Quantitative analysis of intermolecular interactions in 2,2’-((4-bromophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one): insights from crystal structure, PIXEL, Hirshfeld surfaces and QTAIM analysis

Article abstract of DOI:10.1007/s12039-018-1421-8

Abstract: The crystallographic study of 2,2’-((4-bromophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one) reveals that the compound crystallizes in the centrosymmetric space group P2 ₁/ c. In the solid state, the structure of the ti

Full text of DOI:10.1007/s12039-018-1421-8

J. Chem. Sci. (2018) 130:20
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-018-1421-8
REGULAR ARTICLE
Quantitative analysis of intermolecular interactions in
2,2’-((4-bromophenyl)methylene)bis(3-hydroxy-5,5-
dimethylcyclohex-2-en-1-one): insights from crystal structure,
PIXEL, Hirshfeld surfaces and QTAIM analysis
SUBBIAH THAMOTHARANa,∗, JAGATHEESWARAN KOTHANDAPANIb,
SUBRAMANIAPILLAI SELVA GANESANb, NATARAJAN S VENKATARAMANANb,
SHANKAR MADAN KUMARc, KULLAIAH BYRAPPAd, JUDITH PERCINOe and
FERNANDO ROBLESe
aBiomolecular Crystallography Laboratory, Department of Bioinformatics, School of Chemical and
Biotechnology, SASTRA University, Thanjavur, Tamilnadu 613 401, India
bDepartment of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamilnadu
613 401, India
cPURSE Laboratory, Mangalagangotri Mangalore University, Mangalore, Karnataka 574 199, India
dDepartment of Materials Science, Mangalore University, Mangalore, Karnataka 574 199, India
eLab. de Polímeros, Centro de Química, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla,
Complejo de Ciencias, ICUAP, Edif. 103H, 22 Sur y San Claudio, C.P. 72570 Puebla, Puebla, Mexico
E-mail: thamu@scbt.sastra.edu
MS received 16 October 2017; revised 28 December 2017; accepted 29 December 2017
Abstract.
The crystallographic study of 2,2’-((4-bromophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-
one) reveals that the compound crystallizes in the centrosymmetric space group P21/c. In the solid state, the
structure of the title compound exhibits two strong intramolecular O−H · · · O hydrogen bonding interactions.
Further, molecules of the title compound are self-assembled by weak intermolecular C−H · · · O, π · · · π and
H · · · H and C−H · · · Br contacts. Various intermolecular interaction that exist in the crystal structure and their
energetics are quantified using PIXEL, DFT and QTAIM analyses. Six different motifs are identified from the
PIXEL calculation. Lattice energy calculation suggests that the dispersion energy has the highest contribution
for the crystal formation. The relative contributions of various intermolecular contacts in the title compound
and its closely related analogs are evaluated using Hirshfeld surface analysis and the decomposed fingerprint
plots. The common packing features exist between the title compound and its related analogs are identified.
The quantitative molecular electrostatic potential surface diagram depicts the potential binding sites which are
in good agreement with the crystal structure of the title compound. The structures of title compound in gas
and solvent phases are compared with the experimental structure and reveals that they are superimposed very
well. The vibrational modes of the monomer and four most stabilized dimers are characterized using both the
experimental and DFT calculations. The UV-Vis spectrum is calculated using time dependent-DFT (TD-DFT)
method and compared with experimental spectrum. The results indicate that the calculated energy of absorbance
and oscillator strength correlate well with the experimental data.
Keywords. Cyclohexene; hirshfeld surface; keto-enol hydrogen bonding; dispersion interactions; PIXEL;
QTAIM; TD-DFT.
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-018-1421-8) contains
supplementary material, which is available to authorized users.

20 Page 2 of 14
J. Chem. Sci. (2018) 130:20
1. Introduction
(HS) and fingerprint plots (FP). The structure of the
compound I was optimized in the gas phase as well
as in the ethanol solvent using the dispersion corrected
M05-2X functional with 6-31+G(d) basis set. The topo-
logical properties of various interactions observed in
the crystal structure of the compound I was carried
out using the quantum theory of atoms-in-molecule
(QTAIM) approach.29,30 Furthermore, to elucidate the
optical properties of the compound I, we have measured
UV-Vis spectrumand the experimental spectrumis com-
pared with the simulated spectrum computed using the
time-dependent DFT (TD-DFT) calculation.
Derivatives of 2,2’-arylmethylene bis(3-hydroxy-5,5-
dimethyl-2-cyclohexene-1-ones) were used as precur-
sors for the synthesis of heterocyclic compounds, espe-
cially xanthenes and acridinediones, and some of these
derivatives were used as laser dyes.1,2 They also showed
interesting biological activities such as antioxidant,3
tyrosinase inhibition,4 anti-viral5 and anti-bacterial
activities.6 In view of this, these compounds were syn-
thesized from aromatic aldehydes with dimedone (5,5-
dimethyl-1,3-cyclohexanedione) under different condi-
tions, using different catalysts.7–12 However, the title
compound and its closely related analogs were prepared
by an inexpensive zinc chloride as catalyst in environ-
mentally benign water medium.9 Moreover, the product
was isolated from the reaction medium by simple filtra-
tion. Thus, a green protocol was used for the synthesis of
the title compound. It is of interest to note that several
arylmethylene bis(3-hydroxy-5,5-dimethylcyclohex-2-
en-1-one) derivatives have been crystallographically
analyzed.13–20 It is known that the crystal packing
is predominantly controlled by strong intermolecu-
2. Experimental
2.1 Synthesis and crystallization
To a stirred homogeneous solution of dimedone (140 mg, 1
mmol) in water (3 mL), 4-bromobenzaldehyde (93 mg, 0.5
mmol) and ZnCl2 (17 mg, 0.125 mmol) were successively
added and stirred at room temperature. The reaction was mon-
itored by TLC. After completion of the reaction, the solid
lar hydrogen bonds such as O/N−H · · · O/N due to product was isolated by simple filtration, washed with water
the presence of strong donor and acceptor atoms.21,22
Moreover, the weak intermolecular interactions such
(2 × 10 mL) and dried. The crude product was washed with
hexane (2 × 5 mL) and dried under vacuum. Single crystals
as C−H · · · O/N,23,24 C−H · · · halogens,25,26 C−H
of title compound I was produced from ethanol by the slow
evaporation method.
· · · π 27 and π · · · π 28 interactions can also interplay
a crucial role in controlling the crystal packing in the
absence of strong donors and acceptors. In the case
of title compound and its closely related analogs, the
2.2 Spectral characterization
available donor (O−H) and acceptor (C=O) are fully
The solid-state FT-IR spectrum of the compound I was mea-
sured in the frequency region of 4000–400 cm−1 on a Perkin
participated in two intramolecular O−H · · · O hydro-
Elmer FT–IR spectrophotometer using the KBr pellet tech-
nique. The solid-state Raman spectrum was recorded using
the iRaman plus Raman spectrometer (B & W Tek, USA) and
the 532 nm laser line was used for excitation. The UV-Vis
absorption spectrum was measured on an Eppendorf Biospec-
trophotometer in ethanol solvent.
gen bonding interactions. In this situation, a study to
understand how other weak interactions help to stabi-
lize the crystal packing of the title compound and its
analogs gains importance.
In this work, we report the crystal and molecular
structure of 4-bromo derivative, I, namely 2,2’-((4-
bromophenyl)methylene)bis(3-hydroxy-5,5-dimethyl-
cyclohex-2-en-1-one) to understand the nature of inter-
molecular interactions present in the molecule. We also
2.3 Single crystal X-ray diffraction
present a detailed quantitative analysis of energetics TheX-rayintensitydatawascollectedforthecompoundIona
Rigaku AFC12 Saturn724+ diffractometer. The crystal struc-
ture of the compound I was solved by the SIR92 program31
and all the non-hydrogen atoms were refined anisotropically
using the SHELXL2014 program.32 The hydrogen atoms
of various molecular pairs identified from the crystal
structure of compound I using the PIXEL method. Fur-
ther, molecular conformation and lattice energies of
the compound I are compared with the structures of
unsubstituted and several para- substituted derivatives
to understand the influence of substituents on the molec-
ular conformation and crystal packing features.
Moreover, the relative contributions of various inter-
molecular interactions present in the compound I and
its analogs were quantified using the Hirshfeld surface
were placed in idealized geometrical positions (C−H
=
0.93−0.97Å and O−H = 0.82 Å) and constrained to ride on
their parent atoms. The methyl hydrogen atoms were allowed
to rotate freely about the C–C bonds. The ORTEP and pack-
ing figures were produced using the program MERCURY.33
The crystal data and refinement parameters for the compound
I are summarized in Table 1.

J. Chem. Sci. (2018) 130:20
Page 3 of 14 20
2.5 Computational details
Table1. Crystaldataandrefinementparameters
for the compound I.
The initial geometry for optimization was obtained from the
crystal structure. The monomer I was optimized in gas and
solvent phases using the Gaussian 09 program package.42
The solvent (ethanol) effect was introduced in the calcula-
tion using the conductor-like polarizable continuum model
(CPCM)method. Theoptimizedstructureswerefoundtohave
no imaginary frequencies, implying that the structures are
global minima in their potential energy surface. For optimiza-
tion, M05-2X functional46 was used along with 6-31+G(d)
basis set. The choice of M05-2X functional was selected
based on the previous reports which were able to predict
correct binding energies between molecules with weak inter-
actions.40,41,47 The interaction energy Eint was computed
for all six motifs at their crystal structure geometry using
the supramolecular approach. The Eint was corrected for
basis set superposition error (BSSE) using the counterpoise
method.48 The time dependent-DFT (TD-DFT) calculation in
the ethanol solvent was carried out using the time-dependent
Kohn-Sham formalism.49 The topological parameters were
calculated using the AIMALL package50 on selected molec-
ular pairs. For this purpose, the DFT calculation (with density
= current keyword) for these molecular pairs at their crys-
tal geometry (with bond lengths involving H atoms adjusted
to typical neutron diffraction values), was performed at the
M05-2X/6-31+G(d) level of theory.
Formula
C23H27BrO4
Formula weight
Size (mm3)
Crystal system
Space group, Z
a (Å)
447.35
0.25 × 0.25 × 0.20
Monoclinic
P21/c, 4
16.394(3)
10.8984(18)
12.0467(19)
90
99.139(7)
90
296(2)
b (Å)
c (◦Å)
α
(◦)
( )
β(◦)
γ
Temperature (K)
Volume
Wavelength (Å)
Density (Mgm−3
2125.0(6)
0.71075
1.398
)
No. of reflections collected 14172
No. of unique reflections 3715
2
max(◦)
50
260
0.0571, 0.117
1.025
θ
No. of parameters
R1, wR2 (I > 2 (I))
Goodness of fit
σ
2.4 Hirshfeld surface analysis, PIXEL energy
calculation and crystal packing features
3. Results and Discussion
3.1 Molecular geometries
To investigate the similarities and differences in the crys-
tal packing amongst closely related analogs, the Hirshfeld
surface (HS) and the decomposed 2D fingerprint plots were
produced for the compound I using the program CrystalEx-
plorer 3.1.34 A comparative analysis of Hirshfeld surfaces
mapped with different properties such as di, de, dnorm, shape
index and curvedness of the compound I and its 4-substituted
analogs was performed. To quantify the energies associated
with various intermolecular interactions present in the crys-
tal structure of I, PIXEL calculation35–37 was carried out as
reported earlier.38–41 Briefly, the distances involving hydro-
The compound I crystallizes in the centrosymmetric
monoclinic space group P21/c with one molecule in
the asymmetric unit. The ORTEP diagram of the com-
pound I with the atom-numbering scheme is shown in
Figure 1(a). The molecule comprises three ring systems
of which two of them are cyclohexene rings (B and
C). Each cyclohexene ring has one keto and an enol
group. These keto and enol groups form two strong
intramolecular O−H · · · O hydrogen bonding interac-
gen atoms are moved to their neutron values (C−H = 1.089 Å tions. In the compound I, the H · · · O distances are
and O−H = 0.993 Å) and the resultant geometry used for the
calculation. The electron density of the molecule has been
obtained at the MP2/6-31G** level of theory using Gaussian
09.42 The total energy calculated by the PIXEL method is
partitioned into the corresponding Coulombic, polarization,
dispersion and repulsion energies. Six motifs (I to VI) were
identified from the crystal structure based on their interaction
energy calculated by PIXEL method. To identify the common
packing features exist between the compound I and its closely
related analogs, XPAC2.0 program was used.43–45 This pro-
gram provides the dissimilarity index ‘X’ which is a measure
of how far the two crystal structures deviate from perfect geo-
metrical similarity.
1.596 (H3O · · · O2) and 1.691 Å (H1O · · · O4) and the
hydrogen bonding angles are 159 ( O1−H1O · · · O4)
and 164◦( O3−H3O · · · O2). Rings B and C have
an envelope conformation as evidenced by the Cre-
mer and Pople51 puckering parameters [ring B: Q =
0.460(5)Å, q2 = 0.422(5) Å, q3 = −0.184(5)Å, θ =
113.6(6)◦ and ϕ2 = 356.0(7)◦ for the atom sequence
C2−C3−C4−C5−C8−C9 and ring C: Q = 0.457(5)
Å, q2 = 0.412(4) Å, q3 = −0.199(5) Å, θ =
115.8(6)◦ and ϕ2 = 358.8(6)◦ for the atom sequence
C10−C11−C12−C13−C16−C17]. The dihedral angle
between ring A and the rings B/C are 65.2(1) and

20 Page 4 of 14
J. Chem. Sci. (2018) 130:20
Figure 1. ORTEP diagram, atom-labelling scheme and ring labelling for title compound I. Thermal ellipsoids are drawn at
50% probability level. Intramolecular O−H · · · O= C hydrogen bonds which lock the molecular conformation are depicted (b)
Structural superimposition of I and its related analogs [colour codes: 4-Br (blue), 4-Cl (green), 4-F (yellow), 4-OH (orange),
4-Me (maroon), 4-OMe (pink) and 4-NMe2 (purple)].
59.3(1)◦, respectively. Rings B and C are oriented at
an angle of 40.2(1)◦. The geometric parameters of the
O2=C9−C2=C3−O1 and O4=C17−C10=C11−O3
moieties indicate the π-conjugation. One of the char-
acteristic features in this class of compounds is the
orientation of the carbon atom bearing dimethyl group.
In most of the cases, this carbon atom is directed towards
the phenyl ring (A) as observed in the compound I. In the Scheme 1. Synthetic route for title compound I. Three
τ
τ τ
and 3) are indicated.
2
important torsion angles (
,
1
case of 4-F compound (refcode: QIKBOB) and unsub-
stituted compound (refcode: TAHDAV), there are two
molecules in the asymmetric unit in each case. In one
of the molecules, the carbon atom bonded to dimethyl
group is bent away from the phenyl ring.
A CSD search was conducted using the unsubstituted
compound (4-H) as a template. The search revealed that
thereare18hitsfoundinthedatabaseofwhichoneofthe
structures (3-OH derivative) contains a water molecule
(refcode: GURFOO). These hits are reduced to 10 if
considered only 4-substituted derivatives and some of
these derivatives have multiple entries in the database.
The molecular conformation is described by three dif-
structural superimposition (Figure 1(b)). The maximum
root mean squared deviation (rmsd: 0.19 Å) is observed
for the compound I and 4-Cl (refcode: PUFTEP01) pair.
Since, the sign of all three torsion angles are opposite in
the case of 4-F (molecule A), 4-OET, 4-NO2 and unsub-
stituted compound when compared to the compound I,
the structural superimposition has not been carried out
for these molecules.
τ τ
τ
ferent torsion angles ( , 2, and 3) (Scheme 1). These
1
3.2 Hirshfeld surface (HS) analysis
three angles in the compound I are compared to other
4-substituted and unsubstituted structures (Table S1,
Supporting Information). The structural superimposi-
tion is carried out to identify the orientation ofthe phenyl
ring upon different substitutions. It is found that all
three torsion angles are nearly the same in the structures
of 4-NMe2, 4-OH, 4-Me, 4-OMe and in the com-
pound I (4-Br). The conjugated O2=C9−C2=C3−O1
and O4=C17−C10=C11−O3 moieties are used for
Various intermolecular interactions observed in the
crystal structures of I and its related analogs were quan-
tified using Hirshfeld surface analysis. The HS of the
compound I is mapped with dnorm and the 2D finger-
print plots are shown in Figure 2. The analysis suggests
that the intermolecular H · · · H contacts are contribut-
ing more (53.1%) to the crystal packing when compared
to the other contacts present in the crystal structure of I.

J. Chem. Sci. (2018) 130:20
Page 5 of 14 20
Figure 2. Hirshfeld surface (HS) analysis and two-dimensional fingerprints for the compound I (a) two different views of
HS mapped with dnorm distances (b) two-dimensional fingerprints plot showing different intermolecular contacts.
3.3 Molecular pairs in the crystal structure
To quantify all possible intermolecular interactions
present in the compound I, the important molecular
pairs (Figure 4) were retrieved from the crystal pack-
ing and their interaction strengths were quantified using
the PIXEL method. Table 2 shows all possible inter-
molecular interactions (motif I to VI) along with their
interactions energies. The interaction energies for these
motifsarecomparedwiththeenergiesderivedfromDFT
method.
In the crystal structure of I, one of the methylene
(via H12B) groups (atom C12) of ring C is participat-
Figure 3. The relative contributions of various intermolec-
ing in an intermolecular C−H · · · O interaction with
ular interactions in the compound I and its related analogs.
the carbonyl oxygen atom (O2) of ring B (motif I).
This interaction links the molecules into a chain which
runs parallel to the crystallographic c axis. The stabi-
lization energy for this motif I was found to be –9.1
kcal mol−1 as evaluated from the PIXEL calculation. As
shown in Figure 5, it is clearly seen that the major con-
tributor for the stabilization of motif I is the dispersion
interactions (66.7%). Motif II is stabilized by a π · · · π
stacking interaction between 4-bromophenyl rings. The
dispersion interactions contribute nearly 75% towards
the stabilization of motif II. The interaction energy for
this motif was calculated to be –8.9 kcal mol−1. Motif
III is formed by an intermolecular H12B · · · H6A inter-
action and dispersion component contributes about 83%
towards the stabilization. The interaction energy for this
dimer was −7.2 kcal mol−1. Motif IV is generated by
an intermolecular C16−H16A · · · O1 interaction. This
intermolecular interaction interconnects the molecules
into a chain that runs parallel to the c axis. The dimer
form by motif IV score an interaction energy of –6.0 kcal
mol−1 and this dimer is stabilized by the contribution
of the dispersion (66%) and the electrostatic interac-
tions (34%). Furthermore, motifs I and IV are combined
to form a tetrameric supramolecular motif as shown
The relative contributions of other intermolecular con-
tacts such as O · · · H/H · · · O, H · · · Br/H · · · Br and
C · · · H/H · · · C are 19.7, 13.1 and 10.7%, respectively,
to the total HS area of the molecule. Figure 3 displays
the percentage contribution of various intermolecular
contacts observed in the compound I and its related
analogs. It is clearly showing that the intermolecular
H · · · H contacts are predominant in all 4-substituted
structures. Notably, the intermolecular H · · · H contacts
are contributing more (greater than 60%) to the crystal
packing in the unsubstituted (4-H), 4-Me, 4-N(Me)2,
4-OH, 4-OMe, 4-OET and one of the molecules of 4-
F structures. In the case of I (4-Br), 4-Cl and one of
the molecules of 4-F structures, these contacts are less
than 60%. Overall, there are slight variations observed
for intermolecular C · · · H and O · · · H contacts due to
different substituents at the para position. Two different
orientations of Hirshfeld surfaces mapped with different
properties such as di, de, dnorm, shape index and curved-
ness of the compound I and its related analogs are given
in Figure S1.

20 Page 6 of 14
J. Chem. Sci. (2018) 130:20
Figure 4. Selected molecular pairs extracted from the crystal structure of I. (a) Motifs I and IV (b) Motif- II (c) Motif-III
(d) Motif-V and (e) Motif-VI (see Table 1 for motif details).
in Figure 4(a) and these two interactions are clearly It should be noted that the contribution of disper-
visible on the HS (Figure 2(a–b)). Motif V is formed sion energy is predominant (61–75%) in all structures
by the presence of two intermolecular H · · · H interac- towards the stabilization. In the case of 4-OH, the con-
tions (H4A · · · H6C and H4A · · · H8B). It should be tribution of dispersion energy is reduced (61%) and the
noted that the former contact is longer by 0.05 Å, while electrostatic interaction is increased to 39% due to the
the latter is longer by 0.08 Å when compared to the O · · · H contacts as evident from the HS analysis. Fur-
sum of the van der Waals radii of respective interact- thermore, a substantial amount of contribution comes
ing atoms. The stabilization energy for this molecular from C · · · H/H · · · C contacts to the overall stabiliza-
pair was calculated to be –3.0 kcal mol−1. One of the tion in the title compound I and its closely related
methyl groups (via H14A) is involved in an intermolec- analogs (Figure 3). To understand the role of C · · · H
ular C-H · · · Br interaction (motif VI) with the Br atom and H · · · halogen contacts in the stabilization of the
of the neighbouring molecule. It is of interest to note crystals, we thoroughly examined the crystal packing
that this interaction is slightly longer (0.08 Å) than the of the title compound and its closely related analogs
sum of the van der Waals radii of H and Br atoms. The using the PIXEL method. Various molecular pairs for
interaction energy for this dimer was calculated to be these molecules were extracted based on their inter-
−2.7 kcal mol−1 and this pair is primarily stabilized by molecular interaction energies. The selected molecular
the dispersion (∼ 70%) interactions in nature.
pairs stabilized by C · · · H and H · · · halogen contacts
in 8 closely related analogs are given in Figure S2. This
analysis suggests that the C · · · H contacts are mostly
playing a supportive role in the stabilization along with
3.4 Lattice energies and common packing features
Lattice energies for the compound I and its closely intermolecular C−H · · · O/N interactions. In contrast,
related analogs were computed using the PIXEL the molecular pair is formed by intermolecular H · · ·
method. The lattice energies and their components for halogen interaction without any significant additional
these molecules are listed in Table 3. It is found that non-bonded contacts. It is to be noted that these molec-
the overall lattice energies for these compounds are in ular pairs usually form with low interaction energy.
the range of −30.7 to −37.1 kcal mol−1. It is worth
Further, the common packing features exist between
mentioning that the overall lattice energy is stronger the compound I and its closely related analogs were
for the 4-OH and weaker for 4-F and 4-Me structures. analyzed as mentioned in the experimental section. As

J. Chem. Sci. (2018) 130:20
Page 7 of 14 20
Figure 5. The relative contributions of various energy com-
ponents in the different motifs of the crystal structure of I.
shown in Figure 6, we found that the motifs II and III
in the compound I are also observed in 4-OEt and 4-Cl
structures, respectively. The former motif is stronger by
0.7kcalmol−1 inthe4-Clstructure, whilethelattermotif
is stronger by 0.8 kcal mol−1 in the compound I. This
dimer match can be described as 0D similarity. Apart
from this, there is no common mode of crystal pack-
ing existing between compound I and its other closely
related analogs. However, the intermolecular C · · · H
contacts help to stabilize most of the strongest dimers
in this class of compound.
3.5 DFT analysis
To check the conformational flexibilities of I, the
monomeric structure was optimized in the gas phase
as well as in the ethanol solvent using the DFT method.
The optimized structures were compared with the crys-
tal structure. The superimposed image of the DFT
optimized (gas and ethanol solvent) geometry and the
experimentalstructureindicatesthebondparametersare
well reproduced in the DFT calculation. The structural
superimposition diagram is given in the Supplementary
Information(FigureS3). TheRMSD(rootmeansquared
deviation) between X-ray and the optimized structure in
the gas phase involving non-hydrogen atoms is 0.23 Å.
The corresponding value is 0.19 Å for the X-ray and the
optimized structure in ethanol solvent. A close exami-
nation of the three torsion angles (τ1,τ2 and τ3) indicates
that these angles are deviating by 4–20◦ from the crystal
structure geometry (Table S1). These deviations may be
due to the absence of crystal packing effect in the gas
and solvent phases.
3.6 Quantitative molecular electrostatic potential
To understand the nature of interaction that exists in the
crystal packing, we analyzed the quantitative molecu-
lar electrostatic potentials (MESP) for the monomer at

20 Page 8 of 14
J. Chem. Sci. (2018) 130:20
Table 3. Lattice energies (in kcal mol−1) of the compound
I and its closely related analogs (para substituted).
Compound
ECoul Epol EDisp ERep Etot
4-H
−11.0 −4.9 −40.1 24.4 −31.6
4-Br (present study) −9.6 −4.0 −40.1 21.4 −32.3
4-Cl
4-F
−11.8 −4.7 −41.0 23.8 −33.7
−11.1 −4.3 −36.3 21.0 −30.7
−19.6 −8.9 −44.3 35.7 −37.1
−10.5 −5.3 −40.3 25.5 −30.7
−11.8 −5.9 −43.9 27.8 −33.7
−11.2 −4.9 −41.8 23.3 −34.6
−11.6 −5.6 −46.0 27.5 −35.8
4-OH
4-Me
4-OMe
4-OEt
4-N(Me)2
Figure 6. Common packing features observed in the compound I and its closely related analogs.
the 0.001 electrons/Bohr3 isodensity surface using the kcal mol−1, while the hydroxy group has −24.85 kcal
WFA-SAS program.52 The MESP isosurface along with mol−1. In addition, the negative potentials are found on
various positive and negative potentials designated as the bromine atom and on the benzene ring with values
Vs,max (shown in black dots) and Vs,min (shown in blue −16.39 kcal mol−1 and -13.95 kcal mol−1, respectively.
dots) are shown in Figure 7. The most positive Vs,max During crystal formation, the most positive regions can
value of 20.83 kcal mol−1 is observed on the methy- interact with the most negative regions of the neighbor-
lene (C16) hydrogen atoms neighbour to the carbonyl ing molecule thereby leading to the directional structure
group and on the methylene (C4) groups neighbour formation. Thus, methylene hydrogens have a tendency
to the hydroxy group. Similar values on the methy- to form intermolecular interactions with either carbonyl
lene groups (C8 and C12) attached to the carbonyl and group, a hydroxyl group or with bromine atom which is
hydroxy group show that there exists a strong bonding evident from the PIXEL energy calculation.
between them. The other positive regions are found in
the dimethyl groups. The protons on the 4-bromo ben-
zene is found to have a near positive potential of 16.69
kcal mol−1 and the least value is found on the hydro-
gen atom attached to the tertiary carbon which links
rings A, B and C. The most negative potential Vs,min is
observed on the carbonyl oxygen with a value of −31.55
3.7 QTAIM analysis
We performed QTAIM analysis for molecular pairs
(motif I-VI; see Table 1) to confirm the existence of var-
ious intermolecular interactions and to calculate their

J. Chem. Sci. (2018) 130:20
Page 9 of 14 20
Figure 7. Molecular electrostatic potentials of the title compound displayed in two different orientations.
The most positive and negative potentials are indicated.
interaction energies as proposed earlier.53,54 The molec- contacts is slightly higher than the C · · · C contact.
ular graphs for molecular pairs I-VI are displayed and The molecular pair III is formed by three symmetrical
given in the supporting information (Figure S4). The intermolecular H · · · H and C · · · H types of con-
topological parameters such as the electron density tacts. The intermolecular H · · · H contact is slightly
ρ
2 ρ
(
the Laplacian of electron density (∇ ), local stronger when compared to C · · · H contacts. In the
BCP),
potential energy density (V(r)) and kinetic energy den- molecular pair IV, there are four intermolecular BCPs
sity (G(r)) for various intermolecular interactions at the observed. This pair is primarily stabilized by inter-
bond critical points (BCPs) are presented in Table 4. molecular C−H · · · O interactions with EHB values in
The interaction values are computed from the local the range of 2.26 − 0.59 kcal mol−1. Both hydroxy
potential energy density using EHB = −0.5 V(r). The and carbonyl oxygens act as acceptors in this molecular
ρ
BCP for the intramolecular O−H · · · O hydrogen bond- pair. Molecular pair V is stabilized by intermolecular
ing interactions in the optimized monomer and dimers H · · · H type of contact and the molecular pair VI is
at their crystal structure geometry lies in the range formed by intermolecular H · · · Br type of interaction.
of 0.045–0.059 a.u. The EHB was found to be in the The EHB values for these interactions were found to be in
range of 12.40–17.04 kcal mol−1 for these interactions. the range of 0.61–0.53 kcal mol−1. Overall, the QTAIM
It is of interest to note that one of the intramolecu- analysis suggests that the intermolecular H · · · C and
lar O−H · · · O hydrogen bond is stronger by 4 kcal H · · · Br contacts play an important role towards the
mol−1 when compared to another intramolecular hydro- stabilization of the various molecular pairs in the crys-
gen bond.
In the molecular pair I, there are four intermolecular
tal structure of the title compound.
ρ
BCP’s. The
for these interactions lie in the range
BCP
3.8 Spectral analysis
of 0.004–0.010 a.u. The intermolecular H12B · · · O2
ρ
interaction has the maximum
and the EHB for this
The IR and Raman spectra recorded for the compound
I to understand the nature of interactions exist in the
solid state. We also computed the IR and Raman spec-
tra for the monomer and the four most stable dimers
(I-IV). A comparative IR and Raman spectra derived
from experimental and the DFT method for monomer
and four dimers are given in Figures S5–S6. It is clearly
concludedthatthecomputedspectraresembletheexper-
imental spectra. In the experimental IR spectrum, we
observed three intense absorption bands at 1373, 1592
and 2959 (broad) cm−1. These peaks could be assigned
BCP
interaction was 2.34 kcal mol−1. The intermolecular
C · · · H and H · · · Br contacts with EHB values lie in
the range of 0.62–0.75 kcal mol−1 which indicates their
supportive role in the stabilization.
There are four symmetrical intermolecular BCPs
observed in the molecular pair II. The intermolecular
C21 · · · C22 contact indicates the existence of π · · · π
stacking. Further, the existence of H · · · Br and Br · · · O
contacts provide additional stability to this molecular
pair. It is of interest to note that the strength of these

20 Page 10 of 14
J. Chem. Sci. (2018) 130:20
for wagging of hydroxy group, phenyl C–C stretch-
ing and methylene C–H and methyl C–H stretching
vibrations, respectively. It is noted that the broadness
of the latter peak due to the overlap of methylene and
methyl C–H vibrations. In the crystal structure, dimer-
I is stabilized by an intermolecular C12−H12B · · · O2
interaction. The C12–H12B stretching vibration is cal-
culated at 3067 cm−1 which is comparable with the
experimental IR peak at 2962 cm−1. This blue shift is the
consequence of the formation of intermolecular interac-
tion. In dimer-II, the phenyl C–C stretching (red shift)
is calculated at 1563 and 1566 cm−1 which is responsi-
ble for a weak π · · · π interaction. Similarly, dimer-III
is formed by an intermolecular C12−H12B · · · H6A
interaction (between methylene hydrogen and methyl
hydrogen). The stretching vibration for this interaction
is calculated at 3069 cm−1. The C=O stretching vibra-
tion is calculated in the range of 1700–1728 cm−1 in
the monomer and in four dimers. In dimer-IV, due to a
slight conformational change on ring C, intermolecular
interactions C12−H12B · · · O1 is formed which is not
observed in the crystal structure. The stretching vibra-
tion of C12–H12B bond is calculated at 3071 cm−1. In
the experimental Raman spectrum, absorption peaks at
3278, 3154, 3090, 1696 and 1652 cm−1 observed. The
peaks could be assigned for phenyl C–H stretching,
methylene C–H, methyl C–H, phenyl C–C stretching
and wagging of O–H vibrations, respectively.
As mentioned earlier, the UV-visible spectrum for the
compound I was computed in ethanol solvent using the
TD-DFT method with polarizable conductor calcula-
tion model (CPCM) with Klamt sphere radii. Figure 8
shows the overlap diagram of the experimental and the
simulated spectra and in Table 5 we present the excita-
tion energies, oscillator strengths ( f ) and the electron
configurations. The experimental spectrum shows an
intensive absorption peak at 260 nm and the corre-
sponding peak was observed at 239 nm in the TD-DFT
calculation. The frontier molecular orbitals involved in
the transition are shown in Figure 8. The peak calculated
at 263 nm with an oscillatory strength of 0.055 is pri-
marily constituted by the HOMO→LUMO transition.
The excitation at 239 nm with an oscillatory strength
of 0.538 corresponds to HOMO → LUMO + 1 transi-
tion which contribute about 85%. These two excitations
indicate that the charge transfer HOMO → LUMO and
HOMO → LUMO+1 orbitals. The band gap energy for
theformertransitionis7.32eV, whilethelattertransition
is found to be 7.58 eV. It is of interest to note that the
HOMO orbitals are localized over the bromobenzene
ring and π-conjugated moieties as mentioned earlier,
while the LUMO orbital is located on the conjugated
moieties of the cyclohexene rings.

J. Chem. Sci. (2018) 130:20
Page 11 of 14 20
Figure 8. The observed and calculated UV-Vis spectra (left) and HOMO-LUMO orbitals (right).
Table 5. Excitation wavelengths (in nm), oscillator strengths, configura-
tions, and experimental data for the compound I in ethanol solvent.
Excitation Energy
f
Main configuration
Expt.
260
263
239
0.0550 HOMO → LUMO (84%)
HOMO − 2 → LUMO + 1 (7%)
0.5380 HOMO → LUMO+1 (85%)
HOMO − 2 → LUMO (9%)
4. Conclusions
collectively suggest that H · · · C and H · · · halogen
contacts play an important role towards the overall sta-
bilization in this class of compounds. Further, FT-IR and
FT-Raman spectra were derived from experimental and
simulated by the DFT method. The results support the
existence of various intermolecular interactions in the
crystal structure. The analysis of the frontier molecular
orbitals provides evidences for a charge transfer process
is taking place within the molecule.
The compound I was synthesized and characterized
by various experimental and theoretical methods. The
overall conformation of the compound I was compared
with its closely related analogs. The crystal structure of
the compound I revealed that the compound exhibited
two strong intramolecular O−H · · · O hydrogen bond-
ing interactions. Intermolecular C–H· · · O, π · · · π and
H · · · H contacts were responsible for the molecular
self-assembly. Further, the energetics of the various
intermolecular interactions was estimated using PIXEL,
DFT and QTAIM analysis. The relative contributions
of various non-bonded contacts present in the com-
pound I and its closely related analogs were quantified
using Hirshfeld surface analysis. We found that motifs
II and III of the compound I were also existed in its
closely related analogs, 4-OEt and 4-Cl. Apart from
this, there is no common mode of crystal packing exist-
ing between compound I and its other closely related
analogs. The PIXEL, HS and QTAIM calculations
Supplementary Information (SI)
The supplementary information includes the following: Table
S1 contains the selected torsion angles for the title compound
and its related analogs, Figure S1 shows various proper-
ties mapped with Hirshfeld surfaces, Figure S2 displays the
selected molecular pairs of 8 closely related analogs of the
title compound, Figure S3 shows structural superimposi-
tion, Figure S5 depicts the molecular graphs obtained from
QTAIM analysis and Figures S5–S6 provide the experimen-
tal and theoretical FT-IR and FT-Raman spectra. CCDC-
1543019, contains the supplementary crystallographic data

20 Page 12 of 14
J. Chem. Sci. (2018) 130:20
for the title compound I. These data can be obtained
freely via http://www.ccdc.cam.ac.uk/data_request/cif or by
e-mailing to data_request@ccdc.cam.ac.uk or by contact-
ing directly the Cambridge Crystallographic Data Centre
(12 Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223
336033). Supplementary Information is available at www.ias.
ac.in/chemsci.
Simple and cost effective acid catalysts for efficient
synthesis of 8-aryl-1,8-dioxooctahydroxanthene Tetra-
hedron Lett. 54 491
11. Ilangovan A, Malayappasamy S, Muralidharan S and
Maruthamuthu S 2011 A highly efficient green synthesis
of 1,8-dioxo-octahydroxanthenes Chem. Cent. J. 5 81
12. Vaid R, Gupta S, Kant R and Gupta V K 2016 Domino
Knoevenagel/Michael synthesis of 2,2’arylmethy-
lene bis(3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one)
derivatives catalyzed by silica-diphenic acid and their
single crystal X-ray analysis J. Chem. Sci. 128 967
13. Sughanya V and Sureshbabu N 2012 2,2’-[3-Bromo-4-
hydoxy-5-methoxyphenyl)methylidene]bis(3-hydroxy-
5,5-dimethylcyclohex-2-en-1-one Acta Cryst. E68
o2875
14. Sureshbabu N and Sughanya V 2012 2,2’-[(4-Etho-
xyphenyl)methylene]bis(3-hydroxy-5,5-dimethylcyclo-
hex-2-en-1one) Acta Cryst. E68 o2638
15. Bolte M, Degen A, Rühl S 1997 Twinned crys-
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cyclohexenyl)phenylmethane at 150 K Acta Cryst. C53
340
Acknowledgements
ST thanks the DST-SERB (SB/YS/LS-19/2014) for research
funding. Authors would like to thank Laboratorio Nacional de
Supercómputo del Sureste (LNS-BUAP) and Bioinformatics
Resources and Application Facility (BRAF), C-DAC Pune for
computational work. Authors thank DST-PURSE Lab, Man-
galore University for providing single crystal X-ray diffrac-
tion facility. SSG thanks Science and Engineering Research
Board, DST-SERB (EMR/2016/000317) and Council of Sci-
entific and Industrial Research, CSIR (80(0085)/16/EMR-II)
for financial support.
16. Bolte M, Degen A and Rühl S 2001 2,2’-[(3-Hydroxy-
phenyl)methylene]bis(3-hydroxy-5,5-dimethyl-2-cycl-
ohexen-1-one) hydrate Acta Cryst. E57 o170
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