Characterization and Computational Studies of 2-(Benzamido)Thiazol-5-yl Benzoate

Article abstract of DOI:10.1134/S0022476619010190

2-(Benzamido)thiazolylbenzoate is synthesized via a novel method. It is characterized by spectroscopy, micranalysis, and GC-MS. It crystallizes in the monoclinic space group P21/n with a = 19.8990(5), b = 7.3680(2), c = 22.3845(6) ?, β = 113.799(1)°, V = 3002.85(14) ?³Z = 8. The HOMO-LUMO of the reactants and products are considered.

Full text of DOI:10.1134/S0022476619010190

Journal of Structural Chemistry. Vol. 60, No. 1, pp. 136-142, 2019.
Text © 2019 F. Odame, E. Hosten, R. Betz, K. Lobb, Z. Tshentu.
CHARACTERIZATION AND COMPUTATIONAL
STUDIES OF 2-(BENZAMIDO)THIAZOL-5-YL BENZOATE
1
F. Odame , E. Hosten , R. Betz , K. Lobb ,
1
1
2
1
and Z. Tshentu
2-(Benzamido)thiazolylbenzoate is synthesized via a novel method. It is characterized by spectroscopy,
micranalysis, and GC–MS. It crystallizes in the monoclinic space group P21/n with a = 19.8990(5),
3
b = 7.3680(2), c = 22.3845(6) Å, β = 113.799(1)°, V = 3002.85(14) Å , Z = 8. The HOMO–LUMO of the
reactants and products are considered.
DOI: 10.1134/S0022476619010190
Keywords: synthesis, thiazole, benzoyl chloride, HOMO–LUMO, frontier orbitals.
INTRODUCTION
Thiazoles have shown a broad range of biological activities and are found in many potent biologically active
molecules such as Sulfathiazol (antimicrobial drug), Ritonavir (antiretroviral drug), Abafungin (antifungal drug), and
Tiazofurin (antineoplastic drug) [1]. They have exhibited some degree of plant growth regulatory and antifungal activities [2],
whilst some thiazoles have shown anti-infective [3] as well as antibacterial activities [4]. The regio-controlled synthesis of
2,5-disubstituted and 2,4,5-trisubstituted thiazoles from ethyl-2-bromo-5-chloro-4-thiazolecarboxylates using sequential
palladium-catalyzed coupling reactions has been reported [5]. An efficient general method for the preparation of 2,4-di- and
trisubsituted thiazoles is via P–TsOH. H O-Catalyzed cyclization of trisubstituted propargylic alcohols with thioamides has
2
been accomplished with moderate to excellent product yields under mild and standard conditions [6]. In the presence of
3
triethylamine, (Z)-(2-acetoxyl-1-alkenyl) phenyl-λ iodanes reacts with thioureas or thioamides in methanol to afford 2,4-
3
disubstituted thiazoles in good yields. The reaction is thought to proceed by the generation of highly reactive α-λ iodanyl
ketones through ester exchange of the β-acetoxy group with liberation of methyl acetate, followed by nucleophilic
substitutions with thioureas or thioamides [7]. The resolution of (R)- and (S)-2-(1-hydroxyalkyl) thiazoles (S) in high
enantiomeric purity has been reported to be due to a transesterification reaction of the (R) enantiomer with 2,2,2-
trifluoroethyl butanoate (TFEB) in diisopropyl ether under immobilized lipase PS catalysis [8]. Ketones have been reacted
with NBS in the presence of a catalytic amount of p-toluenesulfonic acid to give α-bromoketones in good yields in typical
ionic liquids, such as [bmim]PF and [bmpy]Tf N, with the ionic liquids being reusable. The one-pot conversion of ketones
6
2
into thiazoles by treatment with NBS, and subsequently with thioamides has also been carried out in [bmim]PF and
6
[bmpy]Tf N, respectively [9]. A thiazole derivative has been accessed by the reaction between 5-chlorothiazol-2-amine and
2
1
Department of Chemistry, Nelson Mandela Metropolitan University, Port Elizabeth, South Africa;
2
felixessah15@gmail.com. Department of Chemistry, Rhodes University, Grahamstown, South Africa. Zhurnal Strukturnoi
Khimii, Vol. 60, No. 1, pp. 143-149, January, 2019. Original article submitted August 29, 2017; revised December 22, 2017;
accepted January 04, 2018.
136
0022-4766/19/6001-0136 © 2019 by Pleiades Publishing, Ltd.

2,4-difluorobenzoyl chloride in pyridine with stirring [10]. The preparation of 2,4-di- and trisubstituted thiazoles has been
achieved via p-TsOH and 3H O-catalyzed cyclization of trisubstituted propargylic alcohols with thioamides [11]. N,N-
2
disubstituted β-amino acids and their derivatives with thiazole, aromatic, and heterocyclic substituents have been synthesized
from N-phenyl-N-thiocarbamoyl-β-alanine by the Hantzsch method [12]. The one-pot ring synthesis of novel 4-
hydrazinothiazoles has been reported to be accessed by base-assisted eliminative aromatization in the [4+1] ring synthesis;
hydrazone deprotection is affected by acylation [13]. Palladium-catalyzed selective olefination of thiazoles has been reported
[14]. In this work we report a new method for the synthesis of thiazole and an attempt is made to predict the reactivity from
the HOMO–LUMO of the reactants and products.
EXPERIMENTAL
Reagents and instrumentation. Analytical grade reagents and solvents for the synthesis, such as ammonium
thiocyanate and glycine, were obtained from Sigma Aldrich (USA) whilst acetone, pyridine, dichloromethane, and benzoyl
chloride were obtained from Merck Chemicals (SA). The chemicals were used as received (i.e. without further purification).
1
13
1
H and C NMR spectra were recorded on a Bruker Avance AV 400 MHz spectrometer operating at 400 MHz for H and
13
100 MHz for C NMR using DMSO-d as a solvent and tetramethylsilane as the internal standard. Chemical shifts are
6
expressed in ppm. FT–IR spectra were recorded on a Bruker Platinum ATR Spectrophotometer Tensor 27. Elemental
analyses were performed using Vario Elementar Microcube ELIII. Melting points were obtained using Stuart Lasec SMP30
whilst the masses were determined using an Agilent 7890A GC system connected to 5975C VL–MSC with electron impact as
the ionization mode and detection by a triple-axis detector. GC was fitted with a 30 m × 0.25 mm × 0.25 μm DB-5 capillary
column. Helium was used as the carrier gas at a flow rate of 1.6 ml/min with an average rate of 30.2 cm/s and a pressure of
63.7 KPa.
Synthesis of compound I. Ammonium thiocyanate (0.10 mol, 7.6 g) was dissolved in 100 ml of acetone. Benzoyl
chloride (0.10 mol, 11.3 ml) was added followed by heating under reflux at 100-120 °C for 2 h. The product was filtered and
glycine (0.10 mol, 7.50 g) was added to the filtrate and heated under reflux at 100-120 °C for 6 h. 20 ml of water was then
added and the mixture was heated under reflux for further 2 h. The reaction mixture was extracted with diethyl ether, and the
solvent was removed via rotary evaporation followed by drying the compound under a high vacuum. GC-Mass spectra were
+
recorded for the synthesized compounds and they showed molecular ion (M ) peaks, in addition to the others, which
confirmed the formation of the products. The product recrystallized as a yellow solid from DMSO:toluene (4:1).
–1 1
Yield = 76%, Mp = 198-200 °C. IR (νmax, cm ): 3227 (N–H), 1704 (C=S), 1665 (C=O), 1520 (C=C), 1406 (C=N). H NMR
13
(ppm): 11.50 (s, 1H), 11.15 (s, 1H), 7.95 (d, 2H, Ar–H)), 7.64 (m, 1H, Ar–H), 7.62 (d, 2H, Ar–H), 4.32 (s, 1H, N–H). C
NMR (ppm): 180.6 (C=S), 169.7 (C=O), 168.1 (C=O), 133.1 (Ar–H), 132.1 (Ar–H) 128.5 (Ar–H), 128.4 (Ar–H) 46.6 (CH2).
+
LRMS (m/z, M ): Found for C H N O S = 312.90, expected mass = 312.41. Anal.calcd. for C H N O S: C 50.41, H 4.23,
10
10
2
3
10 10
2
3
N 11.76, S 13.46. Found: C 50.85, H 4.23, N 11.86, S 13.66.
Synthesis of compound II. Compound I (3.24 g, 0.01 mol) was dissolved in acetone (10 ml) and benzoyl chloride
(1.40 g, 1.160 ml, 0.01 mol). Pyridine (3 ml) was added slowly over 30 minutes with stirring; the reaction was heated at
8
0 °C for further two and half h. The solvent was removed at the pump and the product was washed with ethanol to obtain
a light purple solid. The product was recrystallized as a light purple solid from THF. Yield = 53%, Mp = 180-182 °C. IR
–1 1
νmax, cm ): 3031 (N–H), 3058 (N–H), 1726 (C–S) 1693 (C=O), 1661 (C=O), 1600 (C=C), 1316 (C=N). H NMR (ppm):
(
12.59 (s, 1H, N–H), 8.16 (m, 2H, Ar–H), 8.08 (m, 2H, Ar–H), 7.79 (m, 1H, Ar–H), 7.64 (m, 3H, Ar–H), 7.56 (m, 3H, Ar–H).
13
C NMR (ppm): 162.8 (C=O), 134.6 (Ar–H), 130.0 (Ar–H), 129.1 (Ar–H), 128.6 (Ar–H), 128.1 (Ar–H), 127.3 (Ar–H),
+
LRMS (m/z, M ): Found for C H N O S = 324.90, expected mass = 324.35. Anal.calcd. for C H N O S: C 62.95, H 3.73,
17
12
2
3
17 12
2
3
N 8.64, S 9.89. Found: C 62.76, H 3.84, N 8.75, S 9.68.
X-ray crystallography. The X-ray diffraction analysis of compound II was performed at 200 K using a Bruker
Kappa Apex II diffractometer with monochromated MoK radiation (λ = 0.71073 Å). APEXII [15] was used for the data
α
137

collection and SAINT [15] for the cell refinement and data reduction. The structures were solved by direct methods using
SHELXS-2013 [15] and refined by least-squares procedures using SHELXL-2013 [16] with SHELXLE [17] as a graphical
interface. All non-hydrogen atoms were refined anisotropically. Carbon-bound H atoms were placed in calculated positions
(C–H 0.95 Å for aromatic carbon atoms and C–H 0.99 Å for methylene groups) and were included in the refinement in the
riding model approximation, with Uiso (H) set to 1.2Ueq (C). The H atoms of the methyl groups were allowed to rotate with
a fixed angle around the C–C bond to best fit the experimental electron density (HFIX 137 in the SHELX program suite
[16]), with Uiso (H) set to 1.5Ueq (C). Nitrogen-bound H atoms were located in a difference Fourier map and refined freely.
Data were corrected for absorption effects using the numerical method implemented in SADABS [17].
Computational studies. The calculations were carried out using the Gaussian 09 program. Molecular geometries of
the singlet ground state of all the compounds were fully optimised in the gas phase at the density functional theory (DFT)
level of theory using the hybrid B3LYP functional together with the 6-31G(d) basis set. For each compound a frequency
calculation was carried out to ensure that the optimized molecular structure corresponded to a minimum, thus only positive
frequencies were expected. The HOMO and LUMO results were viewed in Avogadro.
RESULTS AND DISCUSSION
1
Synthesis and characterization. The H NMR spectrum of compound I showed a singlet signal at 11.50 ppm for
the proton of the hydroxyl group, and another singlet signal at 11.15 ppm was observed for N–H of the amino acid.
Isothiocyanate N–H occurred at 4.32 ppm as a singlet signal. A doublet for two protons was observed at 7.95 ppm, while
13
another doublet for two protons occurred at 7.62 ppm. A multiplet for one proton was observed at 7.64 ppm. In the C NMR
spectrum the thione carbon atom was observed at 180.6 ppm, and those of the acid carbonyl and benzoyl groups occurred at
169.7 ppm and 168.1 ppm respectively. Aromatic carbon atoms were observed between 133.1 ppm and 128.4 ppm.
A methylene carbon atom was observed at 46.6 ppm. This was also confirmed in the DEPT-135 spectrum. The IR spectrum
–1 –1
showed a signal at 3227 cm for the N–H stretching. A signal was observed at 1704 cm for the C=S stretching, whilst
–1
a signal at 1665 cm was observed for the carbonyl group. A signal for the aromatic C=C stretching was observed at
1
520 ppm. The H NMR spectrum of compound II showed a singlet signal at 12.59 ppm for a proton, a multiplet for two
1
protons was observed at 8.16 ppm, another multiplet for two protons was observed at 8.08 ppm, whilst a multiplet signal for
a proton was observed at 7.79 ppm. Still the aromatic region a multiplet signal for three protons was observed at 7.64 ppm,
13
whilst another multiplet signal for three protons occurred at 7.56 ppm. The C NMR spectrum of compound II gave a signal
at 162.8 ppm for the carbonyl group; signals between 134.0 ppm and 127.3 ppm were observed for aromatic carbon atoms.
–1
–1
–1
The IR spectrum gave signals for N–H at 3031 cm and 3058 cm , the C–S signal was observed at 1726 cm , the carbonyl
–
1
–1
C=O stretchings were observed at 1693 cm and 1661 cm , whilst aromatic C=C was observed at 1600 cm .
–1
Scheme 1. Synthesis scheme for compounds I and II.
138

The reaction is proposed to proceed by the carbonyl attack of benzoyl chloride by the oxygen lone pair of the
hydroxyl group, as indicated in 2a with the loss of hydrochloric acid. Pyridine abstracts a proton from the secondary amine,
as indicated in 2b; the subsequent formation of the C=N double bond led to the migration of electrons from the C=S bond
onto the sulfur atom, which allows it to easily attack the carbonyl group from carboxylic acid. The electrons from the C=O
bond then move onto the oxygen atom which picks up the abstracted proton from pyridine to form a hydroxyl group in 2c.
Further abstraction of a proton from the methylene group led to the loss of water from 2c, leading to the formation of the final
product (II).
Scheme 2. Proposed mechanism for the
synthesis of compound II.
X-ray crystallography. The X-ray crystal structure of compound II was obtained using single crystals grown by
crystallization from THF. Table 1 shows the crystallographic and structure refinement data for compound II. It recrystallizes
in the monoclinic space group P21/n. The crystal structure of II is formed by two crystallographically independent
molecules, one of which is shown in Fig. 1. The S1–C12 and S2–C22 bond distances of 1.737(2) Å and 1.732(2) Å
respectively were consistent with the thione (C=S) bond distance. Whilst the C11–O11 and C15–O13 bond distances for the
carbonyl groups in II were 1.24(2) Å and 1.25(2) Å, respectively (Fig. 1). The N11–C12 and N12–C13 bond distances were
1.384(1) Å and 1.381(2) Å, respectively. The C12–S1–C14 and C22–S2–C24 bond angles of 86.8(1)° and 87.1(1)° were
consistent with the bond angle of a thiazole sulfur atom.
Fig. 1 gives the ORTEP view of compound II with 50% ellipsoids. In the crystal packing the molecules form dimers
through an intermolecular N–H…N H-bond with parameters detailed in Table 2 and Fig. 2. Fig. 2 gives a dimer of compound
II, which is held together by a hydrogen bond between the amide hydrogen atom and the thiazole nitrogen atom. This is also
replicated in another molecule of the dimer.
HOMO–LUMO analysis. Some theoretical studies to characterise the nature of these compounds in terms of the
chemical reactivity have been carried out in order to predict the reactivity of these compounds. The HOMO and LUMO and
their energy gaps have been evaluated by DFT. The HOMO and LUMO are the main orbitals that determine the chemical
139

TABLE 1. Crystallographic Data and Structure Refinement Summary for Compound II
Property
Compound II
Formula
17 12 2 3
C H N O S
CCDC number
Formula weight
Crystal system
Space group
1055089
324.35
Monoclinic
P21/n
a, b, c, Å; β, deg.
19.8990(5), 7.3680(2), 22.3845(6); 113.799(1)
3
V, Å
3002.85(14)
8
Z
3
D(calc), g/cm
1.435
μ(MoK
α
), mm
0.232
F(000)
1344
Crystal size, mm
Temperature, K
Radiation, Å
0.12×0.24×0.33
200
0.71073
θmin–θmax, deg.
2.0-28.3
Dataset
–26:26; –9:9; –29:29
42220, 7477, 0.024
5898
Tot., uniq. data, R(int)
Observed data [I > 2.0σ(I)]
N
ref / Npar
7477 / 423
0.0353 / 0.1003
1.02
R / wR
2
S
Max. and av. Shift/error
Min. / max. residual. dens., e/Å
0.00 and 0.00
–0.20 / 0.32
3
Fig. 1. ORTEP view of compound II showing 50% probability displacement ellipsoids and atom
labelling.
stability of any species [18]. The HOMO represents the ability to donate an electron whilst the LUMO represent the ability to
accept an electron. The LUMO is concentrated on benzoyl chloride when the two reacting species were computed together
for their frontier orbitals. Also the HOMO LUMO gap is lower for the two reacting species together (270.17 kJ/mol) than that
for compound I alone, indicating that the reactivity of compound I (391.86 kJ/mol) is improved by the presence of benzoyl
chloride due to the susceptibility of benzoyl chloride to attack. The HOMO energy is directly related to the ionization
potential whilst the LUMO energy is related to the electron affinity. The HOMO and LUMO energy difference known as the
energy gap determines the stability or reactivity of molecules [19]. The energy gap is a critical parameter in determining
molecular electrical transport properties because it is a measure of the electron conductivity [20]. The hardness of a molecule
140

TABLE 2. Parameters of the Intermolecular N–H…N H-Bond
Donor–H…Acceptor
D–H, Å
H…A, Å
D…A, Å
D–H…A, deg.
N11–H11…N22
N21–H21…N12
0.83(2)
0.83(2)
2.14(2)
2.14(2)
2.947(2)
2.954(2)
167.8(15)
169.1(15)
Fig. 2. Dimer of compound II showing the H-bonding
between the molecules.
TABLE 3. Summary of the HOMO–LUMO Energies for the Reacting Species and Compound II
Parameter
HOMO, kJ/mol
LUMO, kJ/mol
HOMO–LUMO Gap, kJ/mol
Benzoyl chloride
Reacting species
Compound I
–723.06
–523.24
–539.44
–570.55
–203.29
–253.07
–147.58
–156.98
519.77
270.17
391.86
413.57
Compound II
also corresponds to the HOMO–LUMO gap [21]. A large HOMO–LUMO gap indicates a high stability and resistance to
charge transfer; therefore, hard molecules have a large HOMO–LUMO gap.
Table 3 gives the computed LUMO and HOMO energy gap of the reacting species and compound II. The LUMO of
the reacting species shows the delocalization of its orbitals over the benzoyl chloride molecule whilst the HOMO is
delocalised over amide, thione, and carboxylic acid in compound I. The attack of benzoyl chloride is supposed to be critical
for the reaction to happen. In compound II the LUMO is delocalized over the entire molecule, indicating that the entire
molecule is involved in charge transfer to stabilize the compound.
CONCLUSIONS
2-(Benzamido)thiazolylbenzoate has been synthesized and characterized by spectroscopy, micranalysis, and GC–
MS. Its crystal structure has been discussed as well as the HOMO and LUMO of the reactants and the products.
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