Synthesis and quantum calculations of 1,3-thiazoles and 1,3,4-thiadiazole derivatives via pyridinylthioureas

Article abstract of DOI:10.1080/17415993.2012.744409

In this study, the reaction of 4- and 2-aminopyridines with phenyl isothiocyanate afforded the corresponding 1-phenyl-3-(pyridin-4-yl)thiourea 1 and its pyridin-2-yl analog 20. The reaction of 1 with ethyl chloroacetate gave 3-phenyl-2-(pyridin-4-ylimino)thiazolidin-4-one (3B), which upon a condensation reaction with aldehydes furnished 5-benzylidene derivatives 4a-c. Compounds 1 and 20 underwent heterocyclization upon their reaction with hydrazonoyl chloride 5 and gave the corresponding 1,3,4-thiadiazoles 8 and 22; however, the treatment of 1 and 20 with hydrazonoyl chloride 10 afforded the corresponding 1,3-thiazoles 14 and 25. The quantum calculations were studied using the density functional theory of the starting materials and some products.

Full text of DOI:10.1080/17415993.2012.744409

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Synthesis and quantum calculations
of 1,3-thiazoles and 1,3,4-thiadiazole
derivatives via pyridinylthioureas
Kamal M. Dawood a , Adel A. Mohamed b , Mansour A. Alsenoussi c
& Ibrahim H. Ibrahim c
a Department of Chemistry, Faculty of Science, Cairo University,
Giza, 12613, Egypt
b Department of Chemistry, Faculty of Science, Helwan University,
Helwan, Egypt
c Department of Chemistry, Faculty of Science, Sebha University,
Sebha, Libya
Version of record first published: 03 Dec 2012.
To cite this article: Kamal M. Dawood , Adel A. Mohamed , Mansour A. Alsenoussi & Ibrahim
H. Ibrahim (2012): Synthesis and quantum calculations of 1,3-thiazoles and 1,3,4-thiadiazole
derivatives via pyridinylthioureas, Journal of Sulfur Chemistry, DOI:10.1080/17415993.2012.744409
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Journal of Sulfur Chemistry, 2012
http://dx.doi.org/10.1080/17415993.2012.744409
Synthesis and quantum calculations of 1,3-thiazoles and
1,3,4-thiadiazole derivatives via pyridinylthioureas
Kamal M. Dawooda*, Adel A. Mohamedb, Mansour A. Alsenoussic and Ibrahim H. Ibrahimc
aDepartment of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt; bDepartment of
Chemistry, Faculty of Science, Helwan University, Helwan, Egypt; cDepartment of Chemistry,
Faculty of Science, Sebha University, Sebha, Libya
(Received 29 July 2012; final version received 24 October 2012)
In this study, the reaction of 4- and 2-aminopyridines with phenyl isothiocyanate afforded the corresponding
1-phenyl-3-(pyridin-4-yl)thiourea 1 and its pyridin-2-yl analog 20. The reaction of 1 with ethyl chloroac-
etate gave 3-phenyl-2-(pyridin-4-ylimino)thiazolidin-4-one (3B), which upon a condensation reaction with
aldehydes furnished 5-benzylidene derivatives 4a–c. Compounds 1 and 20 underwent heterocyclization
upon their reaction with hydrazonoyl chloride 5 and gave the corresponding 1,3,4-thiadiazoles 8 and 22;
however, the treatment of 1 and 20 with hydrazonoyl chloride 10 afforded the corresponding 1,3-thiazoles
14 and 25. The quantum calculations were studied using the density functional theory of the starting
materials and some products.
Ar
Ph
N
N
Me
N
N
S
Ph
N
S
Ph
Py
and
N
H
N
H
Py
S
N
Py
N
Ph
Py=2(4)-pyridinyl
Keywords: pyridines; 1,3,4-thiadiazoles; 1,3-thiazoles; molecular orbital calculations; density functional
theory
1. Introduction
1,3,4-Thiadiazoles have recently been reported by us and others as highly anti-inflammatory (1, 2)
and anticonvulsant (1, 3) agents. In addition, 1,3-thiazoles have been found to have histamine H3
antagonists that can be used for the treatment of neurological and psychiatric diseases (4) and
to have antimicrobial (5–7), anti-HIV (8), anti-inflammatory (9), pesticidal (10) and anti-cancer
(11) activities. Pyridine derivatives are one of the most used frameworks for medicines, food
flavorings, dyes, agrochemicals, rubber chemicals and adhesives (12). The pyridine ring found
*Corresponding author. Email: dr_dawood@yahoo.com
© 2012 Taylor & Francis

2
K.M. Dawood et al.
in acetylcholine is useful in the treatment of Alzheimer’s disease (13) and has antitumor (14),
antiamnesic (15), anticonvulsant and anti-inflammatory (16) and antiproliferative (17) activities.
Moreover, pyridine derivatives have also been used as cardiotonic (18, 19) agents. In addition,
N, Nꢀ-disubstituted thiourea derivatives have been found to possess antiviral (20), antituberculous
(21), antifungal (22) and herbicidal (23) activities. In continuation of our research work on 1,3,4-
thiadiazole derivatives (23–31), this contribution is aimed at the synthesis of some new 1,3-
thiazoles and 1,3,4-thiadiazole derivatives utilizing the reactive 1-phenyl-3-(pyridin-4-yl)thiourea
1 and its pyridin-2-yl analog 20 as the key starting materials. In addition, the quantum chemical
calculations have been done to study the conformational behavior of the starting substrates 1 and
20. Some of the proposed mechanisms have been studied theoretically for comparison with the
experimental findings. The relative stabilities as well as the thermodynamic functions of some of
the expected products have also been calculated.
2. Results and discussion
1-Phenyl-3-(pyridin-4-yl)thiourea 1 was prepared from the reaction of 4-aminopyridine with
phenyl isothiocyanate in dimethylformamide (DMF), in the presence of potassium hydroxide, at
room temperature according to the literature procedure (Scheme 1) (32). 1-Phenyl-3-(pyridin-4-
yl)thiourea 1 has two labile hydrogen atoms at positions 1 and 3; therefore, it can be drawn in
1
different tautomeric forms 1A–D as illustrated in Scheme 1. However, the H NMR spectrum
in dimethyl sulfoxide (DMSO)-d6 and quantum calculations using the density functional theory
(DFT) proved that compound 1 is mainly present in the 1A form.
SH
Ph
S
S
N
N
H
O
-EtOH
ClCH2CO2Et
EtOH,Et3N
N
N
N
N
OEt
N
NH
O
2B
N
Ph
Ph
Ph
3B
S
1B
S
SH
N
Ph
Ph
NH2
N
N
N
H
HN
N
H
N
PhNCS
DMF,rt
N
H
1C
N
N
H
1
1D
S
SH
S
O
Ph
Ph
-EtOH
N
Ph
HN
N
N
O
OEt
N
ClCH2CO2Et
EtOH,Et3N
NH
N
1A
N
N
3A
2A
Scheme 1. Synthesis of thiazolidin-4-one derivative 3B.
The reaction of 1-phenyl-3-(pyridin-4-yl)thiourea 1 with ethyl chloroacetate in refluxing
ethanol in the presence of triethylamine furnished a single product for which two structures can

Journal of Sulfur Chemistry
3
Table 1. Total energy (Et) in gas and solvents, relative total energy (ꢀEt), reaction enthalpy (ꢀHg), Gibbs free energy
change in gas (ꢀGg) and in solvent (ꢀGosoln), the solvation energy (Gso) and the free energy of solvation (ꢀGos ) of the
different isomers of 1-phenyl-3-(pyridin-4-yl)thiourea calculated using the B3LYP/6-31+G∗ level.
1
1A
1B
1C
1D
Et (g), au
−1026.4
−1026.3
−1026.4
−1026.4
0.20757
0.22138
121.83
14.89
−1026.4
−1026.4
−1026.4
0.20764
0.22165
123.36
10.29
−1026.4
−1026.4
−1026.4
0.21215
0.22549
119.12
8.73
−1026.3
−1026.4
−1026.3
0.20734
0.22133
122.22
27.85
Et (w), au
Et (ct), au
ZPE, au
TC, au
S, cal
ꢀEt, kcal/mol
ꢀHg, kcal/mol
ꢀGg, kcal/mol
Gos , kcal/mol
−1026.4
−1026.4
0.21197
0.22533
120.15
0
0
0
9.65
9.15
−8.45
−3.41
2.23
5.26
4.3
−8.09
−3.26
2.49
1.15
6.79
5.45
8.56
9.87
20.74
20.12
−10.68
−16.87
−15.84
−6.39
−5.16
−4.41
−6.9
ꢀGos , kcal/mol
0
0
0
0
−6.19
−2.49
3.68
1
−1.98
ꢀGosoln, kcal/mol
11.38
10.15
14.96
14.38
18.14
Note: Et(g), total energy in gas; Et(w), total energy in water; Et(ct), total energy in carbon tetrachloride; and S, entropy.
be postulated: 2-(phenylimino)-3-(pyridin-4-yl)thiazolidin-4-one 3A and 3-phenyl-2-(pyridin-4-
ylimino)thiazolidin-4-one 3B (Scheme 1). The formation of thiazolidinone derivative 3A or 3B
presumably proceeds via the elimination of HCl from the interaction of tautomer 1A or 1B with
ethyl chloroacetate followed by intramolecular cyclization with the loss of an ethanol molecule
under the hot basic reaction conditions. The spectral data were in complete accordance with struc-
ture 3A or 3B, but the quantum chemical calculations favored 3B. The 1H NMR spectrum of the
reaction product revealed a singlet signal at δ 4.16 due to the methylene protons in addition to
aromatic multiplets at δ 6.86–7.52. Its mass spectrum exhibited a peak at m/e 289 due to the
molecular ion peak of the reaction product. The formation of 3B is in contrast to the formation of
2-pyridylthiazolidinone that was reported in the literature (33). In addition, quantum calculations
(Tables 1–3) proved that 1B is the most stable isomer and the formation of 3B is endothermically
favored.
3-Phenyl-2-(pyridin-4-ylimino)thiazolidin-4-one 3B underwent a condensation reaction when
treated with benzaldehyde in refluxing ethanol in the presence of a catalytic amount of piperidine
to furnish a product identified as 5-benzylidene-3-phenyl-2-(pyridin-4-ylimino)thiazolidin-4-one
(4a) (Scheme 2). Furthermore, a similar condensation of thiazolidin-4-one derivative 3B with
other examples of aromatic aldehydes (4-chlorobenzaldehyde and 4-methoxybenzaldehyde) in
refluxing ethanol in the presence of catalytic amounts of piperidine afforded the corresponding
5-arylidenethiazolidin-4-ones 42b and c (Scheme 2). The structures of the reaction products were
confirmed from their elemental analysis and spectral data. For example, the 1H NMR spectrum
of 4b was free of the singlet due to CH2 protons in the starting material and revealed instead a
=
singlet at δ 7.81 due to the methine C CH proton in addition to multiplets at δ 6.96–7.57 due to
aromatic hydrogens. Its mass spectrum exhibited a peak at m/z 391 due to the molecular ion of
the reaction product 4b.
The reactivity of 1-phenyl-3-(pyridin-4-yl)thiourea (1) toward hydrazonoyl chlorides was also
studied. Thus, the treatment of 1-phenyl-3-(pyridin-4-yl)thiourea (1) with hydrazonoyl chloride
5 in refluxing ethanol in the presence of triethylamine afforded only one isolable product. There
are two possible reaction pathways, and consequently two expected structures for the reaction
product can be suggested via intermediate 7. The first pathway is the loss of an aniline molecule
from intermediate 7 to give structure 8 and the second pathway is the loss of 4-aminopyridine

4
K.M. Dawood et al.
Table 2. Total energy (Et) in gas and solvents, relative total energy (ꢀEt), reaction enthalpy (ꢀHg), Gibbs free energy
change in gas (ꢀGg) and solvent (ꢀGosoln), the solvation energy (Gso) and the free energy of solvation (ꢀGos ) of the
different isomers of 1-phenyl-3-(pyridin-2-yl)thiourea calculated using the B3LYP/6-31+G∗ level.
20
20A
20B
20C
20D
Et(g), au
Et(w), au
Et(ct), au
ZPE, au
TC, au
S, cal
ꢀEt, kcal/mol
ꢀHg, kcal/mol
ꢀGg, kcal/mol
Gos , kcal/mol
−1026.4
−1026.4
−1026.4
−1026.4
0.20783
0.2215
120.87
16.13
−1026.4
−1026.4
−1026.4
0.20766
0.22102
119.55
8.78
−1026.4
−1026.4
−1026.4
0.21224
0.2255
119.24
8.53
8.69
8.76
−13.75
−5.67
−5.24
−2.07
3.52
−1026.3
−1026.4
−1026.3
0.20756
0.22137
122.07
25.5
20.14
19.36
−11.53
−4.77
−3.02
−1.17
16.34
−1026.4
−1026.4
0.2121
0.22538
119.46
0
0
11.02
10.06
−7.47
−3.07
1.04
0.53
11.1
10.59
3.18
3.15
0
−8.51
−6.2
−3.6
−2.47
ꢀGos , kcal/mol
0
0
0
0
2.31
1.13
5.46
4.28
ꢀGosoln, kcal/mol
6.69
18.19
Note: Values in italic are calculated in carbon tetrachloride solvent.
Table 3. Total energy (Et) in gas and solvents, relative total energy (ꢀEt), activation energy in
gas (Ea) and in solvent (ꢀGosoln) and the solvation energy (Gos ) of the TSs of the isomerization of
1-phenyl-3-(pyridin-2-yl)thiourea calculated using the B3LYP/6-31+G∗ level.
TS20ꢀ20D
TS20ꢀ20C
TS20ꢀ20B
TS20ꢀ20A
Et(g), au
Et(w), au
Et(ct), au
ZPE, au
−1026.3
−1026.3
−1026.3
0.20549
0.21863
35.01
−1026.3
−1026.32839
−1026.32116
0.20581
0.2184
−1026.4
−1026.4
−1026.4
0.20231
0.21993
55.3
−1026.3
−1026.4
−1026.4
0.21687
0.21993
37.13
TC, au
ꢀEt, kcal/mol
Ea, kcal/mol
Gos , kcal/mol
40.43
36.84
27.22
51.26
30.27
−6.82
−7.6
−7.56
−13.75
−2.68
−3.06
−3.19
−5.67
ꢀGosoln, kcal/mol
28.91
37.75
52.21
25.05
28.14
37.2
51.67
28.38
Note: Values in italic are calculated in carbon tetrachloride solvent.
molecule from intermediate 7 to give the other possible structure 9. However, the spectral data
1
(infrared (IR), MS, H NMR and 13C NMR) of the reaction product provided firm evidence
that the reaction product is N-(3,5-diphenyl-1,3,4-thiadiazol-2(3H)-ylidene)pyridin-4-amine 8
(Scheme 3). The 1H NMR spectrum of the product revealed the presence of two doublets at δ 7.71
and 8.03 (J = 7.8 Hz) due to the 3-pyridine-CH and 2-pyridine-CH protons, respectively. The
MS spectrum showed a peak at m/z 330 corresponding to the molecular ion (M+) of the isolated
product 8. Quantum chemical calculations provided evidence that the two reaction pathways are
energetically comparable but that the formation of 8 is slightly favored.
Similarly, when 1-phenyl-3-(pyridin-4-yl)thiourea (1) was allowed to react with hydrazonoyl
chloride 10b in refluxing ethanol in the presence of triethylamine, it afforded a single isolable
product. There are four possible structures 14, 16, 18 and 19 that can be suggested for the reaction
product as displayed in Scheme 4. If the reaction proceeded following the above mechanism in
Scheme 3, then the product will be either 18 or 19; however, the mass spectrum was not compatible
with either of these products. Therefore, it is suggested that the reaction had taken place by a differ-
ent route as depicted in Scheme 4. In addition, the spectral data were in complete agreement with

Journal of Sulfur Chemistry
5
CH
O
Ar
S
S
ArCHO
reflux
N
N
N
O
N
EtOH ,
piperidine
N
Ph
N
Ph
3B
4a-c
Ar
4
a
b
c
C6H5
4-ClC6H4
4-OMeC6H4
Scheme 2. Reaction of thiazolidin-4-one derivative 3B with aromatic aldehydes.
S
Ph
Ph
HN
N
H
N
Cl
EtOH, Et3N
Reflux
S
H
N
N
H
Ph
Ph
+
Ph
Ph
N
HN
N
N
N
5
1
6
NH2
N
Ph
NH2
Ph
Ph
N
N
N
Ph
Ph N
S
N
S
Ph N
S
b
a
N
H
H
N
N
N
Route a
Route b
N
8
N
7
9
Scheme 3. Synthesis of 1,3,4-thiadiazole derivative 8.
structure 14 and not with structure 16. The mass spectrum of the reaction product showed a peak
at m/e 371 due to the molecular ion of 14b. Furthermore, the 1H NMR and 13C NMR spectra were
also fully in accordance with the assigned structure: 4-methyl-5-(phenylazo)-2-(phenylimino)-3-
(pyridin-4-yl)-(2H,3H)-1,3-thiazole (14b) (Scheme 4). The formation of structure 16 via the loss
of an aniline molecule from intermediate 15 was ruled out based on spectral analyses of the reac-
tion product. A similar behavior was observed when we conducted the reaction between thiourea
1 and hydrazonoyl chloride 10a under the same reaction condition to give the corresponding
1,3-thiazole 14a as outlined in Scheme 4.
1-Phenyl-3-(pyridin-2-yl)thiourea 20 was prepared according to the literature procedure by the
treatment of 2-aminopyridine with phenyl isothiocyanate and potassium hydroxide in N, N-DMF.
Then, the reactivity of 1-phenyl-3-(pyridin-2-yl)thiourea (20) toward hydrazonoyl chlorides 5 and
10a and b was examined under similar reaction conditions. Thus, heating of 1-phenyl-3-(pyridin-
2-yl)thiourea (20) with hydrazonoyl chloride 5 in refluxing ethanol in the presence of triethylamine
1
afforded only one isolable product. The spectral data (IR, MS, H NMR and 13C NMR) of the
reaction product strongly supported N-(3,5-diphenyl-1,3,4-thiadiazol-2(3H)-ylidene)-pyridin-2-
amine (22) (Scheme 5) as the product. The reaction took place via the loss of an aniline molecule
from intermediate 21 to give structure 22 but not structure 23.
When thiourea derivative 20 was similarly allowed to react with hydrazonoyl chloride 10a
in refluxing ethanol in the presence of triethylamine, it afforded a single isolable product. The

6
K.M. Dawood et al.
structure of the reaction product is expected to be one of the four possible structures 19 (Scheme 4)
and 25–27 (Scheme 5). The spectral data (IR, MS, 1H NMR and 13C NMR) of the reaction product
was in complete accordance with the assignment of its structure as 25 (Scheme 5) and ruled out
alternative structures 19, 26 and 27. Mechanistically, the reaction took place in a manner similar to
that suggested for the synthesis of compounds 14–19 as shown in Scheme 4. The mass spectrum of
the reaction product showed a peak at m/e 371 due to the molecular ion (M+) of 25. Furthermore,
1
the H NMR and 13C NMR spectra revealed 4-Me-thiazole protons and carbon at δ 2.60 and
24.87, respectively (see Section 4).
3. Molecular orbital calculations
The tautomeric behavior of 1 and its isomer 20 was theoretically studied using the B3LYP
method and 6-31g∗∗ basis set, with the purpose of determining the most stable conformers
O
S
Me
N
Ph
Cl
S
NH
NH
NHAr
Ph
NHAr EtOH, Et3N
Reflux
Me
N
+
NH
N
N
O
N
1
10a,b
11
MeCO
N
S
N
Me
OH
Ar
Ph
N
N
Ar
S
N
NH
Py
NH
Ph
NH
Py
12
17
- PyNH2
-PhNH2
Ar
Ar
Me
N N
Me
N
MeCO
N N
H
HO
Py
MeCO
N
N Ar
N
O
S
S
S
S
N Ar
NH
NH
Py
N
N
Ph
N
Ph
Py
Ph
19
13
15
-PhNH2
Ar
18
-H2O
N
Ar
N
Me
N
10–19: a: Ar = C6H5
Me
N N
b: Ar = 4-MeC6H4
Py
S
O
S
Py = 4-pyridyl
N
N
16
Ph
Py
14
Scheme 4. Synthesis of 1,3-thiazole derivatives 14a,b.

Journal of Sulfur Chemistry
7
S
N
Ph
MeCO
Cl
Ph
H
N
Cl
HN
N
H
H
N
N
N
Ph
MeCO
N
S
Ph
S
HN
Ph
N
N
H
Ph
10a
HN
Ph
5
HN
N
EtOH, Et3N
Reflux
EtOH, Et3N
Reflux
N
Ph
Ph
20
N
N
21
24
-PhNH2
- H2O
Ph
S
Ph
Ph
N
N
Ph
MeCO
N
S
N
Me
N
Ph
N
Me
N N
Ph
N
S
N
S
N
Ph
N
O
S
N
Py
N
N
N
N
Py
Py
Ph
26
25
27
22
23
Py = 2-pyridinyl
Scheme 5. Synthesis of 1,3,4-thiadiazole derivative 22 and 1,3-thiazole derivative 25.
and their populations. In the first step, the three isomers 2-, 3- and 4-aminopyridines and their
imino forms were optimized. The results show that the amino forms are more stable than
the corresponding imino isomers. The differences in energies between the amino and imino
forms were found to be 17.49, 24.17 and 17.31 kcal/mol for the three isomers 2-, 3- and
4-aminopyridines, respectively. The activation energy required for the amino–imino pyridine
interconversion was also calculated. Its value in the case of 2-amino pyridine was 49.47 kcal/mol;
accordingly, the amino form was the predominant isomer in this case, while the imino forms
did not exist.
Second, the tautomerization processes 1 ꢀ 1A-D and 20 ꢀ 20A-D (Figure 1) were carefully
considered in detail. In the gas phase, the most stable structure of each tautomer was determined,
and its total energy, zero-point energy (ZPE) and the thermal corrections (TCs) are given in
Tables 1 and 2. In the case of 1-phenyl-3-(pyridin-4-yl)thiourea (1), the calculations showed that
S
SH
S
SH
SH
Ph
Ph
Ph
Ph
Ph
N
N
H
N
N
HN
N
H
N
N
HN
N
H
N
H
1C
N
H
N
1
N
1B
N
1A
1D
S
SH
S
SH
SH
Ph
Ph
Ph
Ph
Ph
N
N
N
N
HN
N
N
N
HN
N
H
H
H
NH
NH
N
N
N
20C
20D
20
20B
20A
Figure 1. Tautomeric structures of the disubstituted thioureas 1 and 20.

8
K.M. Dawood et al.
the thio form 1 had the lowest total energy; that is, it is the most stable conformer. Structure
1C is higher in energy than 1 by 8.73 kcal/mol (Table 1), while the least stable structure, 1D,
is 27.85 kcal/mol higher in energy than 1. The inclusion of ZPE and TCs did not alter their
stability trend. The calculated ꢀGg values of the 1 ꢀ 1A-D conversions support that 1 is the
main conformer followed by 1B, while 1D cannot exist in the gas phase. Experimentally, the IR
spectrum of compound 1 showed a band at 1340 cm−1 corresponding to the C9S bond and also
1
the H NMR spectrum in DMSO-d6 proved that 1 is present as structure 1A. As a result, we
can conclude that in the gas phase, isomers 1, 1A and 1B exist in equilibrium where the main
one is 1.
The calculated dipole moments of the five conformers were high, lying between 1.15 and
9.57 D. Therefore, a pronounced solvent effect on the above tautomerization was expected to
be found. The polarities of 1D and 1C were the highest, while that of 1A was the lowest. The
tautomerizations were studied in water as a polar solvent and in carbon tetrachloride as a non-polar
solvent. The total energy of each tautomer in solvents, the solvation energy and the free energy in
solvents are given in Table 1. The results show that the five tautomers are more stabilized in polar
solvents than in non-polar ones, which is attributed to their high dipole moments. The solvation
energies of 1D and 1C in water were, respectively, −16.87 and −15.84 kcal/mol, while that of
1B was the lowest, −8.09 kcal/mol. The same trends were found for carbon tetrachloride when it
was used as a solvent. Finally, the free energy in solvents proves that 1 is still the main conformer
in solution and the two isomers 1B and 1A exist in equilibrium with 1 but as minor contributors.
Thetransitionstates(TSs)forthetwoconversions 1 ꢀ 1Aand1 ꢀ 1Bwerelocated.Thecorre-
spondinggaseousactivationenergieswerecalculatedtobe25.61and27.07 kcal/mol, respectively,
as outlined in Table 2. In spite of the stabilization of both TSs in both the solvents, the activa-
tion energies increased to 27.60 and 29.29 kcal/mol in water and to 26.96 and 28.95 kcal/mol in
the non-polar solvent. Since both processes are endothermic and have positive ꢀS values, it is
expected that the amount of 1A and 1B increases at higher temperatures.
The tautomerization processes 20 ꢀ 20A-D were also carefully studied using the same
computational level. As was found for the pyridin-4-yl isomer, the thio form 1-phenyl-3-(pyridin-
2-yl)thiourea (20) was the most stable conformer followed by 20C and 20B, which were 8.53 and
8.78 kcal/mol higher in energy. The free energy changes ꢀGg for the tautomerization processes
20 ꢀ 20A-D were calculated. All the values were positive, revealing that in the gas phase the thio
form 20 is the predominant species. The calculated ꢀGg for the 20 ꢀ 20B conversion was 3.15,
which indicates that in the gas phase the form 20B can only exist as a minor contributor. The free
energy changes in solution were also determined; these values suggest that the thio form 20 is the
main one, while 20B and 20C exist as minor contributors in both the solvents. The four TSs for the
conversions 20 ꢀ 20A-D were also located in both the gas and solvent phases. The correspond-
ing gaseous activation energies were calculated, and they are given in Table 3. The 20 ꢀ 20A
conversion had the lowest activation energy, 27.22 kcal/mol, while the 20 ꢀ 20C conversion had
the highest, 51.26 kcl/mol. The other two conversions 20 ꢀ 20B and 20 ꢀ 20D had the values of
36.84 and 30.27 kcal/mol, respectively. The four TSs were more stable in the solvent phase than
in the gas phase, but the activation energies increased in water and in non-polar solvents, where
compound 20 was found to be more solvated than the TSs. Since both processes are endothermic
and have positive ꢀS values, it is expected that the amount of 1A and 1B increases at higher
temperatures.
Molecular orbital calculations could also be used to predict the most stable isomer among the
two possible structures 3A and 3B that are postulated for the reaction product of 1-phenyl-3-
(pyridin-4-yl)thiourea 1 with ethyl chloroacetate, as shown in Scheme 1. It was found that the
total energies of the two isomers 3A and 3B were −1177.80266 and −1177.80507 au, respec-
tively. Consequently, 3B was relatively stable with lower stabilization energy (1.51 kcal/mol)
than 3A. The proposed mechanism of the above reaction was theoretically studied. Thus, the TSs

Journal of Sulfur Chemistry
9
for the intramolecular cyclization of the two intermediates 2A and 2B were located and their
energy barriers were determined. The results show that the energy barrier of the formation of
3A is 42.66 kcal/mol, while that of 3B is 37.98 kcal/mol. Therefore, the formation of 3B is less
endothermic and theoretically preferable.
As shown in Scheme 3, two products 8 and 9 from the reaction of 1-phenyl-3-(pyridin-4-
yl)thiourea (1) with hydrazonoyl chloride 5 were expected through two possible routes a and b
via intermediate 7. The two routes were theoretically studied in order to evaluate the activation
barrier in each. The total energy of the most stable form of intermediate 7 equals −1637.21148 au.
The TSs corresponding to the two routes a and b were also calculated. The total energy of the TS of
route a (TS1) was found to be −1637.14777 au, which is higher than that of 7 by 39.98 kcal/mol.
However, the energy barrier of theTS of route b (TS2) was found to be 39.32 kcal/mol. Thus, route
a (via the loss of aniline) is energetically preferable and consequently the formation of 8 is favored.
4. Experimental section
4.1. General
All melting points were measured on a Gallenkamp electrothermal melting point apparatus. The
IR spectra were recorded for potassium bromide pellets on Pye Unicam SP 3-300 and FT IR
8101 PC Schimadzu IR spectrophotometers. The 1H NMR spectra were recorded in deuterated
chloroform or DMSOat 300 MHz on aVarian Mercury NMR spectrometer using tetramethylsilane
as an internal reference. Mass spectra were recorded on a GCMS-QP 1000 EX Shimadzu mass
spectrometer at 70 eV. Elemental analyses were carried out at the Microanalytical Center of
Cairo University. Hydrazonoyl chlorides 5 (34), 10a (35) and 10b (36), 1-phenyl-3-(pyridin-
4-yl)thiourea (32) 1 and 1-phenyl-3-(pyridin-2-yl)thiourea (37) 20 were prepared according to
procedures reported in the literature.
4.1.1. 3-Phenyl-2-(pyridin-4-ylimino)thiazolidin-4-one (3B)
To a solution of 1-phenyl-3-(pyridin-4-yl)thiourea (1) (0.23 g, 1 mmol) in ethanol (10 ml), ethyl
chloroacetate (1.25 ml, 1.2 mmol) was added. Triethylamine (0.1 ml) was then added and the
resulting mixture was heated at reflux for 6 h, during which the reactants were dissolved and the
product was precipitated. The solid formed was filtered off, washed with ethanol/water (1:1),
then dried and finally recrystallized from ethanol to afford pale yellow crystals of 1,3-thiazolidin-
4-one derivative 3B in 67% yield. mp. 179–181◦C; IR (KBr) υ (cm−1): 3044 (CH-arom.), 2949
(CH-aliph.), 1633 (C9O), 1587 (C9N); 1H NMR (DMSO-d6): δ 4.16 (s, 2H, CH2), 6.85–7.52 (m,
9H, ArH); MS m/z (%): 268 (M+−1, 8.2), 194 (8.6), 149 (9.0), 104 (22.0), 91 (15.9), 77 (61.2),
51 (100). For C14H11N3OS (269.32): Calcd. C, 62.43; H, 4.12; N, 15.60; S, 11.91. Found: C,
62.29; H, 4.06; N, 15.49; S, 11.85.
4.1.2. Reaction of 1,3-thiazolidin-4-one (3B) with aromatic aldehydes: general procedure
To a solution of 3-phenyl-2-(pyridin-4-ylimino)thiazolidin-4-one 3B (2 mmol) in ethanol (10 ml)
was added the appropriate aromatic aldehyde (2 mmol), followed by the addition of few drops of
piperidine, and the reaction mixture was then heated under reflux for 4–6 h. The reaction mixture
was then left to cool to room temperature. The solid product that formed was collected by filtration,
washed with ethanol and then recrystallized from DMF/water to give a pale yellow powder of the
corresponding 5-arylidenethiazolidin-4-one derivatives 4a–c.

10 K.M. Dawood et al.
5-Benzylidene-3-phenyl-2-(pyridin-4-ylimino)thiazolidin-4-one (4a). Yield (65%); mp. 212–
1
214◦C; IR υ (cm−1) 1640 (C9O), 1581 (C9C); H NMR (DMSO-d6) 6.98 (d, 2H, ArH, J =
8.1 Hz), 7.15–7.20 (m, 1H, ArH), 7.36–7.58 (m, 11H, ArH), 7.82 (s, 1H, C9CH–); MS m/z (%):
357 (M+, 13.6), 356 (M+−1, 53), 194 (74.8), 134 (100), 91 (19.3), 89 (13.9), 77 (52.7), 51 (36).
For C21H15N3OS (357.42): Calcd. C, 70.57; H, 4.23; N, 11.76; S, 8.97. Found: C, 70.42; H, 4.19;
N, 11.55; S, 8.92.
5-(4-Chlorobenzylidene)-3-phenyl-2-(pyridin-4-ylimino)thiazolidin-4-one (4b). Yield (58%);
mp. 192–194◦C; IR (KBr) υ (cm−1) 3027 (CH-arom.), 1646 (C9O), 1597 (C9C); H NMR
1
(DMSO-d6) δ 6.97 (d, 2H, ArH, J = 7.5 Hz), 7.17 (m, 1H, ArH), 7.36–7.57 (m, 10H, ArH), 7.81
(s, 1H, C9CH–); MS m/z (%) 391 (M+, 31.5), 261 (31.5), 194 (100), 168 (77.2), 132 (19.7), 106
(31.5), 91 (44.1), 77 (89.0), 51 (59.8). For C21H14ClN3OS (391.87): Calcd. C, 64.36; H, 3.60; N,
10.72; S, 8.18. Found: C, 64.27; H, 3.53; N, 10.61; S, 8.15.
5-(4-Methoxybenzylidene)-3-phenyl-2-(pyridin-4-ylimino)thiazolidin-4-one (4c).Yield (57%);
mp. 202–204◦C; IR (KBr) υ (cm−1) 1641 (C9O), 1595 (C9C); 1H NMR (DMSO-d6): δ 3.78 (s,
3H, –OCH3), 6.96–7.08 (m, 4H, ArH), 7.17–7.54 (m, 9H, ArH), 7.77 (s, 1H, C9CH–); MS m/z
(%): 387 (M+, 9.6), 386 (M+−1, 28.1), 385 (23), 165 (11.3), 164 (100), 163 (98.1), 148 (28.8),
149 (30), 121 (12.3), 91 (8.1), 77 (29), 51 (17.2). For C22H17N3O2S (387.45): Calcd. C, 68.20;
H, 4.42; N, 10.85; S, 8.28. Found: C, 68.32; H, 4.88; N, 10.68; S, 8.21.
4.1.3. Synthesis of 3,5-diphenyl-2-N-(pyridin-4-yl)imino-(2H,3H)-1,3,4-thiadiazole (8)
To a stirred solution of 1-phenyl-3-(pyridin-4-yl)thiourea (1) (0.23 g, 1 mmol) in ethanol (10 ml),
N−phenylbenzenecarbohydrazonoyl chloride 5 (1 mmol) was added followed by the addition
of triethylamine (0.1 ml). The reaction mixture was heated at reflux for 6 h, during which the
reactants were dissolved and a pale yellow-colored product was precipitated. The solid product
was filtered off, washed with ethanol, dried and finally recrystallized from DMF/water to afford
pale rose crystals of the 1,3,4-thiadiazole 8 derivative. Yield (80%). mp. 121–123◦C; IR (KBr) υ
(cm−1) 1616 (C9N); 1H NMR (DMSO-d6) δ 7.04–7.12 (m, 3H, ArH), 7.31–7.52 (m, 7H, ArH),
7.71 (d, 2H, J = 7.8 Hz), 8.03 (d, 2H, J = 7.8 Hz); 13C NMR (DMSO-d6) δ 120.5, 122.3, 123.9,
125.9, 126.2, 128.7, 129.1, 129.7, 130.7, 139.2, 146.1, 151.8, 154.6; MS m/z (%) 330 (M+, 4.0),
329 (M+−1, 15.8), 227 (2.7), 194 (27.1), 135 (3.0), 104 (6.6), 91 (100), 77 (20.5). For C19H14N4S
(330.40): Calcd. C, 69.07; H, 4.27; N, 16.96; S, 9.70. Found: C, 68.88; H, 4.19; N, 16.77; S, 9.62.
4.1.4. 2-(N-Phenylimino)-5-(arylazo)-4-methyl-3-(pyridin-4-yl)-(2H,3H)-1,3-thiazole (14a
and b)
To a stirred solution of 1-phenyl-3-(pyridin-4-yl)thiourea (1) (0.23 g, 1 mmol) in ethanol (10 ml)
was added the appropriate hydrazonoyl chlorides 10a and b (1 mmol) followed by the addition
of triethylamine (0.1 ml). The reaction mixture was heated at reflux for 6 h, during which the
reactants were dissolved and a pale yellow-colored product was precipitated. The solid product
was filtered off, washed with ethanol, dried and finally recrystallized from DMF/water to afford
an intense yellow powder of the 5-arylazo-1,3-thiazolidines 14a and b derivatives, respectively.
2-(N-Phenylimino)-5-(phenylazo)-4-methyl-3-(pyridin-4-yl)-(2H,3H)-1,3-thiazole
(14a).
1
Yield (62%); mp. 166–168◦C; IR (KBr) υ (cm−1) 1618 (C9N); H NMR (DMSO-d6) δ 2.40
(s, 3H, CH3), 6.91–7.68 (m, 14H, ArH); MS m/z (%) 372 (M+, 5.4), 371 (M+, 12.7), 118 (100),
77 (62.7), 51 (25.7). For C21H17N5S (371.46): Calcd. C, 67.90; H, 4.61; N, 18.85; S, 8.63. Found:
C, 67.81; H, 4.41; N, 18.74; S, 8.48.
2-(N-Phenylimino)-5-(4-tolylazo)-4-methyl-3-(pyridin-4-yl)-(2H,3H)-1,3-thiazole
(14b).
1
Yield (69%); mp. 220–222◦C; H NMR (DMSO-d6) δ 2.31 (s, 3H, CH3), 2.42 (s, 3H, CH3),

Journal of Sulfur Chemistry 11
7.02–7.58 (m, 13H, ArH); 13C NMR (DMSO-d6) δ 13.4, 25.1, 114.8, 120.5, 121.6, 123.5, 128.7,
129.2, 129.5, 130.1, 135.7, 141.8, 146.6, 150.1, 151.9, 156.2; MS m/z (%) 382 (11.9), 261 (55.2),
208 (23.9), 132 (34.3), 106 (100), 91 (23.9), 77 (37.3). For C22H19N5S (385.48): Calcd. C, 68.55;
H, 4.97; N, 18.17; S, 8.32. Found: C, 68.23; H, 4.78; N, 18.05; S, 8.37.
4.1.5. Synthesis of 3,5-diphenyl-2-N-(pyridin-2-yl)imino-(2H,3H)-1,3,4-thiadiazole (22)
To a stirred solution of 1-phenyl-3-(pyridin-2-yl)thiourea (20) (0.23 g, 1 mmol) in ethanol (10 ml),
hydrazonoyl chloride 5 (1 mmol) was added followed by the addition of triethylamine (0.1 ml).
The reaction mixture was heated at reflux for 6 h, during which the reactants were dissolved
and a pale yellow-colored product was precipitated. The solid product was filtered off, washed
with ethanol, dried and finally recrystallized from DMF/water to afford white crystals of 1,3,4-
thiadiazole derivative 22 in 60% yield. mp. 183–185◦C; IR (KBr) υ 1570 (C9N), 1535 (C9C)
cm−1; 1H NMR (DMSO-d6): δ 7.07–8.52 (m, ArH); MS m/z (%): 330 (M+, 5.4), 226 (4.9), 193
(11.4), 136 (11.9), 121 (13.5), 103 (30.3), 91 (74.1), 78 (100), 51 (96.2). For C19H14N4S (330.41)
Calcd. C, 69.07; H, 4.27; N, 16.96; S, 9.70. Found: C, 68.85; H, 4.21; N, 16.83; S, 9.67.
4.1.6. 2-(N-Phenylimino)-5-(phenylazo)-4-methyl-3-(pyridin-2-yl)-(2H,3H)-1,3-thiazole (25)
To a stirred solution of 1-phenyl-3-(pyridin-2-yl)thiourea (20) (0.23 g, 1 mmol) in ethanol (10 ml)
was added hydrazonoyl chloride 10a (1 mmol) followed by the addition of triethylamine (0.1 ml).
The reaction mixture was heated at reflux for 6 h, during which the reactants were dissolved and a
pale red-colored product was precipitated. The solid product was filtered off, washed with ethanol,
dried and finally recrystallized from DMF/water to afford a pale red solid of 1,3-thiazolidine
1
derivative 25 in 69% yield. mp. 176–178◦C; IR (KBr) υ 1575 (C9N), 1536 (C9C) cm−1; H
NMR (DMSO-d6): δ 2.60 (s, 3H, CH3), 7.07–7.93 (m, 13H, ArH), 8.55 (m, 1H, pyridine-2-H);
13C NMR (DMSO-d6): δ 24.87, 114.76, 118.56, 120.27, 123.38, 124.55, 127.80, 128.74, 129.33,
138.16, 141.61, 145.83, 155.46; MS m/z (%): 371 (M+, 3.1), 353 (12.1), 242 (29.2), 143 (11.4),
109 (39.2), 91 (100), 77 (71.1), 51 (80.0). For C21H17N5S (371.46) Calcd. C, 67.90; H, 4.61; N,
18.85; S, 8.63. Found: C, 67.69; H, 4.54; N, 18.78; S, 8.56.
4.2. Computational details
Theoretical calculations were performed using the DFT (38, 39). All calculations were performed
using the GAUSSIAN98 (40). All the structures were fully optimized without any constraints.
The search for TSs was performed by employing the synchronous transit-guided quasi-Newton
method (41, 42) incorporated in the GAUSSIAN98 package. To characterize each stationary point
as a minimum or a TS and to estimate the zero-point vibrational energies (ZPEs), the vibrational
frequencies were computed for all the optimized species. The thermodynamic functions, the
relative energy ꢀEt, the heat of formation ꢀH and the free energy change ꢀG were calculated
using the appropriate equations as shown below:
The relative energy ꢀEt is given by ꢀEt = Et (20A–D)–Et (20).
Enthalpy change is given by ꢀHg = ꢀEt + ꢀZPE + ꢀTC.
The Gibbs free energy change is given by ꢀGg = ꢀHg − TꢀS, where ꢀS is the entropy change.
The solvation energy Gso is calculated by Gso = Et (solution)–Et(g).
The free energy of solvation (ꢀGos ) is calculated by ꢀGos = Gso (20A–D)–Gos (20).
The Gibbs free energy change in solvent ꢀGosoln is calculated by ꢀGosoln = ꢀGg + ꢀGso.

12 K.M. Dawood et al.
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