Synthesis, molecular structure and spectroscopic studies of some new quinazolin-4(3H)-one derivatives; An account on the N- versus S-Alkylation

Article abstract of DOI:10.1016/j.molstruc.2015.12.007

A new series of N- and S-alkylated products of 3-aryl-1H,3H-quinazolin-2,4-dione and 3-aryl-2-mercapto-3H-quinazolin-4-one, respectively, were prepared in good yields via efficient nucleophilic substitution reaction of the SH and NH substrates with methyl

Full text of DOI:10.1016/j.molstruc.2015.12.007

Accepted Manuscript
Synthesis, Molecular Structure and Spectroscopic Studies of Some New
Quinazolin-4(3H)-one Derivatives; An Account on the N- versus S-Alkylation
Mohamed Hagar, Saied M. Soliman, Farahate Ibid, E.S.H. El Ashry
PII:
S0022-2860(15)30496-8
10.1016/j.molstruc.2015.12.007
MOLSTR 22040
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 5 November 2015
Revised Date: 2 December 2015
Accepted Date: 2 December 2015
Please cite this article as: M. Hagar, S.M. Soliman, F. Ibid, E.S.H. El Ashry, Synthesis, Molecular
Structure and Spectroscopic Studies of Some New Quinazolin-4(3H)-one Derivatives; An Account on the
N- versus S-Alkylation, Journal of Molecular Structure (2016), doi: 10.1016/j.molstruc.2015.12.007.
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ACCEPTED MANUSCRIPT

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Synthesis, Molecular Structure and Spectroscopic Studies of Some New
Quinazolin-4(3H)-one Derivatives; An Account on the N- versus S-Alkylation.
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Mohamed Hagara,c, Saied M. Soliman b,c, Farahate Ibid c, E. S. H. El Ashry c*
a. present address: Chemistry Department, Faculty of Science, Taibah University,
Yanbu branch, Yanbu, KSA
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b. present address: Chemistry Department, College of Science & Arts, King Abdulaziz
University, P.O. Box 344 Rabigh 21911, Saudi Arabia
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c. permanent address: Chemistry Department, Faculty of Science, Alexandria
University, Alexandria, Ibrahimia, P.O. Box 426, Alexandria 21321. Egypt. E-mail:
eelashry60@hotmail.com
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Abstract
A new series of N- and S-alkylated products of 3-aryl-1H,3H-quinazolin-2,4-dione
and 3-aryl-2-mercapto-3H-quinazolin-4-one, respectively, were prepared in good
yields via efficient nucleophilic substitution reaction of the SH and NH substrates
with methyl iodide, ethyl bromoacetate, allyl bromide, propagyl bromide, 2- 17
bromoethanol, 1,3-dibromopropane or phenacyl bromide in DMF as a solvent and
anhydrous potassium carbonate. The quinazolin-2,4-dione favored the N-alkylation
while the 2-mercapto-3H-quinazolin-4-one goes via the S-alkylation. DFT reactivity
studies showed that the former have the N-site with higher nucleophilicity compared
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to the O-site. In contrast, the S-site is the more nucleophilic centre than the N-atom of 22
the latter. The structures of the synthesized products have been established on the
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basis of their melting point (m.p), IR and HNMR data. The molecular structures of
the products were calculated using the DFT B3LYP/6-311G(d,p) method. The
electronic and spectroscopic properties (Uv-Vis and NMR spectra) were calculated
using the same level of theory. The chemical reactivity descriptors that could help to
understand the biological activity of the products are also predicted.
Keywords: Quinazoline - DFT- S and N Alkylation- Reactivity

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Introduction
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4(3H)-Quinazolinones are a class of fused heterocycles that of considerable interest
because of the diverse range biological properties, such as anticancer, diuretic, anti-
inflammatory, anticonvulsant and antihypertensive activities [1-5]. Some of 38
aminoquinazoline derivatives were found to be inhibitors of the tyrosine kinase [6, 7]
or dihydrofolate reductase enzymes [8]. The chemistry of the quinazolinone alkaloids
is well documented [9, 10] in a number of comprehensive reviews and monographs
which is continuously updated in Natural Product Reports [11, 12]. Recently, it was
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reported that substituted quinazolines exhibited a good antibacterial activity [13]. 43
Prompted by these findings and continuing our interests devising approaches for the 44
preparations of heterocycles of potential biological activities, the aim of this work is
mainly concerned with studying the activity of N and S of quinazolin-4(3H)-one
derivatives towards alkylation reactions as well as the design and synthesis of an
extension series of quinazolin-4(3H)-one derivatives. Also, the molecular structures,
electronic and spectroscopic properties of the products were calculated using the DFT
method.
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Experimental
General Methods
IR spectral data were recorded with a Tensor 37 Bruker infrared spectrophotometer
(KBr, ν max: cm-1). Mass spectra were recorded at 70 ev by 5980 series II GC
1
coupled with 5989 B mass spectrometer. H NMR spectra were determined with a 55
JEOL spectrometer at 500 MHz. The 13C NMR spectra were recorded with JEOL
spectrometer at 125.7 MHz. The chemical shifts are expressed in the δ scale using
tetramethylsilane as a reference. Melting points were determined on a meltemp
apparatus and are uncorrected. TLC was performed on Merck Kiesel gel; 60-F254
plates, and the spots were detected by UV light absorption.
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General method for synthesis of 2-(alkylthio)-3-(aryl)quinazolin-4(3H)-one (2-5)
A mixture of 3-aryl-2-mercaptoquinazolin-4(1H, 3H)-one 1a-c (0.78 mmol) and
anhydrous potassium carbonate (0.8 mmol) in dry DMF (3 mL) was stirred for 1hr,
alkyl halide (0.78 mmol) was added. The reaction mixture was stirred for further time
10:120 min and then diluted with cold water. The formed precipitate was filtered,
washed with water and recrystallized from ethanol.

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2-(Allylthio)-3-phenylquinazolin-4(3H)-one ( 2a)
Stirring time 5 min, colorless crystals; yield: 67 %; mp 147-148 °C [14].
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2-(Allylthio)-3-(4-chlorophenyl)quinazolin-4(3H)-one (2b)
°
Stirring time 30 min, colorless needles; yield: 78 %; mp 138-140 C, Rf 0.54 (1:6
1
EtOAc-hexane). H NMR (500 MHz, CDCl3): δ = 3.84 (d, 2H, J = 6.7 Hz, CH2S),
5.14 (d, 1H, J = 9.5 Hz, CH-All), 5.30 (d, 1H, J = 1.9 Hz, CH-All), 5.91 (m, 1H, CH-
All), 7.25 (d, 2H, J = 8.6 Hz, Ar-H), 7.40 (t, 1H, J = 7.6 Hz, Quin-H), 7.50 (d, 2H, J =
8.6 Hz, Ar-H), 7.61 (d, 1H, J = 7.6 Hz, Quin-H), 7.73 (t, 1H, J = 6.7 Hz, Quin-H),
8.22 (d, 1H, J = 6.7 Hz, Quin-H). 13C NMR (125.7 MHz, CDCl3): δ = 35.5 (SCH2),
119.8 (CH2 ), 126.0 (C-4a), 127.2 (C-5), 127.4 (C-8), 130.0 (C-6), 132.6 (CH ),
136.2 (C-7), 147.7 (C-8a), 156.4 (C-2), 161.8 (C-4). Anal. Calcd for C17H13ClN2OS:
C, 62.10; H, 3.98; N, 8.52; S, 9.75. Found C, 61.98; H, 3.61; N, 8.23; S, 9.40.
2-(Allylthio)-3-(4-bromophenyl)quinazolin-4(3H)-one (2c)
Stirring time 60 min, colorless crystals; yield: 92%; mp 202-204 °C [15].
2-(1-Oxo-1-phenylethylthio)-3-phenylquinazolin-4(3H)-one ( 3a)
Stirring time 120 min, yellow needles; yield: 55%; mp 201-203°C, Rf 0.38 (1:2
EtOAc- petrolum ether). IR (KBr, in cm-1): 3060 (CH-Ar), 2910 (CH alkane), 1689
1
(CO), 1608 (CON), 1574 (C=N), 1547 (C=C). H NMR (500 MHz, CDCl3): δ = 4.64
(s, 2H, SCH2), 7.28 (d, 1H, J = 8.4 Hz, Ar-H), 7.37 (m, 3H, Ar-H), 7.55 (m, 5H, Ar-
H), 7.63 (dd, 2H, J1 = J2 = 8.4 Hz, Ar-H), 8.09 (d, 2H, J = 6.9 Hz, Ar-H), 8.20 (d, 1H,
13
J = 7.6 Hz, Ar-H). C NMR (125.7 MHz, CDCl3): δ = 39.9 (SCH2), 119.8 (C-4a),
126.2 (C-5), 127.4 (C-6), 147.2 (C-8a), 156.7 (C-2), 161.6 (C-4), 193.5 (CO). Anal.
Calcd for C22H16N2O2S: C, 70.95; H, 4.33; N, 7.52; S, 8.61. Found C, 71.14; H, 4.52;
N, 7.45; S, 8.32.
2-(1-Oxo-1-phenylethylthio)-3-(4-chlorophenyl)quinazolin-4(3H)-one (3b)
°
Stirring time 30 min, colorless needles; yield: 82.1%; mp 213-215 C, Rf 0.46 (1:2
EtOAc-petrolum ether). IR (KBr, in cm-1): 3064 (CH-Ar), 2912 (CH alkane), 1774
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(CO), 1606 (CON), 1596 (C=N), 1490 (C=C). H NMR (500 MHz, CDCl3): δ = 4.64
(s, 2H, SCH2), 7.28 (d, 1H, J = 7.6 Hz, Ar-H), 7.33 (d, 2H, J = 8.4, Ar-H), 7.37 (t, 1H,
J = 7.6, Ar-H), 7.53 (dd, 4H, J = 6.9 Hz, Ar-H), 7.64 (dd, 2H, J1 = J2 = 7.6 Hz, Ar-H),
8.08 (d, 2H, J = 7.6 Hz, Ar-H), 8.18 (d, 1H, J = 7.6 Hz, Ar-H). 13C NMR (125.7 MHz,
CDCl3): δ = 40.1 (SCH2), 119.6 (C-4a), 126.2 (C-6), 127.3 (C-5), 147.1 (C-8a), 156.3
(C-2), 161.5 (C-4). Anal. Calcd for C22H15ClN2O2S: C, 64.94; H, 3.72; N, 6.88; S,
7.88. Found C, 65.17; H, 3.58; N, 6.61; S, 7.54.

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2-(1-Oxo-1-phenylethylthio)-3-(4-bromophenyl)quinazolin-4(3H)-one (3c)
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°
Stirring time 60 min, colorless needles; yield: 74 %; mp 222-224 C, Rf 0.42 (1:2.5
EtOAc-hexane). IR (KBr, in cm-1): 3064 (CH-Ar), 2914 (CH alkane), 1772 (CO),
1606 (CON), 1596 (C=N), 1488 (C=C). 1H NMR (500 MHz, CDCl3): δ = 4.66 (s, 2H,
SCH2), 7.26 (d, 1H, J = 8.4 Hz, Ar-H), 7.29 (d, 2H, J = 8.4, Ar-H), 7.37 (t, 1H, J = 106
7.6, Ar-H), 7.53 (t, 2H, J = 7.6 Hz, Ar-H), 7.64 (dd, 2H, J1 = J2 = 7.6 Hz, Ar-H), 7.70
(d, 2H, J = 8.4 Hz, Ar-H), 8.08 (d, 2H, J = 7.6 Hz, Ar-H), 8.18 (d, 1H, J = 7.6 Hz, Ar-
H). 13C NMR (125.7 MHz, CDCl3): δ = 40.2 (SCH2), 119.7 (C-4a), 126.7 (C-5),
127.3 (C-5), 146.9 (C-8a), 156.3 (C-2), 161.4 (C-4), 193.4 (CO).
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2-(2-Hydroxyethylthio)-3-phenylquinazolin-4(3H)-one (4a)
°
Stirring time 20 min, colorless needles; yield: 68 %; mp 129-131 C, Rf 0.37 (1:1.5
EtOAc- petrolum ether). IR (KBr, in cm-1): 3270 (OH), 3058 (CH-Ar), 2936 (CH
1
alkane), 1608 (CON), 1573 (C=N), 1479 (C=C). H NMR (500 MHz, DMSO-d6): δ =
3.22 (t, 2H, J = 6.1 Hz, SCH2), 3.60 (q, 2H, J = 6.1 Hz, CH2OH), 4.94 (t, 1H, J = 5.3
Hz, OH), 7.41 (m, 2H, Ar-H), 7.44 (d, 1H, J = 6.9 Hz, Ar-H), 7.54 (m, 3H, Ar-H),
7.57 (d, 1H, J = 8.4 Hz, Ar-H), 7.80 (m, 1H, Ar-H), 8.04 (dd, 1H, J1 = 8.4 Hz, J2 = 1.5
Hz, Ar-H). Anal. Calcd for C16H14N2O2S: C, 64.41; H, 4.73; N, 9.39; S, 10.75. Found
C, 64.86; H, 4.51; N, 9.04; S, 10.52.
2-(2-Hydroxyethylthio)-3-(4-chlorophenyl)quinazolin-4(3H)-one (4b)
Stirring time 120 min, colorless needles; yield: 86.3%; mp 165-167 °C [15].
2-(2-Hydroxyethylthio)-3-(4-bromophenyl)quinazolin-4(3H)-one (4c)
°
Stirring time 60 min, colorless needles; yield: 87%; mp 184-185 C, Rf 0.63 (1:2
EtOAc- petrolum ether). IR (KBr, in cm-1): 3566 (OH), 3062 (CH-Ar), 2938(CH
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alkane), 1606 (CON), 1574 (C=N), 1486 (C=C), 530 (C-Br). H NMR (500 MHz,
DMSO-d6): δ = 3.23 (t, 2H, J = 6.1 Hz, SCH2), 3.60 (q, 2H, J = 6.1 Hz, CH2OH), 4.94
(t, 1H, J = 5.3 Hz, OH), 7.42 (d, 2H, J = 8.4 Hz, Ar-H), 7.44 (d, 1H, J = 7.6 Hz, Ar- 127
H), 7.57 (d, 1H, J = 8.4 Hz, Ar-H), 7.74 (d, 2H, J = 8.4 Hz, Ar-H), 7.80 (m, 1H, Ar-
H), 8.03 (d, 1H, J = 6.9 Hz, Ar-H). Anal. Calcd for C16H13BrN2O2S: C, 50.94; H,
3.47; N, 7.43; S, 8.50. Found C, 51.09; H, 3.66; N, 7.72; S, 8.61.
General method for acid hydrolysis of (12a-c)
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A solution of (0.91 mmol) of 9a-c and conc HCl (6mL) was warmed in water path for
1hr, then the reaction mixture was poured into water. The formed precipitate was
filtered, washed with water and recrystalized from ethanol.
3-Phenylquinazoline-2,4(1H,3H)-dione (12a)

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colorless crystals; yield: 82 %; mp 281-283 °C, Rf 0.43 (1.5:1 EtOAc- petrolum ether).
1H NMR (500 MHz, DMSO-d6): 7.19 (dd, 2H, J1 = 7.6, J2 = 6.9, Ar-H), 7.29 (d, 2H, J
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= 8.4 Hz, Ar--H), 7.39 (dd, 2H, J1 = 7.6, J2 = 6.9, Ar-H), 7.45 (dd, 2H, J1 = 8.4, J2 = 138
6.9, Ar-H), 7.67 (dd, 2H, J1 = 8.4, J2 = 6.9, Ar-H), 7.90 (d, 1H, J = 8.4 Hz, Ar-H),
11.53 (s, 1H, NH).
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3-(4-Phlorophenyl)quinazoline-2,4(1H,3H)-dione (12b)
°
Colorless crystals; yield: 88 %; mp 299-300 C, Rf 0.63 (1:2.5 EtOAc- petrolum
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ether). H NMR (500 MHz, DMSO-d6): 7.22 (m, 2H, Ar-H), 7.37 (d, 2H, J = 15 Hz,
Ar-H), 7.54 (d, 2H, J = 15 Hz, Ar-H), 7.70 (m, 1H, Ar-H), 7.93 (d, 1H, J = 11.5 Hz,
Ar-H), 11.55 (s, 1H, NH), m/z: 272.
3-(4-Bromophenyl)quinazoline-2,4(1H,3H)-dione (12c)
Colorless crystals; yield: 91 %; mp 326-328 °C, Rf 0.38 (1:1 EtOAc- petrolum ether).
IR (KBr, in cm-1): 3455 (NH), 1669 (CON), 1581 (C=N), 1515 (C=C). 1H NMR (500
MHz, DMSO-d6): 7.18 (m, 2H, Ar-H), 7.28 (d, 2H, J = 8.4 Hz, Ar-H), 7.66 (m, 3H,
Ar-H), 7.90 (d, 1H, J = 8.4, Ar-H), 11.56 (s, 1H, NH).
General procedure for alkylation reaction of 3-arylquinazolin-2,4(1H,3H)-dione
A mixture of 12a-c (0.6 mmol) and anhydrous potassium carbonate (0.9 mmol) in
dry DMF (3 mL) was stirred for 1hr, appropriate alkyl halide (0.6 mmol) was added.
The reaction mixture was stirred for further time 10:60 min, then diluted with cold
water. The formed precipitate was filtered, washed with water and recrystallized from
ethanol
1-Methyl-3-phenylquinazoline-2,4(1H,3H)-dione (13a)
1
Stirring time 30 min, colorless needles; yield: 91 %; mp 220-221°C. H NMR (500
MHz, CDCl3): δ = 3.64 (s, 3H, CH3), 7.28 (m, 4H, Ar-H), 7.44 (dd, 1H, J1 = 7.6 Hz,
J2 = 6.9 Hz, Ar-H), 7.51 (dd, 2H, J1 = 8.4 Hz, J2 = 6.9 Hz, Ar-H), 7.73 (m, 1H, Ar-H),
8.62 (dd, 1H, J1 = 7.6 Hz, J2 = 1.5 Hz, Ar-H).
1-Methyl-3-(4-Chlorophenyl)quinazolin-2,4(1H,3H)-dione (13b)
Stirring time 20 min, colorless crystals; yield: 99 %; mp 223-225°C. IR (KBr, in cm-
1): 2982 (CH alkane), 1707 (NCON), 1661 (CON), 1482 (C=C), 761 (C-Cl). 1H NMR
(500 MHz, CDCl3): δ = 3.63 (s, 3H, CH3), 7.21 (d, 2H, J = 8.4 Hz, Ar-H), 7.28 (m,
2H, Ar-H), 7.47 (d, 2H, J = 8.4, Ar-H), 7.74 (m, 1H, Ar-H), 8.25 (m, 1H, Ar-H). m/z
286.
1-Methyl-3-(4-bromophenyl)quinazolin-2,4(1H,3H)-dione (13c)

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Stirring time 15 min, colorless crystals; yield: 90 %; mp 214-216 °C. IR (KBr, in cm-
1): 3062 (CH alkane), 1657 (CON), 1715 (NCON), 1481 (C=C), 515 (C-Br). 1H NMR
(500 MHz, CDCl3): δ = 3.63 (s, 3H, CH3), 7.15 (d, 2H, J = 8.4 Hz, Ar-H), 7.28 (m,
2H, Ar-H), 7.63 (d, 2H, J = 8.4, Ar-H), 7.74 (m, 1H, Ar-H), 8.25 (dd, 1H, J1 = 7.6 Hz,
J2 = 1.5 Hz, Ar-H).
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1-Allyl-3-phenylquinazolin-2,4(1H,3H)-dione (14a)
°
Stirring time 30 min, colorless needles; yield: 91 %; mp 160-161 C, Rf 0.59 (1:1
EtOAc-hexane). IR (KBr, in cm-1): 2901 (CH-Ar), 2987 (CH alkene), 1706 (NCON),
1655 (CON), 1478 (C=C). 1H NMR (500 MHz, CDCl3): δ = 4.80 (d, 2H, J = 4.6 Hz,
NCH2), 5.29 (m, 2H, CH2 ), 5.96 (m, 1H, CH ), 7.26 (m, 4H, Ar-H), 7.44 (dd,
1H, J1 = 7.6 Hz, J2 = 6.8 Hz, Ar--H), 7.51 (dd, 2H, J1 = 8.4 Hz, J2 = 6.8 Hz, Ar-H),
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7.69 (m, 1H, Ar-H), 8.26 (m, 1H, Ar-H). C NMR (125.7 MHz, CDCl3): δ = 46.2
(NCH2), 114.0 (C-8), 118.1 (CH2 ), 122.8 (C-4a), 128.0 (C-6), 128.8 (C-5), 129.5
(CH ), 131.2 (C-7), 140.2 (C-8a), 150.9 (C-2), 161.9 (C-4). Anal. Calcd for
C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found C, 73.18; H, 5.28; N, 10.27.
1-Allyl-3-(4-chlorophenyl)quinazolin-2,4(1H,3H)-dione (14b)
°
Stirring time 20 min, colorless needles; yield: 96 %; mp 156-157 C, Rf 0.62 (1:1
EtOAc-hexane). IR (KBr, in cm-1): 3089 (CH-Ar), 3064 (CH alkene), 2988 (CH
alkane), 1722 (NCON), 1666 (CON), 1479 (C=C), 759 (C-Cl). 1H NMR (500 MHz,
DMSO-d6): δ = 4.72 (d, 2H, J = 3.4 Hz, NCH2), 5.29 (2d, J1 = 17.2 Hz, J2 = 10.3 Hz,
2H, CH2 ), 5.90 (m, 1H, CH ), 7.28 (dd, 1H, J1 = 8.0 Hz, J2 = 6.9 Hz, Ar-H),
7.37 (dd, 3H, , J1 = 8.5 Hz, J2 = 8.0 Hz, Ar--H), 7.52 (d, 2H, J = 8.5 Hz, Ar-H), 7.75
(m, 1H, Ar-H), 8.03 (m, 1H, Ar-H). 13C NMR (125.7 MHz, DMSO-d6): δ = 45.8
(NCH2), 115.8 (C-8), 116.1 (CH2 ), 122.9 (C-4a), 123.7 (C-6), 128.7 (C-5), 129.2
(CH ), 131.6 (C-7), 140.5 (C-8a), 150.6 (C-2), 161.8 (C-4), m/z: 312.1. Anal.
Calcd for C17H13ClN2O2: C, 65.29; H, 4.19; N, 8.96.. Found C, 65.58; H, 4.01; N,
8.72.
1-Allyl-3-(4-bromophenyl)quinazolin-2,4(1H,3H)-dione (14c)
Stirring time 15 min, colorless needles; yield: 92 %; mp 177-179 °C, Rf 0.14 (1:1.5
EtOAc-hexane). IR (KBr, in cm-1): 3087 (CH-Ar), 3058 (CH-Ar), 3063 (CH alkene),
2936 (CH alkane), 1722 (NCON), 1662 (CON), 1479 (C=C), 514 (C-Br). 1H NMR
(500 MHz, CDCl3): δ = 4.79 (d, 2H, J = 5.2 Hz, NCH2), 5.29 (m, 2H, CH2-All), 5.95
(m, 1H, CH-All), 7.16 (d, 2H, J = 8.4 Hz, Ar-H), 7.26 (m, 2H, Ar--H), 7.62 (d, 2H, J
= 8.4 Hz, Ar-H), 7.69 (m, 1H, Ar-H), 8.25 (m, 1H, Ar-H). 13C NMR (125.7 MHz,

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CDCl3): δ = 46.3 (NCH2), 114.1 (C-8), 118.2 (CH2 ), 123.7 (C-4a), 129.4 (C-6),
129.8 (C-5), 130.7 (CH ), 131.5 (C-7), 140.1 (C-8a), 150.6 (C-2), 161.7 (C-4).
Computational details
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All the quantum chemical calculations of the studied compounds were performed by 206
applying DFT method with the B3LYP functional and 6‒311G(d,p) basis set using 207
Gaussian 03 software [16]. The geometries were optimized by minimizing the 208
energies with respect to all the geometrical parameters without imposing any 209
molecular symmetry constraints. GaussView 4.1 [17] and Chemcraft [18] programs
have been used to draw the structure of the optimized geometry. The computational
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study of the reactant species was first carried out in gas phase, then, the Self- 212
Consistent Reaction Field (SCRF) theory [19], with Polarized Continuum Model
(PCM) was used to predict the effect of solvent (DMSO) on the stability of the
tautomers studied [20]. The natural atomic charges are calculated using NBO
calculations as implemented in the Gaussian 03 package [21] at the DFT/B3LYP
level. The nucleophilicity index [21] is calculated referred to tetracyanoethylene
(TCE) is given by
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N =EHOMO(Nu)- EHOMO(TCE)
(5)
Fukui functions for electrophilic attack on an atom, k, in an N-electron system was
introduced by Yang and Mortier [8] as
−
k
(7)
f
= q (N) − q (N −1)
k
k
where qk(N) and qk(N-1) are the atomic charges of the system with N and N-1
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224
−
k
electrons, respectively. The condensed Fukui functions
Natural population analysis (NPA) [23].
f
are calculated using
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226
Condensed local nucleophilicity index (Nk) [24] is defined
−
Nk = fk N
(9)
227
Also the molecular structures of the products 2a-c, 14a and 14c were calculated using
the same level of theory. The electronic and spectroscopic properties of the selected
products were also predicted.
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Results and discussion
The starting materials 3-aryl-2-mercapto-3H-quinazolin-4-one 1a-c were prepared
adopting the reported procedure [25]. The 2-mercapto group of 1a-c was alkylated
with a variety of alkyl halides, methyl iodide, allyl bromide, phenacyl bromide and 2- 234
bromoethanol in DMF as a solvent and anhydrous potassium carbonate to give the 235

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thio-ether derivatives, (scheme 1). The structures of the products were confirmed by
their spectral data.
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The treatment of the ester 5a-c with hydrazine hydrate afforded the corresponding
hydrazide 9a-c [26, 27]. The reaction of 9a-c with ammonium mercaptocyanate failed
to give 10 neither in aqueous HCl nor in benzene as a solvent [28] while the reaction
in aqueous HCl proceeds to give 3-aryl-1H,3H-quinazolin-2,4-dione 12a-c instead.
The yield of 12a-c is improved from 42 % in dilute HCl to 91% in concentrated HCl.
The structure was confirmed by IR spectroscopy which showed absence of peaks at
3303 cm-1 corresponding to NH2 group of 9. The mass spectrum of 12b showed the
molecular ion peak at m/z 272.
The NH-group of 12a-c was alkylated with a series of alkyl halides, methyl iodide and
allyl bromide using potassium carbonate in DMF to give 13a-c and 14a-c,
respectively. The structures of these compounds were confirmed by their spectral data.
It is clear that the reactants 1a-c and 12a-c could undergo the tautomeric equilibrium
reactions shown in scheme 3. The relative stability as well as chemical reactivity of
these tautomers in gas phase and in solution have been predicted using DFT/B3LYP
method. The alkylation reaction of the thiones (1a-c) proceeds to the formation of the
S-alkylated products whatever the alkyl halide used. In these cases, the attack occurs
on the S-atom rather than the ring N-atom of the heterocycle. In contrast, the diones
12a-c yielded the N-alkylated products via the attack of the alkyl halide on
quinazoline ring nitrogen instead of the carbonyl O-atom, hence N-alkylated products
were obtained. In this section the stability of the possible tautomers will be
investigated in the framework of the DFT method followed by studying the chemical
reactivity, site reactivity and selectivity towards these alkylation reactions using the 260
well known quantum chemical descriptors described above.
Stability of the studied tautomers
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263
The relative stabilities and the population of these isomers are predicted using
B3LYP/6-311G(d,p) calculations. The B3LYP/6-311G(d,p) calculated energy 264
predictions of the studied tautomers are compared in Table S1 (Supplementary 265
Materials) which shows that T1 tautomers have lower energy values than T2 in all
cases. The relative abundance of the studied tautomers was calculated from: ꢀG = -
RTlnK, where ꢀG denotes the difference between the Gibbs free energies of a given
isomer relative to the most stable one and K is the corresponding equilibrium
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constant. The abundance of the most stable species, T1 tautomer equal ~100.00% at
298 K in the gas phase. The T2 forms have zero total populations and are expected to
be of no importance. Because the solvent effects are important in tautomer stability
phenomena as the polarity differences among isomers can make significant changes in
their relative energies in solution so we used PCM to model the effect of solvent on
these tautomeric equilibrium reactions. Table S2 (Supplementary Information)
showed the total energies and thermodynamic parameters of the studied isomers in
presence of DMSO as solvent. The effect of solvent on the calculated energies and
thermodynamic parameters is shown in Table S2 (Supplementary Information). In
solution, the energy barrier (ꢀE) between the two tautomers increased compared to
the gas phase. It is revealed that the stability of T1 increases in presence of solvent.
Anyway the most stable isomer T1 is almost the only species that could exist in
solution where the T2 has almost null population.
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Reactivity and site selectivity of the reactants
For the studied substrates, the calculated quantum chemical descriptors such as
EHOMO, ELUMO and nucleophilicity index (N) obtained at the DFT/B3LYP/6-311G(d,p)
level of theory are collected in Table 1. The atomic charge densities at the N- and S-
sites of the N (QN) and N-1 (QN-1) systems were calculated and presented in Table 2.
The calculated local nucleophilicity trend of the studied substrates is analyzed using
¯
local nucleophilicity index Nk and Fukui function fk . The values of these local
reactivity descriptors on the N- and S-atoms of compounds 1a-c and 12a-c are given
in Table 2. The most significant results that can be easily concluded from Table 1 is
the lower nucleophilicity index values for compounds b and c due to the presence of
the halogen substitution at the phenyl ring. The nucleophilicity index has maximum
¯
values for compounds a. In a number of studies, NPA charges are usually used for fk
¯
calculations where the atomic centers with maximal fk are interpreted as the most
¯
reactive nucleophilic reaction sites [29-32]. For compounds 1a-c, the Nk and fk
values are higher for the S-sites compared to the N-one. These results indicated the
higher reactivity of the S-site towards nucleophilic attack compared to the N-site,
hence S-alkylated products were obtained. In contrast, the compounds 12a-c have N-
¯
atom with higher nucleophilicity index Nk and Fukui function fk values than the O- 300
atom. The N-alkylation is the best option for 12. From this point of view we could
conclude that, the compounds 1a-c favor the S-alkylation while the 12a-c favor the N-
alkylation reaction.
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Modeling the structure of the products:
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The optimized structures of the products 2a-c, 14a and 14c were calculated using 6-
311G(d,p) level of theory which used as models to describe the geometric structure of
the obtained products. The optimized geometry of these compounds are shown in
Fig.1. The optimized geometric parameters (bond distances and bond angles) were
compared with the X-ray structure of the structurally related compounds [33,34] and
the results were collected in Table 3. The results showed a good agreement between
the calculated geometric parameters and the experimental data. It is worthnoting that,
the quinazoline and phenyl rings are planar. The angle between the plane passing
through the quinazoline ring and the plane passing through the phenyl ring is 88.3º,
69.4º and 68.88º for compounds 2a-c, respectively. Moreover, the angle between the
two ring planes in case of 14a and 14c is 85.5 and 80.1, respectively. The two rings
are perpendicular to one another in compounds a where there is no substituent at the
phenyl ring. The presence of large size halogen (Br) at the phenyl ring make the angle
between the two ring planes becomes less compared to the unsubstituted derivatives, a
i.e, more deviation from the perpendicularity of the two rings takes place. On other
hand the R-groups are not coplanar with the quinazoline ring plane for all the studied
compounds.
The charge calculations at different atomic sites play a crucial role in different
properties such as dipole moment, molecular polarizability as well as electronic
structure of a compound [35]. In this regard, the natural atomic charges (NAC) were
calculated using NBO method at the DFT B3LYP/6-311G(d,p) level of theory and the
results are given in Table 4. The natural charge calculations indicate the
electronegative nature of the O and N-atoms. The maximum natural charges occur at
the O-atoms for all the studied compounds (-0.5864 to -0.6247). All the carbon atoms
are negative except those attached to strong electronegative atoms (O or N atoms).
The most positively charged carbon atoms are C4, C8, C10 and C13 for compounds 2
and C4, C8, C10 and C12 for 14. The maximum positive charge occurs at C10 for the
former and C8 for the latter. The reason is that these C-atoms bonded to larger
number of strong electronegative atoms. All H-atoms have positive charge densities.
The halogen substiuent showed very little effect on the natural charge of the different
atomic sites. Only we noted significant increase in the natural charge values at C16
and C15 of compounds 2b-c and 14c compared to 2a and 14a, respectively. The

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electron withdrawing character of the halogen (Cl or Br) increase the natural charge
value at the C-atom bonded to it compared to compounds a.
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338
339
340
The dipole moments and polarizability of the studied systems are given in Table 5. It
could be seen that the dipole moment is in the order 14c˃14a˃2a˃2b˃2c. The polarity
of the compounds 14 is higher due to the presence of one more O-atom while those 341
having S-atom are less polar compounds. Significantly, the presence of the thione O-
atom and the Br-atom in the same direction is a reasonable factor for the highest
polarity predicted for 14c. It seems that, the presence the hydrophobic moiety bonded
to the S-atom in case of compounds 2 in the same direction with the halogen tends to
decrease the polarity of the mercapto products. Polarizability depends on how the
tendency of electron cloud of molecular system to distort under the effect of
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345
346
347
approaching charge. In fact, this depends on the structure complexity as well as the 348
size of the molecular system. Molecules having large size are more polarizable. We 349
noted that combination of S- and Br-atom in the same molecule leads to show the 350
highest polarizability (2c).
351
352
Frontier molecular orbitals
For chemists and physicist, the properties of the frontier molecular orbitals (FMOs) 353
like energy and electron densities are very important quantum chemical parameters.
The electron densities of these FMOs were used for predicting the most reactive
position in π‒electron systems and also explained several types of reactions in
conjugated system [36]. Moreover, the energies of the lowest unoccupied molecular
orbital (ELUMO) and the highest occupied molecular orbital (EHOMO) and their energy
gap (ꢀE) reflect the chemical reactivity of the molecule. A molecule having high
frontier orbital gap (ꢀE) is less polarizable and is generally associated with a low
chemical reactivity and high kinetic stability [37]. Recently, the energy gap between
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358
359
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361
HOMO and LUMO has been used to prove the bioactivity from intramolecular charge 362
transfer (ICT) [38, 39]. The EHOMO, ELUMO and ꢀE values of the studied compound
were calculated by B3LYP/6‒311G(d,p) method. The HOMO and LUMO pictures are
shown in Fig. 2. For compounds 2, the electron densities of the HOMO and LUMO
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365
are mainly localized on the S-atom. The electron density of the HOMO level on the 366
quinazoline ring is less significant in case of 2b and 2c. For compounds 14, the 367
HOMO is located on the quinazoline and phenyl rings for a and c, respectively. The 368
LUMO of all the studied systems is mainly localized on the π-system of the 369
quinazoline ring.
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In general, the presence of halogen substituent on the phenyl ring stabilizes both
HOMO and LUMO levels. The LUMO is stabilized further in comparison with
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HOMO, hence the energy gap decreased. For compounds 2, the energy gap is in the 373
order a˃b˃c. The molecule (2a) has highest energy gap (4.8208 eV). The presence of
Br-atom attached to the phenyl ring enhances the ability of the system towards
electron transfer process hence 2c is the most polarizable due to the presence of
combination of S and Br-atoms. In comparison, the oxo compounds 14a and 14c has
higher energy gap compared to 2a and 2c, respectively. It is the maximum for 14a
which showed the maximum kinetic stability.
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384
Based on the energies of the frontier molecular orbitals, various chemical reactivity
descriptors such as electronegativity (χ), chemical potential (ꢁ), chemical hardness
(η), global softness (S) and global electrophilicity index (ω) [40-44] were proposed
for understanding the different pharmacological aspects of drug molecules. These
descriptors are calculated using Eqs (1)-(5) given below:
χ = (ꢀꢁꢂ)
1
2
3
4
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388
ꢃ
ꢁ = −χ = − (ꢄꢁꢅ)
ꢃ
η = (ꢀꢆꢂ)
ꢃ
ꢈ
ꢇ = ꢃη
ꢉ
ꢁ
ω =
5
389
ꢃη
The chemical hardness is a measure of the resistance to charge transference [45],
while the electronegativity is a measure of the tendency to attract electrons in a
chemical bond, as is defined as the negative of the chemical potential in DFT [45].
Moreover, the electrophilicity index (ω) measures the stabilization in energy when the
system acquires an additional electronic charge from the environment. It contains
information about both electron transfer (chemical potential) and stability (hardness)
and is a better descriptor of global chemical reactivity (Eq. 5). For the studied
compounds, these chemical reactivity descriptors are given in Table 6. It is seen that
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397
all the studied systems have negative chemical potential and it means that the 398
compounds are stable. The hardness signifies the resistance towards the deformation
of electron cloud of chemical systems under small perturbation encountered during
chemical process. Soft systems are large and highly polarizable, while hard systems
are relatively small and much less polarizable. It is found that the compound (14a) is
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the hardest while 2c is the softest. Moreover, the high value of electrophilicity index
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(ω) of 2c favors its electrophilic behavior to be the highest [46].
Electronic spectra and TD-DFT calculations
The lowest energy electronic transition implies the electron transfer from the highest
occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital
(LUMO). The easiest way, but the less accurate, to calculate the energy of this
transition is to calculate the energy gap between HOMO and LUMO levels. The
calculated transition energy of the studied molecules are shown in Fig. 2. To get the
accurate electronic transitions, we performed the time‒dependant density functional
theory (TD‒DFT) calculations. The TD-DFT results of the spin allowed singlet-
singlet electronic transitions collected in Table S3 (Supplementary Information). The 414
most important electronic transition bands are shown in Table 7 while the theoretical
spectra are shown in Fig. 3. Compound 2a showed two electronic transition bands at
295.4 nm (f=0.0559) and 273.0 (f=0.1968) due to the H→L (87%) and H→L+1
(75%) transitions, respectively. These bands showed significant bathochromic shift in
case of 2b and 2c. On other hand the longest wavelength band for 14c at 289.1nm
(f=0.0701) which is mainly due to H→L (85%) excitation showed slight
bathochromic shift in presence of halogen substitution at the ring.
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Molecular electrostatic potential
Electrostatic potential maps are very useful three dimensional diagrams used to
visualize the charge distributions and charge related properties of molecules. The
MEP is typically visualized through mapping its values onto the surface reflecting the
molecules boundaries so it allows us to visualize the size and shape of molecules. This
can be generated by overlapping the vdW radii of all atoms in the molecule. MEP
diagram has been also used to predict the reactive sites for electrophilic and
nucleophilic attack, and in studies of biological recognition and hydrogen bonding
interactions [47, 48].The MEP of the studied compounds calculated using B3LYP
method with 6‒311G(d,p) basis set is shown in Fig. 4. This figure provides a visual
representation of the chemically active sites and comparative reactivity of atoms.
Potential increases in the order red < orange < yellow < green < blue. For all the
studied compounds, the negative regions (red) are mainly localized over the carbonyl
oxygen atoms (‒0.0271 to ‒0.0409 au). The maximum positive regions (blue) are
localized on the phenyl ring attached to the N-atom of the quinazoline ring in case of 436

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2 and at the carbonyl carbon for 14. We noted that, the presence of halogen group
attached to the phenyl ring shifts its electrostatic potential to more positive value for
compounds 2. Also, the negative MEP values at the fused phenyl ring of the
quinazoline moiety are decreased, hence the ring become deactivated towards
electrophilic attack.
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454
NLO properties
The development of materials with large nonlinear optical (NLO) properties has been
of great interest in past few decades. These materials find numerous device
applications, from lasers to optical switches and electronics [49]. So far, the organic
π-conjugated molecules have been considered mostly for this purpose because of their
easy functionalization to fine tune the desired properties and the ease of fabrication
and integration into devices [50-52]. NLO is very important in areas such as
telecommunications, optical interconnections and signal processing [53, 54].
The components of the static polarizability components (α0) and the average
polarizability (α0) of the studied compound are given in Table 5. The α0 values are
calculated to be in the order 2c˃2b˃2a˃14c ˃14a. The ranking of the HOMO-LUMO
energy gap is in the opposite order. It is well known that compounds having good
NLO activity are characterized by high value of polarizability and low energy gap. It
could be seen from the presence investigation that 2c has the highest polarizability 455
and lowest energy gap; hence 2c could be the best candidates for NLO applications.
456
457
458
NMR spectra
The isotropic magnetic shielding (IMS) values calculated using the GIAO approach at
1
the 6-311G(d,p) level are used to predict the 13C and H chemical shifts (δcalc) for the 459
studied compounds and the results are correlated to the experimental NMR data (δexp)
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1
13
in CDCl3 solvent. The experimental and theoretical H- and C-NMR chemical shift
values of the studied compounds are given in Table S4 (Supplementary Information).
According to these results, the calculated chemical shifts are in compliance with the
experimental findings. A representative example for the correlation between the
experimental and theoretical chemical shifts of the studied is shown in Fig. 5. It can
be seen that, there is good agreement between the experimental and the calculated
chemical shifts. The correlation coefficients for the carbon‒13 (R2 = 0.970) and
proton (R2 = 0.976) are high for 2a.

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Conclusion
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The molecular structure, electronic and spectroscopic properties of newly synthesized
S-alkylated products of the 3-aryl-2-mercapto-3H-quinazolin-4-one; 1 and N-
alkylated products of 3-aryl-1H,3H-quinazolin-2,4-dione; 12 were investigated using
B3LYP/6-311G(d,p) method. The structures of the products were experimentally
1
identified using m.p., IR and HNMR data. The synthesized compounds were
prepared in good yields via efficient nucleophilic substitution reaction of SH and NH
substrates. The chemical reactivity descriptors that could help to understand the
biological activity of the products are also predicted. The reactivity of these substrates
toward the nucleophilic attack at either the N or S/O sites was predicted using the 480
reactivity descriptors obtained from the DFT calculations. DFT reactivity studies 481
showed that 12 have the N-site with the highest nucleophilicity while the S-site is the 482
most nucleophilic in 1.
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References :
1. J. H. Chan,; J. S. Hong,; L. F. Kuyper,; M. L. Jones,; D. P. Baccanari,; R.
L.Tansik,; C. M.Boytos,; S. K.Rudolph,; A. D. Brown, J. Heterocycl. Chem.
1997, 34, 145.
2. S. L. Gackenheimer,; J. M. Schaus,; D. R. Gehlert, J. Pharmacol. Exp. Ther.
113 (1996) 732.
3. R. O. Dempcy,; Skibo, E. B. Biochemistry 30 (1991) 8480.
4. Nordisk-Droge. 18113; Patent, N. A. Ed.; Nordisk Drogeand Kemi- 513
Kalieforretning AIS: Netherlands, 1965.
514
515
516
517
518
519
520
521
522
523
524
5. D. J. Connolly,; D. Cusack,; T. P. O’Sullivan; P. J. Guiry Tetrahedron 61
(2005) 10153.
6. D. W. Fry,; A. J. Kraker,; A. McMichael,; L. A. Ambroso,; J. M. Nelson,; W.
R. Leopold,; R. W. Connors,; A. J. Bridges, Science 265 (1994) 1093.
7. T. M. Traxler,; P. Furet,; H. Melt,; E. Buchdunger,; T. Meyer,; N. Lydon, J.
Med. Chem. 39 (1996) 2289.
8. J. B. Hynes,; A. Tomazić,; A. Kumar,; V. Kumar,; J. H. Freisheim, J.
Heterocycl. Chem. 28 (1991) 1981
9. A. Witt,; J. Bergman, Curr. Org. Chem. 7 (2003) 659.
10. (a) W. L. F. Armarego, Adv. Heterocycl. Chem. 24 (1979) 1; (b) S. Johne,
Prog. Chem. Org. Nat. Prod. 46 (1984) 159; (c) Johne, S. Rodd’s Chemistry 525
of Carbon Compounds (supplements to the 2nd ed.); M. F. Ansell, , Ed.;
Elsevier: Amsterdam 1995; Vol. IV I/J, 223–240; (d) D. J. Brown,
Quinazolines. In The Chemistry of Heterocyclic Compounds (supplement I);
Wiley: New York, NY, 1996, 55. (e) A. L. D’yakonov,; M. Telezhenetskaya,
V. Chem. Nat. Compd. 33 (1997) 221; (f) Johne, S. Rodd’s Chemistry of
Carbon Compounds (second supplements to the 2nd ed.); M.Sainsbury, Ed.;
Elsevier: Amsterdam 2000; IV I/J, 203–231; (g) S. R. Padala,; P. R. Padi,; V.
Thipireddy, Heterocycles 60 (2003) 183; (h) D. J. Connolly,; D.Cusack,; T. P.
O’Sullivan,; P. J. Guiry, Tetrahedron 61 (2005) 10153; (i) Z. Ma, Y. Hano, T.
Nomura, Heterocycles, 65 (2005) 2203. (j) V. S. Patil, V. S. Padalkar,
N. Sekar, J. fluoresce. 24 (2014) 1077-1086, (k) H. S. Bhatti, S. Seshadri,
Coloration Technology 120 (2006) 101 – 107.
526
527
528
529
530
531
532
533
534
535
536
537
538

ACCEPTED MANUSCRIPT
11. M. F. Grundon, Nat. Prod. Rep. 1 (1984) 195; (ii) M. F. Grundon, Nat. Prod.
Rep. 2 (1985) 393; (iii) M. F. Grundon, Nat. Prod. Rep. 4 (1987) 225; (iv) M.
F. Grundon, Nat. Prod. Rep. 5 (1988) 293; (v) M. F. Grundon, Nat. Prod. Rep.
7 (1990) 131; (vi) M. F. Grundon, Nat. Prod. Rep., 8 (1991) 53; (b) (i) J. P.
Michael, Nat. Prod. Rep. 9 (1992) 25; (ii) J. P. Michael, Nat. Prod. Rep. 10
(1993) 99; (iii) J. P. Michael, Nat. Prod. Rep. 11 (1994) 163; (iv) J. P.
Michael, Nat. Prod. Rep. 12 (1995) 77; (v) J. P. Michael, Nat. Prod. Rep. 12
(1995) 465; (vi) J. P. Michael, Nat. Prod. Rep., 14 (1997) 11; (vii) J. P.
Michael, Nat. Prod. Rep. 14 (1997) 605; (viii) J. P. Michael, Nat. Prod. Rep.
15 (1998) 595; (ix) J. P. Michael, Nat. Prod. Rep. 16 (1999) 697; (x) J. P.
Michael, Nat. Prod. Rep. 17 (2000) 603; (xi) J. P. Michael, Nat. Prod. Rep. 18
(2001) 543; (xii) J. P. Michael, Nat. Prod. Rep. 19 (2002) 742; (xiii) J. P.
Michael, Nat. Prod. Rep., 20 (2003) 476; (xiv) J. P. Michael, Nat. Prod. Rep.
21 (2004) 650; (xv) J. P. Michael, Nat. Prod. Rep. 22 (2005) 627.
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
12. S. B. Mhaske,; N. P. Argade Tetrahedron 62 (2006) 9787.
13. A. M. Alafeefy J. Saudi Chem. Soc. 15 (2011) 337.
14. V. V. Orisik; Y. L. Zborovs'kii; A. A. Dobosh; V. I. Staninets; S. M.
Khripak, Ukrainskii Khimicheskii Zhurnal 68 (2002) 36.
15. Y. A. Azey, Chem. Heterocycl. Compd., 43 (2007) 356.
16. M. J. Frisch, et al., Gaussian‒03, Revision C.01, Gaussian, Inc., Wallingford,
CT, (2004).
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
17. GaussView, Version 4.1, R. Dennington II, T. Keith, J. Millam, Semichem
Inc., Shawnee Mission, KS, (2007).
18. G.A. Zhurko, D.A. Zhurko, Chemcraft: Lite Version Build 08 (Freeware),
2005.
19. A. D. Becke, Phys. Rev. A 38 (1988) 3098-3100.
20. W. Wang, W.J. Mortier, J. Am. Chem. Soc. 108 (1986) 5708-5711.
21. E.D. Glendening, A.E. Reed, J.E. Carpenter, F. Weinhold, NBO Version 3.1,
CI,University of Wisconsin, Madison, (1998).
22. D.R. Roy, R. Parthasarathi, J. Padmanabhan, U. Sarkar, V. Subramanium,
P.K. Chattaraj J. Phys. Chem. A 110 (2006) 1084–1093.
23. W. Yang, W.J. Mortier J. Am. Chem. Soc. 108 (1986) 5708–5711.
24. P. Perez, L.R. Domingo, M. Doque-Norena, E. Chamorro J. Mol. Struct.:
(THEOCHEM) 895 (2009) 86–91.
25. V. J. P.Mishra; S. Kashaw; J. P. Stables Eur. J. Med. Chem. 43 (2008).

ACCEPTED MANUSCRIPT
26. F. A. M. Al-Omary, L. A. Abou-zeid, M. N. Nagi, E. E. Habib, A. A.-M.
574
Abdel-Aziz, A. S. El-Azab, S. G. Abdel-Hamide, M. A. Al-Omar, A. M. Al- 575
Obaid, H. I. El-Subbagh, Bioorg. Med. Chem. 18 (2010) 2849.
27. A. S., El-Azab Phosphorus, Sulfur, and Silicon 182 (2007) 333.
28. M.Belkadi; A. A., Othman Arkivoc (2006) 183.
576
577
578
579
580
581
582
583
29. V. Pilepicć, S. Uršić, Nucleophilic reactivity of the nitroso group. Fukui
function DFT calculations for nitrosobenzene and 2-methyl-2-nitrosopropane,
J. Mol. Struct. (Theochem) 538 (2001) 41-49 and reference within.
30. H. Chermette, Chemical reactivity indexes in density functional theory, J.
Comput. Chem. 20 (1999) 129-154.
31. R. K. Roy, F. De Proft, P. Geerlings J. Phys. Chem. A 102 (1998) 7035-7040.
32. W. Langenaeker, F. De Proft, P. Geerlings J. Mol. Struct. (Theochem) 362
(1996) 175-179.
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
33. F. Al-Omran, R. M. Mohareb and A. A. El-Khair, Molecules 16 (2011) 6129-
6147.
34. Y Kitano, M. Kashiwag, Y. Kinoshita, Acta Cryst. (1972). B28, 1223-1231.
35. I. Sidir, Y.G. Sidir, M. Kumalar, E. Tasal, J. Mol. Struct. 964 (2010) 134-151.
36. K. Fukui, T. Yonezawa, H.J. Shingu J. Chem. Phys. 20 (1952) 722–725.
37. N. Sinha, O. Prasad, V. Narayan, S.R. Shukla, J. Mol. Simul. 37 (2011) 153–
163.
38. L. Padmaja, C. Ravikumar, D. Sajan, I. H. Joe, V. S. Jayakumar, G. R. Pettit,
F. O. Neilsen, J. Raman Spectrosc. 40 (2009) 419–428.
39. C. Ravikumar, I. H. Joe, V. S. Jayakumar, Chem. Phys. Lett. 460 (2008) 552–
558.
40. R.G. Pearson, J. Org. Chem. 54 (1989) 1430–1432.
41. R.G. Parr, R.G. Pearson, J. Am. Chem. Soc. 105 (1983) 7512–7516.
42. P. Geerlings, F. De Proft, W. Langenaeker, Chem. Rev. 103 (2003) 1793–
1873.
43. R.G. Parr, L. Szentpaly, S. Liu, J. Am. Chem. Soc. 121 (1999) 1922–1924.
44. K. Chattaraj, S. Giri, J. Phys. Chem. A 111 (2007) 11116–11121.
45. R.G. Parr, W. Yang, Density-Functional Theory of Atoms and Molecules,
Oxford University Press, New York, 1989.

ACCEPTED MANUSCRIPT
46. R. N. Singh, A. Kumar, R. K. Tiwari, P. Rawat, V. P. Gupta, J. Mol. Struct.
1035 (2013) 427–440.
606
607
608
609
610
611
612
613
614
615
616
617
618
619
620
47. E. Scrocco, J. Tomasi, in: P. Lowdin (Ed.), Advances in Quantum Chemistry,
vol. 2, Academic Press, New York, 1978.
48. J.S. Murray, K. Sen, Molecular Electrostatic Potentials, Concepts and
Applications, Elsevier, Amsterdam, 1996.
49. P. N. Prasad, D. J. Williams, Introduction to nonlinear optical effects in
molecules and polymers, (New York: Wiley) 1991.
50. G. A. Lindsay, K. D. Singer, Polymers for second-order nonlinear optics, ACS
Symposium Series, No. 601 (Washington, DC: ACS) 1995.
51. D. Burland Chem. Rev. 94 (1994) 1-2.
52. E. Hanamura Phys. Rev. B37 (1988) 1273-1244.
53. V. M. Geskin, C. Lambert, J. L. Bredas, J. Am. Chem. Soc. 125 (2003) 15651-
15658.
54. D. Sajan, H. Joe, V.S. Jayakumar, J. Zaleski, J. Mol. Struct. 785 (2006) 43-53.
621
622
623
624

ACCEPTED MANUSCRIPT
Table 1 The calculated quantum chemical parameters of the studied reactants.
Compound
EHOMO
ELUMO
ꢀE
N
Gas
-6.0584
-6.1993
-6.1906
-6.6407
-6.7781
-6.7683
-1.8825
-2.0074
-2.0039
-1.6615
-1.8126
-1.8139
4.1759
4.1919
4.1868
4.9792
4.9656
4.9544
3.310
3.169
3.177
2.727
2.590
2.600
1a
1b
1c
12a
12b
12c
Solution
-1.8014
-1.8300
-1.8289
-1.5853
-1.6218
-1.6164
-6.2946
-6.3419
-6.3384
-6.5019
-6.5275
-6.5286
4.4932
4.5120
4.5095
4.9166
4.9057
4.9122
2.623
2.576
2.579
2.416
2.390
2.389
1a
1b
1c
12a
12b
12c

ACCEPTED MANUSCRIPT
Table 2 The reactivity descriptors of the studied reactants.
¯
¯
Compound
fk
Nk
fk
Nk
QN
QN-1
QN
QN-1
Gas (N-site)
Gas (S-site)
-0.5645 -0.5276
-0.5638 -0.5297
-0.5638 -0.5289
0.0369 0.1221
0.0341 0.1080
0.0349 0.1108
-0.1861
-0.1823
-0.1821
0.2886
0.2448
0.2131
0.4746 1.5709
0.4272 1.3536
0.3952 1.2559
1a
1b
1c
Solution (N-site)
Solution (S-site)
-0.5554 -0.5227
-0.5544 -0.5217
-0.5544 -0.5210
0.0328 0.0860
0.0327 0.0841
0.0334 0.0861
-0.3219
-0.3166
-0.3170
0.3594
0.3508
0.3363
0.6813 1.7869
0.6674 1.7188
0.6534 1.6851
1a
1b
1c
Gas (N-site)
Gas (O-site)
-0.6028 -0.4954
-0.6018 -0.5122
-0.6017 -0.5210
0.1074 0.2930
0.0896 0.2320
0.0807 0.2098
-0.6107 -0.5160
-0.6107 -0.5469
-0.6108 -0.5546
0.0947 0.2583
0.0639 0.1654
0.0562 0.1460
12a
12b
12c
Solution (N-site)
Solution (O-site)
-0.6002 -0.4507
-0.5996 -0.4503
-0.5996 -0.4488
0.1495 0.3611
0.1492 0.3567
0.1508 0.3602
-0.6700 -0.5528
-0.6679 -0.5512
-0.6682 -0.5530
0.1172 0.2831
0.1166 0.2788
12a
12b
12c
0.1152
0.2753

ACCEPTED MANUSCRIPT
Table 3 The calculated geometric parameters of the studied compounds (2a-c, 14a
and 14c) using the B3LYP/6-311G(d,p) method.
Parameter
Calc.
Exp.33 Parameter
Calc.
Exp.34
2a
2b
2c
14a
14c
R(1-2)
R(1-6)
R(1-19)
R(2-3)
R(2-20)
R(3-4)
R(3-21)
R(4-5)
R(4-7)
1.404 1.405 1.405 1.388 R(1-2)
1.383 1.383 1.383 1.366 R(1-6)
1.397 1.397 1.415
1.384 1.384 1.386
1.083 1.083
1.388 1.388 1.378
1.084 1.084
1.084 1.084 1.084
1.383 1.383 1.383 1.382 R(2-3)
1.084 1.084 1.084 R(2-19)
1.407 1.406 1.406 1.404 R(3-4)
1.083 1.083 1.083 R(3-20)
R(1-18)
1.405 1.405 1.402
1.079 1.079
1.409 1.406 1.406 1.397 R(4-5)
1.384 1.384 1.384 1.389 R(4-7)
1.402 1.402 1.402 1.398 R(5-6)
1.465 1.463 1.463 1.456 R(5-10)
1.406 1.406 1.392
1.398 1.398 1.379
1.399 1.399 1.391
1.472 1.471 1.478
1.083 1.083
R(5-6)
R(5-10)
R(6-22)
R(7-8)
1.083 1.083 1.083
R(6-21)
1.287 1.286 1.286 1.285 R(7-8)
1.389 1.398 1.398 1.400 R(7-28)
1.788 1.799 1.799 1.761 R(8-9)
1.425 1.431 1.431 1.402 R(8-27)
1.446 1.444 1.444 1.440 R(9-10)
1.214 1.214 1.214 1.219 R(9-12)
1.395 1.393 1.372
1.476 1.476
R(8-9)
R(8-12)
R(9-10)
R(9-13)
R(10-11)
R(12-28)
R(13-14)
R(13-18)
R(14-15)
R(14-23)
R(15-16)
R(15-24)
R(16-17)
R(16-25)
R(17-18)
R(17-26)
R(18-27)
R(28-29)
R(28-30)
R(28-31)
R(31-32)
R(31-33)
R(33-34)
R(33-35)
A(2-1-6)
A(2-1-19)
A(1-2-3)
A(1-2-20)
A(6-1-19)
A(1-6-5)
A(1-6-22)
A(3-2-20)
A(2-3-4)
A(2-3-21)
A(4-3-21)
A(3-4-5)
A(3-4-7)
A(5-4-7)
A(4-5-6)
A(4-5-10)
A(4-7-8)
1.403 1.405 1.414
1.214 1.214 1.201
1.409 1.410 1.383
1.449 1.446 1.455
1.213 1.213 1.213
1.390 1.390 1.396
1.390 1.390 1.391
1.392 1.391 1.423
1.083 1.083
1.393 1.391 1.384
1.084 1.082
1.393 1.391 1.384
1.084 1.917
1.392 1.391 1.399
1.084 1.082
1.083 1.083
1.092 1.092
1.090 1.090
1.505 1.505
1.087 1.087
1.329 1.329
1.087 1.086
1.084 1.084
119.0 119.0 119.4
120.5 120.5
121.3 121.3 120.7
119.9 119.9
120.6 120.5
120.6 120.6 120.1
121.9 121.9
118.8 118.8
120.1 120.1 119.2
119.3 119.3
120.6 120.6
118.6 118.6 120.3
122.0 121.9 119.8
119.4 119.5 119.9
120.5 120.5 120.2
120.8 120.9 119.4
123.0 123.0 124.6
1.849 1.856 1.856
R(10-11)
1.392 1.393 1.393 1.382 R(12-13)
1.392 1.393 1.393 1.378 R(12-17)
1.392 1.391 1.392 1.384 R(13-14)
1.083 1.082 1.082
1.393 1.391 1.391 1.355 R(14-15)
1.084 1.082 1.082 R(14-23)
1.394 1.391 1.391 1.373 R(15-16)
1.084 1.758 1.916 R(15-24)
1.391 1.391 1.391 1.393 R(16-17)
R(13-22)
1.084 1.082 1.082
1.083 1.082 1.083
1.093 1.094 1.094
1.088 1.090 1.090
1.497 1.494 1.495
1.087 1.087 1.087
1.329 1.330 1.330
1.084 1.084 1.084
1.084 1.085 1.086
R(16-25)
R(17-26)
R(28-29)
R(28-30)
R(28-31)
R(31-32)
R(31-33)
R(33-34)
R(33-35)
119.8 120.0 120.0 119.9 A(2-1-6)
120.0 119.9 119.9 A(2-1-18)
120.8 120.7 120.7 120.9 A(1-2-3)
119.6 119.6 119.6
120.2 120.1 120.1
A(1-2-19)
A(6-1-18)
120.0 119.8 119.8 120.4 A(1-6-5)
121.8 121.8 121.8
119.6 119.7 119.7
A(1-6-21)
A(3-2-19)
120.2 119.9 120.0 119.8 A(2-3-4)
121.5 121.9 121.9
118.3 118.1 118.1
A(2-3-20)
A(4-3-20)
118.8 119.2 119.2 118.9 A(3-4-5)
119.2 118.8 118.8 118.6 A(3-4-7)
122.0 122.0 122.0 122.5 A(5-4-7)
120.5 120.4 120.4 120.2 A(4-5-6)
119.6 119.6 119.6
A(4-5-10)
118.5 119.0 119.0 117.3 A(4-7-8)

ACCEPTED MANUSCRIPT
A(6-5-10)
A(5-6-22)
A(5-10-9)
A(5-10-11)
A(7-8-9)
A(7-8-12)
A(9-8-12)
A(8-9-10)
A(8-9-13)
A(8-12-28)
A(10-9-13)
A(9-10-11)
A(9-13-14)
A(9-13-18)
119.9 120.0 120.0 119.9 A(4-7-28)
118.3 118.4 118.4 A(6-5-10)
121.3 121.3
118.7 118.7 120.4
117.4 117.5
114.7 114.6 115.4
124.2 124.3 123.6
115.7 115.7
116.4 116.4 115.2
122.1 122.3 121.6
108.8 108.8
113.8 114.0 114.0 114.0 A(5-6-21)
125.7 125.2 125.2 126.0 A(5-10-9)
124.6 124.2 124.1 124.8 A(5-10-11)
120.7 115.9 115.9 122.0 A(8-7-28)
114.8 119.9 119.9 113.2 A(7-8-9)
121.5 121.1 121.1 121.5 A(7-8-27)
121.5 123.0 122.9 120.2 A(7-28-29)
100.4 102.9 103.0
A(7-28-30)
105.5 105.5
113.5 113.4
117.0 115.8 115.9 118.3 A(7-28-31)
120.6 120.8 120.8 120.0 A(9-8-27)
121.5 121.3 122.9
125.7 125.7 125.4
116.7 116.6 116.5
117.7 117.7 118.1
121.2 121.0 121.0
119.7 119.9 117.9
119.6 119.7 119.0
119.5 119.9 119.9
95.7 A(8-9-10)
119.7 120.0 120.0 119.6 A(8-9-12)
A(12-28-29) 103.0 101.3 101.3
A(12-28-30) 107.4 110.3 110.3
A(12-28-31) 112.7 113.2 113.2
A(10-9-12)
A(9-10-11)
A(9-12-13)
A(14-13-18) 120.8 120.0 120.0 121.5 A(9-12-17)
A(13-14-15) 119.5 120.2 120.2 118.6 A(13-12-17) 120.7 120.4 123.1
A(13-14-23) 119.6 119.7 119.8 A(12-13-14) 119.6 120.1 116.8
A(13-18-17) 119.5 120.2 120.2 118.6 A(12-13-22) 119.6 119.9
A(13-18-27) 119.6 119.9 119.9
A(15-14-23) 120.9 120.1 120.0
A(12-17-16) 119.5 120.1 118.4
A(12-17-26) 119.7 119.9
A(14-15-16) 120.1 119.2 119.2 120.5 A(14-13-22) 120.8 120.1
A(14-15-24) 119.7 120.6 120.4
A(16-15-24) 120.2 120.2 120.5
A(13-14-15) 120.1 119.1 121.2
A(13-14-23) 119.7 120.5
A(15-16-17) 120.1 121.2 121.2 121.2 A(15-14-23) 120.2 120.5
A(15-16-25) 120.0 119.4 119.4
A(17-16-25) 120.0 119.4 119.4
A(14-15-16) 120.0 121.3 120.0
A(14-15-24) 120.0 119.4
A(16-17-18) 120.1 119.2 119.2 119.7 A(16-15-24) 120.0 119.3
A(16-17-26) 120.2 120.2 120.5
A(18-17-26) 119.7 120.6 120.3
A(17-18-27) 120.9 119.9 119.9
A(29-28-30) 109.5 108.1 108.2
A(29-28-31) 111.5 111.1 111.1
A(30-28-31) 112.2 112.2 112.2
A(28-31-32) 116.0 116.0 116.0
A(28-31-33) 124.2 124.0 124.0
A(32-31-33) 119.8 120.1 120.1
A(31-33-34) 121.4 121.5 121.5
A(31-33-35) 121.5 121.7 121.7
A(34-33-35) 117.2 116.8 116.8
A(15-16-17) 120.1 119.1 120.4
A(15-16-25) 120.2 120.5
A(17-16-25) 119.7 120.5
A(16-17-26) 120.8 120.1
A(29-28-30) 108.2 108.1
A(29-28-31) 111.4 111.5
A(30-28-31) 109.2 109.2
A(28-31-32) 115.2 115.2
A(28-31-33) 124.5 124.5
A(32-31-33) 120.2 120.2
A(31-33-34) 121.8 121.8
A(31-33-35) 121.6 121.6
A(34-33-35) 116.6 116.6

ACCEPTED MANUSCRIPT
Table 4 The calculated natural atomic charges of the studied compounds (2a-c, 14a
and 14c) using the B3LYP/6-311G(d,p) method.
Atom
2a
2b
2c
Atom
C1
14a
14c
C1
-0.2091
-0.1703
-0.1995
0.1876
-0.1797
-0.1441
-0.5683
0.3672
-0.5017
0.6919
-0.5943
0.2530
0.1386
-0.1856
-0.1885
-0.1861
-0.1880
-0.1804
0.2046
0.2031
0.2114
0.2238
0.2151
0.2055
0.2037
0.2054
0.2151
-0.5038
0.2185
0.2375
-0.1994
0.1897
-0.3462
0.1868
0.1866
-0.1988
-0.1712
-0.1871
0.1750
-0.1710
-0.1465
-0.5069
0.3529
-0.5031
0.6914
-0.5960
0.2230
0.1486
-0.1779
-0.2227
-0.0106
-0.2207
-0.1717
0.2059
0.2052
0.2181
0.2249
0.2230
0.2223
-0.0030a
0.2226
0.2210
-0.5008
0.2253
0.2120
-0.1969
0.1997
-0.3571
0.1928
0.1782
-0.1989
-0.1712
-0.1871
0.1751
-0.1711
-0.1464
-0.5070
0.3526
-0.5032
0.6916
-0.5960
0.2239
0.1499
-0.1784
-0.2226
-0.0758
-0.2207
-0.1730
0.2059
0.2052
0.2181
0.2249
0.2233
0.2226
0.0612b
0.2229
0.2210
-0.5011
0.2253
0.2124
-0.1969
0.1996
-0.3571
0.1927
0.1783
-0.2213
-0.1536
-0.2455
0.2092
-0.1799
-0.1308
-0.4598
0.8486
-0.5190
0.6958
-0.5869
0.1667
-0.1846
-0.1880
-0.1922
-0.1879
-0.1852
0.2074
0.2044
0.2147
0.2281
0.2098
0.2032
0.2020
0.2032
0.2098
-0.6247
-0.2108
0.1969
0.2449
-0.1807
0.1988
-0.3641
0.1781
0.1933
-0.2201
-0.1522
-0.2447
0.2093
-0.1811
-0.1300
-0.4590
0.8483
-0.5199
0.6960
-0.5864
0.1649
-0.1667
-0.2179
-0.0752
-0.2178
-0.1675
0.2082
0.2052
0.2154
0.2285
0.2157
0.2209
0.0552b
0.2209
0.2159
-0.6247
-0.2107
0.1976
0.2452
-0.1820
0.1988
-0.3626
0.1784
0.1939
C2
C3
C4
C5
C6
N7
C8
N9
C2
C3
C4
C5
C6
N7
C8
N9
C10
C10
O11
S12
C13
C14
C15
C16
C17
C18
H19
H20
H21
H22
H23
H24
H25
H26
H27
C28
H29
H30
C31
H32
C33
H34
H35
O11
C12
C13
C14
C15
C16
C17
H18
H19
H20
H21
H22
H23
H24
H25
H26
O27
C28
H29
H30
C31
H32
C33
H34
H35
aCl bBr

ACCEPTED MANUSCRIPT
Table 5 The dipole moments components ꢀ (D), polarizability components (a.u.) and
the average polarizability α0 of the studied compounds.
Parameter
2a
2b
2c
14a
14c
0.048
2.132
1.353
1.380
0.594
2.0218
341.321
-10.354
192.251
-2.272
-18.986
180.215
1.285
1.252
0.578
1.8848
354.458
-19.983
197.730
-4.388
-19.079
183.689
3.180
-5.267
0.703
-0.177
5.3171
333.474
6.630
194.517
-1.001
-5.168
142.406
ꢁx
ꢁy
ꢁz
-0.666
-0.200
3.2555
280.111
8.181
188.959
-0.499
2.072
-0.215
2.1438
309.146
7.374
218.591
-5.240
-2.834
146.218
ꢁ
αxx
αxy
αyy
αxz
αyz
αzz
136.071
α0
224.652
237.929
201.714
223.466
245.292

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Table 6 The calculated chemical potential (ꢀ), electronegativity (χ), global hardness
(η), softness (S) and global electrophilicity index (ω) (in eV) for the studied
compound.
Descriptor
2a
6.1602
2b
6.4652
2c
6.4554
14a
6.5017
14c
6.6260
I
A
χ
ꢀ
η
s
1.3394
3.7498
-3.7498
2.4104
0.2074
2.9167
1.7271
4.0962
-4.0962
2.3690
0.2111
3.5412
1.7285
4.0919
-4.0919
2.3635
0.2116
3.5423
1.5723
4.0370
-4.0370
2.4647
0.2029
3.3061
1.7037
4.1649
-4.1649
2.4612
0.2032
3.5240
ω

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Table 7 The most important electronic transition bands calculated using the TD-DFT
method for the studied compounds.
2a
295.4 0.0559 H→L (87%)
273.0 0.1968 H→L+1 (75%)
217.9 0.1669 H-5→L+1 (25%), H-4→L+1 (37%)
216.0 0.1903 H-5→L+2 (18%), H-3→L (23%), H-2→L+2 (10%)
2b
311.6 0.0609 H-1→L (17%), H→L (69%)
280.4 0.2085 H-1→L (51%), H→L+1 (25%)
222.2 0.2648 H-7→L (11%), H-3→L+1 (26%), H-1→L+4 (24%)
218.8 0.2171 H-3→L+1 (15%), H-1→L+4 (46%)
2c
311.8 0.0629 H-1→L (15%), H→L (70%)
281.2 0.2217 H-1→L (51%), H→L+1 (28%)
H-7→L (18%), H-6→L (10%), H-4→L+2 (12%), H-3→L+1 (11%), H-2→L+3
222.7 0.1765 (13%)
219.4 0.2112 H-3→L+1 (11%), H-2→L+2 (13%), H-1→L+5 (46%)
14a
289.1 0.0701 H→L (85%)
214.2 0.4694 H-7→L (21%), H-4→L (21%), H→L+1 (16%)
210.6 0.2037 H-7→L (19%), H-2→L+1 (45%)
192.1 0.0875 H-8→L (12%), H-7→L+1 (16%), H-6→L+1 (26%), H→L+5 (13%)
180.4 0.1632 H-2→L+5 (55%)
14c
289.6 0.0736 H→L (85%)
221.3 0.4203 H-6→L (10%), H-1→L+2 (57%)
212.9 0.1044 H-8→L (48%), H-3→L+1 (12%)
211.1 0.2767 H-8→L (31%), H-5→L (10%)
204.8 0.1063 H-10→L (16%), H-4→L+1 (32%), H-2→L+1 (10%), H→L+6 (14%)

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X
X
O
O
RX'
N
N
K2CO
3 , DMF
R
N
S
N
H
S
2a: X=H, R= CH2CH=CH2
2b: X=Cl, R= CH2CH=CH2
1a: X=H
1b: X=Cl
1c: X=Br
2c: X=Br, R= CH2CH=CH2
3a: X=H, R= CH2COPh
3b: X=Cl, R= CH2COPh
3c: X=Br, R= CH2COPh
4a: X=H, R= CH2CH2CH2OH
4b: X=Cl, R= CH2CH2CH2OH
4c: X=Br, R= CH2CH2CH2OH
5a: X=H, R= CH2COOEt
5b: X=Cl, R= CH2COOEt
5c: X=Br, R= CH2COOEt
Scheme 1