Structure-based rational design, synthesis, crystal structure, DFT and molecular docking of 1,4-benzene dicarboxamide isomers with application as hardeners

Article abstract of DOI:10.1039/c9nj01560d

N,N′-Di-n-propyl (nPA) and N,N′-di-iso-propyl 1,4-benzene dicarboxamides (iPA), two structural isomers, have been successfully synthesized through aminolysis of poly(ethylene) terephthalate (PET) waste under catalyst free and ambient conditions. The compounds were characterized by elemental analysis, UV-visible spectroscopy, FTIR, ¹H-NMR, ¹³C-NMR, mass spectrometry, Raman spectroscopy and SEM/EDX analysis. Single crystals of the isomers were grown in dimethylsulfoxide (DMSO) and analyzed through single crystal XRD to gain insight into the crystal structure of the compounds (bond lengths and bond angles). An ab initio Density Functional Theory (DFT) study has been executed at B3LYP (Becke's three parameter functional and Lee-Yang-Parr functional) using the 6-31G basis set to investigate the physical parameters and for theoretical calculation of crystal structures. The vibrational frequencies were optimized by DFT and were found to be in close agreement with the experimental vibrational frequencies. The isomers crystallize in triclinic systems and the bond lengths and bond angles obtained from DFT calculations were in agreement with single crystal experimental data. The thermal characteristics of the derivatives were studied through TGA/DTA and DSC. The antimicrobial activity of the two isomers was assessed through molecular docking study with target proteins sterol 14 α-demethylase and glucosamine-6-phosphate synthase. In order to validate isomers as hardeners for epoxy systems, curing kinetic parameters were determined based on the isothermal method using the DSC823^e kinetic software.

Full text of DOI:10.1039/c9nj01560d

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Structure-based rational design, synthesis, crystal structure, DFT and molecular
docking of 1,4 benzene dicarboxamide isomers with application as hardeners
MeenuTeotiaa, NaziaTarannuma, MohitChauhana, and Rakesh Kumar Sonia
aDepartment of Chemistry, ChaudharyCharan Singh University, Meerut 250004, India
E-mail: teotiameenu@gmail.com, orcid.org/0000-0001-9833-7821, Phone: 09758154719
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Abstract: N, N’ di n-propyl (nPA) and N, N’ diiso-propyl 1,4 benzene dicarboxamides (iPA), the
two structural isomers have been successfully synthesized through aminolysis of poly(ethylene)
terephthalate (PET) waste under catalyst free and ambient conditions. The compounds were
1
characterized by elemental analysis, UV-visible spectroscopy, FTIR, H- NMR and 13C-NMR,
mass spectrometry, Raman spectroscopy and SEM/EDX analysis. Single crystals of the isomers
were grown in dimethylsulfoxide (DMSO) and analyzed through single crystal XRD to insight the
crystal structure of the compounds (bond lengths and bond angles). Ab-initio Density Functional
Theory (DFT) study has been executed at B3LYP (Becke’s three parameter functional and Lee–
Yang–Parr functional) using 6-31G basis set to investigate the physical parameters and theoretical
calculation of crystal structures. The vibrational frequencies were optimized by DFT and found in
close agreement with the experimental vibrational frequencies. The isomers crystallize in triclinic
systems and the bond lengths and bond angles obtained with DFT calculations were in agreement
with single crystal experimental data. The thermal characteristics of the derivatives was studied
through TGA/DTA and DSC. Antimicrobial activity of the two isomers was assessed through
molecular docking study with target proteins sterol 14 α-demethylase and Glucosamine-6-
phosphate synthase. In order to validate isomers as hardeners for epoxy system, curing kinetic
parameters were determined using isothermal method on DSC823e kinetic software.
Keywords: aminolysis; depolymerization; SXRD; DFT; vibrational frequency; docking
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1. Introduction
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Recycling of wastes has always been a global concern in order to minimize the harmful effects
caused by disposal of wastes1. The concerned authorities face waste disposal problem and
seekmethods to combat the adverse effects caused by accumulation of these wastes. PET is a well-
known polymer used in the packaging of food, beverages and other liquid containers and occupies
a large section in the piechart of plastic wastes. Due to large consumption of PET packed items,
the amount of generated waste is very high demanding efficient recycling methods involving
simpler and environmentally safer processes. Considerable research has been conducted towards
chemical recycling of PET waste to obtain a number of useful products. Different techniques such
as alcoholysis2-4, aminolysis5-7, ammonolysis8-9, glycolysis10-14, and hydrolysis15-18 are being
reported for depolymerization of PET. The whereabouts of these methods are available in ref Sinha
et al., 201019. Depolymerization of PET waste through aminolysis method gives aromatic amides
which are least explored among the class of depolymerized end products obtained through
chemical recycling techniques20. Most of the reported methods involves the use of catalysts and
high temperature conditions. Metal chlorides21, sulphates22, acetates22, 23-24, quaternary ammonium
salts6, imidazonium ionic liquids25 etc. increase the electrophilicity of the carbonyl carbon of the
PET backbone, hence facilitating the attack by amine nucleophile. However, the use of catalyst
under high temperature conditions lead to harmful effects to the environment and the exposed
manpower and also enhance the cost of commercialization of the developed technology.
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Microwave assisted techniques are also reported for depolymerization of PET24, 26
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The use of terephthalamides in synthesis of polyurethanes27, thiazolidine derivatives28 has been
revealed in literature. In previous works, terephthalic dihydrazide, an aminolysis product obtained
through depolymerization of PET waste using hydrazine hydrate has been explored as plasticizer29,
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antimicrobial agent30 and also as a precursor to obtain UV curable acrylate oligomer31. However
NN’ dialkyl substituted terephthalamides are not that much reactive to be used in further acrylation
reactions.
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A lot of research is devoted to development of epoxy hardening systems as the later finds profound
application in high performance fiber reinforced composites used in pressure moulding, filament
winding and aerospace applications. The modified epoxy composites are also being used as
transparent infills in manufacturing of laminated glasses which are extensively being used in
structural and architectural applications32-34. Their application area is very wide which makes the
knowledge of cure kinetics of the hardening systems an essential requisite to obtain controlled
degree of cure35-37.Generally compounds bearing amine functionalities are explored as curing
agents for LY 556 resin38. Few reports reveal the use of polyamides as hardeners for epoxy resins39-
40. The curing kinetics of a particular resin is of prime importance in order to optimize the curing
temperatures as these reactions are initiated thermally but are exothermic. In this context,
determination of energy of activation, rate constant, curing temperatures helps the end users for
quality maintenance of the polymerized matrix41-42
.
In previous work, the authors successfully depolymerized PET waste through aminolysis method
using methylamine, ethylene diamine, ethanolamine and butylamine at ambient conditions of
temperature and pressure without using expensive and toxic catalysts to obtain respective 1,4
benzene dicarboxamides43. In the same series, two isomers, N,N’ di n-propyl benzene
1,4dicarboxamide (nPA) and N, N’ diiso-propyl benzene 1,4 dicarboxamide (iPA) have been
obtained without using any catalyst at ambient temperature and pressure condition. The two
compounds are structural isomers and characterized using FTIR, Raman spectroscopy, UV-visible
spectroscopy, NMR (1H and 13C), mass spectrometry, elemental analysis and SEM/EDX analysis.
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The thermal characteristics of the compounds are investigated with the help of DSC and TGA.
Single crystal study of the two isomers provided bond angles, bond lengths, crystal system and
lattice parameters. DFT calculations have been performed to corroborate the vibrational
frequencies and bond lengths and bond angles of the single crystals of the two isomers. The
molecular docking study was performed for the compounds nPA and iPA with target protein sterol
14 α-demethylase and glucosamine-6-phosphate synthase to assess the antimicrobial activity.
Herein, an attempt has also been made to inspect N, N’ dialkyl substituted terephthalamides
(synthesized structural isomers) as curing agents for LY 556 resin and curing kinetics is performed
using isothermal method on DSC823e software.
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2. Material and Methods
2.1 Materials
Post consumed PET water bottles were collected and chopped into small flakes (4x4 mm) after
removing cap. The flakes were washed with soapy water to remove dirt and other impurities and
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then with distilled water. The cleaned flakes were kept at 80 C for 5 h and used for aminolysis
reaction. N-propyl amine (99%), iso-propyl amine (99%), acetic acid (99.8%), acetone (99%),
acetonitrile (99.8%),benzene (98%), chloroform (99.5%),dioxane (99.4%), dimethyl formamide
(DMF; 99%), DMSO (99%), ethanol (99.9%),isopropyl alcohol (99%), toluene (99%),
tetrahydrofuran (THF; 99.8%) and sodium hydroxide (97%) were procured from Fischer Scientific
and used as received without further purification. Cyclohexane (99%) anddichloromethane (99%)
were purchased from Merck and methanol (99%), n-heptane (99%),n-hexane (95%),
triethanolamine (97%)were procured from Qualigen and used without any further treatment.
Epoxy LY556 (density 1.15 g/cm3), with epoxy index 5.30-5.45 eq/Kg and epoxy equivalent (ISO
3001) of 183-189 g/eq was procured from Huntsman.
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2.2 Characterization methods
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Agilent FTIR Spectrometer (ATR module of Cary 630 FTIR, Agilent Technologies) was used to
record FTIR spectra of the isomerswithin the range 600-4000 cm-1. 1H-NMR spectra were recorded
on Multinuclear NMR spectrometer (9.4 T; 400 MHz) using DMSO solvent. 13C-NMR spectra
were obtained with FT NMR Spectrometer model Avance-II [Bruker at field strength 9.4 T (13C
frequency-100 MHz)] using DMSO solvent. UV spectra of the isomers were recorded on UV
double beam spectrophotometer Systronics 2201, with band width 2 nm in DMSO solvent from
200-800 nm. Waters, Q-TOF Microma SS (LCMS) mass spectrometer was used to record mass
spectra. Thermogravimetric (TG) and their derivative (DTG) curves were recorded on Perkin
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Elmer, Diamond TG/DTA at 20.00 C/min in nitrogen atmosphere. Differential Scanning
Calorimetric (DSC) curves of the isomers were recorded on DSC 7020 Hitachi Japan at heating
rate of 10.00 0C/min in nitrogen atmosphere from 30 to 350 0C. Raman spectra were recorded on
indigenously designed Raman spectrometer (RI Instruments & Innovation India). Elemental
analysis was carried on Thermo Scientific (FLASH 2000) CHN Elemental Analyser.
SEM photomicrographs with different magnifications were obtained with Scanning Electron
Microscope, ZIESS EVO 18. Energy dispersive X ray (EDX) experiments for percentage analysis
of different elements was performed on EDAX AMETEK octane Pro-5301 operated at 70 kev.
Concentrated solutions of the isomers in DMSO solvent were used to grow crystals in a vacuum
sealed glass tube (8 mm o.d.). Single-crystal X-ray of the crystals for structural investigations was
performed on a CCD Bruker SMART APEX diffractometer equipped with an Oxford Instruments
low-temperature attachment. Graphite monochromated MoKa radiation with wavelength 0.71073
Å was used to collect data at temperature of 296(2) K. SMART and SAINT software packages
were used to index, integrate and scale the frames44, and SADABS program was used to correct
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the data for absorption45. The structures were solved and refined through SHELXL-2014/7 suite
of programs46. Diamond 3.1e software has been used to generate crystallographic figures of nPA
and iPA47. Crystal data of nPA and iPA has been deposited via joint CCDC/FIZ Karlsruhe
deposition service and assigned the deposition numbers as 1903353 and 1903354 respectively.
2.3 Computational method
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2.3.1. DFT Study
The quantum calculations were done using GAUSSIAN 03 program package48. DFT calculations
were executed using Becke’s three-parameter functional Lee-Yang-Parr functional (B3LYP) and
6-31G basis set was used for ground state geometry optimization49-51
2.3.2. Molecular Docking study
.
The molecular docking study was performed for the compounds nPA and iPA with target protein
sterol 14 α-demethylase and glucosamine-6-phosphate synthase. D-fructose-6-phosphate
amidotransferase (EC2.6.1.16) is also named as glucosamine-6-phosphate synthase (GlcN-6-P
synthase)52. This enzyme undergoes hexosamine metabolism converting D-fructose 6-phosphate (Fru-
6-P) into GlcN6P in the presence of glutamine as an ammonia source and finally forming an N-
acetylglucosamine (NAG)53. NAG is used in cell wall formation in bacteria and fungi, such as
peptidoglycan in bacteria and chitin, mannoproteins in fungi54. Sterol 14 α -demethylase (CYP51)
belongs to cytochrome P450 superfamily and essential for fungal viability55. The enzyme is an
important target to design antifungal agent as it catalyzes a key step in ergosterol biosynthesis in fungi
in which methyl group is removed from the C-14 position in the sterol molecule56-57. The docking has
been performed first using the default setting of standard precision (SP). Best pose has been selected
on the basis of minimum binding energy and interactions with the respective protein space. Auto dock
4.2 was used for molecular docking58. Lamarkian genetic algorithm was used for molecular docking
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with population size of 150 and 0.8 cross over rate. Pymol was used for the visualization of interaction
between protein-ligand complex59. The docked pose was then inspected by exploring the interactions
between the receptor and ligands.
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2.3.2.1. Ligand preparation: Chemical structure of nPA and iPA ligands were drawn with
chemsketchtool60. The drawn structures were optimized with prodrg server61.
2.3.2.2. Protein preparation: The 3D structures of proteins viz. (1). Sterol 14-alpha demethylase
(CYP51B) from a pathogenic filamentous fungus Aspergillusfumigatus (PDB ID: 4UYM) and (2).
Glucosamine-6-phosphate synthase (G6PS) from Escherichia coli (PDB ID: 1JXA) have been
downloaded from RCSB PDB database (https://www.rcsb.org/ ). Protein pdb files were prepared for
Molecular Docking. For protein preparation, heteroatoms and water molecules were deleted from pdb
file.
2.4. Synthesis of N, N’ di n-propyl and N, N’ diiso-propyl 1,4 benzene dicarboxamides
Two structural isomers namely, N, N’ di n-propyl 1,4 benzene dicarboxamide (nPA) and N, N’
di iso-propyl 1,4 benzene dicarboxamide (iPA) were synthesized via aminolysis of PET waste
through an environment friendly facile approach. The reactions were carried out in absence of
catalysts under ambient conditions of temperature and pressure. 100 mL of n-propyl amine (Bottle
A) and 100 mL of isopropyl amine (Bottle B) each were taken in separate sealed reagent bottles.
10 g of PET flakes were added to each bottle and the reagent bottle were sealed properly ensuring
any escape of amine. The reaction products were collected after 25 and 48 days respectively.
DMSO solvent was used to recrystallize the isomers and freshly recrystallized compounds were
subjected to FTIR, 1H-NMR, 13 C-NMR, UV-visible, mass spectrometry, S-XRD, thermal, Raman
and elemental analysis. The respective theoretical and experimental percentages of carbon,
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hydrogen, nitrogen and oxygen of the two structural isomers with the molecular formula
C14H20N2O2 are shown as:
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nPA, C= (67.74%) (68.01%); H= (8.06%) (8.12%); N= (11.29%) (11.08%),
iPA, C= (67.74%) (68.24%); H= (8.06%) (8.23%); N= (11.29%) (11.01%).
2.5. Curing kinetic studies
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Formulations comprising epoxy resin and structural isomers were prepared in 1:1 mole ratio and
dynamic thermal curves were obtained. No curing peaks were observed for these formulations as the
hydrogen bonded to nitrogen is secondary and the lone pair of nitrogen is involved in resonance with
carbonyl group. Hence, sodium hydroxide (2%) and triethanolamine (1%) were used as catalyst and
initiator respectively. Samples were weighed in aluminium pans and dynamic curve for each
formulation were recorded from 30 to 350 0C at heating rate of 10 0C/minute on Differential scanning
calorimeter using modulated DSC. On the basis of curing peak temperatures, certain temperatures
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(100, 105 and 110 C) were chosen for curing kinetic studies through isothermal method using
DSC823estar kineticsoftware. Three isothermal runs were recorded for each formulation. Energy of
activation (Ea), rate constant (In K) and order of reaction (n) were estimated and compared with the
help of isothermal curves kinetic analysis. The basic equation for nth order kinetics is:
ꢀꢁ
= ꢃ(1 − ꢄ)ꢅ
Equation 1
ꢀꢂ
The values of ꢀꢁ and ꢄ were used to calculate K and n for actual temperatures. With three isothermal
ꢀꢂ
measurements, the kinetic data, In K and EA were calculated and for n, mean value of the individual
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The vibrational frequencies of formulations FnPA and FiPA and cured filmswere obtained after
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dynamic runsfrom 600-4000 cm-1 in order to ensure the participation of amides in the crosslinked
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network.
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3. Results and Discussion
The two structural isomers were obtained through depolymerisation of PET via aminolysis
reaction with n-propylamine and isopropylamine at ambient conditions of temperature and
pressure. Bottle A, with nPA showed needle like crystals within two days and only partial
swelling of PET flakes was observed for iPA (Bottle B) even after 4 days. N-propylamine
depolymerised PET flakes completely in 25 days, however nearly 50% conversion was achieved
for isopropylamine (Bottle B). The nucleophilic nitrogen of isopropylamine is attached to an
isopropyl group which results in a sterically hindered approach of the nucleophile to attack the
carbonyl carbon of PET backbone, therefore more time was required in generation of precipitate.
Rate of degradation was also slower and aminolytic degradation of all the folds of PET with
isopropylamine was completed in 48 days. The synthesis was carried out in absence of catalyst
and high temperature eliminating the disadvantage associated with catalytic depolymerization at
high temperature43.
3.1 Solubility
Table 1 depicts the typical solubilities of isomers nPA and iPA in different solvents. The isomers
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were dissolved in excess of solvents at 30 ± 2 C, stirred and kept for 10 h. They dissolved
completely in DMSO, DMF, THF and acetic acid. nPA is soluble in ethyl alcohol and isopropyl
alcohol, however, iPA is completely soluble in the mentioned solvents after heating.
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3.2 FTIR Analysis
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FTIR spectra of the isomers were recorded on Attenuated Total Reflection module in solid state,
as shown in Figure 1. The experimental and theoretical (calculated through DFT) vibrational
frequencies (cm−1) corresponding to important functional groups have been compared in Table 2.
The two prominent absorptions in the region 3294.274 and 3303.427 cm−1and 1622.48 and
1625.35 cm−1 are attributed to N-H stretch and C=O stretch, (characteristic bands of amides for
compounds nPA and iPA). The complete aminolysis of PET flakes was achieved as indicated from
the absence of peak near 1715 cm-1, corresponding to C=O stretch of ester linkage in both the
spectra. The vibrational frequencies of the isomers were further confirmed by complementary
characterization technique Raman spectroscopy. Raman spectra of the isomers have been provided
in the supplementary files (Figure S1).
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Table 1: Solubility of isomers (nPA&iPA) in different solvents1
Solvent
Acetic acid
Acetone
Acetonitrile
Benzene
nPA
+
iPA
+
--
--
--
--
--
+*
+*
--
--
--
--
--
--
+*
+*
--
+
Chloroform
Cyclohexane
Dichloromethane
Dioxane
Distilled water
DMF
+
DMSO
+
+
Ethanol
+
+
--
--
--
+
+*
+*
--
--
--
Isopropyl Alcohol
Methanol
n-heptane
n-hexane
THF
+
Toluene
--
--
1[ (+) =soluble (--) =insoluble (+*) = solubility on heating]
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Figure 1: FTIR spectra of nPA (N, N’ di n-propyl) and iPA (N, N’ di-isopropyl) 1,4 benzene
dicarboxamides
Table 2: Experimental and theoretical vibrational frequencies of nPA and iPA with respect to
functional groups
Amides/
nPA
iPA
Type of Vibration
Experimental
DFT Study
Experimental
DFT Study
3294
1622
3296
1621
3303
1625
3300
1631
N-H Stretch
C=O stretch
(Amide I band)
C=C stretch
1534
1496
1455
1530
1496
1440
1534
1496
1446
1530
1498
1443
1133
1137
1123
1174
1126
1167
C-N Stretch
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3.3 NMR Characterization
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1H-NMR spectra of compounds nPA and iPA are shown in Figure 2. H-NMR spectrum for nPA
shows typical resonances: a triplet at 0.9 δ (3H) due to methyl protons; a multiplet at 1.5 δ (2H) is
attributed to –CH2 protons directly bonded to methyl carbon; a multiplet at 3.2 δ (2H) for –CH2
protons directly bonded to nitrogen atom of amide group; a very strong peak at 7.8 δ (4H) due to
aromatic protons and a triplet at 8.6 δ (1H) attributed to –NH protons. The peaks obtained in 1H-
NMR spectrum for iPA are attributed as: a doublet at 1.19 δ (6H) for methyl protons; a multiplet
at 4.1 δ (1H) due to –CH protons; a sharp singlet at 7.9 δ (4H) for aromatic protons and a doublet
at 8.4 δ (1H) due to –NH protons. A very strong absorption at 3.3 δ is due to the presence of
residual water in DMSO and a peak at 2.5 δ is attributed to residual d5 DMSO in both the spectra62-
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.
Figure 3 depicts 13C-NMR of nPA and iPA in DMSO solvent.13C NMR of nPA shows peaks
at: 11.23 δ (2C, a); 22.27 δ (2C, b); 40.24 (2C, c); 165.99 δ (2C, d); 136.71 δ (2C, e) and 126.79 δ
(4C, f). The typical 13C NMR resonances of iPA are attributed at, 22.08 δ (4C, a); 40.22 δ (2C, b);
165.38 δ (2C, c); 136.81 δ (2C, d) and 126.74 δ (4C, e). Peaks present at 39.75 δ and 78.96 δ are
due to methyl carbons of DMSO and CHCl3 respectively62-63. Hence, the two structural isomers
show nearly similar absorptions except for the side chain carbons.
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Figure 2: 1H NMR spectra of nPA (N, N’ di n-propyl) and iPA (N, N’ di-isopropyl) 1,4
benzene dicarboxamides
Figure 3: 13C NMR spectra of nPA (N, N’ di n-propyl) and iPA (N, N’ di-isopropyl) 1,4
benzene dicarboxamides
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3.4 UV-visible Absorption
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Solutions of nPA and iPA were prepared in DMSO (1mg/10 mL) and irradiated with UV-visible
radiations in 1 cm path quartz cells. UV-visible spectra obtained were quite similar for both the
isomers as the chromophore is same showing very strong absorption in the range 250-300 nm with
λmaxvalue at 268 nm (Figure S2). The molecules undergo π-π* transition due to -HNCO-C6H4-
CONH- group and showed two absorption bands, one intense band at 268 nm and another one at
292 nm.
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3.5 Mass Spectral Analysis
Mass spectra of nPA and iPA were recorded using electrospray ionization technique (Figure S3).
The high resolution MS spectra show molecular ion peaks [M] ionized by H+, peaks at m/z
corresponding to their metal adducts and also their dimers64. The molecular masses of both
compounds were observed as 248.14 from their [M+H]+ peaks. The mass spectrum of nPA shows
base peak at m/z 249.14 (100%) which corresponds to [M+H]+; peak at m/z 250.16 (38%) for
[M+2H]+; peak at m/z 271.16 (18%) for [M+Na]+; peak at m/z 497.36 (9%) for dimer [2M+H]+;
peak at m/z 519.34 (8%) for dimer [2M+Na]+ and a peak at m/z 565.34 (7%) for dimer [2M+Na]+.
In the same way, mass spectrum of iPA reveals base peak at m/z 249.15 (100%) which corresponds
to [M+H]+; peak at m/z 250.17 (38%) for [M+2H]+; peak at m/z 271.16 (22%) for [M+Na]+; peak
at m/z 497.36 (5%) for dimer [2M+H]+; peak at m/z 519.34 (7%) for dimer [2M+Na]+ and a peak
at m/z 565.34 (3%) for dimer [2M+Na]+. A peak at m/z 207.13 (8%) in the mass spectrum of iPA
is attributed to fragment of molecular ion after loss of isopropyl group i.e., [M+2H-CH(CH3)2]+,
which is absent in mass spectrum of nPA.
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3.6 Thermal Characterization
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The crystallized aminolysed end products were subjected to TGA and DSC analysis of
depolymerized aminolysates in order to investigate their physical characteristics and
decomposition behaviour at high temperatures. Although, the two compounds are isomers with
difference of branched and unbranched propyl chain attached to nitrogen atom, which is
contributing to a difference in their melting points, enthalpy change and their decomposition
temperature.The compound nPA follows single step degradation with maximum weight loss (92%)
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0
between 295-3700C with peak maxima at 355.97 C at a rate of 1.452 mg/min leaving 8% char
(Figure 4). The melting point of compound nPA was found as 241.60 0C from DSC curve (Figure
5) with 48.6 J/g enthalpy of melting. The DSC peak is followed by broad exothermic hump which
may be referred to recrystallization of compound nPA.
The decomposition profile of iPA involves two steps with peak maxima at 339.33 0C and 445.07
0C corresponding to ~48% and 35% weight loss, respectively (Figure 4). The first step can be
attributed to loss of two propene and two ammonia molecules which correspond to 47.58% weight
of the compound. The expulsion of neutral molecule propene is further confirmed by the presence
of peak at 207 m/z in its mass spectrum (Figure S2). The second peak in DTG curve may
correspond to evolution of carbon monoxide and carbon dioxide leaving nearly 9% char residue.
Freshly recrystallized and dried sample of compound iPA was used for DSC and scans were
0
collected in triplicate. DSC thermogram of compound iPA depicts a very sharp peak at 284 C
clearly indicating its melting point with 106 J/g enthalpy of melting, which is very high in
comparison to nPA suggesting highly crystalline nature of the compound. A small endothermic
peak is also seen at 268 0C. Generally, polymorphic crystalline compounds exhibit such peaks for
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metastable forms which then convert to stable forms. The study suggested iPA to be polymorphic
crystalline solid.
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Figure 4: TGA/DTG curves of nPA (N, N’ di n-propyl) and iPA (N, N’ di-isopropyl) 1,4
benzene dicarboxamides
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Figure 5: DSC curves of nPA (N, N’ di n-propyl) and iPA (N, N’ di-isopropyl) 1, 4 benzene
dicarboxamides
3.7 SEM Analysis
SEM photomicrographs of compound nPA and iPA with 500 X magnification (Figure 6) depict
crystalline nature of both isomers. Long needle like crystals are seen which have been identified
as triclinic crystal system through S-XRD studies. The carbon weight percentage obtained through
EDX experiments for compounds nPA and iPA are 67.96% and 66.75% respectively which were
in accord with elemental analysis of the two structural isomers.
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Figure 6: SEM photomicrographs with 500 X magnification/EDX analysis of nPA (N, N’ di
n-propyl) and iPA (N, N’ di-isopropyl) 1, 4 benzene dicarboxamides
3.8 Single crystal (S-XRD) studies
Freshly recrystallized samples were used for S-XRD to collect crystal data and structure
refinement. The identified crystal system is triclinic for both isomers which is least symmetric
ꢆ
among crystal systems, centrosymmetric with pinacoidal class and with space group P1. The unit
cell dimensions observed for crystal nPA and iPA are depicted in Table 3. The calculated bond
lengths and bond angles are listed in Table 4 and 5. The three bond angles for carbonyl carbon of
compound nPA, C3C4N1, C3C4O1 and N1C4O1 are 117.4(2)0, 121.3(3)0 and 121.3(3)0
respectively. The distortion in values from trigonal planar geometry is due to repulsive interaction
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of lone pairs of oxygen atom with ortho hydrogen of benzene ring. The similar distortion was
observed for compound iPA with slight increase in N1C4O1 angle (121.70) due to presence of two
methyl groups on the carbon bonded to nitrogen atom. The crystallographic figures of the two
structural isomers are shown in Figure 7.
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Table 3: Unit cell dimensions of nPA and iPA crystals obtained through SXRD analysis2
nPA
iPA
a (Å)
b (Å)
c (Å)
α (Å)
β (Å)
γ (Å)
5.0286(19)
7.660(3)
5.0619(16)
5.1565(17)
13.593(4)
100.634(8)°
96.239(8)°
95.839(8)°
343.93(19)
9.751(4)
105.952(9)°
95.479(9)°
106.190(9)°
340.7(2)
3
Volume (Å )
Figure 7: Crystallographic structures with important atoms labeled of compound nPA and
compound iPA obtained through Diamond 3.1e software (Hydrogen atoms have been
omitted for clear view of carbon skeleton)
2a, ≠ b, ≠ cand  ≠ ,≠ 
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3.9 Density Function Theory (DFT) Study:
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The theoretical study of the isomers were performed at DFT/B3LYP 6-31G basis set method.
Several parameters for the geometry of the isomers are calculated. Several calculated
thermodynamic parameters have been presented in Table 6. The value of the dipole moment of
nPA and iPA was found to be 6.2778 and 6.9593 Debye respectively. The electrostatic field is
pulled in case of iPA as compared to nPA thereby increase the dipole moment value. Both the
molecules have C1 symmetry showing low energy at all levels. Mulliken atomic charges of the
two molecules have been presented as supplementary data (Table TS1). The total energy of the
molecule is the sum of rotational, vibrational, electronic and translational energies. The
experimental bond length and bond angles of the two compounds were compared with DFT data
(Table 4 and 5). The theoretical and experimental vibrational frequencies of the two compounds
were also compared and found to be in accordwith experimental data (Table 2). DFT also helped
in comparing the bond lengths and bond angles of the two isomers with that of S-XRD data (Table
4 and 5).
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Table 4: Comparative table for bond lengths [Å] of crystals of nPA and iPA crystals obtained
through SXRD and DFT calculations
Bond lengths
nPA
Bond lengths
iPA
SXRD
1.233
DFT
SXRD
1.239
DFT
O1 C4
N1 C4
N1 C5
N1 H1A
C3 C1
C3 C2
1.255
1.256
O1 C4
N1 C4
N1 C5
N1 H1A
C2 C1
C2 C3
1.371
1.466
1.008
1.404
1.405
1.331
1.376
1.478
1.015
1.405
1.404
1.337
1.459
0.8600
1.382
1.386
1.451
0.8600
1.379
1.380
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C3 C4
C1 C2
1.498
1.492
1.498
1.392
1.083
1.397
1.083
1.538
1.540
1.093
1.095
1.094
1.097
1.095
1.097
1.096
1.488
1.382
C2 C4
C1 C3
1.392
1.405
1.085
1.085
1.543
1.093
1.099
1.536
1.096
1.099
1.096
1.095
1.097
1.370
0.9300
1.370
C1 C3
C1 H1
C3 C1
1.382
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C1 H1
0.9300
0.9300
1.488
C2 H2
C3 H3
0.9300
1.496
C5 C6
C5 C6
C5 H5A
C5 H5B
C6 C7
C5 C7
0.9700
0.9700
1.516
1.507
C5 H5
0.9800
0.9600
0.9600
0.9600
0.9600.
C6 H6A
C6 H6B
C6 H6C
C7 H7A
C7 H7B
C7 H7C
C6 H6A
C6 H6B
C7 H7A
C7 H7B
C7 H7C
0.9700
0.9700
0.9600
0.9600
0.9600
0.9600
0.9600
Table 5: Comparative table for bond angles [°] of crystals of nPA and iPA crystals obtained
through SXRD and DFT calculations
Bond Angle
nPA
Bond Angle
iPA
SXRD
DFT
SXRD
DFT
C4 N1 C5
C4 N1 H1A
C5 N1 H1A
C1 C3 C2
121.7
125.8
121.3
119.3
119.3
118.4
C4 N1 C5
122.6
118.7
118.7
118.4
119.5
118.2
119.0
C4 N1 H1A
112.8
115.7
118.9
C5 N1 H1A
C1 C2 C3
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C1 C3 C4
C2 C3 C4
123.7
C1 C2 C4
C3 C2 C4
O1 C4 N1
O1 C4 C2
N1 C4 C2
C3 C1 C2
C3 C1 H1
C2 C1 H1
C1 C3 C2
C1 C3 H3
C2 C3 H3
N1 C5 C6
N1 C5 C7
C6 C5 C7
N1 C5 H5
C6 C5 H5
C7 C5 H5
C5 C6 H6A
C5 C6 H6B
H6A C6 H6B
C5 C6 H6C
H6A C6 H6C
H6B C6 H6C
117.8
122.9
120.3
120.0
119.6
120.5
120.7
118.6
120.5
121.1
118.2
110.5
110.5
111.6
106.9
109.2
108.3
110.6
111.4
108.5
110.6
107.8
107.8
122.8
118.8
121.3
121.3
117.4
120.7
119.7
119.7
120.9
119.6
119.6
112.7
109.1
109.1
109.1
109.1
107.8
112.1
109.2
109.2
109.2
109.2
107.9
118.8
122.8
121.7
121.0
117.3
120.8
119.6
119.6
120.8
119.6
119.6
110.6
111.4
111.2
107.8
107.8
107.8
109.5
109.5
109.5
109.5
109.5
109.5
117.6
121.7
121.2
116.9
120.4
118.9
120.51
120.4
121.4
121.5
113.4
106.9
106.9
108.2
108.2
108.1
111.9
108.3
110.1
109.3
110.1
106.9
O1 C4 N1
O1 C4 C3
N1 C4 C3
C2 C1 C3
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C2 C1 H1
C3 C1 H1
C1 C2 C3
C1 C2 H2
C3 C2 H2
N1 C5 C6
N1 C5 H5A
C6 C5 H5A
N1 C5 H5B
C6 C5 H5B
H5A C5 H5B
C5 C6 C7
C5 C6 H6A
C7 C6 H6A
C5 C6 H6B
C7 C6 H6B
H6A C6 H6B
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C6 C7 H7A
C6 C7 H7B
H7A C7 H7B
C6 C7 H7C
H7A C7 H7C
H7B C7 H7C
111.0
C5 C7 H7A
C5 C7 H7B
H7A C7 H7B
C5 C7 H7C
H7A C7 H7C
H7B C7 H7C
110.6
110.7
107.8
110.8
108.4
108.2
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
109.5
111.1
107.8
111.3
107.7
107.8
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109.5
109.5
Table 6: Theoretically calculated physical and thermodynamic parameters of isomers nPA and iPA
Parameters
Dipole moment (Debye)
Total energy (Kcal/mol)
Total Cv (Cal/mol K)
nPA
iPA
6.2778
212.91
52.71
6.9593
212.55
55.34
Entropy (S) (Cal/mol K)
Zero point vibrational energy
(Kcal/mol)
112.58
204.96
112.80
204.47
Thermal correction to Energy
Thermal correction to Enthalpy
Degree of freedom
0.3393
0.3402
108
0.3387
0.3396
111
Full point group
C1
C1
Thermal correction to Gibbs free energy
0.2867
0.2860
3.10 Molecular Docking
The molecular docking study was performed for the compounds nPA and iPA with target protein
sterol 14 α-demethylase (4uym) and glucosamine -6-phosphate synthase (1jxa). The two isomers
showed antimicrobial activity. The two ligands nPA and iPA were incorporated within 4uym in the
same cavity and space. The binding site in the protein was found to have sufficient volume and area
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which can accommodate ligands in the cavity because of its shape and size. The interaction between
the protein (4uym) and ligands are due to non-covalent interactions along with hydrogen bond (H-
bond) to achieve proper binding. nPA is forming 1 H bond with the protein and the interacting amino
acid are Lue304, Gly308, Phe468, Gly465, Ser311, Ser312, Ala469, Leu154, Phe456 which are
labelled in the Figure 8. The amino acids of protein residues that interacted with iPA are Ser312,
Ser311, Ala469, Leu387, Gly465, Phe456, Gly308, Gly465, Phe456. nPA showed better binding with
the protein as compared to iPA. The antifungal activity can be predicted to be good in nPA as
compared to iPA. Table 7 shows minimum binding energy of compounds with two target proteins.
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Table 7: Minimum binding energy of docked compounds (nPA and iPA) in two different
proteins: sterol 14 α-demethylase (4uym) and glucosamine -6-phosphate synthase (1jxa)
Ligands
Minimum
Binding
Energies with
4uym
Hydrogen bonds
formed between
ligand and target
protein
Interacting Amino Acids
(Kcal/mol)
-7.88
nPA
iPA
1
Lue304,Gly308,Phe468,Gly465,Ser311,Ser312
,Ala469,Leu154,Phe456
Ser312,Ser311,Ala469,Leu387,Gly465,Phe456
,Gly308,Gly465,Phe456
-6.01
Ligands
Minimum
Binding
Hydrogen bonds
Interacting Amino Acids
Energies with
1jxa
(Kcal/mol)
-4.92
nPA
iPA
1
1
Lys603,ala602,val605,leu601,ser349,leu501,as
n365,pro377,asn392
Ser604,ser349,gln348,lys603,ser401,leu501,leu
601,ser349,leu484
-5.06
The binding site of glucosamine-6-phosphate synthase (1jxa) is formed mainly by the loop which
can be considered as highly flexible area and not having very deep pocket. Because of its shallow
nature, cavity is exposed to water and abundantly by lipophilic residues in the region but also has
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some hydrophobic residue in the interior65 (Figure 8 (b)). This is the reason why the two ligands
appear to show moderate binding score with 1jxa. The interacting amino acids found for iPA are
Ser604, ser349, gln348, lys603, ser401, leu501, leu601, ser349, leu484 and forms 1 H bond. In
case of nPA, the interacting amino acids found are Lys603, ala602, val605, leu 601, ser349, leu501,
a sn365, pro377, asn392 and forms 1 H bond. The minimum binding energy for iPA was greater
than nPA. The results have shown that the ligands are more susceptible to antifungal activity as
compared to antibacterial study.
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Figure 8: (a) Docking pose of two ligands in the binding site of sterol 14-alpha
demethylasefrom a pathogenic filamentous fungus Aspergillusfumigatus (PDB ID: 4UYM)
and (b) docking pose of two ligands in the binding site of glucosamine-6-phosphate
synthase from Escherichia coli (PDB ID: 1JXA)
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3.11 Curing Kinetics
Dynamic curves of Fnpa and Fipa are depicted in Figure 9. Broad curing peaks were observed in
temperature range 30-350 OC. The films obtained after DSC analysis were subjected to FTIR analysis
to ensure epoxy ring opening and participation of 1,4 benzene dicarboxamides (Figure S4). Absence
of N-H stretch bands in the FTIR spectra of cured samples confirm the participation of amides in the
polymerized matrix. Sodium hydroxide helps in epoxy ring opening making the carbon to be attacked
more electron deficient, hence pushing the reaction in forward direction. Three isothermal runs were
conducted for each formulation shown in Figure 10 for FnPA (a) and FiPA (b), respectively. The
curing kinetic data (Table 8) shows higher activation energy for FnPA formulation by 3.16 KJ/mol,
however order of the reaction was found 0.57 and 0.58 for FnPA and FiPA, respectively. The
conversion tables reveal slightly faster polymerization in FiPA and lower activation energy.
Figure 9: Dynamic curves of FnPA and FiPA formulations from 30-350 0C
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Figure 10: Isothermal curves of (a) FnPA and (b) FiPA formulation at 100, 105 and 110 0C
Table 8: Curing kinetic parameters obtained through isothermal method
S. No.
1.
Kinetic parameters
FnPA
-1.35
13.49
0.57
FiPA
-2.36
10.33
0.58
In(K0)
EA KJ/mol
n
2.
3.
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4. Conclusion
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With effect to growing need for PET bottles as packaging material, it is extremely important to
develop efficient chemical recycling method on their disposal. The current study deals with the
synthesis and structural analysis of generated waste efficient aromatic carboxamides. The two
structural isomers of 1,4 benzene dicarboxamide have been successfully synthesized through
depolymerization of PET without using catalysts at room temperature conditions. The characterization
data obtained confirms the structures as N, N’ di n-propyl and N, N’ di-isopropyl 1,4 Benzene
dicarboxamides. The two isomers possess C1 point group and show triclinic crystalsystem. Bond
angles and bond lengths were obtained through S-XRD technique and were found in good accord with
DFT simulated values. An effort has been putforth to investigate the curing characteristics of two
structural isomers to be used as epoxy hardeners for LY556 resin. The compounds were crosslinked
in epoxy network in presence of catalyst and initiator and depicted close conversion characteristics.
iPA was investigated as slightly faster curing agent owing to its positive inductive effect at nitrogen
atom flanked by two methyl groups. The future work envisages the conversion of amides to amines
to make them active curing agents eliminating the need of catalyst and initiators that may cause the
depletion of finally cured networks over a time range. Further, molecular docking of the isomers were
studied for target proteins sterol 14α-demethylase, and glucosamine-6-phosphate synthase. The
binding energy and interaction between the target protein and ligand have been studied. The antifungal
activity was found to be potentially good for nPA as compared to iPA.
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Conflicts of interest: There are no conflicts to declare.
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Acknowledgement: Authors would acknowledge DST (DST/TSG/Ceramic/2011/77-G) for the
financial assistance. Authors would also like to acknowledge SAIF Centre, Punjab University and
Cochin for carrying out NMR, MS and TGA/DTA analysis.
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