Do hydrogen bonding and noncovalent interactions stabilize nicotinamide-picric acid cocrystal supramolecular assembly?

Article abstract of DOI:10.1016/j.molstruc.2019.06.037

A 1:1 stochiometric cocrystal of nicotinamide with picric acid (C₁₂H₈N₅O₈) has been synthesised successfully by solvent assisted grinding method and structure of the cocrystal is established by single crystal X-

Full text of DOI:10.1016/j.molstruc.2019.06.037

Accepted Manuscript
Do hydrogen bonding and noncovalent interactions stabilize nicotinamide-picric acid
cocrystal supramolecular assembly?
U. Likhitha, B. Narayana, B.K. Sarojini, Anupam G. Lobo, Gopal Sharma, Surbhi
Pathania, Rajni Kant
PII:
S0022-2860(19)30759-8
DOI:
https://doi.org/10.1016/j.molstruc.2019.06.037
MOLSTR 26679
Reference:
To appear in: Journal of Molecular Structure
Received Date: 21 November 2018
Revised Date: 26 March 2019
Accepted Date: 11 June 2019
Please cite this article as: U. Likhitha, B. Narayana, B.K. Sarojini, A.G. Lobo, G. Sharma, S. Pathania,
R. Kant, Do hydrogen bonding and noncovalent interactions stabilize nicotinamide-picric acid cocrystal
supramolecular assembly?, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/
j.molstruc.2019.06.037.
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Do Hydrogen Bonding and Noncovalent Interactions
Stabilize Nicotinamide-Picric Acid Cocrystal
Supramolecular Assembly?
U. Likhithaa, B. Narayanaa b*, B. K. Sarojinia, Anupam. G. Loboc, Gopal Sharmad,
Surbhi Pathaniad, Rajni Kantd
aDepartment of Industrial Chemistry, Mangalore University, Mangalagangothri-574199, India
bDepartment of Studies in Chemistry, Mangalore University, Mangalagangothri-574199, India
cSchool of Chemical Sciences, Mahatma Gandhi University,Kottayam -686560,India.
dDepartment of Physics, University of Jammu, Jammu Tawi - 180 006, India.
Abstract
A 1:1 stochiometric cocrystal of nicotinamide with picric acid (C12H8N5O8) has
been synthesized successfully by solvent assisted grinding method and structure of the
cocrystal is established by single crystal X-ray diffraction studies. The compound
crystallizes in the orthorhombic space group Pbca with unit cell parameters:
a=7.7608(11), b=14.5110 (14), c=24.751 (3) Å and Z=8. The crystal structure was
solved by direct methods and refined to R=0.0723 for 1755 observed reflections.
Current study has primarily focused on hydrogen bonding which is the driving force for
the formation of cocrystal. Hirshfeld surfaces and fingerprint plots indicate that the
structures are stabilized by O···H, N···H intermolecular interactions. In order to make a
better understanding supercell model of nicotinamide-picric acid cocrystal (NICPIC) is
created with crystallographic data. Based on this hydrogen bonding population, radial
distribution function (RDF) and bulk properties are simulated via Molecular Dynamics
(MD). Furthermore, DSC/TGA analysis indicates that the NICPIC maintains its
crystallinity up to 195°C, suggesting its higher st ability compared to individual
components.
Keywords: Crystal structure, Direct methods, Hydrogen bonding, Hirshfeld surface,
molecular dynamics.
1. Introduction
The cocrystallisation tend to enhance the physicochemical properties of APIs
and great impetus is being generated in the recent past. A cocrystal alludes to two or
more than two molecules combined into the same crystal lattice via intermolecular
interactions such as hydrogen bonding, π-π stacking and van der Waals forces with a
fixed stoichiometric ratio, which forms a special multicomponent supramolecular crystal
structure [1]. Its extensive applications in pharmaceutical industry were well

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documented and also attracted much attention in other fields, such as energetic
materials, optical and semiconducting materials because of crystal morphology
modification [2].
Many cocrystals of the compounds containing acid-amides have been
synthesised by employing various cocrystal preparation strategies. Early successful
experiments between nicotinamide and acids were carried out by Fábián and co-
workers. Their investigation resulted that well known acid–aromatic nitrogen
heterosynthon would provide sufficient driving force for cocrystallisation [3]. Examples
of various cocrystals of nicotinamide with respect to those of pure acids, have also
been reported by Kaup et al.
In their work they could control the formation of stoichiometric variations by adjusting
the reaction mixture composition using mechanochemical process which in turn helped
to manifest the mechanism of formation for the hydrogen bonded cocrystals.
Interconvertibility of different stoichiometric variations by liquid assisted grinding was
explored by them and it also offered qualitative rating of the relative stabilities of each
cocrystal of different ratios. [4].
The presence of two nitrogen atoms of pyridine and amide in nicotinamide
enables to construct reliable synthons with other molecules. It is well understood that
picric acid is a known π acceptor and hence forms charge transfer complexes [5-6]
[Figure 1.]. It is used in medicinal formulations in the treatment of malaria, trichinosis,
smallpox and antiseptics. In view of importance of pharmaceutical cocrystals, various
pharmaceutical crystals were synthesised in combination with picric acid and were
reported by our group. Picrate of desipramine was synthesised by Swamy et al. [7] and
its crystal structure was studied. Yathirajan et. al [8] reported the crystal structure of
phthalazine-1(2H)-one in combination with picric acid having 1:1 ratio. Harrison et.al
reported the crystal structure of imipraminium picrate [9]. The crystal of 2-
aminopyrimidinium picrate was obtained by Narayan et.al [10] and its crystal structure
was studied by them. Also, Fun et.al [11] were able to form a crystal of orphenadrinium
picrate picric acid and obtained its crystal structural details. The recent approaches
showed that cocrystal formation has been rationalized by considering the non-covalent
interactions. Previously there have been considerable amount of studies on MD
simulations of cocrystals. This included the study on thermal stability of 1,3-
dinitrobenzene-2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaiso-wurtzitane cocrystal
by Sun et al. The sensitivity studies of another energetic material 2,4,6,8,10,12-
hexanitro-2,4,6,8,10,12-hexaazaiso-wurtzitane with trinitrotoluene studied by Guo et al.
Investigation of binding energy and mechanical properties of explosive cocrystal
Hexaazaisowurtzitane -Nitroguanidine with different molecular ratios was reported by
Ding et al. [12-14].
Presented here is a systematic synthesis and studies on 1:1 NICPIC with its
single crystal structure details and crystal packing. Focussing on simple solvent
assisted grinding process it was attempted to synthesize cocrystal to seek out how
pharmaceutically active small molecules like nicotinamide a part of vitamin B3
interacted with picric acid a known cocrystal former. The hydrogen bonding model is

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established as a key motif in order to have an appropriate representation of NICPIC.
The renowned hydrogen bonding moieties in coformers attracted to synthesize
cocrystals and to further examine their hydrogen bonding patterns. To analyze this
approach, MD simulation was carried out using Schrödinger’s Materials Science Suite.
This evidently engrossed hydrogen bonding as noncovalent interactions were most
important criteria in crystal engineering which was also responsible for the stabilisation
of the molecular crystal [15]. The current study also encompasses FTIR, PXRD,
Hirshfeld surface analysis, RDF and bulk properties simulations which provide
supportive information for the formation of stable cocrystal.
2. Experimental section
2.1. Materials and Method of preparation
The starting materials and other reagents were taken from commercial sources
and were used without further purification. Mixture of nicotinamide (1.262g, 0.01M,
99.5% purity) and picric acid (2.231g, 0.01M, 99.8% purity) was ground properly using
agate mortar and pestle with few drops of acetonitrile solvent. Acetonitrile (20mL) was
added to this mixture and heated at 70°C. Precipita te formed was filtered and dried. It
was purified by using 10 mL of ethanol-water solution (2:1) on heating to 70°C. The
flakes like material obtained on cooling (4 days) was further dissolved using 15 mL of
ethanol to get single crystals.
2.2 Characterization
Infrared spectra were obtained from BRUKER TENSOR II FTIR spectrometer in
the spectral range 400–4000 cm-1 with KBr pellets. The DSC and TGA were carried out
to meet the needs of cocrystal characterisation and analysis. The thermal properties of
NICPIC were examined by Universal V4.5A TA Instruments SDT Q600 V20.9 Build 20
differential scanning calorimeter. The instrument was calibrated using an Indium metal.
The experiments were carried out in nitrogen atmosphere with flow rate 100 mL.min -1.
Around 2-2.5 mg of each sample was loaded into an aluminium pan, and an accurately
weighed blank aluminium pan was used as reference. Original samples of NICPIC and
-1
starting materials were heated from room temperature to 600°C at a rate of 10°C.min .
The cocrystal sample was crushed to reduce particle size by grinding in a mortar
and pestle in order to carry out structural studies on Rigaku miniflex 600 powder X-ray
diffraction with CuKα radiation (0.15406 nm). The scanning rate was 4°mi n-1 over
diffraction angle of 2θ ranging from 3°to 80°. A crystal having good morp hology (0.3 x
0.2 x 0.2 mm) was chosen for three-dimensional X-ray intensity data collection. Data
was collected at 293(2) K by using X’calibur CCD area-detector diffractometer equipped
with graphite monochromated MoK
α radiation (λ = 0.71073 Å). The cell dimensions
were determined by least-squares fit of angular settings of 1727 reflections in the
θ range 3.83 to 28.94o. A total of 6636 reflections were recorded for θ ranging from 3.74
to 25.99o and out of these reflections, 2729 were found unique. 1755 reflections were
treated as observed (I>2σ(I)). Data were corrected for absorption, extinction and

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Lorentz-polarization factors [16]. The structure was solved by direct methods using
SHELXS-97 [17]. All non-hydrogen atoms of the molecule were located in the best E-
map. A full matrix least squares refinement was carried out using SHELXL-2016 [18].
All the hydrogen atoms were also located. The final refinement cycles converged to an
R= 0.0723 and wR(F2) = 0.1918 for the observed data. Residual electron densities
ranged from -0.27 to 0.47eÅ-3. Atomic scattering factors were taken from International
Tables for X-ray Crystallography (1992, Vol.C, Tables4.2.6.8 and 6.1.1.4). The
crystallographic data are summarized in Table1. CCDC–1857852 contains the
supplementary crystallographic data for this paper. The HPLC for the NICPIC was run
and chromatogram has been attached as supplementary material.
2.3. Computational methods
The 3D surface analysis and 2D finger prints speculate about the vicinity of
neighbouring atoms or molecules and hence provide an important insight into crystal
packing due to molecular interactions. The closeness of intermolecular contacts can be
studied by Hirshfeld surfaces by measuring a normalized contact distance (dnorm) based
on de, di and the van Der Waals radii of the atoms [19]. Where dnorm denotes the
distance between two atoms across the surface to the atomic radii of the atoms, de is
the distance to the closest nuclei outside the surface and di is the distance to the
closest nuclei inside the surface from the Hirshfeld surface. These calculations were
performed using CrystalExplorer17 [20]. It is a convenient computational tool that
displays the unique plots for any crystal structure by colour coding short or long-range
contacts [21-22]. In addition to this 3D molecular electrostatic potential is mapped over
the Hirshfeld Surfaces using wave function STO-3G basis set at Hartree-Fock theory
over the range of ±0.25 au.
Based on crystal packing obtained from the XRD analysis the MD simulations
were carried out for NICPIC and established the equilibrium structure. The imported
CIF was prepared for molecular dynamics in OPLS3 force field. The resulting structure
was minimised using Desmond with the maximum iteration of 2000 and convergence
threshold 1kcal.mol-1Å-1. Further, NICPIC model were optimized by MD Multistage
Workflow to obtain reasonable configurations. NVT ensemble were used at temperature
300K.
MD simulation with a total simulation time of 0.100ns was performed to
equilibrate the system. The total number of 7344 of frames of data was collected finally
in the trajectory. After performing the MD simulation on NICPIC system it was
emphasised on characterising the hydrogen bonding population and arrived at
statistical analysis which speculates the number of hydrogen bonding with time
frequency parameters. In this study, it was investigated the dynamics of hydrogen
bonds using the time autocorrelation function, CHB, defined as
CHB(t) = < b (0). b(t) > / < b >,
where b(t) is 1 if a D-H···A hydrogen bond between a given set of donor, D, hydrogen,
H, and acceptor, A, atoms exists at time t, and is zero otherwise [23].
RDF refers to ratio of the area density around the investigated atom and average
density of the entire system, which mainly indicates the distance of a given particle from

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other particles in the system. Thus, we can depict the interactions between molecules
by analysing the distribution of particles in space [24]. To clarify the interactions, RDF
simulation was performed in the cocrystal system. The parameters of bulk properties
here include density, cohesive energy, solubility, heat of vaporisation, stress and strain.
Density is a fundamental structural parameter that can be compared directly to
experiment. Density (ρ) is defined as mass (m) per unit volume(V),
ρ=m/V
Density was computed for each frame over the course of the trajectory.
Inspection of its convergence gives important feedback on the degree of system
convergence. With the OPLS force fields, the fully equilibrated density could be
computed to within 3% of experimental values.
CED implies to the energy required by 1 mole of condensates to overcome
intermolecular forces and turn into gas in unit volume. This technique quantifies the
magnitude of intermolecular forces in the cocrystal system, and it can also provide
theoretical criterion of thermal sensitivity magnitude in a high energy system under
specific conditions. Here the plot of cohesive energy is obtained with respect to different
time intervals in nano seconds.
The heat of vaporization and Hildebrand solubility parameter are closely related
properties. The solubility parameter is useful for estimating the miscibility of various
components being considered for applications requiring multicomponent mixtures. The
solubility parameter (δ) for a pure liquid is defined as
δ = [(∆Hv-RT) / Vm]1/2
where ∆Hv is heat of vaporization and Vm is molar volume. The heat of vaporization,
∆Hv, is measured in kcal/mol and is calculated from the energy of periodic unit cell
minus the sum of the N individual molecules, Ei, averaged over the MD trajectory.
ꢀ
∑
∆Hv= {|Ecell- ꢁꢂꢃ Ei |} + RT
The stress-strain relation is generated by subjecting a cocrystal system into
arbitrary load, hence the deformation by stress and Strain i.e. relative change in the
position of points within a body that has undergone deformation is quantified using MD
simulations.
3. Results and discussions
3.1. FTIR analysis
As displayed in Figure 2. the pure nicotinamide showed -N-H stretching
vibration at 3165cm−1, strong absorption band at 1629cm−1 due to -C=N ring stretching
vibration and the amide I and amide II absorption bands appeared at 1670cm−1(-C=O)
and 1598cm−1(-N-H bend). These observations agree well with the IR data of
nicotinamide reported in literature [25]. The absorption bands of pure picric acid
appeared at 3106 cm−1,1540cm−1,1366cm−1 and 1256cm−1 which correspond to
phenolic -OH stretching, aromatic -NO2 stretching (two bands) and -NO symmetric
stretching vibration respectively. These assignments are also in line with the literature
values [26].

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In the spectrum of synthesised NICPIC stretching modes were very much
prominent, almost all characteristic bonds of nicotinamide and picric acid were evident
and it is represented in Figure 2. The broad band appeared at 3090 cm−1 in NICPIC
indicated that the -OH group of picric acid was likely involved in the intermolecular
hydrogen bonds with -NH group of nicotinamide [27].
3.2. Thermogravimetric studies
The representative DSC and TGA thermographs (Figure 3.) of NICPIC and
starting materials showed distinguishable features. From the DSC profile it was
revealed that picric acid showed endothermic and exothermic peaks at 125.19°C and
255.69°C respectively. For the nicotinamide the DSC curve exhibited endothermic peak
at 131.83°C and another endothermic peak at 258.33° C. TGA curve of the NICPIC
showed the continued weight loss from 200-600°C wit h an endothermic event appeared
at 195.17°C. Hence it exhibited melting point much higher than that of the starting
materials. As a result of these thermal techniques for understanding the stability of
cocrystal revealed that it maintained its relative crystallinity up to 195°C. This indicated
that NICPIC possessed better stability than the nicotinamide and picric acid individually.
3.3. Powder and Single crystal X-ray diffraction analysis
The crystalline states for the starting materials and NICPIC have been presented
in Figure 4. There were obvious differences among these powder X-ray diffraction
patterns. It could be observed that original characteristic peaks of nicotinamide at
2θ=38.05° and picric acid at 2 θ=8.7°, 2 θ=18.02°, 2 θ=23.1° and 2 θ=42.4° have
disappeared or declined, and few existing peaks were highly intensified at the range 6-
75°. New peaks appeared at 2 θ=51.2°2 θ=76.7°in NICPIC spectrum which stipulated
that the obtained spectrum was different from those of the starting materials indicating
the emergence of new crystalline phase. Moreover, NICPIC spectrum exhibited
stronger diffraction peaks than those of two components, hence higher crystalline
quality. This result emphasized that long-term stability of NICPIC would be better than
those of two components [28].
An ORTEP view of the NICPIC with atomic labelling is shown in Figure 5. [29].
The geometry of the molecule was calculated using the PLATON [30] and PARST [31]
software. Bond lengths and bond angles were within expected values [32]. Packing
view of the molecules in the unit cell viewed down the a-axis is shown in Figure 6.
Details of non-hydrogen atoms and hydrogen bonding are given in table 2-4. No
significant C-H…π contacts were observed in the molecular packing of NICPIC. The
crystal structure was further stabilized by π-π interactions and details of π–π interaction
is given in Table 5.
3.4. Hirshfeld surface analysis
From the analysis it was revealed that the O...H (45.2%) bonding appeared to be
a major contributor in the crystal packing, whereas the H···H (13.6%) , N···H (1.5%),
C···H (5.6%), C···C (2.1%), C···O (12.7%), N···C (4.5%), N···N (1.4%), N···O (5.6%),

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O···O (7.9%), contacts have their significant distribution to the total area of the surface
as shown in Figure 7.
As illustrated in Figure 8. circular red spots visible on 3D Hirshfeld surfaces
corresponded to the significant hydrogen bonding contacts such as O-H---O and N-H---
O which played major role as a primary interaction seen on NICPIC. The blue region
arose due to positive electrostatic potential over the Hirshfeld surface constituted
hydrogen donor potential, whereas hydrogen bond acceptors are indicated by red
region which extend a quantitative insight to negative electrostatic potential on the
surface.
3.5. MD simulations
The resulting trajectory was analysed in Desmond-Simulation Event Analysis
Panel for all the simulation work. The subsets of two compounds were selected in
simulation panel and respective hydrogen bonds between these two subsets of
molecules were mapped and monitored. Similarly, the resulting trajectory was imported
into Desmond’s RDF where the radial distance between centre of mass of nicotinamide
and centre of mass of picric acid is calculated by selecting the subsets of NICPIC as
done in simulation event analysis.
Intermolecular interactions(-C=O---N) were observed between -C=O and ring
nitrogen of two nicotinamide molecules and a hydrogen bonding (-N-H---O) between
amide -NH2 of nicotinamide and hydroxyl group of picric acid were observed. According
to the structure of nicotinamide and picric acid they could form hydrogen bond type -N-
H---O. In addition, intramolecular hydrogen bonding between the two ortho nitro groups
and OH group of picric acid was also evident. The short interactions like van der Waals
and long interactions like H-bonding were present among the like molecules and also
with coformers could be observed (Figure 9). Thus, the equilibrating structures were
obtained through MD simulations and is given in Figure 10a-10f.
3.5.1. Determination of hydrogen bonding population
As a way to describe how hydrogen bonding population varies with time
simulation was performed for NICPIC which resulted in varied number of hydrogen
bonds with different time frequency range as depicted in the Figure 11.
It could be seen that there is a probability of 390-415 hydrogen bonds formation
at time frequency 0.0ns-1 and those still existed when frequency reached to 0.032ns-1. It
showed 365-390, 415-440, 340-365 hydrogen bonds when the time frequency ranged
from 0.0ns-1 to 0.004, 0.0025, 0.001 ns-1 respectively. Hence, it could be observed that
there might be formation of hydrogen bonds at time 0 seconds, and still existed to time t
and broke in between. The short time decay or long frequency range was seen at 0.0-
0.032ns-1 which might be from fast motion such as intermolecular interaction in the form
of hydrogen bonding. However, considerably long-time decay was observed at the
range 0.004, 0.0025,0.001 and 0.0005ns-1.
Another point to consider is that the nature of hydrogen bonding also depends
upon its stretching frequency. Nakamoto et al. have obtained the measurements of
hydrogenic stretching frequencies of a number of hydrogen bonded compounds. Their

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work highlighted the behaviour of hydrogen bonds which portrayed straight, bent and
bifurcated bonds would show high and low frequency deviations respectively. Most
intermolecular hydrogen bonds were found to be straight, but a large number of
intramolecular hydrogen bonds must be bent if normal bond angles were to be
preserved [33].
In comparison with the graph obtained from simulation the number of hydrogen
bonds formed at different time frequencies were different. This might be due to the
formation of straight, bent and bifurcated bonds which changes according to its
stretching frequencies. So, complementing evidence of straight type hydrogen bonds
might be formed in large numbers denoting intermolecular interaction in NICPIC.
Hence, these interactions might be the guiding force for stabilizing cocrystal formation.
3.5.2. RDF simulation
A sharp peak in the RDF spectrum (Figure 12.) represents particularly favoured
distance of separation of neighbouring particles to a given particles. Thus, atomic
structure of the simulated system could be studied by RDF analysis. The well-defined
molecular structure of the NICPIC revealed that there was a broad diffraction peak
appearing in the range of 6.2–8.4 Å with a g(r) having value of about 1.15. This meant
that it was only once likely that two molecules could be found at this separation [34].
The radial distribution function then falls and passes through a minimum value at
around distance 9 Å. The chances of finding two molecules with this separation are
less. Due to the varying lengths of hydrogen bond and strong van der Waals forces
ranging from 5.5-8.5 Å it could be deduced that hydrogen bonds and strong van der
Waals forces existed in NICPIC model and they might have a strong impact on the
formation of the cocrystal.
3.5.3. Bulk properties
The average value of density obtained for the simulated structure is 1.16 gcm-3.
It does not show any typical fluctuations as the time ranges to 0.0-0.10ns as shown in
Figure 13., which indicated that density of NICPIC formed does not vary with time
hence it is stable.
Simulation results for solubility and cohesive energy in which the average
solubility and cohesive energy of the NICPIC is 31.99 MPa1/2 and 25.66 kcalmol-1
respectively, did not show any variations with increase in time. Since the cohesive
energy is the sum of the intermolecular forces that hold the material intact [35], it could
be said that hydrogen bonding and van der Waals forces have great impact on the
stability of the cocrystal. It could also be responsible for no change in cohesive energy
in the graph recorded. The heat of vaporisation was found to be 26.26 kcal.mol-1 and it
remained constant with time.
The stress-strain curve of the NICPIC model is represented in Figure 14., in
which deformation response varied considerably. In the early portion of the curve it was
observed that NICPIC fails to withstand a tensile stress and shows a drop from 1.8 GPa
to 1.1 GPa. This was probably because of weak forces like hydrogen bonding and van
der Waals between partners which could play a major role to form cocrystal

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architecture. These non-covalent bonds were broken down and two molecules were
separated. Further, these molecules experienced the stress separately and respective
deformation was observed in the plot.
4. Conclusions
A novel 1:1 NICPIC was synthesized, its X-ray quality single crystals were
obtained and characterized by single crystal XRD, FTIR, PXRD and TGA/DSC. The
obtained melting point of NICPIC was higher than that of the pure components. Its
supramolecular architecture was stabilized by hydrogen bonding. Both the nicotinamide
and picric acid contribute towards hydrogen bonding by C-H--O, N-H--O interactions. It
was evident from the Hirshfeld surface analysis that there exist 45.2% of -O--H bonding
which was the major contributor in the crystal packing of NICPIC. It was also possible to
recognize the hydrogen bonding motifs by RDF and bulk properties simulation. Hence
the results presented herein are step towards the better understanding of hydrogen
bonding through cocrystallisation which results in supramolecular assembly.
5. List of abbreviations
The following are the list of abbreviations used in this paper:
1. CIF — Crystallographic Information File
2. CCDC— The Cambridge Crystallographic Data Centre
Supplementary material
CCDC–1857852 contains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
We thank DST-PURSE Lab, Mangalore University for Thermal analysis data and
Department of Pharmaceutical Chemistry, NGSMIPS, Karnataka for spectral analysis.
BN thanks UGC for financial assistance through BSR one-time grant (SR/S/Z/-
23/2010/32) for the purchase of chemicals. RK thanks Department of Science and
Technology, New Delhi for financial support under research Project No.
EMR/2014/000467. UL is grateful to Mangalore University for research facilities.
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Do Hydrogen Bonding and Noncovalent Interactions
Stabilize Nicotinamide-Picric Acid Cocrystal
Supramolecular Assembly?
U. Likhithaa, B. Narayanaa b*, B. K. Sarojinia, Anupam. G. Loboc, Gopal Sharmad,
Surbhi Pathaniad, Rajni Kantd
aDepartment of Industrial Chemistry, Mangalore University, Mangalagangothri-574199, India
bDepartment of Studies in Chemistry, Mangalore University, Mangalagangothri-574199, India
cSchool of Chemical Sciences, Mahatma Gandhi University, Kottayam -686560, India.
dDepartment of Physics, University of Jammu, Jammu Tawi - 180 006, India.
Table 1: Crystal and experimental data
CCDC No.
1857852
Crystal description
Crystal colour
Block
Colourless
Crystal size
0.30 x 0.20 x 0.20 mm
Empirical formula
Formula weight
C12H8N5O8
350.23
Radiation, Wavelength
Unit cell dimensions
Crystal system
Mo Kα, 0.71073 Å
a = 7.7608 (11), b =14.5110 (14), c = 24.751(3) Å
Orthorhombic
Space group
Pbca
Unit cell volume
2787.3(6)
No. of molecules per unit cell, Z
Temperature
Absorption coefficient
F (000)
8
293(2)
0.144 mm-1
1432
Scan mode
ω scan
θ range for entire data collection
Range of indices
Reflections collected / unique
3.83 <θ< 28.94 º
h= -6 to 9, k= -17 to 13, l= -30 to 24
6636 / 2729
Multi-scan
i. CrysAlis RED
1755
Absorption correction
Reflections observed (I > 2σ(I))
Rint
0.0427
Rsigma
0.0545
Structure determination
Direct methods
Full-matrix least-squares on F2
Refinement
No. of parameters refined
259

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No. of Restraints
Final R
0
0.0723
0.1918
wR(F2)
2
1/ [σ2(Fo ) +( 0.1117 P)2+ 1.7781P]
Weight
2
2
where P= [Fo +2Fc ] / 3
Goodness-of-fit
1.036
0.002
(∆ /σ) max
-0.27< ∆ρ < 0.47 eÅ-3
Final residual electron density
Measurement
Software for structure solution
Software for refinement
Software for molecular plotting
X’calibur system – Oxford diffraction make, U.K.
SHELXL-97 (Sheldrick, 2008)
SHELXL-2016/6 (Sheldrick, 2016)
ORTEP-3 (Farrugia, 2012) PLATON (Spek, 2009)

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Table 2: Bond lengths (Å) and bond angles (o) for non-hydrogen atoms
(e.s.d.’s is given in parentheses)
Bond Lengths (Å)
1.382 (4)
1.387 (5)
1.392 (5)
1.368 (5)
1.506 (4)
1.306 (5)
1.449 (5)
1.454 (5)
1.452 (5)
1.360 (5)
1.464 (5)
1.387 (5)
1.368 (5)
Bond Angles (˚)
119.2 (3)
118.6 (3)
123.3 (3)
118.1 (3)
120.5 (3)
118.2 (4)
120.4 (3)
118.8 (3)
118.1 (3)
123.2 (3)
119.2 (3)
124.2 (3)
116.5 (3)
112.1 (3)
123.3 (3)
124.6 (3)
119.7 (3)
Bond Lengths (Å)
1.380 (5)
C1-C2
C3-C2
C3-C4
C5-C4
C6-C2
C6-N2
C7-C8
C7-N3
C9-C8
C9-C10
C9-N4
C11-C10
C12-C7
C12-C11
N1-C1
N1-C5
N3-O2
N3-O3
N4-O4
N5-C11
N5-O6
O1-C6
O5-N4
O7-N5
O8-C8
1.342 (4)
1.330 (5)
1.218 (5)
1.217 (4)
1.194 (4)
1.449 (5)
1.230 (4)
1.241 (4)
1.217 (4)
1.212 (4)
1.242 (4)
Bond Angles (˚)
N1-C1-C2
C1-C2-C3
C1-C2-C6
C3-C2-C6
C2-C3-C4
C5-C4-C3
N1-C5-C4
N2-C6-C2
O1-C6-C2
O1-C6-N2
C8-C7-N3
C12-C7-C8
C12-C7-N3
C7-C8-C9
O8-C8-C7
O8-C8-C9
C8-C9-N4
C10-C9-C8
C10-C9-N4
C9-C10-C11
C10-C11-N5
C12-C11-C10
C12-C11-N5
C7-C12-C11
C5-N1-C1
123.8 (3)
116.5 (3)
119.6 (3)
118.9 (3)
121.2 (3)
119.9 (3)
119.1 (4)
123.0 (3)
118.7 (3)
120.7 (3)
120.6 (3)
120.2 (3)
122.3 (3)
117.5 (3)
118.5 (3)
118.8 (3)
122.6 (3)
O2-N3-C7
O3-N3-C7
O3-N3-O2
O4-N4-C9
O4-N4-O5
O5-N4-C9
O6-N5-C11
O7-N5-C11
O7-N5-O6

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Table 3: Torsion angles (o) for non-hydrogen atoms (e.s.d.’s is given in parentheses)
Torsion Angles (˚)
Torsion Angles (˚)
N1-C1-C2-C3
-2.2 (6)
N4-C9-C8-C7
179.1 (3)
0.5 (6)
N1-C1-C2-C6
C4-C3-C2-C1
C4-C3-C2-C6
C2-C3-C4C5
N1-C5-C4-C3
N2-C6-C2-C1
N2-C6-C2-C3
O1-C6-C2-C1
O1-C6-C2-C3
C12-C7-C8-C9
C12-C7-C8-O8
N3-C7-C8-C9
N3-C7-C8-O8
C8-C7-N3-O2
C8-C7-N3-O3
C12-C7-N3O2
C12-C7-N3-O3
C10-C9-C8-C7
C10-C9-C8-O8
179.0 (3)
1.3 (6)
N4-C9-C8-O8
C8-C9-C10-C11
N4-C9-C10-C11
C8-C9-N4-O4
0.7 (6)
-179.8 (4)
-0.2 (7)
-179.5 (3)
22.9 (5)
-157.3 (3)
-156.9 (4)
22.9 (5)
-0.4 (6)
-0.1 (7)
C8-C9-N4-O5
5.1 (6)
C10-C9-N4-O4
C10-C9-N4-O5
C12-C11-C10-C9
N5-C11-C10-C9
C11-C12-C7-C8
C11-C12-C7-N3
C7-C12-C11-C10
C7-C12-C11-N5
C5-N1-C1-C2
-173.8 (4)
-174.8 (4)
6.4 (6)
179.8 (3)
-1.2 (6)
1.4 (5)
179.9 (4)
179.3 (3)
-2.1 (6)
-179.2 (3)
0.6 (6)
-179.6 (3)
2.1 (6)
-161.5 (4)
19.7 (5)
16.6 (5)
-162.2 (4)
-1.1 (5)
C1-N1-C5-C4
-0.9 (7)
O6-N5-C11-C10
O6-N5-C11-C12
O7-N5-C11-C10
O7-N5-C11-C12
-3.2 (5)
177.0 (4)
177.6 (4)
-2.2 (6)
-179.7 (4)

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Table 4: Hydrogen bonding geometry (e.s.d`s in parentheses)
D–H…A
D–H(Å)
0.93
0.79
0.94
1.07
0.93
0.96
0.96
0.97
0.97
H…A(Å)
2.43
2.45
2.55
2.54
2.31
2.43
1.82
2.52
2.16
D…A(Å)
2.7494
2.7256
3.4941
3.5099
3.2041
2.8792
2.7716
3.2669
3.0752
D–H…A(o)
100
C3-H3…O1
C12-H12…O7
C4-H4…O5i
C5-H5…O6ii
N2-H21…O3iii
N2-H22…O4iv
N2-H22…O8 iv
C1-H1…O3 iv
C1-H1…O8 iv
102
175
151
161
108
171
134
156
Symmetry code:
(i) x+1/2, y, -z+1/2 (ii) 1-x, y, -z+1/2 (iii) -x+1, y-1/2, -z+1/2(iv) x+1/2, y, -z+1/2
Table 5:Geometry of π−π interactions*
α(o)
β(o)
CgI…CgJ
Cg1…Cg1
CgI…CgJ(Å) CgI…P(Å)
3.8806 3.423
∆(Å)
1.827
4.15
28.20
Symmetry code: x-1/2, y, -z+1/2
Where Cg1 represents the center of gravity of phenyl ring (C7-C12).
Table 6: Bulk properties
Cohesive
Energy
Solubility
vdW
Solubility
Volume Density
Å3 gcm-3
Solubility
MPa1/2
Heat of Vap.
kcalmol-1
Ele
kcalmol-1
MPa1/2
MPa1/2
Average 75261.27 1.67
Stdev. 0.000 0.000
25.66
0.093
31.99
0.058
24.71
0.064
20.32
0.097
26.26
0.093

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Do Hydrogen Bonding and Noncovalent Interactions
Stabilize Nicotinamide-Picric Acid Cocrystal
Supramolecular Assembly?
U. Likhithaa, B. Narayanaa b*, B. K. Sarojinia, Anupam. G. Loboc, Gopal Sharmad,
Surbhi Pathaniad, Rajni Kantd
aDepartment of Industrial Chemistry, Mangalore University, Mangalagangothri-574199, India
bDepartment of Studies in Chemistry, Mangalore University, Mangalagangothri-574199, India
cSchool of Chemical Sciences, Mahatma Gandhi University, Kottayam -686560, India.
dDepartment of Physics, University of Jammu, Jammu Tawi - 180 006, India.
Graphical abstract
Figure 1. Chemical structures of nicotinamide (A) and picric acid (B)

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Figure 2: FTIR spectra within wavenumber ranges of 400−4000 cm−1 from top to bottom:
nicotinamide, picric acid and NICPIC respectively.
Figure 3: DSC (a) and TGA (b) results of pure picric acid, nicotinamide and NICPIC
Figure 4: PXRD patterns of nicotinamide, picric acid and NICPIC

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Figure 5: Showing ORTEP view of the molecule with displacement ellipsoids drawn at the 40%
probability level. Hydrogen atoms are shown as small spheres of arbitrary radii
Figure 6: Packing view of the molecule viewed down the a-axis

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Figure 7: Fingerprint plots of the NICPIC showing molecular interactions. Here di is the closest
internal distance and de is the closest external contacts from a given point on the Hirshfeld
surface.

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Figure 8: 3-D dnorm surfaces mapping with different orientations

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Figure 9: A view of supramolecular chain showing the hydrogen bonding in NICPIC (blue colour
represents intermolecular interactions, violet colour represents intramolecular interactions and
red represents expandable network in NICPIC)
(10 a)

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(10 b)
(10 c)

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(10 d)
(10 e)
(10 f)
Figure 10a-10f: Equilibrium structures of NICPIC - Front view without hydrogen bonding (a), front
view with hydrogen bonding (b), top view without hydrogen bonding (c), top view with hydrogen
bonding (d), side view without hydrogen bonding (e), side view with hydrogen bonding (f) and
hydrogen bonding populations are represented in yellow color.

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Figure 11: Graph of Frequency (ns-1) versus Number of hydrogen bonds obtained from MD
simulation
Figure 12: RDF spectrum of NICPIC

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Figure 13: Graphical representation of bulk properties simulation for NICPIC
Figure 14: Simulated stress-strain curve for NICPIC

ACCEPTED MANUSCRIPT
Do Hydrogen Bonding and Noncovalent Interactions
Stabilize Nicotinamide-Picric Acid Cocrystal
Supramolecular Assembly?
U. Likhithaa, B. Narayanaa b*, B. K. Sarojinia, Anupam. G. Loboc, Gopal Sharmad,
Surbhi Pathaniad, Rajni Kantd
aDepartment of Industrial Chemistry, Mangalore University, Mangalagangothri-574199, India
bDepartment of Studies in Chemistry, Mangalore University, Mangalagangothri-574199, India
cSchool of Chemical Sciences, Mahatma Gandhi University, Kottayam -686560, India.
dDepartment of Physics, University of Jammu, Jammu Tawi - 180 006, India.
Highlights
• Stabilization of molecular cocrystal of nicotinamide with picric acid by
noncovalent interactions.
• Cocrystal crystalized in the orthorhombic Pbca system and refined to R=0.0723
for 1755 observed reflections.
• Molecular dynamic simulations quantified supramolecular architecture of
cocrystal.
• Simulation could be used to predict the types of hydrogen bonds present in the
system.