Understanding the conformational changes and molecular structure of furoyl thioureas upon substitution

Article abstract of DOI:10.1016/j.saa.2016.12.038

1-Acyl thioureas [R¹C(O)NHC(S)NR²R³] are shown to display conformational flexibility depending on the degree of substitution at the nitrogen atom. The conformational landscape and structural features for two closely related thioureas having R¹?=?2-furoyl have been studied. The un-substituted 2-furoyl thiourea (I) and its dimethyl analogue, i.e. 1-(2-furoyl)-3,3-dimethyl thiourea (II), have been synthesized and fully characterized by spectroscopic (FT-IR, ¹H and ¹³C NMR) and elemental analysis. According to single crystal X-ray diffraction analysis, compounds I and II crystallize in the monoclinic space group P21/c. In the compound I, the trans–cis geometry of the almost planar thiourea unit is stabilized by intramolecular N[sbnd]H???O[dbnd]C hydrogen bond between the H atom of the cis thioamide and the carbonyl O atom. In compound II, however, the acyl thiourea group is non-planar, in good agreement with the potential energy curve computed at the B3LYP/6-31?+?G(d,p) level of approximation. Centrosymmetric dimers generated by intermolecular N[sbnd]H???S[dbnd]C hydrogen bond forming R₂²(8) motif are present in the crystals. Intermolecular interactions have been rationalized in terms of topological partitions of the electron distributions and Hirshfeld surface analysis, which showed the occurrence of S???H, O???H and H???H contacts that display an important role to crystal packing stabilization of both thiourea derivatives.

Full text of DOI:10.1016/j.saa.2016.12.038

Accepted Manuscript
Understanding the conformational changes and molecular
structure of furoyl thioureas upon substitution
Raúl Ramos Cairo, Ana María Plutín Stevens, Tamires Donizeth
de Oliveira, Alzir A. Batista, Eduardo E. Castellano, Julio Duque,
Delia B. Soria, Adolfo C. Fantoni, Rodrigo S. Corrêa, Mauricio F.
Erben
PII:
DOI:
Reference:
S1386-1425(16)30771-5
doi: 10.1016/j.saa.2016.12.038
SAA 14851
Spectrochimica Acta Part A: Molecular and Biomolecular
Spectroscopy
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Revised date:
Accepted date:
26 October 2016
16 December 2016
24 December 2016
Please cite this article as: Raúl Ramos Cairo, Ana María Plutín Stevens, Tamires Donizeth
de Oliveira, Alzir A. Batista, Eduardo E. Castellano, Julio Duque, Delia B. Soria, Adolfo
C. Fantoni, Rodrigo S. Corrêa, Mauricio F. Erben , Understanding the conformational
changes and molecular structure of furoyl thioureas upon substitution. The address for
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ACCEPTED MANUSCRIPT
Understanding the Conformational Changes and Molecular Structure of
Furoyl Thioureas upon Substitution
Raúl Ramos Cairo,a Ana María Plutín Stevens,a, * Tamires Donizeth de Oliveira,b Alzir A.
Batista,b Eduardo E. Castellano,c Julio Duque,d Delia B. Soria,e Adolfo C. Fantoni,f
Rodrigo S. Corrêa,g Mauricio F. Erbene, *
a-Laboratorio de Síntesis Orgánica, Facultad de Química, Universidad de La Habana, La
Habana, Cuba.
b-Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, Brazil.
c-Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil.
d- Instituto de Ciencia y Tecnología de Materiales (IMRE), Universidad de La Habana,
Havana, Cuba.
e- CEQUINOR (UNLP-CONICET, CCT La Plata), Departamento de Química, Facultad de
Ciencias Exactas, Universidad Nacional de La Plata, C.C. 962 (1900), La Plata,
Argentina.
f- Instituto de Física La Plata, Departamento de Física, Facultad de Ciencias Exactas,
Universidad Nacional de La Plata, 49 y 115, La Plata, Buenos Aires, República Argentina.
g
Departamento de Química (DeQui), Instituto de Ciências Exatas e Biológicas,
Universidade Federal de Ouro Preto – UFOP, Ouro Preto, Brazil.
*Corresponding authors:
(AMPS) E-mail: anap@quimica.uh.cu.
(MFE) E-mail: erben@quimica.unlp.edu.ar.

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Abstract
1-Acyl thioureas [R1C(O)NHC(S)NR2R3] are shown to display conformational flexibility
depending on the degree of substitution at the nitrogen atom. The conformational landscape
and structural features for two closely related thioureas having R1= 2-furoyl have been
studied. The un-substituted 2-furoyl thiourea (I) and its dimethyl analogue, i.e. 1-(2-
furoyl)-3,3-dimethyl thiourea (II), have been synthesized and fully characterized by
spectroscopic (FT-IR, 1H and 13C NMR) and elemental analysis. According to single crystal
X-ray diffraction analysis, compounds I and II crystallize in the monoclinic space group
P21/c. In the compound I, the trans–cis geometry of the almost planar thiourea unit is
stabilized by intramolecular N–H···O=C hydrogen bond between the H atom of the cis
thioamide and the carbonyl O atom. In compound II, however, the acyl thiourea group is
non-planar, in good agreement with the potential energy curve computed at the B3LYP/6-
31+G(d,p) level of approximation. Centrosymmetric dimers generated by intermolecular
2
N–H···S=C hydrogen bond forming R2 (8) motif are present in the crystals. Intermolecular
interactions have been rationalized in terms of topological partitions of the electron
distributions and Hirshfeld surface analysis, which showed the occurrence of S···H, O···H
and H···H contacts that display an important role to crystal packing stabilization of both
thiourea derivatives.
KEYWORDS: Thiourea derivatives; Molecular conformation; Single crystal structure
determination; Vibrational spectroscopy; Hirshfeld surface analysis; topological study.
2

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1-Introduction
1-Acyl thiourea derivatives, with general formula R1C(O)NHC(S)NR2R3, are
versatile compounds that have attracted much attention in many fields, such as chemical
intermediates in synthesis, biological and pharmaceutical chemistry, and as promising new
materials in environmental applications. Comprehensive review articles can be found in the
recent literature covering the chemistry, structure and applications of these compounds [1-
4].
It has been determined that desired properties depend on the structure and
conformation adopted by the central 1-acyl thiourea group. The interplay between
intermolecular and intramolecular hydrogen bonding greatly affects the chemical properties
of these compounds, including their use as ligand in metal complexes [1], as reagents in
cyclization reactions [4], biological activities and other useful applications. In particular, a
ligand-based structural optimization methodology for the preparation of a series of 1-(acyl)-
3-(mono) and 1-(acyl)-3,3-(di) substituted thioureas has been developed, with potent
smoothened antagonist [5]. Interestingly, a series of analogous acylureas or acylguanidines
compounds displayed similar biological activities [6, 7]. From this similitude, the existence
of common hydrogen-bonding interactions between the ligands and the receptor pocket was
proposed [6]. Similarly, the hydrogen-bonding ability of 1-(acyl)-3-(mono) substituted
thioureas make these molecules candidates for anion receptors [8-10].
Hydrogen bonds also influence the conformational equilibria around the 1-acyl
thiourea core. In effect, several conformations are possible for these compounds, depending
on the orientations adopted by the C=O and C=S double bonds with respect to the C–N
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bonds [11-13]. Following Woldu and Dillen [14], the two main forms are denote as S and U
(the letter reflects the position of the C=O and C=S double bonds relative to the vertically
drawn N–H bond, as shown in Scheme 1). As reported by Becker and coworkers [15], the S
form prevails for 1-(acyl/aroyl)-3-(mono-substituted) thiourea derivatives with R2= H,
because the formation of intramolecular C=O···H–N hydrogen bond strongly stabilize this
conformation [16-18]. On the other hand, 1-(acyl/aroyl)-3,3-(di-substituted) thioureas tend
to adopt the U form since in this case R2 and R3 ≠ H and thus, the formation of a
intramolecular hydrogen bond is disallowed [19].
H
R2
O
C
N
C
O
C
S
C
R2
R1
N
H
S
R1
N
H
N
R3
U
S
Scheme 1. Main conformations observed for 3-mono (S form) and 3,3-di substituted (U
form) 1-acyl thioureas.
Thiourea derivatives containing the 2-furoyl group were synthesized [20-24] and the
complexation ability of these ligands towards various metal ions was investigated [25-28],
with salient analytical applications [29]. In particular, 1-(2-furoyl)-3-substituted thioureas
were probed as useful intermediates used in environmental control and as ionophores in ion
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selective electrodes [26],[30]. Recently, mesoporous silica hybrid materials functionalized
with 1-(2-furoyl) thioureas exhibited good ability to remove Hg(II) from aqueous solutions
[31].
In this article the effect of substitution at the 2-furoyl thiourea core is analyzed by
studying two closely related species, i.e. the “parent” and the novel 3,3-dimethylated
thioureas (compounds I and II in Scheme 2, respectively). Structural characterization
includes experimental spectroscopic (FT-IR and Raman) and X-ray diffraction studies,
complemented with a detailed analysis of intermolecular interactions by Hirshfeld surfaces
and Atom in Molecule (AIM) topological analysis of the electron charge density.
O S
N N
O S
N N
H
CH3
O
O
H H
I
H CH3
II
Scheme 2. 1-(2-furoyl) thioureas I and II studied in this work.
2. Experimental
2.1. Material and measurements. Thin layer chromatography (TLC) was performed on 0.25
mm silica gel pre-coated plastic sheets (40/80 mm) (Polygram SIL G/UV254, Macherey &
Nagel, Düren, Germany) using benzene/methanol (9/1) as eluent. The IR spectra were
recorded on a FT-IR Bomem-Michelson 102 spectrometer, in KBr pellets with a resolution
of 2 cm–1 in the 4000-400 cm–1 range. Raman spectra for compounds I and II were
recorded using a Horiba Jobin Yvon T64000 Raman spectrometer equipped with a liquid
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N2-cooled back-thinned CCD detector. Spectra were recorded as the co-addition of up to 16
individual spectra with CCD exposure times of 10-20 s each. 1H and 13C NMR spectra were
recorded on a Bruker DRX 400 MHz, internally referenced to TMS, chemical shift (δ),
multiplicity (m), spin–spin coupling constant (J), integral (I) are given. CDCl3 was used as
solvent. Partial elemental analyses were carried out in an instrument of CHNS staff EA
1108 of the FISONS. Thermal analyses were performed with Shimadzu TGA-50 unit,
between room temperature and 750 ºC, at a heating rate of 5 ºC/min and nitrogen flow of
50 ml/min.
2.2-Quantum chemical calculations. Optimization of molecular geometries was
accomplished within the frame work of the density functional theory [32, 33] as
implemented in the Gaussian 03 package [34]. Contracted gaussian basis sets of triple-zeta
quality plus polarized and diffuse functions 6-311++G(d,p) for all atoms were used
throughout the present work [35]. The corresponding vibrational analyses were performed
for the optimized geometries (Cartesian coordinates are given in Tables S1 and S2 in the
Supporting Information) to verify whether they are local minima or saddle points on the
potential energy surface of the molecule. Calculated normal modes were also used as an aid
in the assignment of experimental frequencies. Natural Bond Orbital (NBO) population
analysis were performed and the energy of the donor–acceptor interactions estimated by the
second order perturbation theory [36].
Periodic calculations were performed at the B3LYP/6-31G(d,p) level with Crystal14
code [37]. Using the experimental estimations as the starting point, the coordinates of the
hydrogen atoms in the crystal were optimized to minimize the crystal energy with heavy
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atom coordinates and cell parameters fixed at their experimental values. The topology of
the resulting electron density was then analyzed using the TOPOND14 code [38], [39].
2.3. Synthesis of 2-furoyl thioureas. Detailed descriptions of syntheses and characterization
of related furoyl thioureas have been previously reported [13]. A solution of an
appropriately acyl chloride (30 mmol) in acetone (50 mL) was added drop wise to a
suspension of KSCN (30 mmol) in acetone (30 mL). The mixture was stirred until a
precipitate appeared (KCl), indicating the formation of 2-furoyl isothiocyanate. Ammonia
[31] or dimethyl amine (30 mmol), dissolved in acetone was slowly added with constant
stirring of the resulting solution (Scheme 3). The solution was cooled in an ice-water bath
and the stirring was continued at room temperature during 2–9 h, until the reaction was
completed (the reaction progress was monitored by TLC). The reaction mixture was then
poured into 600 mL of cold water. The solid thioureas were collected by filtration and
finally purified by re-crystallization from acetone:water mixture. The identity of the
1
13
products was confirmed by the analysis of the H and C NMR spectra (given in Figures
S1-S4 of the supplementary information) in comparison to similar compounds previously
reported in the literature [13].
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O
S
NH
3 (ac)
H
H
N
H
N
O
I
O
O
Acetone
KSCN
Cl
O
N C S
O
O
S
CH3
CH3
N
H
N
O
CH3
CH3
II
HN
Scheme 3. Synthesis of 2-furoyl thioureas I and II.
2-Furoyl thiourea (I): yield 79 %, mp 146-147 0C. FT-IR [ATR (solid),ν cm-1]: 3336, 3320,
1
3302, 3000, 1679, 1606, 1529, 1350, 1178, 883, 756. H NMR (400 MHz, DMSO-d6):
10.92 (s, 1H, NH, D2O exchangeable); 9.58 (s, 1H, NH, D2O exchangeable); 8.02 (dd, 2H,
J= 2.6 Hz Ar), 7.79 (dd ), 6.73 (dd,). 13C NMR (400 MHz, DMSO-d6): 181.5 (C=S); 157.1
(C=O), 148.1, 144.7, 118.2 and 112.5. Anal. Calc. for C6H6N2O2S (170.01): C, 42.34; H,
3.55; N, 6.46; S, 8.84%; Found: C, 42.00; H, 3.50; N, 5.90; S, 8.90%.
1-(2-furoyl)-3,3-dimethyl thiourea (II): yield 82%, mp 146-1470C. FT-IR [ATR (solid),ν
1
cm-1]: 3161, 2923, 1697, 1571, 1473, 1263, 1178, 929, 761. H NMR (400 MHz, CDCl3):
8.63 (s, 1H, NH, D2O exchangeable); 7.56 (dd), 7.27 (dd), 6.58 (dd), 3.40(s, CH3) and 3.28
(s, CH3). 13C NMR (400 MHz, CDCl3): 179.0 (C=S); 153.4 (C=O), 146.1, 145.5, 117.3,
112.8. Anal. Calc. for C8H10N2O2S (198.05): C, 48.47; H, 5.08; N, 4.13; S, 8.17 %; Found:
C, 48.00; H, 5.30; N, 4.50; S, 8.50 %.
2.4. Crystal structure determination. Single crystals suitable for X-ray diffraction were
obtained by slow evaporation of CHCl3:n-hexane (3:1) solutions of the furoylthioureas I
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and II. Diffraction data were collected on an Enraf-Nonius Kappa-CCD diffractometer with
graphite-monochromated MoKα radiation (λ= 0.71073 Å). The final unit cell parameters
were based on all reflections. Data collections were performed using the COLLECT
program [40], integration and scaling of the reflections were performed with the HKL
Denzo–Scalepack system of programs [41]. Absorption corrections were carried out using
the Gaussian method [42]. The structures were solved by direct methods with SHELXS-97.
[43] The models were refined by full-matrix least-squares on F2 by means of SHELXL-97.
The projection views of the structures were prepared using ORTEP-3 for Windows.[44]
Hydrogen atoms were stereochemically positioned and refined with the riding model. The
crystal and refinement data for title compounds are listed in Table 1 with the CCDC deposit
numbers for supplementary crystallographic data.
Table 1. Crystal data and refinement parameters for compounds I and II.
Compound
I
II
Empirical formula
C6H6N2O2S
170.19
C8H10N2O2S
198.24
Formula weight
Crystal system
Monoclinic
P21/c
Monoclinic
P21/c
Space group
Unit cell dimensions (Å; °)
a (Å)
b (Å)
c (Å)
9.3851(6)
7.3711(5)
10.6129(5)
95.038(4)
731.35(8)
4
4.97290(10)
10.7065(5)
17.7566(7)
94.568(2)
942.40(6)
4
β (°)
Volume (Å3)
Z
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Density calc (Mg/m3)
Absorption coefficient (mm−1)
F(000)
1.546
1.397
2.998
0.312
352
416
θ range for data collection (°)
Index ranges
3.37 to 25.97
-11 ≤ h ≤ 11
-8 ≤ k ≤ 9
-13 ≤ l ≤ 12
4544
2.986 to 25.996
-6 ≤ h ≤ 5
-13 ≤ k ≤ 12
-21 ≤ l ≤ 19
6464
Reflections collected
Independent reflections (Rint)
Goodness-of-fit on F2
R1 [I>2σ (I)]
1419 [R(int) = 0.0351]
1.071
1835 [R(int) = 0.0414]
1.313
R1 = 0.0411
wR2 = 0.1064
0.251 and -0.309
931558
R1 = 0.0336
wR2 = 0.0734
0.294 and -0.326
1502060
wR2 [I>2σ (I)]
Largest diff. peak and hole (eÅ-3)
CCDC deposit number
3. Results and Discussion
3.1. Synthesis and characterization
2-Furoyl thioureas I and II were synthesized according to the general method early
reported by Douglass and Dains [45] and further optimized for 2-furoyl substitutions [13],
[31]. The one-pot procedure involves the in situ reaction between 2-furoyl chloride and
KSCN and the reaction of the intermediate 2-furoyl isothiocyanate with the appropriated
amine. The reaction proceeds via a nucleophilic addition of the amine to the isothiocyanate
with good yields (79 and 82 %, for I and II, respectively). The synthesized compounds
were purified by recrystallization from an acetone:water mixture (1:2) and characterized by
1
1
elemental analysis, H NMR, 13CNMR, and FT-IR spectroscopy. In H NMR, the
compounds exhibited broad signals in the range of 10.92, 9.58 and 8.63 ppm, which were
13
assigned to the N-H protons. C NMR spectrum showed the peaks at about δ 181.5 and
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179.0 for C=S (thioamide) and 157.1 and 153.4 for C=O (amide), respectively. The
elemental analyses closely corresponded to calculated values.
3.2 Vibrational spectra
Infrared and Raman spectroscopies have shown to be very useful for analyzing the
conformational properties, as well as intermolecular and intramolecular hydrogen bond
interactions involving N–H donors of acyl thioureas [11, 46-54]. As early noted by Reguera
et al. [21] the joint analysis of both infrared and Raman spectroscopy are required for study
the effect on the substitution for a series of mono- and di-substituted thioureas. Recently,
we have shown the complementarily of both techniques for the analysis of 1-(adamantane-
1-carbonyl)-3-(mono)- and 3,3-(di) Substituted) thioureas [55]. The 3N–6 = 45 normal
modes of vibration for compound I can be classified as 31 A´ in-plane modes and 14 A"
out-of-plane modes in the CS symmetry group.
In particular, the 1720-1050 cm–1 region of the Raman spectrum of compounds I
and II is shown in Figure 1. The close examination of the (C=O) stretching mode region
reveals a strong absorption at 1679 cm–1, with a counterpart in the Raman spectrum at 1680
cm–1 for compound I, whereas this mode appears shifted toward higher frequencies for
compound II, with values at 1697 cm–1 (IR) and 1693 cm–1 (Raman), as shown in Figure 1.
These values are in good agreement with those previously reported for related acyl
thioureas and 1-acyl-3,3-di-substituted thioureas [56]. The experimental values are well-
reproduced by the quantum chemical calculations, with computed (C=O) frequency values
of 1735 and 1760 cm–1 for I (A´ symmetry species) and II, respectively. The lower force
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constant of the (C=O) stretching found for compound I is associated with the
intramolecular N–H···O=C hydrogen bond.
Intense absorptions in the 1500-1600 cm–1 region due to the δ(N–H) deformation
modes are usually observed in the infrared and Raman spectra of thioureas [57], whereas
only one δ(N–H) band is expected for the 3,3-disubstituted species. The infrared spectra
show very strong and rather broad absorptions at around 1559 (1579 cm–1 Raman) and
1571 cm–1 (1587 cm–1 Raman) for I and II, respectively, in agreement with previous works
[58].
1700
1600
1500
1400
1300
1200
1100
Wavenumber (cm-1)
Figure 1. Selected region of the Raman spectra for the solid phase of compounds I and II.
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The ν(C=S) stretching mode of 1-acyl thiourea compounds is sensitive to the
presence of intermolecular interactions involving the C=S group [46] and it is found in the
600-800 cm–1 range [21, 25, 59, 60]. In accordance with the computed vibrational data, we
assigned this mode to the absorptions observed at 756 and 761 cm–1, with counterparts in
the Raman spectra at 753 and 755 cm–1, for compounds I (A´ symmetry species) and II,
respectively.
3-3. Thermal analysis
In order to know the thermal stability of the two compounds, the thermogravimetric study
(TG) was carried out. The analysis of TG curves indicates that both compounds point
o
toward a similar thermal behavior over the temperature range of 100–750 C, as shown in
Figure 2. Further it can be seen that nearly the total decomposition occur between the
temperature range from 100-300 ºC in both compounds. Compound I decomposes at
slightly higher temperature than compound II. This thermal stability is in agreement with
the nearly planar structure in I, favors in this way the donor acceptor interactions through
the intramolecular, N–H···O=C, hydrogen bonds, as will be discussed below. The first step
observed in the TG curve for compound I with a loss mass of 88.54%, is consistent with the
removal (fragmentation) of furoyl C(O)NC(S) moiety (calculated loss weight of 89.90%).
The second step observed in the TG curve with a loss mass of 9.76 %, is probably due to
the formation of NH3 as a result of a mechanisms simultaneous by a migrating of the NH
hydrogen atoms and the cleavage (homolysis) of C-N bonds (loss of weight calculated 9.98
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%). This thermal fragmentation mechanism is in agreement with that suggested previously
in the pyrolysis of related furoyl thioureas studied by mass spectrometry methods [61, 62].
TGA
mg
I
I
T (oC)
200.00
400.00
600.00
700.00
Figure 2. TGs curves for compounds I (red) and II (blue).
3.4. Molecular Structure
3.4.1- Theoretical Conformational and Natural Bond Orbital Analysis
A rich conformational landscape can be anticipated for the studied compounds. In
particular, several conformations can be adopted depending on the relative orientation of
the C=O and C=S double bonds of the acyl thiourea core. Based on previous reports [11,
12] the most relevant conformational changes are expected by differences in the relative
orientations around the C–N bond joining the amide and thioamide groups [18]. The
potential energy curve around the C–N bond for compounds I and II have been computed
at the B3LYP/6-31+G(d,p) level of approximation, allowing geometry optimizations with
the (CN–CN) dihedral angle varying from 0 to 360º in steps of 20º (Figure 3). For
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compound I, the most stable structure corresponds to the S form (see Scheme 1) with a
dihedral angle of 0º. In this conformation the C2=O1 and H–N1 groups form a pseudo 6-
membered ring, favoring an H-bond intramolecular interaction. For compound II, the
minimum occurs at a dihedral angle ca. 60º, with mutual synclinal orientation of the C1–N1
and C6–N2 bonds (see Figures 4 and 5 for atoms numbering).
The structures with (CN–CN)= 180º correspond in both cases to local maxima in
the potential energy curve, the energy barriers being ca. 15 and 11 kcal/mol, higher for
compound I. Two equivalent local minima are observed at (CN–CN) values of ca. 150 and
210 degrees. These conformers are located higher in energy and correspond to structures
with a nearly antiperiplanar orientation between the C–N and C–N bonds.
16
8
0
0
60
120
180
240
300
360
Dihedral angle (º)
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Figure 3. Calculated [B3LYP/6-31+G(d,p)] potential function for internal rotation around
the (CN–CN) dihedral angle of thioureas I (–■–) and II (–●–).
It is recognized that remote donor-acceptor orbital interactions can play a decisive
role on the peptide backbone conformation [63]. In particular, it has been proposed that
C=O···H–N hydrogen bonds [64] can be analyzed on the basis of the hyperconjugative
interaction involving the partial transfer of a lone pair of electrons of the oxygen atom to
the N–H antibonding orbital [65]. For benzenesulfonylamin acetamide, lpO→ *(N–H)
interaction values of ca. 9.5 kcal/mol were computed by using DFT methods [66].
We applied the Natural Bond Orbital population analysis for determining electron
donations in the studied compounds. For the compound I, the second-order perturbation
analysis of the Fock matrix [B3LYP/6-311++G(d,p) level of approximation] indicates a
lpO1→ *(N1–H) remote interaction, amounting to 8.1 kcal/mol for the S form. The
hyperconjugative interaction increases the electronic population of the σ*(N1–H) orbital
(0.031 e), as compared with that of the second N–H group [σ*(N2–H), with 0.010 e). For
compound II, without the possibility of forming intramolecular hydrogen bond, the σ*(N1–
H), shows an electronic population of 0.016 e.
The NBO analysis for the most stable conformers for compounds I and II,
respectively, indicates the presence of pure p-type [lpp(N)] lone pair orbitals on both amide
and thioamide nitrogen atoms. These orbitals display low electron occupancies (1.675 and
1.650 e and 1.703 and 1.597 e for the lpp(N1) and lpp(N2) of I and II, respectively)
16

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indicating their electron-donating capacity. The donor acceptor interactions reveal that
the lone pair orbital contributes to a strong resonance interactions with the carbonyl bond of
the 2-furoyl group lpp(N2) → π*(C2=O1), leading to the “amide resonance”. The computed
E(2) interaction values are 57.0 and 41.0 kcal/mol for I and II, respectively, in good
agreement with reported values for other 1-acyl thioureas [67].
The resonant forms also can involve the thioamide group and can be evaluated
within the donor→ acceptor approach, being the acceptor the π*(C=S) and *(C=S)
antibonding orbitals. For compound I, the lpp(N) → π*(C1=S) interactions are computed to
be 81.8 and 57.0 kcal/mol for the N1 and N2 nitrogen atoms, respectively. Lower values
are obtained for II, amounting 75.3 and 41.0 kcal/mol, respectively, probably because the
non-planar structure disfavors these interactions.
3.4.2- X-ray molecular structure
The molecular structure of crystalline 2-furoyl thiourea (I) is shown in Figure 4.
The compound I presents a nearly planar conformation, as a result, a pseudo six membered
(O1-C2-N2-C1-N1-H1a) ring is formed, stabilizing an “S”-shaped conformation type. As a
result the C=S and C=O groups are related to a maximum value of the O−S distance [68],
two donor sites rich in electron density and the trans geometry of the thiourea unit is
stabilized by intramolecular N1–H1a….O1 hydrogen bond, with N1···O1 distance of
2.676(2) Å and N1–H···O1 bond angle of 132º. The C1=S1 and O1–C1 bonds show a
typical double bond character with bond lengths of 1.672(2) Å and 1.223(2) Å,
respectively.
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Figure 4. The molecule structure of the compound I in the crystal. Ellipsoids represent
50% probability levels and dashed line indicates intramolecular hydrogen bond.
The Figure 5 shows the molecular structure of the compound II. It is non planar forming a
distorted -“S”-shaped conformation type, this conformation where the carbonyl and
thiourea groups are non-planar with mutual anticlinal (O=C/C=S = 112.8º) orientation of
the C=S and C=O double bonds (see Figure S5 in the Supporting Information) [68]. The
C1=S1 and O1=C1 bonds show a typical double bond character with bond lengths of
1.687(2) Å and 1.221(2) Å, respectively.
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Figure 5. Molecular structure of compound II. Displacement ellipsoids are drawn at the
50% probability level.
The amidic (O)C−N2−H and thioamide N2H−C(S) and (S)C−N1 bonds for I and
(O)C−N1−H and thioamide N1H−C(S) and (S)C−N2 for II are both shorter than a C−N
single bond, typically ca. 1.472(5)Å. This fact indicates that these bonds have a pronounced
double bond character. It is deduced that these thiourea derivatives make up a multi-
electron conjugated π bond, in agreement with the NBO results discussed above. Other
selected geometric parameters (Table 2) are between the ranges obtained for similar
compounds [69].
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Table 2. Selected bond distances (Å) for compounds I and II.
Compound I
S–C1
O2–C3
N1–C1
N2–C2
1.672(2)
1.371(2)
O1–C2
O2–C6
N2–C1
C2–C3
1.223(2)
1.352(2)
1.390(2)
1.455(2)
1.310(2)
1.386(2)
Compound II
1.687(2)
S–C6
O1–C1
O2–C5
N1–C6
N2–C7
C1–C2
1.221(2)
1.365(2)
1.404(2)
1.467(2)
1.464(2)
O2–C2
N1–C1
N2–C6
N2–C8
1.372(2)
1.387(2)
1.321(2)
1.466(2)
3.5-Crystal packing and Topology analysis of the electron densities
Since many of the more relevant intra and intermolecular interactions involve
hydrogen atoms, their positions in the crystal were optimized at the B3LYP/6-31G(d,p)
level, keeping fixed at their crystallographic values the heavy atom positions and cell
parameters. The electron density topology was analyzed and the values of the electron
density and positive principal curvature of the Laplacian at the corresponding (3,-1) critical
point were used as indicators of the interaction strength. Topological parameters of the
predominant intermolecular interactions present in the crystal structures of I and II are
reported in Tables 3 and 4, respectively.
In compound I, the basic crystal substructures are the centrosymmetric molecular
pairs involving, each, a pair of N–H∙∙∙S=C interactions with one of the hydrogen atom in
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the amino group as donor (I in Table 4), these being the most relevant from a topological
2
view point. This pair can be classified as an R2 (8) motif forming a pseudo eight-membered
ring, as shown in Figure S6 (Supporting Information). In the structure of I the H1B···S is
separated by 2.622 Å.
The crystal structure of I, however, can be better described in terms of the infinite
chains expanding in c axis direction (see Fig. 6.a and Table 3), along which molecules are
linked each other mainly through four interactions. The two strongest interactions link the
carbonyl oxygen atom with the amide hydrogen atom and with a hydrogen atom of the
furoyl ring (II and III in Figure 6 and Table 3). The other two interactions link an amino
hydrogen atom with a sulfur atom (IV) and a hydrogen atom of the furoyl group with the
oxygen atom also from a furoyl ring (V). Chains, in turn, are linked each other through the
above mentioned N–H∙∙∙S interactions and the HR∙∙∙S ones (VI). Alternation in the molecule
orientation along a chain (see Fig. 6.b) ensures the main three dimensional interaction
network is thus completed.
Table 3. Topological parameters (atomic units) of the close shell intermolecular (3,-1)
critical points (electron density (ρ), Laplacian (2ρ) and positive curvature (3)) and
geometrical parameters (Å and °) of the interactions used in the structure description of
compound I.
2ρ
3
D-H∙∙∙O/S/N
164.8
ρ
dH∙∙∙O/S/N
2.461
2.185
2.339
2.744
2.472
I
S∙∙∙H2N (i)
0.0175
0.0130
0.0126
0.0100
0.0087
0.0400
0.0444
0.0380
0.0332
0.0312
0.0755
0.0725
0.0642
0.0490
0.0478
II C=O∙∙∙H-N (ii)
III C=O∙∙∙HR (iii)
IV NH2∙∙∙S (iv)
168.6
151.1
125.6
V
OR∙∙∙HR (v)
140.2
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VI HR∙∙∙S (vi)
0.0076
0.0268
0.0388
2.768
159.2
a
Atom or group belonging to the reference molecule on the left of the interaction symbol.
Between parenthesis symmetry operation generating the neighbor molecule (i: -1-x,1-y,-z;
ii: x,1/2-y,1/2+z; iii: x,1/2-y,1/2+z; iv: -1-x,1-y,-z; v: x,1/2-y,1/2+z; vi: 1-x,1/2-y,1/2+z)
V
III
VI
II
c
IV
I
I
a
 
b
 
Figure 6. (a) Two chains view along b axis direction, in the compound I. (b) Six chains
view along c axis direction.
In compound II, the basic substructures are the centrosymmetric molecular pairs
involving, each, a pair of N–H∙∙∙S interactions (I in Table 4 and Fig. 7). Linking of such
pairs through C-H∙∙∙O interactions (III) involving methyl groups and acting in almost
perpendicular directions (see Fig. 7 a), give rise to molecular layers parallel to [1,0,2]. The
main three dimensional interaction network is completed by three interactions that link
layers with each other (see Table 4 and Fig. 7b). Two of them involve carbonyl hydrogen
atoms, a ring hydrogen atom (II) and a methyl hydrogen atom (IV) of the reference
molecule being the donors. The remaining one is a H∙∙∙S interaction (V).
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Table 4. Topological parameters (atomic units) of the (3,-1) critical points (electron density
(ρ), Laplacian (2ρ) and positive curvature (3)) and geometrical parameters (Å and °) of
the intermolecular interactions used in the structure description of compound II.
2ρ
3
D–H∙∙∙O/S/N
157.4
ρ
dH∙∙∙O/S/N
2.425
2.300
2.431
2.463
2.850
I
N–H∙∙∙S (i)
0.0188 0.0427
0.0116 0.0440
0.0104 0.0326
0.0095 0.0304
0.0085 0.0242
0.0810
0.0671
0.0534
0.0494
0.0378
II HR∙∙∙O=C (ii)
III CH3∙∙∙O=C (iii)
IV CH3∙∙∙O=C (iv)
136.8
150.5
157.79
159.7
V
HR∙∙∙S (v)
a Atom or group belonging to the reference molecule on the left of the interaction symbol.
Between parenthesis symmetry operation generating the neighbor molecule (i: 2-x,-y,-z; ii:
2-x,1/2+y,1/2-z; iii: 1-x,-1/2+y,1/2-z; iv: 2-x,-1/2+y,1/2-z; v: 1-x,-y,-z).
II
III
V
III
IV
b
 
a
 
Figure 7. (a) Layer view along a normal to [1,0,2]. (b) Two layers view along b axis
direction in the compound II.
3.6- Hirshfeld surface analysis
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Intermolecular contacts were also explored using both Hirshfeld surfaces and
fingerprint plots. In recent years, many research groups have used Hirshfeld surfaces [70,
71] and their two-dimensional fingerprints as an important tool to visualize and analyze
structural properties in relation to packing patterns [72], including those observed in
thiourea compounds [73, 74]. The intermolecular interactions of I and II were analyzed
using the Hirshfeld surface and the corresponding two-dimensional fingerprint plots [75]
are shown in the Figure 8.
The 3D dnorm Hirshfeld surfaces for I and II are represented in the Figure 8A, in
which the value of dnorm can be negative, positive or zero, when intermolecular contacts are
shorter, longer or equal to van der Waals (vdW) radii, respectively. The dnorm values were
mapped onto the Hirshfeld surface using a color gradient from blue to red indicates that
region able to perform intermolecular interactions. Red regions represent closer contacts
and a negative dnorm value, while blue regions represent longer contacts and a positive dnorm
value. In the surface, white regions represent the distance of contacts equal to exactly the
vdW separation with a dnorm value of zero. As can be seen in the Hirshfeld surfaces of the
compounds I and II the most intense red regions occur near to C=S and N–H groups, due to
bifurcate N–H···S hydrogen bonds present in both structures (see Figure S6 in the
Supporting Information). The compound I also exhibits red regions close to both oxygen
atoms of carbonyl and furoyl groups, as a result of N-H∙∙∙O and C-H∙∙∙O hydrogen bonds,
respectively, such as illustrated in the Figure 6a and discussed in the crystal packing
analysis. Differently, when we look at to Hirshfeld surface of the compound II, it is
observed that the oxygen atom of the furoyl group is not involved in any close
intermolecular contact, resulting in a white-to-blue gradient color in the Hirshfeld surface.
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Meanwhile the less intense red color gradient in II is observed on oxygen atom of the
carbonyl, because this group is involved in a non-classical C-H∙∙∙O hydrogen bond, such as
represented in Table 4 and Figure 7.
The fingerprint plots of the two molecules show the presence of S···H, O···H and
H···H intermolecular contacts (Figure 8B). The relative contribution of the main
intermolecular contacts present in each compound is listed in the Table S3 (Supporting
Information). The biggest contribution includes hydrophobic intermolecular contacts
(H···H, C···H and C···C). In addition, the hydrogen bonding (S···H and O···H) form well
defined contacts as represented in the Figure 8.C-D, acting as driving forces to stabilize the
crystal packing. Therefore, the hydrophobic intermolecular contacts together with the N–
H···S hydrogen bonds provide forces for self-assembly in the compounds.
(A) Hirshfeld surfaces
(B) Full fingerprint plot
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(C) S···H
(D) O···H
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(E) H···H
Figure 8. Hirshfeld surfaces (A) and fingerprint plots (B-E) for compounds I (left) and II
(right). The full fingerprint is represented in (B), and graphics C, D and E depict the S···H,
O···H and H···H intermolecular contacts, respectively.
4. Conclusions
Two 2-furoyl thiourea derivatives (I and II) were prepared and their structural and
spectroscopic properties have been determined. Our results clearly show that the
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conformation of the central acyl-thiourea [–C(O)NHC(S)N<] moiety depends on the
substitution at the nitrogen atom. Thus, the simplest 2-furoyl thiourea (I) adopts a planar
structure with the C=O and C=S double bonds mutually oriented in a pseudo-antiperiplanar
arrange, favoring a strong C=O···H–N intramolecular hydrogen bond. The same
conformation was very recently found in the crystal of the mono-substituted 3-phenyl
thiourea [76]. However, di-methylation of the –NH2 group leads to a different conformation
of the thiourea group: planarity is absent in compound II and anticlinal orientation of the
2
C=S and C=O double bonds is observed. Inversion dimers with an R2 (8) ring motif are
observed for I and II, a supramolecular synthon that is assisted by strong N–H···S=C
hydrogen bonds, as characterized by topological grounds and Hirshfeld surface analysis.
Acknowledgments
DBS, ACF and MFE are member of the Carrera del Investigador of CONICET (República
Argentina). The Argentinean authors thank to the Consejo Nacional de Investigaciones
Científicas y Técnicas (CONICET), the ANPCYT (PICT-2013-2130) and to the Facultad
de Ciencias Exactas, Universidad Nacional de La Plata for financial support. This work was
supported by CAPES (Project Oficio/CSS/CGCI/23038009487/2011-25/DRI/CAPES,
AUX CAPES-MES-Cuba, 339/2011), of Brazil. MFE also thanks Prof. Romano
(CEQUINOR) for helping measuring the Raman spectra.
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Supporting Information
Cartesian coordinates of optimized structures [B3LYP/6-311++G(d,p)] for compounds I
and II are given in Tables S1 and S2, respectively. In Table S3 the relative contribution to
the Hirshfeld surfaces of the important intermolecular contacts present in each compound, I
1
13
and II are given. H and C NMR spectra are given in Figures S1-S4. Conformations of
molecules of compound I are shown in Figure S5 and centrosymmetric dimer the studied
compounds are shown in Figure S6.
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