Experimental and theoretical investigation of new furan and thiophene derivatives containing oxazole, isoxazole, or isothiazole subunits

Article abstract of DOI:10.1007/s11224-016-0863-1

Herein, we present joint experimental and theoretical studies on newly designed thiophene- or furan-based oxazole, isoxazole, and isothiazole derivatives. Our synthetic approach towards the preparation of target compounds is based on Van Leusen reaction. By following this reaction, oxazoles (1 and 2) containing the pertinent heterocyclic systems were obtained from the reaction of suitable furan or thiophene derivatives with tosylmethyl isocyanide (TOSMIC). Hereby, three ring systems of furan or thiophene, linked to the oxazole rings at their 2- and 5-positions (3 and 4), were also successfully synthesized for the first time. Reaction of the starting materials containing acetyl groups in their 2-position with dimethyl acetal and following the treatment by hydroxylamine hydrochloride, desired isoxazole derivatives (5 and 6), were obtained. Additionally, isothiazole derivatives (7 and 8) were prepared by following the similar approach to the isoxazole synthesis. Whole of these cyclization reactions occurred with good to excellent yields. Structural analyses of the synthesized compounds were performed by appropriate spectroscopic methods (UV-vis, FT-IR, LC-MS, ¹H-NMR, ¹³C-NMR, and elemental analysis). We also carried out theoretical studies for identifying the structure-activity relationship and determining chemical properties of the studied molecules. For this purpose, we obtained information about structural properties (bond lengths, bond angles, dihedral angles, and dipole moments), band gap energies, and spectroscopic characteristics (UV-vis, FT-IR, ¹H-NMR, and ¹³C-NMR) of the target compounds. [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11224-016-0863-1

Struct Chem
DOI 10.1007/s11224-016-0863-1
ORIGINAL RESEARCH
Experimental and theoretical investigation of new furan
and thiophene derivatives containing oxazole, isoxazole,
or isothiazole subunits
Pervin Ünal Civcir1 & Gülbin Kurtay1 & Kübra Sarıkavak1
Received: 4 April 2016 /Accepted: 12 October 2016
#
Springer Science+Business Media New York 2016
Abstract Herein, we present joint experimental and theoret-
ical studies on newly designed thiophene- or furan-based
oxazole, isoxazole, and isothiazole derivatives. Our synthetic
approach towards the preparation of target compounds is
based on Van Leusen reaction. By following this reaction,
oxazoles (1 and 2) containing the pertinent heterocyclic sys-
tems were obtained from the reaction of suitable furan or
thiophene derivatives with tosylmethyl isocyanide
(TOSMIC). Hereby, three ring systems of furan or thiophene,
linked to the oxazole rings at their 2- and 5-positions (3 and 4),
were also successfully synthesized for the first time. Reaction
of the starting materials containing acetyl groups in their 2-
position with dimethyl acetal and following the treatment by
hydroxylamine hydrochloride, desired isoxazole derivatives
(5 and 6), were obtained. Additionally, isothiazole derivatives
(7 and 8) were prepared by following the similar approach to
the isoxazole synthesis. Whole of these cyclization reactions
occurred with good to excellent yields. Structural analyses of
the synthesized compounds were performed by appropriate
dipole moments), band gap energies, and spectroscopic char-
1
acteristics (UV-vis, FT-IR, H-NMR, and 13C-NMR) of the
target compounds.
.
.
.
.
Keywords Oxazole Isoxazole Isothiazole Thiophene
.
Furan DFT
Introduction
Heterocyclic azole compounds exhibit important role in broad
variety of physiological cell processes by the contribution of
their good solubility in water and relatively high thermal sta-
bility with respect to other heteroaromatic systems. In addi-
tion, azoles are acceptable as synthons in the preparation of
natural products, pharmaceuticals, and dyes [1–3]. These
compounds are also used in industrial applications such as
corrosion inhibitor or catalyst for polymerization processes
[4–7]. Moreover, researchers have been using oxazole deriv-
atives especially as an antibiotic and anti-proliferative agent
[8–12]. Among the biological activities of the oxazole nucleus
containing drug intermediates, anti-inflammatory [13, 14], an-
algesic [15, 16], antibacterial [17–19], antifungal [20–22],
anti-tuberculosis [23, 24], muscle relaxant [25], and HIV in-
hibitory [26] properties could also be considered. Besides,
isoxazoles are widely used in various heterocyclic compounds
synthesis and their antibacterial [27–29], antimicrobial
[30–32], anticonvulsant [33–35], anthelmintic [36, 37], and
cholesterol-lowering [38] properties are well-known. Similar
to oxazole and isoxazole derivatives, isothiazole ring contain-
ing compounds show also biological activity [38, 39] and are
used in the treatment of schizophrenia and for instance it could
be found in the structure of ziprasidone [40] and perospirone
[41]. Nowadays, azole derivatives are prepared by using dif-
ferent synthetic approaches [42]. In the scope of this research,
1
spectroscopic methods (UV-vis, FT-IR, LC-MS, H-NMR,
13C-NMR, and elemental analysis). We also carried out theo-
retical studies for identifying the structure-activity relationship
and determining chemical properties of the studied molecules.
For this purpose, we obtained information about structural
properties (bond lengths, bond angles, dihedral angles, and
Electronic supplementary material The online version of this article
(doi:10.1007/s11224-016-0863-1) contains supplementary material,
which is available to authorized users.
* Pervin Ünal Civcir
pervin.unal.civcir@science.ankara.edu.tr; pcivcir@yahoo.com.tr
1
Department of Chemistry, Faculty of Science, Ankara University,
06100 Ankara, Turkey

Struct Chem
these above-mentioned facts induced us to synthesize some of
newly oxazole, isoxazole, and isothiazole derivatives (Fig. 1)
possessing a thiophene (or furan) ring systems which contain
a methyl group at their 5-position in order to prevent further
polymerization reactions [43]. As mentioned before, the target
compounds were composed of different ring systems.
Consequently, their synthesis methods also varied.
According to the Van Leusen reaction [44], oxazoles contain-
ing furan or thiophene were obtained in very good yields from
the reaction of suitable starting materials—furan or thiophene
containing an aldehyde group at their 2-position with
TOSMIC [45]. Similarly, the furan or thiophene derivatives
containing two oxazole rings at their 2- and 5-positions were
also synthesized successfully. Reaction of the starting mate-
rials containing acetyl groups in their 2-position with
dimethylacetal, in the presence of N,N-dimethylformamide
and following the treatment by hydroxylamine hydrochloride,
isoxazole derivatives were obtained in good yields.
Isothiazole derivatives were prepared by a similar to isoxazole
synthesis method but consisted of four steps. These molecule
series were also obtained in high yields. Structural analysis of
the synthesized compounds was performed with appropriate
spectroscopic methods.
activated in a hot air oven at 150 °C for 2 to 4 h. Super-dry
ethanol was prepared from commercially available absolute
ethanol. For this purpose, absolute ethanol was refluxed for
1 h in the presence of magnesium and catalytic amount of
iodine. After that, the mixture was warmed until the iodine
color totally disappeared. The resulting mixture was distilled
off directly into the receiving flask and was stored over acti-
vated 4A molecular sieves. All of the other solvents used in
this study, dichloromethane (DCM), N,N-dimethylformamide
dimethylacetal (DMFDMA), diethyl ether, chloroform, meth-
anol, ethyl acetate, and hexane, were stored over a suitable
drying agent (usually 4A molecular sieves) under oxygen-
free nitrogen. Reagents and catalyzers used during the exper-
iments, 5-methyl-2-thiophenecarboxaldehyde, 5-methyl-2-
furancarboxaldehyde, thiophene-2,5-dicarboxaldehyde, fu-
ran-2,5-dicarboxaldehyde, TOSMIC, hydroxylamine hydro-
chloride, phosphoryl chloride, sodium sulfide nonahydrate,
and hydroxylamine-o-sulfonic acid (HSA), were used as re-
ceived from Sigma-Aldrich without any further purification
unless otherwise specified.
Instrumentation
In this study, we also aimed at identifying structural-
activity relationship, determining some properties and com-
paring the experimental and theoretical properties of the target
compounds. Therefore, the structural, chemical, electronic,
and spectral characteristics of target compounds were investi-
gated with both experimental and theoretical methods.
Synthesis and theoretical studies of target compounds were
performed simultaneously.
The FT-IR spectra were acquired on a Perkin-Elmer Spectrum
100 Series FT-IR spectrometer (Perkin Elmer Co.,
Beaconsfield, Bucks, and UK). Measurements were per-
formed in KBr pellets or in ATR mode using the average of
15 scans. The UV–vis spectra were obtained on a Shimadzu
UV-2550 double beam spectrophotometer (Shimadzu
Corporation, Tokyo, Japan) utilizing quartz cuvettes of 1 cm
path length between the wavelength range of 200 and 800 nm
and all measurements were performed at room temperature.
1H-NMR and 13C-NMR spectra were recorded at room tem-
perature on a Varian-Mercury 400 MHz high performance
digital Fourier Transform (FT)-NMR Spectrometer
(Mercury-400BB) (Varian, Fort Collins, CO, USA) and
CDCl3 was utilized as solvent. The 1H-NMR chemical shifts
were reported as δ values in parts per million (ppm) relative to
tetramethylsilane (TMS, δ: 0) as internal standard. Proton cou-
pling patterns were described as singlet (s), doublet (d), triplet
(t), quartet (q), pentet (p), sextet (h), multiplet (m), and broad
(br). Coupling constants J were given in Hz. The 13C-NMR
chemical shifts were also reported as δ values in ppm down-
field from TMS. LC-MS spectra were taken by using a
Waters-2695 Alliance HPLC system (Waters Corporation,
Milford, MA, USA) equipped with DAD detector at 254 nm
was coupled to a Micromass ZQ 2000 electrospray mass spec-
trometer. Elemental analyses were carried out with a
Eurovector EA3000 CHNS elemental analyzer (EuroVector
SpA, Italy) and found to be within a range of 0.4 % of
theoretical values. Thin layer chromatography (TLC) was
used to observe the progress of the experiments. For this pur-
pose, aluminum sheets (Merck, 20 × 20, Silica Gel 60 F254)
Materials and methods
Materials
N,N-Dimethylformamide (DMF) was dried over 4A molecu-
lar sieves (8–12 mesh) and freshly distilled under vacuum just
before use. Anhydrous potassium carbonate and drying agents
(sodium sulfate and magnesium sulfate) were pre-dried and
Fig. 1 Synthesized oxazole (1, 2, 3, 4), isoxazole (5, 6), and isothiazole
(7, 8) derivatives

Struct Chem
were selected. Purification of the products from common im-
purities—including byproducts, unreacted starting materials,
etc.—was carried out by column chromatography or flash
chromatography techniques. For this purpose, silica gel
(SiO2) (Merck, Silica Gel 60, 0.063–0.200 mm, 70–230 mesh
ASTM) was used as the column stationary phase.
reaction mixture was allowed to stir for about 30 min, then the
ice bath was removed and the system was heated in an oil bath
to 70 °C. The reaction was followed by thin layer chromatog-
raphy (TLC) and the experiment was terminated after ~6 h.
The flask was cooled down to the room temperature and
stirred for an extra 10 min following by the addition of
10 mL pure water. The resulting yellowish colored solution
was extracted with dichloromethane (2 × 30 mL). The extracts
were washed with water (3 × 10 mL) and saturated NaCl
solution (3 × 10 mL), respectively. The combined organic
phase was dried over MgSO4. After filtration, dichlorometh-
ane was removed by a rotary evaporator to yield oily products.
Synthetic procedures
In this study, we focused on the preparation of new
isothiazole, oxazole, and isoxazole derivatives containing fu-
ran or thiophene units as heterocyclic system. As mentioned
before, we designed our molecules with a blockage unit in
their α-position of the corresponding heteroaromatic ring in
order to prevent further polymerization reactions. Detailed
experimental procedures were schematized and described
below.
5-(5-Methylfuran-2-yl)oxazole (1): (72 %), yellow colored
oily product 13C-NMR (400 MHz, CDCl3) δC/ppm: 13.5,
1
107.6, 108.6, 120.4, 141.6, 144.2, 149.6, 153.2. H-NMR
(400 MHz, CDCl3) δH/ppm: 2.3 (s, 3H, methyl –CH3), 6.1
(m, 1H), 6.5 (d, J = 3.2 Hz, 1H), 7.1 (s, 1H), 7.8 (s, 1H). MS
(EI) m/z (%) calcd. for C8H7NO2: 149.15; found: 150.14 (M+,
100) (LC): 5.64 min. (100 % ionization peak). IR (ATR),
Synthesis of oxazole derivatives
ν
max/cm−1: 3140 (w, aromatic C-H stretching), 1635 (w,
In accordance with Van Leusen reaction, the target oxazole
derivatives (1–4) including thiophene or furan ring systems
were prepared by the following method. Method A consists of
one-step ring closure reaction (Scheme 1).
C=C stretching), 1585 (w, C=N stretching), 1204, 1105,
1082 (m, C-O stretching), 785 (s, C-H bending).
5-(5-Methylthiophene-2-yl)oxazole (2): (yield: 69 %),
bright yellow colored oily product 13C-NMR (400 MHz,
CDCl3) δC/ppm: 15.2, 120.4, 124.6, 125.9, 127.1, 140.9,
Method A
1
147.1, 149.5. H-NMR (400 MHz, CDCl3) δH/ppm: 2.5 (s,
Into a round bottomed flask fitted with a reflux condenser and
dropping funnel, appropriate starting material (5-methyl-2-
furancarboxaldehyde, 5-methyl-2-thiophenecarboxaldehyde,
furan-2,5-dicarboxaldehyde, or thiophene-2,5-
dicarboxaldehyde) (4.0 mmol) was introduced and the reac-
tion was performed under nitrogen atmosphere and an ice bath
was used in order to maintain the reaction temperature at
around 5 °C. Previously dried K2CO3 (8.0 mmol) and meth-
anol (5 mL) were added to the reaction flask with vigorous
stirring. Then, TOSMIC (4.5 mmol) was dissolved in metha-
nol (10 mL) and added slowly to the mixture via the dropping
funnel over a period of 1 h. After completing additions, the
3H, methyl –CH3), 6.7 (m, 1H), 6.5 (p, J = 4.8 Hz, 1H), 7.0 (t,
J = 3.6 Hz, 2H), 7.8 (s, 1H). MS (EI) m/z (%) calcd. for
C8H7NOS: 165.21; found: 207.14 (M + H + CH3CN),
166.10 (M + H) (LC): 5.99 min. (100 % ionization peak). IR
(ATR), νmax/cm−1: 3124, 3074 (w, aromatic C-H stretching),
2920, 2857 (w, aliphatic C-H stretching), 1611 (w, aromatic
C=C stretching), 1503 (w, aromatic C=N stretching), 1259 (w,
C-O stretching), 1090 (m, C-O-C stretching), 796 (s, C-H
bending).
2,5-Bis(oxazol-5-yl)furan (3): (yield: 80 %) bright yellow
colored oily product 13C-NMR (400 MHz, CDCl3) δC/ppm:
1
109.3, 122.3, 143.2, 143.6, 150.2. H-NMR (400 MHz,
CDCl3) δH/ppm: 6.7 (s, 2H), 7.3 (s, 2H), 7.9 (s, 2H). MS
(EI) m/z (%) calcd. for C10H6N2O3: 202.17; found: 244.45
(M + H + CH3CN), 203.31 (M + H) (LC): 4.22 min. (100 %
ionization peak). IR (ATR), νmax/cm−1: 3101, 2955, 2916,
2849 (m, aromatic C-H stretching), 2916, 2849 (m, aliphatic
C-H stretching), 1516 (w, aromatic C=C stretching), 1456 (w,
C=N stretching), 1203 (w, C-O stretching), 801 (s, C-H
bending).
2,5-Bis(oxazol-5-yl)thiophene (4): (yield: 53 %) yellow-
orange colored oily solid 13C-NMR (400 MHz, CDCl3)
δC/ppm: 121.2, 125.1, 129.6, 146.2, 150.1. 1H-NMR
Scheme 1 Synthetic route to oxazole derivatives (1–4)

Struct Chem
(400 MHz, CDCl3) δH/ppm: 7.2 (s, 2H) 7.3 (s, 2H), 7.8 (s,
2H). MS (EI) m/z (%) calcd. for C10H6N2O2S: 218.23; found:
260.06 (M + H + CH3CN), 219.06 (M + H) (LC): 4.18 min.
(100 % ionization peak). IR (ATR), νmax/cm−1: 3117 (w, aro-
matic C-H stretching), 1659, 1611 (w, aromatic C=C
stretching), 1518, 1491 (w, C=N stretching), 1012 (m, C-O
stretching), 802 (s, C-H bending).
–CH3), 2.8 (s, 3H), 3.1 (s, 3H), 5.6 (d, J = 12.4 Hz, 1H), 6.1 (q,
J = 2.8 Hz, 1H), 6.9 (d, J = 3.6 Hz, 1H), 7.7 (d, J = 12.8 Hz,
1H). IR (ATR), νmax/cm−1: 3105 (w, aromatic C-H stretching),
2916, 2287 (w, aliphatic C-H stretching), 1737 (w, C=O
stretching), 1633, 1546 (aromatic C=C stretching), 1263 (s,
C-N stretching), 1068 (s, C-O stretching), 947 (m, =C-H twist-
ing), 779 (s, aromatic C-H bending). Elemental analysis: anal.
calcd. for C10H13NO2 (179.2): C 67.02 H 7.31 N 7.82; found:
C 66.81 H 7.17 N 7.43.
Synthesis of isoxazole derivatives
(E)-3-(Dimethylamino)-1-(5-methylthiophene-2-yl)prop-
2-en-1-one (ii): (39 %, m.p: 135 °C) brown crystals H-
The target isoxazole derivatives (5 and 6) were obtained by
using Method B. First step of the process consisted of the
reaction of the convenient starting materials with N,N-
dimethylformamide dimethylacetal and the second step in-
cluded the addition of hydroxylamine hydrochloride in the
presence of methyl alcohol (Scheme 2).
1
NMR (400 MHz, CDCl3) δH/ppm: 2.4 (d, J = 0.4 Hz, 3H,
methyl –CH3), 2.7 (s, 1H), 3.0 (s, 1H), 5.6 (d, J = 12 Hz, 1H),
6.7 (t, J = 3.6 Hz, 1H), 7.4 (d, J = 4 Hz, 1H), 7.6 (d, J = 12 Hz,
1H). IR (ATR), νmax/cm−1: 3128, 3084 (w, aromatic C-H
stretching), 2920, 2256 (w, aliphatic C-H stretching), 1610
(aromatic C=C stretching), 1481 (m, C=N stretching), 1263
(s, C-N stretching, 1068 (s, C-O stretching), 914 (s, =C-H
twisting), 783 (s, aromatic C-H bending). Elemental analysis:
anal. calcd. for C10H13NOS (195.3): C 61.50 H 6.71 N 7.17;
found: C 60.97 H 6.15 N 7.01.
Method B
First step Into a 100 mL of round bottom flask equipped with
reflux condenser and dropping funnel; appropriate starting
material (5-methyl-2-furancarboxaldehyde or 5-methyl-2-
thiophenecarboxaldehyde) (5.5 mmol) was added and the re-
action flask was placed into an ice bath. Following the addi-
tion of DMFDMA (5.5 mmol, d: 0.897 g/mL), the color of the
solution turned yellow to orange and then burgundy. The ice
bath was removed after 1 h of vigorous stirring and the mix-
ture was heated in an oil bath to 110 °C. Eight hours later, with
the aid of the one-dimensional TLC analysis, the experiment
was terminated. After then, the system was cooled to room
temperature and the flask was allowed to stand in a salt-ice
bath. The crude products were crystallized from o-xylene.
Second step Appropriate compound synthesized from the first
step of Method B (i or ii) (3.9 mmol) was taken into the
reaction flask and it was dissolved in methanol (10 mL).
After stirring the mixture for 10 min in an ice bath, the forma-
tion of dark brown solution was observed. NH2OH.HCl
(0.295 g, 4.2 mmol) was poured into the solution and a color
fading was observed. The ice bath was removed after a period
of 10 min. The reaction was continued at room temperature
and terminated after 24 h. The crude product was purified by
column chromatography (solvent: ethyl acetate) to give the
target compound.
(E)-3-(Dimethylamino)-1-(5-methylfuran-2-yl)prop-2-en-
1-one (i): (yield: 81 %, m.p: 126–128 °C) dark brown crys-
tals 1H-NMR (400 MHz, CDCl3) δH/ppm: 2.2 (s, 3H, methyl
5-(5-Methylfuran-2-yl)isoxazole (5): (yield: 75 %) dark
brown oily solid 13C-NMR (400 MHz, CDCl3) δC/ppm:
1
13.6, 97.2, 108.1, 111.6, 141.6, 150.3, 154.5, 161.3. H-
NMR (400 MHz, CDCl3) δH/ppm: 2.2 (s, 3H, methyl –
CH3), 6.2 (m, 1H), 6.4 (d, J = 2 Hz, 1H), 6.7 (d, J = 3.2 Hz,
1H), 8.2 (d, J = 2 Hz, 1H). MS (EI) m/z (%) calcd. for
C8H7NO2: 149.15; found: 150.14 (M + H) (LC): 5.68 min.
(100 % ionization peak). IR (ATR), νmax/cm−1: 3158 (w, aro-
matic C-H stretching), 2951, 2846 (w, aliphatic C-H
stretching), 1640 (s, aromatic C=C stretching), 1580,1508 (s,
aromatic C=N stretching), 1286 (m, C-O stretching), 1196 (m,
C-O stretching), 780 (s, C-H bending).
5-(5-Methylthiophene-2-yl)isoxazole (6): (yield: 57 %)
brown oily solid 13C-NMR (400 MHz, CDCl3) δC/ppm:
1
15.3, 97.5, 126.3, 126.7, 127.1, 140.9, 150.6, 164.5. H-
NMR (400 MHz, CDCl3) δH/ppm: 2.4 (s, 3H, methyl –
Scheme 2 Synthetic route to isoxazole derivatives (5–6)
CH3), 6.2 (d, J = 1.6 Hz, 1H), 6.7 (t, J = 1.6 Hz, 1H), 7.2 (d,

Struct Chem
J = 3.6 Hz, 1H), 8.1 (d, J = 1.6 Hz, 1H). MS (EI) m/z (%)
calcd. for C8H7NOS: 165.21; found: 166.09 (M + H) (LC):
5.04 min. (100 % ionization peak). IR (ATR), νmax/cm−1:
3129, 3084 (w, aromatic C-H stretching), 2920, 2857 (w, ali-
phatic C-H stretching), 1611, 1593 (w, aromatic C=C
stretching), 1481 (m, C=N stretching), 1249 (m, C-O
stretching), 914 (m, N-O stretching), 780 (s, aromatic C-H
bending).
removal of the solvent by rotary evaporator and the yellow
colored oily residue was obtained. The content was washed
with saturated solution of sodium perchlorate monohydrate
(2.1 g) in water (5 mL) and the resulting solids (dark
yellow-green colored) was vacuum filtered and washed with
ethanol (10 mL).
(E)-3-(Dimethylamino)-1-(5-methylfuran-2-yl)prop-2-en-
1-one, perchlorate salt (iii): (yield: 47 %, m.p > 250 °C)
brown oily solid IR (ATR), νmax/cm−1: 3110 (w, aromatic C-
H stretching), 2874 (w, aliphatic C-H stretching), 1644 (s,
C=S stretching), 1590 (aromatic C=C stretching), 1550,
1426, 1292 (w, C-N stretching), 1188 (s, C-S stretching),
972 (m, =C-H twisting), 814 (s, aromatic C-H bending).
Synthesis of isothiazole derivatives
In isothiazole synthesis, “thio-enamine” derivatives (v and vi)
were synthesized instead of “keto-enamine” (i and ii) ones
which were used as a starting material for the ring closure step
in the formation of isoxazoles (Scheme 2). First step of the
isothiazole synthesis was the synthesis of appropriate “keto-
enamine” derivative as it was in the synthesis of the oxazoles.
Second step was consisted of the transformation of “thio-en-
amine” derivatives, which were prepared at first step, into
corresponding “perchlorate” salts with POCl3 and NaClO4.
At the third step, “perchlorate” salt was transformed into ap-
propriate “thio-enamine” derivative with Na2S.9H2O. At the
fourth step, ring closure was completed with the reaction be-
tween hydroxylamine-o-sulfonic acid (HSA) and the “thio-
enamine” derivatives which were obtained at the third step
(Scheme 3). This procedure was entitled as Method C.
(E)-3-(Dimethylamino)-1-(5-methylthiophen-2-yl)prop-2-
en-1-one, perchlorate salt (iv): (yield: 91.2 %,
m.p > 250 °C) yellow solid IR (ATR), νmax/cm−1: 3078 (w,
aromatic C-H stretching), 2856 (w, aliphatic C-H stretching),
1642 (m, C=S stretching), 1564 (m, aromatic C=C stretching),
1262 (s, C-N stretching, 1238, 1082 (s, C-O stretching), 812
(s, =C-H twisting).
Second step The corresponding perchlorate salt (iii or iv)
(2.3 mmol) which was prepared in the preceding step was
transferred to a round bottom one-neck flask and the system
was placed into an ice bath. Pre-dried DMF (5 mL) was added
dropwise into the yellow colored mixture. Na2S.9H2O
(2.3 mmol) solution was prepared by the addition of 1-mL
pure water and poured into the reaction flask. Red-orange
viscous solution was stirred for about 2 h at room temperature.
After the dilution with 30 mL of water, the flask content was
stored in the refrigerator overnight. The brick-red-colored pre-
cipitate was observed into the residual mixture and the crude
product was then filtered off under vacuum.
Method C
First step Previously synthesized appropriate prop-2-en-1-
one derivatives (i or ii) (6.0 mmol) were dissolved in pre-
distilled dichloromethane (15 mL) solution and added into a
three-neck reaction flask. Then, POCl3 (6.0 mmol) was added
dropwise to the mixture with vigorously stirring. After 10 min,
the ice bath was removed and the reaction flask was kept in the
refrigerator for about 15 h. Following step included the
(E)-3-(Dimethylamino)-1-(5-methylfuran-2-yl)prop-2-en-
1-thione (v): (yield: 80 %, m.p: 142 °C) 13C-NMR
(400 MHz, CDCl3) δC/ppm: 14.2, 38.2, 45.9, 106.6, 110.1,
118.1, 155.5, 157.4, 158.1. 1H-NMR (400 MHz, CDCl3) δH/
ppm: 2.3 (s, 3H), 3.0 (s, 3H), 3.2 (s, 3H), 6.0 (d, J = 2.8 Hz,
1H), 6.6 (d, J = 12 Hz, 1H), 7.2 (s, 1H), 8.3 (d, J = 11.6 Hz,
1H). MS (EI) m/z (%) calcd. for C10H13NOS: 195.28; found:
196.10 (M + H) (LC): 4.50 min. (100 % ionization peak). IR
(ATR), νmax/cm−1: 3100 (w, aromatic C-H stretching), 2910
(w, aliphatic C-H stretching) 1598, 1510, 1492 (aromatic C=C
stretching), 1259 (m, C-O stretching), 947 (m, =C-H twisting),
788 (s, aromatic C-H bending). Elemental analysis: anal.
calcd. for C10H13NOS (195.3): C 61.50 H 6.71 N 7.17; found:
C 60.86 H 6.47 N 7.08.
(E)-3-(Dimethylamino)-1-(5-methylthiophene-2-yl)prop-
Scheme 3 Synthetic route to isothiazole derivatives (7 and 8).
2-en-1-thione (vi): (yield: 74 %, m.p: 152 °C) 13C-NMR

Struct Chem
(400 MHz, CDCl3) δC/ppm: 16.0, 38.1, 45.9, 107.0, 125.7,
126.6, 148.8, 152.2, 157.2. 1H-NMR (400 MHz, CDCl3) δH/
ppm: 2.4 (s, 3H), 3.0 (s, 3H), 3.4 (s, 3H), 6.5 (d, J = 12 Hz,
1H), 6.7 (d, J = 2.8 Hz, 1H), 7.4 (s, J = 4 Hz, 1H), 8.3 (d,
J = 11.6 Hz, 1H). MS (EI) m/z (%) calcd. for C10H13NS2:
211.35; found: 212.05 (M + H) (LC): 4.67 min. (100 % ion-
ization peak). IR (ATR), νmax/cm−1: 2922, 2850 (w, aliphatic
C-H stretching), 1600, 1481, 1442 (aromatic C=C stretching),
1249 (m, C-O stretching), 814 (m, =C-H twisting), 771 (s,
aromatic C-H bending). Elemental analysis: anal. calcd. for
C10H13NS2 (211.4): C 56.83 H 6.20 N 6.63; found: C 55.57
H 6.08 N 6.21.
Theoretical studies
As mentioned before, we aimed at comparing some experi-
mental properties with theoretical values of the target com-
pounds. For these purposes, chemical, electronic and spectral
characteristics of our newly synthesized compounds were in-
vestigated with theoretical methods. All calculations were per-
formed with Gaussian 09 W (Revision D.01) program pack-
age and GaussView 5.0.8 molecular visualization program
[46, 47]. In the first step of the computational studies, the
conformers which had the lowest energy values for each com-
pound were determined by conformational analysis. The
Density Functional Theory (DFT) [48] employed in scan cal-
culations was B3LYP (Becke three-parameter hybrid correla-
tion functional combined with Lee–Yang–Parr correlation
functional) [49, 50] with 6-31G(d,p) basis set [51]. For the
rest of the quantum chemical calculations, we applied similar
methods which are used for this kind of molecules in the
literature [52–54]. For the geometry optimization, target com-
pounds in the ground state are computed by performing
Hartree-Fock (HF) method [55] with the aug-cc-pVDZ basis
set [56], DFT hybrid meta exchange-correlation functional
(M06-2x) [57] at the aug-cc-pVDZ level and B3LYP method
with the 6-31G(d,p), aug-cc-pVDZ, and cc-pVTZ [58] basis
sets. All of these computational studies were performed in the
gas-phase. Structural properties of the molecules (bond
lengths, bond angles, dihedral angles, dipole moments, and
polarizabilities), band gap energies and spectroscopic charac-
teristics (UV-vis, FT-IR, 1H-NMR and 13C-NMR) were inves-
tigated and the results were assessed in detail. Following sec-
tions are organized based on these approaches and our out-
comes set light to deeper understanding of the electrical and
structural properties of the azole ring systems.
Third step Corresponding starting materials (v or vi)
(1.5 mmol) were dissolved in absolute ethanol (10 mL) and
poured into a two-neck reaction flask fitted with a reflux con-
denser and it was placed into a hot water bath at 60 °C.
Pyridine (3.0 mmol) was added dropwise by stirring to the
red-colored solution over 10 min and the mixture was stirred
for an extra 30 min at same temperature. Following the addi-
tion of HSA (1.5 mmol), the color of the mixture turned to tan
within 2 h. After completion of the reaction, excess of ethanol
was removed under pressure to give a yellow-brown oily
solid.
5-(5-Methylfuran-2-yl)isothiazole (7): (yield: 57 %)
yellow-brown oily solid 13C-NMR (400 MHz, CDCl3) δC/
ppm: 13.6, 108.3, 109.9, 117.5, 144.5, 153.7, 156.0, 157.5.
1H-NMR (400 MHz, CDCl3) δH/ppm: 2.3 (s, 3H), 6.0 (d,
J = 1.2 Hz, 1H), 6.5 (d, J = 3.2 Hz, 1H), 7.2 (d, J = 1.6 Hz,
1H), 8.3 (d, J = 1.2 Hz, 1H). MS (EI) m/z (%) calcd. for
C8H7NOS: 165.21; found: 166.35 (M + H) (LC): 6.02 min.
(100 % ionization peak). IR (ATR), νmax/cm−1: 3125 (w, aro-
matic C-H stretching), 2918 (w, aliphatic C-H stretching),
1605, 1555 (aromatic C=C stretching), 1478 (m, C=N
stretching), 1240 (m, C-O stretching), 914 (m, =C-H twisting),
780 (s, aromatic C-H bending).
Structural analysis
A search for stationary points on the multidimensional PESs
for azoles was performed with B3LYP/6-31G(d,p) level of
theory. In order to obtain the different conformations, internal
rotations around the C5–C6 single bond for the two-ring sys-
tems and the C6–C2 and C5-C11 single bonds for the three-ring
systems were performed, as can be seen in the geometry pre-
sented in Fig. 2, with the atoms numbered. For two-ring sys-
tems, two-dimensional (2D) PESs were obtained by changing
the dihedral angle φ1 from 0 and 360° with the increment of
60° without restriction of symmetry (Fig. 2). The dihedral
angle φ1 is defined by the atoms X1-C5-C6-O10. A rough
geometry of the likely minimum energy structures could be
guessed with the help of the PES and two local minimums
(corresponding to syn- and anti-conformers) with respect to
the C5–C6 single bond as shown in ESI† were obtained on the
PES diagrams for the compounds 1, 2, 5, 6, 7, 8.
5-(5-Methylthiophen-2-yl)isothiazole (8): (yield: 62 %)
yellow-brown colored oily solid 13C-NMR (400 MHz,
CDCl3) δC/ppm: 15.3, 119.4, 126.4, 126.5, 130.2, 142.2,
1
157.8, 160.1. H-NMR (400 MHz, CDCl3) δH/ppm: 2.5 (d,
J = 1.2 Hz, 3H), 6.7 (d, J = 1.2 Hz, 1H), 7.1 (d, J = 3.6 Hz, 1H),
7.2 (s, 1H), 8.3 (d, J = 2 Hz, 1H). MS (EI) m/z (%) calcd. for
C8H7NS2: 181.28; found: 182.10 (M + H) (LC): 5.84 min.
(100 % ionization peak). IR (ATR), νmax/cm−1: 3078, 3140
(w, aromatic C-H stretching), 2914, 2855 (w, aliphatic C-H
stretching), 1557 (w, aromatic C=C stretching), 1456 (m, C=N
stretching), 812 (s, =C-H twisting), 795 (m, aromatic C-H
bending).

Struct Chem
angle between the two rings system is 180°. The calculated
dihedral angles showed that all of the studied azole derivatives
possessed a planar structure due to the stabilizing effects of the
delocalization of non-bonding p electrons of oxygen, nitro-
gen, and sulfur atoms. That means the unpaired p electrons
of the heteroatoms participate in the π-conjugation increased
the stability of the ring systems. After determining the most
stable conformers of the target compounds, the optimized ge-
ometries were recomputed with different calculation ap-
proaches in order to compare the accuracy of the calculations.
Unless otherwise indicated, the results which were calculated
with B3LYP/cc-pVTZ level of theory will be discussed in the
following sections. The optimized structures for the global
minimum are given in Fig. 3.
Fig. 2 Numbering atoms o1f target molecules for PES scan and
definition of the dihedral angles. For clearance of the manuscript,
illustration was presented here depicted only oxazole derivatives, but
the same approach was used for preparing the scan analysis inputs of
isoxazole and isothiazole derivatives
For the three ring systems, the three-dimensional (3D) po-
tential energy surface of the molecules was obtained by vary-
ing the dihedral angles φ1 and φ2 (see Fig. 2). In this case, the
dihedral angles φ1 and φ2 rotated from 0° to 360° with the
increment of 60°. The dihedral angles φ1 and φ2 are defined
by the atoms O11-C6-C2-X1 and X1-C5-C11-O15, respectively.
Three possible structures (syn-syn, anti-anti, and syn-anti con-
formers) corresponding to a local minimum for the molecules
3 and 4 were obtained (see ESI†). These possible conformers
were submitted to full geometry optimization using B3LYP/6-
31G(d,p) level to find the most stable conformer. The con-
formers found with DFT were characterized as true minima
on the potential energy surfaces by harmonic frequency anal-
ysis. The positive frequencies allowed us to determine the
global minimum. The global minimum energy was found to
be for the most stable conformer (anti) for each compound.
The energy values for the anti-conformers 1, 2, 3, 4, 5, 6, 7,
and 8 are −514.243, −837.218, −719.806, −1042.78,
−514.209, −837.183, −837.213, and −1160.190 Eh, respec-
tively. On the other hand, the energies of the syn conformers
in which the ring heteroatoms oriented to the same direction
are quite close to the energies of the anti-conformers and the
energy values for syn conformers 1, 2, 3, 4, 5, 6, 7, and 8 are
−514.241, −837.217, −719.801, −1042,78, −514.206,
−837.183, −837.211, and −1160.180 Eh, respectively. It could
be beneficial to underline that maximum energy difference
between syn and anti-conformers are 0.010 Eh (6.28 kcal/
mol). From the conformation analysis results, for each of our
studied compounds, we selected only one conformation which
had the lowest energy value and hence the most stable con-
former (anti) and then, we continued with the lowest ones in
subsequent calculations.
Bond length calculations Our literature search revealed that
our target compounds are not present in any published com-
putational or experimental studies. Therefore, we tried to com-
pare our computational results with similar unsubstituted
single-ring compounds (furan, thiophene, oxazole, isoxazole,
or isothiazole). In order to make the comparison, we wanted to
find the most appropriate method and basis set which calculate
the bond lengths closest to the experimental bond lengths for
unsubstituted five membered rings. Our results show that the
B3LYP method with cc-pVTZ basis set is the most appropri-
ate for calculation of the bond lengths for unsubstituted five-
membered rings. Experimental and calculated bond lengths of
some comparable heterocyclic compounds (Table 1) and our
calculated bond lengths for the studied oxazole, isoxazole, and
isothiazole derivatives are given in Tables 2 and 3, respective-
ly. The calculated bond lengths of unsubstituted heterocyclic
rings are in line with the experimental data.
As can be seen from Tables 2 and 3, the computed C-C
bond lengths of the target compounds are in the range of
1.411–1.426 Å. The calculated C-C bond lengths for the cor-
responding unsubstituted five-membered heterocyclic rings
are between 1.419 and 1.432 Å (Table 1). The C-C bond
lengths between the ring’s carbons that connect to the different
rings are a little larger than that of ring’s C-C bond lengths,
which are between 1.430 and 1.444 Å. Due to the presence of
conjugation between the two different ring systems, all these
bonds have average C-C single and C=C double bond lengths,
as expected. Moreover, the calculated C=C bond lengths of
the molecules vary from 1.359 to 1.377 Å and similarly, cal-
culated values of their primitive homologs are between 1.349
and 1.366 Å. The calculated C–C and C=C bond lengths of
the studied compounds are in line with calculated values of
thiophene, furan, oxazole, isoxazole, and isothiazole ring
systems.
According to the conformational analysis and full geome-
try optimization results, for all of our cases, we observed that
heteroatoms (oxygen or sulfur) that situated in oxazole,
isothiazole, or isoxazole systems are in the opposite side to
the other ring’s heteroatoms—oxygen for the furan ring and
sulfur for the thiophene ring—as expected. In other words,
dihedral angle between those two heterocyclic rings is 180°.
Similar results are observed for our three-ring systems con-
taining oxazole derivatives (3 and 4). The ring’s heteroatoms
are oriented again towards different side and each dihedral
Generally, the C–N bond lengths are a bit shorter than the
C–C bond lengths. The C-N and C=N bond lengths of the
oxazole ring in two or three ring systems are calculated as
about 1.384 and 1.287 Å, respectively. Furthermore, the

Struct Chem
derivatives are about 1.664 Å. DFT calculation results
[B3LYP/cc-pVTZ] are in good agreement with the experi-
mental values for the unsubstituted heterocyclic rings
(Table 1). Moreover, the calculated bond lengths of the studied
azoles are also in line with the calculated values of the corre-
sponding unsubstituted rings. However, there are very small
differences between the bond lengths of the substituted and
unsubstituted molecules. This is due to larger conjugation of
two or three ring systems, which have different heteroatoms
compared to a single ring system and also to their electroneg-
ativity characters.
Dipole moment and polarizability calculations Since our
compounds’ dipole moments and polarizabilities are not
known yet, we wanted to see how these properties of this sort
of ring systems change. It is also wanted to investigate the
effects of calculation methods and the basis set on the electric
properties. For these purposes, we studied the structure-dipole
moment and polarization relationship for azoles. Dipole mo-
ment (μ) and polarizability (α) are, without doubt, among the
most fundamental electrical properties. Therefore, calculation
of these values with various theoretical models will provide a
good basis for understanding the reliability of the calculation
of the electronic states [65–67]. The electric dipole moments
(μ) and the mean polarizabilities (ᾱ) of target compounds can
be calculated by finite field method using different methods/
basis sets. In order to calculate the electric dipole moments
and the polarizabilities of the compounds, the origin of the
Cartesian coordinate system (x, y, z) = (0, 0, 0) was chosen
at the center of mass of the molecules. The total dipole mo-
ment μ, the mean polarizability ᾱ, and their x, y, z coordinates
in components are defined below.
Fig. 3 The most stable conformers of target compounds
Dipole moment formula [68] is
calculated values of the C-N and C=N bond lengths in
unsubstituted oxazole ring are found 1.389 and 1.288 Å.
The C=N bond lengths of unsubstituted isoxazole and
isothiazole rings are calculated about 1.306 and 1.314 Å, re-
spectively. These values are in line with the calculated values
(1.305 and 1.314 Å) for unsubstituted isoxazole and
isothiazole rings, respectively.
The C–O bond lengths are slightly shorter than the C–N
bond lengths. The calculated C-O bond lengths are between
1.349 and 1.376 Å, and the calculated data for the correspond-
ing unsubstituted derivatives are between 1.361 and 1.368 Å.
The C-S bond lengths for thiophene and isothiazole in the
studied molecules are between 1.738 and 1.749 Å and 1.735
and 1.738 Å, respectively, and their corresponding
unsubstituted analogs’ values are 1.726 and 1.713 Å. The
computed N-O bond lengths of isoxazole derivatives are ap-
proximately 1.400 Å and the corresponding values for
unsubstituted analogs are 1.397 Å. The calculated N-S bond
lengths of isothiazole are approximately 1.666 Å and the cal-
culations show that the bond lengths for the unsubstituted
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
In the equation below, α is a second rank tensor property
called the dipole polarizability and mean polarizability formu-
la [69] is
μ ¼ μ2x þ μ2y þ μ2z
.
À
Á
α ¼ αxx þ αyy þ αzz
3
The calculated dipole moments and polarizabilities depend
on a basis set and calculation method. Therefore, it is apparent
that a large basis set and correlation is needed to get at
reliable values. Since there is no information about the
computational or experimental dipole moments and polar-
izabilities of the studied molecules in the literature, calcu-
lated dipole moments of the target compounds were again
compared to their unsubstituted analogs. The calculated
and experimental dipole moments of unsubstituted hetero-
cyclic compounds (furan, thiophene, oxazole, isoxazole,
or isothiazole) are given in Table 4 and their dipole

Struct Chem
Table 1 Bond lengths determined by X-Ray and calculated by B3LYP/
cc-pVTZ for the unsubstituted heterocyclic compounds (Å)
However, the calculated mean polarizabilities for
unsubstituted derivatives are varied as thiophene, isothiazole,
furan, isoxazole, and oxazole in descendent order. The results
calculated by B3LYP/cc-pVTZ level of theory are in good
agreement with available experimental dipole moments and
polarizabilities for the unsubstituted derivatives.
Bond Thiophenea,b Furana,c Oxazoled Isoxazolee Isothia-
type
zolef
C-C
1.423
1.431
–
–
1.425
1.420
1.356
1.354
–
1.397 Exp.
1.424
1.432
1.419 Calc.
1.380 Exp.
1.366 Calc.
The permanent dipole moments for the studied azoles are
calculated with three different methods using three basis sets
and the results are given in Table 5. The calculated data shows
that dipole moment values of furan derivatives except
oxazoles (1, 2) are higher than thiophene derivatives. By the
guidance of Table 5, we could see that the calculated dipole
moment values of the studied molecules are varied as
isothiazole, isoxazole, and oxazole in descendent order, re-
spectively. This result is in good agreement with previously
given results for the unsubstituted derivatives. Calculations
with different basis sets (6-31G(d,p), aug-cc-pVDZ, and cc-
pVTZ) for the studied compounds give very similar results.
Our result also shows that basis set effects are relatively lower
but the electron correlation effects are dominant. For instance,
the result obtained from DFT (B3LYP, MO6-2x) calculations
gives different values in comparison to HF method. The di-
pole moments calculated with HF/aug-cc-pVDZ level of the-
ory for oxazole derivatives are underestimated whereas for
isoxazole derivatives are overestimated.
The mean polarizability (ᾱ) values of the studied com-
pounds are calculated by using different methods and basis
sets and the corresponding results are given in Table 6. The
mean polarizability values of thiophene derivatives are higher
than that of the furan derivatives and the polarities of the three-
ring systems are higher than the two ring systems, as expected.
According to obtained results, polarizability order for the stud-
ied azoles is similar to their corresponding unsubstituted de-
rivatives and the order is
C=C
C-N
C=N
C-O
C-S
1.370
1.361
1.353
1.349
1.395
1.389
1.292
1.288
1370
1.368
–
1.363
1.355
–
–
–
–
Exp.
–
–
–
Calc.
–
–
1.309
1.305
–
1.316 Exp.
1.314 Calc.
–
–
–
–
1.362
–
–
Exp.
1.361
–
Calc.
1.714
1.726
1.079
1.080
–
–
–
1.715 Exp.
1.713 Calc.
1.076 Exp.
1.077 Calc.
1.661 Exp.
1.664 Calc.
–
–
–
C-H
N-S
N-O
1.076
1.075
1.075
–
1.075
1.076
–
1.076
–
–
–
–
–
–
–
–
–
1.399
1.397
–
–
Exp.
–
–
Calc.
a Reference [59]
b Reference [60]
c Reference [61]
d Reference [62]
e Reference [63]
f Reference [64]
moments are in the following order:
Isoxazole > isothiazole > oxazole > furan > thiophene
Table 2 Calculated bond lengths
for oxazole derivatives (1–4) (Å)
Bond
type
1
2
3
4
Furan
moiety
Oxazole
moiety
Thiophene
moiety
Oxazole
moiety
Furan
moiety
Oxazole
moiety
Thiophene
moiety
Oxazole
moiety
C-C
C-Ca
C=C
1.426
1.432
–
1.419
1.437
–
1.420
1.430
1.366
–
1.411
1.435
–
1.359
1.363
1.361
1.365
1.362
1.361
1.373
1.363
1.370
C-N
C=N
C-O
–
–
1.385
1.287
1.372
1.358
–
–
1.385
1.287
1.376
1.356
–
–
–
1.384
1.287
1.372
1.357
–
–
–
–
1.383
1.288
1.375
1.356
–
–
–
1.368
1.366
C-S
–
1.741
–
1.743
1.079
1.745
1.079
C-H
1.075
1.076
1.076
1.075
1.075
1.076
a C-C bond lengths between the ring’s carbons that connect to the different rings

Struct Chem
Table 3 Calculated bond lengths for isoxazole and isothiazole derivatives (5–8) (Å)
Bond
type
5
6
7
8
Furan
moiety
Isoxazole
moiety
Thiophene
moiety
Isoxazole
moiety
Furan
moiety
Isothiazole
moiety
Thiophene
moiety
Isothiazole
moiety
C-C
C-Ca
1.424
1.434
1.361
1.414
1.365
1.416
1.440
1.414
1.366
1.424
1.436
1.361
1.414
1.376
1.416
1.444
1.414
C=C
1.366
1.370
–
1.366
1.371
–
1.377
1.363
–
1.365
–
C=N
C-O
1.306
1.349
1.306
1.351
1.314
1.314
1.365
1.369
–
–
1.364
1.373
–
–
–
–
C-S
–
1.739
1.744
1.081
–
1.735
1.738
1.749
1.081
1.739
C-H
N-O
N-S
1.079
1.076
1.401
–
1.079
1.399
–
1.076
1.078
–
1.079
–
–
–
–
–
–
–
–
–
1.667
1.666
a C-C bond lengths between the ring’s carbons that connect to the different rings
Isothiazole > isoxazole≈oxazole
be seen from Table 6, HF/aug-cc-pVDZ level gives smaller
values for the polarizabilities, while B3LYP/cc-pVTZ level
gives higher values.
However, the observed polarizability order for the studied
compounds is different from their dipole moment order. The
observed results could be explained by the interaction be-
tween atomic contributions, distance-dependent charge sepa-
ration between heteroatoms, and number of resonance struc-
tures. The larger distance between charges should lead to a
larger dipole moment of the compounds. Therefore, polariz-
ability values of isothiazole compounds are higher than other
compounds. On the other hand, the polarizability values ob-
tained by different method and basis set are different. This
means that basis set and electron correlation effects are impor-
tant in calculation of the polarizabilities of the azoles. As can
Spectroscopic analysis
Computational and experimental UV-vis spectra The ab-
sorption spectrum is related to the molecular structure, and the
relationship between the maximum absorption and the molec-
ular structure is important in explaining the molecular proper-
ties. The time-dependent DFT (TD-DFT) is one of the most
widely used methods in quantum chemistry because of its
accuracy and relatively small computing time [76]. The meth-
od is able to detect accurate absorption wavelength and the
calculated value corresponds to the vertical electronic transi-
tions computed on the ground state geometry. Thus, we
attempted to determine the maximum absorption peaks
(λmax) in the ultraviolet and visible (UV-vis) spectra of the
studied compounds and then, we compared to our experimen-
tal and computational results.
Table 4 Permanent dipole moment μ (Debye) and average
polarizabilities (ᾱ) of unsubstituted heterocyclic compounds
Molecule
μ
ᾱ
DFT Experiment
DFT Experiment
Thiophene 0.52 0.533 0.0005a 72.65 60.6c, 65.2 2.1d, 66.1e,
64.9 0.6f
Table 5 Dipole moments (μ, in Debye)
Entry HF/aug- M06-2x/aug- B3LYP/6– B3LYP/aug- B3LYP/
Furan
0.61 0.661 0.006b 53.65 49.1 2.2d
cc-pVDZ cc-pVDZ
31 G(d,p) cc-pVDZ
cc-pVTZ
Oxazole
Isoxazole 2.94 2.90a
Isothiazole 2.34 2.44 0.2a
1.51 1.50a
48.44
49.20
68.38
1
2
3
4
5
6
7
8
2.541
2.584
1.016
1.056
4.054
4.343
4.022
4.154
2.675
2.520
2.962
2.448
3.805
3.654
3.747
3.655
2.679
2.485
2.891
2.395
3.844
3.612
3.930
3.789
2.815
2.667
2.982
2.408
3.986
3.815
3.973
3.870
2.680
2.787
2.887
2.354
3.855
3.678
3.778
3.677
a Reference [70]
b Reference [71]
c Reference [72]
d Reference [73]
e Reference [74]
f Reference [75]

Struct Chem
Table 6 Calculated mean polarizability (ᾱ, in hartree)
and azoles exhibit single absorption band in methanol. This
result indicates that the excitations correspond to the electron
transitions from the HOMO energy level to LUMO energy
level and the excitations correspond to the π–π* transitions.
Our results show that the λmax values of the sulfur-containing
derivatives (thiophene, isothiazole) shift to longer wave-
lengths relative to the corresponding values of the oxygen-
containing derivatives (furan, oxazole, isoxazole). Moreover,
the theoretical UV–Vis. spectra of the azoles in methanol are
similar to those of gas phase with one band, but the lowest
energy electronic transitions shift to a longer wavelength by
approximately 10 nm because of the solvent effects.
Entry HF/aug-
cc-
M06-2x/
aug-
B3LYP/6–
31
B3LYP/
aug-
B3LYP/
cc-
pVTZ
pVDZ
cc-pVDZ
G(d,p)
cc-pVDZ
1
2
3
4
5
6
7
8
105.28
120.56
143.57
159.17
105.48
120.61
120.80
133.96
111.80
127.69
153.16
171.06
111.86
127.25
127.88
143.19
97.50
111.64
139.03
156.47
98.09
118.36
134.51
166.48
185.68
118.47
123.80
135.21
151.18
168.057
192.487
259.717
300.356
168.617
192.804
186.810
211.973
111.91
112.39
126.34
In order to test the accuracy of the experimental and calcu-
lated absorption spectra for the azole derivatives, we com-
pared our theoretical results with the experimental absorption
spectra of the unsubstituted heterocyclic compounds. The ex-
perimental λmax values for the unsubstituted furan, thiophene,
oxazole, isoxazole, and isothiazole rings are 207, 237, 205,
215, and 245 nm, respectively, in methanol [78, 79]. It is well
known that the substituents attached to the carbon atoms (C-2
or C-5 positions) of furan and thiophene rings affect the exci-
tation energy. Because of the increasing effect on the π–elec-
tron density of the electron–donor substituents on C–2 or C-5
of furan or thiophene, the transition energies from HOMO to
LUMO become lower and as a result of this, λmax becomes
longer. Therefore, it could be concluded that λmax values of
the two ring systems are significantly increased compared to
the single ring derivatives. When the second ring system is
attached to C–5 position of furan or thiophene ring (3 and 4),
the molecules become larger, the conjugation increases, and
the absorption bands shift to longer wavelengths. The calcu-
lated absorption bands of the molecules, except 3 and 4, are in
line with their experimental values. λmax values of the mole-
cules (3 and 4) calculated by B3LYP with 6-31G(d,p), 6-
311++G(d,p), and cc-pVTZ basis sets in methanol are greater
than their experimental values. There are 16, 22; 29, 36; and
Calculations of λmax for the target molecules in the gas
phases are carried out with TD-DFT (B3LYP/6-31G(d,p))
method by using the same functions and basis sets, which
were used in the geometry optimization. TD-HF method is
also used in order to observe the variations between the com-
putational methods. For the TD-DFT calculations, the
Conductor-like Polarizable Continuum Model (CPCM) [77]
is also used to take care of the solvent effects and CPCM-TD-
B3LYP with 6-31G(d,p), 6-311++G(d,p), and cc-pVTZ basis
sets in methanol solution is applied to the azole derivatives.
On the basis of the fully optimized ground-state structure of
the target compounds, vertical excitation energies, oscillator
strength, and absorption wavelengths are obtained both in gas
phase and methanol solution. The absorption spectra are sim-
ulated using GABEDIT program. The excited states are inter-
polated by a Lorentzian convolution with the full-width at
half-maximum of 0.15 eV. The experimental and calculated
λ
max values are given in Table 7 and their UV spectra are given
in ESI†.
The observed and the calculated spectra of the azoles are
between 290 and 319 nm and 291 and 361 nm, respectively,
Table 7 Calculated vs. experimental UV absorption values (λmax, nm)
Gas Phase
Methanol
Entry TD-HF/aug- TD-M062x/
TD-B3LYP/ TD-B3LYP/6- TD-B3LYP/ TD-B3LYP/ TD-B3LYP/6- TD-B3LYP/ Experimental
cc-pVDZ
aug-cc-pVDZ 6-31G(d,p)
311++G**
cc-pVTZ
6-31G(d,p)
311++G**
cc-pVTZ
1
2
266.11
281.53
305.39
326.31
265.93
279.06
284.63
295.45
0.90834
269.7
285.55
309.73
331.18
270.24
284.02
292.78
302.78
0.9437
276.99
291.6
279.84
295.38
324.73
344.25
278.9
280.86
297.35
329.52
350.27
280.2
293.43
302.31
324.34
341.81
296.16
295.56
312.77
319
291.19
303.58
337.02
354.99
295.6
291.12
305.10
341.33
360.99
292.69
303.09
317.73
323.88
0.9028
290.00
301.00
308.00
319.00
292.00
298.00
308.00
310.00
3
325.62
345.76
276.15
290.29
299.66
309.54
0.8963
4
5
6
292.13
302.39
303.35
0.8723
294.38
303.59
313.21
0.8984
303.9
7
320.31
317.87
0.8935
8
R2
0.913

Struct Chem
Methanol
Table 8 Calculated band gap
energies (ΔEgap = ELUMO-
EHOMO, in eV)
Gas
Entry HF/aug-cc-
pVDZ
M06-2x/aug-
cc-pVDZ
B3LYP/aug-
cc-pVDZ
B3LYP/cc-
pVTZ
TD-B3LYP/
cc-pVTZ
TD-B3LYP/
cc-pVTZ
1
2
3
4
5
6
7
8
8.663
8.866
8.477
8.676
8.993
9.154
8.971
9.372
6.792
6.526
6.106
5.804
6.850
6.620
6.439
6.380
4.501
4.303
3.866
3.654
4.509
4.352
4.205
4.122
4.609
4.413
3.949
3.742
4.605
4.455
4.315
4.241
4.415 (39–40)
4.167 (43–44)
3.763 (52–53)
3.534 (56–57)
4.425 (39–40)
4.212 (43–44)
4.084 (43–44)
3.959 (47–48)
4.259 (39–40)
4.064 (43–44)
3.632 (52–53)
3.435 (56–57)
4.236 (39–40)
4.091 (43–44)
3.902 (43–44)
3.828 (47–48)
33, 42 nm differences between calculated and experimental
absorption bands of the molecules (3 and 4), respectively. The
6-31G(d,p) basis set gives better results than the other two
basis sets.
are between 3.5 and 4.4 eV. However, the band gap values of
isothiazole derivatives are found to be slightly lower than the
other two systems. Additionally, for all derivatives, the band gap
values vary from thiophene to furan ascending order. On the
other hand, for the systems including two oxazole rings (3, 4),
in which the conjugated system becomes larger with the inclu-
sion of second oxazole ring, the conjugation in the molecules
increases and their band gaps decreases. The band gaps of two
oxazole containing derivatives are dropped ~0.6 eV contrast to
their two ring derivatives.
In order to consider the effect of calculation methods on
absorption spectra, the calculated absorption wavelengths are
plotted against the experimental values. As can be seen from
the Table 7, the correlation coefficients (R2) for the calcula-
tions with different methods in gas phase are between 0.87
and 0.94 and the corresponding value in methanol is almost
0.90. This close agreement between calculated and experi-
mental values indicated that TD-B3LYP with 6-31G(d,p) ba-
sis set gives satisfactory result for understanding the absorp-
tion spectra of azoles.
In molecular interaction perspective, the Highest Occupied
Molecular Orbital (EHOMO) and the Lowest Unoccupied
Molecular Orbital (ELUMO) interacts with each other and they
are accepted as the most significant energy levels [80, 81]. For
our cases, the HOMO and LUMO energies and their energy
difference (ΔE = ELUMO-EHOMO) of the studied molecules are
determined and the band gap energies are summarized in
Table 8. It is well known that the energy of HOMO is related
to the ionization potential whereas the energy of LUMO is
related to the electron affinity. The energy gap reflects the
chemical activity of molecules. In addition, the band gap is
considered as a measure of the charge transfer and it is accept-
ed as a relevant parameter in determining the molecular elec-
trical transport property and the reactivity. If the energy gap
between HOMO and LUMO decreases, then it will be easier
to excite the electrons, which occupied the HOMO energy
level. If the energy level of LUMO is low, it will be easier
for LUMO to accept electrons, which excited from the
HOMO energy level. As can be seen from the corresponding
table, the computed results vary depending on the calculation
method and basis set as expected.
Computational and experimental FT-IR spectra In this
part, the calculated harmonic vibrations of the target
compounds are discussed and the results are compared
with experimental FT-IR spectra. The harmonic vibra-
tional wavenumbers and the absolute intensities are cal-
culated by HF and DFT methods for the corresponding
optimized geometries. There are 48 fundamental modes
of vibrations associated with two-ring system and 57 for
the three ring systems. Instead of discussing all individ-
ual modes, the most characteristic peaks are selected
and the following explanations are made according to
them. The scaled (scale factor: 0.965) [82, 83] funda-
mental vibrational wavenumbers of the target com-
pounds are calculated with B3LYP/cc-pVTZ approach
in gas phase and the results are given in Table 9. The
frequencies calculated by DFT are smaller than the fre-
quencies calculated by HF method due to electron cor-
relation in density functional theory to a certain extent
makes the frequency values smaller in comparison with
the HF approach (see ESI†).
The presence of one or more heteroaromatic rings in a molecule
are normally determined from the C-H and C=C ring vibrations. In
this kind of organic compounds, the C-H IR stretching vibrations
normally occur at 3100–3000 cm−1 [84]. The result calculated by
B3LYP/cc-pVTZ shows that the vibrational wavenumbers in
range of 3063–3167 cm−1 are assigned to aromatic C-H stretching
The theoretical studies show that the band gaps are very
similar for all optimized molecules and the values in gas phase

Struct Chem

Struct Chem
modes for the molecules 1–8. The corresponding experimental
values for the same molecules are between 2849 and 3158 cm−1.
The difference between the experimental and calculated vibration-
al wavenumbers could be attributed to the fact that the experimen-
tal results are taken in solvent phase while the theoretical results are
obtained in gas phase. Another reason is harmonic approach used
for calculations while, experimentally, many modes have highly
anharmonic character.
The ring stretching vibrations of the heteroaromatic compounds
are also extremely important. In several resources, highly charac-
teristic peaks, which are observed for the aromatic compounds, are
given in details [84]. In accordance with this information, carbon-
carbon ring stretching vibrations occur in the region of 1430–
1640 cm−1. The experimental C=C stretching vibrations for the
molecules 1–8 are observed in the range of 1516–1659 cm−1 and
the calculated ring stretching vibrations (between 1520 and
1619 cm−1) are in line with the experimental data.
It is well known that the C=N stretching vibration bands are
generally observed in the range 1566–1672 cm−1. The experimen-
tally observed peaks between 1456 and 1585 cm−1 and the calcu-
lated bands between 1456 and 1508 cm−1 in FT-IR spectrum are
identified as C=N vibrations of heterocyclic rings. Additionally, for
the target compounds, the calculated C-N stretching modes are
observed between 1359 and 1249 cm−1. The corresponding exper-
imental values are observed as a medium band at 1373 cm−1 and
very strong band at 1250 cm−1 in FT-IR. Moreover, the C-O-C
stretching vibrations generally occur in the range of 1050–
1253 cm−1. The experimental C-O stretching vibrations are mea-
sured in the range of 988–1286 cm−1 for molecules 1–8, respec-
tively. The corresponding calculated vibrations are between 966
and 1241 cm−1.
The C-S symmetric and asymmetric vibrations of thiophene for
molecules 2, 4, and 6 are calculated at 650, 651, and 680 cm−1,
respectively, and the C-S symmetric vibrations of isothiazole for
compounds 7 and 8 are calculated at 663 and 647 cm−1, respec-
tively. The experimental C-S stretching vibrations of thiophene
ring are observed at 673, 637; 665, 638, and 683 cm−1 and the
C-S-N stretching vibrations for the isothiazole ring are also ob-
served at 750 and 748 cm−1 for molecules 7 and 8, respectively.
The calculated frequencies at 719 and 721 cm−1 are assigned to C-
S-N stretching vibrations for thiophene and isothiazole rings, re-
spectively. N-O ring stretching vibrations are observed in the range
of 868–916 cm−1 and the corresponding calculated values are
between 864 and 914 cm−1.
by using their relevant experimentally determined shifts,
we aimed to determine the best fitting computational
1
method. As mentioned before, our experimental H and
13C magnetic resonance spectra are recorded in CDCl3
1
solution and the calculated H and 13C NMR chemical
shifts of the target compounds are obtained by the
gauge-independent atomic orbital (GIAO) [85, 86] ap-
proach with B3LYP/6-31G(d,p) level of theory, which
has precedent for NMR shielding tensor calculation espe-
cially in the case of reasonably larger molecules [85, 87].
It is well known that B3LYP method is strongly influ-
enced by the basis set. Therefore, in order to assess the
accuracy of the selected basis set, we also utilized a
Dunning’s correlation consistent basis set, cc-pVTZ with
B3LYP which demands more computational efforts than
6-31G(d,p). For this purpose, first of all, the shielding of
tetramethylsilane (TMS), which is used as a general stan-
dard, are calculated by using the selected calculation
method and basis set. Then, the chemical shifting of the
target molecules is calculated by using the same level of
theory on fully optimized geometries. The extraction of
the two evaluated values (σTMS − σcalc.) gave the desired
1
chemical shifts of the molecules. The calculated H and
13C isotropic chemical shielding of TMS at the B3LYP/6-
31G(d,p) level in gas phase are 31.62 and 192.98 ppm,
respectively. In the case of B3LYP/cc-pVTZ, the corre-
1
sponding H and 13C isotropic chemical shielding values
of TMS are calculated as 31.745 and 184.455 ppm. The
1
experimental values for H isotropic chemical shift and
13C isotropic chemical shift for TMS are 30.84 and
188.1 ppm, respectively. The calculated values of 1H
and 13C chemical shifts by B3LYP/6-3G(d,p) and
B3LYP/cc-pVTZ methods in the gas phase together with
experimental values are given in Table 10.
The aromatic protons of five-membered heterocyclic rings are
normally observed in the range of 6–8 ppm; the methyl protons
of these cyclic compounds give peaks between 2 and 2.5 ppm.
Our measured and calculated corresponding protons are within the
limits given above. The maximum deviation between the calculat-
ed and experimental values is 0.4 ppm, thus it is concluded that 1H
NMR chemical shifts calculated by using DFT method are in good
agreement with the experimental values. The same trend is ob-
served for the 13C NMR, but the maximum deviation ( 1.1) is
1
The aliphatic C-H stretching vibrations normally occur at
3100–2850 cm−1 and the C-H stretching vibrations of the methyl
group connected aromatic rings are observed in the region of
2951–2849 cm−1. Our calculated wavenumbers in the range of
3013–2920 cm−1 are assigned as C-H stretching of CH3.
higher than H NMR chemical shifts. In order to evaluate the
accuracy of the theoretical methods used in NMR calculations,
we analyzed statistically the correlation between calculated and
experimental chemical shifts. The correlations including both pro-
ton and carbon NMR results are given in ESI†. The correlations
expressed by R2 between measured and calculated NMR param-
eters are obtained (y = ax + b, a values close to 0.5 and R2 values
close to 1 for each studied compound. The correlation coefficients
evaluated for each compounds are higher than 0.90 except for 4.
Computational and experimental 1H-NMR and 13C-NMR
analysis In this section, we focused on the calculation of
1H and 13C chemical shifts of our studied molecules and

Struct Chem
Table 10 Experimental and calculated (a) 1H-NMR chemical shifts (ppm) and (b) 13C-NMR chemical shifts (ppm) of target molecules
1
2.3
2.3
2.4
6.1
6.2
6.2
6.5
6.7
6.7
7.1
7.4
7.3
7.8
7.6
7.6
0.992
0.994
2
2.5
2.6
2.6
6.5
6.4
6.7
6.7
6.8
7.2
7.0
6.9
7.3
7.8
7.9
7.6
0.998
0.923
3
4
5
2.3
2.3
2.4
6.2
6.3
6.3
6.7
7.0
7.1
6.4
6.4
6.4
8.2
8.1
8.2
0.995
0.994
6
2.4
2.4
2.6
6.2
6.2
6.8
7.2
7.2
7.6
6.7
6.7
6.2
8.1
8.1
8.1
1.000
0.926
7
2.3
2.3
2.4
6.0
6.2
6.2
6.5
6.7
6.8
7.2
7.2
7.3
8.3
8.3
8.3
0.998
0.998
8
6.7
6.8
6.9
7.3
7.5
7.5
7.9
7.7
7.7
−
7.2
7.3
7.4
7.3
7.5
7.4
7.8
7.7
7.7
−
2.5
2.5
2.6
6.7
6.7
6.7
7.1
7.1
7.2
7.2
7.2
7.2
8.3
8.3
8.3
1.00
1.00
Exp.
Cal.a
Cal.b
Exp.
Cal.a
Cal.b
Exp.
Cal.a
Cal.b
Exp.
Cal.a
Cal.b
Exp.
Cal.a
Cal.b
a
b
c
a)
d
e
−
−
−
−
−
−
−
−
R2
a
0.907
0.923
0.871
0.871
R2
b
b)
1
2
3
4
5
6
7
8
13.5
15.2
109.3
106.9
113.3
122.3
120.2
127.8
143.2
140.7
151.3
150.2
142.6
154.2
143.6
140.8
152.0
−
121.2
119.5
128.4
125.1
120.1
128.0
129.6
140.7
154.4
150.1
143.7
154.1
146.2
142.8
141.2
−
13.6
15.3
13.6
15.3
Exp.
Cal.a
Cal.b
Exp.
Cal.a
Cal.b
Exp.
Cal.a
Cal.b
Exp.
Cal.a
Cal.b
Exp.
Cal.a
Cal.b
Exp.
Cal.a
Cal.b
Exp.
Cal.a
Cal.b
Exp.
Cal.a
Cal.b
R2 a
a
15.2
15.1
15.2
17.7
15.2
15.2
18.1
17.9
15.2
15.1
9.0
17.8
149.5
141.7
159.9
107.6
105.8
113.1
108.6
106.5
112.1
153.2
147.8
151.5
141.6
139.9
152.1
120.4
118.6
125.9
144.2
141.3
153.1
0.999
0.993
147.1
150.9
152.7
120.4
114.6
130.3
124.6
120.6
127.2
149.5
151.9
141.9
127.1
133.4
155.1
125.9
122.3
126.4
140.9
144.8
153.2
0.991
0.989
150.3
144.4
161.4
108.1
107.0
113.7
111.6
109.4
116.2
154.5
149.3
151.6
161.3
157.0
169.4
97.2
94.9
99.2
141.6
140.0
154.5
0.999
0.991
140.9
144.6
155.8
126.3
121.5
131.1
126.7
121.6
130.9
150.6
146.4
141.2
164.5
159.9
172.5
97.5
95.1
99.8
127.1
133.4
154.7
0.991
0.952
153.7
148.3
160.1
109.9
108.9
113.8
117.5
111.7
115.6
156.0
150.5
154.1
157.5
157.6
166.7
108.3
107.1
119.4
144.5
142.6
161.7
0.998
0.984
142.2
136.4
154.6
126.4
111.8
130.9
126.5
112.1
130.1
157.8
141.3
145.9
160.1
153.2
171.9
119.4
102.8
130.2
130.2
128.7
161.7
0.984
0.935
b
c
d
e
f
−
−
−
−
−
−
g
h
−
−
−
−
−
−
−
−
−
−
0.986
0.989
0.718
0.409
R2 b
a B3LYP/6-31G(d,p) method
b B3LYP/cc-pVTZ method
Therefore, it can also be concluded that the GIAO method and
B3LYP/6-31G(d,p) level of theory is sufficient to estimate 1H and
13C NMR chemical shifts values for our corresponding furan and
thiophene derivatives.
derivatives with good to excellent yields. In a general point
of view, it could be concluded that the obtained experimental
results from this research are compatible with theoretical re-
sults. The results of the calculations done by DFT (B3LYP/cc-
pVTZ) method for the bond lengths, bond angles, dipole mo-
ments, and polarizabilities are in line with their unsubstituted
analogs. The calculated band gap values for all molecules are
in a logical trend. Furthermore, spectral analyses of the target
molecules are performed with consecutive experimental and
theoretical calculations. Theoretical UV, IR, and NMR spec-
tral analyses are done by different methods and basis sets. Due
to the compatibility of the calculated and experimental results,
Conclusions
Our present work represents joint experimental and theoretical
studies of newly designed thiophene- or furan-based oxazole,
isoxazole, and isothiazole derivatives. A convenient and effi-
cient method is reported in order to synthesize azole

Struct Chem
as potential analgesic agents. 1. (Imidazolylmethyl)oxazoles and -
thiazoles. J Med Chem 42:5064–5071. doi:10.1021/jm990005a
16. Gürsoy A, Demirayak Ş, Çapan G, Erol K, Vural K (2000)
Synthesis and preliminary evaluation of new 5-pyrazolinone deriv-
atives as analgesic agents. Eur J Med Chem 35:359–364.
doi:10.1016/S0223-5234(00)00117-3
17. Broom NJP, Cassels R, Cheng HY, Elder JS, Hannan PC, Masson
N, O'Hanlon PJ, Pope A, Wilson JM (1996) The chemistry of
pseudomonic acid. 17. Dual-action C-1 oxazole derivatives of
pseudomonic acid having an extended spectrum of antibacterial
activity. J Med Chem 39:3596–3600. doi:10.1021/jm950882q
18. Lu X, Liu X, Wan B, Franzblau SG, Chen L, Zhou C, You Q (2012)
Synthesis and evaluation of anti-tubercular and antibacterial activ-
ities of new 4-(2,6-dichlorobenzyloxy)phenyl thiazole, oxazole and
imidazole derivatives. Part 2. Eur J Med Chem 49:164–171.
doi:10.1016/j.ejmech.2012.01.007
19. Stokes NR, Baker N, Bennett JM, Chauhan PK, Collins I, Davies
DT, Gavade M, Kumar D, Lancett P, Macdonald R, Macleod L,
Mahajan A, Mitchell JP, Nayal N, Nayal YN, Pitt GR, Singh M,
Yadav A, Srivastava A, Czaplewski LG, Haydon DJ (2014) Design,
synthesis and structure-activity relationships of substituted oxazole-
benzamide antibacterial inhibitors of FtsZ. Bioorganic Med Chem
Lett 24:353–359. doi:10.1016/j.bmcl.2013.11.002
20. Bull JA, Balskus EP, Horan RAJ, Langner M, Ley S V (2007) Total
synthesis of potent antifungal marine bisoxazole natural products
bengazoles a and b. Chem Eur J 13:5515–5538. doi:10.1002
/chem.200700033
B3LYP method with 6-31G(d,p) basis set could be accepted as
an appropriate method for the azole derivatives for under-
standing the corresponding spectral properties.
Acknowledgments Pervin Ünal Civcir would like to express her grat-
itude to AU-BAP (Project No: 13H4240002) for financial support. The
numerical calculations reported in this research were performed at
TUBITAK-ULAKBİM. High Performance and Grid Computing Center
(TR-Grid e-Infrastructure).
References
1. Maertens JA (2004) History of the development of azole deriva-
tives. Clin Microbiol Infect 10(Suppl 1):1–10. doi:10.1111/j.1470-
9465.2004.00841.x
2. Linder J, Moody CJ (2007) The total synthesis of siphonazole, a
structurally unusual bis-oxazole natural product. Chem Commun
1508–1509. doi: 10.1039/b618160k
3. Danilo D, Gloria S (2010) Thiazole and oxazole alkaloids: isolation
and synthesis. Mar Drugs 8:2755–2780. doi:10.3390/md8112755
4. Yamada K, Yajima O, Yoshizawa Y, Oh K (2013) Synthesis and
biological evaluation of novel azole derivatives as selective potent
inhibitors of brassinosteroid biosynthesis. Bioorganic Med Chem
21:2451–2461. doi:10.1016/j.bmc.2013.03.006
5. Gomma GK (1998) Effect of azole compounds on corrosion of
copper in acid medium. Mater Chem Phys 56:27–34. doi:10.1016
/S0254-0584(98)00086-8
21. Ryu C-K, Lee RY, Kim NY, Song AL (2009) Synthesis and anti-
fungal activity of benzo[d]oxazole-4,7-diones. Bioorg Med Chem
Lett 19:5924–5926. doi:10.1016/j.bmcl.2009.08.062
6. Mahdavian M, Ashhari S (2010) Mercapto functional azole com-
pounds as organic corrosion inhibitors in a polyester-melamine
coating. Prog Org Coatings 68:259–264. doi:10.1016/j.
porgcoat.2010.04.002
7. Kovačević N, Kokalj A (2013) The relation between adsorption
bonding and corrosion inhibition of azole molecules on copper.
Corros Sci 73:7–17. doi:10.1016/j.corsci.2013.03.016
8. Hughes RA, Moody CJ (2007) From amino acids to
heteroaromatics-thiopeptide antibiotics, nature's heterocyclic pep-
tides. Angew Chem Int Ed 46:7930–7954. doi:10.1002
/anie.200700728
9. Zhang J, Ciufolini MA (2011) An approach to the bis-oxazole
macrocycle of diazonamides. Org Lett 13:390–393. doi:10.1021
/ol102678j
10. Liu XH, Lv PC, Xue JY, Song BA, Zhu HL (2009) Novel 2,4,5-
trisubstituted oxazole derivatives: synthesis and antiproliferative
activity. Eur J Med Chem 44:3930–3935. doi:10.1016/j.
ejmech.2009. 04.019
11. Zhou J, Jin J, Zhang Y, Yin Y, Chen X, Xu B (2013) Synthesis and
antiproliferative evaluation of novel benzoimidazole-contained
oxazole-bridged analogs of combretastatin A-4. Eur J Med Chem
68:222–232. doi:10.1016/j.ejmech.2013.08.006
12. Li YM, Milne JC, Madison LL, Kolter R, Walsh CT (1996) From
peptide precursors to oxazole and thiazole-containing peptide anti-
biotics: microcin B17 synthase. Science 274:1188–1193.
doi:10.1126/science.274.5290.1188
22. Tomi IHR, Tomma JH, Al-Daraji AHR, Al-Dujaili AH (2015)
Synthesis, characterization and comparative study the microbial
activity of some heterocyclic compounds containing oxazole and
benzothiazole moieties. J Saudi Chem Soc 19:392–398.
doi:10.1016/j.jscs.2012.04.010
23. Moraski GC, Chang M, Villegas-Estrada A, Franzblau SG,
Möllmann U, Miller MJ (2010) Structure–activity relationship of
new anti-tuberculosis agents derived from oxazoline and oxazole
benzyl esters. Eur J Med Chem 45:1703–1716. doi:10.1016/j.
ejmech.2009.12.074
24. Sasahara K, Shimokawa Y, Hirao Y, Koyama N, Kitano K, Shibata
M, Umehara K (2015) Pharmacokinetics and metabolism of
delamanid, a novel anti-tuberculosis drug, in animals and humans:
importance of albumin metabolism in vivo. Drug Metab Dispos 43:
1267–1276. doi:10.1124/dmd.115.064527
25. Yale HL, Losee K (1966) 2-amino-5-substituted 1,3,4-oxadiazoles
and 5-imino-2-substituted delta-2-1,3,4-oxadiazolines. A group of
novel muscle relaxants J Med Chem 9:478–483. doi:10.1021
/jm00322a007
26. Kempf DJ, Sham HL, Marsh KC, Flentge CA, Betebenner D,
Green BE, McDonald E, Vasavanonda S, Saldivar A, Wideburg
NE, Kati WM, Ruiz L, Zhao C, Fino L, Patterson J, Molla A,
Plattner JJ, Norbeck DW (1998) Discovery of ritonavir, a potent
inhibitor of HIV protease with high oral bioavailability and clinical
efficacy. J Med Chem 41:602–617. doi:10.1021/jm970636+
27. Kang YK, Shin KJ, Yoo KH, Seo KJ, Hong CY, Lee CS, Park SY,
Kim DJ, Park SW (2000) Synthesis and antibacterial activity of new
carbapenems containing isoxazole moiety. Bioorg Med Chem Lett
10:95–99. doi:10.1016/S0960-894X(99)00646-0
13. Dinarello CA (2010) Anti-inflammatory agents: present and future.
Cell 140:935–950. doi:10.1016/j.cell.2010.02.043
14. Fernandes E, Costa D, Toste SA, Jose LF, Lima SR (2004) In vitro
scavenging activity for reactive oxygen and nitrogen species by
nonsteroidal anti-inflammatory indole, pyrrole, and oxazole deriv-
ative drugs. Free Radic Biol Med 37:1895–1905. doi:10.1016/j.
freeradbiomed.2004.09.001
28. Calí P, Nærum L, Mukhija S, Hjelmencrantz A (2004) Isoxazole-3-
hydroxamic acid derivatives as peptide deformylase inhibitors and
potential antibacterial agents. Bioorganic Med Chem Lett 14:5997–
6000. doi:10.1016/j.bmcl.2004.09.087
15. Boyd RE, Press JB, Rasmussen CR, Raffa RB, Codd EE, Connelly
CD, Bennett DJ, Kirifides AL, Gardocki JF, Reynolds B,
Hortenstein JT, Reitz AB (1999) Alpha(2) adrenoceptor agonists
29. Solankee A, Solankee S, Patel G (2008) Synthesis and antibacterial
evaluation of some novel isoxazole and pyrazoline derivatives.
Rasayan J Chem 1:581–585

Struct Chem
30. Rahbaek L, Christophersen C (2001) The isoxazole alkaloids.
Alkaloids Chem Biol 57:185–233. doi:10.1016/S0099-9598(01
)57004-2
45. Leusen DV, Leusen AMV (2004) Synthetic uses of tosylmethyl
isocyanide (TosMIC). Org React 57:417–666. doi:10.1002
/0471264180.or057.03
46. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb M,
Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson
GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF,
Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K,
Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O,
Nakai H, Vreven T, Montgomery Jr JA, Peralta JE, Ogliaro F,
Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN,
Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant
JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene
M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts
R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C,
Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth
GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas
Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian
09, Revision D.01. Gaussian, Inc., Wallingford CT
31. Conti P, Tamborini L, Pinto A, Sola L, Ettari R, Mercurio C, De
Micheli C (2010) Design and synthesis of novel isoxazole-based
HDAC inhibitors. Eur J Med Chem 45:4331–4338. doi:10.1016/j.
ejmech.2010.06.035
32. Gehling VS, Hewitt MC, Vaswani RG, Leblanc Y, Côté A,
Nasveschuk CG, Taylor AM, Harmange JC, Audia JE, Pardo E,
Joshi S, Sandy P, Mertz JA, Sims 3rd RJ, Bergeron L, Bryant BM,
Bellon S, Poy F, Jayaram H, Sankaranarayanan R, Yellapantula S,
Bangalore SN, Birudukota S, Albrecht BK (2013) Discovery, de-
sign, and optimization of isoxazole azepine BET inhibitors. ACS
Med Chem Lett 4:835–840. doi:10.1021/ml4001485
33. Künig G, Niedermeyer B, Deckert J, Gsell W, Ransmayr G,
Riederer P (1998) Inhibition of [3H]α-amino-3-hydroxy-5-meth-
yl-4-isoxazole-propionic acid [AMPA] binding by the anticonvul-
sant valproate in clinically relevant concentrations: an autoradio-
graphic investigation in human hippocampus. Epilepsy Res 31:
153–157. doi:10.1016/S0920-1211(98)00022-9
47. Dennington R, Keith T, Millam J (2009) GaussView, Version 5.0.8.
GaussView, Version 5.0.8
48. Kohn W, Sham LJ (1965) Self-consistent equations including ex-
change and correlation effects. Phys Rev 140:A1133–A1A38
49. Becke AD (1988) Density-functional exchange-energy approxima-
tion with correct asymptotic-behavior. Phy Rev A 38:3098–3100.
doi:10.1103/PhysRevA.38.3098
34. Bolvig T, Larsson OM, Pickering DS, Nelson N, Falch E,
Krogsgaard-Larsen P, Schousboe A (1999) Action of bicyclic
isoxazole GABA analogues on GABA transporters and its relation
to anticonvulsant activity. Eur J Pharmacol 375:367–374.
doi:10.1016/S0014-2999(99)00263-0
50. Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti
correlation-energy formula into a functional of the electron density.
Phys Rev B 37:785–789. doi:10.1103/PhysRevB.37.785
51. Ditchfield R, Hehre WJ, Pople JA (1971) Self-consistent molecu-
lar-orbital methods. IX. An extended Gaussian-type basis for
molecular-orbital studies of organic molecules. J Chem Phys 54:
724–728. doi:10.1063/1.1674902
52. Ha TK (1979) A theoretical study of the electronic structure and
properties of some five-membered heterocyclic compounds:
pyrazole, imidazole, furan, isoxazole, 1,2,5-oxadiazole and 1,3,4-
oxadiazole. J Mol Struct 51:87–98. doi:10.1016/0022-2860(79
)80272-0
53. Pace A, Pierro P, Buscemi S, Vivona N, Barone G (2009)
Experimental and DFT studies on competitive heterocyclic rear-
rangements. 3. A cascade isoxazole-1,2,4-oxadiazole-oxazole rear-
rangement. J Org Chem 74:351–358. doi:10.1021/jo802081k
54. Li LC, Wang XL, Cai WF, Tian AM (2011) Theoretical investiga-
tion on the reaction mechanism of aryl alcohols and p-
toluenesulfonylmethyl isocyanide catalyzed by InCl3. Comput
Theor Chem 964:182–187. doi:10.1016/j.comptc.2010.12.020
55. Froese FC (1977) The Hartree-Fock method for atoms: a numerical
approach. John Wiley and Sons, New York ISBN 047125990X
56. Dunning TH (1989) Gaussian basis sets for use in correlated mo-
lecular calculations. I. The atoms boron through neon and hydro-
gen. J Chem Phys 90:1007–1023. doi:10.1063/1.456153
57. Zhao Y, Truhlar DG (2008) The M06 suite of density functionals
for main group thermochemistry, thermochemical kinetics,
noncovalent interactions, excited states, and transition elements:
two new functionals and systematic testing of four M06-class func-
tionals and 12 other function. Theor Chem Accounts 120:215–241.
doi:10.1007/s00214-007-0310-x
35. Stefan H, Feuerstein TJ (2007) Novel anticonvulsant drugs.
P h a r m a c o l T h e r 11 3 : 1 6 5 – 1 8 3 . d o i : 1 0 . 1 0 1 6 / j .
pharmthera.2006.07.005
36. Epe C, Kaminsky R (2013) New advancement in anthelmintic
drugs in veterinary medicine. Trends Parasitol 29:129–134.
doi:10.1016/j.pt.2013.01.001
37. Carr JB, Durham HG, Hass DK (1977) Isoxazole anthelmintics. J
Med Chem 20:934–939
38. White AD, Purchase CF, Picard JA, Anderson MK, Mueller SB,
Bocan TM, Bousley RF, Hamelehle KL, Krause BR, Lee P,
Stanfield RL, Reindel JF (1996) Heterocyclic amides: inhibitors
of acyl-CoA:cholesterol O-acyl transferase with
hypocholesterolemic activity in several species and
antiatherosclerotic activity in the rabbit. J Med Chem 39:3908–
3919. doi:10.1021/jm9604033
39. Burak K, Machoń Z (1992) Synthesis of isothiazole derivatives
with potential biological activity. Pharmazie 47:492–495
40. Keck PE, Versiani M, Potkin S, West SA, Giller E, Ice K (2003)
Ziprasidone in the treatment of acute bipolar mania: a three-week,
placebo-controlled, double-blind, randomized trial. Am J
Psychiatry 160:741–748. doi:10.1176/appi.ajp.160.4.741
41. Araki T, Yamasue H, Sumiyoshi T, Kuwabara H, Suga M, Iwanami
A, Kato N, Kasai K (2006) Perospirone in the treatment of schizo-
phrenia: effect on verbal memory organization. Prog Neuro-
Psychopharmacology Biol Psychiatry 30:204–208. doi:10.1016/j.
pnpbp.2005.10.015
42. Zificsak CA, Hlasta DJ (2004) Current methods for the synthesis of
2-substituted azoles. Tetrahedron 60:8991–9016. doi:10.1016/j.
tet.2004.07.016
43. Roncali J, Garnier F, Garreau R, Lemaire M (1987) Reduction of
the steric hindrance to conjugation in 3,4-disubstituted
poly(thiophenes); cyclopenta[c]thiophene and thieno[c]thiophene
as precursors of electrogenerated conducting polymers. J Chem
Soc Chem Commun 19:1500–1502. doi:10.1039/c39870001500
44. Oldenziel OH, Leusen DV, Leusen AMV (1977) Chemistry of
sulfonylmethyl isocyanides. 13. A general one-step synthesis of
nitriles from ketones using tosylmethyl isocyanide. Introduction
of a one-carbon unit. J Org Chem 42:3114–3118. doi:10.1021
/jo00439a002
58. Kendall RA, Dunning TH, Harrison RJ (1992) Electron affinities of
the first-row atoms revisited. Systematic basis sets and wave func-
tions. J Chem Phys 96:6796–6806. doi:10.1103/PhysRev.136.
B864
59. Schomaker V, Pauling L (1939) The electron diffraction investiga-
tion of the structure of benzene, pyridine, pyrazine, butatidene-1,3-
cyclopentadiene, furan, pyrrole, and thiophene. J Am Chem Soc 61:
1769–1780. doi:10.1021/ja01876a038
60. Hartough HD (2009) The chemistry of heterocyclic compounds,
thiophene and its derivatives. John Wiley & Sons, New York

Struct Chem
61. Bak B, Christensen D, Dixon WB, Hansen-Nygaard L, Andersen
JR, Schottländer M (1962) The complete structure of furan. J Molec
Spect 9:124–129
62. Kumar A, Sheridan J, Stiefvater OL (1978) The microwave spec-
trum of oxazole I. The complete structure by DRM microwave
spectroscopy. Z Naturforsch 33a:145–152
63. Stiefvater OL (1975) The complete structure of isoxazole from
naturally occurring isotopic forms by double resonance modulated
microwave spectroscopy. J Chem Phys 64:2560. doi:10.1063
/1.431647
64. Elgazwy ASH (2003) The chemistry of isothiazoles. Tetrahedron
59(38):7445–7463. doi:10.1016/S0040-4020(03)01070-6
65. Onsager L (1936) Electric moments of molecules in liquids. J Am
Chem Soc 58:1486–1493. doi:10.1021/ja01299a050
66. Dzuba VA, Flambaum VV (2010) Current trends in searches for
new physics using measurements of parity violation and electric
dipole moments in atoms and molecules. arXiv:1009.4960
67. Gierke TD, Tigelaar HL, Flygare H (1972) Calculation of molecular
electric dipole and quadrupole moments. J Am Chem Soc 94:330–
338. doi:10.1021/ja00757a003
75. Coonan MH, Craven IE, Hesting MR, Ritchie GLD, Spackman
MA (1992) Anisotropic molecular polarizabilities, dipole moments,
and quadrupole moments of (CH2)2X, (CH3)2X, and C4H4X (X = 0,
S, Se). Comparison of experimental results and ab initio calcula-
tions. J Phys Chem 96:7301
76. Stratmann RE, Scuseria GE, Frisch MJ (1998) An efficient imple-
mentation of time-dependent density-functional theory for the cal-
culation of excitation energies of large molecules. J Chem Phys
109:8218. doi:10.1063/1.477483
77. York DM, Karplus M (1999) Smooth solvation potential based on
the conductor-like screening model. J Phys Chem A 103:11060–
11079
78. Van Veen EH (1976) Triplet π→π* transitions in thiophene, furan
and pyrrole by low-energy electron-impact spectroscopy. Chem
Phys Lett 41:535–539. doi:10.1016/0009-2614(76)85411-5
79. Lang SA Jr, Lin Y (1984) In: Potts KT (ed) Comprehensive het-
erocyclic chemistry. Pergamon, New York
80. Scuseria GE (1999) Linear scaling density functional calculations
with Gaussian orbitals. J Phys Chem A 103:4782–4790.
doi:10.1021/jp990629s
68. Berendsen HJC, Grigera JR, Straatsma TP (1987) The missing term
in effective pair potentials. J Phys Chem 91:6269–6271.
doi:10.1021/j100308a038
81. Brus L (1986) Electronic wave functions in semiconductor clusters:
experiment and theory. J Phys Chem 90:2555–2560. doi:10.1021
/j100403a003
69. Guggenheim EA (1949) A proposed simplification in the procedure
for computing electric dipole moments. Trans Faraday Soc 45:714.
doi:10.1039/tf9494500714
70. McClellan AL (1974) Tables of experimental dipole moments.
Rahara Enterprises, El Cerrito, CA
82. Sinha P, Boesch SE, Gu C, Wheeler RA, Wilson AK (2004)
Harmonic vibrational frequencies: scaling factors for HF, B3LYP,
and MP2 methods in combination with correlation consistent basis
sets. Phys Chem A 108:9213–9217. doi:10.1021/jp073974n
83. Merrick JP, Moran D, Radom L (2007) An evaluation of harmonic
vibrational frequency scale factors. J Phys Chem A 111:11683–
11700. doi:10.1021/jp073974n
71. McClellan AL (1963) Tables of experimental dipole moments.
Freeman WH, San Francisco, CA
72. Le Fe’vre CG, Le Fe’vre RJW, Rao BP, Smith MRJ (1959)
Molecular polarisability. Ellipsoids of polarisability for certain fun-
damental heterocycles. J Chem Soc 1188–1192. doi: 10.1039/
JR9590001188
73. Dennis GR, Gentle IR, Ritchie GLD, Andrieu CG (1983) Field-
gradient-induced birefringence in dilute solutions of furan, thio-
phene and selenophene in cyclohexane. J Chem Soc Faraday
Trans 2(79):539–545. doi:10.1039/F29837900539
84. Silverstein RM, Bassler GC, Morrill TC (1991) Spectrometric iden-
tification of organic compounds. Wiley, New York
85. Wolinski K, Hinton JF, Pulay P (1990) Efficient implementation of
the gauge-independent atomic orbital method for NMR chemical
shift calculations. J Am Chem Soc 112:8251–8260. doi:10.1021
/ja00179a005
86. Ditchfield R (1974) Self-consistent perturbation theory of diamag-
netism. Mol Phys 27:789–807. doi:10.1080/00268977400100711
87. Cheeseman JR, Trucks GW, Keith TA, Frisch MJ (1996) A com-
parison of models for calculating nuclear magnetic resonance
shielding tensors. J Chem Phys 104:5497. doi:10.1063/1.47178
74. Zhao MT, Singh BP, Prasad PN (1988) A systematic study of po-
larizability and microscopic third-order optical nonlinearity in thio-
phene oligomers. J Chem Phys 89:5535. doi:10.1063/1.455560