced due to the
presence of hydrogen bonds established between the exocyclic
amino groups from cytosine rings and the monodentate chlorines
2
6
2
belonging to the Hg
2
Cl
anions at both sides of each stacking
…
˚
couple [distances and angles: Cl1 N4, 3.343(4) A and 169.4(3)u;
Cl3 N24, 3.350(5) A and 170.4(3)u; Cl2 N44, 3.266(5) A and
76.5(3)u; Cl4…N64, 3.426(4) A and 159.8(3)u]. The presence of
…
˚
…
˚
˚
1
22
two H-bonds at each side of the Hg
2
Cl
6
anions is responsible
Fig. 9 Zenithal view of the 2D stacked layers in 1. The hexyl chains and
hydrogen atoms have been omitted for clarity. The lower layer rings are
colored.
for the formation of a planar ribbon (intercalation of anions and
cations), which is extended in the b direction of the crystal by
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and the protonated cytosine (see Fig. 11). This protonated
cytosine also establishes numerous interactions coplanar to the
molecular plane, as has been described above. An interesting and
rare feature of this anion–p interaction is that the bromide is
located over one nitrogen atom of the cytosine ring. Therefore,
we have analyzed two aspects of this interaction: first the
location of the anion and second the binding energy associated
with the interaction. It should be mentioned that some of us have
2
…
recently demonstrated in Cl
triazine complexes that the anion
can be located at any point over the triazine ring without losing
much in the way of interaction energy with respect to the
3
5
minimum.
Fig. 10 Carbonyl–carbonyl and C–H/p interactions observed in the
formation of the 2D layer stacking and some energetic features of the
assembly (BSSE corrected) at the SCS-RI-MP2/aug-cc-pVDZ level.
In an effort to rationalize if the anion–p interaction is in part
responsible for the unexpected location of the bromide, we have
computed the electrostatic potential energy surface of
a
˚
Distances are in A.
theoretical model (see Fig. 12). In this model a methyl group
has been used instead of the hexyl chain and, in order to use a
neutral system, we have included the bromide ion that is
interactions are also complemented by attractive dispersion
interactions between the thymine rings. The distance of the
…
coplanar to the ring and forms two strong N–H Br bonds. Blue
contours indicate regions where the interaction with anions is
favourable. As expected, the most favourable region is coplanar
to the ring; however it is not available since it is occupied by
neighbouring molecules or anions in the crystal structure. Over
…
˚
antiparallel carbonyl carbonyl interaction is 3.049 A and the
2
computed energy (BSSE corrected) is –4.4 kcal mol , in
1
3
agreement with previous theoretical studies. This interaction
4
energy has been computed using the two thymine rings (A and
…
the ring, there is a very small region where the potential is
21
A9) that establish the CLO CLO interaction of the assembly
5
5 kcal mol and a more extended region (lighter blue) where
shown in Fig. 10. In addition, two equivalent C–H/p interactions
are established in the assembly shown in Fig. 10. They are
formed between one hydrogen atom of the methyl group of the
thymine of one layer and the thymine ring of the other layer. The
energy associated with the C–H/p and thymine–thymine disper-
21
the potential is 40 kcal mol . Interestingly, this region also
includes the nitrogen atom that interacts with the bromide in the
crystal. Obviously, the final location of the anion is determined by
the rest of intermolecular interactions also present in the crystal.
The computed anion–p interaction energy at the RI–MP2/aug-cc-
2
1
sion attraction interaction is –3.8 kcal mol (computed using A
and B). Finally, the hydrogen bonding interaction represented in
Fig. 10 is part of the extended hydrogen bonding network that
governs the formation of the 2D layers (see Fig. 3) and its
21
pVDZ level of theory is –21.7 kcal mol (see Fig. 11 and S3{).
Finally, we have studied several aspects of the base stacking
found in compound 4. As aforementioned, one protonated
1
-hexylcytosine and one neutral hexylcytosine moiety form an
2
1
interaction energy is –3.9 kcal mol (computed using A and B9).
It should be mentioned that the interaction energies shown in
Fig. 10 are probably overestimated because in the solid state
other neighbouring interactions are also present. We have also
optimized the model system shown in Fig. 10 and we have
compared the total formation of the assembly using the X-ray
coordinates and the optimized geometry (shown in Fig. S2, see
supporting information{). The formation energy using the X-ray
asymmetric base pair comprising three hydrogen bonds. The
21
computed interaction energy for this basis pair is 255.5 kcal mol
The formation of this complex is very preferred mainly because the
central hydrogen bond is strong due to the cationic nature of the
.
…
+
N–H group. In addition, this supramolecular complex (Cyt Cyt )
forms a p-stacking interaction with itself (see Fig. 13, left) forming a
multicomponent assembly. The surprising feature of this stacking is
…
+
that each supramolecular Cyt Cyt complex is positively charged
2
1
coordinates is –18.7 kcal mol (BSSE corrected) at the SCS-RI-
MP2/aug-cc-pVDZ level of theory, which strongly agrees with
the formation energy using the optimized assembly, which is
(+1) and therefore a repulsive electrostatic interaction in the
2
1
.
–
16.4 kcal mol
For compound 3 the theoretical study is focused on the
2
analysis of the anion–p interaction observed between the Br
Fig. 11 Top (right) and perpective views of the anion–p interaction
observed in the solid state of compound 3. The binding energy (BSSE
˚
corrected) of the anion–p interaction is also indicated. Distances are in A.
2
Fig. 12 EPS of compound 2. Energies in kcal mol . Each 3D contour
1
2
is plotted every 15 kcal mol .
1
5
782 | CrystEngComm, 2012, 14, 5777–5784
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Concluding remarks
In conclusion, we have synthesized and X-ray characterized
some thymine and cytosine compounds. Obviously, hydrogen
bond and ion-pair interactions govern the primary structural
motifs that constitute the backbone of the supramolecular
network arrangement. For instance, they control the self-
association of the nucleobases to form 2D layers in 1-hexylthy-
mine (1) and the formation of the asymmetric base pair
comprising three hydrogen bonds in 4. However, less conven-
tional and predictable noncovalent interactions, i.e. anion–p, C–
H/p and carbonyl–carbonyl (or dispersion p–p) contacts, are
found to have a pivotal role in the final solid-state architecture of
the molecules.
Fig. 13 Partial views of the crystal structure of compound 4. Distances
˚
are in A. Some energetic features of the assemblies (BSSE corrected) are
indicated.
The investigation herein reported also reflects that the
comprehensive understanding of weak intermolecular forces
that govern crystal packing should potentially allow a rational
design of solids with tailored physical and chemical properties.
The results described above are certainly of importance in this
regard, especially the combined experimental and theoretical
results obtained in the analysis of dispersion-dominated
CLO…CLO and C–H/p interactions in compound 1, anion–p
interactions in compound 3 and stacking interactions in
compound 4.
assembly can be anticipated. We have analyzed this issue and also
the particular binding mode of the stacking between individual
bases where the amino groups interact with the p-systems (see
Fig. 13, right). This type of stacking between aromatic ring-
36
containing nitrogen atoms has been described before, and it is
energetically favourable.
We have examined, using the theoretical model shown in
Fig. 13, the energetic characteristics of the different stacking
interactions observed in compound 4, paying special attention to
…
+
the stacking of the two sets of Cyt Cyt complexes [the
… …
Cyt Cyt ) assembly] and the individual Cyt Cyt stacking
2
+
+
(
Acknowledgements
interaction. In the theoretical model the hexyl chain has been
replaced by a methyl group. We have first computed the
We thank CONSOLIDER–Ingenio 2010 (projects CSD2010-
…
+
formation energy of the (Cyt Cyt )
2
assembly from the
0
065 and CSD2007-00041) and the MICINN of Spain (projects
…
+
previously formed base pair (Cyt Cyt ) complex. As expected,
the interaction energy is positive (see Fig. 13) due to the
electrostatic repulsion. However, this repulsive energy is not
large considering the short distance between the two charged N–
CTQ2011-27512 and CTQ2009-12520-C03-03, FEDER funds)
for financial support. We thank the Direcci o´ General de
Recerca, Desenvolupament Tecnol o` gic i Innovaci o´ del Govern
Balear (Accions Especials, 2011) and the Catalan government
+
H groups. This is due to the formation of two p–p stacking
(
grant 2009SGR-203) for financial support. We thank the
interactions between one neutral and one charged cytosine. It is
CESCA for computational facilities. B. A. B. acknowledges a
Master thesis grant from Fundaci o´ n Carolina (MAEC,
Gobierno de Espa n˜ a). M. B.-O. thanks Roland K. O. Sigel
and Bernhard Spingler for all the help received as well as the
Institute of Inorganic Chemistry of the University of Z u¨ rich for
the use of the facilities and infrastructure.
2
very favourable (28.6 kcal mol ) indicating that this binding
1
mode is energetically preferred. This favourable interaction
…
+
explains the modest repulsive energy of the (Cyt Cyt )
2
assembly.
+
Once the p–p stacking interaction was examined, we focused
our attention on the effect of the counterion. As shown above,
…
+
the (Cyt Cyt ) assembly is energetically unfavourable, how-
2
ever it is formed in the crystal structure because of the decisive
2
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784 | CrystEngComm, 2012, 14, 5777–5784
This journal is ß The Royal Society of Chemistry 2012