Chemical Data Collections

Molecular Salts of Pipemedic acid and Crystal structure, spectral properties, and
Hirshfeld surface analysis
--Manuscript Draft--

Manuscript Number:

Article Type: Data article

Section/Category: Organic Chemistry

Keywords: Pipemedic acid, FT-IR, DSC, XRD, 3-D Hirshfeld surface, 2-D fingerprint plots

Corresponding Author: K.Anand solomon

Dayananda Sagar University
Bangalore, Karnataka INDIA

First Author: K.Anand solomon

Order of Authors: K.Anand solomon

Shwetha JC JC, M.Sc

Anamika Sharma, M.Sc,Ph.D

Abstract: The 1:1 salts of Pipemedic acid (PMA) with oxalic acid (OA), salicylic acid (SA) and p-
Toluene sulfonic monohydrate (BS), are prepared by a slow evaporation method,
which is characterized by FT-IR, DSC, Single XRD, and DFT calculations. The proton
is transferred from oxalic, salicylic acid, and p-toluene sulfonic monohydrate to pyridine
nitrogen of PMA.Supramolecular centrosymmetric ring motifs are formed by N—H...O
hydrogen bonds between protonated nitrogen of the pyridone ring and the carboxylic O
atom of the oxalate ion, in both 1OA and 2SA. The Hirshfeld surfaces and the related
2D fingerprint plots were explored which uncovered that more than two-thirds of close
contacts were related to H⋯H, C–H, N–H, and C–C bonding interactions whereas in
3BS, the structure is stabilized by N–H···O and N–H···S hydrogen bonding interactions.
These weak associations assume a significant role in crystal packing was revealed by
the Hirshfeld surfaces and the related 2D fingerprint plots.

Suggested Reviewers: Akiko Hori, M.Sc,PhD

Associate Professor, Shibaura Institute of Technology
ahori@shibaura-it.ac.jp
expertise

Neratur Krishnappagowda Lokanath, M.Sc,PhD

Professor, University of Mysore
lokanath@physics.uni-mysore.ac.in
expertise in this field

Mahalaxmi Rathnanand, M.Sc,PhD

Professor, Manipal Academy of Higher Education
mahalaxmi.r@manipal.edu
expertise in the field

Ramu Samineni, M.Sc,PhD

Associate Professor, Vignan's Foundation for Science Technology and Research
samineniramu123@gmail.com
expertise in the field

Opposed Reviewers:

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Cover Letter

From 06/01/2023

Dr.K.Anand Solomon,

Professor.

Department of Chemistry,

Dayananda Sagar University,

Bangalore 560068, India

To

The Editor,

Chemical Data Collections

Dear Professor,

Regd. Submission of manuscript

I am submitting a manuscript titled “Molecular Salts of Pipemedic acid and their

Crystal structure, spectral properties, and Hirshfeld surface analysis” to be considered for publication in
Chemical Data Collections.
The paper reports the synthesis of three molecular salts of pipemedic acid. They have
been characterized by FT-IR,DSC and SCXRD techniques. Their electronic properties have been studied
using DFT studies and their quantitative intermolecular interactions have been studied through Hirshfeld
analysis.

Yours Sincerely

{K.Anand Solomon]
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Manuscript File Click here to view linked References

Molecular Salts of Pipemedic acid and Crystal structure, spectral properties, and
Hirshfeld surface analysis

Shwetha JC1, Anamika Sharma2 , Anand Solomon K3#

1 Sri Sathya Sai University for Human Excellence, Nallakadirenahalli 561211, Chikkaballapura India
2 Department of Chemistry, Prayoga Institute of Education Research, Bengaluru 560082, India
3 Department Of Chemistry, Dayananda Sagar University, Bengaluru 560068, India

Corresponding author: # anand.dcb@gmail.com . Tel: 080 4909 2924. Fax :080 26660789

ABSTRACT

The 1:1 salts of Pipemedic acid (PMA) with oxalic acid (OA), salicylic acid (SA) and p-
Toluene sulfonic monohydrate (BS), are prepared by a slow evaporation method, which is
characterized by FT-IR, DSC, Single XRD, and DFT calculations. The proton is transferred from
oxalic, salicylic acid, and p-toluene sulfonic monohydrate to pyridine nitrogen of PMA
Supramolecular centrosymmetric ring motifs are formed by N—H...O hydrogen bonds between
protonated nitrogen of the pyridone ring and the carboxylic O atom of the oxalate ion, in both
1OA and 2SA. The Hirshfeld surfaces and the related 2D fingerprint plots were explored which
uncovered that more than two-thirds of close contacts were related to H⋯H, C–H, N–H, and C–C
bonding interactions whereas in 3BS, the structure is stabilized by N–H···O and N–H···S
hydrogen bonding interactions. These weak associations assume a significant role in crystal
packing was revealed by the Hirshfeld surfaces and the related 2D fingerprint plots.

Keywords: Pipemedic acid, FT-IR, DSC, XRD, 3-D Hirshfeld surface, 2-D fingerprint plots

1. Introduction
In recent years, plenty of cocrystal drugs have arrived on the market [1] even though the
meaning of cocrystal is yet a subject of discussion [2, 3]. A drug cocrystal is a crystalline solid
that contains at least two distinct parts that may be drug-drug or drug-co-former. The multi-
component framework of the stoichiometric ratio is bonded through hydrogen bonding, π-
stacking, etc. [4, 5]. The formation of cocrystal is a typical favoured choice for ionizable drugs
to increase their solubility [6]. The cocrystal can be synthesized with the help of two different
approaches which are solid-state or solution-based methods [7, 8]. The approaches to be used
are determined based on the quantity of solvent used and the rate of evaporation. Slow
evaporation is the predominantly used technique for cocrystal preparation, especially to get a
single crystal [9]. Despite having many therapeutic properties, poor solubility is one of the
limiting factors for API not being utilized in clinics [5]. Finding a new drug is a very expensive
process because it takes a long time, costs a lot of money, takes a lot of effort, and takes a lot
of time and the success rate is very low.
Pipemedic acid (PMA) is one such active pharmaceutical ingredient (API), a well-known
antibiotic drug for Urinary Tract Infection (UTI) and is one of the essential medications
required in the health system. Instability due to hydration and poor solubility are the main
limitations to using this drug for clinical purposes even though it has many therapeutic
properties. The formation of salt crystals, which is an exceptional sort of co-crystal and has a
salt structure with a neutral conformer has combined the advantage of the salt and co-crystal
totally with the novelty and improved stability, and solubility [10, 11, 12] dissolution including
upgraded bioavailability [5] thus, reducing hygroscopicity [13, 14]. It’s observed that for
thermodynamic reactions, anhydrated drugs are more water-soluble than hydrated drugs [15].
Thus, drug co-crystal screening has turned into a very useful strategy to enhance the physio-
chemical behavior of an API by tailoring the drug molecule [16]. Besides cocrystallization
offers the opportunity for intellectual property (IP) protection and the possibility of extending
the life cycles of old APIs in pharmaceutical industries [17].
Without any experimental proof, ΔpKa serves as a tool to predict whether the achieved
crystal complex is a salt or a cocrystal. The development of salt or a cocrystal is directed by
the pKa rule, which expresses that salt is formed when the ΔpKa is at least 1 whereas a cocrystal
is formed if the ΔpKa is less than 1 [18].

2. Experimental
2.1 Materials
The starting material i.e., PMA (≥99%, CAS No 51940-44-4) purity and the conformers OA, SA,
and (BS) including solvents viz. methanol, propanol 2, and acetonitrile with HPLC grade purity were
purchased from Yarrow Chem Products, Mumbai, and Lab Reagents, and Allied Products, Bengaluru
(India) respectively.

2.2 Synthesis and growth of molecular salts 1OA, 2SA, and 3BS

The 1:1 ratio of PMA(0.050mg) and OA(0.020mg) was dissolved in equimolar mixture
of 12mL methanol and water. The mixture was heated below 800 C and kept for slow
evaporation. Light, blue-colored transparent cubic crystals had formed within 72hrs.
Similarly, the 1:1 stoichiometric ratio of PMA(0.050mg) and 0.027mg of SA were
taken and ground well by liquid-assisted grinding, using the equimolar volume of Propanol-2
and Acetonitrile for 20 minutes. Heated this mixture to 500C to ensure the complete dissolution
and then subjected to slow evaporation at room temperature after 24 hours crystals of needle-
shaped transparent crystals were formed.
The 1:1 ratio of PMA(0.050mg) and p-Toluene sulfonic monohydrate (0.020mg) was
dissolved in an equimolar mixture of 12mL ethanol and water. The mixture was heated below
700 C and kept for slow evaporation. Light, yellow-colored rod-shaped crystals had formed
within 72hrs.

2.3 Fourier Transform-Infrared spectroscopy (FT-IR)

Infrared spectra of pure PMA and its binary solids were recorded on an FTIR spectrometer
(Thermo Nicolet 6700, Thermo Scientific, Waltham, MA) in which the samples were spread in KBr
pellet, in the spectral range 4000 to 400 cm-1. Data were analyzed using spectrum software version
2(JASCO, Easton, Maryland, USA)

2.4 Differential scanning calorimetry (DSC)

Thermal analysis of PMA and all three of its salts formed was recorded individually on
Mettler Toledo model no. DSC00f3MAYA, company: Netzsch Samples were placed in
crimped but vented aluminum sample pans with nitrogen purging.
2.5 Elemental Analysis (EA)
Elemental analyses (C, H, N, and S) were conducted on a LECO Truspec Micro Analyser.

2.6 Single Crystal X-ray diffraction (SCXRD)

Single X-ray diffraction measurements of the 1:1 salts of PMA with OA, SA, and BS
were carried out on a Bruker aXS KAPPA APEX-II. CCD Diffractometer with Mo Kα
radiation at 293K. Data reduction was performed with the SAINT program [19] and the
structure was solved using the SIR92 program [20]. Structure refinement was done by using
the SHELX program [21]. Besides the structures of 1OA, 2SA and 3BS were drawn by using
the Olex2 program [22]. Both primary and secondary atom site locations were found from the
structure invariant direct method and difference Fourier map respectively. Hydrogen atom site
areas were induced at neighboring ring sites. The crystal data and data processing are given in
Table 1. The final fractional atomic coordinates are listed in Table 2 whereas Table 3 gives
information about bond lengths and bond angles. The entire details of structural parameters in
the CIF format are accessible from the Cambridge Crystallographic Database Centre under No.
CCDC 2114663, CCDC 2114662 and CCDC 2144823 respectively for 1OA, 2SA and 3BS

Table 1. Crystal data and structure refinement for 1OA, 2SA, and 3BS

1OA 2SA 3BS

C16 H19 N5 O7 C21 H23 N5 O6 C21 H27 N5 O7 S

Empirical formula
Formula weight 393.36 441.44 493.53
 Temperature 296(2) K 296(2) K 297(2) K
Wavelength 0.71073 Å 0.71073 Å 0.71073 Å
Crystal system Monoclinic Monoclinic Monoclinic
Space group P 21/c P 21/n P 21/c
Unit cell dimensions
a = 9.923(3) Å a = 6.8877(3) Å a = 9.3352(4) A
b = 9.443(3) Å b = 13.9149(6) Å b = 12.7754(5) A
c = 18.248(5) Å c = 21.5313(10) Å c = 19.5462(8) A
= 90°. = 90°  = 90°
= 92.470(10) °. = 98.092(2) = 97.722(2) °
 = 90° °  =90°
 = 90°

Volume
1708.3(9) Å3 2043.05(16) Å3 2309.96(16) Å3
Z
4 4 4
Density (calculated) 1.529 Mg/m3 1.435 Mg/m3 1.419 Mg/m^3
Absorption coefficient 0.122 mm-1 0.107 mm-1 0.193 mm-1
F(000) 824 928 1040
Crystal size 0.300 x 0.250 x 0.200 0.280 x 0.150 x 0.100
0.300 x 0.250 x 0.200 mm3
mm3 mm3
Theta range for data collection 2.979 to 30.554°. 2.407 to 25.726°. 3.189 to 31.523°
Index ranges -14<=h<=14, -13<=k<=13, -8<=h<=8, -16<=k<=16, -13<=h<=13, -
-22<=l<=26 -26<=l<=26 18<=k<=18, -28<=l<=28
Reflections collected 66086 67026 113687
Independent reflections 5230 [R(int) = 0.0350] 3888 [R(int) = 0.0417] 7699 [R(int) = 0.0577]
Completeness to theta =
25.242° 99.70% 99.80% 99.7 %
Absorption correction Semi-empirical from empirical from Semi-empirical from
equivalents equivalents equivalents
Max. and min. transmission 0.7461 and 0.6959 0.7458 and 0.7038 0.746 and 0.650
Refinement method Full-matrix least-squares on Full-matrix least-squares Full-matrix least-squares
F2 on F2 on F2
Data / restraints / parameters 5230 / 0 / 270 3888 / 449 / 416 7699 / 47 / 320
Goodness-of-fit on F2 1.051 1.059 1.061
Final R indices [I>2sigma(I)] R1 = 0.0452, R1 = 0.0486,
R1 = 0.0433, wR2 = 0.1160
wR2 = 0.1148 wR2 = 0.1260
R indices (all data) R1 = 0.0608,
R1 = 0.0535,
R1 = 0.0508, wR2 = 0.1258 wR2 = 0.1393
wR2 = 0.1228
Extinction coefficient n/a t 0.023(2) 0.0069(12)
Largest diff. peak and hole
0.405 and -0.410 e.Å-3 0.183 and -0.209 e.Å-3 0.484 and -0.442 e. Å-3
CCDC Numbers
2114663 2114662 2144823

2.7 Hirshfeld surface analysis

For all three crystals (1OA,2SA, and 3BS), Hirshfeld surface calculations were performed using
CrystalExplorer17 [23]. All the surfaces (including 2D fingerprints) were generated at a high
standard surface resolution [24, 25, 26]. The crystallographic information file (CIF) of 1OA
2SA and 3BS was read directly into the CrystalExplorer 17 program. The Hirshfeld surface
maps are that of normalized contact distance, dnorm, which is defined in terms of the distance to
the nearest atoms outside (de), the distance to the nearest atoms inside (di), and the van der
Waals radii of the two atoms external and internal to the surface [27]. The dnorm ranges used to
map the Hirshfeld surfaces were -0.6504 to 1.3026 (1OA), −0.5619 to 1.2844 (2SA), and -
0.5956 to 1.4123 (3BS).

2.8 Theoretical Calculations

For theoretical calculations, a crystal unit was selected as the initial structure from crystals 1OA,
2SA, and 3BS. DFT-B3LYP/6-311G++(d,p) methods in Gaussian 09 were used to [28,
29]optimize the structure of the title compounds at a default temperature of 298.15 K [30, 31].
Vibration analysis showed that the optimized structure represented a minimum on the potential
energy surface (no negative eigenvalues). Molecular parameters as estimated from XRD are
very much upheld by the DFT computations. Crystal Explorer 17.5 software was used to
generate molecular Hirshfeld surfaces and visualize intermolecular interactions in molecular
crystals. The program accepts a structured input file in the CIF format [18].

Table 2. Selected bond lengths [Å] Torsion angles [°] for 1OA, 2SA, and 3BS
1OA

C(15)-O(4) 1.1976(14) O(7)-C(16)-C(15) 114.58(10) N(1)-C(1)-C(2)-N(2) 58.54(11)

C(15)-O(5) 1.3177(14) C(4)-N(1)-C(1) 113.00(8) N(2)-C(3)-C(4)-N(1) -51.92(12)

C(15)-C(16) 1.5468(17) C(4)-N(1)-H(1C) 110.9(11) N(4)-C(6)-C(7)-C(8) 1.71(15)

C(16)-O(6) 1.2361(13) C(1)-N(1)-H(1C) 109.3(10) N(4)-C(6)-C(7)-C(11) 179.66(10)

C(16)-O(7) 1.2418(14) N(1)-H(1C) 0.908(17) N(1)-H(1D) 0.885(19)

2SA

C(19)-C(20) 1.392(4) C(3)-N(1)-C(2) 111.59(14) C(18)-C(19)-C(20)-O(6) 178.9(2)

C(19)-H(19) 0.9300 C(3)-N(1)-H(1D) 116.6(16) C(18)-C(19)-C(20)-C(15) -1.5(4)

C(20)-O(6) 1.340(4) C(2)-N(1)-H(1D) 102.4(16) C(16)-C(15)-C(20)-O(6) 179.7(3)

C(21)-O(4) 1.239(3) C(21)-O(5) 1.267(3)

3BS
O(4)-S(1) 1.4590(11) N(4)-C(9)-C(10) 110.49(12)

O(5)-S(1) 1.4447(13) C(10)-N(5)-C(12) 111.38(10)

O(6)-S(1) 1.4425(14) N(5)-C(12)-C(11) 109.59(12)

O(1W)-H(1B) 0.895(17) N(4)-C(11)-C(12) 109.82(11)

N(5)-H(5A) 0.882(14) C(15)-C(16)-C(17) 119.91(19)

N(5)-H(5B) 0.888(14) C(18)-C(19)-C(20) 121.8(2)

Table 3. Hydrogen bonds parameters for 1OA, 2SA, and 3BS
D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

1OA

N(1)-H(1C)...O(4) 0.908(17) 2.328(17) 2.8741(15) 118.4(13)

N(1)-H(1C)...O(6) 0.908(17) 2.145(18) 3.0104(15)/\753 158.9(14)

N(1)-H(1D)...O(6)#2 0.885(19) 2.082(19) 2.9368(15) 162.2(16)

O(2)-H(2)...O(3) 0.98(3) 1.60(2) 2.5273(15) 157(2)

2SA

C(14)-H(14)...N(3) 0.96 2.44 3.034(15) 119.7

O(2)-H(2)...O(3) 0.82 1.76 2.532(2) 155.0

N(1)-H(1C)...O(5) 0.872(15) 1.896(16) 2.762(3)

172(2)

N(1)-H(1C)...O(4) 0.872(15) 1.97(2) 2.715(10)

143(2)

O(6)-H(6)...O(5) 0.82 1.84 2.555(3) 145.3

3BS

O(1)-H(1)...O(3) 0.82 1.74 2.5105(16) 155.0

O(1W)-H(1A)...O(5) 0.869(17) 2.07(2) 2.887(2) 156(3)

O(1W)-H(1B)...O(4)#4 0.895(17) 2.20(2) 2.992(2)

146(3)

N(5)-H(5A)...O(2)#5 .882(14) 1.953(15) 2.7751(16) 154.5(17)

N(5)-H(5B)...O(4) 0.888(14) 1.909(15) 2.7802(17) 166.5(18)

 N(5)-H(5B)...S(1) 0.888(14) 2.840(15) 3.7045(13) 164.9(16)

Symmetry transformations used to generate equivalent atoms:

1OA
#1 x,-y+1/2,z-1/2 #2 -x,y-1/2,-z+1/2 #3 x,-y+1/2,z+1/2
#4 x-1,-y+1/2,z-1/2 #5 -x,-y+1,-
22SA
#1 x+1,y,z #2 -x+1,-y+2,-z+1 #3 x,y-1,z #4 -x+2,-y+2,-z+1
#5 x-1,y,z
3 BS
Symmetry transformations used to generate equivalent atoms:
#1 x+1,y,z #2 -x+1,-y+1,-z+1 #3 -x+1,y-1/2,-z+1/2
#4 -x,y+1/2,-z+1/2 #5 x-1,-y+1/2,z-1/2

3. Result and Discussion

3.1 FT-IR spectral analysis

This is generally used in the characterization of cocrystal interactions and through which
we can distinguish the salts from cocrystals [4]. The hydrogen bonding patterns of a molecule
will change after the formation of cocrystal which results in the change of vibration modes of
functional group and IR frequencies [32]
PMA shows an IR absorption frequency at 1640cm-1 for CO (of the carboxylic group),
CO of (pyridone) ketone at 1616 cm-1, and for OH, the absorption frequency was found to
at3383cm-1 as a medium peak [33]. However, we can observe the changes in the CO stretching
of (the carboxylic group) from 1640cm-1 to 1732 cm-1 which indicates the formation of salt
rather than a cocrystal for 1OA, whereas in the case of 2SA the shift is found in the region of
1729 cm-1 as shown in Fig.2. In the FT-IR spectrum of PMA, the peak at 1627 cm−1 was
assigned to the N–H bending vibration of the quinolones. In the spectrum of the 3BS the –NH
stretching region of PMA (3366 cm−1) [33] is shifted at 3446 cm−1.

3.2 Thermal analysis:

The specific melting point of the PM, OA, SA, and BS and salt formed were obtained
by DSC investigation. The difference in the melting point of the salt when compared to that of
pure PMA indicates interaction between the drug and conformers which proves that first-order
transformation that is meting endotherm has disappeared.

Table 4. Melting endotherms of PMA and 1OA, 2SA and 3BS

Sample Melting endotherm (0C)

PMA pure 254-259
OA pure 101-103
SA pure 158-161
BS pure 105-107
1OA 265-269.5
2SA 235-243
3BS 280.9-283.5

Figure 1. DSC thermograms showing melting behaviour of PMA,1OA, 2A, and 3BS

3.3 Elemental Analysis

Table 5. NCSH analysis of 1OA, 2SA, and 3BS

Ref. No: SAIF/CH/5157/220624

Sample
Sample
SI. No N% C% S% H% Weight
Name
(mg)
1 1OA 19.67 47.28 ND 8.57 6.88
2 2SA 14.95 54.38 ND 6.05 6.84
3 3BS 14.67 53.30 5.46 6.46 6.53

ND-Not detected

3.4 Single-crystal X-ray analysis

3.4.1. Description of the crystal structure of molecular salt 1OA.
 The molecular salt crystallizes as light blue color cubic-shaped
crystals. The structural determination shows that the PMA forms a 1:1 molecular
salt in the monoclinic P 21/c space group with Z= 4 as shown in Fig.2.

Figure 2. Molecular interactions between oxalic acid and pipimedic acid in 1OA

In 1OA, the OA is connected to PMA through the two intermolecular hydrogen bond i.e. N(1)-
H(1C)...O(6) and N(1)-H(1C)...O(4) . The proton transfer of OA on the N1 site has also resulted in
the change in the small ∆C-O value. The torsion angles N1–C2–C2–N2 and N1–C4–C3–N2 is
58.54(11)°, and -51.81(12) ° respectively, which implies that both the amine groups are nearly
in the same plane as the benzene ring of the anion [18]. In the crystal, the PMA anion and
oxalate moiety of OA form a dimer unit by C1–H1A···O4 hydrogen bonding interactions
through R2 2(7) heterosynthon supramolecular ring motif. the PMA molecule has also formed
intramolecular O2–H2···O3 hydrogen bond interactions. Fig. (3).

Figure 3. O–H···N hydrogen bond between COOH group of oxalic acid and N of
Pipemidic acid.

3.4.2. Description of the crystal structure of molecular salt 2 (PMA-SA)

 The molecular salt 2SA crystallizes as colorless needle-shaped crystals. The
structural determination shows 2 forms of 1:1 2SA molecular salt in the monoclinic P21/n
space group with Z = 4, with the asymmetric unit (Fig. 4)

Figure 4. Molecular structure of pipimedic acid co-crystals with salicylic acid, showing the atom-labeling scheme
and H atoms are shown as small spheres of arbitrary radius; hydrogen bonds are represented by dashed lines.

Proton transfer is evidenced by the difference between the C–O bond distances C21–
O5=.260(16) Å, and C21–O4=1.251(15) Å of the carboxylate group with the ∆DC-O value of
0.009 Å a relatively small value, which is expected for the carboxylate group [18]. The
protonation of SA on the N1 site has resulted in, a change in the bond angle. The angle at the
unprotonated ring N atom is 118.56(13)° [34], while for protonated ring N atom, the angle (C3-
N1-C2) is 111.59(14) The torsion angles O6–C20–C19–C18 and O4–C21–C15–C16 are
178.9(2)°, and -11.8(4)°, respectively. This shows that both the amine groups are nearly in the
same plane as the benzene ring of the anion. In the crystal, the PMA anion and oxalate moiety
of SA form a dimer unit by N1–H1C···O5 hydrogen bonding interactions as in Fig. (4).

3.2.3. Description of the crystal structure of molecular salt 3 (PMA-3BS)

The molecular salt 3BS crystallizes as yellow rod-shaped crystals. The structural
determination shows that salt 3, forms a 1:1 (PMA-SA) molecular salt in the monoclinic P21/n
space group with Z=4, with the asymmetric unit. The crystal was stabilized by inter-molecular
N–H···O and N–H···S hydrogen bonding interactions fig (5). There is a complete transfer of a
proton from the sulphonic group to the N of the pyrimidine group of PMA, which is evidenced
by an increase in the bond length of S(1)–O(4), from 1.451(2) [35] to 1.459(11) and the new
bond formed N(5)-H(5B)=0.888(14). Besides, the torsion angles, C(18)-C(19)-C
(20)=121.8(2) and C(15)-C(16)-C(17)=119.91(19) of the p-toluene sulfonic monohydrate and
the torsion angles, of PMA i.e., N(5)-C(10)-C(9)=110.72(11) and N(4)-C(11)-
C(12)=109.82(11) shows that they are in the same plane as shown in the fig(8). The crystal is
also stabilized by inter and intramolecular interactions [36]. viz, N(5)-H(5B)...S(1) , N(5)-
H(5B)...O(4) and O(1)-H(1)...O(3) respectively.

Figure 5. Intermolecular N–H···S and N–H···O and Intramolecular O–H···O– hydrogen bonding
patterns in the basic supramolecular packing unit of 3BS. H atoms are shown as small spheres of
arbitrary radius; hydrogen bonds are represented by dashed lines

3.5 Salt or cocrystal by ΔpKa

ΔpKa is one of the tools used to determine whether the formed substance is a co-crystal
or a salt [37] ΔpKa<0 indicates the formation of a co-crystal whereas, salt is formed if ΔpKa>3
and ΔpKa value is found to be in between, then it is considered partial proton transfer [38]. The
pKa values of PMA, OA, SA, and BS are 8.57, 1.23, 4.19, and -2.1 respectively. So, the
corresponding ΔpKa value of the complex formed is 7.34, 4.38, and 10.67 indicating the
formation of salts, not cocrystals.

3.6. Hirshfeld surface analysis

The detailed proximity of intermolecular interactions in crystal packing was studied by

Hirshfeld surface analysis. Fig.6 shows the Hirshfeld surface mapped over dnorm based on van
der Waals in 1OA, 2SA, and 3BS. Dark red indicates negative norm values indicating contacts
shorter than the sum of van der Waals radii. Dark blue indicates positive dnorm values indicating
contacts longer than the sum of van der Waals radii while white depicts zero dnorm values
(contact distances close to van der Waals).
Figure 6. dnorm mapped on Hirshfeld surfaces for 1OA, 2SA, and 3BS.

The fingerprint plots for the O---H, H---H, and C---H interactions are depicted in Fig.7. The
central spike of the fingerprint plot corresponds to the percentage of H---H interactions for 1OA
(26.9%), 2SA(40.3%), and 3BS (45.6%). The large spikes show the O---H interactions in the
crystals which were 43.4%, 32.1%, and 31.8% for 1OA, 2SA, and 3BS, respectively.

Figure 7. Fingerprint plot for 1OA, 2SA, and 3BS depicting percentages for O---H, H---H, and C---H contacts
in the total Hirshfeld surface area.

The contribution of all interactions is shown as a histogram in Fig.8, for crystals (1OA, 2SA,
and 3BS). The bond distances were found to be in good agreement with those of crystal data.
The three major contributions were found to be from O---H, H---H, and C---H interactions.
Figure 8. Percentage contribution of each interaction between atoms in 1OA, 2SA, and 3BS.

3.7. Theoretical Calculations

Theoretical calculations were performed using Gaussian09 in the gaseous phase [7]. Geometry
optimization was performed using density functional theory (DFT) employing the B3LYP
(Becke three parameters Lee–Yang–Parr exchange-correlation functional), which combines
the hybrid exchange functional of Becke with the gradient-correlation functional of Lee, Yang,
and Parr using 6–311G ++ (d,p) basis set was performed in the gas-phase at 298.15 K [8]. Input
geometries were taken from X-ray refined data. The optimized geometry results in the free
molecule state were found to be consistent with those in the crystalline state (Fig.9). No
negative vibrational modes were obtained. The DFT calculated structure and geometric
parameters (bond lengths and bond angles) agreed with each other. Optimized structures of
1OA and 2SA, both had a C1 point group. The presence of intermolecular H-bonding is evident
from the proton transfer from oxalic acid to 1 in the case of 1OA and from salicylic acid to 2
in the case of 2SA.

Figure 9. Optimized structure of 1OA, 2SA, and 3BS

3.8. Frontier Orbital Energy calculations

Molecular Total Energy and Frontier Orbital energy levels were calculated using DFT (Fig.10).
The energy gap (ΔE) has been calculated for both crystals as shown in Table 5. The energy gap
between HOMO and LUMO was calculated by the B3LYP method using the 6-311G ++ (d,p)
basis set. The compounds 1OA, 2SA, and 3BS showed an energy gap (ΔE) for HOMO →
LUMOofs 4.43, 3.98, and 4.38 eV, respectively (Table 6). HOMO and LUMO are essential
factors that affect bioactivity, chemical reactivity and electron affinity, and ionization potential.
Thus, a study of the frontier orbital energy can provide useful information about the biological
and chemical reaction mechanism. The HOMO–LUMO gap in 2SA (3.98 eV) was smaller than
1OA (4.43 eV) and 3BS (4.38 eV), thereby indicating its high reactivity.

Figure 10. HOMO and LUMO molecular orbitals in 1OA,2SA and 3BS with band gaps.

Table 5. Total energy and frontier orbital energy.

1OA 2SA 3BS

Etotal in Hartree -1421.97194022 -1539.71715088 -2015.52611622
ELUMO in Hartree -0.10264 -0.09232 -0.09264
EHOMO in Hartree -0.26539 -0.23874 -0.25374
ΔE* in Hartree 0.16275 0.14642 0.16110
ΔE* in eV 4.43 3.98 4.38
* ΔE = LUMO-HOMO; 1 Hartree = 27.2 Ev

CONCLUSIONS
To sum up, we have reported, Crystal growth and its X-ray analysis and Hirshfeld surface
analysis of 1OA, 2SA, and 3BS. Proton transfer is evidenced by the change between CO
bond length in OA (1.18A0) and PMA (1.60 A0). The ∆C-O was 0.42, with a newly formed
bond which is further confirmed by the bathochromic shift in FT-IR analysis. Further, the
DSC analysis also provided evidence for the formation of new compounds by showing the
change in the melting points from that of initial compounds. The Hirshfield analysis reveals
the percentage of contribution of O---H, H---H, and C---H interactions and other
inteinteractions in the atoms of 1OA,2SA and 3 BS. We calculated the band structure and
energy gap (ΔE) by B3LYP method.

Conflicts of interest
The authors declare no conflicts of interest in the manuscript.

4. Acknowledgments
SJC, thanks Sri Sathya Sai University for Human Excellence for all the support and
encouragement. The authors acknowledge SAIF, IIT Madras for single-crystal X-ray data
collection.
Declarations

Ethical Approval: not applicable

Competing interests: The authors declare no competing interests.
Authors' contributions:shwetha- carried-out the experimental work and spectral
characterization, A Sharma- carried out the DFT studies and Hirshfeld analysis
Anand S - Analysed the SCXRD results and wrote the manuscript
Funding: not applicable
Availability of data and materials: The data that support the findings of this study are
included within the article and supplementary file.

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Conflict of Interest

Declaration of interests

☒The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
Validation Report

checkCIF/PLATON report
Structure factors have been supplied for datablock(s) shelx

THIS REPORT IS FOR GUIDANCE ONLY. IF USED AS PART OF A REVIEW PROCEDURE FOR
PUBLICATION, IT SHOULD NOT REPLACE THE EXPERTISE OF AN EXPERIENCED
CRYSTALLOGRAPHIC REFEREE.

No syntax errors found. CIF dictionary Interpreting this report

Datablock: shelx

Bond precision: C-C = 0.0016 A Wavelength=0.71073

Cell: a=9.923(3) b=9.443(3) c=18.248(5)

alpha=90 beta=92.47(1) gamma=90
Temperature: 296 K

Calculated Reported
Volume 1708.3(9) 1708.3(9)
Space group P 21/c P 21/c
Hall group -P 2ybc -P 2ybc
Moiety formula C14 H18 N5 O3, C2 H O4 C14 H18 N5 O3, C2 H O4
Sum formula C16 H19 N5 O7 C16 H19 N5 O7
Mr 393.36 393.36
Dx,g cm-3 1.530 1.529
Z 4 4
Mu (mm-1) 0.122 0.122
F000 824.0 824.0
F000’ 824.45
h,k,lmax 14,13,26 14,13,26
Nref 5245 5230
Tmin,Tmax 0.964,0.976 0.696,0.746
Tmin’ 0.964

Correction method= # Reported T Limits: Tmin=0.696 Tmax=0.746

AbsCorr = MULTI-SCAN

Data completeness= 0.997 Theta(max)= 30.554

wR2(reflections)=
R(reflections)= 0.0433( 4506)
0.1258( 5230)
S = 1.051 Npar= 270
The following ALERTS were generated. Each ALERT has the format
test-name_ALERT_alert-type_alert-level.
Click on the hyperlinks for more details of the test.

Alert level C
PLAT250_ALERT_2_C Large U3/U1 Ratio for Average U(i,j) Tensor .... 2.9 Note
PLAT480_ALERT_4_C Long H...A H-Bond Reported H1A ..O3 . 2.61 Ang.
PLAT480_ALERT_4_C Long H...A H-Bond Reported H1B ..O7 . 2.62 Ang.
PLAT911_ALERT_3_C Missing FCF Refl Between Thmin & STh/L= 0.600 6 Report

Alert level G
PLAT883_ALERT_1_G No Info/Value for _atom_sites_solution_primary . Please Do !
PLAT910_ALERT_3_G Missing # of FCF Reflection(s) Below Theta(Min). 4 Note
PLAT912_ALERT_4_G Missing # of FCF Reflections Above STh/L= 0.600 5 Note
PLAT933_ALERT_2_G Number of OMIT Records in Embedded .res File ... 4 Note
PLAT978_ALERT_2_G Number C-C Bonds with Positive Residual Density. 6 Info

0 ALERT level A = Most likely a serious problem - resolve or explain

0 ALERT level B = A potentially serious problem, consider carefully
4 ALERT level C = Check. Ensure it is not caused by an omission or oversight
5 ALERT level G = General information/check it is not something unexpected

1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data

3 ALERT type 2 Indicator that the structure model may be wrong or deficient
2 ALERT type 3 Indicator that the structure quality may be low
3 ALERT type 4 Improvement, methodology, query or suggestion
0 ALERT type 5 Informative message, check
 It is advisable to attempt to resolve as many as possible of the alerts in all categories. Often the minor
alerts point to easily fixed oversights, errors and omissions in your CIF or refinement strategy, so
attention to these fine details can be worthwhile. In order to resolve some of the more serious problems
it may be necessary to carry out additional measurements or structure refinements. However, the
purpose of your study may justify the reported deviations and the more serious of these should
normally be commented upon in the discussion or experimental section of a paper or in the
"special_details" fields of the CIF. checkCIF was carefully designed to identify outliers and unusual
parameters, but every test has its limitations and alerts that are not important in a particular case may
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attention. It is up to the individual to critically assess their own results and, if necessary, seek expert
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PLATON version of 13/07/2021; check.def file version of 13/07/2021

Datablock shelx - ellipsoid plot
Validation Report

checkCIF/PLATON report
Structure factors have been supplied for datablock(s) shelx

THIS REPORT IS FOR GUIDANCE ONLY. IF USED AS PART OF A REVIEW PROCEDURE FOR
PUBLICATION, IT SHOULD NOT REPLACE THE EXPERTISE OF AN EXPERIENCED
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No syntax errors found. CIF dictionary Interpreting this report

Datablock: shelx

Bond precision: C-C = 0.0026 A Wavelength=0.71073

Cell: a=6.8877(3) b=13.9149(6) c=21.5313(10)

alpha=90 beta=98.092(2) gamma=90
Temperature: 296 K

Calculated Reported
Volume 2043.05(16) 2043.05(16)
Space group P 21/n P 21/n
Hall group -P 2yn -P 2yn
Moiety formula C14 H18 N5 O3, C7 H5 O3 C14 H18 N5 O3, C7 H5 O3
Sum formula C21 H23 N5 O6 C21 H23 N5 O6
Mr 441.44 441.44
Dx,g cm-3 1.435 1.435
Z 4 4
Mu (mm-1) 0.107 0.107
F000 928.0 928.0
F000’ 928.46
h,k,lmax 8,16,26 8,16,26
Nref 3903 3888
Tmin,Tmax 0.968,0.979 0.704,0.746
Tmin’ 0.968

Correction method= # Reported T Limits: Tmin=0.704 Tmax=0.746

AbsCorr = MULTI-SCAN

Data completeness= 0.996 Theta(max)= 25.726

wR2(reflections)=
R(reflections)= 0.0452( 3313)
0.1228( 3888)
S = 1.059 Npar= 416
The following ALERTS were generated. Each ALERT has the format
test-name_ALERT_alert-type_alert-level.
Click on the hyperlinks for more details of the test.

Alert level C
PLAT088_ALERT_3_C Poor Data / Parameter Ratio .................... 9.35 Note
PLAT480_ALERT_4_C Long H...A H-Bond Reported H1B ..O4 . 2.61 Ang.
PLAT480_ALERT_4_C Long H...A H-Bond Reported H4A ..O1 . 2.65 Ang.
PLAT906_ALERT_3_C Large K Value in the Analysis of Variance ...... 2.545 Check
PLAT911_ALERT_3_C Missing FCF Refl Between Thmin & STh/L= 0.600 6 Report

Alert level G
PLAT002_ALERT_2_G Number of Distance or Angle Restraints on AtSite 31 Note
PLAT003_ALERT_2_G Number of Uiso or Uij Restrained non-H Atoms ... 26 Report
PLAT007_ALERT_5_G Number of Unrefined Donor-H Atoms .............. 3 Report
PLAT172_ALERT_4_G The CIF-Embedded .res File Contains DFIX Records 6 Report
PLAT176_ALERT_4_G The CIF-Embedded .res File Contains SADI Records 5 Report
PLAT178_ALERT_4_G The CIF-Embedded .res File Contains SIMU Records 3 Report
PLAT186_ALERT_4_G The CIF-Embedded .res File Contains ISOR Records 1 Report
PLAT301_ALERT_3_G Main Residue Disorder ..............(Resd 1 ) 14% Note
PLAT302_ALERT_4_G Anion/Solvent/Minor-Residue Disorder (Resd 2 ) 100% Note
PLAT302_ALERT_4_G Anion/Solvent/Minor-Residue Disorder (Resd 3 ) 100% Note
PLAT304_ALERT_4_G Non-Integer Number of Atoms in ..... (Resd 2 ) 12.63 Check
PLAT304_ALERT_4_G Non-Integer Number of Atoms in ..... (Resd 3 ) 2.37 Check
PLAT417_ALERT_2_G Short Inter D-H..H-D H1D ..H6’ . 1.43 Ang.
1+x,y,z = 1_655 Check
PLAT432_ALERT_2_G Short Inter X...Y Contact O6’ ..C2 2.99 Ang.
-1+x,y,z = 1_455 Check
PLAT811_ALERT_5_G No ADDSYM Analysis: Too Many Excluded Atoms .... ! Info
PLAT860_ALERT_3_G Number of Least-Squares Restraints ............. 449 Note
PLAT883_ALERT_1_G No Info/Value for _atom_sites_solution_primary . Please Do !
PLAT910_ALERT_3_G Missing # of FCF Reflection(s) Below Theta(Min). 2 Note
PLAT912_ALERT_4_G Missing # of FCF Reflections Above STh/L= 0.600 8 Note
PLAT913_ALERT_3_G Missing # of Very Strong Reflections in FCF .... 1 Note
PLAT933_ALERT_2_G Number of OMIT Records in Embedded .res File ... 1 Note
PLAT978_ALERT_2_G Number C-C Bonds with Positive Residual Density. 3 Info

0 ALERT level A = Most likely a serious problem - resolve or explain

0 ALERT level B = A potentially serious problem, consider carefully
5 ALERT level C = Check. Ensure it is not caused by an omission or oversight
22 ALERT level G = General information/check it is not something unexpected

1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data

6 ALERT type 2 Indicator that the structure model may be wrong or deficient
7 ALERT type 3 Indicator that the structure quality may be low
11 ALERT type 4 Improvement, methodology, query or suggestion
2 ALERT type 5 Informative message, check
 It is advisable to attempt to resolve as many as possible of the alerts in all categories. Often the minor
alerts point to easily fixed oversights, errors and omissions in your CIF or refinement strategy, so
attention to these fine details can be worthwhile. In order to resolve some of the more serious problems
it may be necessary to carry out additional measurements or structure refinements. However, the
purpose of your study may justify the reported deviations and the more serious of these should
normally be commented upon in the discussion or experimental section of a paper or in the
"special_details" fields of the CIF. checkCIF was carefully designed to identify outliers and unusual
parameters, but every test has its limitations and alerts that are not important in a particular case may
appear. Conversely, the absence of alerts does not guarantee there are no aspects of the results needing
attention. It is up to the individual to critically assess their own results and, if necessary, seek expert
advice.

Publication of your CIF in IUCr journals

A basic structural check has been run on your CIF. These basic checks will be run on all CIFs
submitted for publication in IUCr journals (Acta Crystallographica, Journal of Applied
Crystallography, Journal of Synchrotron Radiation); however, if you intend to submit to Acta
Crystallographica Section C or E or IUCrData, you should make sure that full publication checks are
run on the final version of your CIF prior to submission.

Publication of your CIF in other journals

Please refer to the Notes for Authors of the relevant journal for any special instructions relating to CIF
submission.

PLATON version of 13/07/2021; check.def file version of 13/07/2021

Datablock shelx - ellipsoid plot
Validation Report
1/27/22, 11:11 AM checkCIF/PLATON page 2

checkCIF (basic structural check) running

Checking for embedded fcf data in CIF ...

Found embedded fcf data in CIF. Extracting
fcf data from uploaded CIF, please wait . . . .

checkCIF/PLATON (basic structural check)

Structure factors have been supplied for datablock(s) shelx

THIS REPORT IS FOR GUIDANCE ONLY. IF USED AS PART OF A REVIEW

PROCEDURE FOR PUBLICATION, IT SHOULD NOT REPLACE THE EXPERTISE
OF AN EXPERIENCED CRYSTALLOGRAPHIC REFEREE.

No syntax errors found. CIF dictionary

Please wait while processing .... Interpreting this report

Structure factor report

Datablock: shelx
Bond precision: C-C = 0.0024 A Wavelength=0.71073
Cell: a=9.3352(4) b=12.7754(5) c=19.5462(8)
alpha=90 beta=97.722(2) gamma=90
Temperature: 297 K
Calculated Reported
Volume 2309.96(16) 2309.96(16)
Space group P 21/c P 21/c
Hall group -P 2ybc -P 2ybc
Moiety formula C14 H18 N5 O3, C7 H7 O3 S, H2 O ?
Sum formula C21 H27 N5 O7 S C21 H27 N5 O7 S
Mr 493.54 493.53
Dx,g cm-3 1.419 1.419
Z 4 4
Mu (mm-1) 0.193 0.193
F000 1040.0 1040.0
F000' 1041.00
h,k,lmax 13,18,28 13,18,28
Nref 7721 7699
Tmin,Tmax 0.966,0.981 0.650,0.746
Tmin' 0.947
Correction method= # Reported T Limits: Tmin=0.650 Tmax=0.746 AbsCorr =
MULTI-SCAN
Data completeness= 0.997 Theta(max)= 31.523
wR2(reflections)= 0.1393(
R(reflections)= 0.0486( 6379)
7699)
S = 1.061 Npar= 320

The following ALERTS were generated. Each ALERT has the format

test-name_ALERT_alert-type_alert-level.

Click on the hyperlinks for more details of the test.

Alert level C

PLAT242_ALERT_2_C Low 'MainMol' Ueq as Compared to Neighbors of S1 Check

PLAT242_ALERT_2_C Low 'MainMol' Ueq as Compared to Neighbors of C18 Check

PLAT250_ALERT_2_C Large U3/U1 Ratio for Average U(i,j) Tensor .... 2.1 Note

PLAT906_ALERT_3_C Large K Value in the Analysis of Variance ...... 2.245 Check

PLAT910_ALERT_3_C Missing # of FCF Reflection(s) Below Theta(Min). 8 Note

https://checkcif.iucr.org/cgi-bin/checkcif_hkl.pl 1/3
1/27/22, 11:11 AM checkCIF/PLATON page 2
PLAT911_ALERT_3_C Missing FCF Refl Between Thmin & STh/L= 0.600 6 Report

PLAT975_ALERT_2_C Check Calcd Resid. Dens. 0.83Ang From O1W . 0.41 eA-3

Alert level G

PLAT002_ALERT_2_G Number of Distance or Angle Restraints on AtSite 6 Note

PLAT003_ALERT_2_G Number of Uiso or Uij Restrained non-H Atoms ... 7 Report

PLAT007_ALERT_5_G Number of Unrefined Donor-H Atoms .............. 1 Report

PLAT172_ALERT_4_G The CIF-Embedded .res File Contains DFIX Records 3 Report

PLAT178_ALERT_4_G The CIF-Embedded .res File Contains SIMU Records 1 Report

PLAT380_ALERT_4_G Incorrectly? Oriented X(sp2)-Methyl Moiety ..... C21 Check

PLAT432_ALERT_2_G Short Inter X...Y Contact O3 ..C11 . 3.01 Ang.

1+x,y,z = 1_655 Check

PLAT480_ALERT_4_G Long H...A H-Bond Reported H12A ..O6 . 2.64 Ang.

PLAT860_ALERT_3_G Number of Least-Squares Restraints ............. 47 Note

PLAT883_ALERT_1_G No Info/Value for _atom_sites_solution_primary . Please Do !

PLAT912_ALERT_4_G Missing # of FCF Reflections Above STh/L= 0.600 8 Note

PLAT913_ALERT_3_G Missing # of Very Strong Reflections in FCF .... 1 Note

PLAT933_ALERT_2_G Number of HKL-OMIT Records in Embedded .res File 6 Note

PLAT978_ALERT_2_G Number C-C Bonds with Positive Residual Density. 8 Info

PLAT992_ALERT_5_G Repd & Actual _reflns_number_gt Values Differ by 2 Check

0 ALERT level A = Most likely a serious problem - resolve or explain

0 ALERT level B = A potentially serious problem, consider carefully

7 ALERT level C = Check. Ensure it is not caused by an omission or oversight

15 ALERT level G = General information/check it is not something unexpected

1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data

9 ALERT type 2 Indicator that the structure model may be wrong or deficient

5 ALERT type 3 Indicator that the structure quality may be low

5 ALERT type 4 Improvement, methodology, query or suggestion

2 ALERT type 5 Informative message, check

It is advisable to attempt to resolve as many as possible of the alerts in all categories. Often the minor alerts
point to easily fixed oversights, errors and omissions in your CIF or refinement strategy, so attention to these
fine details can be worthwhile. In order to resolve some of the more serious problems it may be necessary to
carry out additional measurements or structure refinements. However, the purpose of your study may justify
the reported deviations and the more serious of these should normally be commented upon in the discussion
or experimental section of a paper or in the "special_details" fields of the CIF. checkCIF was carefully
designed to identify outliers and unusual parameters, but every test has its limitations and alerts that are not
important in a particular case may appear. Conversely, the absence of alerts does not guarantee there are no
aspects of the results needing attention. It is up to the individual to critically assess their own results and, if
necessary, seek expert advice.

Publication of your CIF in IUCr journals

A basic structural check has been run on your CIF.

These basic checks will be run on all CIFs submitted for
publication in
IUCr journals (Acta Crystallographica, Journal of Applied Crystallography,
Journal of
Synchrotron Radiation); however, if you intend to submit to Acta
Crystallographica Section C or E or
IUCrData, you should make sure that
full publication
checks are run on the final version of your CIF prior to
submission.

Publication of your CIF in other journals

Please refer to the Notes for Authors of the relevant journal for any special instructions relating to CIF
submission.

PLATON version of 20/01/2022; check.def file version of 19/01/2022

Datablock shelx - ellipsoid plot

https://checkcif.iucr.org/cgi-bin/checkcif_hkl.pl 2/3
1/27/22, 11:11 AM checkCIF/PLATON page 2

Download CIF editor (publCIF) from the IUCr

Download CIF editor (enCIFer) from the CCDC
Test a new CIF entry

https://checkcif.iucr.org/cgi-bin/checkcif_hkl.pl 3/3