Dual Roles of N,N-Dimethylformamide in Benzothiazoles Synthesis from N-Benzoyl-N′-(2,4,6-trichlorophenyl)thiourea

Article abstract of DOI:10.1007/s10870-019-00796-3

Abstract: N,N-Dimethylformamide (DMF) is not only a common polar solvent in chemistry, but also a reaction reagent, a catalyst and a stabilizer. In this paper, a new reaction was found accidently where DMF acted as both solvent and catalyst. By dissolving

Full text of DOI:10.1007/s10870-019-00796-3

Journal of Chemical Crystallography
https://doi.org/10.1007/s10870-019-00796-3
ORIGINAL PAPER
Dual Roles of N,N‑Dimethylformamide in Benzothiazoles Synthesis
from N‑Benzoyl‑N′‑(2,4,6‑trichlorophenyl)thiourea
Qianjin Li1,2 · Dan Wang3 · Min Chen2 · Baoping Ling4 · Piotr Kujawski5 · Chunlong Yang2 · Qianyong Cao3 ·
Fenying Wang3
Received: 14 March 2019 / Accepted: 20 June 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
N,N-Dimethylformamide (DMF) is not only a common polar solvent in chemistry, but also a reaction reagent, a catalyst and
a stabilizer. In this paper, a new reaction was found accidently where DMF acted as both solvent and catalyst. By dissolv-
ing N-benzoyl-N′-(2,4,6-trichlorophenyl)-thiourea (BAD) in DMF and evaporating the solvent slowly, single crystals were
obtained but their composition was determined to be 2-benzoylamino-4,6-dichloro-benzothiazole (BTT) with DMF molecule
(BTT–DMF), not BAD. The single crystals of BAD could be obtained by crystallization from the solvents of acetonitrile or
ethanol. The crystal structures of BAD and BTT–DMF were measured and analysed. Based on the hydrogen bonding inter-
actions in their crystal structures, a possible reaction mechanism was proposed. All in all, DMF is a really multifunctional
chemical, it may still have other potential functions which are interesting and valuable to be developed.
Graphic Abstract
A new reaction was found by dissolving N-benzoyl-N′-(2,4,6-trichlorophenyl)-thiourea (BAD) in DMF and evaporation of
the solvent slowly to grow single crystals.
Keywords N,N-dimethylformamide · Catalyst · Solvent · Crystal structure · Arylthiourea · Benzothiazole
2
* Qianjin Li
liqianjinnju@163.com
College of Science, Nanjing Agricultural University,
Nanjing 210095, Jiangsu, China
3
4
5
* Chunlong Yang
College of Chemistry, Nanchang University,
Nanchang 330029, Jiangxi, China
ycl@njau.edu.cn
* Qianyong Cao
School of Chemistry and Chemical Engineering, Qufu
Normal University, Qufu 273165, Shandong, China
cqyong@ncu.edu.cn
Fenying Wang
Institute of Chemical Technology and Engineering, Poznań
University of Technology, Pl. M. Skłodowskiej – Curie 2,
60-965 Poznan, Poland
wangfenying@ncu.edu.cn
1
School of Public Health, Nanchang University,
Nanchang 330019, Jiangxi, China
Vol.:(0123456789)
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Journal of Chemical Crystallography
ethanol were still BAD. A reaction mechanism was proposed
mainly based on the analysis of their crystal structures.
Introduction
N,N-dimethylformamide (DMF) is a common polar sol-
vent with formula of (CH3)2NCHO. It can dissolve vari-
ous classes of compounds, and has a high boiling point of
153 °C. Not only as a solvent, DMF also plays other roles
in the chemical world, particularly in organic chemistry e.g.
as a reaction reagent to supply building block units such as
CHO, O, CO, (CH3)2 and CH3 [1–3]; as a ligand to form
metallic complexes [4]; as a catalyst in organic reactions [5].
In addition, DMF can be used as a stabilizer for preparation
of some metal nanoparticles [5, 6]. Why DMF exhibits so
many functions? The reason can be found from its unique
molecular structure, in which there is a nucleophilic O atom,
an electrophilic N atom, an active H atom, and two hydro-
phobic CH3 groups (Scheme 1). So, it can act as an electro-
philic reagent to attack a nucleus, as well as a nucleophilic
reagent to attack an electro-rich atom [1, 5, 7]. Although the
steric obstacles of the two methyl groups can block the elec-
trophilic activity of the N atom, the electronegative activ-
ity of the O atom is improved due to the pushing electron
behavior from the two methyl groups, resulting in the O
atom being a good hydrogen bond acceptor [8]. The active
H atom in the HC=O group is a good hydrogen bond donor,
it can form a relatively stable ring complex with another
molecule who has both hydrogen bond donor and acceptor,
particularly together with its neighbor O atom [9]. All in all,
DMF attracts increasing attention from chemists to study its
new functions and applications.
Experimental
Chemicals and Instruments
Analytical grade reagents of N,N-Dimethylformamide
(DMF, 99.5%) and ethanol (99.7%) were purchased from
Tianjin Damao Chemical Reagent Factory (Tianjin, China).
Acetonitrile (99.0%) was from Xilong Science Co., Ltd.
(Guangdong, China). Benzoic acid (99.5%), sodium thiocy-
anate (NaSCN, 98%) and benzoyl isothiocyanate (96%) were
from J&K Scientifc (Shanghai, China). Thionyl chloride
(SOCl2, 99%) and 2,4,6-trichlorophenylamine (98%) were
bought from Macklin (Shanghai, China). All the reagents
were used without further purifcation.
UV spectra were recorded on Varian Cary 50 UV–Vis
spectrophotometer (Agilent Technologies, USA). IR spec-
tra were recorded on a FTIR-Tensor27 spectrophotom-
eter (Bruker, Germany) using KBr discs in the range of
4000–600 cm−1. Mass spectroscopy determination was
1
performed on GCMS-2010 (Shimadzu, Japan). H NMR
spectra were recorded on DD2-400MR (Agilent Technolo-
gies, USA) using CDCl3 as the solvent. The melting point
was determined using a WRS-1B digital melting-point appa-
ratus (Shanghai YiCe Apparatus & Equipment co., LTD,
China). The crystal data of the compounds were collected
on a CAD4/PC X-ray single crystal difractometer (Enraf
Noius, Netherlands).
In this paper, a new reaction was found accidently
by using DMF as the solvent to grow single crystals of
N-benzoyl-N′-(2,4,6-trichlorophenyl)thiourea (BAD). The
BAD was synthesized in acetonitrile with a higher yield
than that synthesized in ethanol or DMF. To obtain the BAD
single crystals suitable for X-ray difraction analysis, three
solvents were employed to grow its single crystals. We were
surprised to fnd that the chemical composition of the single
crystals obtained from DMF was not BAD at all, although
the composition of the single crystals from acetonitrile and
Synthesis of BAD and BTT and Their Single Crystals
N-benzoyl-N′-(2,4,6-trichlorophenyl)-thiourea (BAD) was
synthesized as following procedure: benzoic acid (1.22 g,
0.01 mol) and SOCl2 (7.3 mL, 0.1 mol) were mixed together
and refuxed in oil bath (100 °C) for 4 h, then the residual
SOCl2 was removed by evaporation under vaccum to get ben-
zoylchloride. The benzolychloride was dissolved in acetoni-
trile (20 mL), then NaSCN (1.22 g, 0.015 mol) was added
at room temperature (25 °C). After removal of unreacted
NaSCN by fltration, 2,4,6-trichlorophenylamine (1.96 g,
0.01 mol) dissolved in acetonitrile (5 mL) was added, then
the mixture was stirred and refuxed in oil bath (100 °C)
for 2 h. After the solvent evaporation under vacuum, crude
product (light yellow) was obtained and re-crystallized from
acetonitrile. The fnal product was colorless, yield of 83%.
BAD was also synthesized in ethanol and DMF sepa-
rately as following procedure. At frst, benzoyl isothio-
cyanate (1.63 g, 0.01 mol) was dissolved into ethanol (or
DMF, 20 mL); then, add 2,4,6-trichlorophenylamine (1.96 g,
0.01 mol) dissolved in ethanol (or DMF, 5 mL) with stirring
Scheme 1 Molecular structure of N,N-dimethylformamide
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Journal of Chemical Crystallography
Table 1 Crystal structure and
refnement details
Compound name
N-benzoyl-N′-(2,4,6-
2-benzoylamino-4,6-dichloro-
benzothiazole, N,N-dimethylfor-
mamide
trichlorophenyl)-thiourea
Chemical formula
CCDC Deposit No.
Color
Crystal dimensions (mm)
Formula weight
Crystal system
Space group
Unit cell dimensions
a (Å)
C28H18Cl6N4O2S2
643496
Colorless
0.40×0.30×0.30
719.28
Monoclinic
P21/n
C14H8Cl2N2OS,(CH3)2NCHO
643497
Colorless
0.30×0.30×0.20
396.28
Monoclinic
C2/c
7.8170(16)
36.372(7)
10.745(2)
17.402(4)
8.1280(16)
26.551(5)
b (Å)
c (Å)
β (°)
90.96(3)
3054.6(11)
4
1.564
0.734
Nonius CAD4
MoKα (λ=0.71073)
1.12–25.99
6437/5994
−9:9, 0:44, 0:13
Psi-scan
5994/0/379
1.080
R=0.0659, wR=0.1574
R=0.1229, wR=0.1928
0.324 and −0.364
293(2)
106.60(3)
3599.1(12)
8
1.463
0.493
Nonius CAD4
MoKα (λ=0.71073)
1.60–25.98
3526/2176
−21:20, 0:10, 0:32
Psi-scan
3526/0/226
1.097
R=0.0629, wR=0.1273
R=0.1132, wR=0.2024
0.474 and −0.446
293(2)
Cell volume
Z
Density (calculated, g.cm−3
)
Absorption coefcient (mm−1
Difractometer
)
Radiation
θ range (°)
Refections collected/unique
Range of h, k, l
Absorption correction
Data/restraints/parameters
Goodness-of-ft on F2
Final R indices [I>2σ(I)]
R indices (all data)
Largest feature (e/Å3)
Temperature (K)
at room temperature; fnally, the mixture was heated in oil
bath (100 °C) for 2 h. After cooling down, the solvent was
removed under vacuum to obtain crude product, which was
re-crystallized in acetonitrile. The fnal yield of BAD was
17% in ethanol and 35% in DMF.
to remove the DMF in the crystal. Finally, the yield of BTT
was ~46%.
Compounds Characterization
Crystals of 2-benzoylamino-4,6-dichloro-benzothiazole
(BTT) with DMF molecules were obtained by the following
prodedure. At frst, BAD (0.20 g, 0.56 mmol) was dissolved
in DMF (10 mL) in a beaker (50 mL); then, the beaker was
sealed by cling wrap with several holes and put in the fume-
hood at room temperature (25 °C). Colorless crystals pre-
sented in the beaker after a week. The crystals were collected
by fltration using flter paper until the DMF was evapo-
rated completely. The solid crystals were washed with DMF
(2 mL) once and ethanol twice (each time 5 mL) to remove
the residues, then dried at room temperature to obtain the
crystals of BTT with DMF molecule (BTT–DMF). The pure
BTT compound can be obtained by drying at 50 °C for 12 h
Compound BAD: m.p.=192–193 °C; 1H NMR (CDCl3, δ):
12.01 (1H, s, NHCO), 9.38 (1H, s, NHCS), 7.91 (2H, d,
ArH), 7.65 (1H, t, ArH), 7.53 (2H, t, ArH), 7.44 (2H, s,
ArH); IR (KBr, cm−1, ν): 3383 (m), 3355 (m), 3176 (m),
3130 (m), 3086 (m), 1659 (s), 1600 (s), 1580 (s), 1555 (s),
1497 (s), 1382 (m), 1319 (m), 1266 (m), 1188 (m), 1158
(s), 1086 (m). The 1H NMR and IR characterizations agreed
with the reference reported [12].
Compound BTT: m.p.=207–209 °C; 1H NMR (CDCl3,
δ): 8.02-7.44 (7H, m, ArH); MS (M+, m/z)=322; IR (KBr,
cm−1, ν): 3378 (m), 3077 (m), 1678 (s), 1589 (s), 1538 (s),
1432 (m), 1387 (m), 1283 (m), 1144 (m), 1077 (m). The
melting point agreed with the reference reported [18].
1 3

Journal of Chemical Crystallography
Table 2 Hydrogen bond lengths (Å) and bond angles (°)
is shown in Table 1 and selected hydrogen bond lengths and
bond angles are in Table 2.
D–H···A
D–H
H···A
D···A
∠DHA
In the single crystal of BAD
N1–H1A···O2
N2–H2A···S2i
N2–H2A···O1
N3–H3A···O1ii
N4–H4B···S1
N4–H4B···O2
C1–H1B···Cl5iii
C11–H11A···Cl6iv
0.86
2.38
2.74
2.03
2.52
2.70
2.01
2.74
2.81
3.221 (5)
3.369 (5)
2.664 (5)
3.324 (5)
3.302 (5)
2.681 (5)
3.633 (7)
3.717 (6)
166
131
130
157
128
134
161
166
Results and Discussion
0.86
0.86
0.86
0.86
0.86
0.93
0.93
N-benzoyl-N′-(2,4,6-trichlorophenyl)thiourea (BAD),
which showed potential biological activities [10–12], was
synthesized in acetonitrile in a yield of 83%, a little lower
than that synthesized in tetrahydrofuran [12]. We also
used ethanol and DMF separately as the reaction solvent
to synthesize BAD by the same experimental procedure.
The yield of BAD was much lower in ethanol (17%) and
DMF (35%) comparing with the yield in acetonitrile, dem-
onstrating the reaction solvent can signifcantly afect the
product yield.
In the single crystal of BTT-DMF
N1–H1A···O2v
C4–H4A···O2v
C6–H6A···O1
0.86
0.93
0.93
0.93
0.96
0.93
1.96
2.34
2.46
2.51
2.36
2.50
2.802 (7)
3.181 (9)
2.771 (9)
3.387 (7)
2.776 (9)
3.236 (9)
167
150
100
157
105
136
C13–H13A···O1vi
C16–H16A···O2
C17–H17A···N2v
In order to obtain the BAD single crystals suitable
for X-ray diffraction analysis, different solvents were
employed to grow single crystals by solvent evaporation
method. We were surprised to fnd that the chemical com-
position of the single crystals obtained from DMF was
not BAD, although the chemical composition of the sin-
gle crystals from acetonitrile and ethanol were both still
BAD. The BAD single crystals can also be obtained from
the mixture of ethanol/dichloromethane (1/1, v/v) [12]. As
shown in Scheme 2, BAD was frstly dissolved into DMF,
after 7 days of solvent evaporation at room temperature
(25 °C), single crystals presented in the solution. The sin-
gle crystals were collected by fltration using flter paper
and determined by X-ray difraction method. The ana-
lytical result demonstrated that the chemical composition
in the single crystal was 2-benzoylamino-4,6-dichloro-
benzothiazole (BTT) with DMF molecule (BTT–DMF),
not BAD at all. To confrm this result, we repeated the
recrystallization experiment and measured the pH changes
of the solution before and after reaction. Clearly, the pH
decreased after the crystallization (Scheme 2), suggesting
Symmetry transformations used to generate the equivalent atoms: i:
x, y, 1+z; ii: x, y, −1+z; iii: 1/2+x, 1/2−y, 1/2+z; iv: 2−x, −y,
2−z; v: −1/2−x, 1/2−y, −z; vi: 1/2−x, 1/2−y, −z
X‑Ray Crystallography
The single crystals of BAD or BTT–DMF was mounted
on an Enraf–Nonius CAD-4 diffractometer with MoKα
radiation (λ=0.71073 Å). The angle of the ω/2θ scan mode
was in the range 1.60°–25.98°. Psi-scan corrections were
employed. The crystal structure was resolved by direct meth-
ods using SHELX97 software. The non-hydrogen atoms
were refned anisotropically and hydrogen atoms isotropi-
cally. H atoms were positioned geometrically and treated as
riding model, with C–H = 0.93 Å, N–H = 0.86 Å and Uiso
(H)=1.2 Ueq (C, N). Crystal and structure refnement data
Scheme 2 Synthesis of 2-benzoylamino-4,6-dichloro-benzothiazole (BTT) from N-benzoyl-N′-(2,4,6-trichlorophenyl)thiourea (BAD) in DMF
at room temperature by slow solvent evaporation method. pH value was measured by the pH test strip before and after the reaction
1 3

Journal of Chemical Crystallography
Fig. 1 1H NMR (a), UV (b) and IR (c) spectra of the compounds of I, II and III recrystallized from acetonitrile, ethanol and DMF, respectively
that hydrochloric acid molecules might generate during
the reaction process.
the DMF molecule, it was difcult to observe its 1H NMR
signal here (Fig. 2).
The compounds recrystallized from acetonitrile(I),
To study if co-solvents could afect the reaction, we per-
formed the recrystallization of BAD in the co-solvents of
DMF/acetonitrile (1/1, v/v) and DMF/ethanol (1/1, v/v)
instead of pure DMF at room temperature. The composi-
tion of the crystals precipitated from the co-solvents were
determined to be BAD, demonstrating that the addition of
acetonitrile or ethanol in DMF would inhibit the reaction,
which might due to the BAD crystal was prior to precipitate
in ethanol or acetonitrile comparing with DMF by solvent
evaporation method. In addition, diferent BAD solutions
(100 mg in 5 mL DMF, or DMF/acetonitrile (1/1, v/v), or
DMF/ethanol (1/1, v/v), respectively) were prepared and
sealed in separate tubes and kept at temperature of 50 °C
for 7 days. The compound in these solutions was determined
by UV, and the result showed that the BAD didn’t change,
indicating that BAD could not convert to BTT at a high
temperature (50 °C) even in DMF. Based on these investiga-
tions, we speculated that the reaction might happen at the
interface of the liquid and the crystal when the crystal was
growing.
1
ethanol(II) and DMF(III), were all characterized by H
1
NMR, UV and IR (Fig. 1). From their H NMR spectra
(Fig. 1a), it is clear to see that the peaks at chemical shifts
of 12.0 and 9.4 ppm (two protons of NH groups in BAD)
were only found in the spectra of compounds I and II,
demonstrating that compound III was diferent from com-
pounds I and II. The peaks at chemical shifts of 2.8 and
2.9 ppm in the spectrum of compound III were due to
the DMF molecules in the crystal. As shown in Fig. 1b,
comparing with the UV spectra of compounds I and II,
the UV absorption band of compound III showed a red
shift, indicating there was a bigger aromatic ring in III
than the benzyl ring in I and II. From their IR spectra in
Fig. 1c, it is also easy to see that compound III was dif-
ferent from compounds I and II, which were the same. So,
we were now completely sure of that the crystals recrystal-
lized from acetonitrile and ethanol were BAD, while the
crystals from DMF were BTT–DMF. As the active H in
the CONH group of BTT formed a hydrogen bond with
1 3

Journal of Chemical Crystallography
Fig. 2 Molecular structure of BAD (a, CCDC643496) and BTT–
DMF (b, CCDC643497) with displacement ellipsoids at the 50%
probability level. The packing structure of BAD (c) and BTT–DMF
(d) to show the intermolecular hydrogen bond interactions. Dashed
lines mean hydrogen bonds
BTT is one of the benzothiazole derivatives, which have
wide applications and can be synthesized from many start-
ing materials such as phenylthiourea derivatives [13–18].
BTT was frstly reported by Papke et al. using 2-amino-
4,6-dichloro-benthiazole as the starting material to react
with benzoyl chloride without catalyst, and recrystallized
from pyridine/ethanol in a yield of 95% [18]. However, in
order to obtain benzothiazoles from phenylthiourea deriva-
tives, all the reported reactions required metal catalysts such
as Pd or Cu catalysts together with some bases [19, 20], Fe
catalysts together with some oxidants [21, 22], or Cs2CO3
[23, 24]. Moreover, these reactions were usually performed
at a high temperature (80–130 °C). In our knowledge, there
is no report to synthesize benzothiazoles from phenylthi-
ourea derivatives without catalyst at room temperature. In
this paper, BTT was obtained by recrystallization of BAD
in DMF at room temperature. As DMF can act as catalyst in
some organic reactions [5], we speculated that it might also
play a role of catalyst during the recrystallization process
and help BAD convert to BTT. So, next question is how
about the catalytic mechanism?
To investigate the reaction mechanism, we analyzed
the hydrogen bonds in the single crystals of BAD and
BTT–DMF (Tables 1, 2). As shown in Fig. 2, in the BAD
crystal there was no solvent molecule, while DMF molecules
were observed in the BTT-DMF crystals, indicating DMF
1 3

Journal of Chemical Crystallography
Scheme 3 A possible reaction mechanism catalysed by DMF for conversation of BAD to BTT
might take part in the conversion process of BAD to BTT.
Two isomers of BAD were stabilized by the intramolecu-
lar N–H···O hydrogen bonds, as well as the intermolecular
N–H···O and N–H···S hydrogen bonds (Fig. 2a), which fur-
ther linked the isomers into a ribbon (Fig. 2c) [12]. Diferent
ribbons were linked together into three dimensional (3D)
structure of BAD by the intermolecular C–H···Cl hydro-
gen bonds [25]. However, in the BTT–DMF crystal, there
were no intramolecular and intermolecular N–H···O and
N–H···S hydrogen bonds (Fig. 2b, d). Instead, the solvent
molecule of DMF formed intermolecular C–H···O, N–H···O
and C–H···N hydrogen bonds to stabilize the BTT molecu-
lar structure into a plane. The planes were further linked
into 3D structure by the intermolecular C–H···O hydro-
gen bonds and the Cl···Cl weak interactions. As shown in
Fig. 2d, the short distance of Cl2···Cl2i [symmetry code:
(i) −1/2−x, 1/2−y, −z] was determined to be 3.478(2) Å
(C10–Cl2···Cl2 i =159.1(2)°), which is a little longer than
3.364(3) Å (C–Cl···Cl = 158.1(3)°) reported in the crystal
of N-(2,4-dichlorophenoxyacetyl)-N’-(4-nitrophenyl)thio-
urea [26], suggesting the halogen bonding interaction is
also important for the crystal structure packing. By com-
paring the hydrogen bonds in these two crystal structures,
we speculated that DMF might help BAD convert to BTT
through hydrogen bond interactions.
(complex B in Scheme 3), which could give the negative
S atom more chance to attack the C nucleus of C–Cl group
in the benzene ring to form a transition state C (Scheme 3).
Then, the negative Cl would leave and react with the posi-
tive proton-conjugated DMF to generate a HCl molecule.
Finally, BTT-DMF crystals were formed. Computational
study was employed to investigate the proposed reaction
mechanism by using the density functional method (DFT)
in Gaussian 09 program [27]. Unfortunately, the calcula-
tion results suggested the complex B and the transition
state C had high potential energy barriers, more eforts
are still needed and in process to reveal the real reaction
mechanism.
In summary, a new DMF-catalyzed reaction was
reported here. In the solvent of DMF, the phenylthiourea
derivative BAD could convert to the benzothiazole deriva-
tive BTT during the single crystal growing process by slow
solvent evaporation method. Such synthetic method took
a long time, but the product was easy to purify and the
reaction at room temperature could save thermal energy as
well. The reaction mechanism is still unclear and requires
more eforts to be fgured out.
Acknowledgements We acknowledge the fnancial supports from the
National Natural Science Foundation of China (21705073, 21603116
and 51406074) and the Fundamental Research Funds for the Central
Universities of China (KYZ201223).
Based on the catalytic mechanisms using metal or base
catalysts to synthesize benzothiazoles from phenylthiourea
derivatives [19–24], a possible reaction mechanism was
proposed in Scheme 3. The nucleophilic O atom of DMF
might attack the proton in the thiol group of conformation
A, at the same time another DMF molecule could form a
complex with BTT through hydrogen bond interactions
and try to stabilize the complex into a planar structure
Compliance with Ethical Standards
Conflict of interest All authors states that there is no confict of inter-
est.
1 3

Journal of Chemical Crystallography
molecules in medicinal chemistry. Eur J Med Chem 89:207–251.
https://doi.org/10.1016/j.ejmech.2014.10.059
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