Synthesis, characterization and density functional theory study of some new 2-anilinothiazoles

Article abstract of DOI:10.1016/j.molstruc.2014.05.009

We report here a comparative theoretical and experimental study of anilinothiazoles. The anilinothiazoles are synthesized by acid catalyzed condensation of N-phenylthioureas and 2-chloro-1,1-dimethoxyethane. Substituted anilines were employed to introduce substitution in 2-anilinothiazoles. The experimental geometric and spectroscopic properties of the anilinothiazoles are compared with the theoretically calculated ones. The model developed here comprises of geometry optimization at B3LYP method of DFT at 6-31+G(d) basis set. The optimized geometric parameters of anilinothiazoles show nice correlations with values obtained from X-ray crystal structure. Differences of up to 0.02 ? in bond length and 1.0° in bond angles are observed except SC2N6 and C7N6C2 where this difference is 1.77°and 6.01°, respectively. The vibrational spectra are calibrated with a common scaling factor of 0.9613 and show nice correlations with the experimental IR spectra. The UV-Vis spectra calculated at 190-450 nm range show 20-25 nm difference from the experimental spectra. The consistent difference may be attributed to the condensed phase nature of anilinothiazoles however the theoretical spectra are for single molecules. In addition HOMO, LUMO and the associated band gaps are also calculated and depicted.

Full text of DOI:10.1016/j.molstruc.2014.05.009

Accepted Manuscript
Synthesis, Characterization and Density Functional Theory Study Of Some New
2-Anilinothiazoles
Ayesha Babar, Huma Khalid, Khurshid Ayub, Sarah Saleem, Amir Waseem,
Tariq Mahmood, Munawar Ali Munawar, Ghulam Abbas, Ather Farooq Khan
PII:
S0022-2860(14)00468-2
DOI:
http://dx.doi.org/10.1016/j.molstruc.2014.05.009
MOLSTR 20608
Reference:
Journal of Molecular Structure
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 January 2014
5 May 2014
5 May 2014
Please cite this article as: A. Babar, H. Khalid, K. Ayub, S. Saleem, A. Waseem, T. Mahmood, M.A. Munawar, G.
Abbas, A.F. Khan, Synthesis, Characterization and Density Functional Theory Study Of Some New 2-
Anilinothiazoles, Journal of Molecular Structure (2014), doi: http://dx.doi.org/10.1016/j.molstruc.2014.05.009
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Synthesis, Characterization and Density Functional Theory Study Of Some New 2-
Anilinothiazoles
Ayesha Babar,a,e Huma Khalid,c Khurshid Ayubb,c,* Sarah Saleem,a Amir Waseem,d Tariq
Mahmood,c Munawar Ali Munawar,e Ghulam Abbasa, Ather Farooq Khan,a,*
aInterdisciplinary Research Centre in Biomedical Materials, COMSATS Institute of Information
Technology, Defence Road, Off Raiwind Road, Lahore, Pakistan
bDepartment of Chemistry, College of Science, King Faisal University, Al-Hafouf, 31982, Saudi
Arabia
cDepartment of Chemistry, COMSATS Institute of Information Technology, University Road,
Tobe Camp, Abbottabad, 22060, Pakistan
dDepartment of Chemistry, Quaid-i-Azam University, 45320 Islamabad, Pakistan
eInstitute of Chemistry, University of the Punjab, Lahore 54590, Pakistan
Keywords; 2-anilinothiazoles, Density Functional Theory, TD-DFT, UV-Vis and IR spectra,
HOMO-LUMO gap
To whom correspondence should be addressed, Email: atherfarooq@ciitlahore.edu.pk
kayub@kfu.edu.sa ,
1

Abstract
We report here a comparative theoretical and experimental study of anilinothiazoles. The
anilinothiazoles are synthesized by acid catalyzed condensation of N-phenylthioureas and 2-
chloro-1,1-dimethoxyethane. Substituted anilines were employed to introduce substitution in 2-
anilinothiazoles. The experimental geometric and spectroscopic properties of the anilinothiazoles
are compared with the theoretically calculated ones. The model developed here comprises of
geometry optimization at B3LYP method of DFT at 6-31+G(d) basis set. The optimized
geometric parameters of anilinothiazoles show nice correlations with values obtained from X-ray
crystal structure. Differences of up to 0.02Å in bond length and 1.0o in bond angles are observed
except S-C2-N6 and C7-N6-C2 where this difference is 1.77 and 6.01o, respectively. The
vibrational spectra are calibrated with a common scaling factor of 0.9613 and show nice
correlations with the experimental IR spectra. The UV Vis spectra calculated at 190-450nm
range show 20-25nm difference from the experimental spectra. The consistent difference may be
attributed to the condensed phase nature of anilinothiazoles however the theoretical spectra are
for single molecules. In addition HOMO, LUMO and the associated band gaps are also
calculated and depicted.
2

Introduction:
Synthesis of small, easily accessible molecules, showing specific inhibition of various kinases
represents an appealing therapeutic approach. Anilinothiazoles show potent biological activity
therefore scientists have turned their attention towards various structural modifications of these
anilinopyrimidines. It turned out in structure activity relationship (SAR) studies that the
phenylamino-pyrimidine(pyridine) part seems to be a prerequisite for PKI activity . The aim of
this work is to synthesize the protein kinase inhibitors based on anilino-pyrimidine molecules,
which are heterocyclic molecules as they are one of the most integral part of most of the drugs. It
is reported in the literature that more than 50% of biologically active compounds contain
heterocycles. In the present study the different heterocyclic compounds are synthesized in which
the pyrimidine ring will be replaced by the thiazole to obtain the compounds which will be more
effective than the compounds already reported in the literature. Azole and its derivatives are
found as vital building blocks of many natural as well as synthetic drugs ranging from penicillin,
cephalosporin to modern antitumor agents. Azole drugs such as fluconazole, itraconazole and
voriconazole are efficient antimycotics [1]. These drugs act primarily as protein kinase inhibitors
and specifically bind to enzyme active site thereby retarding the activity of enzymes. More
specifically thiazole, found in vitamin B12, is one of the most important pharmacological
member of azole family. It shows a wide variety of biological properties including anesthetics
[2], antifungal [3], and antibacterial actions [4]. Its cytotoxicity towards cells, renders its ability
to flourish as an anti-tumor agent [5].
2-Aminothiazoles and their derivatives have vast potential as enzyme inhibitors since they have
specific bent geometry which renders them the ability to bind specifically with the active sites of
3

enzymes [6]. In addition, the presence of nitrogen and sulfur provide the possibility of hydrogen
bond formation which are quite vital for enzyme inhibition process. The present study aims
towards the comparative synthesis and DFT studies of various 2-anilino-1,3-thiazole with
different active substituents providing structural diversity.
Various 1,2,4-triazole derivatives and their N-bridged heterocyclic analogues have been reported
to show anti-tumor, antiviral, anti-inflammatory, analgesic and antidepressant activities and have
been used for the synthesis of some important biologically active heterocycles [7] [8, 9].
Aryliden-thiosemicarbazole compound showed anti-thrombic activities. while hydrazinothiazole
showed activities on Monoamine Oxidase Inhibitors [10].
Moreover thiazoles also find application in organic materials. From the last two decades,
thiazoles have been widely used in organic electronics. Thiazole fragment has electron accepting
role in organic electronics because the thiazole is electron-accepting heterocyclic compound due
to electron withdrawing effect of nitrogen of imine. Thiazole based polymers and their close
analogues were used as n and p-type semiconductors in OEFTs, with high electron and hole
mobilities. Field effect transistors (FETs) made up of thiazolothiazole [Tz]-based polymers have
shown higher hole mobilities. Thiazole containing moieties, like bithiazole, thiazolothiazole and
benzobisthiazloe have been used in organic synthesis for a long time (Figure 1).
Insert Figure 1
Chemicals and apparatus
All chemicals and solvents were purchased from Alfa Aesar, and were used without further
purification. The 1H NMR spectra were recorded in CDCl3 on a Bruker 300 MHz NMR
spectrometer. The multiplicities are abbreviated as bs = broad singlet, s = singlet, d = doublet, m
= multiplet. The melting points were determined on MP-1/02 Melting point apparatus from
4

PCSIR labs, and are uncorrected. The UV-Vis spectra were recorded in dichloromethane on
Perkin elmer Lambda 25 UV/Vis instrument.
Synthesis
The following procedure was used for the synthesis of various 2-anilino 1,3-thiazoles (Scheme
1) [11].
General Procedure 1
Insert Scheme 1
2-Anilino thiazoles were prepared by acid catalyzed condensation of N-phenylthioureas and 2-
chloro-1,1-dimethoxyethane. A mixture of N-phenylthiourea and 2-chloro-1,1-dimethoxyethane
in 1:1 mol ratio and a few drops of concentrated HCl were dissolved in water (100 ml). The
reaction mixture was refluxed for 2 hours. Cold water (100mL) was added to the reaction
mixture, followed by aqueous NaOH to make the solution alkaline (pH 8). The resulting
precipitates were filtered on Buchner Funnel and washed with cold water. It was recrystallized
from chloroform and hexane (3:1).
Using the above procedure, the derivatives (8-19) were prepared:
N-Phenylthiazol-2-amine 8 [12, 13]
1
8, (53.84 mg, 88%) was obtained as a white crystalline solid (M.P. 121-123°C). H-NMR (300
MHz, Chloroform-d) δ 8.85 (bs, 1H, NH), 7.69 (2H, m, Ph), 7.29 (1H, d, J = 3.6 Hz, NC-H),
7.18 (2H, m, Ph), 6.9 (1H, d, J = 3.6 Hz, SC-H), 6.71 (1H, m, Ph). 13C NMR (75 MHz / CDCl3)
5

δ : 150 (Cq), 140 (Cq), 135 (CH), 129 (CH), 125 (CH), 115(CH), 110 (CH). IR ν (KBr): 3100,
C
2945, 1594, 1561, 1513, 1491 cm-1. UV (dichloromethane), λmax (εmax ), 231.5 nm (3.9570).
N-(2-Fluorophenyl)thiazol-2-amine 9
1
9 (42.80 mg, 75%) was obtained as a white crystalline solid (M.P. 95-97°C). H-NMR (300
MHz, Chloroform-d) δ 9.01 (bs, 1H, NH), 7.73 (td, J = 8.0, 1.9 Hz, 2H, Ph, NC-H), 7.42 – 7.15
(m, 3H, Ph), 6.54 (d, J = 3.6, 1H, SC-H). 13C NMR (75 MHz / CDCl3) δ :160 (Cq), 156 (Cq), 140
C
(CH), 131 (Cq), 128 (CH), 125 (CH), 124 (CH), 119 (CH), 114 (CH). IR ν (KBr): 3155, 2950,
1595, 1561, 1513, 1491 cm-1. λ
(εmax) 323.5 nm (1.4573). HR-MS (EI) m/z: Calcd. for
max
[C9H7FN2S] 194.0314 found: 194.0310
N-(2-Chlorophenyl)thiazol-2-amine 10
1
10 (50.1 mg, 89%) was obtained as a white crystalline solid (M.P. 78-82°C). H-NMR (300
MHz, Chloroform-d) δ 8.2 (bs, 1H, NH), 7.84 – 7.74 (m, 1H, Ph), 7.56 – 7.45 (m, 1H, Ph), 7.38
– 7.28 (m, 2H, Ph), 7.17 (d, J = 3.7Hz, 1H, NC-H), 6.47 (d, J = 3.7Hz, 1H, SC-H). 13C NMR (75
MHz/CDCl3) δ : 159 (Cq), 140 (Cq), 135 (CH), 131 (CH), 125 (CH), 122(Cq), 120
C
(CH),110(CH). IR ν (KBr):: 3200, 2950, 1605, 1561, 1545, 1480 cm-1. λ
(εmax) 326.5 nm
max
(1.4906). HR-MS (EI) m/z: Calcd. for [C9H7ClN2S]: 210.0018 found: 210.0031
6

N-(4-Fluorophenyl)thiazol-2-amine 11
1
11 (39.93 mg, 70%) was obtained as a white crystalline solid (M.P. 128-131°C). H-NMR (300
MHz, Chloroform-d) δ 8.88 (bs, 1H, NH), 7.73-7.52 (m, 4H, Ph), 7.28 (d, J = 3.6, 1H, NC-H),
6.67 (d, J = 3.6, 1H, SC-H). 13C NMR (75 MHz / CDCl3) δ : 160 (Cq), 157 (Cq), 138 (CH), 136
C
(Cq), 120 (CH), 115 (CH), 112 (CH). IR ν (KBr): 3200, 2955, 1596, 1570, 1515, 1490 cm-1 λ
max
(εmax) 325 nm (1.5818). HR-MS (EI) m/z: Calcd. for [C9H7FN2S] 194.0314 found 194.0326.
N-(4-Bromophenyl)thiazol-2-amine 12
12 (55.19 mg, 100%) was obtained as a white crystalline solid (M.P. 154-157°C). 1H-NMR (300
MHz, Chloroform-d) δ 8.56 (bs, 1H, NH), 7.62 – 7.51 (m, 1H, Ph), 7.46 – 7.35 (m, 1H, Ph), 7.32
– 7.20 (m, 3H, Ph, NC-H), 6.54 (d, J = 3.6 Hz, 1H, SC-H). 13C NMR (75 MHz / CDCl3) δ : 160
C
(Cq), 141 (Cq), 138 (CH), 133 (CH), 115 (CH), 113 (Cq), 110 (CH). IR ν (KBr): 3150, 2951,
1595, 1565, 1523, 1490 cm-1. λ
(εmax) 298 nm (2.478) HR-MS (EI) m/z: Calcd. for
max
[C9H7BrN2S]: 253.9513 found: 253.9503
7

N-(2,4-Difluorophenyl)thiazol-2-amine 13
1
13 (47.92 mg, 85%) was obtained as a white crystalline solid (M.P. 110-112°C). H-NMR (300
MHz, Chloroform-d) δ 8.65 (bs, 1H, NH), 7.53-7.22 (m, 4H, Ph, CN-H), 6.67 (d, J = 3.6, 1H,
SC-H). 13C NMR (75 MHz / CDCl3) δ
160 (Cq), 159 (Cq), 155 (Cq), 140 (CH), 123 (CH),
C:
119 (CH), 112 (CH), 111 (CH), 106 (CH) IR ν (KBr): 3300, 2950, 1595, 1561, 1513, 1491 cm-1.
λ
max (εmax) 325 nm (1.5818).
N-(2,4-Dichlorophenyl)thiazol-2-amine 14
1
14 (43.22 mg, 78%) was obtained as a white crystalline solid (M.P. 98-101°C). H-NMR (300
MHz, Chloroform-d) δ 8.20 (d, J = 8.9 Hz, 1H, NH), 7.58 (s, 1H, Ph), 7.48 – 7.22 (m, 3H, Ph,
13
NC-H), 6.77 (d, J = 3.6 Hz, 1H, SC-H). C NMR (75 MHz / CDCl3) δ : 160 (Cq), 138 (CH),
C
134 (Cq), 132 (CH), 129 (CH), 126(Cq), 124 (Cq), 120 (CH), 112 (CH). IR ν (KBr): 3400, 2950,
1599, 1561, 1513, 1491 cm-1. λmax (εmax) 337 nm (1.9363).
N-(2,6-Dichlorophenyl)thiazol-2-amine 15
8

1
15 (38.80 mg, 70%) was obtained as a white crystalline solid (M.P. 128-130°C). H-NMR (300
MHz, Chloroform-d) δ 8.85 (bs, 1H, NH), 7.53 – 7.34 (m, 2H, Ph), 7.33 – 7.12 (m, 2H, Ph, NC-
13
H), 6.61 (d, J = 3.6 Hz, 1H, SC-H). C NMR (75 MHz / CDCl3) δ 160 (Cq), 140 (Cq), 138
C:
(CH), 136 (Cq), 129 (CH), 121 (CH), 112(CH). IR ν (KBr): 3400, 2945, 1600, 1565, 1510, 1491
cm-1. λmax (εmax) 323.5 nm (1.8172). HR-MS (EI) m/z: Calcd. for [C9H6Cl2N2S]: 243.9629 found:
243.9676
N-(3,4-Dichlorophenyl)thiazol-2-amine 16
1
16 (48.88 mg, 88%) was obtained as a white crystalline solid (M.P. 164-166°C). H-NMR (300
MHz, Chloroform-d) δ 8.13 (dd, J = 8.3, 1.5 Hz, 1H, NH), 7.50 – 7.22 (m, 3H, Ph, NC-H), 6.99
13
(td, J = 7.7, 1.5 Hz, 1H, Ph), 6.75 (d, J = 3.6 Hz, 1H, SC-H). C NMR (75 MHz / CDCl3) δ
C:
160 (Cq), 140 (Cq), 138 (CH), 132 (Cq), 125 (Cq), 122 (CH), 121 (CH), 112 (CH). IR ν (KBr):
3460, 2955, 1605, 1561, 1513, 1491 cm-1. λ 325.5 (εmax) (1.5940). HR-MS (EI) m/z: Calcd.
max
for [C9H6Cl2N2S]: 243.9629 found: 243.9661.
N-(2-Chloro-4-methoxyphenyl)thiazol-2-amine 17
1
16 (39.22 mg, 70%) was obtained as a white crystalline solid (M.P. 79-81°C). H-NMR (300
MHz, Chloroform-d) δ 8.65 (bs, 1H, NH), 7.34 (d, J = 3.6 Hz, 1H, Ph), 7.21-6.97 (m, 3H, Ph,
NC-H), 6.92 (d, J = 3.6 Hz, 1H, SC-H), 3.88 (s,3H, -CH3). 13C NMR (75 MHz / CDCl3) δ 160
C:
9

(Cq), 155 (Cq), 138 (CH), 126 (Cq), 126 (Cq),125 (Cq), 119 (CH), 118 (CH), 115 (CH), 112 (CH),
58 (CH3). IR ν (KBr): 3480, 2960, 1601, 1564, 1513, 1491 cm-1. λ 325 (εmax) (1.6370). HR-
max
MS (EI) m/z: Calcd. for [C10H9ClN2OS]: 240.0124 found: 240.0101
N-(2,3-Dimethylphenyl)thiazol-2-amine 18
1
(43.06 mg, 76%) was obtained as a white solid (M.P. 104-106°C) H-NMR (300 MHz,
Chloroform-d) δ 8.88 (bs, 1H, NH), 7.21 (d, J = 3.6 Hz, 1H, NC-H),7.01- 6.97 (m, 3H, Ph), 6.44
13
(d, J = 3.6 Hz, 1H, SC-H), 2.29 (d, J = 11.9 Hz, 6H, -2CH3). C NMR (75 MHz / CDCl3) δ
C:
160 (Cq), 141 (Cq), 138 (Cq), 137 (CH), 132 (Cq), 130 (CH), 126 (CH), 125 (CH), 115 (CH), 22
(CH3), 19 (CH3). IR ν (KBr): 3400, 2955, 1594, 1565, 1515, 1490 cm-1. λ
(εmax) 299.5nm
max
(2.34). HR-MS (EI) m/z: Calcd. for [C11H12N2S]: 204.01 found: 204.0119
N-Mesitylthiazol-2-amine 19
1
(49.44 mg, 88%) was obtained as a white solid (M.P. 116-119°C). H-NMR (300 MHz,
Chloroform-d) δ 8.81 (d, J = 9.9 Hz, 1H, NH), 7.20 (d, J = 3.6 Hz, 1H, NC-H), 6.97 (s, 2H, Ph),
6.43 (d, J = 3.6 Hz, 1H, SC-H), 2.29 (m, 9H, -3CH3). 13C NMR (75 MHz / CDCl3) δ 158 (Cq),
C:
138 (CH), 137 (Cq), 134 (Cq), 130 (CH), 128 (Cq), 118 (CH), 20 (CH3), 19.5 (CH3) IR ν (KBr):
3364, 2954, 1601, 1564, 1517, 1490 cm-1. λ (εmax) 304nm (0.5609). HR-MS (EI) m/z: Calcd.
max
for [C12H14N2S]: 218.0878 found: 218.0801.
10

Computational details:
Molecular structures of thiazole and its derivatives were optimized using B3LYP method of DFT
with 6-31G+(d) basis set without any symmetry constraints. The optimized structures were
confirmed to be true minima by frequency analysis (no imaginary frequency). A Scaling factor
(0.9613) was applied on the calculated frequencies, in order to get better correlation between the
calculated and the experimental frequencies. HOMO, LUMO and their band gap energies
calculations were performed on optimized structures. The band gap was calculated as the
difference between the HOMO and LUMO orbital energies. The UV- visible calculations were
performed through the same basis set and method as used for geometry optimizations using time
dependent-DFT formalism. The solvent used for UV-visible calculations was dichloromethane.
Result and discussion:
Synthesis
Many methods for the synthesis of 2-anilino-1,3-thiazole derivatives are reported in the literature
(Insert Scheme and Scheme 3) [14]: However, these methods deliver low yields and lead to
the formation of side products, which can be transformed to the desired thiazole, but this
demands additional synthetic step(s).
Insert Scheme 2
Insert Scheme 3
Nucleophilic substitution of 2-bromothiazole leads to the synthesis of 2-anilino-1,3-thiazole
derivatives (Insert Scheme ) [14]. This is a single step reaction that takes place in the presence
of p-toluene sulphonic acid, however, the reported yields are very low with very long reaction
time.
11

Insert Scheme 4
Conventional Hantzsch synthesis (Insert Scheme ) for the synthesis of 2-anilino-1,3-thiazoles
was followed in this study [14]. 2-anilino thiazoles were prepared by acid catalyzed condensation
of N-phenylthioureas and 2-chloro-1,1-dimethoxyethane. In this work, mono, di and
trisubstituted thiazole amines were synthesized. The substituents were incorporated on the
phenyl ring. The substitution on the thiazole part was not possible due to the synthetic route. For
mono and disubstituted thiazole amines, only halogens were used as substituents except for 17
and 18 where methoxy and methyl substituents were incorporated, respectively. All the
synthesized compounds were found stable to their melting points. The synthesized compounds
1
are characterized by H NMR, IR and UV-Vis spectroscopic analysis. The synthesized
anilinothiazoles are soluble in organic solvents and are stable towards air and moisture.
Geometric analysis
DFT calculations have been performed to get structural insight into the synthesized compounds.
Information about bond lengths, bond angles and dihedral angles was obtained by applying
B3LYP method of DFT at 6-31G+(d) basis set. Theoretical results about bond lengths and bond
angles are listed below in Table 1-3. Detailed geometric analysis of only the chlorinated
compound 14 (Figure 2) is presented because X-ray crystal structure data is available for this
compound and can be easily compared to the theoretical data (Table 1).
Insert Figure 2
Insert Table 1
Compound 14 contain two C-N single bonds (C5-N6 and C7-N6) and the experimental bond
lengths for C2-N6 and C7-N6 are 1.38 and 1.39Å, respectively and these bond lengths are
significantly different than a typical C-N bond which is 1.47Å however their comparison with
12

the calculated bond lengths indicate that the computational method chosen here very nicely
predicts the geometric features of these anilinothiazoles. For example, the calculated bond length
for C2-N6 is 1.36 Å and C7-N6 is 1.36 Å respectively and these bond lengths are very close to the
one observed experimentally in X-ray structure (vide supra). The relatively short bond lengths
may be attributed to the delocalization and partial double bond character in these bonds. The
shorter C2-N6 bond indicates that the delocalization of the lone pair of the nitrogen is more
towards thiazole ring compared to the benzene ring. The other two C-N bond lengths in X-ray
structure are 1.30 Å (C2-N3), 1.38 Å (C4-N3), these number are also very close to the calculated
bond lengths (see Table 1). The difference in the bond lengths may be attributed to the bond
fixation in the thiazole ring. Typically, C-S bond lengths are 1.78 Å while in title compound
these values are 1.76 Å for C2-S1 and 1.74 Å for C5-S1 in X-ray structure and both of these bond
lengths are indicative of single bond character. The C=C bond lengths are 1.37-1.39 Å
(experimental). The calculated C-C bond lengths are about 0.02 Å longer than the calculated
values. The difference of 0.02 Angstroms is not very significant and the above data indicate that
the computational method chosen very nicely predicts the geometries of these compounds.
We have also analyzed and compared the bond angles between the experimental (X-ray) and
theoretical values. The S1-C2-N6 bond angle is 123.54o in the crystal structure however its
calculated value is 125.31o. Another angle for which a significant difference is observed between
the calculated structure and the experimental one is C7-N6-C2; 125.53 is the angle observed in the
x-ray structure whereas its calculated value is 131.54 (Table 2). All other bond angles show
deviation of less than a degree between the theoretical and experimental values which clearly
illustrate the accuracy of the chosen method.
Insert Table 2
13

Insert Table 3
A few selected theoretical bond lengths for other compounds containing some other
functionalities such as methoxy, Br and F are given in Table 3. The calculated bond length for
C-Br is 1.90 Å whereas the C-F bond length is typically around 1.36 Å. Bond angles of
substitutions on title compounds are given in Table 3. Bond angles of C-C-Cl, C-C-F and C-C-Br
are 119.77o, 119.31o and 119.93o respectively. C-C-OMe bond angle is 114.55º while C-C-CH3
bond angle is 121.70o.
Infra-red spectra
Since the reaction involves the conversion of thiourea into thiazole ring therefore the formation
of the product may be analyzed either by the disappearance of the characteristic band of
substituted thiourea, or by the appearance of thiazole ring. The NH2 band of the thiourea
derivatives is displayed at 3400 cm-1 which was lost during the reaction and NH band was
observed at 2900-3200 cm-1 in the product. Moreover the C=C stretching of the thiazole ring is
observed at 1473-1620 cm-1. All these characteristic peaks in the IR spectrum indicated the
formation of the product. We have also theoretically calculated the vibrational spectrum of
thiazole amine derivatives. A Scaling factor (0.9613) was applied to minimize systematic error in
calculated frequencies. This scaling factor is reported in the literature for better correlation of the
calculated spectra with the experimental one. Major band peaks of title compounds are 1473-
1603 cm-1, 1259-1395 cm-1, 1519-1597 cm-1, 2919-3245 cm-1, 668-799 cm-1 and are given below
in Table 4. For aromatic compounds like thiazole and thiazole esters theoretical C=C frequency
band is observed in the range 1473-1620 cm-1 which shows strong correlation with calculated
frequency 1473-1603 cm-1. Theoretical frequency bands in the range 668-799 cm-1 are concerned
14

with the presence of C-S group while calculated bands are also observed in this range (705-731
cm-1).
Theoretical and experimental C-halogen bands for compounds 9-17 are observed in the range
550-850 cm-1 (Table 4). Theoretical bands in the range 1548-1597cm-1 are assigned to the
stretching vibrations of C=N bond while calculated frequencies of C=N bond are observed in the
region 1519-1540 cm-1, hence, both theoretical and calculated frequencies are in close proximity.
Similarly, theoretical bands in the region of 2919-3245 cm-1 are attributed to the presence of C-H
stretching vibrations, which are in close agreement with experimental C-H stretching vibrations
2980-3290 cm-1. However, calculated H-N stretching vibrations are observed in the range 3567-
3601 cm-1 but the experimentally observed NH stretching band is observed at 2900-3200 cm-1.
The lower wavenumber of this NH stretching band in the experimental IR spectrum may be
attributed to the hydrogen bonding interactions. These IR frequencies confirmed presence of
important functional groups.
Insert Table 4
UV-Vis spectra
Experimental UV-Vis spectra of 8-18 are shown in Table 5. The simulated UV Vis spectra of
these compounds at TD-B3LYP/6-31G(d) in dichloromethane solvent (check gas phase) are
given in the supporting information. The maximum absorbance λmax for compound 9 is observed
at 320 nm. The λ
calculated for the compound 9 in dichloromethane solvent is 300nm. The
max
absorption band may be attributed to π – π* transition. The simulated value is 20 nm lower
compared to the experimental one however this difference is consistent for all compounds under
study. A difference of 20-25 nm in the maximum absorption wavelength is observed between the
theoretical and experimental values for all compounds except 11 where this difference is
15

relatively small (15 nm). The oscillator strength has been taken as a measure of the absorption
intensity therefore it serves an alternative to absorbance. (Table 5) Theoretical and experimental
absorption maxima for compounds 9-19
Insert Table 5
HOMO and LUMO energies and Band gap
The HOMO and LUMO energies of title compounds and their band gaps are given in Table 6.
Thiazole and thiazole derivatives contain π – π* and n - π* transitions (Figure 3). Conjugation
effect enhances HOMO energy while it decreases LUMO energy which leads to decrease the
band gap. The band gap is almost constant for all compounds at 0.17 except for compound 19
where the calculated bang gap is 0.18. The data clearly indicates that the substitution has no
significant effect on the electronic band gap. Since no experimental information on the band gaps
for these compounds is available in the literature therefore no comparison can be made.
Insert Figure 3
Insert Table 6
Conclusions
We report here a comparative theoretical and experimental study of anilinothiazoles. The
anilinothiazoles are synthesized by acid catalyzed condensation of N-phenylthioureas and 2-
chloro-1,1-dimethoxyethane. Substituted anilines were employed to introduce substitution in 2
anilinothiazoles. The experimental geometric and spectroscopic properties of the anilinothiazoles
are compared with the theoretically calculated ones. The model developed here comprises of
geometry optimization at B3LYP method of DFT at 6-31+G(d) basis set. The optimized
geometric parameters of anilinothiazoles show nice correlations with values obtained from X-ray
16

crystal structure. Differences of 0.02Å in bond length and 1.0o in bond angles are observed. The
vibrational spectra are calibrated with a common scaling factor of 0.9613 and show nice
correlations with the experimental IR spectra. The UV Vis spectra calculated at 190-450nm show
20-25nm difference from the experimental spectra. The consistent difference may be attributed
to the condensed phase nature of anilinothiazoles however the theoretical spectra are for single
molecules. HOMO, LUMO and the associated band gaps are also calculated and depicted.
Acknowledgement:
This study was financially supported by Higher Education Commission (HEC) of Pakistan
Project No. 1690 and 1899 under National Research Program for Universities (NRPU)
17

References
[1] D.J. Sheehan, C.A. Hitchcock, C.M. Sibley, Clinical Microbiology Reviews, 12 (1999) 40-79.
[2] S.C. Mehra, S. Zaman, A.A. Khan, Journal of the Indian Chemical Society, 57 (1980) 829-832.
[3] A. Tsuruoka, Y. Kaku, H. Kakinuma, I. Tsukada, M. Yanagisawa, K. Nara, T. Naito, Chemical &
Pharmaceutical Bulletin, 46 (1998) 623-630.
[4] K.J. Wilson, C.R. Illig, N. Subasinghe, J.B. Hoffman, M.J. Rudolph, R. Soll, C.J. Molloy, R. Bone, D.
Green, T. Randall, M. Zhang, F.A. Lewandowski, Z. Zhou, C. Sharp, D. Maguire, B. Grasberger, R.L.
DesJarlais, J. Spurlino, Bioorganic & Medicinal Chemistry Letters, 11 (2001) 915-918.
[5] K. Taori, V.J. Paul, H. Luesch, Journal of the American Chemical Society, 130 (2008) 1806-1807.
[6] A. Gallardo-Godoy, J. Gever, K.L. Fife, B.M. Silber, S.B. Prusiner, A.R. Renslo, Journal of Medicinal
Chemistry, 54 1010-1021.
[7] C.S. Reddy, L.S. Rao, A. Nagaraj, Acta Chim. Slov, 57 (2010) 726-732.
[8] Z.A. Kaplancıklı, G. Turan-Zitouni, A. Özdemir, G. Revial, European Journal of Medicinal Chemistry, 43
(2008) 155-159.
[9] D.H. Purohit, B.L. Dodiya, R.M. Ghetiya, P.B. Vekariya, H.S. Joshi, Acta Chimica Slovenica, 58 (2011)
53-59.
[10] V. Zaharia, A. Ignat, N. Palibroda, B. Ngameni, V. Kuete, C. Fokunang, M. Moungang, B. Ngadjui,
European journal of medicinal chemistry, 45 (2010) 5080.
[11] A. Babar, M.A. Munawar, M.N. Tahir, A.F. Khan, M.I. Tariq, Acta crystallographica. Section E,
Structure reports online, 68 (2012) o2441-o2441.
[12] A.F. Khan, M. Schnurch, M.D. Mihovilovic, P. Stanetty, Letters in Organic Chemistry, 6 (2009) 171-
174.
[13] M. Schnuerch, B. Waldner, K. Hilber, M.D. Mihovilovic, Bioorganic & Medicinal Chemistry Letters, 21
(2011) 2149-2154.
[14] M. Schnuerch, A.F. Khan, M.D. Mihovilovic, P. Stanetty, European Journal of Organic Chemistry,
(2009) 3228-3236.
18

Figure Captions:
Figure 1. Structures of different thiazole moieties present in bioactive molecules
Figure 2. Optimized Geometry of Compound 14 Structure
Figure 3. HOMO and LUMO of compound 14, plotted at isovalue of 0.04
Scheme 1: Synthesis of 2-anilino 1,3-thiazole
Scheme 2: Synthesis of 2-Anilino-1,3-thiazole from isothiocyanate
Scheme 3: Use of p-TsOH for complete conversion into 2-Anilino-1,3-thiazole
Scheme 4: Nucleophilic Substitution on Thiazole
19

Figure 1.
Figure 2.
Figure 3.
Scheme 1.
20

Scheme 2.
Scheme 3.
Scheme 4.
21

Graphical abstract
22

Table 1: Comparison of calculated bond lengths (Å) with experiment (X-ray) for compound
14
Atoms
Bond Length
(Experimental)
Bond length (theoretical
S1-C5
1.72
1.34
1.38
1.30
1.36
1.36
1.39
1.38
1.375
1.37
1.38
1.39
1.73
1.74
1.74
1.75
1.36
1.38
1.31
1.38
1.39
1.41
1.39
1.39
1.39
1.39
1.41
1.76
1.76
1.77
C5-C4
C4-N3
N3-C2
C2-N6
N6-C7
C7-C8
C8-C9
C9-C10
C10-C11
C11-C12
C12-C7
C8-Cl
C10-Cl
C2-S1
Table 2: selected calculated and experimental bond angles (degrees) for 14
Angle
Bond Angle (Exp)
123.54
125.53
88.89
109.99
110.10
120.67
118.39
122.15
Bond Angle (calcd.)
125.31
131.54
88.46
109.65
110.89
119.28
118.17
123.74
S1-C2-N6
C7-N6-C2
C2-S1-C5
S1-C5-C4
C4-N3-C2
N6-C7-C8
Cl1-C8-C7
N6-C7-C12
Table 3: Selected bond lengths and bond angles for anilinothiazole derivatives
Compound
C-OCH3
C-CH3
Bond lengths (Å)
1.37
1.51
Compound
C-C-OMe
C-C-CH3
Bond lengths (Å)
114.55
121.70
23

C-Br
C-F
1.90
1.36
C-C-Br
C-C-F
119.93
119.31
Table 4 Comparison of a few representative experimental and theoretical (unscaled and
scaled) stretching vibrational frequencies
Functional group
Experimental
Calculated
frequencies cm-1
(scaled)
1473-1603
1548-1597
550-850
Calculated
frequencies
cm-1 (unscaled)
1533-1668
frequencies cm-1
C=C aromatic
C=N
C-X
1473-1620
1519-1540
550-850
668-799
2919-3245
1307-1395
-
1581-1603
C-S
705-731
734-761
C-H stretching
C-N stretching
N-H
2980-3290
1259-1327
3428-3461
3100-3300
1310-1381
3567-3601
Table 5. Comparative experimental and theoretical UV-Vis spectra of anilinothizaoles
Compound
λ
max (Experimental)
λ
max (Theoretical)
9
320
325
320
298
325
320
325
325.5
335
299
304
300
300
305
303
305
295
303
295
310
303
280
10
11
12
13
14
15
16
17
18
19
24

Table 6. Calculated band gap for compounds 9-19
Compound
9
HOMO
-0.2126
-0.2137
-0.2111
-0.2125
-0.2158
-0.2183
-0.2193
-0.2189
-0.204
LUMO
-0.0407
-0.0424
-0.0385
-0.0431
-0.0445
-0.0500
-0.0498
-0.0495
-0.0312
-0.0238
Gap
0.1719
0.1713
0.1726
0.1694
0.1713
0.1683
0.1695
0.1694
0.1728
0.1846
10
11
12
13
14
15
16
18
19
-0.2084
25