On the supramolecular outcomes of fluorination of cyclohexane-5-spirohydantoin derivatives

Article abstract of DOI:10.1039/d0ce01841d

The quantitative assessment of intermolecular interactions and their cooperative effects has been performed in spirohydantoin-based model compounds, 3-benzoyl-1,3-diazaspiro[4.5]decane-2,4-dione (1) and 3-(4-fluorobenzoyl)-1,3-diazaspiro[4.5]decane-2,4-dione (2), through single crystal X-ray crystallography and quantum chemical studies. In both crystal structures, molecules generate the same hydrogen-bonded centrosymmetric R22(8) synthon. The extended supramolecular architectures depend on the C-HO, C-Hπ, stacking interactions and parallel interactions at large offsets, which lead to molecular sheets and further, with the assistance of the C-HF interaction in the case of2, to three-dimensional networks. Electrostatic potential maps have indicated that formation of the intermolecular FF interaction in the crystal structure of2results in a new region with a larger surface area and a higher negative potential in comparison to the individual fluorine atoms. Establishment of this interaction leads to strengthening of the interaction of one of the fluorine atoms with a third molecule from the environment which does not interact with both of them. When this third molecule interacts with both fluorine atoms simultaneously, the calculations have shown that the effect of strengthening of the individual interactions due to formation of the FF interaction is absent.

Full text of DOI:10.1039/d0ce01841d

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PAPER
On the supramolecular outcomes of fluorination
of cyclohexane-5-spirohydantoin derivatives†
Cite this: CrystEngComm, 2021, 23,
2606
Kristina Gak Simić,a Ivana Đorđević,b Anita Lazić,a Lidija Radovanović,a
Marija Petković-Benazzouz,c Jelena Rogan,d
b
Nemanja Trišovićd and Goran Janjić
*
The quantitative assessment of intermolecular interactions and their cooperative effects has been
performed in spirohydantoin-based model compounds, 3-benzoyl-1,3-diazaspiro[4.5]decane-2,4-dione (1)
and 3-(4-fluorobenzoyl)-1,3-diazaspiro[4.5]decane-2,4-dione (2), through single crystal X-ray
crystallography and quantum chemical studies. In both crystal structures, molecules generate the same
hydrogen-bonded centrosymmetric R22(8) synthon. The extended supramolecular architectures depend on
the C–H⋯O, C–H⋯π, stacking interactions and parallel interactions at large offsets, which lead to
molecular sheets and further, with the assistance of the C–H⋯F interaction in the case of 2, to three-
dimensional networks. Electrostatic potential maps have indicated that formation of the intermolecular
F⋯F interaction in the crystal structure of 2 results in a new region with a larger surface area and a higher
negative potential in comparison to the individual fluorine atoms. Establishment of this interaction leads to
strengthening of the interaction of one of the fluorine atoms with a third molecule from the environment
which does not interact with both of them. When this third molecule interacts with both fluorine atoms
simultaneously, the calculations have shown that the effect of strengthening of the individual interactions
due to formation of the F⋯F interaction is absent.
Received 19th December 2020,
Accepted 19th February 2021
DOI: 10.1039/d0ce01841d
rsc.li/crystengcomm
been synthesized and clinically evaluated, so today 20–25% of
marketed drugs contain at least one fluorine atom in their
Introduction
Over the past two decades introduction of the fluorine atom
into an organic molecule has been recognized as a routine
strategy to address many challenges encountered in drug
design and development.1 Owning to its resemblance to
hydrogen, high electronegativity and low polarizability, the
fluorine atom as a substituent at the specific site can
simultaneously influence many important properties of a
drug candidate, including control of conformation,
improvement of metabolic stability, modulation of pKa,
lipophilicity and protein binding affinity.1 Because of this, a
number of compounds based on scaffolds with fluorine have
structures.1b A need to balance processability, stability and
bioavailability of drugs has motivated identification of their
various polymorphs. Namely, the dissolution rate and oral
absorption of poorly water-soluble drugs are determined by
the physical state, while the crystal morphology can influence
possibility of formulation of different solid dosage forms. A
thorough understanding of the strength and directional
preferences of diverse intermolecular interactions enable to
control and predict development of the crystal structure.
Having in mind the frequent occurrence of fluorine in many
drugs, its participation in the formation of these interactions
have been widely investigated.2 Although individually weak,
the total energy of these interactions can become significant.
In contrast to anionic fluoride, the capability of the C–F
group to form hydrogen bonds has been questioned due to
the low proton affinity and its inability to modify this by
intramolecular electron delocalization.3 However, when the
carbon acidity is at least at the level of fluorobenzenes and
competing acceptors such as oxygen or nitrogen are absent,
the C–F⋯H–C interactions exhibit the directional
characteristics of weak hydrogen bonds.4 Additionally, a
Cambridge Structural Database (CSD)5 search has offered a
conclusion that fluorine from the C(sp3)–F group is a better
a Innovation Centre of the Faculty of Technology and Metallurgy, Karnegijeva 4,
11120 Belgrade, Serbia
b Institute of Chemistry, Technology and Metallurgy, National Institute of the
Republic of Serbia, University of Belgrade, Njegoševa 12, 11001 Belgrade, Serbia.
E-mail: goran.janjic@ihtm.bg.ac.rs
c Faculty of Physics, University of Belgrade, Studentski trg 12, 11001 Belgrade,
Serbia
d Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4,
11120 Belgrade, Serbia
† Electronic supplementary information (ESI) available. CCDC 2045907 and
2045908. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d0ce01841d
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hydrogen bond acceptor than fluorine from the C(sp2)–F
group.6 Loader et al. have examined the asymmetry of
bifurcation in (C–F)2⋯H–C bifurcated hydrogen bonds.7
Although asymmetry in distance does not require asymmetry
in angle and vice versa, a geometric analysis of these
hydrogen bonds has indicated a preference for symmetrically
bifurcated interactions.
Fig. 1 Chemical structures of 3-benzoyl-1,3-diazaspiro[4.5]decane-
2,4-dione (1) and 3-(4-fluorobenzoyl)-1,3-diazaspiro[4.5]decane-2,4-
dione (2).
When compared with the other halogens, the F⋯F
interactions have been regarded as controversial. The
anisotropy of repulsion has
a greater effect on short
interatomic contacts in lighter halogen than attraction
caused by weak polarization, which dominates the Br⋯Br
and I⋯I interactions.8 The results of the energy
decomposition have shown that electrostatic and dispersion
energies have similar contribution to the total interaction
energy and both overcome the repulsive component at
distances greater than 3.0 Å.9 Regarding their stereochemical
characteristics, Ramasubbu et al. have identified two types of
angular preferences around the halogen centres.10 Namely, a
“side-on” approach, nearly normal to the C–X bond, is not
necessarily stabilizing and it is caused by close packing (type
I), while a polarization of halogen atoms results in a “head-
on” approach, behind the C–X bond (type II). Although the
majority of the C–F⋯F–C interactions is of type I, Barcelo-
Oliver et al. have suggested that they are not caused by the
close packing only.11 Based on quantum chemical
calculations of model dimers of hexafluorobenzene,
Karnoukhova et al. have confirmed that the most favorable is
the interaction with C–F⋯F–C angles of 90° and the
interaction energy being around −2.7 kcal mol−1.12 The
interaction of type II with angles equal to 90° and 180° has
almost two times lower energy, while the least favorable is
the linear configuration. Bauzá and Frontera have
demonstrated the capability of metal coordination, hydrogen
and halogen bonding interactions to electrostatically enhance
F⋯F interactions involving the aromatic fluorine atoms
which leads to significant cooperative effects.13 An analysis of
the crystal structure of compounds with a perfluorinated
chain has enabled to identify an additional three point type
of the C–F⋯F–C interaction between one fluorine atom from
one molecule and two fluorine atoms from a neighboring
molecule with the interaction energy ranging from 1 to 20
kcal mol−1.14
important scaffold present in many biologically active
compounds and drugs, including blockbusters such as
phenytoin(5,5-diphenylhydantoin,
anticonvulsant),
nilutamide(5,5-dimethyl-3-(4-nitro-3-(trifluoromethyl)phenyl)
hydantoin, antineoplastic hormonal agent), nitrofurantoin(1-
((Z)-((5-nitrofuran-2-yl)methylidene)amino)hydantoin,
antibiotic) and β-D-glucopyranose spirohydantoin (glycogen
phosphorylase inhibitor).15 Notably, spirohydantoins have
been identified as a class of highly efficient, short-acting
prolyl hydroxylase 1–3 inhibitors causing
a
robust
erythropoietin upregulation in vivo in multiple preclinical
species.16 A spirohydantoin derivative, BMS-688521, has been
recognized as a potent antagonist of the interaction between
integrin leukocyte function associated antigen-1 and
intercellular adhesion molecules and further advanced into
clinical trials.17
Although the primary motifs, which constitute the
backbone of the supramolecular structure of hydantoin
derivatives, are governed by hydrogen bonding, special
attention in this work has been paid to the changes in the
supramolecular structures caused by replacement of the
hydrogen atom by the fluorine atom. An emphasis has
been given to the quantitative assessment of intermolecular
interactions involving fluorine, particularly the C–H⋯F and
F⋯F interactions, and the cooperative effect in systems
dominated by hydrogen bonding. A mutual influence of the
individual cyclic fragments of
1
and
2
has been
investigated and supported by a CSD survey. Having in
mind versatile biological activities of hydantoin derivatives,
especially spirohydantoins, it is expected that the obtained
results will help in affording guidelines for design of
supramolecular assemblies for the applications in the life
sciences.
In our previous paper,9 we have shown that the shift of
the electron density in the area of the F⋯F interaction leads
to formation of a new region with a larger surface area, a
higher negative potential, and, hence, a more pronounced
accepting ability. This new region has a greater ability to Results and discussion
build simultaneous intermolecular interactions with species
from the environment, thus compensating for the reduction
Molecular structures
¯
of the accepting capacity of the neighboring groups in the
molecule. Here, we present the synthesis and determination
of the crystal structure of two derivatives of cyclohexane-5-
spirohydantoin (1,3-diazaspiro[4.5]decane-2,4-dione) where
the benzoyl or 4-fluorobenzoyl group is introduced in
position 3 of the heterocyclic ring (Fig. 1). Hydantoin is an
Compounds 1 and 2 crystallize in the triclinic P1 space group
with Z = 2 (Fig. S1,† Table 1). In 2, the unit cell parameter a
is shorter than the corresponding parameter in 1 (for around
0.3 Å), whereas the parameters b and c are longer (for around
0.6 Å), which results in the larger unit cell volume of 2 than
of 1 (for ca. 3%).
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Table 1 Crystallographic and refinement data for 1 and 2
Representative ORTEP diagrams of 1 and 2 are shown in
Fig. 2. Selected molecular geometry parameters of the
investigated compounds are presented in Table S1.†
Compound
1
2
Formula
C15H16N2O3
272.30
C15H15FN2O3
290.29
As expected, the central hydantoin moiety is essentially
planar and nearly perpendicular to the mean plane of the
cyclohexyl ring (the corresponding dihedral angles of 88.7° in
1 and 89.7° in 2). An increase in the dihedral angle between
the hydantoin and phenyl rings, separated by a carbonyl
group, is observed in 2 (81.9°) relative to that in 1 (53.8°),
possibly caused by electronic effects of the fluorine atom.
The bond lengths and angles in the hydantoin ring are in
a good agreement with the values found in the related
cycloalkane-5-spirohydantoins.18 A shortening of the C2–N3
and N3–C4 bonds in 2 relative to those in 1 reflects the
transmission of electronic effects of the fluorine atom.
Introduction of this atom also causes enlargement of the N3–
C11 bond and shortening of C11–C12 bond in the bridge.
Bending of the C11O3 carbonyl bond is somewhat larger in
2 than 1. Namely, the C12–C11–O3 angle is greater than the
N3–C11–O3 angle in both crystal structures.
Molecular weight/g mol−1
Crystal system
Space group
Triclinic
P1
Triclinic
P1
¯
¯
a/Å
b/Å
c/Å
α/°
6.3079(13)
10.573(2)
11.415(2)
67.21(3)
78.84(3)
76.16(3)
677.1(3)
2
5.9981(12)
11.148(2)
12.073(2)
108.98(3)
101.57(3)
105.27(3)
699.3(3)
β/°
γ/°
V/Å3
Z
2
Dc/g cm−3
μ/mm−1
F(000)
1.336
0.094
288
1.379
0.106
304
Crystal size/mm
θ range/°
Limiting indices
0.75 × 0.25 × 0.18
3.45–25.34
−7 ≤ h ≤ 7
−12 ≤ k ≤ 10
−13 ≤ l ≤ 13
5159
2484
1919
0.0194
0.72 × 0.30 × 0.11
3.30–25.35
−7 ≤ h ≤ 7
−10 ≤ k ≤ 13
−14 ≤ l ≤ 13
4747
2559
1812
0.0189
Measured reflections
Independent reflections
Reflections with I > 2σ(I)
Rint
Final R indices [I > 2σ(I)]
R1 = 0.0606
wR2 = 0.1620a
R1 = 0.0772
wR2 = 0.1746
1.058
181
0.295, −0.175
R1 = 0.0482
wR2 = 0.1073b
R1 = 0.0733
wR2 = 0.1198
1.031
190
0.137, −0.174
Hirshfeld surface analysis
To quantify the intermolecular interactions present within
the crystal structures of 1 and 2, the Hirshfeld surface and
R indices (all data)
S
subsequent
fingerprint
plots
have
been
initially
Parameters
calculated.18c,19 The Hirshfeld surfaces mapped over dnorm
are illustrated in Fig. S2.† The bright-red spots show the N–
H⋯O hydrogen bonds, while faint-red spots in 2 are due to
the comparatively weak C–H⋯O interaction.
Δρmax, Δρmin/e Å−3
a
2
b
w = 1/[σ2(Fo2) + (0.1081P)2 + 0.0399P] where P = (Fo + 2Fc2)/3. w =
1/[σ2(Fo2) + (0.0549P)2 + 0.0354P] where P = (Fo2 + 2Fc2)/3.
A simple visual inspection shows that the fingerprint plots
of 1 and 2 are different (Fig. S3 and S4†). As expected, the
Fig. 2 a) ORTEP diagram of 1 and 2 with the atom numbering scheme. The thermal ellipsoids are drawn at the 50% probability level, b) overlay of
1 (green) and 2.
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H⋯H, H⋯O, H⋯C and especially H⋯F interactions in the
case of 2 have the highest contributions (Fig. S5†). Namely,
the H⋯H contribution in 2 is for 16.3% lower than in 1,
while the contributions from the other intermolecular
contacts are similar. The shortest H⋯H interactions are
depicted as a pair of broad spikes at de + di ∼ 2.2–2.4 Å,
whereby a subtle splitting typical for a three-atom contact
can be observed.19 The H⋯O interactions with a contribution
of around 30% have a symmetrical distribution of points,
whereby N–H⋯O hydrogen bonds are represented by a pair
of spikes at the bottom left of the fingerprint plot.19 The
H⋯C contacts, as the measure of the C–H⋯π interactions,
contribute with 14% to the overall fingerprint plot and are
presented as scattered wings. The presence of a pair of two
smaller spikes at de + di ∼ 2.6–2.8 Å in the fingerprint plot
arises from short intermolecular H⋯F contacts with the
contribution of 12.6%. The contributions of other contacts to
the Hirshfeld surface seem to be negligible.
Crystal packing
The lattice energies of both crystal structures have been
calculated using PIXEL20 and further partitioned into
coulombic, dispersive, polarization and repulsive factors
(Table S2†). As already observed for structurally-related
cyclohexane-5-spirohydantoin
rather than coulombic or polarization, has the dominant
contribution to the total lattice energy.
The evolution of the crystal structure has been further
considered in terms of different dimeric motifs as the basic
building blocks, which are associated with the presence of
intermolecular interactions. CrystalExplorer has been used to
roughly estimate the distribution patterns of the interaction
energy between a pair of molecule (electrostatic, polarization,
dispersion and repulsion, Tables S3 and S4†).21
To obtain more accurate values of interaction energies,
the calculations at TPSSh-D3/def2TZVP level have been
performed in the Gaussian09 program. Concerning
derivatives,18b
dispersion,
Fig. 3 Dimeric motifs H1–H8 extracted from the crystal structure of 1 with their interaction energies.
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compound 1, the structures of these dimeric motifs and the
corresponding interaction energies (ΔE) are presented in
Fig. 3. The molecules associate into a hydrogen bonded
centrosymmetric R22(8) dimeric motif (motif H1, ΔE = −20.88
kcal mol−1). This motif, together with the motif H2 (ΔE =
−7.99 kcal mol−1) of bifurcated C(sp3)–H⋯O hydrogen bonds
pointing towards the O2 atom, builds a supramolecular chain
running along the c-axis. On the other side, the double chain
along the b-axis is generated by the action of the motifs H1
and H3.
The relative position of the molecules in the motif H3 (ΔE
= −10.54 kcal mol−1) is such that, besides two pairs of the
bifurcated C(sp2)–H⋯O hydrogen bonds, there is a parallel
interaction at a large offset (PILO, Cg⋯Cg distance 4.362 Å).
Fig. 4 Part of the crystal structure of 1 showing formation of a sheet (a) and a double chain (b).
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Although weaker than C(sp2)–H⋯π and stacking interactions
with ΔE of about −2.9 kcal mol−1, PILOs between two benzene
molecules (with ΔE of about −2.0 kcal mol−1) are more
frequent in the crystal structures than the these two. Namely,
this interaction is responsible for the higher interaction
energy of the motif H3 relative to the motif H2.22
The interaction between the chains, which involves motifs
H4 and H6, then produces a continuous sheet parallel to the
bc-plane (Fig. 4a). An additional stabilization in motifs H4,
generated by translation, and H6, generated by inversion, is
provided over hydrophobic interactions between the
cyclohexyl and phenyl rings (ΔE being −1.95 and −0.80 kcal
mol−1, respectively). Here, hydrophobic interactions are
understood as an attraction between hydrophobic fragments
(cyclohexyl and aromatic rings), which do not involve the
π-system of the phenyl rings.
Besides the interaction energy, symmetry seems to be an
important factor in these sheets. The sheets are then linked
into a three-dimensional framework by means of the motifs
H7 and H8. The molecules within the motif H1 are linked
into a double chain parallel to the a-axis by means of the
motifs H7 and H8. The motif H7 (ΔE = −6.67 kcal mol−1),
generated by translation, involves two pairs of C–H⋯O
interactions sharing the same acceptors (O2 and O3). Paired
N–H⋯O hydrogen bonds where O3 acts as an acceptor in a
combination with two pairs of C(sp2)–H⋯π interactions
create the motif H8 (ΔE = −12.31 kcal mol−1). These double
chains are themselves linked, among others, by hydrophobic
contacts of the motif H5 (ΔE = −1.32 kcal mol−1).
The structures of dimeric motifs extracted from the crystal
packing of 2 and the corresponding interaction energies are
presented in Fig. 5. Again, as in 1, the molecules of 2 are
Fig. 5 Dimeric motifs F1–F9 extracted from the crystal structure of 2 with their interaction energies.
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linked by paired N–H⋯O hydrogen bonds into
a
As in 1, symmetry controls the molecular assembly, i.e.,
development of the crystal packing. The chains are linked by
motifs F3, F4 and F5 and thus formed a sheet (Fig. 6). The
motif F4 is highly dispersive; the hydrophobic interactions
involve the cyclohexane rings of the paired molecules (ΔE =
−1.27 kcal mol−1). In the motif F5 (ΔE = −1.31 kcal mol−1),
which is generated by translation, the mean plane of the
cyclohexyl ring of one molecule is nearly parallel to the
phenyl ring of another molecule, so interaction between
them can be considered as a PILO (Cg⋯Cg distance of 6.02
Å). This motif also involves a C(sp2)–H⋯F interaction. In the
motif F3 (ΔE = −9.03 kcal mol−1), a pair of molecules is linked
centrosymmetric R22(8) dimer unit (motif F1, ΔE = −21.12 kcal
mol−1). In this case, the N–H⋯O bond is shorter than the
one within the isostructural motif of 1 (2.10 and 2.03 Å for 1
and 2, respectively), thus resulting in slightly higher
interaction energy. As expected, the shorter N–H⋯O bond in
2 also results in an increase of both electrostatic and
repulsion terms (Tables S3 and S4†). Two weak C(sp3)–H⋯O
hydrogen bonds (3.23 and 3.43 Å) together with two C(sp3)–
H⋯π interactions with the distance between the H atom and
the π plane of 3.03 Å link molecules into the motif F2 (ΔE =
−11.73 kcal mol−1). The alternation of the motifs F1 and F2
further results in formation of a chain running along the
b-axis.
by two C(sp2)–H⋯O hydrogen bonds and
a stacking
interaction of the phenyl rings (Cg⋯Cg distance of 4.14 Å).
This motif can be regarded as a governing force in the
assembly process, while the motifs F4 and F5 resulted from
the packing.
When comparing interaction energy of the motifs H2 and
F2, both oriented along the same direction, an important
difference resulting from the fluorination of the phenyl ring
can be noticed. In H2, both cyclohexyl rings interact with the
hydantoin moieties and form the C(sp3)–H⋯O hydrogen
bonds. On the other side, in F2, the cyclohexyl rings are
shifted towards the phenyl rings, thus resulting in the
C(sp3)–H⋯π interactions. The net result is the higher
interaction of the motif F2 than ΔE of the motif H2. This
indicates that the fluorinated phenyl ring establishes
stronger C(sp3)–H⋯π interactions than the non-substituted
one.
Finally, the motifs F6, F7, F8 and F9 join together
neighboring sheets into a three-dimensional network. Two
translation-related molecules in the motif F6 (ΔE = −7.31 kcal
mol−1) are linked by pairs of C(sp3)–H⋯O and C(sp2)–H⋯F
hydrogen bonds as well as a PILO (Cg⋯Cg distance of 6.00
Å). The molecules in the motif F7 (ΔE = −9.09 kcal mol−1)
participate in a pair of bifurcated C(sp3)–H⋯O hydrogen
bonds and a pair of C(sp3)–H⋯N hydrogen bonds. The motif
F8 (ΔE
=
−2.74 kcal mol−1
)
contains two C(sp3)–H⋯F
Fig. 6 Part of the crystal structure of 2 showing formation of a sheet.
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hydrogen bonds which result in formation of
a
centrosymmetric R22(24) ring. In the motif F9 (ΔE = −5.04 kcal
mol−1), the molecules are linked through a pair of C(sp2)–
H⋯O hydrogen bonds, thus resulting in a R22(10) ring.
When comparing 1 and 2, changes in the unit cell
parameters might result from differences in the total
interaction energy of all the motifs oriented along the same
axis, i.e., the higher this interaction energy is, the more the
dimension of the unit cell along this axis decreases.
In 1, the molecule orientation along the a-axis is uniform
and corresponds to the motif H7, with the distance between
the centers of mass of 6.308 Å. There is no contact between
the cyclohexyl rings in this case. In 2, the molecules orientate
along the a-axis similarly as in 1, but are shifted more closely
to each other. This can be presented by the motif F6. The
shifting results in formation of a contact between the
cyclohexyl rings and distancing of the cyclohexyl and
hydantoin rings. The net result is an increase in the
interaction energies. The molecules are closer to each other
than in 1, as reflected by the center of mass distance of 5.998
Å. The center of mass distances are equal to the values of a
parameter of the corresponding unit cells. Hence, the
decrease of 0.3 Å (relative to the center of mass distance in 1)
corresponds to the shortening of the unit cell parameter a
of 2.
Fig. 7 The most stable structures of homo- and heterodimers of
benzene, cyclohexane and hydantoin.
calculations have been performed on a model of dimer
systems containing molecules of benzene (PhH), cyclohexane
(ChH) or hydantoin (Hyd). The optimization has been applied
on the initial structures, which has one of the following
geometries: face-to-face, T-shaped, displaced, displaced with
large offset or planar orientation. The representations of the
initial and optimized structures with the assigned
orientations and interaction energy are given in the ESI†
(Tables S6–S11). The most stable orientations for individual
homo- and heterodimeric systems are shown in Fig. 7.
Quantum chemical calculations on model systems derived
from the cyclic units present in 1
It is well known that interaction energy of two benzene
rings has two minima, one with the T-shaped geometry,
The analysis of the motifs (Fig. 3) used to describe the crystal
packing of 1 has revealed that the hydantoin ring forms the
largest number of contacts with the cyclohexyl ring (3
contacts; H2 and H7 motifs).
corresponding to the C–H⋯π interactions (−2.86 kcal mol−1
)
and another one with parallel displaced orientation,
corresponding to stacking interactions (−2.66 kcal mol−1).
However, one another geometry of the benzene dimer has
been identified, corresponding to a PILO (−1.98 kcal mol−1).
This is the most frequent orientation in the crystal structures
(Fig. S6†).23
Here, under the contact we understand a group of
intermolecular interactions between two cyclic fragments,
whereby those of the bridging carbonyl group are ascribed to
the phenyl ring. With another hydantoin ring (H1 and H8
motifs) and the phenyl ring (H3 motif), on the other side, the
hydantoin ring establishes two contacts (Table S5†).
Interactions between the hydantoin rings can be classified as
N–H⋯O hydrogen bonds, while interactions with the
cyclohexyl and phenyl rings are usually C–H⋯O interactions
wherein the hydantoin carbonyl oxygen atom participates as
an acceptor. On the other hand, the cyclohexyl ring has the
highest affinity toward the phenyl ring (5 contacts; H4, H5,
H7 and H8 motifs). There is only one contact wherein two
cyclohexyl rings participate; it is the hydrophobic interaction.
The phenyl ring, in addition to a high affinity toward the
cyclohexyl ring and two contacts with the hydantoin ring,
forms two contacts with other phenyl rings; one is a stacking
interaction, while another one is a PILO.
In the case of the cyclohexane dimers (Table S7†), the
starting face-to-face geometry has not changed after
optimization convergence. When the T-shaped geometry and
displaced geometry at large offset have been taken as the
starting point in calculation, two T-shaped orientations are
obtained. The face-to-face geometry of the cyclohexane dimer
is more stable (Fig. 7, −3.02 kcal mol−1) than the most stable
T-shaped geometry of two cyclohexanes (Fig. 7, −2.71 kcal
mol−1). According to the calculated interaction energies, it
can be concluded that the interactions associated with the
parallel orientation of the benzene molecules are slightly
weaker than the interactions with the parallel orientations of
mean planes of the cyclohexane molecules (the cyclohexane
mean plane containing the carbon atoms at positions 1, 2, 4
and 5 is observed), while interactions associated with the
T-shaped geometry are slightly stronger in the case of the
benzene dimers.
The total interaction energy of one molecule with all
surrounding molecules in the crystal structure of 1 has a
value of −62.5 kcal mol−1.
To determine the contribution of the individual cyclic
fragments (phenyl, cyclohexyl and hydantoin), DFT
Replacement of one of the cyclohexane molecules with
benzene has led to formation of ChH:PhH heterodimers,
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which gave, after optimization, only one orientation (Table
S9†) with the displaced geometry and interaction energy of
−3.49 kcal mol−1 (Fig. 7). This points out that cyclohexane
and benzene have higher affinities for heterodimers than
homodimers. The conclusion is consistent with the data
obtained from the crystal structure of 1, which also confirms
that the cyclohexane ring has a higher affinity for the phenyl
ring than for another cyclohexane ring.
motifs). Although there is only one contact with another
hydantoin ring (F1 motif), this contact (a pair of N–H⋯O
hydrogen bonds) is multiply stronger than the interactions
with the other two rings – mainly C–H⋯O interactions
involving the hydantoin O atom. The cyclohexyl ring has no
affinity towards the same ring (only 1 contact; a weak
hydrophobic interaction in the motif F4). However, the
cyclohexyl ring has the highest affinity toward the phenyl
ring (7 contacts; motifs F2, F5, F7 and F8) and their
interactions are very diverse (C–H⋯π, C–H⋯F and C–H⋯O
interactions involved) wherein the cyclohexane C–H groups
act as donors. There are also three types of interactions
between the aromatic rings: C–H⋯π interaction, stacking
interaction and PILO (motifs F3, F6 and F9). Introduction of
the fluorine atom into the aromatic moiety results in an
increase of the number of interactions with all, the hydantoin
(3 contacts; motifs F3 and F6), cyclohexyl ring (7 contacts;
motifs F2, F5, F7 and F8) and aromatic ring (3 contacts;
motifs F3, F6, and F9).
The total interaction energy of one molecule with all
molecules from the neighbourhood is slightly higher (−68.6
kcal mol−1) in the crystal packing of 2 than in the crystal
packing of 1 (−62.5 kcal mol−1). This data indicates that
fluorination of the aromatic ring increased the stability of the
crystal structure. To determine the contribution of the
interactions of the individual fragments (aromatic,
cyclohexane and hydantoin) to the overall stability of the
crystal structure, DFT calculations have been performed for
the model systems of homodimers of fluorobenzene (PhF)
and heterodimers containing the molecules of cyclohexane
(ChH), fluorobenzene (PhF) or hydantoin (Hyd). The initial
structures with face-to-face, T-shaped, displaced, displaced at
a large offset or planar geometry have been optimized.
Representations of the initial and optimized structures, with
the appropriate geometry and interaction energies, are given
in the ESI† (Tables S13–S15). The most stable geometries for
the individual dimer systems are shown in Fig. 8.
Fig. 7 shows the optimized hydantoin dimer – a planar
system wherein these molecules form a pair of N–H⋯O
hydrogen bonds with the interaction energy of −17.83 kcal
mol−1. This is the strongest interaction among the examined
motifs. After optimization, the initial structures of ChH:Hyd
heterodimer gave only one orientation (Table S10†), which
corresponds to a displaced geometry with the interaction
energy of −3.82 kcal mol−1 (Fig. 7). According to these
calculations, it should be expected that the cyclohexyl group
has a slightly higher affinity for the hydantoin ring than for
the phenyl ring. However, cyclohexane is located above the
hydantoin ring in the mentioned dimer (ChH:Hyd dimer,
Fig. 7). In 1, this position is sterically hindered by the
cyclohexyl and aromatic moieties. In accordance with this,
only orientations out of the ring, which contains the
cyclohexyl group interacting with the carbonyl group, have
been found here. The C–H⋯O interactions are significantly
weaker than interaction within the displaced geometry.
Replacement of hydantoin with benzene (ChH:PhH) causes a
slightly smaller decrease in interaction energy (−3.49 kcal
mol−1).
Optimization of the initial geometries of Hyd:PhH dimers
has led to several different orientations with the T-shaped
geometry (Table S11†); the most stable among them (−6.36
kcal mol−1) is shown in Fig. 7. In this orientation, the
molecules build N–H⋯π hydrogen bond, which is further
enhanced by a C–H⋯O interaction. These calculations have
implied that the phenyl group has a higher affinity toward
the hydantoin ring than for the cyclohexane ring or another
phenyl ring. However, this orientation (Hyd:PhH dimer,
Fig. 7) does not occur in the crystal structure of 1, because
one N–H group has already been engaged in the formation of
hydrogen bond, present in the motif H1, which is more
energetically favorable. Only C–H⋯O interactions between
the hydantoin and phenyl rings have been found in the
crystal structure of 1. These interactions are weaker (energy
about −1.7 kcal mol−1)22 not only than the stacking
interactions between two benzene molecules (−2.66 kcal
mol−1), but also than their PILO (−1.98 kcal mol−1).23
Fluorination of the benzene ring has resulted in an
increase in energy of the stacking interaction (−3.68 kcal
mol−1, Fig. 8) and the C–H⋯π interaction (−3.24 kcal mol−1
,
Quantum chemical calculations on model systems derived
from the cyclic units present in 2
By analyzing the contacts of the individual rings in the crystal
structure of 2 (Table S12†), it can be concluded that the
hydantoin ring builds the largest number of contacts with
the cyclohexyl ring (5 contacts; F2, F6, and F7 motifs),
followed by those with the phenyl ring (3 contacts; F3 and F6
Fig.
8 The most stable structures of individual homo- and
heterodimers involving fluorobenzene.
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Fig. 8) when compared to unsubstituted benzene (Fig. 7). The
increase is more pronounced for stacking interaction (about
1 kcal mol−1). When optimizing the initial structures of the
heterodimeric system, PhF:ChH (formed by replacing
fluorobenzene with cyclohexane), in most cases, a dimer with
the parallel displaced geometry is obtained with interaction
energy of −3.69 kcal mol−1. In this case, interaction energy for
these multifurcated C–H⋯π interactions is the same as the
stacking interaction between two fluorobenzenes (PhF:PhF-1),
but slightly higher than the C–H⋯π interaction between
these two molecules (PhF:PhF-2). This indicates that
reason for a larger number of contacts of the cyclohexyl ring
with the phenyl ring in the crystal structure of 2. Seven
contacts between cyclohexane and fluorobenzene have been
identified in the crystal structure of 2, whereby three of them
are C–H⋯F interactions. The reason why the interactions of
the aromatic and hydantoin rings are less abundant than the
interactions involving the cyclohexane ring, despite being
multiply stronger, has already been partially indicated. In two
most stable geometries of the PhF:Hyd dimer, the aromatic
ring is located above the hydantoin ring and this approach is
sterically hindered. In the planar geometry (PhF:Hyd-3
dimer), the interaction involves the hydantoin N–H and CO
groups. In the crystal structure, however, these groups are
engaged in hydrogen bonding with other hydantoin rings
and this type of interaction is significantly stronger than the
interaction in the planar geometry.
cyclohexane is
a better C–H donor than benzene and
fluorobenzene. In the most stable orientation of the PhF:ChH
dimer, in addition to the C–H⋯π interaction, there is also
the C–H⋯F interaction. This is probably a reason why the
PhF:ChH dimeric system is more stable than the most stable
ChH:PhH dimeric system wherein benzene and cyclohexane
interact. Interestingly, one of the optimized structures with
the PhF:ChH dimer, with a PILO, has higher energy (−2.13
kcal mol−1, Table S14†) than the system of the benzene dimer
(−1.98 kcal mol−1).22 Replacement of one fluorobenzene
molecule in PhF:PhF dimer with a hydantoin molecule (PhF:
Hyd heterodimer) has led to an increase in the interaction
energy (−6.10 kcal mol−1, Fig. 8), which is almost twice as
high as the energy of PhF:PhF dimer with parallel displaced
geometry (PhF:PhF-1). The PhF:Hyd-2 dimer with the
A CSD study
Replacement of the hydrogen atom with the fluorine atom
has led to changes in the crystal packing as a consequence of
differences in the strengths and types of interactions that
occur between the phenyl ring and other two rings. This is
also indicated by the data on the nature of atoms located at a
distance less than 4 Å from the fluorine atom in 2, i.e., from
the hydrogen atom in the same position in 1.
Seven hydrogen atoms and one oxygen atom are in contact
with the fluorine atom in the crystal packing of 2. Six
hydrogen atoms originate from four neighboring cyclohexane
rings, one hydrogen atom from the neighboring aryl group,
while the oxygen atom belong to the carbonyl group of the
hydantoin ring. In the case of 1, there are six hydrogen atoms
from three neighboring cyclohexane rings and one oxygen
atom from the bridging carbonyl group. Replacement of the
hydrogen atom with the fluorine atom has led not only to an
increase in the number of the contact rings, but also to a
transition from hydrophobic to C–H⋯F interactions. It is
interesting that the fluorine atom interacts even with the
oxygen atom through the CO⋯F interaction.
T-shaped geometry (−5.94 kcal mol−1
, Fig. 8), which
represents simultaneous N–H⋯π, C–H⋯F and C–H⋯O
interactions, has a slightly lower interaction energy.
The planar geometry of these two molecules, where N–
H⋯F and C–H⋯O interactions simultaneously occur, has
also a significantly higher interaction energy (−5.67 kcal
mol−1, Fig. 8). Despite the fact that the most stable
interaction of two fluorobenzenes (PhF:PhF-1) is equal to the
strength of the most stable interaction between cyclohexane
and fluorobenzene (PhF:ChH), in the crystal structure of 2
the cyclohexyl ring builds the largest number of interactions
with the phenyl ring. To understand why this happens, it has
been necessary to consider the structure of the studied
compound. Namely, the hydantoin ring, as the central part of
the compound, forms a pair of N–H⋯O hydrogen bonds with
another hydantoin ring. The approach of the cyclohexyl ring
from the upper side of the hydantoin ring is sterically
hindered by the cyclohexyl and phenyl rings, thus making
the cyclohexyl ring accessible only for the weak C–H⋯O
interactions. The interaction with another cyclohexane ring
(in the most favorable orientation is −3.02 kcal mol−1, ChH:
ChH-1 dimer, Fig. 7) is slightly weaker than the interaction
with the fluorobenzene ring. In addition, the cyclohexane
ring is more voluminous than the fluorobenzene ring, so a
greater number of simultaneous interactions of the
cyclohexane ring with this ring is possible. When it comes to
ring-overlapping interactions, the cyclohexane ring can build
C–H⋯F interactions with the fluorobenzene ring, which is
energetically more favourable than the hydrophobic one.
Precisely, these interactions (C–H⋯F interactions) are the
Scheme 1 The model systems and geometric parameter used for
searching of the CSD. The V1/P parameter is the angle between the
vector V1 and the plane P of the aromatic ring. In search 1, the vector
V1 is the (AX) → vector, while, in search 2, the vector V1 represents the
ƒƒƒ!
ΩABX vector, where ΩAB is the center of mass of the A and B atoms.
ƒƒƒƒ!
Concerning search 3, it is the ΩABCX vector where ΩABC represents the
center of mass of the A, B and C atoms.
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Table 2 Results of the CSD search for interaction of the F atoms bonded
to the aromatic ring
interactions between the σ-hole and the free electron pairs of
the fluorine atom.
The statistical analysis of the geometrical parameters for
the F⋯F interactions (Fig. 9) has shown that the distances of
the interacting fragments are in the range from 2.0 to 4.0 Å,
with the maximum distribution between 2.8 and 3.2 Å. It is
important to emphasize that the number of interactions
decreases when the distance d is greater than 3.2 Å, but not
drastically. The relative orientation of the interacting
fragments is mostly parallel (the V1/P angle close to 90°).
The distribution of the α angles (C–F⋯X) indicates that
the number of the structures decreases when this angle is
greater than 130°. A similar distribution has been found for
the α angles in the range from 90° to 130°, thus indicating
that the interacting fluorine atom is not above the aromatic
ring nor the fluorine atom, but it is located outside the
aromatic group.
Search
1
Search Search
2
2
Number of structures
Number of interactions
17 906
472 648 4447
2745
196
258
Percentage of cetrain atoms in position X 70.2% H 47% O 18% C
27.1% F 21% S
20% N
To obtain a more extensive insight into the interactions
involving the fluorine atom, a statistical analysis of the data
obtained by the CSD search has been performed (Scheme 1).
Namely, 17 906 structures with 472 648 F⋯X interactions
have been identified in search 1, 2745 structures with 4447
F⋯X interactions have been found in search 2 and 196
structures with 258 F⋯X interactions have been retrieved in
search 3 (Table 2). The statistical analysis of interactions has
shown that a hydrogen atom (70.2%) and a fluorine atom
(27.1%) have mainly been found in position X in the
structures obtained in search 1.
The other elements are significantly less represented
(1.2% O, 0.8% Cl, 0.2% Br and 0.2% I). Search 2 has revealed
that an oxygen atom is in position X in 47% of the
interactions, while a sulphur atom and a nitrogen atom are
in 21 and 20% of the interactions, respectively. The smallest
set of the structures has been obtained in search 3 and these
structures have a sulphur, nitrogen, carbon, oxygen or
phosphorus atom in position X, with the abundance of
carbon being 18%, while other atoms have an abundance of
about 10%.
A similar trend has been obtained with the boundary
distance of 3.5 Å, although this search includes the fluorine
atom bound not only to the phenyl ring but also to other
groups and rings.9 Therefore, it can be concluded that
reduction of a boundary criterion of the distance d leads to
an increase in the number of hydrogen atoms (X–H⋯F
interactions), while the abundance of other atoms decreases.
The F⋯F interactions (127 972 interactions) are the second
most common in the crystal structures (after X–H⋯F
interactions). Moreover, the F⋯F interactions are multiply
larger in number than interactions involving other halogen
elements with the ability to form the σ-hole (Cl, Br, and I),
which further results in the possibility of the electrostatic
F⋯F interactions in the crystal structure of 2
In the crystal packing of 2, there are no F⋯F interactions
which fulfil the above defined geometrical criteria. However,
an interaction between the fluorine atoms at the distance d
larger than the limiting one (4.26 Å) has been identified, the
energy of which is −0.17 kcal mol−1. Although energetically
non-significant, this interaction might have a supramolecular
importance. Interaction energy of the motif, wherein the
para-substituent in 2 has been replaced by the hydrogen
atom, is only −0.02 kcal mol−1 (Fig. S7†). As the carbonyl
group (part of the para-substituent) exerts electron-
withdrawing effects, reduced negative potential of the F atom
can be expected. This might be a reason of a higher
interaction energy in the case of 2. Namely, this reduction in
the negative potential led to lower repulsion which is a
significant component of the interaction energy between two
electronegative atoms.
To determine the value of the distance d which is
acceptable as the optimal distance, we have performed the
calculations on the model system presented in Fig. 10 in a
way that the relative orientation of the molecules has been
kept constant and the distance d has been systematically
changed. Namely, the values of the distance d of 4.26, 3.50,
3.25 and 3.0 Å have been considered, thus resulting in the
interaction energies of −0.17, −0.39, −0.46 and −0.43 kcal
mol−1, respectively. It can be concluded that the shortening
Fig. 9 Distributions of the geometrical parameters for description of the F⋯F interactions in the crystal structures extracted from the CSD.
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useful in examining the cooperative effect and the effects of
simultaneous interactions, which will be discussed below.
In fluorobenzene, the part with the most negative
potential is located on the fluorine atom (Fig. 11). Also, the
π-system has a negative potential, although smaller than that
on the F atom. The negative potential increases as moving
from the edge of the ring towards the centre of the π-system.
The positive potential is located on the hydrogen atoms. By
comparing this map with the potential map of 2 (Fig. 11), it
can be noted that substitution in the para position relative to
the fluorine atom has led to colour changes in the maps.
Namely, the carbonyl group in the para position has an
electron-withdrawing character, which further has led to a
shift of the electron density from the ring to the substituent.
This shift causes a decrease of the negative potential above
the π-system and an increase of the positive potential on the
hydrogen atoms. There is also a decrease of the negative
potential on the fluorine atom. From the supramolecular
point of view, introduction of the carbonyl group as a
substituent should lead to a decrease in the strength of
interactions wherein the aromatic fragment has the accepting
role and an increase in the strength of interactions wherein
this ring has the hydrogen bond donating role. The most
negative part in 2 is located on the carbonyl oxygen atoms,
while the cyclohexyl ring has a positive potential at its entire
surface.
Fig. 10 Model system extracted from the crystal packing of 2 formed
through the F⋯F interaction with interaction energy of −0.17 kcal
mol−1
.
the distance results in the interaction strengthening with a
shallow minimum of interaction energies from −0.40 to −0.50
kcal mol−1 corresponding to the range from 3.0 to 3.5 Å.
Anyway, the F⋯F interactions are very weak in this case,
although a slight increase in the interaction energy can be
identified. For comparison, the energy of the strongest F⋯F
interaction between two molecules of fluoromethane is −1.44
kcal mol−1.9 To analyze the supramolecular significance of
the F⋯F interaction, its cooperative effect as well as the
effect of simultaneous interactions should be taken into
account. The cooperative effect can be rationalized as the
effect of a species from the environment on the F⋯F
interaction. On the other side, the effect of simultaneous
interactions is reflected on the strength of interactions which
a species from the environment forms with both F atoms.
The formation of the C(sp3)–F⋯F–C(sp3) interactions
results in an increase in the electron density, i.e., the negative
potential in the contact region.13 To examine whether the
C(sp2)–F⋯F–C(sp2) interactions cause the changes in the
electron density and the electrostatic potential, MEPs of the
motif extracted from the crystal structure of 2 have been
calculated for a set of the intermolecular distances (3.0, 3.5
and 4.26 Å, Fig. 12). Based on these maps, it can be
Map of electrostatic potential (MEP)
Beside the dispersion, the electrostatic component of energy
often makes the greatest contribution to the total interaction
energy.9 To obtain an insight into the distribution of
potentials, i.e., the distribution of electron density, and,
hence, to explain why some fragments of the interacting
species are attracted to each other, electrostatic maps of
potentials have been analyzed. These maps are also very
Fig. 12 Maps of electrostatic potential of the motif extracted from the
crystal structure of 2 for a set of distances between the molecules.
Fig. 11 Maps of electrostatic potential of fluorobenzene and 2.
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concluded that there is no significant change in the blue
colour above the C–H groups of the benzene ring, which
indicates a positive potential and, therefore, no significant
changes of the donating abilities of this fragment should be
expected. By analysing the π-system from the outer side of
the model system, it can be noticed that, with a decrease of
the distance d, there is a decrease of the area with green
colour (neutral potential) and a slight increase of the blue
region (slightly positive potential). The sides of the π-system
facing the F⋯F interaction do not have any significant
change in potential with a distance change. The formation of
F⋯F interaction leads to an increase in the intensity of the
yellow colour on the fluorine atoms, in comparison to the
fluorine atom in monomers, which indicates an increase of
the negative potential in the region of the F⋯F interaction.
fluorine atom involved in the F⋯F region (from the F2
species, corresponding to motif the F8). However, the total
interaction energy of the interactions that this molecule
(species A) simultaneously builds with both molecules of the
F⋯F region (ΔE = −4.81 kcal mol−1) is similar to the sum of
the energies of the individual C–H⋯F interactions (ΔE =
−4.83 kcal mol−1). Even when the energy of F⋯F (F1⋯F2
species) interaction of the observed motif (ΔE = −0.17 kcal
mol−1) is added to the total interaction energy, it cannot be
claimed that the formation of the F⋯F interaction leads to a
unsubstantial increase in energy in this case, i.e., there is no
pronounced effect originating from the simultaneous
interactions. In the second case, a molecule from the
surrounding (species B, Fig. 11) forms stronger interactions
with both molecules involved in formation of the F⋯F region
(ΔE = −12.83 kcal mol−1) in comparison to interactions with
the individual molecules (formation of trifurcated C–H⋯π
interaction with ΔE = −11.73 kcal mol−1 and bifurcated C–
H⋯F interaction with ΔE = −1.13 kcal mol−1, corresponding
to the motifs F5 and F2 motifs). In this system, there is no
effect of simultaneous interactions, because the total
interaction energy is similar to the sum of the individual
energies (the sum of the ΔE is −12.86 kcal mol−1).
Effects of simultaneous interactions
By analysing electrostatic potential maps, it can be concluded
that the F⋯F interactions lead to formation of a new
acceptor region with a larger surface area and a slightly
higher negative potential in comparison to the individual
fluorine atoms. All these changes result in formation of more
simultaneous interactions with the surrounding species, thus
allowing the denser crystal packing.
In the crystal structure of 2, the F⋯F region
simultaneously interacts with four surrounding molecules,
which, due to symmetry, can be associated with two
interaction types. Regarding the first type, a molecule from
the surrounding (species A, Fig. 13) formed a C–H⋯F
interaction (ΔE = −1.71 kcal mol−1) with the first fluorine
atom from the F⋯F region (from the F1 species,
corresponding to the motif F5) and a C–H⋯F interaction (ΔE
= −3.12 kcal mol−1) with the molecule bearing the second
Cooperative effect of the F⋯F interaction
To determine whether the change in the strength of the F⋯F
interaction cooperatively affects other interactions wherein
only one of the molecules involved in the F⋯F interaction
participates, calculations have been performed on model
trimeric systems extracted from the crystal structure of 2
Fig. 13 Trimeric systems, extracted from the crystal packing of 2,
used for investigation of effect of simultaneous interactions.
Fig. 14 Trimeric systems modelled for investigation of the
cooperative effect resulting from formation of the F⋯F interaction.
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Table 3 Results of calculations performed on the dimeric and trimeric
systems modelled to examine the cooperative effect resulting from
formation of the F⋯F interactions (interaction energy, ΔE is in kcal mol−1
and the distances d is in Å)
to the spirohydantoin moiety by a carbonyl bridge. The
greatest contribution to the stabilization of the crystal
packing comes from the hydantoin moieties which build a
pair of N–H⋯O hydrogen bonds with interaction energy of
around −21 kcal mol−1. Additionally, this moieties are
connected to other rings by means of C–H⋯O interactions.
In the crystal packing of 1, the phenyl ring has the highest
affinity towards the cyclohexyl ring and established five
interactions with it. When the fluorine atom is introduced
into the phenyl ring, this affinity increases (seven
interactions) due to formation of the C–H⋯F interactions.
Although fluorination of the phenyl ring results in
strengthening of the interactions between these two rings,
only two interactions (stacking interactions and PILO)
between the aromatic rings can be identified in both crystal
structures. A reason is strengthening and interaction between
the cyclohexyl and fluorinated phenyl ring.
The analysis of the contact atoms in the neighbourhood
of the fluorine atom in the crystal packing of 2 has shown
that the hydrogen atoms are the most frequent as a result of
the C–H⋯F interactions. Besides, the carbonyl oxygen atom
has also been found, thus resulting in formation of the F⋯O
interaction. However, the results of an analysis of the contact
atoms at distances shorter than 4 Å to the fluorine atoms in
the crystal structures deposited in the CSD is only in a partial
agreement with that observed in the crystal packing of 2.
Namely, the fluorine atoms establish interactions with the
hydrogen atoms most often, then come the F⋯F interactions,
while interactions with the oxygen atoms are at the third
place. Although the fluorine atom exerts a higher affinity
toward F⋯F interactions, formation of F⋯O interaction in
the crystal packing of 2 is supported by simultaneous
stacking interaction between the phenyl rings. In this case,
the F⋯F interaction at a large distance (d = 4.26 Å) has been
recognized. In this dimeric motif, there are no simultaneous
interactions between the other structural fragments of 2, thus
resulting in the low interaction energy (−0.17 kcal mol−1). The
DFT calculations indicate that shortening of the distance d
does not lead to significant changes in the interaction
energies being, in the best case, up to −0.5 kcal mol−1.
Despite the unfavourable geometry, the symmetry elements
of this motif indicate its supramolecular significance. The
electrostatic potential maps show that formation of the F⋯F
interaction causes an increase in the negative potential on
the interacting fluorine atoms, a decrease in the negative
potential above the π-system as well as an increase in the
positive potential surface above the hydrogen atoms of the
phenyl ring. The calculations on the trimeric model systems
demonstrate that these changes in the potentials are followed
by the cooperative effect. Namely, formation of the F⋯F
interactions can lead to strengthening of interaction of one
of the fluorine atoms with a molecule from the environment
which does not simultaneously interact with both of them. It
is evident that formation of the F⋯F interaction is followed
by strengthening of stacking interactions, while C–H⋯O
interactions weakens. When the third molecule interacts with
Crystal structure
Model systems
d = 3.00
ΔE(F1/F2)
−0.43
d = 3.25
d = 3.50
−0.39
d = 4.26
−0.17
ΔE(F1/F2)
−0.17
−0.46
−9.16
−4.92
ΔE(C/F1)
−9.03
ΔE(C/F1F2)
−9.22
−9.10
−9.00
ΔE(D/F1)
−5.04
ΔE(D/F1F2)
−4.92
−4.92
−4.93
(Fig. 14). In the first model system, a molecule from the
surrounding (species C) builds a stacking interaction with
one of the molecules involved in the F⋯F interaction (with
the species F1, corresponding to the motif F3), with the
interaction energy of 9.03 kcal mol−1. When the third
molecule (species F2 involved in the F⋯F interaction) from
the crystal packing of 2 has been taken into account, this
stacking interaction slightly strengthens. When examining
this effect, the changes in strength of the stacking interaction
between the C and F1 species has been monitored by
changing the length of the F⋯F interaction. The highest
interaction energy of −9.22 kcal mol−1 corresponds to the
distance d of 3.0 Å. The strengthening of the stacking
interaction as a result of the F⋯F interaction (−0.19 kcal
mol−1) and the energy of F⋯F interaction within the motif
(−0.43 kcal mol−1) give the total cooperative effect of −0.62
kcal mol−1.
In the second model system,
a molecule from the
surrounding (species D) interacts with one of the molecules
involved in the F⋯F interaction (species F1) through a pair
of the C–H⋯O interactions (corresponding to the motif F9).
The interaction (D/F1) energy of −5.04 kcal mol−1 is slightly
higher than that of the trimeric system (D/F1F2 system) with
the second molecule (species F2) involved in the F⋯F
interaction. In this case, interaction energy is −4.93 kcal
mol−1. A decrease in the distance d of F⋯F interaction does
not affect the strength of the C–H⋯O interactions (Table 3).
The highest cooperative effect of −0.34 kcal mol−1
corresponds to the distance d of 3.25 Å (the energy of the
F⋯F interaction of −0.46 kcal mol−1 + energy reduction of a
pair of the C–H⋯O interactions due to establishment of the
F⋯F interaction of 0.12 kcal mol−1).
Having in mind both model systems, it can be concluded
that the strengthening of the F⋯F interactions has a greater
impact on the strength of the stacking interaction than on the
C–H⋯O interaction (Table 3). In other words, the strengthening
of the F⋯F interactions causes greater changes of the π-system
than in the donating abilities of the C(sp2)–H groups.
Conclusion
The presented crystallographic and quantum chemical study
is focused on effects of fluorination of the phenyl ring linked
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both fluorine atoms simultaneously, the calculations show
that the effect of strengthening of individual interactions due
to formation of F⋯F interactions is absent.
to the mixture and stirred at room temperature overnight.
After the completion of the reaction, pyridine was evaporated
under vacuum and the residue was dissolved in ethyl acetate.
The solution was washed with 5% NaOH and water and dried
over anhydrous MgSO4. The residual solvent was removed
and the crude product was purified by recrystallization from
ethyl alcohol.
Although the effect of simultaneous interactions has not
been observed, formation of F⋯F interactions is favoured for
a reason which still involves the ability of the system to build
simultaneous interactions. Namely, through formation of
F⋯F interactions a region of the increased electron density
with the surface greater than the one of the individual
fluorine atoms emerges. Therefore, formation of F⋯F
interactions leads to an increase in the surface with the
accepting ability, which, not only has the greater electron
density in comparison with the individual fluorine atoms,
but also enables establishment of a greater number of
simultaneous interactions with the surrounding species. A
greater number of species in the environment of F⋯F
interaction further causes an increase in number of
interactions with the F⋯F region, as well as an increase in
the number of their interactions with other structural
fragments of the molecules forming F⋯F interaction. Finally,
this increase in the number of interactions and, hence, the
higher interaction energy result in a denser crystal packing.
An analogous phenomenon should be expected for F⋯O
interactions, thus explaining their abundance contrary to the
chemical intuition which does not support frequent
formation of interactions between two electronegative atoms.
3-Benzoyl-1,3-diazaspiro[4.5]decane-2,4-dione (1). Yield:
0.41 g (30%); m.p.: 163–166 °C; IR (ATR): ν = 3226, 3112,
2930, 2861, 1791, 1744, 1692, 1448, 1378, 1345, 1295, 1259,
1
1135, 1101, 1016, 996, 926, 843, 810, 759, 691, 634 cm−1; H
NMR (400 MHz, DMSO-d6): δ = 9.21 (s, 1H, NH), 7.85 (d, 2H, J
= 7.6 Hz, –C6H5), 7.73 (t, 1H, J = 7.6 Hz, –C6H5), 7.56 (t, 2H, J
= 7.6 Hz, –C6H5), 1.77–1.55 (m, 9H, cycC6H10), 1.36–1.23 (m,
1H, cycC6H10) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 175.3,
167.9, 152.6, 135.1, 132.7, 130.6, 129.3, 62.0, 33.8, 24.7, 21.2
ppm; elemental analysis calcd (%) for C15H16N2O3: C 66.15,
H 5.92, N 10.29; found: C 66.18, H 5.83 N, 10.35.
3-(4-Fluorobenzoyl)-1,3-diazaspiro[4.5]decane-2,4-dione (2).
Yield: 0.68 g; (47%); m.p.: 198–201 °C; IR(ATR): 3187, 3106,
2927, 2866, 1780, 1708, 1594, 1504, 1468, 1453, 1433, 1384,
1346, 1290, 1274, 1257, 1219, 1154, 1134, 1101, 1007, 978,
928, 826, 801, 760, 726, 713, 679, 614 cm−1; 1H NMR (400
MHz, DMSO-d6): δ = 9.21 (s, 1H, NH), 7.96 (q, 2H, J = 4.8 Hz,
–C6H4–), 7.39 (t, 2H, J = 8.8 Hz, –C6H4–), 1.81–1.52 (m, 9H,
cycC6H10), 1.34–1.27 (m, 1H, cycC6H10) ppm; 13C NMR (100
MHz, DMSO-d6): δ = 175.2, 166.3 (d, J = 254 Hz), 166.2, 152.5,
133.8 (d, J = 9.9 Hz), 129.4 (d, J = 2.6 Hz), 116.5 (d, J = 23 Hz),
62.0, 33.7, 24.7, 21.1 ppm; elemental analysis calcd (%) for
C15H15FN2O3: C 62.06, H 5.21, N 9.65; found: C 61.97; H 5.18;
N 9.56.
Experimental
Synthetic procedure
The investigated compounds 1 and 2 were obtained following
the synthetic protocol shown in Scheme 2. Cyclohexane-5-
spirohydantoin was synthesized by the method of Bucherer
and Lieb24 and it was further acylated using a modified
procedure described previously.25
Crystal structure determination
Single crystals suitable for an X-ray structure determination
were obtained by slow evaporation of acetonitrile solutions at
room temperature. Single-crystal X-ray diffraction data were
collected at room temperature on an Oxford Gemini S
diffractometer equipped with CCD detector using
monochromatized MoKα radiation (λ = 0.71073 Å). Intensities
were corrected for absorption using the multiscan method.
The structures were solved by direct methods using SIR2014
(ref. 26) and refined on F2 by full-matrix least-squares using
the programs SHELXL-2018/3 (ref. 27) and WinGX.28 All non-
hydrogen atoms were refined anisotropically. The positions
of the H atoms connected to the C and N atoms were
calculated on geometric criteria and refined by the riding
model with Uiso = 1.2Ueq(C, N). Selected crystal data and
refinement results for 1 and 2 are listed in Table 1. CCDC
2045907 and 2045908 for 1 and 2, respectively contain the
ESI† crystallographic data for this paper.
The investigated compounds were characterized by
melting point determination, FT-IR, 1H and 13C NMR
spectroscopy and elemental analysis. The melting point was
measured on an electrothermal melting point apparatus
without correction. The FT-IR spectra were measured using
1
Bomem MB spectrophotometer and H and 13C NMR spectra
were recorded on a Bruker AC 250 spectrometer. Elemental
analyses were carried out using microanalyzer Elemental
Vario EL III.
General procedure for synthesis of the investigated
compounds. Cyclohexane-5-spirohydantoin (0.84 g, 0.005
mol) was suspended in dried pyridine (5 ml) and the
corresponding acyl chloride (0.005 mol) was added dropwise
Quantum-chemical calculations
To understand the crystal packing of 1 and 2, the quantum-
chemical calculations at TPSSh-D3/def2TZVP level were
performed in the Gaussian 09 software.29 All model systems
Scheme 2 Synthesis of compounds 1 and 2.
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were extracted from the crystal structures and used to
estimate the strength of non-covalent interactions. The
atomic coordinates are maintained from the solved crystal
structures, except for the positions of the H atoms. The
positions of the H atoms are determined by optimization of
model systems, with frozen non-hydrogen atoms (with this
approach, the accuracy of the H position was achieved). The
interaction energies (ΔE) were computed as the difference in
energy between the dimer and the sum of the optimized
energies of the isolated monomers, corrected for basis set
superposition error (BSSE) by the counterpoise method.30
The Hirshfeld surface analysis and associated 2D
fingerprint plots were carried out using the CrystalExplorer
17.5.31 The dnorm surface was mapped with the color scale in
the range −0.5614 au (red) to 1.2927 au (blue). The 2D
fingerprint plots (di vs. de) were displayed using the standard
range. Calculations were done at accurate B3LYP/6-31g(d,p)
level of theory using Gaussian 09 program package.
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Gaussian 09 program package and PIXELC module19 from
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The search for the crystal structures from the Cambridge
Structural Database (CSD, version 5.36)5 was based on the
model system shown in Scheme 1. Using the program
ConQuest 1.10,32 all structures containing F⋯X interaction
with the d distance less than 4.0 Å were extracted. In
addition, the structures were considered as a hit if the angles
α(C–F⋯X) and β(F⋯X–A, F⋯X–B, and F⋯X–C) were greater
than 90° in order to avoid structures where F⋯X interaction
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This work was supported by the Ministry of Education,
Science and Technological Development of the Republic of
Serbia (Contract No. 451-03-9/2021-14/200135; 451-03-9/2021-
14/200287, 451-03-9/2021-14/200026 and OI 171035).
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