Synthesis and structural characterization of novel 2-benzimidazolylthioureas: Adducts of natural isothiocyanates and 2-amino-1-methylbenzimidazole

Article abstract of DOI:10.1007/s11224-010-9632-8

Adducts of natural allyl, phenethyl, and benzyl isothiocyanates and 2-amino-1-methylbenzimidazole were synthesized. After optimization of the reaction conditions, the target 2-benzimidazolylthioureas were obtained in reasonable yields. The detailed molecu

Full text of DOI:10.1007/s11224-010-9632-8

Struct Chem (2010) 21:955–964
DOI 10.1007/s11224-010-9632-8
ORIGINAL RESEARCH
Synthesis and structural characterization of novel
2-benzimidazolylthioureas: adducts of natural isothiocyanates
and 2-amino-1-methylbenzimidazole
´
Anna Smiechowska Witold Przychodzen
•
•
´
•
Jarosław Chojnacki Piotr Bruzdziak
•
´
Jacek Namiesnik Agnieszka Bartoszek
•
´
Received: 3 February 2010 / Accepted: 26 May 2010 / Published online: 17 June 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Adducts of natural allyl, phenethyl, and benzyl
isothiocyanates and 2-amino-1-methylbenzimidazole were
synthesized. After optimization of the reaction conditions,
the target 2-benzimidazolylthioureas were obtained in
reasonable yields. The detailed molecular and crystal
structures of these compounds were characterized by
spectroscopic and X-ray methods. Spectral analysis dem-
onstrated that N-(1-methylbenzimidazolyl)-N0-allylthio-
urea, N-(1-methylbenzimidazolyl)-N0-benzylthiourea, and
N-(1-methylbenzimidazolyl)-N0-phenethylthiourea exist in
solution in an unprecedented three tautomeric forms,
whose structures were corroborated unambiguously.
and ITCs yields unsymmetrical thioureas, which are sig-
nificant biologically active products [3], modern catalysts in
organic synthesis, [4], selective neutral receptors for inor-
ganic anion recognition [5–7], as well as valuable building
blocks [8] for self-assembled diverse hydrogen-bonded
networks in the solid state and in solution. Therefore, it is
crucial to determine the exact molecular and supramolec-
ular structure of unsymmetrical thioureas if we are to design
them rationally and to understand their activity and selec-
tivity in the reactions they catalyze.
Until now, only one report has been published of the
reaction between 1 and phenylisothiocyanate (PITC). On
the basis of X-ray crystallographic data and NMR spectra,
Morkovnik [9] claimed that the thus obtained N-(1-meth-
ylbenzimidazolyl)-N0-phenylthiourea adopts only one 1,3-
dihydrobenzimidazolinylidene tautomeric form in crystals
and in solution. Quantum-chemical calculations (DFT,
B3LYP/6-31G**) have confirmed that this sole tautomer
has the lowest energy.
Keywords Thioureas ꢀ Isothiocyanates ꢀ
2-Aminobenzimidazole ꢀ Tautomerism
Introduction
Isothiocyanates (ITCs) are reactive electrophilic agents
[1] capable of modifying proteins and other biologically
important molecules. Whereas, 2-amino-1-methylbenzimi-
dazole 1 (MABI) is an interesting compound because the
structure of the benzimidazole unit is a constituent of var-
ious important molecules like vitamin B12 [2]. The reaction
between heterocycles containing an exocyclic amino group
In this work, we present an optimized procedure for the
conversion of natural ITC to 2-benzimidazolylthioureas
2a–c (Scheme 1), as well as the results of a study of the
structure of their isomers in solution and in crystals. DFT
calculations were conducted to rationalize the unusual
existence of 2 in three tautomeric forms in solution.
Experimental section
Electronic supplementary material The online version of this
article (doi:10.1007/s11224-010-9632-8) contains supplementary
material, which is available to authorized users.
Methods
´
´
A. Smiechowska (&) ꢀ W. Przychodzen ꢀ J. Chojnacki ꢀ
All reagents (AITC, BITC, PEITC, and 1) and solvents
were purchased from the Aldrich Chemical Company.
Solvents were purified and dried using standard
procedures.
´
´
P. Bruzdziak ꢀ J. Namiesnik ꢀ A. Bartoszek
´
Chemical Faculty, Gdansk University of Technology,
ul. Narutowicza 11/12, 80-233 Gdansk, Poland
e-mail: anna_smiechowska@o2.pl
123

956
Struct Chem (2010) 21:955–964
Scheme 1 Synthesis of
S
N
N
N
thioureas 2a–2d and 2e—
derivatives of 1 and 2-amino-N-
(2-phenoxyethyl)benzimidazole
10, respectively (compounds 2d
and 2e were prepared by
Morkovnik [9])
C
NH2
+
R'
N
C
S
NHR'
NH
N
R
R
2a R = CH3, R' = CH2CH=CH2
2b R = CH3, R' = CH2Ph
2c R = CH3, R' = CH2CH2Ph
2d R = CH3, R' = Ph
1 R = CH3
1' R = CH2CH2OPh
2e R = CH2CH2OPh, R' = Ph
The course of reaction and homogeneity of the products
was monitored by TLC using Merck silica gel plates (60F-
254) and the hexane/ethyl acetate (7:3) solvent system.
1H, 13C, and 15N NMR spectra were recorded at 298 K
on a Varian Unity 500 Plus spectrometer in CDCl3 and
DMSO-d6. 1D NOE and ROESY experiments were per-
formed using Varian standard pulse sequences.
5 file was produced), which gave excess of reflections
above the number expected for a non-twinned crystal.
Selected twinning details: twin matrix [0.9987 -0.0040
-0.0007 -0.6223 -0.9986 -0.0019 -0.9401 0.0054
-0.9977], components ratio 0.4106/0.5894, isolated reflns
3243/3238, overlapped 1721.
All calculations using density functional theory (DFT)
were carried out using Gaussian 03 program [13].
The UV–Vis spectra (CHCl3 and CH3CN solution) were
obtained with the aid of a Thermo Scientific NanoDrop
2000c spectrophotometer working under Thermo SCIEN-
TIFIC software.
Synthetic procedure
Elemental analysis for carbon, hydrogen, nitrogen, and
sulfur was performed on a CHNS-Carlo Erba EA-1108
Analyzer.
A single portion of ITC (6.79 mmole) was added to a
solution of 1 (1 g, 6.79 mmole) in MeCN (5 mL). After
being stirred for 2 h (for AITC) or 6 h (for BITC and
PEITC) at 50 °C the solvent was evaporated. The residue
was passed through a short pad of silica gel and the crude
product was purified on a silica gel column using hexane/
ethyl acetate (7:3) as eluent. The products were fully
characterized by multinuclear NMR (1H, 13C, and 15N)
spectroscopy, MS, and elemental analyses. The atom
numbering for all three compounds is shown in Fig. 1 and
is different from the conventional IUPAC numbering.
Mass spectra were obtained using a 4000 Q TRAP
hybrid triple quadrupole linear ion trap mass spectrometer
(Applied Biosystems/MDS Sciex).
ATR spectra of crystals (crystallized substances) were
recorded on a Nicolet 8700 spectrometer (Thermo Electron
Co.) operating under OMNIC software. ATR spectra were
recorded using the Golden Gate ATR accessory (Specac)
equipped with a single-reflection diamond crystal. The
temperature during measurements was kept at 25 0.1 °C
using an electronic temperature controller (Specac). For
each spectrum, 64 scans were collected with a resolution of
N-(1-methylbenzimidazolyl)-N0-allylthiourea 2a
4 cm-1
.
Yield 42%; mp 81–82 °C;
Recrystallization from ethyl acetate–cyclohexane (1:1)
using slow cooling of the saturated solution technique
afforded single crystals of 2 suitable for X-ray analysis.
The experimental diffraction data were collected on a
KM4CCD (Oxford Diffraction, now part of Varian) kappa-
geometry diffractometer equipped with a Sapphire-2 area
detector. An enhanced X-ray Mo Ka radiation source with
a graphite monochromator was used. The data reduction
was conducted using CrysAlis software package [10].
Structure solution and final refinement were carried out
using the SHELX-97 program package [11]. Packing dia-
grams were prepared using Mercury visualization software
[12].
UV [kmax, (lg e), solvent] 344 (4.32), CH3CN; 340
(2.60), CHCl3;
1H NMR (DMSO-d6) d 3.52, 3.55, 3.78 (3 9 s, CH3,
T1B, T1A, and T2A, respectively), 4.00, 4.12, 4.35 (2 9 t
and br t, J = 6 Hz, CH2NH, T1A, T1B, and T2A,
respectively), 5.08 (2 9 d, J = 10 Hz, CH = CH2 cis,
T1A and T1B, respectively), 5.16 (2 9 d, J = 17 Hz,
S1
C10 C11
C2
C5
C9 N4
N2
N1
C3
C4
C1
C6
C8 N3
The merging of reflections for compound 2a (CCDC
751508) was omitted due to technical reasons. Crystals of
2a turned out to be rotational twins. The twinning was
resolved by software at the data reduction stage (the HKLF
C7
Fig. 1 The numbering of atoms in products 2
123

Struct Chem (2010) 21:955–964
957
CH=CH2 trans, T1A and T1B, respectively), 5.20 (d,
J = 10 Hz, CH=CH2 cis, T2A), 5.32 (d, J = 17 Hz,
CH=CH2 trans, T2A), 5.85–5.95 (2 9 m, CH=CH2, T1A
and T1B), 5.95–6.06 (m, CH=CH2, T2A), 7.15–7.25 (m,
2H, H-3, and H-4), 7.37 (d, J = 7.7 Hz, H-5, T1B), 7.43
(d, J = 7.7 Hz, H-5, T1A), 7.46, 7.50 (2 9 d, J = 7.7 Hz,
H-2 and H-5 for T2A), 7.55 (d, J = 7.7 Hz, H-2, T1B),
7.61 (d, J = 7.7 Hz, H-2, T1A), 8.15 (t, J = 6 Hz, N4–H,
T1A), 8.48 (t, J = 6 Hz, N4–H, T1B), 10.80 (s, N3–H,
T2A), 11.60 (t, J = 6 Hz, N4–H, T2A), 13.10 (s, N2–H,
T1B), 13.25 (s, N2–H, T1A).
1H NMR (CDCl3) d 3.57, 3.55, 3.70 (2 9 s and br s,
CH3, T1B, T1A, and T2A, respectively), 4.20, 4.32, 4.48
(2 9 t and br t, J = 6 Hz, CH2NH, T1A, T1B, and T2A,
respectively), 5.18, 5.21 (2 9 d, J = 10 Hz, CH=CH2 cis,
T1A and T1B, respectively), 5.28, 5.32 (2 9 d,
J = 17 Hz, CH=CH2 trans, T1A and T1B, respectively),
5.90–6.00 (2 9 m, CH=CH2, T1A and T1B), 6.35 (br s,
N4–H, T1A), 6.60 (br s, N4–H, T1B), 7.18–7.36 (m, Ar–H,
T1A and T1B), 13.60 (br s, N2–H, T1A and T1B).
There are additional broad peaks in the spectrum cen-
tered at 3.70, 4.48, 5.40, and 6.05 ppm that correspond to
traces of T2A tautomer (about 3–4%);
-250.5 (N4 for T2A), -247.5 (N4 for T1A), -245.5 (N4
for T1B);
1H NMR (CDCl3) d 3.58 (s, CH3, T1A), 3.70 (br s, CH3,
T1B), 4.78 and 4.90 (2 9 d, J = 6 Hz, CH2NH, T1A
and T1B, respectively), 6.25 (br s, N4–H for T1B), 6.60
(t, N4–H for T1A), 7.20–7.50 (m, Ar–H), 13.65 (br s, N2–H,
T1A and T1B);
13C NMR (125.7 MHz, CDCl3) d 28.2 (CH3), 48.0 and
48.5 (NCH2 for T1A and T1B, respectively), 109.0 (C5),
111.7 (C2), 123.4 and 123.4 (C3 and C4), 127.5 (C14),
127.7 and 127.8 (C12/16 for T1B and T1A, respectively),
128.0 (C6), 128.8 and 128.9 (C13/15 for T1A and T1B,
respectively), 130.5 (C1), 138.7 (C11), 153.8 (C=N), 184.7
(C=S);
IR mmax: 3236, 3185, 3072, 3026, 2935, 1622, 1610,
1581, 1529, 1491, 1442, 1400, 1383, 1346, 1308, 1254,
1190, 1153, 1095, 1080, 931, 912, 739, 702, 656, 642, 621,
658, 571 cm-1
;
MS/MS (m/z) 297.3 (M ? 1), 295.2 (M - 1);
Anal. Calcd. for C16H16N4S: C, 64.84; H, 5.44; N,
18.90; S, 10.82%. Found: C, 64.86; H, 5.45; N, 19.01; S,
10.81%.
13C NMR (125.7 MHz, CDCl3): 28.1 (CH3), 46.5 and
47.0 (NCH2 for T1A and T1B, respectively), 108.8 and
109.0 (C5 for T1B and T1A, respectively), 111.3 and 111.7
(C2 for T1B and T1A, respectively), 116.8 and 117.0 (C12
for T1A and T1B, respectively), 123.1, 123.2, and 123.4
(C3/4 for T1A and T1B), 128.0 (C6), 130.5 (C1), 134.0
and 134.5 (C11 for T1B and T1A, respectively), 153.8
(C=N), 184.7 (C=S);
N-(1-methylbenzimidazolyl)-N0-phenethylthiourea 2c
Yield 63%; mp 141–142 °C;
UV [kmax, (lg e), solvent] 341 (5.60), CH3CN; 338
(2.59), CHCl3;
1H NMR (DMSO-d6) d 2.88, 2.90, 2.98 (3 9 t,
J = 7 Hz, PhCH2, T1A, T1B, and T1B), 3.52, 3.59, 3.74
(3 9 s, CH3, T1B, T1A, and T2A), 3.59, 3.70, 3.90
(3 9 q, J = 7 Hz, NHCH2, T1A, T1B, and T2A), 7.14–
7.62 (m, 9H, Ar–H), 8.10 (t, J = 6 Hz, N4–H, T1A), 8.42
(t, J = 6 Hz, N4–H, T1B), 10.70 (s, N4–H, T2A), 11.55
(t, J = 6 Hz, N3–H, T2A), 13.10 (s, N2–H, T1B), 13.27
(s, N2–H, T1A).
IR mmax 3230, 3174, 2989, 2925, 1624, 1612, 1581,
1514, 1479, 1446, 1429, 1402, 1377, 1332, 1315, 1294,
1254, 1242, 1192, 1163, 1144,1126, 1095, 1064, 999, 980,
941, 918, 874, 837, 812, 739, 661, 644, 611, 573 cm-1
;
MS/MS (m/z) 247.2 (M ? 1), 245.0 (M - 1);
Anal. Calcd. for C12H14N4S: C, 58.51; H, 5.73; N, 22.74;
S, 13.02%. Found: C, 58.56; H, 5.73; N, 22.74; S, 13.01%.
Aliphatic proton signals for 2c tautomers cannot be
assigned unambiguously owing to their nearly equal pop-
ulations (Table 1).
N-(1-methylbenzimidazolyl)-N’-benzylthiourea 2b
1H NMR (CDCl3) d 2.95 and 3.02 (2 9 t, J = 7 Hz,
PhCH2, T1A and T1B, respectively), 3.52 and 3.65 (2 9 s,
CH3, T1B and T1A, respectively), 3.80 and 3.95 (2 9 q,
Yield 59%; mp 161–163 °C;
UV [kmax, (lg e), solvent] 342 (4.98), CH3CN; 340
(3.55), CHCl3;
1H NMR (DMSO-d6) d 3.50, 3.53, 3.78 (3 9 s, CH3,
T1A, T1B, and T2A, respectively), 4.59, 4.75, 4.97
(3 9 d, J = 6 Hz, CH2NH, T1A, T1B, and T2A, respec-
tively), 7.13–7.60 (m, ArH), 8.55 (t, J = 6 Hz, N2–H,
T1A), 8.85 (t, J = 6 Hz, N2–H, T1B), 10.80 (s, N3–H,
T2A), 11.85 (t, J = 6 Hz, N4–H, T2A), 13.10 (s, N2–H,
T1B), 13.27 (s, N2–H, T1A);
Table 1 Solvent-dependent relative population (%) of isomers
1
derived from H NMR data for 2 (average results of CH3, CH2, and
NH proton signals integration; nd not detected)
Compound
CDCl3
DMSO-d6
T1A
T1B
T2A
T1A
T1B
T2A
2a
2b
2c
60
55
55
37
45
37
3
39
43
35
34
36
32
27
21
33
nd
7
15N NMR (DMSO-d6, CH3NO2) d -261.0 (N3 for
T2A), -257.5 (N2 for T1B), -256.0 (N2 for T1A),
123

958
Struct Chem (2010) 21:955–964
J = 7 Hz, NHCH2, T1A and T1B, respectively), 6.38 (br
s, N4–H, T1A), 6.60 (br s, N4–H, T1B), 7.18–7.40 (m, 9H,
Ar–H), 13.65 (br s, N2–H, T1A and T1B).
reaction mixture. The yields (42–63%) are the mean values
of at least three experiments and correspond to the amounts
of products isolated following chromatographic purification.
Although the target thioureas 2 were obtained only in mod-
erate yields, these results are quite similar to those achieved
during aminolysis of aliphatic ITC with various 2-amino
substituted nitrogen heterocycles [4, 16]. The reason why the
reaction tends to stop at moderate conversion even after a
prolonged reaction time ([3 days) is not understood at the
present time.
There are additional broad peaks in the spectrum cen-
tered at 3.10 and 4.08 ppm that correspond to traces of
T2A tautomer (about 7%);
13C NMR (125.7 MHz, CDCl3) d 28.2 (CH3), 35.3 and
35.9 (CH2Ph, T1B and T1A, respectively), 45.3 and 45.5
(NCH2, T1A and T1B, respectively), 108.7 and 109.0 (C5,
T1B and T1A, respectively), 111.3 and 111.7 (C2, T1B
and T1A, respectively), 123.0, 123.2, and 123.4 (C3/4, for
T1B and T1A, respectively), 126.7 (C15), 128.0 (C6),
128.8, 128.9, 129.0, and 129.1 (C13/17 and C14/16, T1A
and T1B), 130.5 (C1), 139.3 (C11), 153.8 (C=N), 184.7
(C=S);
NMR analysis
According to a previous report [9], PITC adducts 2d and
2e in CDCl3 and DMSO solutions at room temperature
adopt one tautomeric form only. On the basis of NMR
analysis, we concluded that adducts 2a–c consist of a
mixture of at least three isomers in both solutions. At first
sight, 1H NMR spectra of chloroformic solutions of 2
contained only two sets of well-resolved resonances for
each CH proton and three signals of exchangeable NH
protons. However, careful NMR analysis revealed the
presence of additional broad peaks (4–7%) resulting from a
dynamic process between two additional isomers. Also, for
spectra recorded in DMSO, all CH triplicate signals and
six sharp peaks of exchangeable NH protons were
observed, indicating the presence of three isomers for 2a,
2b, and 2c.
IR mmax 3296, 3186, 3062, 3026, 2935, 1622, 1614,
1595, 1479, 1446, 1402, 1373, 1350, 1322, 1286, 1246,
1149, 1128, 1093, 1064, 999, 933, 742, 698, 661, 634, 617,
573 cm-1
;
MS/MS (m/z) 311.1 (M ? 1), 309.2 (M - 1);
Anal. Calcd. for C17H18N4S: C, 65.78; H, 5.84; N,
18.05; S, 10.33%. Found: C, 65.93; H, 5.90; N, 17.81; S,
10.23%.
Results and discussion
Synthesis
If we consider only the partial double bond character of
four C–N bonds (N2–C8, C8–N3, N3–C9, and C9–N4),
there are up to eight possible isomers of 2. In contrast, the
presence of four adjacent basic sites—three on a nitrogen
atom and one on a sulfur atom with two acidic protons—
suggests the possible existence of additional tautomers. It is
well known that ZE isomers of unsymmetrically disubsti-
tuted thioureas are more stable than the respective ZZ/EE
isomers, and isomers able to form strong intramolecular
bonding are preferred over others [17].
The efficient synthesis of the respective thioureas 2 appears
to be simple, but the MABI–aliphatic ITC system was
expected to exhibit low reactivity. The mechanism of
aminolysis was studied in detail only for aromatic ITCs
[14]. MABI is a base about 103 times weaker than typical
aliphatic amines, and aliphatic ITCs are less reactive than
aryl ITCs (owing to the lack of the crucial negative reso-
nance effect of the phenyl ring). Deprotonation consider-
ably enhances the nucleophilicity of 1, but in this case the
formation of double addition byproducts would be pre-
ferred, as shown, e.g., for the structurally related 2-amino-
1-methyl-5-nitroimidazoles [15].
It should be mentioned that an enaminethiol form of
thiourea derivatives has never been detected in the ground
state because of its extremely low population in the equi-
librium state. However, a few years ago, Nowak detected
an unstable enaminethiol tautomer of thiourea in a cryo-
genic argon matrix after UV irradiation [18]. Among the
trial structures, we selected the most probable isomers that
satisfy the above conditions; some of them are presented in
Fig. 2.
The synthesis of the target 1-benzimidazolylthioureas 2
was carried out after the optimization of reaction condi-
tions based on the model reaction between 1 and PEITC
leading to 2c. The effect of solvent, stoichiometry, con-
centration, temperature, and base on the course of the
above reaction was studied.
We tested various solvents (iPrOH, EtOH, MeOH, THF,
DMF), but the best results were obtained when the reaction
took place in MeCN. Neither the reagent ratio (using 1 or ITC
in two-fold excess), nor longer reaction times, nor a higher
temperature pushed the reaction to completion. In all runs,
there was always some unreacted 1 or ITC present in the
As mentioned above, three NH proton signals appeared
in CDCl3 solutions, one about 14 ppm and two at a lower
frequency (6–7 ppm). It is well known that the NH signal
observed at a higher frequency is of intermolecular H-bond
origin (chelated) and thus corresponds to the structures
T1A, T1B, or T2A. A small difference in the chemical
123

Struct Chem (2010) 21:955–964
959
Fig. 2 The most plausible
isomers of adducts 2. Structures
T1C and T2B are excluded due
to either lack of chelated
R
H
H
H
S
N
R
H
S
N
H
R
H
N
N
H
N
N
N
N
N
N
S
N
N
N
N
S
N
protons or NOE correlations
(see text for explanation)
CH3
CH3
CH3 HN
T1C
CH3
R
T1A
T1D
T1B
R
H
N
S
H
R
S
N
N
N
NH
NH
N
N
CH3
CH3
T2B
T2A
shifts of both non-chelated NH protons (Dd = 0.5 ppm)
suggests a structural similarity between these two tautom-
ers; they are denoted by T1A and T1B.
the following order: T1A \ T1B \ T2A (for NCH2
protons) and T1A * T1B \ T2A (for CH3 protons).
The last sequence indicates again (see above) that T2A
tautomers differ significantly in structure from both
T1A and T1B, mainly in the benzimidazolyl fragment.
The following important information was extracted from
our ROESY experiments. We found significant NOE
effects that unambiguously indicated the orientation of
the main structural units of 2. Therefore, N–CH3 pro-
tons in T1A correlate with N(4)CH2 protons while N–CH3
protons in T2A correlate with the N(3)H proton. The
lack of NOEs for N–CH3 and N(4)H means that the
postulated structure T1C for the main tautomer can be
ruled out. The correlated 1H–15N gHSQC spectrum of
2b in DMSO makes it possible to distinguish between
all the tautomers detected. It was found that the N4
nitrogens for all three tautomers are more deshielded
than the N2/N3 ones (Dd = 8.5–12 ppm). For T1A and
T1B tautomers, the N2 and N4 signals are close to each
other, but for T2A both signals appear at a higher field
(3.5–5 ppm).
The observed multiplicity of N(4)H proton signals
(triplets) enabled differentiation of the respective signals in
1
every H NMR spectrum recorded in DMSO (Fig. 3).
Both NH proton peaks of T2A tautomers occurred
between the N(2)H and N(4)H proton peaks of T1A and
T1B. The N(4)H proton in T2A was always more deshielded
(about 12 ppm) than the N(3)H proton (about 11 ppm). For
tautomers T1B and T2A, the trend was reversed. The N(2)H
protons in all 2 were the most deshielded (d 13.2 and
13.1 ppm for T1A and T1B, respectively). Otherwise, the
N(4)H proton signals lie about 4 ppm upfield (d 8.0 and 8.2
for T1A and T1B, respectively). This means that the N(4)H
proton in T2A has a significantly different surrounding and
that its increased deshielding, compared to the correspond-
ing signals for T1A and T1B (Dd * 4 ppm), is an effect of
intramolecular hydrogen bonding.
An interesting feature was observed for CH protons.
The chemical shift measured in DMSO-d6 decreases in
Fig. 3 1H NMR spectra of 2 in
DMSO-d6
123

960
Struct Chem (2010) 21:955–964
IR analysis
The main conclusion is that the reported chemical shifts
confirm that the N2 nitrogens in T1A and T1B, as well as
the N3 nitrogen in T2A are all sp3-hybridized.
ATR spectra in the characteristic 2500–4000 cm-1 range
of compounds 2 are displayed in Fig. 4. In the higher
wavenumber region, 3100–3300 cm-1, there are several
bands that are characteristic of the asymmetric and sym-
metric stretching vibrations of the NH bonds involved in
the formation of intra- and intermolecular hydrogen bonds
in the crystals. The shift of the m(N–H) band of 2c toward
higher wavenumbers (ca. 3300 cm-1) may suggest that the
hydrogen bonds involved in dimer formation in crystals are
weaker than in the case of 2a and 2b [19].
The bands in the 739–742 cm-1 region are characteristic
of m(C=S), and the absence of S–H stretching vibrations at
ca. 2550 cm-1 indicates that the compounds in the solid
state remain as a thione tautomer [20].
The absorptions observed at 1479–1491 cm-1 [21] and
1093–1095 cm-1 ranges correspond to N–C–N stretching
vibrations in thioureas. The increase in frequency in rela-
tion to the thioureas described in the literature [22] can be
attributed to the greater double bond character of the C–N
bond in products 2.
Additional valuable information can be derived from 13
C
NMR spectra. The observed significant shielding (refer-
enced to 1) of C1 tertiary carbon (Dd2–1 = -11.4 ppm),
together with the shielding of the aromatic C2 carbon
(Dd2–1 = -3.4 ppm), reveal once again that N2 is sp3-
hybridized, which is an additional proof for the proposed
structures of both T1A and T1B tautomers. Interestingly, all
the T1B signals in 13C NMR spectra recorded in chloroform
are broad and not always detectable. Broadening of the
respective signals for T1B and T2A in their 1H NMR spectra
may indicate a relationship between T1B and T2A and their
possible interconversion. The mechanism of such an
interconversion remains an unsolved problem. On the
other hand, the conversion of T1A to T1B appears
to proceed because of the restricted rotation about the
C9–N4 bond.
It should be mentioned that the 1H NMR spectrum of 2b
recorded immediately after its dissolution in DMSO con-
tained only T1A and T1B signals; signals of T2A arose
slowly over time.
X-ray structure analysis
The thiocarbonyl C=S chemical shift of 184.7 ppm (the
same for all 2) is different from that of other unsymmetrical
thioureas containing alkyl and heteroaryl residues
(d = 176–181 ppm) [4, 16]. This extra deshielding is
caused by the partial ionic character of the C=S bond (vide
infra the observed C–S bond length in crystal).
The general and crystallographic data for compounds 2a,
2b, and 2c are listed in Table 2. The numbering of atoms
in products 2 is shown in Fig. 1. The main geometrical
features of the structures of these compounds are given in
Table 3. All the data in Tables 3, 4, 5 are compared to the
parameters of the published previously N-(2-phenoxyeth-
yl)benzimidazolyl-N0-phenethylthiourea 2e [9]. Only one
isomer is observed in the crystals of 2a–2c, and its
structure corresponds to one of those (namely T1A)
deduced from NMR analysis. Therefore, T1A predomi-
nates in all the compounds under investigation in the solid
state and in solution. It forms centrosymmetric dimers in
all cases.
In our hands, the most accurate method for determining
1
the 2a–2c tautomer ratio was H NMR spectroscopy. In
DMSO, the observed exchange reactions are slow enough
to see all NH protons as sharp isolated signals, which make
the populations of all three tautomers easily measurable.
The results obtained for NH, as well as for CH protons
were found to be comparable. However, this approach
cannot be used for 2c, where the populations of all three
tautomers are comparable (Table 1).
Fig. 4 ATR spectra of products
2 in the crystalline state in the
4000–2500 cm-1 range
123

Struct Chem (2010) 21:955–964
961
Table 2 Summary of crystal
data, intensity collection, and
structure refinement for
Compounds
2a
2b
2c
Code
CCDC 751508
Yellow prism
C12H14N4S1
246.33
CCDC 752764
Yellow prism
C16H15N4S1
296.39
CCDC 751509
Colorless prism
C17H18N4S1
310.41
compounds 2a, 2b, and 2c
Crystal color and habit
Empirical formula
Mr
Temperature (K)
120(2)
120(2)
120(2)
˚
Wavelength (A)
0.71073
0.71073
0.71073
ꢀ
Triclinic, P1
ꢀ
Triclinic, P1
ꢀ
Triclinic, P1
Crystal system, space group
Unit cell parameters
˚
a (A)
9.672(3)
7.541(3)
9.267(3)
90.39(3)
111.58(3)
104.63(3)
604.5(4)
2
9.1003(5)
9.1926(5)
10.2034(4)
89.760(4)
82.410(4)
60.603(5)
735.33(6)
2
9.6509(9)
9.7089(13)
10.3757(17)
65.086(14)
64.455(12)
79.705(9)
795.5(2)
2
˚
b (A)
˚
c (A)
a (°)
b (°)
c (°)
3
˚
Cell volume (A )
Z
Density (g cm-3
)
1.353
1.339
1.296
Absorption coefficient (mm-1
)
0.251
0.219
0.205
F(000)
260
312
328
˚
Table 3 Selected bond lengths (A) for 2a–2c and 2e (taken from ref. [9])
Compound
C9–S1
C9–N3
C9–N4
C8–N3
C8–N2
C8–N1
N1–C7
N4–C10
2a
2b
2c
2e
1.724(2)
1.726(2)
1.721(2)
1.725(1)
1.343(2)
1.348(2)
1.349(2)
1.341(2)
1.340(2)
1.344(2)
1.341(2)
1.364(2)
1.322(2)
1.325(2)
1.327(2)
1.335(2)
1.361(2)
1.360(2)
1.354(2)
1.350(2)
1.362(2)
1.361(2)
1.364(2)
1.367(2)
1.457(2)
1.457(2)
1.455(2)
1.458(2)
1.462(2)
1.464(2)
1.456(2)
1.417(2)
˚
Table 4 Selected interatomic distances (A), valence, torsion, and dihedral angles (°) for 2a–2c and for 2e (taken from ref. [9])
Compound
Intramolecular hydrogen bond parameters
Dihedral angles
Torsion angles
N(2)HꢀꢀꢀS(1)
N(2)ꢀꢀꢀS(1)
\N(2)HS
\(P1, P2)
\(P1, P3)
h1
h2
2a
2b
2c
2e
2.352
2.356
2.315
2.287
2.990
2.984
2.975
2.946
130
131
131
133
4.1
5.6
47.4
139.2
66.5
7.0
-1.8
-1.6
-8.3
-0.5
177.4
177.4
169.2
179.9
13.3
5.3
h1 = C8–N3–C9–S1; h2 = S1–C9–N4–C10; P1 = benzimidazolyl ring, P2 = thiourea plane, P3 = phenyl ring or ethene plane
The crystal structures described here resemble the ones
previously reported for analogous N-substituted derivatives
of 1 and PITC (2e). However, the C9–N4 bond in 2a, 2b,
and 2c is shorter than in 2e because of the direct N4 atom
bonding to the aromatic ring (phenyl) instead of alkyl
contribution of the respective resonance forms for 2a and
2b. Otherwise, there is a remarkable distortion of molecule
of 2c manifested in the large dihedral angle between
benzimidazolyl ring and thiourea plane (P1 and P2) (13.3°)
and deviation from planarity in the thiourea core (h1 and
h2: –8.3 and 169.2°). Despite the smallest interplanar dis-
tance between thiourea planes P2–P20 in the hydrogen
˚
carbon. Typically, the C=S bond length is 1.60 A [23], but
the C9–S1 bond in all thioureas 2 under investigation
˚
undergoes resonance lengthening (1.72 A). The fact that
˚
bond linked dimeric system (0.16 A, almost flat dimer)
the benzimidazole ring is nearly coplanar with the thiourea
core (see Table 4) indicates that there is a significant
and shorter HꢀꢀꢀS distance found for 2c, it could not form
an intermolecular hydrogen bonding network that was
123

962
Struct Chem (2010) 21:955–964
˚
Table 5 Intermolecular hydrogen bonds and p–p stacking parameters (°, A) for dimeric 2a–2c and for 2e (taken from ref. [9])
Compound \N(2)HS0 N(2)HꢀꢀꢀS(1)0 N(2)ꢀꢀꢀS(1)0 Interplanar distance P2–P20 in dimers Shortest centroid-to-centroid distances
2a
2b
2c
2e
167.0
161.4
166.9
163.5
2.565
2.596
2.546
2.627
3.379
3.407
3.399
3.466
1.05
0.33
0.16
0.60
4.153(2) (Imid ? Imid’)
3.905(2) (Imid ? Benz) 4.023(2) (Ph ? Ph)
4.443(2) (Imid ? Benz)
–
Prime denotes the symmetry equivalent atom or group (by inversion). Imid: ring C1–N2–C8–N1–C6, Benz: ring C1–C6, Ph: C11–C16
stronger than in 2a and 2b. It could be explained by the loss
of more energy for conformation change required to form
the dimer (see text below and Fig. 9). As mentioned above,
ATR results confirmed that the N–H stretching vibration
band for 2c is shifted to the left (about 100 cm-1), which
indicates weaker intramolecular bondings in its dimers.
On the other hand, the strength of the connections
between dimers in 2c is smaller than the respective inter-
actions between 2a and 2b dimers (Figs. 5, 6, 7). The lack
of p–p stacking interactions (see Table 5; for comparison:
˚
interplanar distance in graphite is 3.35 A) or other relevant
bonding contacts induces larger distances between dimers
in chains and between parallel chains. As expected, the
crystal of 2c has the lowest density, too.
Fig. 7 Crystal packing in 2c. Thiourea dimers held together by weak
p–p stacking (Imid–Benz rings)
Table 6 Relative energies (B3LYP/6-311?G(d,p)//B3LYP/6-31G(d,p),
ZPE corrected, kcal/mole) calculated for isomers of 2
Compound
T1A
T1B
T2A
2a
0
0
0
0
-0.64
?2.89
?2.97
?2.19
?5.0
Fig. 5 Crystal packing in 2a. Thiourea dimers held together by weak
p–p stacking of the Imid–Imid rings
2b
-0.94
2c
-0.90
2d (EtOH)
Not reported
Isomer T1B is a rotamer of T1A, while T2A is a tautomer of T1A
Calculations
To confirm the identity of the tautomers present in solution,
DFT calculations of optimized geometries were carried out
on 2 (Table 6). It was found for 2b and 2c that in the gas
phase, the energies of T1A tautomers are significantly
lower than those of T2A tautomers. Isomers T2A of 2a, 2b,
and 2c are less stable with relative energies of ?2.89,
?2.97, and ?2.19 kcal/mole, respectively. These values
are smaller than previously reported for 2d (?5.0 kcal/
mole) in ethanol [9]. This could lead to measurable coex-
isting populations of all isomers of 2a–c in solution after
taking into account the extra stabilization of T2A by
DMSO.
Fig. 6 Crystal packing in 2b. Two p–p stackings (between Imid–
Benz and Ph–Ph rings) bind thiourea dimers
123

Struct Chem (2010) 21:955–964
963
Fig. 8 Relaxed potential
energy scan (B3LYP/6-
31G(d,p)) for rotation about the
C9–N4 bond for 2a (left), 2b
(right), and 2c (below). The
scan coordinate is the torsion
angle H–N4–C9–S1; other
geometrical parameters were
allowed to optimize. The
25
20
15
10
5
25
20
15
10
5
0
0
-200
-100
0
100
200
-200
-100
0
100
200
different slopes on the left and
right sides of the curves stem
from the transition from sp2 to
sp3 hybridization mode at the
nitrogen atom during rotation.
Rotational barriers for 2a, 2b,
and 2c can be estimated as 18.1,
18.8, and 19.9 kcal/mole,
respectively
Torsion angle
Torsion angle
25
20
15
10
5
0
0
-200
-100
100
200
Torsion angle
Surprisingly, the calculations revealed that the energy of
T1A is slightly higher than that of T1B in isolated mole-
cules (note: the formation of dimers can reverse the energy
preferences). Therefore, T1B, not T1A is the lowest-
energy tautomer for 2a, 2b, and 2c.
Conclusion
Crystallographic results regarding the structures of 2-ben-
zimidazolylthiourea 2 adducts of aliphatic ITCs and MABI
confirm that in the solid state their only form is the tau-
tomer T1A, existing as the T1A–T1A centrosymmetric
dimer, as found previously for the respective adducts of
PITC [9]. The data presented here provide spectroscopic
evidence that the intramolecular hydrogen bonds observed
in the solid state are also maintained in DMSO solution for
the main isomer T1A.
Another unexpected feature of thioureas 2 is the
unusually high rotational barrier about the C9–N4 bond
(based on B3LYP/6-31G(d,p) PES scan). Both calculated
energies are up to 7–9 kcal/mole higher than those deter-
mined experimentally for 1,3-dialkyl thioureas [24]. Since
it is well known that the respective theoretical values for
thioureas are usually 3–4 kcal/mole smaller [25], actual
energy barriers in DMSO should be even higher than
predicted theoretically for isolated molecules. The calcu-
lations also showed that mutual interconversion
T1A¡T1B requires about 2 kcal/mole more energy in the
case of 2c than 2b (Fig. 8).
Being typical unsymmetrical thioureas, 2 are bonded
into dimers through double intermolecular NHꢀꢀꢀS bonds.
N-Substituents in 2 strongly affected contacts and the
strength of H-bonding was indicated by comparison of the
respective structural parameters. Otherwise, in solution, 2
exists as a mixture of three tautomers. In chloroform, T1A
is clearly dominant over T1B and T2A, whereas in DMSO
all three isomers exist in nearly equal proportions. The
structures of all tautomers were predicted theoretically and
unequivocally elucidated experimentally. It was quite sur-
prising to find unusual NOE interactions for T1A in solu-
tion. This provides additional proof for the enhanced
double bond nature of N4–C9 in 2, which makes them
more rigid and also strengthens the intermolecular bonding
in their dimers.
Overlays of experimental and calculated structures of
T1A are presented in Fig. 9. Clearly, formation of the
dimers can induce conformational changes in the mole-
cules. This effect is more marked for 2c.
The structure of T1A corresponds to that found in
crystal; on dissolving in DMSO, thiourea dimers T1A–
T1A start to dissociate slowly. As a result of rotation about
the C9–N4 bond, T1A is transformed into isomer T1B
(nearly equal in energy according to calculations). It cannot
form dimers because of the opposing positions of the C=S
acceptor group and the N(4)H donor. The calculated
barrier to rotation about the C9–N4 bond is equal to ca.
18–20 kcal/mole for all thioureas 2. During dissolution,
Fig. 9 The overlay of X-ray and calculated (red) structures of 2b
(left), and 2c (right). The hydrogen bond network is additionally
shown for the crystal structures. The benzimidazole residue was
chosen as the basis for fitting. (Color figure online)
123

964
Struct Chem (2010) 21:955–964
6. Zhang Y-M, Cao Ch, Wei W, Xie T-B (2007) Chin J Chem
25:709–713
7. Lee GW, Singh N, Jank DO (2008) Tetrahedron Lett 49:1952–1956
8. Succaw GL, Weakley TJR, Han F, Doxsee KM (2005) Cryst
Growth Des 5(6):2288–2298
9. Morkovnik AS, Divaeva LN, Nelyubina YV, Lyssenko KA,
Vasilchenko IS (2007) Mendeleev Commun 17:224–226
10. Oxford Diffraction Ltd, Abingdon, England (2006) CrysAlis
CCD, CrysAlis RED and associated programs. Oxford Diffrac-
tion Ltd, Abingdon, England
rotation about the N3–C9 bond yielded the rotamer T1D as
a precursor of tautomer T2A. Tautomers T2A arise as a
result of proton transfer from nitrogen N(2) to N(3) and are
higher energy isomers (about 3 kcal/mole). T2A is not able
to form dimers either.
We conclude that DMSO as a solvent balances the
energy differences between all the isomers with the special
stabilization of T2A, the most polar one in solution. Our
results, obtained from NMR and crystallographic data, are
corroborated by theoretical calculations.
11. Sheldrick GM (2008) Acta Cryst A64:112–122
12. Macrae CF, Bruno IJ, Chisholm JA, Edgington PR, McCabe P,
Pidcock E, Rodriguez-Monge L, Taylor R, van de Streek J, Wood
PA (2008) J Appl Cryst 41:466–470
This is the first report of three isomers of unsymmetrical
thioureas existing in equilibrium with an exchange rate at
room temperature that is sufficiently slow to permit the
unambiguous resolution of their structures. Due to the fact
that analogous 2d exists as one isomer at room tempera-
ture, we claim that the observed different behaviors of
thioureas 2a–c are their unique feature. Therefore, the
statement that 2-benzimidazolylthioureas exist exclusively
as one 1,3-dihydrobenzimidazolinylidene tautomer [9] is
not general and should be reserved only for the relevant
N0-phenylthioureas.
13. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA,
Cheeseman JR, Montgomery Jr JA, Vreven T, Kudin KN, Burant
JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B,
Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada
M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nak-
ajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE,
Hratchian H P, Cross JB, Bakken V, Adamo C, Jaramillo J,
Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R,
Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA,
Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels
AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghava-
chari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S,
Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P,
Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng
CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B,
Chen, W, Wong MW, Gonzalez C, Pople JA (2004) Gaussian 03,
revision D.01. Gaussian, Inc., Wallingford, CT
Acknowledgments The studies were supported by the Polish
Ministry of Science and Higher Education, grant No. 312244336 and
by the European Union (European Social Fund) within the framework
of the project ‘‘InnoDoktorant—Scholarships for PhD students, 1st
edition.’’ Calculations were carried out at the Academic Computer
Center in Gdansk (TASK).
14. Satchell DPN, Satchell RSJ (1990) Chem Soc Perkin Trans
2:1415–1420
15. Sudarsanam V, Nagarajan K, Arya VP, Kaulgud AP, Shenoy SJ,
Shah RK (1982) Indian J Chem 21B:989–996
16. Saxena A, Pike RD (2007) J Chem Crystallogr 37:755–764
17. Sudha LV, Sathyanarayana DN (1984) J Mol Struct 40:751–755
´
18. Rostkowska H, Lipinski L, Khvorostov A, Nowak MJ (2003)
J Phys Chem A 107:6373–6380
References
19. Marechal Y (2007) The hydrogen bond and the water molecule.
Elsevier, Amsterdam, pp 85–89
20. Weiqun Z, Wen Y, Lihu Q, Yong Z, Zhengfenh Y (2005) J Mol
Struct 749:89–95
21. Kirubavathi K, Selvaraju K, Kumararaman S (2008) Spectrochim
Acta A 71:1–4
22. Kirubavathi K, Selvaraju K, Valluvan R, Kumararaman S (2007)
Mater Lett 61:4173–4176
23. Borjesson K, Sandin P, Wilhelmsson LM (2009) Biophys Chem
139(1):24–28
24. Sullivan RH, Price E (1975) Org Magn Reson 7:143–150
25. Haushalter KA, Lau J, Roberts JD (1996) J Am Chem Soc
118:8891–8896
1. Mukerjee AK, Ashare R (1991) Chem Rev 91:1–24
´
´
2. de Dios A, Shih C, Lopez de Uralde B, Sanchez C, del Prado M,
Cabrejas LMM, Pleite S, Blanco-Urgoiti J, Lorite MJ, Nevill
CRJ, Bonjouklian R, York J, Vieth M, Wang Y, Magnus N,
Campbell RM, Anderson BD, McCann DJ, Giera DD, Lee PA,
Schultz RM, Li LC, Johnson LM, Wolos JA (2005) J Med Chem
48:2270–2273
3. Saedd S, Rashid N, Jones PG, Ali M, Hussain R (2010) Eur J
Med Chem 45:1323–1331
4. Tsogoeva SB, Hateley MJ, Yalalov DA, Meindl K, Weckbecker
C, Huthmacher K (2005) Bioorg Med Chem 13:5680–5685
5. Gunnlaugsson T, Glynn M, Tocci GM, Kruger PE, Pfeffer FM
(2006) Coord Chem Rev 250:3094–3117
123