Synthesis and comprehensive structural studies of a novel amide based carboxylic acid derivative: Non–covalent interactions

Article abstract of DOI:10.1016/j.molstruc.2016.12.045

The presented work studies the geometric and electronic structures of the crystalline network of a novel amide based carboxylic acid derivative, N–[(4–chlorophenyl)]–4–oxo–4–[oxy] butane amide, C₁₀H₁₀NO₃Cl (1), constructed

Full text of DOI:10.1016/j.molstruc.2016.12.045

Accepted Manuscript
Synthesis and comprehensive structural studies of a novel amide based carboxylic
acid derivative: Non–covalent interactions
Mohammad Chahkandi, Moazzam H. Bhatti, Uzma Yunus, Shahida Shaheen,
Muhammad Nadeem, Muhammad Nawaz Tahir
PII:
S0022-2860(16)31362-X
10.1016/j.molstruc.2016.12.045
MOLSTR 23243
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 28 October 2016
Revised Date: 14 December 2016
Accepted Date: 15 December 2016
Please cite this article as: M. Chahkandi, M.H. Bhatti, U. Yunus, S. Shaheen, M. Nadeem, M.N. Tahir,
Synthesis and comprehensive structural studies of a novel amide based carboxylic acid derivative: Non–
covalent interactions, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2016.12.045.
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Graphical Abstract
∆Etot = ‒227.59 kJ mol−1
1-mon
6 ×
1–net

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Synthesis and comprehensive structural studies of a novel amide based
carboxylic acid derivative: Non–covalent interactions
Mohammad Chahkandi a,* Moazzam H. Bhatti b,*, Uzma Yunus b, Shahida Shaheen b,
Muhammad Nadeemb, Muhammad Nawaz Tahir c
a Department of Chemistry, Hakim Sabzevari University, Sabzevar 96179-76487, Iran.
b Department of Chemistry, Allama Iqbal Open University, Islamabad, Pakistan.
c Department of Physics, University of Sargodha,Sargodha, Pakistan.
*To whom correspondence should be addressed:
Mohammad Chahkandi: E-mail: m.chahkandi@hsu.ac.ir; chahkandimohammad@gmail.com. Tel.:
+985144013342; fax: +985144013170.
Moazzam H. Bhatti: E-mail: moazzamhussain_b@yahoo.com.
Abstract
The presented work studies the geometric and electronic structures of the crystalline
network of a novel amide based carboxylic acid derivative, N–[(4–chlorophenyl)]–4–oxo–
4–[oxy] butane amide, C10H10NO3Cl (1), constructed via hydrogen bonds (HBs) and
stacking non–covalent interactions. Compound 1 was synthesized and characterized by
1
13
FTIR, H, and C–NMR, and UV–Vis spectra, X–ray structural, DTA–TG, and EI–MS,
analyses. DFT calculations about molecular and related network of 1 were performed at
hybrid B3LYP/6–311+G (d, p) level of theory to support the experimental data. The neutral
monomeric structures join together via inter−molecular conventional O/N−H···O and
non−conventional C−H···O HBs and O−H···π and C−O···π stacking interactions to create
2−D architecture of the network. The results of dispersion corrected density functional
theory (DFT−D) calculations within the binding energy of the constructive non−covalent
interactions demonstrate that HBs, especially conventional O−H···O and N−H···O, govern
the network formation. The calculated electronic spectrum show five major bands in the
range of 180–270 nm which confirm the experimental one within an intense band around
250 nm. These charge transfer bands result from shift of lone pair electron density of
phenyl to chlorine or hydroxyl or phenyl functional groups that possess π → π* and π → n
characters.
Keywords: N–[(4–chlorophenyl)]–4–oxo–4–[oxy] butane amide; Binding energy of
non−covalent interaction; DFT−D; electronic transition.
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1. INTRODUCTION
The amide functionality is a common feature in small or complex synthetic or natural
molecules. It is universal in life, as proteins play a vital role in virtually all biological
processes such as enzymatic catalysis (nearly all known enzymes are proteins),
transport/storage (hemoglobin), immune protection (antibodies) and mechanical support
(collagen).
Crystal engineering through control of intra–molecular interactions especially non–
covalent ones, try to design of new solid network include of desired chemical and physical
properties [1]. They are H–bonding, stacking, van der Waals [2], dipole–dipole [3], and
more recently the halogen bond [4] which form the basis for designing of supramolecular
architecture and related crystalline network [5]. The strength of halogen bond is
intermediate between the strong (O–H…O) and weak (C–H…O) hydrogen bonds (HBs). It
can be said that among all of them HB is more effective in control of the structure,
properties and dynamics of chemical and living systems [6]. The structure of molecules can
define using Bader's theory called Quantum Theory of Atoms In Molecules (QTAIM) [7].
This theory has been successfully applied to study of covalent and non–covalent atom–
atom interactions in metal complexes [8], molecular clusters [9], proteins [10], and so on.
The non–covalent proteasome inhibitors, constructing different moderate inter–molecular
HBs even if less widely investigated because of their potential advantages such as
improved selectivity, moderate reactivity, reduced instability, and the lack of all drawbacks
and side–effects might be a promising alternative to employ in therapy [5]. Some
compounds including amide functional groups reported as the novel non–covalent
inhibitors [6, 11-13]. In the presented new amide compound, strong O–H…O and N–H…O
HBs form the pertinent network (see section 3.4.) that can facilitate the H‒bonding and
charge transfer (CT) interactions with acceptor molecules like DNA. In supramolecular
catalyst, ligand, metal, organo–catalyst, substrate, additive, and metal counterion are
reaction partners that can be held together by the non–covalent interactions [14]. Moreover,
many of the inorganic–organic hybrid compounds with interesting electro–conductive,
optical and magnetic properties formed using HBs [15, 16]. However, molecular
functionalities, e.g. amino, amid, hydroxyl, carbonyl, and carboxylate play key role in
adjusting of the fragments and following in formation of supramolecular synthons [11-13].
An in–depth analysis of the Comprehensive Medicinal Chemistry (CMC) database
revealed that the carboxamide group appears in more than 25% of the known drugs [17].
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There is evidence that amides, of dicarboxylic acid like maleic, succinic, and phthalic
acids, containing compounds obtained by acylating of certain heterocyclic amines with the
corresponding acid anhydrides, possess hypo and hypertensive, hypo and hyperglycemic,
analgesic, anti–inflammatory, and anti-bacterial properties [18]. For the drug loading
capacity it can be exampled that, to increase drug loading level, using the HBs of carbonyl
group in doxorubicin (an amphiphilic anticancer drug), urea functional groups were built
into the core of polymeric micelles [19]. Atorvastatin, the top selling drug worldwide since
2003, blocks the production of cholesterol and contains an amide bond as do Lisinopril
(inhibitor of angiotensin converting enzyme), Valsartan (blockade of angiotensin–
Receptors) and Diltiazem (calcium channel blocker used in the treatment of angina and
hypertension. Different types of amides can be synthesized by acylation of the
corresponding amines and phenyl acetic acid with maleic anhydride under mild conditions
[
20]. Amide bonds are typically synthesized from the union of carboxylic acid and amines.
The carboxylic acid can be activated as acyl halides, acyl azide, ester, anhydride etc. There
are different ways of coupling reactive carboxyl derivatives with amines [21]. The choice
of coupling reagent is however critical. Our main aim was to synthesis ligand (amide bond)
which have both amide and carboxylate groups as potential donor sites, for this purpose the
best selection is anhydride, as anhydride readily react with vast range of nucleophiles such
as alcohols, thiols amines and aromatic amine. The anhydride is succinic and chloroaniline
as aromatic amine along with ethyl acetate as solvent.
Computational results as a complementary to experimental ones can help to determine the
stabilized molecular and network structures, their binding and stabilization energy,
vibrational frequencies of intermolecular interactions, potential energy and free energy
surfaces. Beside of applying theoretical methods, Density Functional Theory (DFT)
calculations provide significant results in studying of different organic and inorganic
clusters at a relatively low computational cost compared with other post-Hartree-Fock
methods [22-25].
In this paper we are reporting the synthesis, characterization, crystal structural, and DFT
calculations of a novel amide based carboxylic acid derivative, N–[(4–chlorophenyl)]–4–
oxo–4–[oxy] butane amide, C10H10NO3Cl (1). DFT/B3LYP/6‒311 + G(d, p) methods
performed to determine the free energy of 1 and stabilization energy of the related network
constructed via the most important non‒covalent interactions. Vibrational, electronic
1
transition assignments, frontier molecular orbital (FMO) analysis, and H, 13C, and 15N–
NMR chemical shifts of 1 in the ground state have been calculated. Since non‒covalent
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interactions play basic role for constructing the respective crystal networks, understanding
this matter would be useful for designing new desired compounds.
2. Experimental
2.1. Materials and measurements
All chemicals used in this work were analytical A.R grade. FTIR spectra were
recorded on thermo Scientific Nicolet iS10 spectrophotometer in ATR mode (4000–
400 cm–1) in KBr discs for the free ligands and all the prepared compounds. Melting
points were determined via Gallenkamp (UK) 50 Hz220/240 volt melting point
1
apparatus. The H and 13C–NMR spectrum were recorded at room temperature in
DMSO on a Bruker Avance Digital 300 MHz spectrometer (Switzerland)
respectively. Chemical shifts are given in ppm and coupling constant (J) values are
given in Hz. The multiplicities of signalling are given with chemical shifts; (s =
singlet, d = doublet, t, triplet, dd = doublet of a doublet). The EI–MS was performed
on JEOL MS 600H–1. Thermal decomposition patterns (TG and DTA) of compound
was carried out under nitrogen atmosphere up to 800°C utilizing a heating rate of
10°C/min on a DTG–60H Simultaneous DTA–TG analyzer.
2.2. Experimental procedure for the synthesis of compound 1
The independently prepared ethyl acetate solutions of 4–chloroaniline (2.5 mmol) and
succinic anhydride (2.5 mmol) were mixed together drop wise. The white precipitates were
appeared spontaneously after mixing. The mixture was stirred at room temperature for next
6 hours and left for overnight (Scheme 1). The precipitates were filtered, washed first by
HCl (to remove unreacted aniline) and then with distilled water (to remove the unreacted
succinic acid and succinic anhydride). The air dried precipitates were dissolved in acetone
and set aside for recrystallization. After four weeks, needle–like white single crystals were
obtained.
Yield: 43%: M.p. 178°C: Mol. Wt.: 227.1: IR (cm–1): 3296 ν( OH); 3182 ν (NH); 1695 ν
(carboxylic C=O); 1662 ν (ν (C=O) amide); 821 ν (ν (P–substituted stretch of benzene); 1H
NMR (DMSO–d6, 300 MHz) δ(ppm): 12.11 (s,1H; OH); 10.1 (s, 1HNH); 7.62 (d, 2H,
3
3
H6,6’, J[1H,1H] = 8.7Hz); 7.32 (d, 2H, H7,7’8, J[1H,1H] = 9Hz); 2.53 (t, 2H, H2,
3
3J[1H,1H] = 7.5 Hz); 2.52 (t, 2H, H3, J[1H,1H] = 9 Hz): 13C NMR (DMSO–d6, 75 MHz)
δ(ppm): 173 (C1); 30 (C2); 28 (C3); 170 (C4); 128 (C5); 126 (C6,6'); 120 (C7,7'); 138
(C8): EI–MS, m/z(%): [C10H10ClNO3 ]+, 229, M+2 (29); [C10H10ClNO3 ]+, 227, M (80);
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[C10H9ClNO2 ]+, 210, (4); [C9H9ClNO ]+, 182, (1.3); [C7H5ClNO ]+, 154, (3); [C6H6ClN ]+,
127, (100); [C6H4Cl ]+, 111, (3.3); [C4H5O3 ]+, 101, (18); [C6H6N ]+, 92, (8); [C3H5NO2 ]+,
73, (15); [C3H3O ]+, 55, (14); [CHO2 ]+, 45, (7).
2.3. Structure determination
Crystal data were collected at 150 (2) K on a Bruker Apex II CCD diffractometer.
All the non–hydrogen atoms were refined using anisotropic atomic displacement
parameters, and hydrogen atoms bonded to carbon were inserted at calculated
positions using a riding model. Hydrogen atoms bonded to O or N was located from
difference maps and their coordinates refined. SHELXS–97 was used to solve and
SHELX2012 to refine the structure. The crystal data and refinement of
1 are given in
Table 1. The structure of the title compound
1 is shown in Fig. 1.
2. 4. Computational details
As starting point to geometry optimization of 1 the non‒hydrogen atoms were fixed at the
coordinates obtained from the crystal structure and the positions of the hydrogen atoms
optimized. Then the optimization of structure of the smallest independent fragment of 1
(1‒mon, see Fig. 1) along with the vibrational frequencies were performed. Following this,
in order to find intermolecular interactions energies, larger fragments of 1‒mon (1‒frag1
and 1‒frag2; 1‒frag3 and 1‒frag4 containing a three and two monomer units, respectively
see Fig. 1) and the final network (1‒net, see Fig. 2) containing 6 monomer units and
bearing all possible non‒covalent interactions were optimized. All fragments were
performed in the framework of the DFT method using a hybrid functional B3LYP [26‒28]
and the triple—ζ 6–311+G(d, p) basis set. The interaction energies were corrected for the
basis set superposition error (BSSE) using the Boys‒Bernardi counterpoise technique [29].
In order to take into account dispersion effects, the B3LYP‒D [30] functional was used in
the dispersion‒corrected DFT method. The calculated vibrational frequencies indicated that
the structure was stable (no imaginary frequencies). The resulting non‒covalent interaction
energies and related equilibrium distances and angles of the experimental and optimized
network have been summarized in Tables 2 and 3. The computed geometrical parameters
of 1‒mon with available experimental data have been compared (see Table 4). The
UV‒Vis spectrum was calculated for the optimized geometry with the time‒dependent
DFT (TD‒DFT) method. Singlet and triplet excited states were both considered; however
as expected, all excitations to triplet states were prohibited. Natural bond orbital (NBO)
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analyses were also performed based on the optimized geometries. Partial atomic charges
were computed according to natural population analysis (NPA) [31]. The isotropic 1H, 13C,
and 17O NMR chemical shifts were computed employing the same theoretical level used for
the optimization calculations. Their values were reported with respect to the absolute
computed isotropic shielding values of Si(CH3)4 and H2O (with a calculated isotropic
magnetic shielding of 31.99 (1H), 184.01 (13C), and 322.5 (17O) ppm, respectively)
optimized at the same respective level used for other compounds. All calculations with
fully geometry optimization have been performed with Gaussian 09 [32].
3. Results and discussion
3.1. Molecular geometric: Crystal and optimized structures
Single−crystal
X−ray
diffraction
analysis,
revealed
the
formation
of
N−[(4−chlorophenyl)]−4−oxo−4−[oxy] butane amide (1). The single crystal data of 1
shows that the monoclinic system of unit cell belongs to the space group P21/n with
a=10.9284(7) Å, b= 5.0641(3) Å, c=18.9707(14) Å, α= γ = 90°, and β= 97.280(3) Å (see
more information in Table 1). Selected experimental and theoretical optimized geometrical
parameters including bond lengths, bond angles, and torsion angles are listed in Tables 4.
The conformation of the N−H and the C=O bonds in amide segment are anti to each other.
In the side chain the amide C=O is anti to adjacent C−H bond, while carboxyl C=O is syn
to adjacent to C−H bond. The bond distance N1−C4 is 1.349(2) Å. The carboxylate group
has asymmetric bond distance O2−C1=1.241(3) Å representing the double bond character
which is slightly higher than reported value of 1.225 (2) Å and O1−C1=1.275(2) Å
representing the single bond character. The neutral molecular compound of 1 optimized as
the asymmetric monomeric unit. However, its crystalline network constructed from the
molecular units through intermolecular interactions that causes to difference of
experimental and optimized structural parameters of 1 (cf. Fig. 1 and Table 4). Actually a
double set of every N1−H1A···O3, O1−H1···O2, C7−H7···O1, and C1−O1··· π(phenyl) fix the
monomer in the related fragments (1‒frag1 to 1‒frag4) and the network and prevent the
structural geometry of huge changing that occurred in isolated monomeric units in the gas
phase. The largest differences of experimental and calculated measured structural
parameters can be highlighted as 0.7 Å for O1–C1 bond length, 5.3° and 4° for O2–C1–C2
and C5–N1–H1A angles, and 351° for C5–N1–C4–C3 torsion angle (cf. Table 4). In the
network, formation of O1−H1···O2 hydrogen bond (HB) causes to deacreasing of O1−H1
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from and in following deacreasing of O1–C1 (1.275 (Exp.) and 1.355 Å (Calc.)) bond
lengths in comparison to isolated optimized monomer. Moreover, involving of monomer
unit in the formation of mentiond HBs resulted in changing of mentioned bond (120.89
(Exp.) and 126.17 ° (Calc.)) and torsion (176.52 (Exp.) and 175.70 ° (Calc.)) angles. In
addition, it should be noted that another driving force for the mentioned structural changing
of 1−mon is the formation of the intra−molecular C4–O3···H6´ HB. Actually the carbonyl
group of amide functionality turns to phenyl ring that caused the changing of C5–N1–C4–C3
torsion angle from 176.5 (Exp.) to –175.7 (Calc.) in the 1‒mon optimized structure (see
Table 4).
3.2. Spectroscopic studies
3.2.1. Infrared spectrum
The FT−IR spectrum reveals different frequencies assigned to important functional
groups of 1 (Fig. 3). The important features in the IR spectrum of 1 are stretching vibration
of the N‒H (Exp. 3295.8, Calc. 3615 cm–1) and the intense peaks that attributed to the
stretching frequencies of the C=O of acid (Exp. 1696, Calc. 1807 cm–1) and amide (Exp.
1662, Calc. 1751 cm–1) functionality of the compound. However, the whole FT−IR spectra
peaks of synthesized and experimentally recorded spectra of similar compounds [33–36]
and B3LYP/6-311G+(d,p) optimized of 1 show good consistency (cf. Table 5). As we
know, IR spectroscopy is as powerful and sensitive tool for recognition of HB formation
through stretching frequency changing of D–H···A (D: donor, A: acceptor) bond. The
main changes between optimized and crystal structures, as highlighted vide supra, are seen
for O–H, N–H, and C=O functional groups participating in formation of intra–molecular
HBs (for more clarity see Table 2). Significant blue shift of ʋ(O‒H) (Exp. 3296 and Calc.
3759 cm–1), ʋ(N‒H) (Exp. 3182 and Calc. 3615 cm–1), ʋ(C=O, amid) (Exp. 1662 and Calc.
1751 cm–1), and ʋ(C=O, acid) (Exp. 1695 and Calc. 1807 cm–1) between crystal and
optimized structures confirm the formation of the related HBs (see Tables 2, 3, and 5 and
Figs. 1 and 2).
3.2.2. NMR spectra
1
13
The H and C‒NMR spectra for the compound was recorded in DMSO utilizing as the
outside standard and the information are given in the experimental section. The numbering
of the compound is as indicated by that appeared in Scheme 1. The characteristic peak for
the OH bond in the spectrum of the compound at 12.11 ppm (Calc. 5.8 ppm) shows the
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presence of the carboxylic acid. The NH gives a singlet broad peak at 10.07 ppm (Calc.
6.43 ppm) which also shows the formation of the amide bond in the ligand. This
significance difference of experimental and theoretical chemical shifts of protons of
hydroxyl and amide groups reveals the formation of pertinent moderate HBs [6] (O–H···O
and N–H···O) in crystalline network that deshield their mentioned protons more than of
optimized structure (see section 3.4.). The aliphatic protons at positions 2 and 3 (–CH2–
CH2–) appear as triplets at 2.53ppm (3J = 7.5Hz) (Calc. 2.48 and 3.32 ppm) and 2.52 ppm
(3J = 9Hz) (Calc. 2.89 and 2.05 ppm), respectively. The protons at the aromatic ring gives
3
doublets at 7.32 ppm (H7, H7, J = 9Hz) (Calc. 7.33 and 7.5 ppm) and at 7.62 ppm (H6,
3
H6´, J = 8.7Hz) (Calc. 6.6 and 9.13 ppm) further confirm the structure containing p–
substituted phenyl ring. The higher chemical shift of H6´ comparison with H6 in optimized
structure relates to formation of C4–O3···H6´ non–conventional intra–molecular HB that
1
deshields H6´ more than H6. The H‒NMR data is given in Table 6 (Fig. 1S (see
supplementary materials.).
The most downfield singlet at 173 ppm (Calc. 179 ppm) due to carbonyls (C=O)
resonance for carboxylic acid at (C1) and for amide (C4) at 170 ppm (Calc. 172 ppm). The
signal due to aliphatic carbons (C2 and C3) appear at 30 ppm (Calc. 29.5 ppm) and 28 ppm
(Calc. 34.5 ppm) while for (C5) and (C8) signal appear at 128 ppm (Calc. 143.6 ppm) and
138 ppm (Calc. 142.5 ppm), respectively. The obtained results show that carbons
participating in HBs or bond to more electronegative elements of nitrogen and chlorine
became more deshielded. However the signals for phenyl carbons (C6, C6´) and C7, C7´)
appeared in their respective regions, i.e., at 126 ppm (Calc. 120 and 124 ppm) and 120 ppm
(Calc. 133 and 135 ppm). All these values are in agreement with each other confirm the
structure of the ligand. The 13C–NMR data of the ligand was in agreement with the
1H‒NMR and FT–IR data for the formation of ligand. The 13C‒NMR data is given in Table
7 (Fig. 2S (see supplementary materials.). It could be expected that the localization of
excess electrons on the acceptor group and deficiency of electrons of the donor group
cause to increasing the positive charge of proton because of deshilding and following
promotion of the related HB. Therefore, there are lesser electron density on oxygens of
carbonyl (–0.607, –0.625) (as acceptor involving in C3–H···O2 and C6´–H···O3 intra–
molecular HBs) than oxygen of hydroxyl (–0.692) (as donor). However, signals of 17O–
NMR of O2 (Calc. 414 ppm) and O3 (Calc. 419 ppm) as HB donor and O1 (Calc. 204
ppm) as HB acceptor confirm more deshielding of two first ones.
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3.2.3. Electronic spectrum
The experimental electronic spectrum of 1 includes one absorption band around 180–270
nm with a maximum at 250 nm (Fig. 4 (a)). However, the B3LYP/6‒311+G (d, p)
calculated UV spectrum shows six major peaks in that range at 261.5, 248.3, 204.2, 199.5,
190.7, and 189.2 nm (see Fig. 4 and Table 8). The maximum at 250 nm of the wide
experimental peak recorded at 180–270 nm band could assigned with the intense calculated
band at 248.3 nm. It can be concluded that the experimental and theoretical electronic
spectra of 1 are consistent with each other (cf. Fig.4 and Table 8). In order to study the
experimental UV spectrum and the electronic property of 1, we need to employ the
calculations of natural population analyses (NPA) of molecular orbital (MO) via
considering its optimized ground state geometry. The optimized structure has 59 occupied
MOs within singlet electron multiplicity. In followings, the constitution of FMOs that
involve in CT will be discussed that all of them are organized of s and/or p and/or d atomic
orbitals. The first and second mentioned calculated bands at 261.5 and 248.3 nm could
assigned to the CT from 59 (HOMO) to 61 (LUMO+1), and 60 (LUMO), respectively. The
59 (HOMO), 60 (LUMO), and 61 (LUMO+1) consist primarily π bonding electrons of
phenyl ring, empty atomic orbital of chlorine (comprising p 51.3% d 48.7%), and empty
atomic orbitals of carbons of phenyl ring (p 71.12% d 28.88%) with π* character. The third
calculated band at 204.2 nm is assigned to the transition from 58 (HOMO–1) to 60
(LUMO). The 58 (HOMO–1) consist primarily of π bonding electrons of phenyl ring.
According to Fig. 5 the first three electronic transitions (ET) (261.5, 248.3, and 204.2 nm)
belong to phenyl → chlorine/phenyl and assigned to π → π*. The fourth band of calculated
electronic spectrum at 199.5 nm is attributed to CT from 58 (HOMO–1) to 60 (LUMO)
and from 59 (HOMO) to 66 (LUMO+6). The 66 (LUMO+6) consist primarily of empty
atomic orbital of O1 of hydroxyl group (comprising s 4.42% p 87.8% d 7.8%). Therefore,
this ET belongs to amide → chlorine/hydroxyl and attributed to π → π* and π → n. The
fifth calculated band at 190.7 nm is related to the electronic transition from 57 (HOMO–2)
to 63 (LUMO+3). The 57 (HOMO–2) and 63 (LUMO+3) consist primarily of lone pair (s)
electrons of atomic orbital of O3 of amide (comprising s 58% p 42%) and empty atomic
orbital of chlorine (comprising s 19.39% p 87.78% d 7.8%). This electronic transition
belongs to amide → chlorine and assigned to n → π*. The last band of the calculated UV
spectrum at 189.2 nm is assigned to CT from 58 (HOMO–1) to 61 (LUMO+1). Therefore,
this ET belongs to amide → phenyl and attributed to n → π* (for all transitions see Fig. 5).
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3.2.4. EI-MS spectrometry
Electron impact ionization (EIMS) method was used to obtain the mass spectral data for
the compound. The data are given in the experimental section along with m/z and %
intensity. The resultant fragments are in good agreement with the expected structures of the
compounds. In the mass spectrum molecular ion peak presented in Fig. 3S (see
Supplementary materials) at m/z = 227.1 show the molecular mass of compound which is
in excellent agreement with formula mass of the ligand. The [M+2] peak shows the
presence of chlorine in the molecule, the base peak appear at m/z=127. The fragments are
observed at m/z(%): [C10H10ClNO3 ]+, 229, M+2 (29); [C10H10ClNO3 ]+, 227, M (80);
[C10H9ClNO2 ]+, 210, (4); [C9H9ClNO ]+, 182, (1.3); [C7H5ClNO ]+, 154, (3); [C6H6ClN ]+,
127, (100); [C6H4Cl ]+, 111, (3.3); [C4H5O3]+, 101, (18); [C6H6N ]+, 92, (8); [C3H5NO2 ]+,
73, (15); [C3H3O ]+, 55, (14); [CHO2 ]+, 45, (7) confirmed the formation of this compound.
3.3. TG–DTA analysis
The thermal analyses does not show any weight loss up to 160°C indicating the absence
of any coordinated or lattice water molecules in the ligand. Its thermal degradation
occurred in two steps endothermally. These two steps in the range of temperature 165–
200°C & 201-305°C showed the decomposition of 1. These two stages are in connection
with a weight loss of 99%. The calculated weight loss value in these two stages is 100%.
These results show good agreement with the theoretical values of total loss. The thermo
analytical data are summarized in Table 9 (Fig. 4S).
3.4. DFT study of the network constructed by non-covalent interactions
The non‒covalent bonds like HBs and stacking interactions hold the monomers together
that stabilize the finally formed crystalline network. Herein, the binding energy of
non−covalent interactions and stabilization energies of the constructed fragments and
network have been fully studied. For this purpose a successful method [14, 37] explained
below: First of all, the smallest independent part of CIF of 1 selected as monomer (1‒mon)
and then optimized at B3LYP/6‒311+G (d, p) method. In following, using DFT‒D
calculations the optimization of bigger fragments (1‒frag1 to 1‒frag4) and the pertinent
network (1‒net) determine the binding energies of the involving non‒covalent interactions
(see Figs. 1 and 2). In the optimized and crystalline network of 1, conventional and
non‒conventional HBs N−H···O and C−H···O, and unusual C−O···π stacking contacts
govern their formation. The optimized structure of 1‒mon, with structural changing related
to the experimental structure, stabilized as −48.95 kJ mol–1 through the intra‒molecular
10

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HBs C−H···O (C6’−H6’···O3 and C2−H2A···O3). Actually, because of the larger number
and more stranger of every HB than stacking one, the conventional HB govern the
formation of fragments and especially the network (see Table 2 and Figs. 1 and 2). For the
first equation (∆E1), one double set of N1−H1A···O3 (2.126Å) and C6’−H6A’···O3 (2.305Å)
stabilize the 1‒frag1 trimmer as –146.54 kJ mol–1. The second trimmer fragment, 1‒frag2,
stabilize through a double set of C7−H7···O1 (2.452Å) as ∆E1 = –40.22 kJ mol–1. For the
third and fourth equations (∆E3 and ∆E4), one double set of every O1−H1···O2 (1.787Å) and
C1−O2···π(phenyl) (3.598 Å) stabilize the 1−frag3 and 1−frag4 dimmers as –99.06 and –
32.60 kJ mol–1, respectively. Finally, the related network 1−net containing 7 monomers
stabilized via all the mentioned non−covalent interactions and the interplay effects of them.
There are a set of double N1−H1A···O3 (2.089Å), a bond of every C7−H7···O1 (2.427Å),
O1−H1···O2 (1.764Å), C7−H7···O1 (2.441Å), O1−H1···π(phenyl) (3.651 Å), O1−H1···π(phenyl)
(3.689Å), O1−H1···O2 (1.851Å), C1−O2···π(phenyl) (3.697Å), and C1−O2···π(phenyl) (3.610 Å)
that generally stabilize the network as ∆Etot = –277.59 kJ mol–1. They are a weak π···π
interactions between the oxygen atom (O2) of carbonyl group and the centroid of phenyl
ring that reflects a weak interaction of the delocalized charge density of N atoms of the
triazolo ring with the π cloud of the phenyl ring and vice versa (a strong interaction should
be identified with a separation distance below 3.03 Å) [38]. The calculated negative of
network formation energy (nfe) (Enfe = Enetwork ‒ nEmonomer) indicates that its constructed
structure stabilized via non−covalent interactions. It should be pointed out that interplay
effects of different D−A sites involving in HBs result in reinforcement or weakening of
them. Three kinds of interplay effects could be categorized. In type A, one atom
participates as Lewis acid and base in two HBs, simultaneously that resulting in
reinforcement of both of them. If one atom acts as a Lewis acid (donor) or a base (acceptor)
in two or three HBs simultaneously, all of them weak each other (types B and C, see
Scheme 2) [14, 25b, 37]. However, there are different interplay effects of involving
non−covalent interactions in the presented fragments and network of 1. In 1-frag1 there are
the diminutive effect between N1−H1A···O3 (2.103Å) and C6’−H6A’···O3 (2.219Å) bearing
O3 atoms that participates as an acceptor sites in both HBs, caused to bond length
increasing of first ones by 0.23 Å related to CIF value and 0.086 Å for the second ones
related to optimized structure of 1−mon and raising the related stabilized energy of 1−frag
around 1.70 kJ mol–1 (primary values in parenthesis. cf. Table 2 and Fig. 1). Also, in 1−net
because of the participating of O2 in the same acceptor sites, the weakening effect between
O1−H1···O2 (1.818Å) and C1−O2···π(phenyl) (3.625Å), and a cooperative effect between
11

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C7−H7···O1 (2.482Å) and O1−H1···π(phenyl) (3.724 Å) could be found (CIF values in
parenthesis. cf. Tables 2 and 3 and Fig. 2). These diminutive effects increse the bond
lengths of the mentioned interactions by 0.033 and 0.072 Å and the cooperative effects
deacrese them by 0.041 and 0.073 Å which generally results in raising of the network
formation energy by ~ 0.5 kJ mol–1. It can be pointed out that our calculated results of
binding energies of non-covalent interactions especially HBs are in good agreement with
other reported calculated results using QTAIM of Bader theory [39]. Accordance to
calculated binding energies of non−covalent interactions (Table 2) it can be highlighted
that the conventional and non−conventional N−H···O, O−H···O, and C−H···O HBs
govern the 1−net formation as they provide more than 79% of stabilization energy of the
network. Finally, this below stabilization order of the involving non−covalent interactions
can be concluded: O1−H1···O2 > N1−H1A···O3 > C7−H7···O1 > O1−H1···π(phenyl)
>
C1−O2···π(phenyl). It is attractive to say that our calculated results of binding energies of
non−covalent interactions and network stabilization energies show good accordance with
other theoretical and experimental measured data [14, 37, 40].
4. Conclusion
In this work, the synthesis of a novel amide based carboxylic acid derivative, N–[(4–
chlorophenyl)]–4–oxo–4–[oxy] butane amide reported and its geometric and electronic
1
13
structures characterized by FTIR, H, and C–NMR, Mass, and UV–Vis spectra, single
crystal X-ray diffraction, and DTA–TG analysis. However, the
DFT−B3LYP/6−311+G(d,p) optimized geometrical parameters, vibrational, and
spectroscopic results show good consistency with the experimental ones. The optimized
DFT–D−B3LYP/6−311+G(d,p) 1–net bearing 7 monomer units stabilized with HBs and
stacking contacts including the conventional O/N−H···O and non−conventional C−H···O
and O−H···π and C−O···π. The calculation results show that conventional HBs govern the
1–net formation somehow the below stabilization sequence of the van der Waals contacts
can be concluded: O−H···O > N−H···O > C−H···O > O−H···π(phenyl) > C−O···π(phenyl). UV
calculated spectrum through TD−DFT method along with NBO analyses propose that the
main electronic bands could attributed to the ET from phenyl to chlorine/hydroxyl/phenyl
functional groups possessing π → π* and π → n molecular orbital characters.
Supplementary materials
12

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1
13
X–ray crystallographic information file (CIF), experimentally recorded H–and C–NMR
and EI–MS spectra and TG–DTA curves of 1.
Acknowledgment. MCH gratefully acknowledges the financial support by the Hakim
Sabzevari University, Sabzevar, Iran. UY and MHB are thankful Allama Iqbal Open
University, Islamabad, Pakistan, for providing research facilities.
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Captions
Table 1. Crystal data collection and structure refinement details for 1.
Table 2. The calculated non‒covalent interactions distances (Ǻ), angles (º), and their binding
energies (kJ mol–1) of 1‒net.
Table 3. Selected experimental and calculated HBs for 1.
Table 4. Selected experimental and calculated atomic distances (Å) and angles (°) for 1‒mon.
Table 5. Vibrational frequencies with X‒ray structure, and B3LYP/6‒311+G(d, p) optimized
structures of 1.
Table 6. Experimental 1H–NMR data of 1.
Table 7. Experimental 13C–NMR data of 1.
Table 8. Calculated and experimental electronic data for 1.
Table 9. Thermal data of 1.
Scheme 1. The synthetic route for the synthesis of N–[(4–chlorophenyl)]–4–oxo–4–[oxy] butane
amide (1).
Scheme 2. Spatial arrangement of interacting fragments in assisting (Type A) and debilitating
(Type B and C) HBs. D and A denote donor and acceptor sites [25b, 41].
Figure 1. ORTEP diagram of the 1 drawn at 50 % probability level. The H‒atoms are drawn as
small circles of arbitrary radii and B3LYP/6‒311+G(d, p) Optimized structures of monomer
(1‒mon) and fragments of 1; the equations used to evaluate the different non‒covalent interactions
in compound (distances are given in Å).
Figure 2. Formation energy of 1‒net from 1‒mon (distances are given in Å). The calculated
stabilization energy is only relative to expansion of molecular compound to its network.
Figure 3. Experimental FTIR (cm–1) spectrum for 1.
Figure 4. Experimental electronic spectra in methanol (a) and calculated–B3LYP/6‒311+G(d, p)
one (b) for 1.
Figure 5. Frontier molecular diagrams for 1 involving in CT obtained according to the
B3LYP/6‒311G+ (d, p).
17

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Table 1.
Compound
Empirical formula
1
C10 H10 Cl N O3
Formula weight
Temperature
Crystal system
Wavelength (Å)
Space group
Unit cell dimension
a (Å)
227.64
296(2)
Monoclinic
0.71073
P21/n (No. 14)
10.9284(7)
10.9284(7)
18.9707(14)
90
b (Å)
c (Å)
α (o)
β (o)
97.280(3)
90
γ (o)
V(Å3)
1041.42(12)
4
Z
Crystal size (mm)
θ Range for data collection (o)
D calc (Mg/m3)
Absorption coefficient(mm-1)
F(000)
0.42 x 0.22 x 0.20
3.541 to 27.488
1.452
0.352
472
Reflections collected
S (goodness of fit) on F2
Independent reflections
2386
1.028
1718
18

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Table 2.
d(H···A)
1.764
< (DHA)
169.65
Binding Energy
−50.08
O1−H1···O2
O1−H1···O2
1.851
172.36
−44.61
N1−H1A···O3
C7−H7···O1
2.089
2.427
2.441
3.651
3.610
3.689
3.697
167.70
160.29
161.14
107.37
94.68
−42.17
−20.73
−20.39
−15.16
−14.82
−14.26
−13.20
C7−H7···O1
O1−H1···π(phenyl)
C1−O2···π(phenyl)
O1−H1···π(phenyl)
C1−O2···π(phenyl)
108.95
95.09
Interaction Types
Stabilization Energy
'
'
2 × (N1−H1A···O3 (2.126 Å*), C6 −H6 ···O3 (2.305 Å*))
∆E1 –146.54
∆E2 –40.22
∆E3 –99.06
∆E4 –32.60
2 × (C7−H7···O1 (2.452 Å))
2 × (O1−H1···O2 (1.787 Å))
2 × (C1−O2···π(phenyl) (3.598 Å))
2 × (N1−H1A···O3 (2.089 Å)) + C7−H7···O1 (2.427 Å), O1−H1···O2
(1.764 Å) + C7−H7···O1 (2.441 Å), O1−H1··· π(phenyl) (3.651 Å) +
O1−H1··· π(phenyl) (3.689 Å) + O1−H1···O2 (1.851 Å*), C1−O2···π(phenyl)
(3.697 Å*) + C1−O2···π(phenyl) (3.610 Å)
∆Etot –277.59
*The weakened interactions by diminutive effects shown as italic form.
* The reinforced interactions by cooperative effects shown as underline format.
19

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Table 3.
D−H···A
d(D−H)
d(H···A)
d(D···A)
<(DHA)
O1−H1···O2
0.820(e), 0.833(c) 1.818(e), 1.764(c) 2.625(e), 2.589(c)
168.3(e), 172.1(c)
N1−H1A···O3
C7−H7···O1
0.860(e), 851(c)
2.103(e), 2.089(c) 2.946(e), 2.874(c) 166.6(e), 169.0(c)
2.482(e), 2.427(c) 3.365(e), 3.312(c) 158.6(e), 162.5(c)
0.930(e), 0.917(c)
Symmetry codes: 1+x,y,z , 1/2−x,1/2+y,1/2−z, −1+x, −1+y,z , −1−x,1−y, −z, x,2−y, −z
e: experimental, c: calculated
20

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Table 4.
Compound 1: C10H10NO3Cl
Experimental Calculated
Experimental
1.512(3)
Calculated
1.527
Experimental Calculated
O1–C1
O2–C1
O3–C4
N1–C4
N1–C5
Cl1–C8
C1–C2
C2–C3
O1–H1
1.275(2)
1.241(3)
1.220(2)
1.349(2)
1.413(2)
1.743(2)
1.492(3)
1.503(3)
0.820
1.355
1.206
1.218
1.376
1.412
1.759
1.509
1.525
0.969
C3–C4
C6–C7
C6–C7–C8
N1–C5–C10
119.32
121.58
117.00
114.57(14)
176.52
−4.77
119.24
123.48
114.94
113.72
–175.70
2.63
1.383(3)
126.46(15)
109.00
1.389
C4–N1–C5
C1–O1–H1
O1–C1–C2
O2–C1–C2
O1–C1–O2
C4–N1–H1A
H3A–C3–H3B
129.21
107.30
111.34
126.17
122.48
115.82
106.13
C5–N1–H1A
N1–C4–C3
115.38(17)
120.89(17)
123.69(17)
117.00
C5–N1–C4–C3
C5–N1–C4–O3
C2–C3–C4–O3
C3–C2–C1–O1
C4–N1–C5–C10
8.34
27.38
–167.34
−35.58
–172.14
–1.23
107.81
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Table 5.
Assignments
Calc. for 1
Exp. for 1
Exp. for others
[33-36]
(B3LYP/6‒311+G(d,
p))
C–O–H bend.
(out of plane)
653 s
‒
–
C–NH2 bend.
(out of plane)
723 vw
–
758
CH3 bend. (in plane)
C–C Al. str.
1035 m
1079 m
1103 s
–
–
1014
1090–1053
1089–1096
–
C–Cl Ar (P–substituted)
821
–
C–O–H bend.
(in plane)
1146 vs
C–N str. (N–ph)
CH2 wagging
CH2 scissoring
C=N str.
1261 m
1369–1427 m-s
1463, 1472 m-s
1547 vs
–
–
1266
1428, 1452
–
–
–
–
C=C & C–N str. (N–ph)
C=O str. (amide)
C=O str. (acid)
C–H Al. str.
1627, 1636 m
1751 vs
–
1500–1600
1694
1662
1695
2360
1807 vs
1730–1760
2910–2982
3038–3092 w-m
C–H Ar str.
N–H str. (amide)
O–H str.
3615 m
3759 s
3182
3296
3574
3440–3630
The abbreviations are, Al: aliphatic, Ar: aromatic, str: stretching, bend: bending, ph: phenyl, s: strong, m:
medium, w: weak, and vw: very weak.
22

ACCEPTED MANUSCRIPT
Table 6.
Chemical shift (ppm)
Multiplicity
Integration
Proton Assignment
CH2 [H2]
CH2 [H3]
Ar-H[H7,7´]
Ar-H[H6,6´]
NH
2.52
2.53
7.32
7.62
10.11
12.11
t, 3J[1H,1H] = 9 Hz
2H
2H
2H
2H
1H
1H
t, 3J[1H,1H] = 7.5 Hz
d, 3J[1H,1H] = 9 Hz
d, 3J[1H,1H] = 8.7 Hz
s
s
OH
t = triplet, d = doublet, s = singlet
Table 7.
Chemical shift (ppm)
Carbon assignment
173
170
120
126
30
C1
C4
C7,C7´
C6,C6´
C2
28
C3
128
138
C5
C8
23

ACCEPTED MANUSCRIPT
Table 8.
Exp.
Wave length(nm)
of 1
Calc. of 1 (NPA & TD-DFT)
Wave
Length(nm)
Oscillator
strength
Assignment
180-270
180-270
180-270
180-270
261.5
0.017
0.503
0.056
0.152
59 (HOMO) → 61 (LUMO+1)
59 (HOMO) → 60 (LUMO)
58 (HOMO‒1) → 60 (LUMO)
248.3
204.2
199.5
58 (HOMO‒1) → 60 (LUMO)
59 (HOMO) → 66 (LUMO+6)
180-270
190.7
189.2
0.110
0.297
57 (HOMO‒2) → 63 (LUMO+3)
58 (HOMO‒1) → 61 (LUMO+1)
180-270
.
24

ACCEPTED MANUSCRIPT
Table 9.
Thermogravimetry(TG)
Number
Temp.
Tmax. (oC)
150-380
Compound
Mass Loss (%) Mass Loss (%)
of Stages range (oC)
Observed
calculated
165-200
181 (+)
260 (+)
9.8
N-[(4-
chlorophenyl)]-
4-oxo-4-[oxy]
butanamide
2
201-305
89.4
> 99
100
25

ACCEPTED MANUSCRIPT
Scheme 1: Synthesis of 4-[(4-chlorophenyl)amino]-4-oxobutanoic acid
H
O
O
O
+
C
N
H
C
CH2
CH2
Ethyl acetate
O
-
O
Cl
NH2
+
R.T, stirring
Cl
O
O
Numbering scheme for NMR interpretation
O
H
N
6
H
3
OH
N
4
5
7
1
OH
2
O
Cl
O
6'
8
Cl
4-[(4-chlorophenyl)amino]-4-oxobutanoic acid
7'
Scheme 1.
A
D
D
A
H
H
H
H
D
H
A
D
H
A
D
H
A/D
A
H
D
H
D
Type C
Type A
Type B
Scheme 2.
26

ACCEPTED MANUSCRIPT
∆E1 = ‒146.54 kJ mol−1
× 3
1-frag1
∆E2 = ‒40.22 kJ mol−1
3 ×
1-mon
Figure 1.
1-frag2
27

ACCEPTED MANUSCRIPT
∆E4 = ‒32.60 kJ mol−1
× 2
2 ×
∆E3 = ‒99.06 kJ mol−1
1-frag4
1-frag3
Figure1. Continued.
28