A facile microwave assisted synthesis and structure elucidation of (3R)-3-alkyl-4,1-benzoxazepine-2,5-diones by crystallographic, spectroscopic and DFT studies

Article abstract of DOI:10.1016/j.saa.2019.117995

The use of microwave (MW) irradiation in organic synthesis has become increasingly popular within the pharmaceutical and academic arenas because it is a new enabling technology for drug discovery and development. It is a rapid way of synthesis, which involves faster reaction rates and high selectivity to conventional heating method of syntheses. The MW-assisted 7-exo-tet cyclization of N-acylanthranilic acids afforded (3R)-3-alkyl-4,1-benzoxazepines-2,5-diones in very short duration (20 min) with extraordinary high yields in comparison to conventional heating mode of synthesis. The method development, comparative yields of MW-assisted and thermal method of syntheses, crystallographic, spectroscopic and density functional theory (DFT) studies are reported herein. Four novel compounds with chemical formulas C₁₀H₉BrClNO₃ 5m, C₁₉H₁₉NO₃ 6e, C₁₃H₁₄ClNO₃ 6h and C₁₂H₁₁Br₂NO₃ 6h were synthesized, validated by ¹HNMR, ¹³CNMR, FT-IR, UVVis, EIMS spectroscopic techniques and confirmed by using single crystal X-ray diffraction (SC-XRD) study. The DFT and TDDFT calculations at B3LYP/6-311 + G(d,p) level of theory were performed for comparative analysis of spectroscopic data, optimized geometries, frontier molecular orbitals (FMOs), natural bond orbital (NBO) analysis and nonlinear optical (NLO) properties of 5m, 6e, 6h and 6o. Overall, experimental findings were supported nicely by corresponding DFT computed results. The NBO analysis confirmed that the presence of non-covalent interactions, hydrogen bonding and hyper- conjugative interactions are pivotal cause for the existence of 5m, 6e, 6h and 6o in the solid-state. NLO analysis showed that 5m, 6e, 6h and 6o have significant NLO properties as compared to prototype standard compound which disclosed their potential for technology related applications.

Full text of DOI:10.1016/j.saa.2019.117995

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A facile microwave assisted synthesis and structure elucidation of
(3R)-3-alkyl-4,1-benzoxazepine-2,5-diones by crystallographic,
spectroscopic and DFT studies
Abdul Rauf Raza, Bushra Nisar, Muhammad Khalid, Humaira
Yasmeen Gondal, Muhammad Usman Khan, Sara Figueirêdo de
Alcântara Morais, Muhammad Nawaz Tahir, Ataualpa Albert
Carmo Braga
PII:
S1386-1425(19)31394-0
https://doi.org/10.1016/j.saa.2019.117995
SAA 117995
DOI:
Reference:
Spectrochimica Acta Part A: Molecular and Biomolecular
Spectroscopy
To appear in:
Received date: 4 September 2019
Revised date:
21 December 2019
25 December 2019
Accepted
date:
Please cite this article as: A.R. Raza, B. Nisar, M. Khalid, et al., A facile microwave
assisted synthesis and structure elucidation of (3R)-3-alkyl-4,1-benzoxazepine-2,5-diones
by crystallographic, spectroscopic and DFT studies, Spectrochimica Acta Part A:
Molecular
and
Biomolecular
Spectroscopy(2018),
https://doi.org/10.1016/
j.saa.2019.117995
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A Facile microwave assisted synthesis and structure elucidation of (3R)-3-
alkyl-4,1-benzoxazepine-2,5-diones by crystallographic, spectroscopic and
DFT studies
Abdul Rauf Raza,1* Bushra Nisar,2 Muhammad Khalid,3* Humaira Yasmeen Gondal,1
Muhammad Usman Khan,4 Sara Figueirêdo de Alcântara Morais,5 Muhammad Nawaz
Tahir,6 Ataualpa Albert Carmo Braga,5
1Ibn-e-Sina Block, Department of Chemistry, University of Sargodha, Sargodha-40100, Pakistan
2Department of Chemistry, The University of Lahore, Sargodha Campus, Sargodha-40100,
Pakistan
3Department of Chemistry, Khwaja Fareed University of Engineering & Information
Technology, Rahim Yar Khan-64200, Pakistan
4Department of Applied Chemistry, Government College University, Faisalabad,38000, Pakistan
5Departamento de Química, Fundamental, Instituto de Química, Universidade de São Paulo,
Avenida Professor LineuPrestes, 748, São Paulo 05508-000, Brazil
6Ibn-ul-Hathim Block, Department of Physics, University of Sargodha, Sargodha-40100,
Pakistan
Corresponding author1* E-mail address: rauf.raza@uos.edu.pk
Corresponding author3* E-mail address: Khalid@iq.usp.br ; muhammad.khalid@kfueit.edu.pk
Abstract
The use of microwave (MW) irradiation in organic synthesis has become increasingly popular
within the pharmaceutical and academic arenas because it is a new enabling technology for drug
discovery and development. It is a rapid way of synthesis, which involves faster reaction rates
and high selectivity to conventional heating method of syntheses. The MW-assisted 7-exo-tet
cyclization of N-acylanthranilic acids afforded (3R)-3-alkyl-4,1-benzoxazepines-2,5-diones in
very short duration (20 min) with extraordinary high yields in comparison to conventional
heating mode of synthesis. The method development, comparative yields of MW-assisted and
thermal method of syntheses, crystallographic, spectroscopic and density functional theory
(DFT) studies are reported herein. Four novel compounds with chemical formulas
C10H9BrClNO3 5m, C19H19NO3 6e, C13H14ClNO3 6h and C12H11Br2NO3 6h were synthesized,
1
validated by H-NMR, 13C-NMR, FT-IR, UV-Vis, EIMS spectroscopic techniques and
confirmed by using single crystal X-ray diffraction (SC-XRD) study. The DFT and TDDFT
calculations at B3LYP/6-311+G(d,p) level of theory were performed for comparative analysis of

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spectroscopic data, optimized geometries, frontier molecular orbitals (FMOs), natural bond
orbital (NBO) analysis and nonlinear optical (NLO) properties of 5m, 6e, 6h and 6o. Overall,
experimental findings were supported nicely by corresponding DFT computed results. The NBO
analysis confirmed that the presence of non-covalent interactions, hydrogen bonding and hyper-
conjugative interactions are pivotal cause for the existence of 5m, 6e, 6h and 6o in the solid-
state. NLO analysis showed that 5m, 6e, 6h and 6o have significant NLO properties as compared
to prototype standard compound which disclosed their potential for technology related
applications.
Keywords: (3R)-3-alkyl-4,1-benzoxazepine-2,5-diones; Microwave irradiation; N-acylanthranilic
acids; Chiral pool approach; Spectroscopic data; DFT
Introduction
The microwave assisted synthesis offers high reaction rates in shorter time in comparison to
conventional heating. The microwave irradiation (MWI) comprises a reduced amount of heating
in less time; whereas, greater time and high temperature is required in conventional heating
method. For attaining high temperature in conventional heating system an oil bath is used which
transfer heat in the system in extended time. The MW passes through the sample and transfer
heat to the substrate directly (involving transitions in rotational energy levels) instead of heating
whole reaction vessel, thus speeding up a chemical reaction to obtain required results in shorter
time interval. The MW speeds up a chemical reaction by transferring heat to the substrate
directly (involving transitions in rotational energy levels)rather than heating entire reaction pot in
order to obtain desired results in less time thus offering high reaction rates with low utilization of
energy. In comparison to conventional heating reaction, MW assisted synthesis offers high
reaction rates with energy-conservation while main drawback of conventional heating is the
utilization of high heat energy [1, 2]. The benzoxazepines, a flexible heterocycle, offers a wide
range of biological activities [3-6]. Due to diversity in activities benzoxazepines attained
admirable importance in medicinal chemistry and drug industry; therefore, their synthesis have
been of great interest. Mostly reported syntheses, involves conventional heating methods to yield
racemic 4,1-benzoxazpine. No MW studies has been reported for the synthesis of 4,1-
benzoxazepines.

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The synthesis of 1,4-benzoxazepine-3,5-dione reported in literature involves the condensation of
2-bromoethyl-4-oxo-1,3-benzoxaziniumperchlorate with PhCHO followed by treatment with
NaOEt solution and intramolecular cyclization [7]. In another report, condensation of the 2-
aminophenol with substituted malonyl dichloride afforded 1,5-benzoxazepine-2,4-diones [8].
Single step synthesis of 4,1-benzoxazepine have also been reported by the reaction of N-tosyl-
1,3-amino- alcohols with bromoethylsulfonium salts followed by intramolecular cyclization [9].
The asymmetric synthesis is gaining popularity in pharmaceutical industry because medicines used
nowadays are racemic modifications of two or more enantiomers. Both enantiomers may have
different activities and side effects of medicines may be associated with vestigial isomer [10]. To
avoid such side-effects asymmetric synthesis (synthesis leading towards pure enantiomer) is the
desperate need. High cost of enantiopure / chiral drugs makes them unaffordable/ inaccessible
for a community. This factor may be eliminated using inexpensive commercially available
starting materials; especially natural products. To synthesize a pure enantiomer, chiral pool
methodology (or chiron approach) is an economic method. Our current work not only involved
MW assisted synthesis but also involves asymmetric synthesis adopting chiral pool strategy. Our
group have reported asymmetric synthesis of (3R)-4,1-benzoxazepine-2,5-diones by conventional
heating method (3 h heating at 80 °C) in high ee [11, 12]. Similar result can be obtained in
excellent yield to afford (3R)-3-alkyl-4,1-benzoxazepine-2,5-diones via MW assisted synthesis (20
min at 100°C).
Herein, we report the synthesis of four novel (3R)-3-alkyl-4,1-benzoxazepine-2,5-diones namely;
(2′S)-2-(2′-chloropropanamido)-5-bromobenzoic acid (5m), (3R)-3-iso-butyl-4,1-benzoxa-
zepines-3,5-dione (6e), (3R)-7-chloro-9-methyl-3-iso-propyl-4,1-benzoxazepines-3,5-dione (6h)
and (3R)-7,9-dibromo-3-iso-propyl-4,1-benzoxazepines-3,5-dione (6o). The synthesized
1
compounds (5m, 6e, 6h and 6o) are validated by H-NMR, 13C-NMR, FT-IR, UV-Vis
spectroscopic, EIMS spectrometric techniques and finally confirmed by using single crystal X-
ray diffraction (SC-XRD) study. Furthermore, utilizing our synthetic as well as computational
study background [13-22], we have performed the computational calculations with density
functional theory (DFT) to countercheck the spectroscopic and structural characteristics of 5m,
6e, 6h and 6o. The DFT based computations are performed to estimate frontier molecular orbital
(FMO), natural bond orbital (NBO), global reactivity parameters and NLO properties with

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respect to 5m, 6e, 6h and 6o. The ultimate goal of this study involves a precise and thorough
account of experimental and theoretical data for clear understanding of structural and
spectroscopic aspects of investigated compounds (5m, 6e, 6h and 6o).
Materials and methods
All chemicals and reagents of analytical grade were purchased from Merck, Sigma-Aldrich, or
Fluka. The pre-coated silica gel (0.25 mm thick layer over Al sheet, Merck) TLC was used to
monitor the reaction. The IR and UV/Vis spectra were recorded on Shimadzu (Prestige 21) FT-
IR spectrometer as KBr discs and Thermo Spectronic (UV-1700) spectrophotometer in
1
CHCl3/MeOH. The H-NMR and 13C-NMR were recorded in CDCl3 on a Bruker AVANCE
DPX300/500 (300 or 500 MHz) spectrometer using Me4Si as internal standard. The EIMS was
recorded at 70 eV on Fisons Instrument VG Autospec Mass Spectrometer available at HEJ
Research Institute of Chemistry (HEJRIC), University of Karachi, Karachi. The single crystal X-
Ray data were recorded on Bruker Kappa APEX 11 CCD diffractometer at Department of
Physics, University of Sargodha (Pakistan).
Computational procedure
The overall quantum chemical calculations for investigated compounds (5m, 6e, 6h and 6o) were
accomplished with the help of DFT [23-25] employing Gaussian 09 program package [26]. The
XRD driven crystal structures were used for elucidating the initial geometry of 5m, 6e, 6h and
6o. Complete geometrical optimization was done without symmetry restrictions by applying
B3LYP level of DFT and 6-311+G(d,p) basis set combination. The frequency analysis based on
DFT/B3LYP/6-311+G(d,p) level of theory was used for confirmation of stability associated with
the optimized geometries. The absence of negative eigen values among all calculated frequencies
reflected that optimized geometries of 5m, 6e, 6h and 6o correspond to true minimum at
potential energy surfaces. The FMO and NLO analysis was conducted at B3LYP level of DFT
and 6-311+G(d,p) basis set conjunction. The NBO analysis was carried out at B3LYP/6-
311+G(d,p) level of theory using NBO 3.1 program package [27]. The UV-Vis analysis was
performed employing time dependent density functional theory (TDDFT) calculations at
B3LYP/6-311+G(d,p) level of theory for estimation of photophysical characteristics of 5m, 6e,

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6h and 6o. The input files were organized with the help of Gaussview 5.0 [28]. The Gaussview
5.0, Avogadro [29] and Chemcraft [30] programs were employed for interpreting output files.
Experimental
Synthesis of (2S)-2-chlorocarboxylic acids (2a-d)
The (2S)-2-chlorocarboxylic acids (2a-d) were prepared from commercially available
inexpensive natural (2S)-aminoacids1a-d (alanine, phenylalanine, valine and leucine) by
following Koppenhoefer’s procedure (involving diazotization sequence) [11, 31].
Synthesis of (2S)-2-chlorocarboxylic acid chlorides (3a-d)
The (2S)-2-chlorocarboxylic acid chlorides 3a-d were prepared by heating (2S)-2-
chlorocarboxylic acids 2a-d (3.7 mmol, 1 eq) in SOCl2 (4.1 mmol, 1.1 eq) with two drops of
DMF at 80 ºC for 1 h. The reaction demands anhydrous conditions for better results. The
resulting (2S)-2-chlorocarboxylic acid chlorides (3a-d) were used as such without any
purification.
Synthesis of N-acyl anthranilic acids (5a-p)
The (2S)-2-chlorocarboxylic acid chloride 3a-d (0.51 mmol, 1.1 eq) was added to a flask
containing anthranilic acid 4 (0.46 mmol, 1 eq) in dry DMF (10 mL) and Et3N (3.7 mmol, 4 eq).
The addition was completed below 0 ºC using ice bath and the resulting solution was stirred
overnight at room temperature. The chilled H2O was added, partitioned with EtOAc (3×15 mL),
combined organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure to afford brown oil, which was column chromatographed over silica gel
to afford N-acyl anthranilic acids 5a-p as colourless crystalline solid upon elusion with 1-5%
EtOAc in n-hexane.
(2′S)-N-acyl anthranilic acids 5a-j [11]
(2′S)-2-(2′-Chloro-4′-methylpentanamido)-4-chlorobenzoic acid 5k: Rf: 0.25 (EtOAc/n-hexane
3:7); mp: 126 ºC; ύ (cm-1): 1678 (OC=O), 1593 (NC=O), 687 (C‒Cl); λmax(log ϵ): 307 nm
(3.4792 L.cm-1.M-1); δH(300 MHz, CDCl3) in ppm: 0.96, 0.98 (3H each, d, J = 6.6 Hz, H5′& CH3
at C4′), 1.85‒1.98 (3H, m, H3′& H4′), 4.52 (1H, dd, J = 9.6, 4.8 Hz, H2′), 7.18 (1H, dd, J = 8.4, 1.8

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Hz, H5), 8.07 (1H, d, J = 8.4, H6), 8.69 (1H, d, J = 1.8. Hz, H3); δC (75 MHz, CDCl3) in ppm:
21.5, 23.0 (q, both C5′& CH3 at C4′), 26.5 (d, C4′), 45.4 (t, C3′), 60.4 (d, C2′), 116.4 (s, C1), 120.9
(d, C5), 124.5 (d, C3), 134.0 (d, C6), 141.1 & 142.8 (s, C2& C4), 170.3 and 170.4 (s, both C=O);
m/z in amu (% abundance): 307, 305, 303 (1:6:9) [M]+∙, 251, 249, 247 (1, 6, 9) [M ‒ C4H8]+∙,
182, 180 (1:3) [M ‒ ˙C5H10Cl ‒ H2O]+∙, 172, 170 (1:3) [M ‒ ˙C5H10Cl ‒ CO]+∙, 154, 152 (1:3) [M
‒ H2O ‒ CO ‒ ˙C5H10Cl]+∙.
(2′S)-2-(2′-chloro-4′-methylpentanamido)-5-bromobenzoic acid 5n: Rf: 0.27 (EtOAc/n-hexane
3:7); mp: 117 ºC; ύ (cm-1): 3259 (O‒H bs), 3044 (N‒H), 1685 (OC=O), 1531 (NC=O), 713 (C‒
Cl), 559 (C‒Br); λmax(log ϵ): 317 nm (3.4789 L.cm-1.M-1); δH(500 MHz, CDCl3) in ppm: 0.96,
0.98 (3H each, d, J = 6.5 Hz, H5′& CH3 at C4′), 1.84‒1.97 (3H, m, H3′& H4′), 4.51 (1H, dd, J =
8.4, 6.9 Hz, H2′), 7.69 (1H, d, J = 9.0, 2.5 Hz, H4), 8.17 (1H, dd, J = 2.5 Hz, H6), 8.53 (1H, d, J =
9.0 Hz, H3); δC(125 MHz, CDCl3) in ppm: 21.6, 23.1 (q, both C5′& CH3 at C4′), 25.5 (d, C4′), 45.5
(t, C3′), 60.5 (d, C2′), 116.7 (s, C1), 120.3 (s, C5), 123.2 (d, C3), 135.7 (d, C4), 137.8 (d, C6), 140.9
(s, C2), 169.8 and 170.3 (s, both C=O); m/z in amu (% abundance): 351, 349, 347 (1:9:6) [M]+∙,
305, 303, 301 (1:9:6) [M ‒ H2O ‒ CO]+∙, 244, 242 (1:1) [M ‒ ˙C5H10Cl]+∙, 295,293,291 (1:9:6)
[M ‒ C4H8]+∙, 216, 214 (1:1) [M ‒ ˙C5H10Cl ‒ CO]+∙.
(2′S)-2-(2′-chloro-4′-methylpentanamido)-3,5-dibromobenzoic acid 5p: Rf: 0.3 (EtOAc/ n-hexane
3:7); ύ (cm-1): 1689 (OC=O), 1573 (NC=O), 719 (C‒Cl); λmax(log ϵ): 301 nm (3.4065 L.cm-1.M-
1); δH(300 MHz, CDCl3) in ppm: 0.95, 0.99 (3H each, d, J = 6.3 Hz, H5′& CH3 at C4′), 1.84‒1.90
(3H, m, H3′& H4′), 4.34 (1H, dd, J = 9.0, 3.0 Hz, H2′), 8.03 (bs, N‒H), 8.20 (1H, d, J = 1.3 Hz,
H4), 8.38 (1H, d, J = 1.3 Hz, H6); δC(75 MHz, CDCl3) in ppm: 21.3, 22.6 (q, both C5′& CH3 at
C4′), 25.2 (d, C4′), 43.4 (t, C3′), 55.0 (d, C2′), 121.0 (s, C1), 129.5, 130.0 (s, C3& C5), 136.1 (d, C4),
141.0 (d, C6), 147.3 (s, C2), 168.8 and 170.3 (s, both C=O).
Synthesis of 4,1-benzoxazepines 6a-p
A mixture of N-acyl anthranilic acid 5 (1 mmol, 1 eq) and anhydrous K2CO3 (1.5 mmol, 1.5 eq)
in DMF (1 mL) was heated under microwave radiations at 100 °C for 20 min. The chilled H2O
was added in excess. The reaction mixture was neutralized with dilute HCl (5 mL) and extracted
with EtOAc (2×15 mL). The combined organic extract was dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure to afford the crude product. It was purified by

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either column chromatography over silica gel or crystallization from EtOAc / n-hexane to yield
4,1-benzoxazepines (6a-p) in excellent yield (74-100%).
(3R)-3-Alkyl-4,1-benzoxazepine-2,5-diones 6a-j [11]
(3R)-7-Bromo-3-iso-butyl-4,1-benzoxazepines-3,5-dione 6n: Rf: 0.70 (EtOAc/n-hexane 3:7); mp:
183.3 ºC; ύ (cm-1):1734 (OC=O), 1674 (NC=O), 547.78 (C‒Br); λmax (log ϵ) 256.0 nm (3.5956
L.cm-1.M-1); δH (500 MHz, CDCl3) in ppm: 0.99, 1.02 (3H each, d, J = 6.3 Hz, H3′ and CH3 at
C2′), 1.66 (1H, m, H2′), 1.97 (1H, ddd, J = -13.4, 6.2, 1.5 Hz, H1′α), 2.17 (1H, ddd, J = -13.1, 6.1,
1.8 Hz, H1′β), 4.47 (1H, m, H3), 7.70 (1H, dd, J = 9.0, 2.5 Hz, H8), 8.04 (1H, s, N‒H), 8.28 (1H,
d, J = 2.5 Hz, H6), 8.66 (1H, d, J = 9.0 Hz, H9); δC (125 MHz, CDCl3) in ppm: 21.3, 25.2 (q, both
C3′& CH3 at C2′), 28.0 (d, C2′), 46.1 (t, C1′), 59.9 (d, C3), 115.9 (s, C5a), 117.2 (s, C7), 122.1 (d,
C8), 134.3 (d, C9), 137.8 (s, C9a), 140.0 (d, C6), 168.9 and 170.4 (s, C2& C5).
(3R)-7,9-Dibromo-3-iso-propyl-4,1-benzoxazepine-2,5-dione 6o: Rf: 0.75 (EtOAc /n-hexane
3:7); mp: 179 ºC; ύ (cm-1): 1708 (OC=O), 1579 (NC=O), 549 (C‒Br); λmax (log ϵ): 249.0 nm
(3.4643 L.cm-1.M-1); δH (500 MHz, CDCl3) in ppm: 0.91, 0.99 (3H each, d, J = 6.9 Hz, both CH3
showing extended diastereotopy), 2.05 (2H, m, H1′), 4.51 (1H, m, H3), 8.01 (1H, bs, N‒H), 8.11
(1H, d, J = 2.4 Hz, H6), 8.30 (1H, d, J = 2.5 Hz, H8); δC (125 MHz, CDCl3) in ppm: 22.0, 24.9 (q,
both CH3), 29.7 (d, C2′), 58.5 (d, C3), 116.4 (s, C5a), 127.8 (d, C8), 131.3 (s, C7), 133.0 (s, C9),
137.7 (s, C9a), 139.4 (d, C6), 169.5 and 170.8 (s, C2& C5).
(3R)-7,9-Dibromo-3-iso-butyl-4,1-benzoxazepine-2,5-dione 6p: Rf: 0.66 (EtOAc /n-hexane 3:7);
mp: 176.4 ºC; ύ (cm-1): 1711 (OC=O), 1632 (NC=O), 551 (C‒Br); λmax (log ϵ): 234.0 nm (3.2569
L.cm-1.M-1); δH (500 MHz, CDCl3) in ppm: 0.89, 1.00 (3H each, d, J = 6.9 Hz, H3′ and CH3 at
C2′), 1.57 (1H, m, H2′), 2.08 (2H, m, H1′), 4.54 (1H, m, H3), 7.99 (1H, bs, N‒H), 8.07 (1H, d, J =
2.6 Hz, H6), 8.26 (1H, d, J = 2.6 Hz, H8); δC (125 MHz, CDCl3) in ppm: 22.5, 24.4 (q, both C3′&
CH3 at C2′), 30.0 (d, C2′), 44.1 (t, C1′), 57.7 (d, C3), 116.1 (s, C5a), 129.1 (d, C8), 130.9 (s, C7),
133.3 (s, C9), 138.2 (s, C9a), 139.0 (d, C6), 169.9 and 171.1 (s, C2& C5).

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Results and discussion
Keeping the importance of chiron approach and MW assisted organic synthesis in view, the
present work is concerned with MW assisted asymmetric (Chiron based) synthesis of 4,1-
benzoxazepines. For this purpose (‒)-(S)-2-chlorocarboxylic acids 2a-d were prepared in high ee
(95%–98%) via diazotization of naturally occurring (+)-(S)-amino acids 1a-d (alanine,
phenylalanine, valine and leucine) [31]. These (‒)-(S)-2-chlorocarboxylic acids 2a-d were
converted to (S)-2-chlorocarboxylic acid chlorides 3a-d and coupled with substituted anthranilic
acids 4 to afford (2′S)-N-acylanthranilic acids 5a-p. Conventionally, the base mediated 7-exo tet
cyclization of (2′S)-N-acylanthranilic acids 5a-p takes longer duration (3 h) to afford (3R)-3-
alkyl-4,1-benzoxazepine-2,5-diones 6a-p. Whereas, MW assisted synthesis of (2′S)-N-
acylanthranilic acids 5a-p affords (3R)-3-alkyl-4,1-benzoxazepine-2,5-diones 6a-p in shorter
interval with excellent yield (Scheme 1, Table 1).
O
V
COOH
O
X
Y
X
Y
c
OH
W
W
R1
R1
2`
NH
R2
N
O
Z
Z
Cl
R2
V
5
4
1 NH2 OH
2 Cl OH
3 Cl Cl
a
d
b
O
5
X
O
5 / 6 R1 = Me, Bn, iPr, iBu
R2 = H, Ph
6
R1
3
9
1
N
Y
X, Y, Z = H, Me, Cl, Br
O
Z
R2
Reagents and condition: a) aq NaNO2, HCl (10N), below ‒10°C;b) SOCl2 (1.1 eq), DMF (1 drop); c)
drop wise addition of 3 to 4, DMF, 0 °C; d) K2CO3, DMF, 100 °C (20 min), MWI.
Scheme 1: Methodology designed for the synthesis of (3R)-3-alkyl-4,1-benzoxazepine-2,5-diones 6a-p.

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Table1: Comparison of %yield of 4,1-benzoxazepines obtained via conventional heating and MW
assisted organic synthesis.
Substituents
% Yield
MW^
Entry
6
R1
Me
iPr
R2
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
H
H
X
H
H
H
H
H
H
H
Cl
Cl
H
H
H
Br
Br
Br
Br
Y
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
H
H
H
H
Z
H
H
H
H
C*
76
70
71
50
66
62
86
65
62
68
59
63
55
49
51
33
94
90
75
80
89
100
93
97
100
75
85
94
82
89
81
75
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
a
b
c
d
e
iBu
Bn
iBu
iPr
H
Me
Me
Me
Me
H
H
H
H
H
f
iBu
iPr
g
h
i
j
k
l
m
n
o
p
iBu
Me
iBu
Bn
Me
iBu
iPr
Br
Br
iBu
*Conventional heating; ^MW irradiation
In current study, the main focus was to probe the effect of temperature (°C) and time (min) on
MW assisted heating on the final cyclization step in contrast to conventional heating method. So,
the reaction conditions were primarily inspected by changing temperature followed by time. For
optimization of cyclization reaction under MW exposure, different reaction conditions were
employed including variation in temperature (50-150 °C) and time (5-30 min) (Table 2). It was
observed that at 50 °C no product formation was observed at variable time duration (5-30 min).
The best results were obtained at 100 °C for 20 min duration exposure to MW irradiations. Upon
increasing reaction duration at 100 °C, a number of products start appearing; whereas, at 150 ºC
it decomposed to black mass.
Table 2: Optimization of reaction temperature and time duration for 5c.
Entry T (°C)§
Time (min)
6c (%)
Entry
19
T (°C)§
Time (min)
6c (%)
15
1
2
3
5
-
-
-
-
-
-
5
10
15
20
25
30
20
10
15
20
25
30
20
21
25
50
4
80
22
25
5
6
23
30
24
30

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7
5
*
*
25
26
27
28
29
30
31
32
33
34
35
36
37
5
35
8
10
15
20
25
30
5
10
15
20
25
30
5
35
9
*
40
60
70
90
10
11
12
13
14
15
16
17
18
*
45
*
50
*
50
2
60
10
15
20
25
30
6
10
15
20
25
30
5
65
8
70
100
150
10
10
15
75
^
^
Decompose
§200 W power lamp; *product formed in traces; ^number of products formed
Based on the initial trails, it is concluded that best reaction time is 20 min and best reaction
temperature is 100 °C for maximum conversion of a N-acylanthranilic acid 5 to a 4,1-
benzoxazepine-2,5-dione 6. The final cyclized 4,1-benzoxazepines 6a-p were identified through
mass spectrometry coupled with GC. The results of the GC/MS analysis showed the formation of
pure benzoxazepine, which were identified by mass spectrometry coupled to GC (Figure 1).
Figure 1. The GC/MS analysis of 4,1-benzoxazepines 6h. The gas chromatogram (left) is
ensuring the purity of 6h. The Electron Impact mass spectrum(right) is characterizing the
compound, which is showing same fragmentation pattern to already synthesized compounds by
conventional heating.

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The EIMS of all synthesized 4,1-benzoxazepines 6a-p by MWI were found in match with
already synthesized 4,1-benzoxazepines 6a-o by conventional heating method. The molecular
ions of 6b and 6c were observed at 219 and 233 amu respectively, which confirms the formation
of 4,1-benzoxazepines under MW exposure. Following fragmentation pattern is suggested for 6b
and 6c. These molecular ions subsequently fragmentize by logical loss of oxirane ring (following
β-keto cleavage or step-wise cleavage) to result a common radical cation A (Figure 2).
O
O
O
O
O
-keto
cleavage
C
O
-
R
O
O
R
O
R
NH
NH
N
H
O
A
A
6b R = iPr
6c R = iBu
NH
6
b
c
[M]+• (%)
A (%)
219 (20)
233 (40)
119 (100)
119 (32)
Figure 2. The mass fragmentation pattern of a few synthesized 4,1-benzoxazepines (6b-c).
Crystallographic Description
The parameters of data collection along with data refinements for crystals of 5m, 6e, 6h and 6o
are presented in following Table 3.
Table 3: Crystallographic data of compounds 5m, 6e, 6h and 6o.
Crystal data
CCDC
Chemical formula
Mr
5m*
6e*
6h*
6o*
1940454
C10H9 BrClNO3
306.54
1940457
C13H14ClNO3
267.70
1940455
C12H11Br2NO3
377.04
1940456
C19H19NO3
309.35
Crystal system, space Triclinic, P¯1
orthorhombic, Pbca Monoclinic, P21/c Triclinic, P¯1
group
Temperature (K)
296
296
296
296
a, b, c (Å)
4.8491 (6)
10.5133 (14)
12.2128 (17)
76.894 (4)
83.670 (3)
82.599 (4)
599.22 (14)
10.9472 (15)
9.2516 (11)
33.456 (6)
90
90
90
8.8100 (7)
21.1270 (16)
6.9337 (5)
90
97.740 (4)
90
5.2145(6)
9.584 (2)
13.919 (3)
87.284 (5)
80.424 (7)
86.318 (6)
684.0 (2)
, ,  (°)
V (Å3)
1286.15(17)
3388.4 (8)

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Z
2
4
2
8
Density (calculated)
F(000)
3
3
3
3
1.699 Mg/m
304
1.213 Mg/m
1312
1.383 Mg/m
560
1.831Mg/m
368
Radiation type
Wavelength (λ)
µ (mm-1)
Mo K
0.71073 Å
3.643
0.082
0.296
5.924
Crystal size (mm)
Data Collection
Diffractometer
0.38 × 0.26 × 0.22 0.35 × 0.18× 0.16
0.30 × 0.24 × 0.20 0.40 × 0.26 × 0.24
Bruker APEXII CCD diffractometer
Absorption correction Absorption correction:multi-scan (SADABS; Bruker, 2007)
No. of measured, 7179, 2576, 1803 13106, 3151, 1576 11414, 2794, 2011 7797, 2958, 1882
independent
and observed [I> 2s(I)]
reflections
Rint
0.030
0.060
0.042
0.040
Theta range for data 2.905 to 27°
collection
1.217 to 25.5°
1.928 to 27°
1.332 to 27°
Index ranges
-5 h 6, -13 k  -8 h 13, -7 k  -11 h 11, -26 k -6 h 6, -12 k 
13, -15 l  15
0.639
11, -37  l 40
0.606
26, -5  l 8
0.639
12, -17 l 17
0.639
(sin θ/λ)max (Å-1)
Refinement
R[F2> 2σ(F2)], wR(F2), 0.051, 0.140, 1.04 0.053, 0.142, 1.00 0.053, 0.152, 1.05 0.043, 0.090, 1.01
S
No. of reflections
No. of parameters
H-atom treatment
2576
147
2794
167
2958
165
3151
210
H-atom parameters H-atom parameters H atoms treated by H-atom parameters
constrained
constrained
a
mixture
of constrained
and
independent
constrained
refinement
0.37, -0.25
Δmax, Δmin (e Å-3)
0.59, -0.54
0.15, -0.19
0.67, -0.63
*The compounds (5m, 6e, 6h and 6o) are given SWA7UOS, BN-III-68, BN-III-86 and SWC1UOS code names in
CIF files.
Table 4: Hydrogen-bond geometry (Å, º) in 5m, in 6e, 6h and 6o.
D—H···A
D—H
0.82
0.86
0.93
0.97
0.93
0.93
0.86
0.86
0.86
H···A
1.82
2.00
2.44
2.51
2.40
2.44
2.06
2.10
2.75
D···A
D—H···A
177
O1—H1···O2i
N1—H1A···O2
C5—H5···O3ii
C16—H16A···O2iii
C4—H4···O2iv
C12—H12···O3v
N1—H1A···O3vi
N1—H1A···O3vii
N1—H1A···Br2
2.643 (3)
2.660 (3)
3.345 (4)
3.463 (3)
3.271 (3)
3.295 (4)
2.909 (3)
2.933 (4)
3.035 (3)
133
165
166
157
153
170
164
101
5m
6e
6h
6o

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Symmetry codes: (i) –x−1, −y, −z+1; (ii) –x+1, −y+1, −z+1; (iii) –x+1/2, y+1/2, z; (iv) –x+3/2, y+1/2, z;
(v) x+1/2, y, −z+1/2; (vi) −x, −y, −z; (vii) − x, − y, − z + 1.
(2′S)-2-(2′-Chloropropanamido)-5-bromobenzoic acid 5m
In 5m (Figure 3a), the 2-amino-5-bromobenzoic acid moiety A (C1-C7/N1/O1/O2/Br1) and 2-
chloropropanoyl part B (C8-C10/O3) are planar with r. m. s. deviation of 0.0300 and 0.0010 Å,
respectively. The dihedral angle between A/B is 13.1 (5)°. The Cl1 atom is at a distance of -
1.0461 (13) Å from the mean square plane of B or the orientation of Cl1-atom can be evaluated
from the torsion angle of N1-C8-C9-Cl1 which is 43.2(7). The intramolecular H-bonding of N-
H…O and N-H…Cl1 complete S (6) and S (5) loops [32] respectively. The molecules are
2
dimerized through conventional loops R2 (8) due to O-H…O bonding [Figure 3b, Table 4]. The
2
dimers are further interlinked due to C-H…O bonds and complete R2 (14) loop.
(a) The ORTEP presentation
(b) The H-bonding pattern
Figure 3. (a) The ORTEP presentation of 5m with thermal ellipsoids drawn at 50 % probability
level with H-atoms drawn as small circles of arbitrary radii; (b) The H-bonding pattern showing
the C(6) chain due to N-H…O interaction.
(3R)-3-Iso-butyl-4,1-benzoxazepines-3,5-dione 6e
In 6e (Figure 4a), the benzene ring A (C2-C7) and the aniline moiety B (C10-C15/N1) are planar
with r. m. s. deviations of 0.0026 and 0.0104 Å respectively. The iso-butyl moiety is roughly
planar with r. m.s. deviation of 0.2044 Å. The dihedral angle between A/B, A/C and B/C is 78.56
(7)°,54.68 (12)° and 81.77 (10)° respectively. The part of carboxyl group D (C1/O1/O2) and the
ethylene part E (C8/C9/O3) are of course planar. The dihedral angle between C/D, C/E and D/E
is 87.24 (24)°, 30.7 (3)° and 61.8 (3)° respectively. Each molecule is attached through three C-

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H····O bonding with three adjacent molecules (Figure 4b, Table 4). There does not exist any
appreciable π····π interaction.
(a) The ORTEP presentation
(b) The H-bonding pattern
Figure 4. (a) The ORTEP presentation of 6e with thermal ellipsoids drawn at 50 % probability
level with H-atoms drawn as small circles of arbitrary radii; (b) The H-bonding pattern showing
that the molecules are linked with three adjacent molecules due to H-bonding.
(3R)-7-Chloro-9-methyl-3-iso-propyl-4,1-benzoxazepines-3,5-dione 6h
In 6h (Figure 5a), the 4-chloro-2-methylaniline moiety A (C1-C6/C10/N1/Cl1) is planar with r.
m. s. deviation of 0.0113 Å. The lactonic part B (C7/O1/O2), the ethanoylpart C (C8/C9/O3) and
iso-propyl moiety D (C11/C12/C13) are of course planar. The dihedral angles between A/B,
A/C, A/D, B/C, B/D and C/D are 38.32 (14), 36.95 (25), 86.6 (3), 65.2 (3), 76.2 (4) and
76.0 (3) respectively. The molecules are dimerized due to N‒H····O boding and complete
2
R2 (8) loop (Figure 5b, Table 4).

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(b) The H-bonding pattern
(a) The ORTEP presentation
Figure 5. (a) The ORTEP presentation of 6h with thermal ellipsoids drawn at 50 %
probability level with H-atoms drawn as small circles of arbitrary radii; (b) The H-bonding
2
pattern showing the R2 (8) loop.
(3R)-7,9-Dibromo-3-iso-propyl-4,1-benzoxazepines-3,5-dione 6o
In 6o (Figure 6a), the benzene ring A (C1-C6) is planar with r. m. s. deviation of 0.0068 Å. The
attached bromine atoms (Br1 and Br2) are at a distance of -0.024 (5) and 0.123 (5) Å from the
mean square plane. The seven membered ring is like a boat conformation with basal plane B
(N1/C7/O1/C9) having r. m. s. deviation of 0.0096 Å. The apical planes of boat conformation are
C (C5/C6/C7/N1) (r. m. s. deviation of 0.0061 Å) and D (C8/C9/O1). The dihedral angle
between A/B, B/C and B/D is 28.6 (2)°, 32.7 (2)° and 61.3 (2)° respectively. The molecules are
2
dimerized due to N‒H····O bonding with R2 (8)loop (Figure 6b, Table 4). The deviation of Br2
from the benzene ring is due to N‒H····Br bonding with it (as shown in the Figure 6b). The N‒
H····Br bonding complete S(5) ring.

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(a) The ORTEP presentation
(b) The H-bonding pattern
Figure 6. (a) The ORTEP presentation of 6o with thermal ellipsoids drawn at 50 % probability
level with H-atoms drawn as small circles of arbitrary radii; (b) The H-bonding pattern showing
that molecules are dimerized.

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Computational studies
Geometric structures
The optimized geometric parameters (bond lengths and bond angles) of 5m, 6e, 6h and 6o have
been determined by using B3LYP/6-311+G(d,p) functional. The comparative study is done
between DFT calculated and experimentally determined parameters obtained through XRD.
Atom numbering scheme as shown in Figures 3a, 4a, 5a and 6a for respective 5m, 6e, 6h and 6o
compounds are used to calculate the DFT and XRD structural parameters and results are
collected in Tables S1-S4 (Supplementary Information). A graphical representation of
comparison between SC-XRD and DFT based bond lengths and bond angles have been
portrayed in Figures S1-S4 (Supplementary information) respectively.
Overall, maximum deviation in bond lengths is observed in the ambient of 0.048 ± 0.005Å,
0.033 ± 0.004Å, 0.035 ± 0.007Å and 0.032 ± 0.013Å in 5m, 6e, 6h and 6o respectively. In case
of bond angles, 8.7° ± 2.6°, 1.3° ± 0.8°, 2.4° ± 1.1° and 1.9° ± 1.1° are the divergence ranges
noticed in 5m, 6e, 6h and 6o respectively. In 5m, the maximum and minimum deviation in bond
length is noticed for C(9)-C(10) and O(2)-C(1) bonds respectively. The bond angles which are
deviated utmost and least in 5m are found to be in Cl(1)-C(9)-C(10) and O(2)-C(1)-C(2)
respectively. The bond lengths C(13)-C(14) and O(1)-C(9) are found to be with maximum and
minimum deviation in 6e. The bond angle in 6e is diverged to large extent in O(1)-C(1)-C(2) and
minutely in C(1)-O(1)-C(9), O(1)-C(1)-O(2), O(1)-C(9)-C(16) respectively. The maximum and
minimum deviation in bond lengths of 6h is found to be for N(1)-C(9) and O(3)-C(9), N(1)-C(5)
respectively. Similarly, C(7)-O(1)-C(8) and O(3)-C(9)-N(1) are the bonds of 6h in which
maximum and minimum deviations of angles are observed. In case of 6o, bond length and angle
are found be deviated to large extent in N(1)-C(9), C(5)-N(1)-C(9) and to less extent in O(3)-
C(9), Br(2)-C(4)-C(3) bonds respectively. The comparative analysis revealed that SC-XRD and
DFT based empirically determined values of bond angles and bond lengths coincide nicely with
each other. The third digit difference between SC-XRD and DFT functional findings is observed
in most of the values. Briefly, some DFT values deviates when comparing with the SC-XRD
data and these differences are probably due to intramolecular interactions in the solid state.
Despite of these minute differences, the calculated geometrical parameters attained using DFT

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and SC-XRD indicate that both structural parameters are in good agreement with each other and
can provide a starting point to calculate other properties.
For a fair comparison between the experimental and TD-DFT/DFT study regarding optimization,
error was further calculated with the help of the following equations 1-4:
푛
푡=1
∑
|퐸푋푃−퐷퐹푇|
Mean Absolute Deviation (MAD) =
Equation 1
푛
Where n is total number of Bond Length or Bond Angle values considered, t is number of bond
length or bond angle value, EXP is the experimental bond length or bond angle value and DFT is
the DFT study based bond length or bond angle value. The mean absolute deviation (MAD) is
the sum of absolute differences between the experimental value and the DFT study based value
divided by the total number of bond length or bond angle values taken.
푛
푡=1
2
∑
(퐸푋푃−퐷퐹푇)
Mean Square Error (MSE) =
Equation 2
푛
Mean square error is commonly used error metric. It penalizes large errors because squaring
larger numbers has a greater impact than squaring smaller numbers.
푛
푡=1
2
∑
(퐸푋푃−퐷퐹푇)
√
Root Mean Square Error (RMSE) =
Equation 3
푛
The root mean square error (RMSE) is the square root of MSE and is the most commonly used
error metric and had been especially considered for the derivatives under study.
퐸푋푃−퐷퐹푇
퐸푋푃
푛
푡=1
∑
|
|
Mean Absolute Percentage Error (MAPE) =
× 100 Equation 4
푛
Mean Absolute Percentage Error (MAPE) is the average of absolute errors divided by the
experimental values.
As discussed, the error calculations from equations 1-4 are presented in Table S5
(Supplementary information). The RMSE value is considered to be the most commonly used
one, so, for the derivatives, the values for RMSE are found good in case of bond lengths and the
bond angles. But, in case of bond angles, the values in 5m showed larger figures due to the C-Cl
bonds.

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FT-IR analysis
In present study, nature of vibrational modes, harmonic frequencies and intensities of the
vibrational bands present in 5m, 6e, 6h and 6o were examined theoretically at DFT/B3LYP/6-
311+G(d,p) level of theory. Utilizing Gaussview animation option, vibrational modes present in
5m, 6e, 6h and 6o were assigned. The experimental spectrums of 5m, 6e, 6h and 6o are
displayed in Figures S5-S8 (Supplementary information). The calculated FT-IR results along
with their detailed assignments and experimental FT-IR results of 5m, 6e, 6h and 6o are
presented in Tables S6-S9 (Supplementary information) correspondingly.
C–H stretching vibrations
It is revealed from literature study that vibrational bands in the ambient of 3100-3000 cm-1 are
observed as a consequence of C-H vibrations of aromatic ring [33]. In present study, the
aromatic ring C–H stretching vibrations for 5m, 6e, 6h and 6o are measured in the ranges of
3243-3093 cm-1, 3205-3168 cm-1, 3217-3192 cm-1 and 3219-3217 cm-1 respectively (Tables S6-
S9). Pure symmetric and asymmetric vibrations in 5m are observed with stretching frequencies
of 3093 cm-1, 3231 cm-1, 3243 cm-1 and 3199 cm-1 respectively. In 6e, bands observed with
frequencies 3194 cm-1, 3204 cm-1, 3205 cm-1 are assigned to pure symmetric vibrations, while
pure asymmetric C-H stretching vibrations are observed at 3168 cm-1, 3174 cm-1, 3185 cm-1,
3189 cm-1 and 3201 cm-1 wavenumbers. Similarly, pure symmetric vibrational bands are
calculated with stretching frequencies 3192 cm-1, 3217 cm-1 in 6e and 3217 cm-1, 3219 cm-1 in 6h
respectively. The rocking mode of vibrations in 5m, 6e, 6h and 6o are located with vibrational
bands present in the span of 934-1635 cm-1, 633-1352 cm-1, 739-1617 cm-1 and 767-1581 cm-1
respectively.
C-C stretching vibrations
The stretching frequency associated with C-C bond of ring frame work and derivatives usually
appears in the range of 1650-1400 cm-1 [34, 35]. In our investigated molecules 5m, 6e, 6h and
6o, sharp bands in the ranges of 428-1635 cm-1, 418-1639 cm-1, 408-1624 cm-1 and 476-1615
cm−1 respectively are computed due to C-C stretching vibrational modes (Tables S6-S9).
Furthermore, almost similar peaks have been found for both theoretical and experimental
findings. The C-C stretching vibrations in 5m have been observed through DFT at 528, 808,

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1309, 1417 and 1483 cm−1 which are strongly supported by experimental C-C vibrational
wavenumbers located at 534, 807, 1311, 1423 and 1486 cm−1 respectively (Table S6).
The DFT calculated data in 6e showed vibrational bands at 432, 520, 619, 696, 769, 997, 1132,
1253 and 1330 cm−1 which show good resemblance with the experimentally observed bands at
428, 518, 616, 693, 771, 993, 1137, 1258 and 1326 cm−1 respectively (Table S7). In 6h,
stretching modes of C-C computed at 790, 929, 1024, 1132, 1261, 1298 and 1423 cm−1 describe
excellent agreement with experimental bands found at 793, 933, 1021, 1131, 1267, 1283 and
1429 cm−1 respectively (Table S8). Similar trend is noticed in 6o molecule with nice harmony
among DFT computed bands (695, 904, 1232, 1309, 1417 and 1589 cm−1) and experimental
calculated stretching frequencies (698, 923, 1232, 1319, 1412 and 1581 cm−1) respectively
(Table S9).
Methyl group vibrations
The skeleton of 5m, 6e, 6h and 6o contain methyl groups. The characteristics
region to recognize the attendance of methyl group C–H stretching vibrations is 3000-2800 cm-1
[36]. In 5m, vibrational bands located at 3042, 3110 cm−1 and 3142 cm−1 are assigned to the
symmetric and asymmetric C–H stretching vibrations of methyl group respectively (Table S6).
The peaks for symmetric and asymmetric methyl group vibrations in 6e are observed at wave-
numbers 3012, 3016, 3026, 3041 cm−1 and 3052, 3072, 3079, 3082, 3091 cm−1 respectively
(Table S7). In 6h, methyl group C–H bands observed at 3014, 3017, 3019, 3021, 3054 cm−1 are
due to pure symmetric stretching vibrations, while those observed at 3067, 3080, 3089, 3117,
3119, 3121 cm−1 are owing to the asymmetric vibrational modes of methyl group (Table S8).
Similarly in 6o, symmetric vibrations of methyl group C–H are found to be with wavenumbers
3019, 3020, 3023 and 3055 cm−1, whereas asymmetric vibrational modes of methyl group C–H
are observed with stretching frequencies 3082, 3091, 3121 and 3122 cm−1 respectively (Table
S9). Furthermore, DFT computed wavenumber at 3072 in 6e and 3080, 3089 in 6h exhibit good
agreement with experimental calculated stretching frequency values found at 3072 in 6e and
3086 in 6h respectively. The rocking mode of vibrations present in methyl group C–H bond of
5m, 6e, 6h and 6o molecules are located in the ambient of 233-1378 cm-1, 233-1377 cm-1, 211-
1369 cm-1 and 215-1404 cm-1 respectively.

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C=O group vibration
According to our findings, the C=O stretching modes are observed with sharp bands at 1764 cm-1
in 5m, at 1756, 1785 cm-1 in 6e, at 1769, 1785 cm-1 in 6h and at 1776, 1788 cm-1 in 6o
respectively.
N-H group vibration
Owing to the possibility of overlapping with several other vibrations, the evaluation of N-H
bands is usually hard. The stretching vibrations for pure N-H group are found to be at 3443 cm-1,
3587 cm-1 and 3554 cm-1 in 5m, 6h and 6o respectively.
From the preceding discussion, it is evident that DFT computed results associated well with the
corresponding experimental results given in Tables S6-S9 (Supplementary information)
Natural bond orbitals (NBO) analysis
NBO investigation was carried out at B3LYP/6-311+G(d,p)level of theory using Gaussian
embedded NBO 3.1 program package [27] to examine the charger transfer between filled (donor)
Lewis-type bonding NBOs to the vacant (acceptor) non-Lewis anti-bonding NBOs [37, 38],
hyper-conjugative interactions (HCI), inter and intra-molecular bonding and presence of
hydrogen bonding (HB) in 5m, 6e, 6h and 6o. The second order stabilization energy E(2) has laid
on the line association to the intensity of energy between donor and acceptor. The second order
stabilization energy E(2) can be defined by equation 5 [39].
(F )2
i, j
E(2)  q
Equation (5)
i  j i
Where qi is the donor orbital occupancy, 휀 and 휀푖 are diagonal elements and F(i,j) is the off-
푗
diagonal NBO fock matrix element. The second order perturbation theory analysis display
diverse description of HCIs among which representative NBO values are displayed in Table 5.

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Table 5: Representative natural bond orbital (NBO) data for 5m, 6e, 6h and 6o.
E(2)a
[kcal/mol]
E(j)_E(i)b
F(i;j)c
[a.u.]
0.075
0.060
0.073
0.125
0.110
0.098
0.075
0.060
0.073
0.125
0.110
0.098
0.101
0.101
0.057
0.069
0.070
0.070
0.071
0.069
0.069
0.069
0.101
0.128
0.124
0.112
0.042
0.070
0.069
0.070
0.097
0.128
0.103
0.123
Compound Donor(i) Type Acceptor (j) Type
[a.u.]
0.28
0.28
0.27
0.31
0.71
0.27
0.28
0.28
0.27
0.31
0.71
0.27
0.70
0.70
0.74
1.14
0.30
0.28
0.28
0.29
0.28
0.28
0.38
0.62
0.68
0.28
0.71
0.31
0.28
0.29
0.39
0.61
0.64
0.26
C2-C7
C3-C4
C5-C6
O1
π
π
C3-C4
C2-C7
C2-C7
O2-C1
O1-C1
C2-C7
C3'-C4'
C2'-C7'
C2'-C7'
O2'-C1'
O1'-C1'
C2'-C7'
O1'-H1'
O1-H1
N1-H1A
N1'-H1A'
C3-C4
C5-C6
C2-C7
C14-C15
C10-C11
C10-C11
O2-C1
O1-C1
N1-C8
O3-C8
C9-H9
C3-C4
C5-C6
C1-C2
O1-C7
O1-C7
C8-C9
O3-C9
π*
π*
π*
π*
σ*
π*
π*
π*
π*
π*
σ*
π*
σ*
σ*
σ*
σ*
π*
π*
π*
π*
π*
π*
π*
σ*
σ*
π*
σ*
π*
π*
π*
π*
σ*
σ*
π*
24.20
14.92
24.08
59.91
20.53
41.99
24.20
14.92
24.08
59.91
20.53
41.99
17.64
17.64
5.16
π
LP(2)
LP(1)
LP(1)
π
O2
N1
C2'-C7'
C3'-C4'
C5'-C6'
O1'
π
5m
π
LP(2)
LP(1)
LP(1)
LP(2)
LP(2)
LP(2)
LP(1)
π
O2'
N1'
O2
O2'
O2
O2'
5.24
C2-C7
C3-C4
C5-C6
C10-C11
C12-C13
C14-C15
O1
19.66
21.62
21.74
20.18
21.32
21.38
33.61
32.13
27.59
53.48
2.84
π
π
π
π
π
6e
LP(2)
LP(2)
LP(2)
LP(1)
LP(2)
π
O2
O3
N1
O2
C1-C2
C3-C4
C5-C6
O1
20.29
21.13
21.15
30.17
32.51
20.40
69.55
π
π
LP(2)
LP(2)
LP(2)
LP(2)
6h
O2
O3
N1

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C1'-C2'
C3'-C4'
C5'-C6'
O1'
π
C3'-C4'
C5'-C6'
C1'-C2'
O2'-C7'
O1'-C7'
C8'-C9'
O3'-C9'
N1'-H1A'
N1-H1A
C8-H8
π*
π*
π*
π*
σ*
σ*
π*
σ*
σ*
σ*
σ*
π*
π*
π*
π*
σ*
σ*
π*
π*
π*
π*
π*
σ*
σ*
π*
σ*
σ*
σ*
σ*
20.29
21.13
21.15
30.17
32.51
20.40
69.55
8.40
0.31
0.28
0.29
0.39
0.61
0.64
0.26
0.71
0.71
0.94
0.94
0.28
0.29
0.29
0.39
0.62
0.74
0.27
0.28
0.29
0.29
0.39
0.62
0.74
0.27
0.70
0.70
0.72
0.72
0.070
0.069
0.070
0.097
0.128
0.103
0.123
0.070
0.070
0.036
0.036
0.074
0.071
0.072
0.099
0.128
0.112
0.120
0.074
0.071
0.072
0.099
0.128
0.112
0.120
0.062
0.062
0.042
0.042
π
π
LP(2)
LP(2)
LP(2)
LP(2)
LP(2)
LP(2)
LP(1)
LP(1)
π
O2'
O3'
N1'
O3
O3'
8.40
O1
1.70
O1'
C8'-H8'
C3-C4
1.70
C1-C2
C3-C4
C5-C6
O1
23.75
20.59
21.97
31.86
32.04
20.75
64.54
23.75
20.59
21.97
31.86
32.04
20.75
64.54
6.55
π
C5-C6
π
C1-C2
LP(2)
LP(2)
LP(2)
LP(1)
π
O2-C7
O2
O1-C7
O3
N1-C9
N1
O3-C9
C1'-C2'
C3'-C4'
C5'-C6'
O1'
C3'-C4'
C5'-C6'
C1'-C2'
O2'-C7'
O1'-C7'
N1'-C9'
O3'-C9'
N1'-H1A
N1-H1A
C8-H8
π
6o
π
LP(2)
LP(2)
LP(2)
LP(1)
LP(2)
LP(2)
LP(2)
LP(2)
O2'
O3'
N1'
O3
O3'
6.55
O1
2.87
O1
C8'-H8'
2.87
It is evident from Table 5 that different types of non-covalent interactions (NCIs) are present in
5m, 6e, 6h and 6o. The intermolecular and intramolecular hydrogen bonding are the most
attentive interactions among them. In the dimeric structure of 5m, intermolecular hydrogen
bonding is observed owning to the delocalization of the lone pair of O2LP(2) and O2'LP(2) to
the antibonding sigma orbitals (σ*) of O1'-H1' and O1-H1 respectively. Consequently, the
stabilization energy as 17.64 kcal/mol is offered to the dimeric 5m structure by both hydrogen

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bonds. Similarly, intramolecular HB offers 5.16 kcal/mol and 5.24 kcal/mol stabilization energy
to the dimeric 5m structure by delocalizing the lone pairs from O2LP(2) and O2'LP(1) to the σ*
orbital of N1-H1A and N1'-H1A' respectively. In 6e, intramolecular HB is endorsed by the
transition in which effective delocalization of the lone pair of electron from O2LP(2) to the
antibonding sigma orbitals (σ*) of C17-H18 is observed which leads to stabilization energy
value of 2.84 kcal/mol. The dimeric structure 6h likewise involves both intermolecular and
intramolecular HBs. The intermolecular HB in 6h is the result of delocalization of lone pair of
electrons from O3LP(2) and O3'LP(2) to the σ* of N1'-H1A' and N1-H1A respectively. In these
cases, the stabilization energy value is reported to be 8.40 kcal/mol respectively. The
intramolecular HB in 6h is evident from LP1(O1)→σ*(C8-H8) and LP1(O1')→σ*(C8'-H8')
transitions which provide same stabilization energy value of 1.70 kcal/mol to the dimeric 6h
structure. The reasonable explanation to the presence of intermolecular and intramolecular
hydrogen bonding interactions in 6o dimeric structure is given by intermolecular transitions
O3LP(2)→σ*(N1'–H1A),
O3'LP(2)→σ*(N1–H1A)
and
intramolecular
interactions
O1LP(2)→σ*(C8–H8), O1'LP(2)→σ*(C8'–H8') respectively. The stabilization energy values
6.55 and 2.87 kcal/mol to the dimeric 6o structure is given by above mentioned intermolecular
and intramolecular transitions respectively. Apart from the HBs, delocalization of π-electrons
from bonding orbitals of C-C to their anti-bonding orbitals play a key role for stabilization of
rings and overall architecture. Thus existence of conjugation is well proven in 5m from
transitions π(C2–C7)→π*(C3–C4), π(C3–C4)→π*(C2–C7), π(C5–C6)→π*(C2–C7), π(C2'–
C7')→π*(C3'–C4'), π(C3'–C4')→π*(C2'–C7') and π(C5'–C6')→π*(C2'–C7') with stabilization
energy values 24.20, 14.92, 24.08, 24.20, 14.92 and 24.08 kcal/mol respectively. The existence
of conjugation in 6e is confirmed from π→π* interactions as π(C6–C15)→π*(C7–C9), π(C7–
C9)→π*(C11–C13),
π(C11–C13)→π*(C6–C15),
π(C19–C20)→π*(C26–C28),
π(C22–
C24)→π*(C19–C20) and π(C26–C28)→π*(C19–C20) with substantial stabilization energy
values 19.66, 21.62, 21.74, 20.18, 21.32 and 21.38 kcal/mol respectively. Similarly, the
transitions π(C1–C2)→π*(C3–C4), π(C3–C4)→π*(C5–C6), π(C5–C6)→π*(C1–C2), π(C1'–
C2')→π*(C3'–C4'), π(C3'–C4')→π*(C5'–C6') and π(C5'–C6')→π*(C1'–C2') with substantial
stabilization energy values 20.29, 21.13, 21.15, 20.29, 21.13 and 21.15 kcal/mol respectively
proved the presence of conjugation in 6h dimeric structure. The delocalization of π-electrons

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from bonding orbitals of C-C to their anti-bonding orbitals in 6o is observed in π(C1–
C2)→π*(C3–C4), π(C3–C4)→π*(C5–C6), π(C5–C6)→π*(C1–C2), π(C1'–C2')→π*(C3'–C4'),
π(C3'–C4')→π*(C5'–C6') and π(C5'–C6')→π*(C1'–C2') transitions which offers stabilization
energy values 23.75, 20.59, 21.97, 23.75, 20.59 and 21.97 kcal/mol respectively to the 6o
dimeric structure. The large stabilization energy values to the structure of investigated molecules
5m, 6e, 6h and 6o are offered in case of resonance. Some probable transitions noticed due to
resonance in 5m are O1(LP2)→π*(O2-C1), O2(LP1)→σ*(O1-C1), N1(LP1)→π*(C2-C7),
O1'(LP2)→π*(O2'-C1'), O2'(LP1)→σ*(O1'-C1') and N1'(LP1)→π*(C2'-C7') with stabilization
energy values 59.91, 20.53, 41.99, 59.91, 20.53 and 41.99 kcal/mol respectively. In 6e, the large
stabilization energy values 33.61, 32.13, 27.59 and 53.48 are offered by the resonance owing to
O1(LP2)→π*(O2-C5), O2(LP2)→σ*(O1-C5), O3(LP2)→σ* (N4-C16) and N4(LP1)→π*(O3-
C16) interactions respectively. Similarly, the transitions due to resonance observed in 6h and 6o
are O1(LP2)→π*(O1-C7), O2(LP2)→σ*(O1-C7), O3(LP2)→σ*(C8-C9), N1(LP2)→π*(O3-
C9),
N1'(LP2)→π*(O3'-C9') and O1(LP2)→π*(O2-C7), O2(LP2)→σ*(O1-C7), O3(LP2)→σ*(N1-
C9), N1(LP1)→π*(O3-C9), O1'(LP2)→π*(O2'-C7'), O2'(LP2)→σ*(O1'-C7'),
O1'(LP2)→π*(O1'-C7'),
O2'(LP2)→σ*(O1'-C7'),
O3'(LP2)→σ*(C8'-C9'),
O3'(LP2)→σ*(N1'-C9'), N1'(LP1)→π*(O3'-C9') with stabilization energy values 30.17, 32.51,
20.40, 69.55, 30.17, 32.51, 20.40, 69.55 and 31.86, 32.04, 20.75, 64.54, 31.86, 32.04, 20.75,
64.54 kcal/mol respectively. From preceding discussion, it can be concluded that presence of
hydrogen bonding in investigated molecules 5m, 6e, 6h and 6o proves a good agreement
between NBO and XRD findings. The extended conjugation is present in all compounds 5m, 6e,
6h and 6o. Successful intramolecular and intermolecular charge transfer due to delocalization of
electrons on whole systems and hyper-conjugative interactions (HCIs) among bonds provide
stability to the investigated compounds and are pivotal cause for the existence of investigated
compounds 5m, 6e, 6h and 6o in the solid-state.
UV-Visible study
Ultraviolet-Visible (UV–Vis) spectroscopy is recognized as an important tool to describe the
probability of charge transfer, contributing configurations to the transitions and electronic
transition nature within the investigated molecules. Herein, photophysical characteristics of 5m,

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6e, 6h and 6o were explained by performing ultraviolet spectral characterization at B3LYP/6-
311+G(d,p) level of theory. The calculated results of excitation energy (EDFT), absorption
wavelengths (λmax), dominant molecular orbital (MO) contributions and oscillator strength (f) of
5m, 6e, 6h and 6o are collected in Table 6.
Table 6: Wave length, excitation energy and oscillator strength for 5m, 6e, 6h and 6o
푬푫푭푻
(eV)
3.7658 0.1368
4.3410 0.0021
4.6586 0.2248
Compoun
d
Cal.
휆푚푎푥 (nm)
329.21
285.59
266.12
f
MO contributions
H→L(95%)
H-1→L(85%), H-1→L+1(11%)
H-2→L(13%), H→L+1(84%)
H-7→L(15%), H-6→L(30%), H-3→L(18%),
H-1→L+1(30%)
H→L+2(95%)
H-6→L(15%), H-3→L(14%), H-1→L(12%),
H-1→L+1(50%)
251.58
245.33
243.49
297.32
265.77
4.9279 0.0009
5.0535 0.0001
5.0917 0.0005
5m
4.1698 0.0955 H→L(94%)
H-3→L(11%), H-2→L(12%), H-1→L(12%),
H→L+1(48%)
H-5→L(18%), H-2→L(14%), H-1→L(20%),
H→L+1(35%)
4.6647 0.0269
4.7858 0.0633
259.05
6e
254.73
253.46
247.33
295.39
266.82
253.29
251.18
4.8669 0.0464
4.8913 0.0101
5.0125 0.0253
H→L+2(64%)
H-3→L(20%), H-1→L(41%)
H-1→L+2(17%),H→L+2(14%),H→L+3(46%)
4.1970 0.0608 H→L(90%)
4.6465 0.0114
4.8947 0.1388
4.9357 0.0251
H-3→L(21%), H-1→L(60%)
H-3→L(21%),H-1→L+1(13%), H→L+1(49%)
H-2→L(57%), H→L+1(16%)
H-3→L(16%), H-2→L(11%), H-2→L+1(22%),
H-1→L(13%), H-1→L+1(20%)
H-3→L(18%), H-2→L(14%), H-1→L+1(19%),
H→L+1(13%), H→L+2(15%)
H→L(91%)
6h
6o
236.69
223.16
5.2379 0.0393
5.5555 0.2885
305.69
271.48
267.99
258.99
256.46
4.0556 0.0565
4.5667 0.0112
4.6262 0.0005
4.7869 0.1846
H-3→L(21%), H-1→L(58%), H→L+1(10%),
H→L+2(97%)
H-3→L(14%), H→L+1(62%)
4.8342 0.0001 H-3→L(12%), H-2→L(56%), H-2→L+1(12%)
H-3→L(21%), H-2→L+1(25%), H-1→L(15%),
H-1→L+1(18%)
243.87
5.0836 0.0171
E = Excitation energy (eV); 휆=wave length (nm); f = oscillator strength; MO = molecular orbitals; H = HOMO,
L = LUMO; 휆 (nm) Cal. = Calculated.

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Results indicate that first vertical transition is found to be as major transitions having maximum
absorption values appeared at 329.21 nm, 297.32 nm, 295.39 nm and 305.69 nm originated from
HOMO→LUMO (95%), HOMO→LUMO (94%), HOMO→LUMO (90%) and HOMO→
LUMO (91%) of 5m, 6e, 6h and 6o respectively. Due to minute structural difference, calculated
absorption maxima (λmax) values are found very close to each other. Overall, highest vertical
transition among all investigated molecules is observed in 5m with absorption value 329.21 nm.
Compound 6o is placed at second position, while 6e and 6h hold the third and fourth positions in
terms of maximum absorption values observed in all vertical transitions. The decreasing order of
λmax values are noted as: 5m > 6o > 6e > 6h. This order is exactly inverse to the HOMO-LUMO
gap order 5m < 6o < 6e < 6h which indicate that molecule with less energy gaps are shifted
towards longer wavelength. It can also be seen from Table 6 that wavelengths 266.12 nm, 297.32
nm, 223.16 nm and 258.99 nm in compounds 5m, 6e, 6h and 6o are observed with maximum
oscillator strength values of 0.2248, 0.0955, 0.2885 and 0.1846 respectively.
Another important factor that offers useful insights into the charge transfer character is transition
or excitation energy of investigated molecules. Literature suggests that molecules holding lower
transition energy values contain higher charge transport ability and easy excitation between
HOMO to LUMO. The increasing order for EDFT values are found to be:
[5m (3.7658 eV)] < [6o (4.0556 eV)] < [6e (4.1698 eV)] < [6h (4.1970eV)]
This increasing order is also found in accordance with the HOMO-LUMO gap order describing
the reasons for shifting in absorption maximum toward longer wavelength. The MO contribution
also indicates that maximum intramolecular charge in 5m, 6e, 6h and 6o are transferred from
HOMO to LUMO electronic transition which is the characteristic of soft molecules, hence, may
have potential of utilization in biological and NLO applications.
Frontier molecular orbital (FMO) analysis
Different characteristics including molecular interactions, reactivity, charge transfer, optical
properties and electronic features of molecules under investigation are studied using frontier
molecular orbitals (FMOs) namely highest occupied molecular orbital (HOMO) and lowest
unoccupied molecular orbital (LUMO) [40, 41]. These FMOs take the responsibility of any

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chemical reaction. The HOMO is designated as an electron donor, while LUMO is assigned for
acceptance of the electron. The molecular chemical stability can be defined through the energy
gap between HOMO and LUMO (∆E = ELUMO-EHOMO). The molecular electrical transport
properties can be determined using energy gap of frontier molecular orbitals [42]. The bonding
framework of investigated molecules is elucidated through the surface of FMOs. Hence, two
paramount molecular orbital pairs HOMO, HOMO-1 and LUMO, LUMO+1, which reflect both
the donor and acceptor levels, one energy state above LUMO and one level below HOMO for
5m, 6e, 6h and 6o respectively are examined. The pictorial representation is shown in Figure 7 in
which red color specifies the negative phase while green color indicates the positive phase of
molecular orbitals respectively. The energy data for four molecular orbitals of 5m, 6e, 6h and 6o
along with their energy differences are shown in Table 7.
Table 7: Computed energies (E) for compounds 5m, 6e, 6h and 6o.
5m
6e
6h
6o
MO(s)
E (eV) ∆E (eV) E (eV)
∆E (eV)
E (eV)
-6.938
-2.092
-7.685
-1.493
∆E (eV)
E (eV)
-7.109
-2.395
-7.815
-1.813
∆E (eV)
HOMO
LUMO
-6.747
-2.445
-7.687
-1.545
-6.671
-1.835
-7.329
-1.281
4.302
6.142
4.836
4.846
4.714
HOMO-1
LUMO+1
6.048
6.192
6.002
E = energy, ∆E (eV) = ELUMO - EHOMO; HOMO = highest occupied molecular orbital; LUMO = lowest unoccupied
molecular orbital; MO = molecular orbital
The energy for four molecular orbitals (HOMO, LUMO, HOMO-1, LUMO+1) of 5m, 6e, 6h
and 6o are found to be negative which indicates that investigated molecules are stable [43]. The
energy gaps values of 6e and 6h are found close to each other with only a third digit difference.
The smallest energy gap value among investigated compounds (5m, 6e, 6h and 6o) is found to be
in 5m with ∆E value of 4.302 eV. This might due to the presence of two weakly deactivating Cl
and Br groups at opposite ends of the 5m architecture. In contrast, computational findings reflect
that the highest ∆E value of 4.846 eV is observed in 6h. Overall, the increasing order of HOMO-
LUMO energy gap is noticed as: 5m <6o <6e < 6h.