1-Ethyluracil, a New Scaffold for Preparing Multicomponent Forms: Synthesis, Characterization, and Computational Studies

Article abstract of DOI:10.1021/acs.cgd.1c00175

In this work, we describe the successful preparation of a series of cocrystals of the modified nucleobase 1-ethyluracil with different coformers in a 1:1 or 2:1 (nucleobase:coformer) ratio including urea (URE) or some compounds containing carboxylic and hydroxyl groups such as l-malic acid (MAL), l-tartaric acid (TAR), 2-hydroxybenzoic acid (SAL), 4-hydroxybenzoic acid (4HB), and 2,4-dihydroxybenzoic acid (DHB). The influence of the hydroxyl substituent on the alkyl chain for 1·TAR and 1·SAL cocrystals or the phenyl ring for 1·SAL, 1·4HB, and 1·DHB multicomponent solids was studied. All of the compounds were characterized by powder X-ray diffraction, FT-IR, and thermal methods. Moreover, for those whose single-crystal structures could be determined, computational studies were also performed to investigate the factors that may affect the cocrystal formation, the recurrent motifs, and the energies associated with the H-bonding interactions using DFT calculations and a combination of the quantum theory of atoms in molecules (QTAIM) and the noncovalent interaction index (NCIplot) computational tools.

Full text of DOI:10.1021/acs.cgd.1c00175

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Article
1
‑Ethyluracil, a New Scaffold for Preparing Multicomponent Forms:
Synthesis, Characterization, and Computational Studies
Yannick Roselló, Mónica Benito, Miquel Barceló-Oliver, Antonio Frontera,* and Elies Molins*
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sı Supporting Information
ABSTRACT: In this work, we describe the successful preparation
of a series of cocrystals of the modified nucleobase 1-ethyluracil
with different coformers in a 1:1 or 2:1 (nucleobase:coformer)
ratio including urea (URE) or some compounds containing
carboxylic and hydroxyl groups such as L-malic acid (MAL), L-
tartaric acid (TAR), 2-hydroxybenzoic acid (SAL), 4-hydrox-
ybenzoic acid (4HB), and 2,4-dihydroxybenzoic acid (DHB). The
influence of the hydroxyl substituent on the alkyl chain for 1·TAR
and 1·SAL cocrystals or the phenyl ring for 1·SAL, 1·4HB, and 1·
DHB multicomponent solids was studied. All of the compounds
were characterized by powder X-ray diffraction, FT-IR, and
thermal methods. Moreover, for those whose single-crystal structures could be determined, computational studies were also
performed to investigate the factors that may affect the cocrystal formation, the recurrent motifs, and the energies associated with the
H-bonding interactions using DFT calculations and a combination of the quantum theory of atoms in molecules (QTAIM) and the
noncovalent interaction index (NCIplot) computational tools.
INTRODUCTION
antiparasitic, or vasodilator/antihypertensive compounds. Re-
■
cently, istradefylline has been FDA approved for Parkinson’s
In recent years, crystal engineering has emerged as a predictive
tool for studying and understanding the arrangement of
molecules, giving birth to different solid materials with modified
13−17
disease in adults.
Among the nucleobases, uracil and its derivatives contain N−
H and CO groups, which are suitable hydrogen-bonding
donors and acceptors, respectively, and could result in strong
1
,2
physicochemical properties and performances. Especially in
the pharmaceutical industry but also in other areas such as
energetic materials, the objective has been to overcome
undesirable properties (chemical instability, low solubility,
hygroscopicity, untableting, ...) before the commercialization
of drugs or to ameliorate the viability of the available
6
hydrogen-bonded synthons. Up to now, several uracil
derivatives have also been described for cocrystallization with
18−21
other nucleobases
or with several small molecules used as
coformers. This is the case for the modified uracils: 6-
3
,4
22
explosives.
Although traditionally polymorphic and salt
chlorouracil and 6-chloro-3-methyluracil, 6-methyl-2-thiour-
2
3
24
screenings have been the selected methods for exploring these
versatile solid materials, more recently cocrystals have re-
emerged as useful alternatives. Cocrystals are defined as
multicomponent solids in which individual molecules are held
together by noncovalent interactions, often hydrogen bonds as
acil, orotic and isoorotic acids, and the well-known
5
,25−31
antineoplastic agent 5-fluorouracil
tegafur.
and its analogue,
5
,6
32
In this paper, we explore the ability of 1-ethyluracil (1), a
modified uracil with a N−H group blocked as observed in many
other known APIs (such as 5-fluoro-1-propargyluracil, idoxur-
idine, telbivudine, floxuridine, carmofur, ...), as a new scaffold for
cocrystallization by liquid-assisted grinding (LAG) and solvent
crystallization. The molecular structures of 1-ethyluracil and the
coformers selected in our study are depicted in Scheme 1.
7
−10
well as halogen bonding,
and π−π stacking interactions. As
reviewed recently, thanks to the effort done by academic and
industry researchers in finding new solid forms/cocrystals, a few
pharmaceutical cocrystals have been approved and commercial-
1
1
ized.
Nonetheless, not just active pharmaceutical ingredients and
energetic materials have been studied from a crystal engineering
point of view. Biomolecules such as nucleobases have also
attracted interest, first because their base-pairing nature in the
Received: February 15, 2021
Revised: July 21, 2021
12
solid state could be correlated to natural DNA or RNA.
Second, they are well recognized as integral components of a
great number of pharmaceuticals mostly having antiviral and/or
antitumoral activity as well as acting as antibacterial,
©
XXXX The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.cgd.1c00175
Cryst. Growth Des. XXXX, XXX, XXX−XXX
A

Crystal Growth & Design
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Article
Synthesis of 1-Ethyluracil−L-Tartaric Acid (1·TAR). A mixture
Scheme 1. Molecular Structures of 1-Ethyluracil and Selected
Coformers Used in This Work
of 1-ethyluracil (100.66 mg, 0.718 mmol) and L-tartaric acid (53.59 mg,
0
.357 mmol) was placed in a grinding jar with two drops of distilled
water. The mixture was milled for 30 min. Suitable single crystals were
obtained by dissolving the product in ethanol and using cyclohexane as
an antisolvent by vapor diffusion evaporation.
Synthesis of 1-Ethyluracil−2-Hydroxybenzoic Acid or Sali-
cylic Acid Cocrystal (1·SAL). A mixture of 1-ethyluracil (100.19 mg,
0.715 mmol) and salicylic acid (99.35 mg, 0.719 mmol) was placed in a
grinding jar with two drops of methanol. The mixture was milled for 30
min. Suitable crystals were afforded by dissolving the product in a
water−methanol mixture (1:1) and filtering the solution allowing it to
evaporate at room temperature.
Synthesis of 1-Ethyluracil−4-Hydroxybenzoic Acid Hy-
drated Cocrystal (1·4HB·H O). A mixture of 1-ethyluracil (75 mg,
2
0
.535 mmol) and 4-hydroxybenzoic acid (73.97 mg, 0.536 mmol) was
placed in a grinding jar with two drops of distilled water. The mixture
The selected coformers include urea, the two aliphatic
carboxylic acids L-tartaric acid and L-malic acid, and several
monohydroxyl- and dihydroxyl-substituted benzoic acids. All of
them are categorized as GRAS/EAFUS (generally recognized as
safe/everything added to food in the United States)
was milled for 30 min. From slow evaporation of a water−ethanol
solution of the previous solid, single crystals of 4HB·H O were
2
obtained.
Synthesis of 1-Ethyluracil−4-Hydroxybenzoic Acid Cocrystal
(
(
1·4HB_FI). 1·4HB·H O was dried at 50 °C under vacuum for 4 h.
2
3
3
Synthesis of 1-Ethyluracil−4-Hydroxybenzoic Acid Cocrystal
molecules. For instance, the presence of malic and tartaric
acids is very common in some fruits (pears, bananas, apples, and
grapes). 2-Hydroxybenzoic acid, also known as salicylic acid, is a
recognized drug used for aches and pain treatment, and its
structural isomer, 4-hydroxybenzoic acid, is used as a flavoring or
1·4HB_FII). A mixture of 1-ethyluracil (75.14 mg, 0.536 mmol) and 4-
hydroxybenzoic acid (74.10 mg, 0.536 mmol) was placed in a grinding
jar with two drops of methanol. The mixture was milled for 30 min.
Single crystals were obtained from a mixture of acetonitrile and propyl
acetate by slow evaporation.
34
adjuvant agent and has antioxidant properties.
1-Ethyluracil (75.10 mg, 0.536 mmol) and 4-hydroxybenzoic acid
74.06 mg, 0.536) were dissolved in methanol (1 mL) at room
(
EXPERIMENTAL METHODS
All reagents were purchased from Sigma-Aldrich Co. Analytical-grade
solvents were used for the crystallization experiments.
temperature. The solution was filtered using a 0.20 μm Nylon syringe
filter and allowed to slowly evaporate at room temperature. The
resulting solid was smoothly ground to obtain a fine powder.
■
Synthesis of 1-Ethyluracil−2,4-Dihydroxybenzoic Acid Coc-
Synthesis of 1-Ethyluracil (1). The modified uracil was obtained
35
rystal (1·DHB). A mixture of 1-ethyluracil (99.97 mg, 0.713 mmol) and
following a synthesis described previously. Briefly, the synthesis of 1-
ethyluracil was carried out in two steps. In the first step, the silylation of
carbonyl groups of uracil was afforded as follows. Hexamethyldisilazane
HDMS, 200 mL, 950 mmol, d = 0.774 g mL ) and uracil (11.208 g,
00 mmol) were mixed in the presence of catalytic amounts of
ammonium sulfate under a nitrogen atmosphere. The mixture was
stirred under reflux for 4 h. Then the excess HDMS was distilled. The
remaining product was stored under nitrogen. The second step includes
substitution of silylated units by ethyl groups. O,O′-Bis(trimethylsilyl)-
uracil (15 mmol), α-bromoethane (15 mmol), and anhydrous
acetonitrile (30 mL) were mixed in a 45 mL Parr digestion vessel.
The mixture was placed in an oven at 130 °C for 36 h. The resulting
product was first washed with boiling methanol (50 mL) for 30 min to
eliminate residual bromide and then concentrated in a rotary
evaporator to allow precipitation of fine white needles. The purity of
2,4-dihydroxybenzoic acid (110.18 mg, 0.715 mmol) was placed in a
grinding jar with two drops of distilled water. The mixture was milled
for 30 min. Single crystals were obtained by dissolving the product in a
water−methanol mixture (1:1) and filtering and slowly evaporating the
solution at room temperature.
−
1
(
1
Stability Study. The solids 1·4HB_FI and 1·4HB_FII were stored
in a desiccator at 40 °C for 1 week under a relative humidity (RH) level
of 75% by using a sodium chloride saturated salt solution to study the
effect of humidity on the stability of these two compounds.
1
Proton Nuclear Magnetic Resonance ( H NMR). Spectra were
recorded on a Bruker AMX 300 Advance spectrometer. Samples were
1
dissolved in deuterated dimethyl sulfoxide (DMSO-d ) ( H at 300
6
MHz). Chemical shifts are given in parts per million (ppm) relative to
the given solvent. The multiplicity is as follows: s = single, d = doublet,
dd = doublet of doublets, t = triplet, q = quartet. All of the data were
acquired and processed with MestReNova.
the solid was confirmed by proton NMR.
1
H NMR (DMSO-d , 300 MHz) δ, ppm: 11.17 (1 H, s, N(3)-H),
6
Powder X-ray Diffraction (PXRD). PXRD data were collected
using a Siemens D5000 powder X-ray diffractometer with Cu Kα
radiation (λ = 1.54056 Å), with 35 kV and 45 mA voltage and current
applied. An amount of powder was gently pressed on a glass slide to
afford a flat surface and then analyzed. The samples were scanned from
7
3
.63 (1 H, d, H(6), J = 7.8 Hz), 5.51 (1 H, dd, H(5), J = 7.8 and 2.4 Hz),
.65 (2 H, q, H(7), J = 7.1 Hz), 1.12 (3 H, t, H(8), J = 7.0 Hz).
Screening by Grinding. The mechanochemical synthesis of
cocrystals was performed by using a Retsch MM400 ball mixer in 10
mL agate grinding jars with two 5 mm agate balls. 1-Ethyluracil and the
selected coformer in a 1:1 or 2:1 stoichiometric molar ratio were ground
with two drops of solvent for 30 min at 30 Hz.
Synthesis of 1-Ethyluracil−Urea (1·URE). A mixture of 1-
ethyluracil (100.12 mg, 0.714 mmol) and urea (43.43 mg, 0.723 mmol)
was placed in a grinding jar with two drops of distilled water or
methanol. The mixture was milled for 30 min. Single crystals were
obtained in nitromethane with a few drops of ethanol.
2
θ = 2−50° using a step size of 0.02° and a scan rate of 1°/s.
Single-Crystal X-ray Diffraction (SC-XRD). Suitable crystals of 1·
URE, 1·DHB, and 4HB·H O were selected for X-ray single-crystal
2
diffraction experiments and mounted at the tip of a glass fiber on an
Enraf-Nonius CAD4 diffractometer producing graphite-monochro-
mated MoKα radiation (λ = 0.71073 Å). After a random search of 25
reflections, an indexation procedure gave rise to the cell parameters.
Intensity data were collected in the ω−2θ scan mode and corrected for
Lorenz and polarization effects at 294(2) K. The structural resolution
Synthesis of 1-Ethyluracil−L-Malic Acid Cocrystal (1·MAL). A
mixture of 1-ethyluracil (100.07 mg, 0.714 mmol) and L-malic acid
36
(
47.87 mg, 0.357 mmol) was placed in a grinding jar with two drops of
procedure was made using the WinGX package. The solution of
37
nitromethane. The mixture was milled for 30 min. Single crystals were
obtained by dissolution of the solid in nitromethane by heating. The
solution was cooled to room temperature, and suitable crystals were
obtained after a couple of days.
structure factor phases was performed with SHELXS-2013, except for
38
1·URE, for which SIR2014 was used, and the full matrix refinement
37
was carried out with SHELXL2014/7. Non-H atoms were refined
anisotropically. For 1·DHB, the aliphatic chain of the uracil (ethyl
B
https://doi.org/10.1021/acs.cgd.1c00175
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
pubs.acs.org/crystal
Article
Table 1. General and Crystallographic Data for Cocrystals 1·URE, 1·MAL, 1·TAR, 1·SAL, 1·4HB_ FII, and 1·DHB and Coformer
4
HB·H O
2
1·URE
1·MAL
1·TAR
1·SAL
1·4HB_FII
1·DHB
4HB·H O
2
molecular formula
C H N O
C H N O
C H N O
C H N O
C H N O
C H N O
C H N O
3
7
12
4
3
16 22
4
9
16 22
4
10
13 14
2
5
13 14
2
5
13 14
2
6
6
10
2
formula mass
200.21
414.37
430.37
278.26
278.26
294.26
156.13
cryst syst
space group
monoclinic
triclinic
P1
triclinic
P1
triclinic
P1
̅
triclinic
P1
̅
orthorhombic
Pnma
triclinic
P1
̅
P2 /c
1
a/Å
b/Å
c/Å
α/deg
β/deg
γ/deg
V/Å3
4.981(4)
13.264(5)
14.555(6)
90
93.61(5)
90
959.7(9)
294(2)
4
7.010(5)
8.166(6)
9.062(7)
82.511(15)
67.387(14)
79.049(15)
469.2(6)
294(2)
1
6.9897(10)
8.2046(11)
9.0659(13)
83.135(2)
68.120(2)
79.314(2)
473.37(12)
294(2)
7.458(4)
8.072(5)
7.6435(6)
7.8752(6)
10.8760(8)
90.140(3)
104.635(2)
94.228(3)
631.56(8)
100.0
14.3590(19)
6.797(3)
13.880(3)
90
90
90
1354.7(7)
294(2)
4
1.443
0.116
6.186(4)
6.898(6)
8.910(4)
102.02(10)
103.67(6)
94.77(6)
357.8(4)
294(2)
11.598(7)
71.510(9)
78.728(9)
84.409(9)
648.9(6)
294(2)
2
T/K
Ζ
1
2
2
Dcalc/g cm−
3
1.386
0.110
1.467
0.121
1.510
0.127
1.424
0.111
1.463
0.964
1.449
0.120
μ/mm−
1
F(000)
424
218
226
292
292.0
616
164
no. of collected/unique rflns
no. of data/restraints/params
1745/1679
1679/0/148
0.15, −0.142
0.0461
0.1242
1.036
10230/4642
4642/3/284
0.155, −0.169
0.0491
0.1177
1.028
7308/4127
7763/2998
36973/2223
2223/0/184
0.20, −0.21
0.0366
0.0947
1.102
2591/1294
1294/0/144
0.175, −0.149
0.0403
0.1188
1.019
1468/1264
1264/3/117
0.241, −0.195
0.0467
0.1348
1.071
4127/3/277
0.20, −0.21
0.0552
0.1192
1.096
2298/0/185
0.20, −0.20
0.0397
0.1122
1.065
Δρ , Δρmin/e Å3
max
2
2
R (F > 4σ(F ))
2
R (F )
w
goodness of fit, S
substitution, C7 and C8) was split into two equivalent positions (50%
fractional occupancy) to account for the observed disorder. For 1·
DHB, H atoms were introduced in calculated positions, except those of
hydroxyl groups, which were found in a Fourier map and refined riding
atoms were refined anisotropically. H atoms were introduced in
calculated positions and refined riding on their parent atoms.
The structures were checked for higher symmetry with the help of
the program PLATON. In Table 1 general and crystallographic data
for the new cocrystals and 4-hydroxybenzoic acid monohydrate are
summarized. Hydrogen-bond parameters for all of the solved structures
can be found in Table S1 in the Supporting Information.
43
on their parent atoms. For 4HB·H O, H atoms were introduced in
2
calculated positions and refined riding on their parent atoms, except for
those bound to oxygen atoms, which were located in the Fourier map
and refined isotropically with U (H) = 1.5U (O). For 1·URE, H
Thermogravimetric Analysis−Differential Scanning Calo-
rimetry (TGA-DSC). Thermal analyses were carried out on a
simultaneous thermogravimetric analysis (TGA)−differential scanning
calorimetry/differential thermal analysis (heat flow DSC/DTA)
NETZSCH -STA 449 F1 Jupiter system. Samples (3−8 mg) were
iso
eq
atoms were introduced in calculated positions and refined riding on
their parent atoms, except for those bound to nitrogen atoms, which
were located in the Fourier map and refined isotropically with U (H) =
iso
1
.5U (N).
eq
−
1
A suitable crystal of 1·MAL was selected for an X-ray single-crystal
placed in an alumina pan and measured at a scan speed of 10 °C min
from ambient temperature to 250 °C under an N atmosphere as a
diffraction experiment and mounted at the tip of a nylon CryoLoop on a
BRUKER APEX-II CCD diffractometer using graphite-monochro-
mated Mo Kα radiation (λ = 0.71073 Å). Crystallographic data were
collected at 294(2) K. Frames taken with a 0.3° separation afforded
2
protective and purge gas (their respective flow velocities were 20 and 40
mL/min).
Attenuated Total Reflection Fourier Transform Infrared
Spectroscopy (ATR-FT-IR). Infrared spectra were recorded with a
Jasco 4700LE spectrophotometer with an attenuated total reflectance
1
0230 reflections up to 2θmax value of ca. 56°. Data reduction was
39
performed using SAINT V6.45A and SORTAV in the diffractometer
package. Data were corrected for Lorentz and polarization effects and
for absorption by SADABS. The structural resolution procedure was
carried out using SHELXT. Non-H atoms were refined anisotropi-
cally. H atoms were introduced in calculated positions, except those of
hydroxyl groups, which were found in a Fourier map and refined riding
on their parent atoms.
−1
accessory. The scanning range was 4000 to 400 cm at a resolution of
40
−1
4.0 cm .
41
Theoretical Calculations. The theoretical study reported herein
44
was carried out using the Gaussian-16 program package and the
45
PBE1PBE-D3/def2-TZVP level of theory. Since we intend to
estimate the interactions in the solid state, the crystallographic
coordinates have been used. This level of theory and methodology
Suitable crystals of 1·TAR and 1·SAL 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 a Bruker-Nonius X8 APEX-II KAPPA CCD diffrac-
tometer using graphite-monochromated Mo Kα radiation (λ = 0.7107
Å). Crystallographic data were collected at 294(2) K. Data were
corrected for Lorentz and polarization effects and for absorption by
46−48
have previously been used to evaluate similar interactions.
In this
work the binding energy and interaction energy terms have been used
interchangeably. They were computed as the difference between the
energies of the isolated monomers and their assembly and were
corrected for the basis set superposition error (BSSE) by using the
49
Boys−Bernardi counterpoise method. Bader’s quantum theory of
“atoms in molecules” (QTAIM) and the noncovalent interaction index
(NCIPlot) have been used to characterize the noncovalent interactions
40
SADABS. A suitable crystal of 1·4HB _FII was selected, covered with
oil (Infineum V8512, formerly known as Paratone N), and mounted at
the tip of a nylon CryoLoop on a Bruker D8 Venture diffractometer
using Cu Kα radiation (λ = 1.54178 Å). The crystal was kept at 100 K
50
using the AIMall program. The molecular electrostatic potential
(MEP) surfaces have been generated using the Gaussian-16 software
and the PBE1PBE-D3/def2-TZVP wave functions. The 0.001 au
isosurface has been used as the best estimate of the van der Waals
surface.
42
during data collection. Using Olex2, the structure was solved with the
XT structure solution program using intrinsic phasing and refined with
37
the XL refinement package using least-squares minimization. Non-H
C
https://doi.org/10.1021/acs.cgd.1c00175
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
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Article
Figure 1. Comparison of the experimental and calculated PXRD patterns of 1 and the as-synthesized cocrystals 1·URE, 1·TAR, 1·MAL, 1·SAL, 1·
4
HB·H O, 1·4HB_FI, 1·4HB_FII, and 1·DHB.
2
RESULTS AND DISCUSSION
close to 1, the highest value for identical patterns. Furthermore,
■
the unit-cell similarity index (Π) was also calculated by a
Powder X-ray Diffraction. Figure 1 presents the exper-
5
4,55
previously described method.
When Π is close to zero, the
imental and the calculated PXRD patterns for 1-ethyluracil and
the prepared cocrystals showing the excellent agreement among
them. Moreover, they also indicate the purity of the resulting
solids by the absence of the respective former compounds after
grinding.
two unit cells are very similar. In our case, a Π value of as low as
.001 was obtained. Thus, both compounds are both
0
isostructural and isomorphous.
The use of 4-hydroxybenzoic acid has allowed us to identify
three different forms (Figure 1). LAG in the presence of water
It is interesting to note that the powder patterns of the as-
synthesized cocrystals 1·MAL and 1·TAR show many character-
istic features in common, rendering what is known as
afforded a crystalline solid (1·4HB·H O), which was concluded
2
to be a hydrated form according to its TGA trace (Figure S1).
However, the use of methanol during the grinding process gave a
different XRD pattern (1·4HB_FII). On this occasion it was an
anhydrous form, as no weight loss was observed before
degradation during its thermogravimetric analysis (see Figure
51
isostructural solids. The formation of isostructural cocrystals
or salts due to the presence of solvent molecules or because of
the similarity among coformers is not an uncommon process,
and several interesting examples have been well described in the
5
2,53
S1). Moreover, drying 1·4HB·H O at 50 °C under vacuum gave
literature.
The resemblance between L-malic and L-tartaric
2
a new solid (1·4HB_FI), different from its parent compounds or
acids is considerable, and this isostructurality according to their
powder diffractograms means that the presence of an additional
hydroxyl group in the L-tartaric acid with respect to L-malic acid
does not greatly alter its tridimensional network but reinforces it.
The crystal structural similarity (CSS) tool from Mercury
1
·4HB_FII, which was also anhydrous. This means that a
second anhydrous crystalline form between 1-ethyluracil and 4-
hydroxybenzoic acid molecules was obtained (Figure S1).
Numerous efforts were made in order to obtain single crystals of
the three forms to confirm these observations. Nevertheless,
only adequate single crystals of 1·4HB_FII were obtained. In
contrast, single crystals of the coformer 4-hydroxybenzoic acid
monohydrate were obtained and will be discussed in the next
section. The stability of these two anhydrous forms was explored
under 75% relative humidity at 40 °C for 1 week. The PXRD
analyses for the two solids after this period showed that both
(
Materials module) of the CSD applied to two cocrystal
structures resulted in the structures being isostructural within
the distance and angle default tolerance values of 20% and 20°,
respectively, and with a default size of the molecular cluster of 15
molecules (the central molecule plus 14 others). With this set of
parameters, a root-mean-square deviation (RMSD) of 0.057 and
a PXRD similarity index of 0.992 were obtained, which is very
D
https://doi.org/10.1021/acs.cgd.1c00175
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
pubs.acs.org/crystal
Article
Figure 2. (a) Urea double chains along the a axis with their respective stacked 1-ethyluracils. (b) Self-assembly of a 1-ethyluracil and aromatic CH
interaction with urea. (c) Interactions among 1-ethyluracil and L-malic acid molecules and (d) π−π stacking. Interactions between L-tartaric acid and 1-
ethyluracil, forming (e) chains and (f) π−π stacking. Distances shown are in Å.
forms were stable, as they did not transform into the hydrated
cocrystal.
Crystal Structure Descriptions. 1·URE. The cocrystal was
prepared by slow evaporation from a nitromethane−ethanol
solution at room temperature. The crystal structure of this
compound was solved and refined in the monoclinic space group
distance, 2.861(3) Å (in red); angle, 150(2)°) and along the
sides to form the double chain (N(4)−H···O(1) distance, 2.951
Å (in green); angle, 176(2)°). The remaining nitrogen atom is
bound to 1-ethyluracil through N(2)−H···O(2) (distance,
2.955(4) Å (in blue); angle, 171(3)°). This chain is further
reinforced through π−π stacking within 1-ethyluracil molecules
(π−π interplanar distance 3.377 Å). Chains are communicated
by uracil molecules in a self-assembling arrangement, forming
planes parallel to the ac plane (N(3)−H···O(4) distance,
2.834(3) Å (in orange in Figure 2b); angle, 177(2)°). Planes are
connected through the hydrogen bond established between
uracil and the aromatic CH in the sixth position of 1-ethyluracil
(C(6)−H···O(1) distance, 3.477(3) Å (in purple); angle,
158.5°) (see Figure 2b).
P2 /c containing one molecule of 1-ethyluracil and a molecule of
1
urea in the asymmetric unit. In the supramolecular structure,
hydrogen bonds were formed by homosynthons between two 1-
ethyluracil molecules (imide−imide) or urea−urea molecules
(
amide−amide) and heterosynthons (amide−imide) in urea−1-
ethyluracil. The overall structure consists of columns of face-to-
face urea molecules and columns of 1-ethyluracil molecules as
shown in Figure 2.
The interactions with successive urea molecules form an
infinite double chain through the a axis (see Figure 2a) with
hydrogen bonds along the chain direction (N(4)−H···O(1)
1·MAL. Single crystals were afforded in nitromethane after
slowly heating the mixture and cooling it to room temperature.
The cocrystal crystallizes in the triclinic space group P1
E
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Figure 3. Chains (a) and stacking (b) observed in 1·SAL. (c) Contacts and d) packing in 1·4HB FII. Planes (e) and stacking (f) formed in the cocrystal
·DHB among 1-ethyluracil and DHB molecules. Only one orientation of the ethyl substituent in 1·DHB is shown. Distances are shown in Å.
1
containing two molecules of 1-ethyluracil and a molecule of L-
malic acid in the asymmetric unit. No solvent molecules are
observed, confirming the anhydrous state determined by
thermal methods.
confirms the noncentrosymmetric space group P1. This
substituent established further hydrogen bonds with a carbonyl
from the modified nucleobase through O(5)(H···O(2)C
(distance, 2.806(5) Å; angle, 175.1°) and O(5A)−H···O(4)
C (distance, 2.989(14) Å; angle, 168.8°).
No hydrogen bonds are observed among 1-ethyluracil
molecules. However, a π−π interaction is established: the
electronegative carbonyl groups interact with the electropositive
central region of the aromatic orbital deployed both above and
below the ring (O(2)···centroid, 3.351 Å; O(12)···centroid,
3.340 Å; O(14)···centroid, 3.451 Å; O(4)···centroid, 3.438 Å),
as shown in Figure 2d. Further contacts are formed, as shown in
Table S1.
L-Malic acid acts as a bridge between two 1-ethyluracil
molecules. From one side, hydrogen bonds among the −OH
group from carboxylic acid and OC from 1-ethyluracil were
established through O(6)−H···O(14)C (distance, 2.610(5)
Å (in black); angle, 172.8°) and O(1)−H···O(14)C
(
distance, 2.627(5) Å (in red); angle, 173(4)°) interactions.
There were also hydrogen bonds through the carbonyl from the
carboxylic acid by CO(3)···H−N(3) (distance, 2.867(6) Å
(
2
in blue); angle, 179.2°) and CO(7)···H−N(13) (distance,
.906(6) Å (in green); angle, 167.0°) contacts.
1·TAR. This crystal was prepared by antisolvent crystallization
from an ethanol−cyclohexane mixture. The crystal structure of
this compound was solved and refined in the triclinic space
group P1, containing two molecules of 1-ethyluracil and a
molecule of L-tartaric acid in the asymmetric unit. No solvent
Moreover, in this structure the −OH group from malic acid is
disordered and presents two possible orientations with 75% and
2
5% occupation factors. Both disordered positions are S chiral
centers, as expected for the reactant L-malic acid. This also
F
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molecules are observed. As noted previously in the Powder X-
ray Diffraction section, 1·TAR and 1·MAL are isostructural,
which is confirmed by an analysis of the hydrogen-bonding
interactions obtained by SC-XRD in each cocrystal. In a fashion
similar to that of the cocrystal with L-malic acid, herein the
dicarboxylic coformer L-tartaric acid also acts as a bridge
between two 1-ethyluracil units, establishing hydrogen bonds
first among O−H groups from carboxylic acids and C(4)O
groups in 1-ethyluracil, H21 and O4 (O(21)−H···O(4)
distance, 2.599(4) Å (in purple); angle, 165.3°) and H26 and
O14 (O(26)−H···O(14) distance, 2.621(5) Å; angle, 164.5°)
2.6051(14) Å (in blue); angle, 173.4°) (Figure 3c). Moreover,
the nucleobase and the coformer interact through the carbonyl
from 1-ethyluracil and the hydroxyl group from the 4HB
molecule (C(4)O(4)···H(14)−O(14): distance, 2.7434(14)
Å (in red); angle, 160.1°). These zigzag tapes are intercon-
nected, forming planes by further interactions through the
second carbonyl from 1ETURA and the aromatic C(13)−H
from 4HB (C(2)O(2)····H−C(13): distance, 3.294 Å; angle,
149.44°) or C(6)−H from the nucleobase and the carbonyl
from carboxylic acid in the coformer 4HB (C(17)O(17)····
H−C(6): distance, 3.330 Å; angle, 142.54°). Finally, the
tridimensional structure is accomplished by piling of these
sheets through π−π stacking among the uracil and aromatic
rings from the coformer.
(
see Figure 2e), and second among the carbonyl groups from
carboxylic units and the free N−H units from 1-ethyluracil,
N(13)−H···O(25) (distance, 2.921(5) Å (in red); angle,
1
75.3°) and N(3)−H···O(22) (distance, 2.908(5) Å (in
1·DHB. A cocrystal (1:1) of 1-ethyluracil and 2,4-dihydrox-
orange); angle, 165.4°).
ybenzoic acid was identified from solvent evaporation
performed in a water−methanol (1:1) solution. This compound
crystallized in the orthorhombic space group Pnma. The
asymmetric unit consists of one molecule of 1-ethyuracil and
one molecule of 2,4-dihydroxybenzoic acid.
L-Tartaric acid establishes further interactions through its two
alcohol substituents to the C(4)O group from 1-ethyluracil
molecules: O(24)−H···O(14)−C (distance, 2.790(5) Å (in
blue); angle, 158.0°) and O(23)−H···O(12)-C (distance,
2
.845(4) Å; angle, 169.8°).
Similarly to 1·MAL, the cocrystal does not form hydrogen
In this structure, 1-ethyluracil interacts mainly with 2,4-
dihydroxybenzoic acid, forming chains parallel to the c axis (see
Figure 3c). The acid group of 2,4-dihydroxybenzoic acid forms
two hydrogen bonds with O(2) and N(3) of 1-ethyluracil
bonds between 1-ethyluracil molecules. However, again a
certain π−π interaction is established; the electronegative
carbonyl groups interact with the electropositive central region
of the aromatic orbital deployed both above and below the ring
(
O(1)−H···O(2) distance, 2.633(3) Å (in red); angle 175(4)°;
N(3)−H···O(3) distance, 2.808(3) Å (in blue); angle 168.8°).
At the same time, an hydroxyl group in a para position from
another 2,4-dihydroxybenzoic acid bonds to the hydroxyl group
in an ortho position from the former 2,4-dihydroxybenzoic acid
(
for instance: O(12)···centroid, 3.351 Å; O(2)···centroid, 3.328
Å or O(14)···centroid, 3.602 Å; O(4)···centroid, 3.516 Å), as
shown in Figure 2f. Further contacts are observed, as shown in
Table S1.
(
1
O(5)−H···O(6) distance, 2.952(3) Å (in orange color); angle,
1
·SAL. This cocrystal was prepared by slow evaporation from
a methanol−water solution (1:1). The new compound crystal-
lized in the triclinic system with space group P1. The asymmetric
23(3)°) and to O(4) from 1-ethyluracil (O(6)−H···O(4)
distance, 2.697(3) Å (in green); angle, 178(3)°). These chains
are interconnected, forming planes parallel to the bc plane by
another hydrogen bond, within the aromatic C(6) in 1-
ethyluracil and the acid group in 2,4-dihydroxybenzoic acid
̅
unit consists of a 1-ethyluracil molecule and a salicylic acid
molecule.
In this case, 1-ethyluracil molecules present a self-assembling
arrangement using its Watson−Crick edge by tandem N(3)−
H···O(2) hydrogen bonds (distance, 2.8600(17) Å (in black);
angle, 168.8°). The interaction between 1-ethyluracil and
salicylic acid is established through the Hoogsteen edge with
the acid group edge (O(18)−H···O(4) distance, 2.5911(16) Å
(
1
C(6)−H···O(1) distance, 3.296(3) Å (in black); angle,
67.5°).
The aliphatic substituent presents orientational disorder on
both sides of the molecular plane as imposed by the space group
mirror plane. The planes stack on top of one another through
π−π stacking within 1-ethyluracil and 2,4-dihydroxybenzoic
acid molecules (π−π interplanar distance, 3.397 Å). Chains can
either be facing each other between planes, establishing van der
Waals forces, or opposing. These two configurations alternate
through the different planes (Figure 3d).
(
in red); angle, 165.1°; C(5)−H···O(17) distance, 3.444(2) Å
(
in blue); angle, 144.0°). Salicylic acid also establishes an
intramolecular hydrogen bond within its hydroxyl group and its
acid group (O(12)−H···O(17) distance, 2.5770(19) Å (in
green); angle, 146.2°). These interactions can be seen in Figure
4
HB·H O. During solvent evaporative crystallizations be-
3
a.
The planes formed through the described interactions are
2
tween 1-ethyluracil and 4-hydroxybenzoic acid, single crystals of
the latter were obtained in a water−ethanol mixture as the
solvent. The crystal structure obtained was triclinic with space
then piled on top of each other, thanks to stacking interactions
between 1-ethyluracil and salicylic acid molecules (N(3)···
salicylic acid centroid distance, 3.322 Å), thus completing the
whole structure as seen in Figure 3b.
̅
group P1 containing one molecule of 4-hydroxybenzoic acid and
one molecule of water in the asymmetric unit. After a search in
the Cambridge Structural Database (version 5.41, August 2020
update), our structure was found to be different from those
1
·4HB_FII. A suitable single crystal was obtained from slow
evaporation of a mixture of acetonitrile and n-propyl acetate.
The compound crystallized in the triclinic space group P1. A
5
6
described previously with refcodes PHBZAC04 and
̅
57
molecule of 1-ethyluracil and a molecule of 4-hydroxybenzoic
acid are included in the asymmetric unit.
PHBZAC05 or that previously described by Fukuyama et
58
al. In our case, the supramolecular structure is obtained by
carboxylic dimers in addition to water molecules participating in
OH···OH bridges with the hydroxyl groups from 4-hydrox-
ybenzoic acid and also with the carboxylic homosynthons, giving
birth to planes (Figure S1a). The planes are further piled up by
π−π interactions (π−π inteplanar distance, 3.437 Å), creating
the full 3D molecular arrangement (Figure S1b).
In this case, two different homosynthons were observed in the
supramolecular structure: those formed by self-assembly
between 1-ethyluracil molecules (C(4)O(4)···H−N(3)
distance, 2.8831(15) Å (in black); angle, 172.9°) and between
4
-hydroxybenzoic acid coformers by a strong carboxylic acid−
carboxylic acid synthon (O(18)−H(18)···O(17) distance,
G
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−
1
Spectroscopic Analysis of Cocrystals. 1-Ethyluracil,
coformers, and the new compounds were analyzed by Fourier
transform infrared spectroscopy in attenuated mode (ATR-FT-
IR) to detect changes in the vibrational modes of the functional
groups that could indicate new hydrogen-bonding interactions
among parent compounds and thus indicate cocrystal formation.
Their FTIR spectra are displayed in Figures S2−S7 in the
Supporting Information.
range of 1800−1500 cm , other changes can also be detected.
−1
The bands corresponding to CO (at ca. 1772−1708 cm )
from 1-ethyluracil disappeared for the cocrystal 1·4HB·H O,
2
−
1
and only bands at 1664 and 1643 cm appeared. Nevertheless,
−
1
for the anhydrous forms some bands at 1700−1726 cm can be
−
1
observed in addition to peaks at 1670−1650 cm .
Finally, in the FTIR spectrum of our last coformer, 2,4-
dihydroxybenzoic acid, bands at 3358, 2955, 2847, and 2547
−
1
The FTIR spectrum of compound 1 shows characteristic
bands in the range between 3150 and 3000 (3147, 3090, and
cm are assigned to O−H and C−H stretching vibrations. The
CO and CC vibrational modes appear at 1627 and 1520
−
1
−1
−1
59
3
011) cm for N−H, between 2980 and 2800 cm for CH,
cm , respectively. In the FTIR spectrum of the new
compound 1·DHB, the O−H band from the coformer and the
CO stretching mode from 1-ethyluracil have completely
−
1
−1
at 1772, 1739, and 1708 cm for CO, and at 1643 cm for
CC. In the FTIR spectrum of urea, characteristic bands at
427, 3328, and 3254 cm− (N−H) and 1674 cm (CO) are
1
−1
−1
3
disappeared and only a band at 1664 cm can be observed, thus
observed. After 1·URE cocrystal formation, the FTIR spectrum
confirming the formation of a new hydrogen-bonded compound
(see Figure S7).
(
Figure S2) shows some increasing values for bands of N−H
−1
vibrations (at 3451, 3350, and 3191 cm ). Other changes are
also observed for CO and CN stretching vibrations. These
new bands confirm the participation of all these functional
groups in the hydrogen bonds as deduced by the single-crystal
resolution.
Thermal Analysis. Finally, to gain more insight into the
physical properties, all of the new forms prepared and 1-
ethyluracil were analyzed with a simultaneous thermogravi-
metric analysis (TGA)−differential scanning calorimetry/differ-
ential thermal analysis (DSC/DTA). The TGA-DSC thermo-
grams are shown in Figures S8−S14 in the Supporting
Information. Relevant data such as temperatures of melting
(as Tpeak) for the new cocrystals and former compounds (1-
ethyluracil and coformers) are summarized in Table 2.
In the FTIR spectrum of L-tartaric acid, characteristic bands at
−
1
3
(
400, 3329, and 3104 cm1 for O−H (CHOH) and O−H
COOH) and at 1714 cm− for CO are observed. However,
the spectrum after grinding with compound 1 shows only a band
−
1
at 3412 cm for N−H and O−H vibrations and two overlapped
−
1
broad, intense bands with maxima at 1683 and 1648 cm for
CO and CC stretching modes, respectively, confirming the
new phase 1·TAR (Figure S3).
Table 2. Melting Points of Compound 1, Coformers, and the
New Cocrystals
b
compound
mp (°C)
144.9
130.6
104.9
120.2
104.2
72.3, 125.6
126.9
116.5
173.8
coformer
mp (°C)
The FTIR spectrum of L-malic acid shows typical vibrational
bands at 3524, 3380, and 2957 cm− for hydroxyl groups from
1
1
−
−
1
1
1
1
1
1
1
1
1
1
·URE
·MAL
·TAR
·SAL
URE
MAL
TAR
SAL
133
130
171−174
158.6
214.5
the chain and the carboxylic groups and at 2874 and 2671 cm
for −C−H (Figure S4). CO stretching appears at 1686 cm
as a strong band. After cogrinding of 1 and L-malic acid, the IR
−
1
spectrum of 1·MAL shows only one band at 3393 cm
a
·4HB-H O
4HB
associated with the hydroxyl group. In the region of CO,
2
·4HB_FI
·4HB_FII
·DHB
CN and CC vibrations, three strong bands at 1683, 1664,
−
1
and 1640 cm can be identified.
DHB
208−211
The FTIR spectrum of salicylic acid shows characteristic
−
1
a
b
bands at 3231 and 3004 cm for O−H from the phenol and at
Desolvation and melting. Sigma-Aldrich.
−
1
2
849 and 2532 cm for O−H from carboxylic acid and C −H.
ar
The CO vibrational bands from the carboxylic group appear
The TGA traces for 1 and all the other cocrystals have little
loss on dryings (lod) before degradation takes place, except for
−
1
at 1654 and 1609 cm and that of the CC stretch at 1578
−
1
cm . In the spectrum of the cocrystal 1·SAL, the band at 3231
the cocrystal 1·4HB-H O, which confirms the unsolvated state
2
−
1
cm from the salicylic acid has completely disappeared and
even the CO vibrational bands from the 1-ethyluracil and only
a band at 1652 cm−1 is observed (see Figure S5), indicating that
a new compound was obtained.
of 1-ethyluracil and these new cocrystals. For 1·4HB-H O, a 2%
2
loss on drying (calculated 2.1% for 1/3·H O) was observed,
2
corresponding to a dehydration process, which was accom-
panied by an endothermic peak at a Tpeak value of 72.3 °C in the
DSC thermogram, followed by a melting process (Tpeak = 125.6
°C). This observation agrees with the thermal behavior observed
for 1·4HB_FI. For all of the other cocrystals only a single
endotherm was observed in their respective DSC traces,
attributed to the melting of the multicomponent solids followed
by degradation.
The next group of compounds consisted of the use of the
coformer 4-hydroxybenzoic acid (Figure S6). In its FTIR
spectrum, typical bands for vibrational modes at 3354 and 3054
−
1
cm for O−H from the phenol and at 2947, 2811, 2653, and
−
1
2
541 cm for O−H (COOH) are observed. The CO and
−
1
CC stretching bands appear at 1669, 1605, and 1592 cm . In
LAG experiments, the use of water or methanol afforded two
different crystalline solids. When water was used , a hydrated
Frequently, melting points are used as an indicator of the
relative stability of the new compounds versus the parent
formers. According to the results obtained herein, all of the new
multicomponent solids showed melting peaks lower than those
of the former 1-ethyluracil and their respective coformers, except
for the 1·DHB cocrystal. The melting temperature of 1·DHB
lies between the melting peaks of its precursors. Thus, the
cocrystal 1·DHB shows a better thermal stability in comparison
to the modified nucleobase selected for this study.
cocrystal, 1·4HB·H O, resulted, as confirmed by the presence of
2
−
1
a band at 3498 cm that can be assigned to the OH group from
−
1
water molecules and another band at 3350 cm for OH from 4-
hydroxybenzoic acid. However, for the new 1·4HB_I and _II no
bands were observed in the OH region. This confirmed the
formation of new interactions for these compounds with respect
to the former compounds or even the hydrated cocrystal. In the
H
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Figure 4. MEP surfaces of 1 (a), SAL (b) URE (c), TAR (d), and 4HB (e) at the PBE1PBE-D3/def2-TZVP level of theory. Isosurface: 0.001 au. The
values at selected points of the surface are given in kcal/mol.
2
2
Figure 5. (a) QTAIM distribution of bond and ring CPs (red and yellow spheres, respectively) and NCIplot of the R (8) dimer of 1·4HB_FII. (b)
2
2
QTAIM distribution of bond and ring CPs (red and yellow spheres, respectively) and NCIplot of the tetramer of 1·4HB. (c) R (8) dimer of the 4HB
coformer in compound 1·4HB_FII. The dissociation energies of the H-bonds derived from the G values are indicated in red (in kcal/mol). The
r
formation energies (ΔE) computed at the PBE1PBE-D3/def2-TZVP level of theory are also indicated.
DFT Calculations. In this theoretical study we analyze the
energetic features of several supramolecular assemblies observed
in the solid state of the cocrystals, focusing on some recurrent
motifs and assigning individual energies to the different H-
bonding interactions. This analysis is convenient to evaluate the
relative importance of the interactions that govern the crystal
packing and to give insight into the ability of uracil to participate
in H-bonding networks with itself (self-assembly) and/or
hydrogen bond donor groups.
Figure 4 shows the molecular electrostatic potential of
compound 1 and several of the coformers used in this work. It
can be observed that in compound 1 the most negative atom is
the O4 atom (−40 kcal/mol) followed by the O2 atom (−33
kcal/mol) and the most positive value corresponds to the C−H
group adjacent to N1 (+38 kcal/mol) followed by the N−H
I
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Figure 6. (a) QTAIM distribution of bond and ring CPs (red and yellow spheres, respectively) and NCIplot of the pentamer retrieved from the X-ray
structure of 1·TAR. (b) QTAIM distribution of bond, ring, and cage CPs (red, yellow, and blue spheres, respectively) and NCIplot of a dimer of 1·
TAR. The dissociation energies of the H-bonds derived from the G values are indicated in red (in kcal/mol). The formation energies (ΔE) computed
r
at the PBE1PBE-D3/def2-TZVP level of theory are also indicated.
group, which has a value that is slightly lower (+34 kcal/mol).
strong O−H···O H-bonds with two adjacent 4-hydroxybenzoic
acid molecules and two additional C−H···O bonds involving the
aromatic C−H bonds. The formation energy of the tetramer
The MEP is more positive at the C−H group due to the
influence of the adjacent CH group of the ethyl group (the
2
2
MEP merges at the same spatial region). With regard to the
coformers, urea is the molecule of the series that presents
identical (in absolute value) maximum and minimum MEP
values (±50 kcal/mol): at the O atom, the minimum, and in the
from the R (8) motif dimer is ΔE = −22.9 kcal/mol. The
2
2
assembly has been characterized using the quantum theory of
atoms in molecules (QTAIM) in combination with the NCIplot
index. The QTAIM shows that each H-bond is characterized by
a bond CP that connects the O atom to the H atom belonging to
an O−H, N−H, or C−H group. The individual energetic
contribution of each hydrogen bond (dissociation energy) was
middle of both NH , groups the maximum. The most positive
2
MEP values in this series are located on the acidic H atoms of the
carboxylic groups (+47 to +56 kcal/mol) and the phenolic H
atom of 4HB (+58 kcal/mol). The MEP values at the O atoms
of the carboxylic groups (ranging from −27 to −37 kcal/mol)
and phenolic groups (−18 and −24 kcal/mol) are smaller than
those of the O atoms of 1 (−33 and −40 kcal/mol) and urea
also calculated using the kinetic energy density (G ) value
r
measured at the bond (CP) that characterizes the H-bond. It has
60
been estimated according to the approach by Vener et al. that
was explicitly developed for H-bonds (energy = 0.429G ). For
r
(
−50 kcal/mol). This MEP analysis anticipates that the H-
pure closed-shell H-bonds, this proportionality is equivalent to
bonding networks observed in the solid state of the cocrystals
that with the parallel curvature of the electron density λ (r ), as
3
CP
61,62
and compound 1 are expected to be energetically very strong.
G(r ) is linearly related with λ (r ).
The individual
CP
3
CP
2
2
Figure 5a shows the uracil R (8) dimer observed in the solid
dissociation energy of each H-bond is given in red in Figure 5.
state of 1·4HB_FII. The interaction energy of the dimer ΔE =
For the tetramer, the strongest H-bonds correspond to O−H···
1
−
10.4 kcal/mol (using the X-ray geometry of 1·4HB FII), thus
O (6.4 kcal/mol) followed by N−H···O (5.2 kcal/mol) of the
2
2
indicating that each H-bond is moderately strong. Interestingly
R (8) motif. This is also confirmed by the NCIplot method,
2
2
this R (8) dimer establishes two symmetrically equivalent and
which shows blue isosurfaces located between the O and H−O/
J
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Figure 7. (a) QTAIM distribution of bond and ring CPs (red and yellow spheres, respectively) and NCIplot of the urea tetramer retrieved from the X-
2
ray structure of 1·URE. (b) QTAIM distribution of bond and ring CPs (red and yellow spheres, respectively) and NCIplot of the R (8) dimer of 1·
2
URE. (c) QTAIM distribution of bond and ring CPs (red and yellow spheres, respectively) and NCIplot of the hexamer of compound 1·URE, where
the dissociation energies of the H-bonds derived from the G values are indicated in red (in kcal/mol). The formation energies (ΔE) computed at the
r
PBE1PBE-D3/def2-TZVP level of theory are also indicated.
N groups (see Figure 5b). The C−H···O bonds are significantly
energies are large (8.7 and 9.4 kcal/mol) and the NCIPlot
isosurfaces that characterize these H-bonds are dark blue. The
N−H···O H-bonds are weaker (4.3 and 4.4 kcal/mol, light blue
NCIPlot isosurfaces) and similar to the O−H···O H-bonds
involving the hydroxyl group of the tartaric acid (4.5 and 4.6
kcal/mol; latter value from Figure 6b). The ancillary C−H···O
H-bonds are significantly weaker, ranging from 0.6 to 0.9 kcal/
mol. The pentameric assembly represented in Figure 6a shows
that there is one remaining hydroxyl group that is available for
establishing additional interactions. In Figure 6b we show the H-
bond formed by this remaining hydroxyl group with the adjacent
uracil moiety in the X-ray structure. The combined QTAIM and
NCIplot analyses show that, in addition to the O−H···O H-
bond, several van der Waals and C−H···O contacts are also
established, which are characterized by the green isosurfaces
located between both monomers. The resulting interaction
weaker (1.9 and 1.6 kcal/mol), also in agreement with the
NCIplot that shows green isosurfaces between the O and H
2
2
atoms. Finally, the typical R (8) motifs are formed between the
carboxylic groups (see Figure 5c) in the solid state of this
cocrystal. These H-bonds are very strong (9.8 kcal/mol), thus
explaining the formation of the 4HB homodimers in the crystal
packing of 1·4HB_FII.
Figure 6a shows the pentameric assembly present in the X-ray
structure of 1·TAR, where the central tartaric acid is surrounded
by four uracil moieties. The QTAIM analysis reveals an intricate
combination of H-bonds, where up to 12 H···O contacts are
established. The formation energy of this assembly is very large
(
ΔE = −41.7 kcal/mol) and is comparable to the sum of the
3
individual dissociation energies, thus confirming that this
assembly is governed by O−H···O and C−H···O contacts and
also indicating the reliability of the QTAIM method in
estimating the H-bond energies. It should be emphasized that,
energy of this dimer is ΔE = −9.0 kcal/mol, which is larger in
4
absolute value than the sum of the dissociation energies of all H-
bonds (6.3 kcal/mol) due to these additional van der Waals
contacts.
in contrast to the rest of the cocrystals, the uracil ring in 1·TAR
2
2
does not form the self-assembled R (8) recurring motif.
Instead, it forms strong C−O···H−O H-bonds where the most
basic O4 atom and the most acidic H atoms of carboxylate
groups interact. This agrees well with the information extracted
by the QTAIM and NCIplot methods. That is, the dissociation
Figure 7a shows a tetrameric fragment retrieved from the
infinite 1D tape formed by the urea molecules in the solid state
of 1·URE (see also Figure 2a). The tape is formed by successive
2
4
R (8) and R (8) synthons, where the carbonyl group of each
2
4
K
https://doi.org/10.1021/acs.cgd.1c00175
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
pubs.acs.org/crystal
Article
2
Figure 8. (a) QTAIM distribution of bond and ring CPs (red and yellow spheres, respectively) and NCIplot of the R (8) dimer of 1·SAL. (b) QTAIM
2
distribution of bond and ring CPs (red and yellow spheres, respectively) and NCIplot of the tetramer of compound 1·SAL, where the dissociation
energies of the H-bonds derived from the G values are indicated in red (in kcal/mol). The formation energies (ΔE) computed at the PBE1PBE-D3/
r
def2-TZVP level of theory are also indicated.
urea establishes two N−H···O bonds with the neighboring
CONCLUSIONS
■
molecules. The formation energy of this tetramer is ΔE = −38.3
5
In this study eight cocrystals with the modified nucleobase 1-
ethyluracil and different types of coformers (urea and carboxylic
acid derivatives) were successfully synthesized and characterized
by powder X-ray diffraction, FT-IR spectroscopy, and TGA-
DSC analysis. The crystal structures for six of them and a new
hydrate of the coformer 4-hydroxybenzoic acid have been
determined from single-crystal X-ray diffraction. Only for half of
kcal/mol, which is larger than the sum of the dissociation
energies of all H-bonds (27.8 kcal/mol), likely indicating the
existence of favorable cooperativity effects. This interesting
tetrameric assembly causes the NH groups (two of them are
2
highlighted in Figure 7a by yellow circles) to point toward the
exterior of the tape, thus creating a region adequate for
interacting with electron-rich atoms. In the solid state of 1·URE,
these six solved cocrystals was self-assembly between uracil units
2
the uracil ring self-assembles via double N−H···O H-bonds
forming R (8) uracil dimers observed, while for the other
2
2
(
R (8) motif), forming dimers similar to those described for 1·
compounds (1·MAL, 1·TAR, and 1·DHB), the main
interactions are established through hydrogen bonds with the
coformer. Moreover, the cocrystals containing the dicarboxylic
linear coformers L-malic and L-tartaric acids are isostructural and
isomorphous, as deduced by a comparison of the PXRD patterns
and unit cells.
The interactions were studied through DFT calculations, and
in general, the behavior of the cocrystals reported herein agrees
well with the MEP surface analysis, since in 1·TAR and 1·SAL
the most basic O4 atom interacts with the acidic protons.
Moreover, in 1·4HB two different R (8) homodimers are
2
4
HB_FII (see Figure 5). This motif interacts with the urea tape
by means of the available O2 atom that establishes a bifurcated
H-bond with two NH groups, as confirmed by the QTAIM
2
analysis and the corresponding bond CPs and bond paths. A
hexameric model of the cocrystal is represented in Figure 7c,
where the interaction energy of the tetrameric urea assembly
2
with two R (8) dimers is ΔE = −27.4 kcal/mol.
2
6
In contrast to 1·4HB_FII, 1·SAL presents a self-assembled
R (8) dimer in the solid state, where O2 instead of O4
2
2
2
2
participates in the N−H···O H-bonds (see Figure 8a). The
formed, one involving uracil and the other the carboxylic groups
of the 4HB coformer. It is also interesting to note the solid-state
architecture of 1·URE cocrystal, where the infinite 1D tape
dimerization energy (ΔE = −9.4 kcal/mol) is smaller (in
7
2
absolute value) than that of the R (8) dimer of 1·4HB_FII due
2
to the participation of the less basic O2 atom. However, this
allows the most basic O atoms to form strong H-bonds with the
most acidic H atoms of the adjacent SAL molecules, thus
forming the tetrameric assembly shown in Figure 8b. The
formation energy of the tetramer considering the self-assembled
situates the NH groups pointing to the exterior of the tape,
2
2
2
allowing the R (8) dimers to be accommodated via the
formation of bifurcated H-bonds with the available O2 atom.
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.cgd.1c00175.
■
2
2
R (8) dimer previously formed is ΔE = −20.9 kcal/mol, which
8
*
is similar in absolute value to the sum of the dissociation energies
of the H-bonds (21.4 kcal/mol). The O−H···O H-bond is
characterized by the corresponding bond CP and bond path and
also a dark blue isosurface, in agreement with the large
dissociation energy (9.5 kcal/mol) of this H-bond. It is
interesting to highlight that the dissociation energy of this
strong H-bond is slightly smaller than that computed for the
homodimer of 4HB in the 1·4HB_FII cocrystal (9.8 kcal/mol;
see Figure 5). However, 1·SAL does not form carboxylic acid
homodimers likely due to the existence of the ancillary C−H···O
H-bonds (1.2 kcal/mol, see Figure 8b) that largely compensates
for the small energetic difference between the O−H···O4
dissociation energy in 1·SAL with respect to the O−H···O
dissociation energy in the COOH···COOH homodimer in the
Packing graphs of the crystal structure of 4-hydrox-
ybenzoic acid monohydrate 4HB·H O, FT-IR spectra,
TGA-DSC thermograms of the new compounds, and
hydrogen bond parameters for all the solved structures
2
(PDF)
Accession Codes
CCDC 2059088−2059094 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
1·4HB cocrystal.
L
https://doi.org/10.1021/acs.cgd.1c00175
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
pubs.acs.org/crystal
Article
(
9) Makhotkina, O.; Lieffrig, J.; Jeanning, O.; Fourmigué, M.; Aubert,
AUTHOR INFORMATION
Corresponding Authors
Antonio Frontera − Departament de Química, Universitat de
les Illes Balears, E-07122 Palma de Mallorca, Spain;
orcid.org/0000-0001-7840-2139; Email: toni.frontera@
uib.es
■
E.; Espinosa, E. Cocrystal or Salt: Solid State-Controlled Iodine Shift in
Crystalline Halogen-Bonded Systems. Cryst. Growth Des. 2015, 15,
3
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464−3473.
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Gobetto, R.; Metrangolo, P.; Pilati, T.; Resnati, G.; Terraneo, G.
Polymorphs and co-crystals of haloprogin: an antifungal agent.
CrystEngComm 2014, 16, 5897.
Elies Molins − Institut de Cien
̀
cia de Materials de Barcelona
(
11) Kavanagh, O. N.; Croker, D. M.; Walker, G. M.; Zaworotko, M. J.
(
ICMAB-CSIC), 08193 Bellaterra, Spain; orcid.org/
Pharmaceutical cocrystals: from serendipity to design to application.
Drug Discovery Today 2019, 24, 796−804.
0
000-0003-1012-0551; Email: elies.molins@icmab.es
Authors
Yannick Roselló − Departament de Química, Universitat de les
Illes Balears, E-07122 Palma de Mallorca, Spain
Mónica Benito − Institut de Ciencia de Materials de Barcelona
ICMAB-CSIC), 08193 Bellaterra, Spain
(12) Koch, E. S.; McKenna, K. A.; Kim, H. J.; Young, V. G.; Swift, J. A.
Thymine cocrystals based on DNA-inspired binding motifs. CrystEng-
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antibacterial agents. Front. Microbiol. 2019, 10, 952.
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Substituted Uracil Derivatives. Org. Prep. Proced. Int. 2009, 41, 479−
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15) Chakraborty, S.; Ganguly, S.; Desiraju, G. R. Synthon
(
(
Miquel Barceló-Oliver − Departament de Química, Universitat
de les Illes Balears, E-07122 Palma de Mallorca, Spain
5
(
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.cgd.1c00175
transferability probed with IR spectroscopy: cytosine salts as models
for salts of lamivudine. CrystEngComm 2014, 16, 4732−4741.
(16) de la Torre, B. G.; Albericio, F. The Pharmaceutical Industry in
Author Contributions
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019. An Analysis of FDA Drug Approvals from the Perspective of
Molecules. Molecules 2020, 25, 745.
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Cancer 2002, 38, 3−9.
18) Pedireddi, V. R.; Ranganathan, A.; Ganesh, K. N. Cyanurate
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
(
(
Notes
Mimics of Hydrogen-bonding patterns of Nucleic Bases: Crystal
Structure of a 1:1 Molecular Complex of 9-Ethyladenine and N-
Methylcyanuric Acid. Org. Lett. 2001, 3, 99−102.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(19) Portalone, G.; Colapietro, M. The 1:1 complex of cytosine and 5-
fluorouracil monohydrate revisited. Acta Crystallogr., Sect. C: Cryst.
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This work has been carried out through MINECO/FEDER
grant ENE2015-63969. M.B. and E.M. are grateful to the Severo
Ochoa FunFuture project (MICINN, CEX2019-917S) and the
Generalitat de Catalunya (2017SGR1687). M.B.-O. thanks the
Vice-Rector for Research and International Relations of the
University of the Balearic Islands for financial support in setting
up the single-crystal X-ray diffraction facility. A.F. thanks the
MICIU/AEI from Spain for financial support (Project
CTQ2017-85821-R, Feder funds).
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