An intramolecular 1,5-chalcogen bond on the conformational preference of carbonyl thiocarbamate species

Article abstract of DOI:10.1039/c9nj06417f

Two closely related compounds, namely, O-methyl (4-fluorobenzoyl)carbamothioate (I) and O-methyl (4-methylbenzoyl)carbamothioate (II) were prepared in good yields by the reaction of the corresponding benzoyl isothiocyanates and methanol. The structural an

Full text of DOI:10.1039/c9nj06417f

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DOI: 10.1039/C9NJ06417F.
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Intramolecular 1,5-Chalcogen Bond on the Conformational Preference of
Carbonyl Thiocarbamate Species
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c, d
Pervaiz Ali Channar,a Aamer Saeed,a* Fayaz Ali Larik,a Ulrich Flörke,b Hesham El-Seedi,
Lucas S. Rodríguez Pirani,e Mauricio F. Erbene,*
a Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan.
b
Department Chemie, Fakultät für Naturwissenschaften, Universität Paderborn,
Warburgerstrasse 100, D-33098 Paderborn, Germany.
c
International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang
212013, China.
d Al-Rayan Research and Innovation Center, Al-Rayan Colleges, Medina, 42541, Saudi Arabia.
e
CEQUINOR (UNLP, CONICET-CCT La Plata), Departamento de Química, Facultad de
Ciencias Exactas, Universidad Nacional de La Plata, Boulevard 120 N° 1465. La Plata,
República Argentina.
*Corresponding authors:
(AS) E-mail: aamersaeed@yahoo.com, Tel: +92 51 9064-2128, Fax: +92 51 9064 2241.
(MFE) E-mail: erben@quimica.unlp.edu.ar, Tel/Fax: +54 221 445 4393.
1

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Abstract
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Two closely related compounds, i.e. O-methyl (4-fluorobenzoyl) carbamothioate (I) and O-
methyl (4-methylbenzoyl) carbamothioate (II) were prepared in good yields by the reaction of
the corresponding benzoyl isothiocyanates and methanol. Structural and conformational
properties of both compounds have been analyzed using a combined approach including single-
crystal X-ray diffraction and quantum chemical calculations. A rich conformational landscape is
envisaged for the vacuum isolated species around the central carbamothioate group, with the
pseudo-anti conformation (C=O and C=S double bonds pointing toward opposite orientations)
being the most stable form. The X-ray molecular structure shows the presence of this form in the
crystalline phase for both compounds. The occurrence of a 1,5-O···O intramolecular short
distance is observed, suggesting the relevance of chalcogen···chalcogen interactions in the
conformational preference. Natural Bond Orbital population analysis and quantum chemical
calculations through isodesmic reaction scheme are applied for better understanding of the
conformational preference and the nature of the O···O intramolecular interactions. The quantum
theory of atoms in molecules has been also used to examine the electronic densities around the
S(5) pseudo ring formed through the intramolecular interaction in the carbamothioate moiety.
Furthermore, vibrational features were analyzed by measuring the infrared and Raman spectra.
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1-
Introduction
Carbamothioates with general formula RNHC(S)OR´ are the esters of thioamides and
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versatile building blocks for several heterocyclic systems and exhibit a wide range of biological
activities.1, 2 The carbamothioate moiety is an integral part of antifungal drugs such as tolnaflate
and tolciclate and also some new anti-infective and human 5-HT2 receptor binding natural and
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semisynthetic compounds from Smenospongia aurea
TRPV1 antogonists.5 In addition, S-
propyl N,N-dipropylthiocarbamate, also known as vernolate, has been used to select
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thiocarbamate-tolerant tobacco cell lines and employed to deliver carbonyl sulfide (COS),
which is quickly converted to H2S in the inverse-electron demand Diels–Alder (IEDDA) click
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reaction between a thiocarbamate-functionalized trans-cyclooctene and a tetrazine (Figure 1).
Moreover, carbamothioates haven employed in the synthesis of oxazolidinones,
oxazolidinthiones, imidazolidinthiones, and imidazolidinones.8, 9
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Figure 1. Selected examples of carbamothioate compounds with biological applications.
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When the thioamide group >NC(S)O- is substituted with a carbonyl group, carbonyl
thiocarbamate compounds are formed, with general formula RC(O)NHC(S)OR2. With regard to
conformational preferences, the pseudo syn or anti configurations (Scheme 1) can be adopted
depending on the relative orientation of thiocarbonyl moiety with respect to the amide group.
Interestingly, X-ray crystallographic structures have been reported showing the occurrence of
both confirmations depending on specific inter- or/and intramolecular interactions in the crystal
packing.10-13
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R
S
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C
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C
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O
R
N
H
R
S
N
H
syn
anti
Scheme 1. Possible conformations around the thioamide moiety for carbonyl thiocarbamates
compounds.
The nonbonding interactions present in the crystal packing around the molecules are important
factors that directly influence in one or another orientation. It is well know that these interaction
are divided into strong, moderate and weak, since the hydrogen bond a classical example of the
strong, specific and highly directional interaction.14 In absence of the classical hydrogen bond,
weak and moderate interactions type of C-H···O,14 C-H···N,15 C-H···F,16 C-H···X (X=
halogen),13 and π-π,17 are important to determine the most stable conformation in the crystal. For
example, in the O-isopropyl-N-(2-furoyl) thiocarbamate there are two intramolecular hydrogen
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interactions that determine the anti conformation adopted around carbonyl thiocarbamate
moiety.12, 18 Also, the intermolecular N-H···S=C hydrogen bond interaction is responsible for the
same orientation adopted in the O-ethyl-N-(ethoxycarbonyl) thiocarbamate.19-21 However, others
molecules of the same family, as O-alkyl-N-benzoyl thiocarbamates, prefer the syn orientation
around the central thioamide moiety. Similarly, the crystal structure of O-butyl-N-benzoyl
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thiocarbamate shows the occurrence of three intramolecular hydrogen bonds that stabilize the
syn structure. In the related O-ethyl-N-benzoyl thiocarbamate,10 two intermolecular hydrogen
bond interactions of the type N-H···O and C-H···O bonds, are responsible for the syn orientation
adopted in the crystal. Even more complex molecules as O,O´-diethyl N,N´-(p-phenylene-
dicarbonyl)bis(thiocarbamate) shows a cis-S,O orientation, with the two C=S and C=O groups
anti relative to each other. 22, 23
Less attention, however, has received the effect exerted by chalcogen-chalcogen interactions 24 in
the conformational properties of carbonyl thiocarbamate compounds. These kind of interactions
refers to highly directional attractive interaction between the chalcogen (or halogen) atom in R-
X, and a negative site (B= lone pairs of Lewis base or electrons of the π system).25-27 Moreover,
these interactions are stabilized at certain bond angles (R–X···B), depending of electrophilic or
nucleophilic character of the interactions. Strong nucleophilic centers are expected to form an
angle close to 180º, whereas electrophilic centers promote R–X···B angles between 90-120º. In
this line, R–X···B intermolecular interactions have been reported to be a decisive factor in the
stabilization of certain configuration adopted in the crystal packing of organo-halogen and
organo-chalcogen species.28-30 In particular, intramolecular S···O chalcogen bonding and its
effects on the conformational equilibrium were examined for sulfamethizole31 and
acetazoleamide.32 The occurrence of S···O interactions were also for determine the geometries of
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molecules containing a ether substituted phenyl ring joined to the trigonal bipyramidal SF3
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moeity.
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In this contribution, and with the aim of deepening conformational studies around carbonyl
thiocarbamate moiety, two close related thiocarbamate compounds have been synthetized by
using the isothiocyanate route and the X-ray structures have been determined for O-methyl (4-
fluorobenzoyl) carbamothioate (I) and O-methyl (4-methylbenzoyl) carbamothioate (II). The
electron-withdrawing and -donor fluoro and methyl groups, respectively, have been selected as
4-substituents in the benzoyl ring. The conformational landscape has been determined in
combination with quantum chemical calculations and interpreted in terms of chalcogen-
chalcogen interactions in the frame of the Natural Bond Orbital Analysis (NBO),34 Atoms in
Molecules (AIM)35 and isodesmic reaction schemes.
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2- Experimental
2.1- General procedure for synthesis of carbamothioates
4-Methylbenzoic acid, 4-flourobenzoic acid and thionyl chloride were purchased from Aldrich.
Analytical grade acetone and methanol (E. Merck) were dried and freshly distilled prior to use.
Reactions were protected from moisture with dry tubes. Acetone and MeOH were freshly
distilled and dried before use. All volatiles were removed under reduced pressure.
4-Methyl and 4-fluoro substituted benzoic acid (1.0 mmol) was placed in a 100 ml two neck
round bottom flask, fitted with a reflux condenser and a gas trap. Thionyl chloride (1.2 mmol)
was added, followed by two drops wise addition of dry DMF. The reaction mixture was heated
under reflux for 1h until the formation of the acid chloride. To a stirred solution of potassium
thiocyanate (1.0 mmol) in 20 ml dry acetone, placed in a 250 ml two necked round bottom flask
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fitted with a reflux condenser, freshly prepared 4-methyl or 4-fluoro benzoyl chloride (1.0 mmol)
was added dropwise and the mixture was refluxed for 30 min. After the initial reaction has
subsided, dry methanol (20 ml) was added slowly and the reaction mixture stirred for 20 min
under reflux. The progress of the reaction was monitored by thin layer chromatography using
solvent system n-hexane-ethyl acetate (8:2). After the completion, the reaction mixture was
poured into crushed ice. The precipitated solids were filtered off, washed well with cold distilled
water, dried and recrystallized from ethanol to afford carbamothioates I and II in high purity and
good yields.
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Scheme 2. Synthetic route for carbamothioates I and II.
o
O-Methyl (4-fluorobenzoyl)carbamothioate (I) :Yield (88%); m.p 223-224 C; Rf: 0.61 (n-
hexane: ethyl acetate, 1:4); FTIR (cm-1): 3348 (NH), 3030 (sp2 CH), 2995 (sp3 CH), 1680 (C=O),
1489,1587 (Ar-C=C), 1325; 1H NMR (300 MHz, DMSO-d6) δ (ppm): (8.4 bs, NH), 7.95 (d, 2H,
Ar-H), 7.09 (d, 2H, Ar-H), 3.85 (3H, s), 2.54 (1H, NH); 13C NMR (75MHz, DMSO-d6) (ppm):
191.2 (C=S), 166.9 (C=O), 164.4 , 132.9, 130.5, 116.4, 58.9 (O-CH3).
o
O-Methyl (4-methylbenzoyl)carbamothioate (II): Yield (86%); m.p 219-220 C; Rf: 0.51 (n-
hexane: ethyl acetate,1:4); FTIR (cm-1): 3188 (NH), 3028 (sp2 CH), 2950 (sp3 CH), 1693 (C=0),
1
1599 (Ar-C=C), 1335; H NMR (300 MHz, DMSO-d6) δ (ppm): (8.1 bs, NH), 7.92 (d, 2H Ar-
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H), 7.25 (d, 2H Ar-H), 3.62 (3H, s), 2.5 (1H, s CH3); C NMR (75MHz, DMSO-d6) δ(ppm):
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194.1 (C=S), 168.2 (C=O),162.1 ,144.2 , 133.3 , 125.6, 58.1 (O-CH3), 28.2 (CH3).
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2.2- Instrumentation. The progress of reaction was monitored by TLC using commercial glass
backed thin layer chromatography (TLC) plates (Merck Kieselgel 60 F 254). The plates were
observed under UV light at 254 and 365 nm.
FTIR spectra were recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer with a Pike
Miracle Ge ATR accessory (Pakistan). Solid-phase (in KBr pellets) infrared spectra were
recorded with a resolution of 2 cm–1 in the 4000-400 cm–1 range on a Bruker EQUINOX 55
FTIR spectrometer (Argentina). Raman spectra were recorded using a Horiba Jobin Yvon
T64000 Raman spectrometer equipped with a liquid N2-cooled back-thinned CCD detector.
Spectra were recorded as the co-addition of up to 16 individual spectra with CCD exposure times
of 10-20s each. 1H NMR spectra were recorded on a Bruker Avance at 300 MHz while 13C NMR
spectra were at 75 MHz, respectively).
2.3- Crystal structure determination. The intensity data were collected using a Bruker
SMART APEX CCD diffractometer with graphite monochromated MoKα radiation
(λ = 0.71073 Å) at T = 130(2) K. 8674 reflections collected 1.9 >  > 27.9°; 2240 independent
reflections I > 2(I), Rint = 0.022. Structure solution by direct methods, full-matrix least squares
refinement based on F2 and 128 parameters.36 All but H-atoms were refined anisotropically,
hydrogen atoms were clearly located from difference Fourier maps, refined at idealized positions
riding on the carbon atoms with isotropic displacement parameters Uiso(H) = 1.2Ueq(C/N) or
1.5Ueq(CH3) and C-H 0.95- 0.98 Å and N-H 0.88 Å. Refinement converged at R1 = 0.033
[I > 2σ(I)], wR2 = 0.090 [all data] and S = 1.04; min./max. F -0.21 / 0.38 e/ų.
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Crystal data for compound I: C9H8FNO2S, Mr = 213.2, colourless crystal, size 0.32 x 0.22 x
0.15 mm³, monoclinic space group P 21/c with Z = 4, a = 11.7032(18), b = 8.7287(13), c =
9.8686(15) Å, = 111.415(3)°, V = 938.5(2) ų; Dc = 1.509 Mg/m³,  = 0.331 mm-1, F(000) =
440.
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Crystal data for compound II: C10H11NO2S, Mr = 209.3, colourless crystal, size 0.45 x 0.22 x
0.18 mm³, monoclinic space group P 21/c with Z = 4, a = 11.7767(16), b = 9.1218(13), c =
9.7623(14) Å, = 106.287(3)°, V = 1006.6(2) ų; Dc = 1.381 Mg/m³,  = 0.293 mm-1, F(000) =
440. Data collection as for 1, 9276 reflections collected 1.8 >  > 27.9°; 2400 independent
reflections I > 2(I), Rint = 0.022. Structure solution and refinement as for 1, refinement
converged at R1 = 0.034 [I > 2σ(I)], wR2 = 0.098 [all data] and S = 1.02; min./max. F -0.19 /
0.36 e/ų.
Crystallographic data for the structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publications (CCDC-1437471 and
CCDC-1437472 codes for compounds I and II, respectively). Copies of available material can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by e-mailing
data_request@ccdc.cam.ac.uk, or contacting the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
2.4- Computational details. Quantum chemical calculations have been performed with the
Gaussian 03 program package.37 Geometries optimization and frequencies calculations for the
stable conformers were performed using B3LYP method and employing standard basis sets up to
the extended valence triple-ξ basis set augmented with diffuse and polarization functions for all
atoms (6-311++G**). The natural population analysis and second-order donor → acceptor
interaction energies were computed through the NBO analysis implemented in the Gaussian 03
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program.38 The topology of the resulting electron density was analyzed with MULTIWFN
version 3.639 program.
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3.
Results and Discussion
3.1
Synthesis and characterization
Carbamothioates I and II were prepared by slight modification of Falack and Plutin
method involving conversion of the carboxylic acids into corresponding acid chlorides.40, 41 The
corresponding aroyl isothiocyanates were obtained by reaction of acid chlorides with potassium
thiocyanate in anhydrous acetone. Reaction of the aroyl isothiocyanates with anhydrous
methanol under reflux afforded the desired products in good yields.
The synthesized compounds were characterized by FTIR, Raman, 1H NMR and 13C NMR
1
spectroscopy. In the H NMR, the characteristic peak of N-H protons of carbamothioates
appeared at 8.1-8.3 ppm value, deshielded due to flanked by carbonyl and thiocarbonyl groups.
The characteristic two doublets for 1, 4-di-substituted aromatic protons can be observed in the
13
region 7.09-7.92 ppm, besides the singlet of three methyl protons around 3.6-3.8 ppm. The C-
NMR also confirmed the presence of C=S and C=O groups, the C=S signal is relatively
deshielded respect to C=O, possibly due to the heavy atom effect. The aromatic carbons
appeared in the region 130-140 ppm values, with the ipso carbon appearing as a low intensity
signals. The singlet signals around 58 ppm confirm the presence of methoxy group. The FTIR
and Raman spectra are analyzed in the Vibrational Spectroscopy Section below.
3.2. Quantum Chemical Calculation
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Different conformers are expected for the title species, depending on the dihedral angle values
adopted around carbonyl thiocarbamate moiety (-C(O)NHC(S)C-). The internal rotations around
δ(OC-NC), δ(CN-CS) and δ(SC-OC) dihedral angles have been explored at the B3LYP/6-
311++G** levels of approximations with the primary aim to find the most stable conformations
(Figure S5, ESI material). The curves indicate the presence of minima around the syn (δ= 0º) and
anti (δ= 180º) orientations for the three dihedral angles and the geometry of the (2)3=8 expected
conformers were further optimized and the harmonic frequencies calculated. The most stable
conformer adopts dihedral angles values of δ(OC-NC)~ 7º (syn), δ(CN-CS)~ 170º (anti) and
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δ(SC-OC)~ 2º (syn), hereafter named as syn-anti-syn. Figure 2 shows the molecular structure of
the four most stable rotamers and Table 1 lists the relative energies (Eº) and Gibbs free energies
(Gº) for the eight conformations computed for both compounds. It is interesting to note that the
same trend in the conformational preference is observed for compounds I and II, with similar
energy differences between the conformers. The most stable conformation and the second stable
one differ in energy (∆E0) by 1.45 and 1.17 kcal/mol, respectively. The syn-syn-syn conformer is
located higher in energy by 2.01 and 1.97 kcal/mol for compounds I and II, respectively.
In the most stable conformation, the C=O and C=S double bonds point toward opposite
directions, decreasing the dipole-dipole bond interaction. Moreover, it is worth noticing that 1-5-
chalcogen-chalcogen interactions of the type O···O and O···S are favored for both syn-anti-syn
and syn-syn-syn conformations, respectively. Indeed, attractive interactions can be envisaged
since relative short distances are computed between the C=O and the methoxy groups, as well as
between the C=O and C=S double bonds, with 1-5-chalcogen···chalcogen distances, O···O and
O···S, of ca. 2.71 and 3.13 Å for syn-anti-syn and syn-syn-syn conformers, respectively, for
compounds I and II.
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Compound I
Compound II
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syn-anti-syn
syn-anti-syn
anti-anti-syn
anti-anti-syn
syn-syn-syn
syn-syn-syn
anti-syn-syn
anti-syn-syn
Figure 2. Four most stable conformers optimized at the B3LYP/6-311++G** level of
approximation for compounds I and II.
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Table 1. Calculated (B3LYP/6-311++G**) relative energies (kcal/mol) for stable
conformers of compounds I and II.
8
9
syn-anti- anti-
syn-syn- anti-syn- syn-anti- anti-anti- syn-syn- anti-syn-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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26
27
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29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
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53
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60
syn
anti-syn syn
syn
anti
anti
anti
anti
Compound I
∆E° 0.00a
∆G° 0.00 b
1.45
2.00
2.01
1.88
2.80
3.47
7.08
7.08
10.90
11.53
11.90
12.17
11.06
11.72
Compound II
∆E° 0.00 c
∆G° 0.00 d
1.17
1.35
1.97
2.04
2.36
2.61
7.25
7.54
11.08
11.35
12.07
12.07
10.74
10.98
Calculated energy values, in Hartree: E°= -991.090410, bG°= -991.134353, cE°= -1051.065611,
a
dG°= -1051.107350
Different approaches exist for estimating intramolecular interaction energies and thus elucidate
the contribution to the global stability of a certain conformation. One computational method
involves the application of an isodesmic reaction scheme, through which the breaking/formation
bond would lead to reveal the specific intramolecular interactions that stabilize the conformation
adopted.42, 43 For the studied compounds, the enthalpies of the intramolecular interactions are
assessed by comparing the energies of the different conformers, which can be related with the
enthalpy change of the specific isodesmic reaction. Thus, Scheme 3 shows the selected
isodesmic reactions for the hypothetical formation of the studied species. Table S1 (Supporting
Information) lists the computed values for the thermochemistry associated with these reactions.
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8
CH3
CH3
S
O
CH3
CH3
O
O
C
O
C
C
S
R
C
+
C
R
+
C
N
H
S
H2N
N
H
H2N
S
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60
Scheme 3. Isodesmic reactions for the hypothetical formation of the title compounds.
Since minor intramolecular interactions can be supposed for the selected methylated reagents, it
is hypothesized that the difference in the reaction enthalpy is associated with intramolecular
interactions in the products. In particular, 1,5-O···O, 1,4-O···H and 1,5-O···S intermolecular
interactions occur in the syn-anti-syn, anti-anti-syn, and syn-syn-syn forms, respectively. The
quantum chemical calculations at the B3LYP/6-311++G** level of approximation show a
qualitative agreement between the computed reaction enthalpy for the isodesmic reactions and
the relative energy for each conformation. The 1,5-O···O is the most favorable interaction,
amounting ca. 3 kcal/mol for both compounds.
3.3. Vibrational spectroscopy
The vibrational analysis for the benzoyl thiocarbamates in the solid phase has been performed
using infrared and Raman spectroscopy (FTIR and FT-Raman spectra in the solid phase are
shown in Figures S6-8 and collected in Tables S2 and S3 in ESI material). Harmonic frequencies
were computed at the B3LYP/6-311++G** level of approximation and the assignment of the
bands has been carried out by comparison with similar molecules already reported.11, 12, 20, 44, 45
Table 2 shows the main experimental and theoretical vibrational frequencies of the –
C(O)N(H)C(S)O- moiety, together with tentative mode assignment. The characteristic stretching
[ν(N-H)] and in-plane deformation mode [δ(N-H)] vibrational mode associated with the N-H
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group are observed at 3277 cm-1/3188 cm-1 and at 1503/1530 cm-1 for compounds I and II,
respectively, in very good agreement with previous report in similar carbonyl thiocarbamates
species 45.
The carbonyl stretching mode ν(C=O) is observed at similar frequencies 1681 cm-1 and 1693 cm-
1, for I and II, respectively. These values are in good agreement with the expected values for
carbonyl thiocarbamates,11, 12, 45 but the values are lower than those computed at the B3LYP/6-
311++G** for the isolated species, that amount up 1774 cm-1 and 1772 cm-1, respectively. The
low frequency values found in the solid phase suggest that the carbonyl bond experience strong
intermolecular and intramolecular interactions in the crystal.
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Instead it, the bands corresponding to the thiocarbonyl stretching mode, ν(C=S), have been
observed at 1261 and 1252 cm-1 for I and II compounds, respectively, in very good agreement
with the theoretical calculations and experimental reports, which reaffirms that the carbonyl
group presents strong interactions with its environment.
The very strong bands observed at 1223 and 1226 cm-1 for I and II, respectively, were assigned
to combinations between ν(C-O) and δ (N-H) vibrational mode, in according with the theoretical
calculations. The out-of-plane deformation modes (δoop) correspond to the CO and NH bonds
were observed at 757 and 667 cm-1 for compound I, and at 756 and 687 cm-1 for compound II,
respectively. These results are in very good agreement with theoretical calculations and previous
experimental reports for related thiocarbamate species.20
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Table 2. Experimental and theoretical (B3LYP/6-311++G**) vibration frequencies
for the –C(O)N(H)C(S)O- moiety of compounds I and II.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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Experimental
Calculated
Compound I Compound II Compound I Compound II Assignment
3349 m
1681 s
1503 s
1326 s
1261 m
1223 vs
966 s
3188 m
1693 s
1530 vs
1335 vs
1252 m
1226 vs
964 s
3623 (8)
1774 (70)
1529 (97)
1327 (100)
1266 (49)
1227 (51)
1048 (28)
884 (11)
771 (10)
657 (8)
3624 (7)
1772 (60)
1531 (84)
1326 (100)
1267 (33)
1236(17)
1049 (23)
882 (6)
ν (N-H)
ν (C=O)
δ (N-H)
νas (N-C(S))
ν (C=S)
ν O-C(S) + δ (N-H)
νas (N-C(O))
δ (OC-N)
δoop (C=O)
δoop (NH)
836 s
841 s
757 vs
667 m
627 w
756 vs
687 m
619 m
759 (10)
661 (5)
631 (5)
635 (3)
δoop (C=S)
3.4. Structural analysis.
ORTEP drawings of the molecular structure of I and II are shown in Figure 3. A summary of the
key crystallographic information is given in Table S3. The main geometric parameters derived
from the structure refinement are shown in Table 3. Both O-methyl N-(4-substituted-benzoyl)
thiocarbamates here studied crystallize in the monoclinic space group P 21/c, and contain four
molecules in the unit cell.
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Figure 3. Molecular structure of compound I (left) and compound II (right), anisotropic
displacement ellipsoids are drawn at the 50% probability level.
The presence of only one conformer is observed in the crystal, with the C=O and the C=S double
bonds pointing toward mutual anti orientation. For both compounds, the carbonyl and metoxy
groups are in nearly planar with torsion angles of C8-N1-C1-O1 = -7.8(2)º and C1-N1-C8-O2 =
9.9(2)º, for compound I, and C9-N1-C1-O1 = 9.8(2)º and C1-N1-C9-O2 = -7.8(2)º, for
compound II. Both compounds present very similar conformations, as confirmed by comparing
the dihedral angles around the carbonyl thiocarbamate moiety, which adopts the same syn-anti-
syn orientation, in accordance with the theoretical calculations. The different substitution in the
phenyl ring is reflected in the twist of this thioamide group with respect to the aromatic ring,
with C3/7-C2-C1-N1 torsion angles of -21.4(2)° and 25.8(2)° for I and II, respectively.
It is important to note that the substitution on the phenyl group influences the conformation
adopted around C-N-C moiety. Thus, the most stable conformation found for the unsubstituted
“parent” compound, the N-(methoxy) methanethioylbenzamide,46 shows the carbonyl and the
thiocarbonyl groups on the same side of the molecule.
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As shown in Figure 4, six short intermolecular contacts can be found in the crystal packing of
both compounds. Table 4 lists the geometrical parameters describing these interactions. In both
cases, the strongest interaction corresponds to the O1···H1 hydrogen bond (symmetry code: x,-
1/2-y,-1/2+z and x,1/2-y,-1/2+z for compounds I and II, respectively). The O···H distances are
2.041 and 2.085 Å for compound I and II, respectively, which are considerably shorter than the
sum of the corresponding van der Waals radii (2.72 Å).
10
11
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60
Other non-bonding contacts are found in the crystal structures that can be classified as
“chalcogen bond”,29 “halogen bond”,47 and CH/π interactions.17 Although the F···F halogen
48, 49
bond is one of the most difficult non-bonding interaction that occur in a crystalline packing
a weak interaction between F···F (symmetry code: 1-x,-2-y,1-z) short contact is observed in
compound I, with a distance of 2.88 Å and an angle of 169.21º near the optimal directionality
(i.e. 180º) expected for the halogen bond. On the other hand, compound II presents a weak S···S
chalcogen···chalcogen bond, with a distance of 3.56 Å and an angle of 160.4º (symmetry code:
2-x,-y,2-z). Finally, CH/π interactions can be also observed between the methoxy groups (H9A
and H10C for compound I and II, respectively) and the respective aromatic rings. This type of
interaction plays an important role in various fields of the chemistry and biology sciences.17
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Figure 4. Short-contact intermolecular interactions for compound I (left) and compound II
5
6
(right).
7
8
9
10
11
12
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Table 3. Experimental (X-ray) and calculated (B3LYP/6-311++G**) geometric
parameters for compounds I and II.
Compound I
Compound II
Parameters
Exp.
Calc- Parameters
Exp.
Calc.
S(1)-C(8)
O(1)-C(1)
O(2)-C(8)
O(2)-C(9)
N(1)-C(8)
N(1)-C(1)
C(1)-C(2)
C(2)-C(3)
C(2)-C(7)
C(3)-C(4)
C(4)-C(5)
C(5)-C(6)
C(5)-F(1)
C(6)-C(7)
C(8)-O(2)-C(9)
C(8)-N(1)-C(1)
O(1)-C(1)-N(1)
O(1)-C(1)-C(2)
N(1)-C(1)-C(2)
C(3)-C(2)-C(7)
C(3)-C(2)-C(1)
C(7)-C(2)-C(1)
C(4)-C(3)-C(2)
C(5)-C(4)-C(3)
C(4)-C(5)-C(6)
C(4)-C(5)-F(1)
C(6)-C(5)-F(1)
C(7)-C(6)-C(5)
C(6)-C(7)-C(2)
O(2)-C(8)-N(1)
O(2)-C(8)-S(1)
N(1)-C(8)-S(1)
1.644(1) 1.660 S(1)-C(9)
1.643(1) 1.662
1.218(2) 1.209
1.319(2) 1.319
1.456(2) 1.438
1.388(2) 1.382
1.393(2) 1.410
1.488(2) 1.499
1.393(2) 1.398
1.397(2) 1.401
1.392(2) 1.393
1.389(2) 1.397
1.398(2) 1.402
1.506(2) 1.507
1.380(2) 1.386
117.9(1) 119.2
128.9(1) 130.4
123.0(1) 123.7
121.5(1) 122.6
115.5(1) 113.5
119.2(1) 118.7
123.9(1) 123.8
116.9(1) 117.4
119.9(1) 120.4
121.1(1) 121.1
118.7(1) 118.0
120.9(1) 121.3
120.4(1) 120.6
120.5(1) 121.1
120.7(1) 120.5
112.6(1) 112.5
126.6(1) 126.6
120.8(1) 120.8
1.214(2) 1.209 O(1)-C(1)
1.321(2) 1.318 O(2)-C(9)
1.453(2) 1.438 O(2)-C(10)
1.382(2) 1.384 N(1)-C(9)
1.386(2) 1.408 N(1)-C(1)
1.495(2) 1.500 C(1)-C(2)
1.398(2) 1.400 C(2)-C(3)
1.392(2) 1.400 C(2)-C(7)
1.383(2) 1.391 C(3)-C(4)
1.374(2) 1.386 C(4)-C(5)
1.377(2) 1.388 C(5)-C(6)
1.357(2) 1.350 C(5)-C(8)
1.389(2) 1.388 C(6)-C(7)
117.7(1) 119.2 C(9)-O(2)-C(10)
128.9(1) 130.2 C(9)-N(1)-C(1)
123.1(1) 123.9 O(1)-C(1)-N(1)
121.5(1) 122.3 O(1)-C(1)-C(2)
115.4(1) 113.6 N(1)-C(1)-C(2)
119.5(1) 119.1 C(3)-C(2)-C(7)
116.5(1) 123.6 C(3)-C(2)-C(1)
124.0(1) 117.1 C(7)-C(2)-C(1)
120.5(1) 120.6 C(4)-C(3)-C(2)
118.2(1) 118.4 C(5)-C(4)-C(3)
123.2(1) 122.4 C(4)-C(5)-C(6)
118.4(1) 118.7 C(4)-C(5)-C(8)
118.3(1) 118.7 C(6)-C(5)-C(8)
118.2(1) 118.4 C(7)-C(6)-C(5)
120.4(1) 120.7 C(6)-C(7)-C(2)
112.8(1) 112.4 O(2)-C(9)-N(1)
126.3(1) 126.7 O(2)-C(9)-S(1)
120.8(1) 120.7 N(1)-C(9)-S(1)
C(9)-O(2)-C(8)-S(1) 2.0(2)
1.8
C(10)-O(2)-C(9)-S(1) -3.0(2)
1.7
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C(9)-O(2)-C(8)-N(1) -177.6(1) -179.6 C(10)-O(2)-C(9)-N(1) 176.6(1) -179.6
O(1)-C(1)-N(1)-C(8) -7.8(2) 7.3 O(1)-C(1)-N(1)-C(9) 9.8(2) 7.1
C(2)-C(1)-N(1)-C(8) 173.7(1) -173.9 C(2)-C(1)-N(1)-C(9) -170.6(1) -174.1
C(1)-N(1)-C(8)-S(1) -169.8(1) -169.2 C(1)-N(1)-C(9)-S(1) 171.9(1) -170.4
C(1)-N(1)-C(8)-O(2) 9.90(2) 12.1 C(1)-N(1)-C(9)-O(2) -7.80(2) 10.8
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60
Figure 5 shows and Table 5 lists the most important intramolecular interactions, which are
relevant to explain the conformational preference adopted for both compounds. The strongest
intramolecular contact is the 1-5 chalcogen-chalcogen interaction between O1 and O2 with a
O1···O2 distance of 2.609 and 2.612 Å for compounds I and II, respectively, and an
approximate overlap of 14 %. The O1···O2–C9/10 angles amount 151.5 and 151.2º for
compounds I and II, respectively. This no-covalent intramolecular contact seems to be the key
factor controlling the configuration adopted around the central conjugated C-N-C moiety.
On the other hand, the syn conformation adopted around τ(CO-CS) dihedral angle is stabilized
by two intramolecular contacts between the sulfur atom and the hydrogen atoms of the methyl
group, generating orbital overlaps of ca. 4-7 %.
Figure 5. Intramolecular contacts for compounds I (left) and II (right) determined in the crystal.
Table 4. Intermolecular and intramolecular interactions for compounds I and II.
Distance (Å) Angle
Sum of the VdW % of Contact type
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9
(degree) radii (Å)
overlap
Intermolecular Contact
O1···H1
O1···H7
O1···H4
2.04
2.42
2.720
143.8
153.1
105.0
131.7
169.2
151.1
157.8
132.1
118.55
146.9
160.4
167.2
2.72
2.72
2.72
3.00
2.94
2.90
2.72
2.72
2.72
2.90
3.60
3.40
25.0
11.0
0
Hydrogen bond
Hydrogen bond
Hydrogen bond
Hydrogen bond
Halogen bond
CH/π interaction
Hydrogen bond
Hydrogen bond
Hydrogen bond
CH/π interaction
Chalcogen bond
H9B···S1 2.865
F1···F1 2.88
C6···H9A 2.785
4.50
2.04
3.96
23.3
11.1
1.58
7.24
0.97
2.64
10
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60
O1···H1
O1···H3
2.085
2.417
O2···H10 2.677
C4···H10 2.690
S1···S1
C8···C8
3.565
3.310
Intramolecular Contact
O1···O2 2.609
151.5
98.3
97.0
90.0
81.7
3.04
2.72
2.75
3.00
3.00
14.2
8.53
4.33
7.07
1.70
Chalcogen bond
Hydrogen bond
Hydrogen bond
Hydrogen bond
Hydrogen bond
O1···H3A 2.488
N1···H7A 2.631
S1···H9C 2.788
S1···H9A 2.949
O1···O2
2.612
151.2
97.0
96.8
86.7
3.04
2.72
2.75
3.00
14.1
7.32
3.74
4.33
Chalcogen bond
Hydrogen bond
Hydrogen bond
Hydrogen bond
O1···H7A 2.521
N1···H3A 2.647
S1···H10A 2.870
S1···H10C 2.886
85.8
3.00
3.8
Hydrogen bond
3.5. NBO population analysis and topology of the electron density
With the primary aim of analyze the influence of the electronic delocalization over the
conformational preference adopted in the carbonyl thiocarbamate moiety (-C(O)N(H)C(S)O-) of
the title compounds, the electronic interaction between the frontier orbitals have been analyzed
with the NBO population analysis. Electronic interactions that promote the stabilization of a
certain conformation correspond to the interactions between occupied Lewis-type NBO orbitals
(bond or lone pair) and formally unoccupied non-Lewis NBO orbitals (antibond or Rydberg).
Table 5 shows the principal donor-acceptor interactions energies computed at the B3LYP/6-
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6
311++G** level of approximation, and the characters of the selected frontier molecular orbitals
calculated for compounds I and II are shown in Figure 6.
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8
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The result of both compounds indicate the presence of p-type out-of-plane lone pair orbitals,
more specifically lp2(S), lpπ(O1), lpπ(O2) and the lp(N) orbitals, in which the electron-donating
capacity is reflected by its low electron occupancy, of ca. 1.87, 1.85, 1.75 and 1.65 e,
respectively. The interactions involving lp(N)→ π*(S=C), lpπ(O2)→ π*(S=C) and lp(N)→
π*(O=C) are the most important electronic effects that stabilize the planar conformations around
the carbonyl and thiocarbamate moieties, providing interactions energies of 61.1, 58.3 and 40.1
kcal/mol, respectively. As a consequence, the electron occupancies of these formally vacant
antibonding orbitals are quite high, amounting up to 0.40 and 0.23 e for the π*(S=C) and
π*(O=C) orbitals for both compounds, respectively. These delocalizing interactions reveals that
the lone pair over nitrogen, lp(N), contributes to the resonance interactions with both adjacent
π*(S=C) (LUMO) and π*(O=C) (LUMO+3 for compound I and LUMO +1 for compound II)
antibonding orbitals (see Scheme 4).
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CH3
S
CH3
S
CH3
S
O
C
O
C
O
C
O
C
O
C
O
C
R
R
R
N
H
N
H
N
H
Scheme 4. Resonant structures for title compounds around carbonyl thiocarbamate moiety (-
C(O)N(H)C(S)O-).
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Compound I
Compound II
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LUMO +3, π*(O=C)
LUMO +1, π*(O=C)
LUMO, π*(S=C)
LUMO, π*(S=C)
HOMO, lp2(S)
HOMO, lp2(S)
HOMO -5, lp(N)
HOMO-7, lpπ(O2)
HOMO-5, lp(N)
HOMO-7, lpπ(O2)
Figure 6. Plots of selected frontier molecular orbitals calculated for compounds I and II.
For both compounds studied here, the NBO calculations reveal that donor-acceptor electronics
interactions are important factors that stabilize the most stable syn-anti-syn conformer. More
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specifically, the resonance interaction in the thiocarbamate group, lpπ(O3) → π*(S=C), seems to
be decisive to stabilize the anti configuration.
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Table 5. Second order donor → acceptor interaction energies computed (B3LYP/6-
311++G**) for compounds I and II (for atom numbering see Figure 3).
Compound I / II
Donor →acceptor interaction
syn-anti-syn anti-anti-syn syn-syn-syn
lp2(S) → σ* (O2-C9) / (O2-C10) 15.73 / 15.82 16.61 / 16.71 17.32 / 17.31
lp2(S) → σ* (N-C1) 11.09 / 11.24 11.44 / 11.57 13.36 / 13.52
lpσ(S) → σ* (O2-C9) /(O2-C10) 3.52 / 3.58
3.70 / 3.74
3.46 / 3.47
3.48 / 3.54
4.23 / 4.21
lpσ(S) → σ* (N-C1)
lpπ(O1) → σ* (C2-C2)
lpπ(O1) → σ* (N-C1)
lpπ(O2) → π* (S=C)
lpσ(O2) → σ* (S=C)
lpσ(O2)→ σ* (N-C1)
lp(N) → π* (S=C)
3.00 / 3.01
18.23 / 18.74 17.15 / 17.43 18.84 / 19.14
30.53 / 30.29 27.99 / 27.82 30.15 / 29.93
57.33 / 58.31 49.88 / 50.50 46.76 / 47.04
9.40 / 9.39
3.35 / 3.39
8.95 / 8.91
3.12 / 3.13
8.26 / 8.30
3.03 / 3.05
61.16 / 60.95 57.84 / 58.12 62.99 / 61.30
40.08 / 40.01 27.02 / 27.58 40.16 / 40.09
lp(N) → π* (O=C)
lpσ(O2) → σ*(C=O)
lpπ(O1) → σ*(C8–O2)
lpπ(O1) → σ*(C9–O2)
lpπ(O3) → σ*(C9–O2)
lpπ(S) → σ*(C=O)
0.14 / 0.11
0.10 / 0.08
0.27 / 0.14
- / -
- / -
- / -
- / -
- / -
- / -
- / -
- / -
- / -
0.16 / 0.24
0.26 / 0.12
- / -
It has been proposed that chalcogen bonding can be analyzed on the basis of the
hyperconjugative interaction involving the partial transfer of a lone pair of electrons of one
50, 51
chalcogen atom (donor) to antibonding orbitals of the second chalcogen atom (acceptor)
.
The close analysis of the second-order perturbation analysis of the Fock matrix shows the
occurrence of remote 1,5-donor-acceptor chalcogen···chalcogen interactions in both, the syn-
anti-syn and syn-syn-syn conformers. The most stable conformation is stabilized by 1,5-
oxygen···oxygen electron donation from the O2 (methoxy group) into the antibonding C=O
orbital, as well as from the carbonyl oxygen lone pair donation toward the antibonding σ*(C8–
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O2) and σ*(C9–O2), roughly amounting up to 0.51 and 0.33 kcal/mol for compounds I and II,
respectively. Interestingly, 1,5-oxygen···sulfur interactions are observed for the syn-syn-syn
conformer, through weak donor-acceptor electron donation between the lpπ(O3) → σ*(C9–O2)
and lpπ(S) → σ*(C=O) orbital interactions.
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Further AIM calculations were performed to check for the predominant attractive interactions
between C=O and O atoms in the most stable syn-anti-syn conformation. In AIM theory,52 (3,-1)
critical points are characterized by a low positive value of the Laplacian of the electron density
(2ρ) and a low value of the electron density (ρ) and can be used as an indicator of the
interaction strength. As shown in Figure 7, the molecular graphs show clear bond paths between
C=O and O for compounds I and II. The charge density topological characterization of the
intramolecular O···O region provides further insights into the strength and nature of this
interaction. The values of ρ (0.0131 and 0.0140) at the bond critical point and its Laplacian
(0.058 and 0.057) indicate the occurrence of a covalent intramolecular chalcogen bond.
Moreover, the occurrence of ring critical points (3,+1) confirm the pseudo five-membered ring in
the planar thiocarbamate group favoring the S(5) motif.
ρ= 0.01401, 2ρ= 0.05751
ρ= 0.01314, 2ρ= 0.05802
Figure 7. Molecular graphs for the energy minima of compounds I (left) and II (right). Violet,
red and yellow dots represent critical points (3,-3), bond critical points (3,-1), and ring critical
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points (3,+1), respectively. Topological properties of the O···O intramolecular interaction:
electron density (ρ, e Å-3), and Laplacian (2ρ, e Å-5) evaluated at the corresponding (3,-1)
critical points.
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4.
Conclusion
Two novel carbamothioates species were synthesized successfully using the isothiocyanate route.
The structural and spectroscopy properties have been studied and analyzed in combination with
theoretical calculation.
The X-ray structure reveals the presence of inter and intramolecular non-covalent interactions
that determine the conformational preference in the crystal packing. The comparison between
both compounds allows analyzing the role exerted by the 4-substituents over the phenyl group in
the conformations adopted in around the carbonyl and thiocarbonyl moiety.
The most stable syn-anti-syn conformer is computed for the vacuum isolated species and also the
only conformation found in the crystal. This conformation is strongly stabilized by 1-5-O···O
chalcogen···chalcogen intramolecular interaction, forming a bonded R(5) motif which is
characterized by short non-bonded distances of ca. 2.61 Å in the crystal.
The NBO calculation allowed us to analyze the role of the sulfur, oxygen and nitrogen lone pairs
orbitals in the electronic delocalization over the carbonyl and thiocarbonyl moieties. The
calculation showed the strong electron interactions (resonance) between these lone pairs and
mainly the π*(S=C) and π*(O=C) antibonding orbitals.
Moreover, weak 1,5-remote electronic interactions between the O and C=O fragments in the
thiocarbamate moiety are found for the most stable syn-anti-syn form. The AIM results also
indicate the presence of a bond critical points (3,-1) and a ring critical points (3,+1) in the
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thiocarbamate moiety, suggesting the occurrence of intramolecular O···O bond for the most
5
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stable syn-anti-syn conformation in both compounds here analyzed.
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Electronic Supplementary Information
Potential energy curves calculated for internal rotation for compounds I and II are given in
Figure S1. The energies computed (B3LYP/6-311++G**) for the isodesmic reaction routes are
shown in Table S1. FTIR and FT-Raman spectra in the solid phase are shown in Figures S2-S4
and collected in Tables S2 and S3.
Acknowledgements
LSRP and MFE are members of the Carrera del Investigador of CONICET (Argentina). The
Argentinean authors thank the Consejo Nacional de Investigaciones Científicas y Técnicas
(CONICET), the Agencia Nacional de Promoción Científica y Tecnológica (ANPCYT, PICT-
2130), and the Facultad de Ciencias Exactas, Universidad Nacional de La Plata (11/X794) for
financial support. MFE thanks Prof. Dr. R. M. Romano (CEQUINOR) for her help during the
recording of Raman spectra. The authors thank C. Gustavo Pozzi for helpful discussion on the
topological analysis.
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