Intermolecular interactions in crystalline 1-(adamantane-1-carbonyl)-3-substituted thioureas with Hirshfeld surface analysis

Article abstract of DOI:10.1039/c5ce01373a

The conformationally congested species 1-(adamantane-1-carbonyl)-3-(2,4,6-trimethylphenyl)thiourea has been prepared and fully characterized by elemental analyses, FTIR, ¹H NMR, ¹³C NMR and mass spectrometry. Its crystal structure was determined by single-crystal X-ray diffraction. The dihedral angle between the plane of the 2,4,6-trimethylphenyl group and the plane of the thiourea fragment was optimized by theoretical calculations applying the B3LYP/6-311++G(d,p) level for the purpose of investigating the conformational effects on the stabilization of the crystal packing. A detailed analysis of the intermolecular interactions in a series of six closely related phenylthiourea species bearing the 1-(adamantane-1-carbonyl) group has been performed based on the Hirshfeld surfaces and their associated two-dimensional fingerprint plots. The relative contributions of the main intermolecular contacts as well as the enrichment ratios derived from the Hirshfeld surface analysis establish the 1-acyl thiourea synthon to be a widespread contributor.

Full text of DOI:10.1039/c5ce01373a

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Intermolecular Interactions in Crystalline 1ꢀ(Adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀ
substituted Thioureas with Hirshfeld Surface Analysis†
Aamer Saeed,a,* Michael Bolte,b Mauricio F. Erben,c,* and Hiram Pérezd,*
a Department of Chemistry, QuaidꢀIꢀAzam University, Islamabad 45320, Pakistan.
b
Institut für Anorganische Chemie, J.W.ꢀGoetheꢀUniversität, MaxꢀvonꢀLaueꢀStr.7, Dꢀ60438
Frankfurt/Main, Germany.
c CEQUINOR (UNLP, CONICETꢀCCT La Plata), Departamento de Química, Facultad de Ciencias
Exactas, Universidad Nacional de La Plata, C.C. 962 (1900). La Plata, República Argentina.
d Departamento de Química Inorgánica, Facultad de Química, Universidad de la Habana, Habana
10400, Cuba.
†
Electronic supplementary information (ESI) available: Tables S1 and S2 list selected bondꢀ
distances/angles and ring puckering parameters, respectively, for compound 1. Revevant data from
the Hirshfeld analysis (including CXY
, Sx (%), RXY and EXY values) of the main intermolecular
interactions for compounds 1ꢀ6 are given in Table S3.
Keywords: thiourea, crystal structure, vibrational analysis, hydrogen bonding, Hirshfeld surface
analysis.
*Corresponding authors:
(AS) Eꢀmail: aamersaeed@yahoo.com, Tel: +92ꢀ51ꢀ9064ꢀ2128; Fax: +92ꢀ51ꢀ9064ꢀ2241.
(MFE) Eꢀmail: erben@quimica.unlp.edu.ar, Tel/Fax: +54ꢀ211ꢀ425ꢀ9485.
(HP) Eꢀmail: hperez@quimica.uh.cu, Tel: 53ꢀ78703922; Fax: 53ꢀ78783641.
1

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Abstract
The
conformational
congested
species
1ꢀ(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀ(2,4,6ꢀ
1
trimethylphenyl)thiourea has been prepared, fully characterized by elemental analyses, FTIR, H,
13C NMR and mass spectroscopy, and the crystal structure determined by using single crystal Xꢀray
diffraction study. The dihedral angle between the plane of 2,4,6ꢀtriꢀmethylphenyl group and the
plane of thiourea fragment was optimized by theoretical calculations applying the B3LYP/6ꢀ
31++G(d,p) level, for the purpose to investigate conformational effects on the stabilization of
crystal packing. A detailed analysis of the intermolecular interactions in a series of six closely
related phenylthiourea species bearing the 1ꢀ(adamantaneꢀ1ꢀcarbonyl) group have been performed
based on the Hirshfeld surfaces and their associated twoꢀdimensional fingerprint plots. The relative
contributions of the main intercontacts, as well as the enrichment ratios derived from the Hirshfeld
surface analysis establishes the 1ꢀacyl thiourea synton to be a widespread contributor.
1ꢀIntroduction
1ꢀAcyl substitued thiourea species have been known since a long time, the preparation of
CH3C(O)NHC(S)NH2 was reported by Neucki as early as 1873.1 The current and continuously
increasing interest in these compounds is probably twofold: 1) potential applications in a wide range
of fields are being investigated, and 2) and these compounds are relatively easily prepared. Most
promising applications include the use of 1ꢀacyl thioureas as collectors in froth flotation processes,2,
3
as ionophores in ion selective electrodes,4ꢀ6 and as precursor for metal sulfide nanoparticles.7, 8 1ꢀ
Acyl substitued thiourea species are versatile reagents for the synthesis of a variety of heterocyclic
and organosulfur compounds.9 Furthermore, biological importance of this kind of compounds has
been highlighted recently.10, 11 In particular, substituted 1ꢀ(benzoyl)ꢀ3ꢀ(phenyl) thioureas have been
evaluated for antitumor activity with promising results.12
2

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As has been recognized, the structural and conformational properties of 1ꢀacyl theories are
linked to the achievement of many of these applications. In particular, the formation of proper
hydrogen bonds with particular receptors is a key factor acting in many fields, from analytical
applications of 1ꢀacyl thioureas as chemosensors for selective and sensitive nakedꢀeye recognition
for anions 13ꢀ16 as well as in chemical biology and drug design.17ꢀ20
Increasing attention has been paid to the study of nonꢀcovalent interactions acting on the
crystal structure and packing of sulfurꢀcontaining compounds,21 a topic of interest not only in
24, 25
organic chemistry,22 but also in transition metal complexes.23 Very recently, Eccles at al.
demonstrate the versatility of the thioamide functional group [–C(S)NH2] as a key moiety for
crystal engineering. The supramolecular arrangement of 1,2,4ꢀtriazoleꢀ5ꢀ(4H)ꢀthione derivatives
involves the formation of a short centrosymmetric
N–H···S synthon in the solid.26, 27 It has
been shown that the formation of centrosymmetric N–H···S=C hydrogen bond dimer in
thiosemicarbazone is favored by the high polarizabilitity of the electron density of the lone pair
formally located at the sulfur atom.28
The crystal packing of 1ꢀ(acyl)ꢀthiourea compounds, with the possibility of different donor
and acceptor groups, is usually dominated by hydrogen bonds, mostly determined by both N–
H···O=C and N–H···S=C interactions.29, 30 Bifurcated hydrogen bonds are usually observed,31ꢀ33 the
N–H group forming both an intramolecular and intermolecular N–H···O hydrogen bonds.34 As
reported recently,35 440 crystal structures for acyl thiourea were searched in the Cambridge
Structural Database, the majority (236 structures) displaying a characteristic intermolecular pattern
forming dimers via N–H···S hydrogen bonding adopting an
hydrogenꢀbonding motif.36 In
combination with other patterns, very versatile structures are attainable, including infinite chains,37
38
2ꢀdimensional sheets or 3ꢀdimensional networks.39 By using periodic system electron density,
topological and NBO analysis, we recently showed that strong hyperconjugative lpS→ σ*(N–H)
remote interactions ꢀbetween the molecules forming the dimeric arrangeꢀ are responsible for
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intermolecular interactions in the simple 1ꢀ(2ꢀchlorobenzoyl)thiourea species.40
In this article, as part of our ongoing project41, 42 aimed at understanding the structural
features of 1ꢀ(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀsubstituted thioureas (see Scheme 1), a novel derivative ꢀ
namely 1ꢀ(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀ(2,4,6ꢀtrimethylphenyl)thiourea– has been synthesized and
characterized by singleꢀcrystal Xꢀray diffraction, infrared and nuclear magnetic resonance (NMR)
spectroscopies and mass spectrometry. The influence of steric impediment induced by the 2ꢀ6ꢀdiꢀ
methyl substitution in the conformational properties was analyzed by quantum chemical
calculations at the B3LYP/6ꢀ311++G(d,p). The study of Xꢀray crystal structure of six adamantaneꢀ
based acylthiouras reveals that hydrogen bonding and other weaker forces such as π· · ·π and CꢀH· ·
·π interactions participate in a cooperative way to control the supramolecular architectures.
Although the π interactions have been widely investigated during the past two decades,43 an
increased number of theoretical and experimental studies have been recently carried out to
understand the true nature of π· · ·π and CꢀH· · ·π interactions.44ꢀ46 These nonꢀcovalent interactions
could be used as tools in crystal engineering for the design of crystalline adamantaneꢀbased
thioureas. To get a better understanding of the intermolecular interactions toward the crystal
packing, the Hirshfeld surface analysis47ꢀ49 for a series of six closely related 1ꢀ(adamantaneꢀ1ꢀ
carbonyl)ꢀ3ꢀsubstitutedꢀphenyl thioureas has been analyzed. Thus, the surfaces of all compounds
are mapped by using of dnorm, whereas shapeꢀindex and curvedness are properties mapped on the
surfaces in order to facilitate a more detailed identification of the πꢀπ interactions experienced by
molecules in various studied compounds.44 The present study allowed us to investigate the effect of
molecular conformation adopted by the substitutedꢀphenylthiourea group on the stabilization of
crystal packing in these compounds, as well as to quantify the propensity of the intermolecular
interactions to form the supramolecular assembly.
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O
C
H
N
N
H
C
R
S
Scheme 1. Representation of 1ꢀ(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀsubstituted thioureas.
2ꢀExperimental
2.1ꢀInstrumentation. Melting points were recorded using a digital Gallenkamp (SANYO) model
1
13
MPD.BM 3.5 apparatus and are uncorrected. H and C NMR spectra were determined in CDCl3 at
300 MHz and 75.4 MHz respectively using a Bruker spectrophotometer. Fourier transform infrared
spectroscopy (FTIR), spectra were recorded on an FTS 3000 MX spectrophotometer (Pakistan).
Infrared spectra were recorded in KBr pellets with a resolution of 2 cm–1 in the 4000ꢀ400 cm–1 range
on a Bruker EQUINOX 55 FTIR spectrometer (Argentina). Mass Spectra (EI, 70eV) on a GCꢀMS
instrument Agilent technologies, and elemental analyses were conducted using a LECOꢀ183 CHNS
analyzer.
2.2ꢀ Synthesis of 1ꢀ(adamantaneꢀ1ꢀcarbonylꢀ3ꢀ(2,4,6ꢀtrimethylphenyl))thiourea. The reaction
sequence leading to the formation of thioureas is depicted in Scheme 2. The starting material 1ꢀ
adamantane carbonyl chloride was obtained via the reaction of 1ꢀadamantane carboxylic acid with
thionyl chloride at room temperature according to the standard procedure [1]. A solution of
adamantaneꢀ1ꢀcarbonyl chloride (10 mmol) in dry acetone (50 ml) was treated with an equimolar
quantity of ammonium thiocyanate (10 mmol) in dry acetone (30 ml) and the reaction mixture was
refluxed for 30 minutes under nitrogen to afford the adamantaneꢀ1ꢀisothiocyanate as intermediate. An
equimolar quantity of 2,4,6ꢀtrimethylaniline (10 mmol) in acetone (10 ml) was added and the reaction
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mixture refluxed for 4 h. On completion (TLC control), the reaction mixture was poured into cold
water and the precipitated thiourea (1) was recrystallized from aqueous ethanol.
O
O
+
S- NH4
O
N
N
/ dry acetone
-NH4Cl
OH
Cl
C
S
H3C
dry acetone
H3C
H2N
CH3
HN
CH3
H3C
HN
O
S H3C
(1)
Scheme 2. Synthetic route to 1ꢀ(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀ(2,4,6ꢀtrimethylphenyl)thiourea.
1ꢀ(Adamantaneꢀ1ꢀcarbonylꢀ3ꢀ(2,4,6ꢀtrimethylphenyl))thiourea (1); yield 87%, mp 196°C. FTꢀIR
1
(ν cm−1): 3336, 3034, 2909, 2849, 1675, 1575, 1457, 1370; H NMR (300 MHz, CDCl3): 12.81 (br
δ
s, 1H, NH, D2O exchangeable); 8.73 (br s, 1H, NH, D2O exchangeable); 7.63 (d, 2H, Ar), 2.31 (s,
3H, ArCH3), 2.11 (s, 6H, ArCH3 x2) 2.12 (brs, 3H, adamantaneꢀCH), 2.03 (s, 6H, adamantaneꢀCH2),
1.81 (q, 6H, adamantaneꢀCH2, J = 8.6 Hz); 13C NMR (75.5 MHz, CDCl3): 179.1 (C=S), 176.9 (C=O),
134.1 (Ar), 128.6, 126.9 125.3, 123.6, 121.6 (ArCs), 41.9, 41.9, 39.2, 38.6, 36.1, 36.0, 31.6, 28.0,
27.8 (adamantaneꢀC), 22.3 (ArCH3), 18.7 (ArCH3); Anal. Calcd. for C21H28N2OS (356.53): C, 70.75;
H, 7.92; N, 7.86; S, 8.99 %; Found: C, 71.21; H, 7.89; N, 7.90; S, 8.94%. EIMS m/z: 356.1 (M+, 41
%).
2.3ꢀQuantum chemical calculations. Optimization geometry was accomplished within the frame
work of the density functional theory50, 51 using the hybrid functional with nonꢀlocal exchange due
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to Becke52 and the correlation functional due to Lee, Yand and Parr,53 (B3LYP)as implemented in
the Gaussian 03 package.54 Contracted gaussian basis sets of tripleꢀzeta quality plus polarized and
diffuse functions 6ꢀ311++G(d,p) for all atoms were used throughout the present work.55 The
corresponding vibrational analyses were performed for the optimized geometries 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.
2.4ꢀXꢀray data collection and structure refinement. The crystal and refinement data for compound 1
are listed in Table 1. Data of compound (1) were collected at 173(2) K on a STOE IPDS II twoꢀ
56
circleꢀdiffractometer using MoKα radiation. The structure was solved by direct methods
and
refined with fullꢀmatrix leastꢀsquares techniques on F2. All nonꢀhydrogen atoms were refined
anisotropically, and all H atoms bonded to C were placed in their calculated positions and then
refined using the riding model. The H atoms bonded to N were freely refined. The geometry of the
56
molecule was calculated using the WinGX 57 and PARST 58, 59 software. XP in SHELXTLꢀPlus ,
ORTEPꢀ3 60 and Mercury 61 programs were used for molecular graphics.
Full crystallographic data for compound 1 have been deposited with the Cambridge
Crystallographic Data Centre (CCDC 1410273). Enquiries for data can be directed to: Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, UK, CB2 1EZ or (eꢀmail)
deposit@ccdc.cam.ac.uk or (fax) +44 (0) 1223 336033.
Table 1. Crystal data and structure refinement for compound (1).
Empirical formula
Formula weight
Temperature / K
Crystal system
C21H28N2OS
356.51
173(2)
triclinic
Space group
Pꢀ1
Unit cell dimensions
a =7.6584(7) Å
b =10.2121(8) Å
c =13.1295(11) Å
α
β
γ
=108.228(6)o
= 97.789(7)o
= 92.502(7)o
Volume / Å3
Z
962.26(15)
2
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ρ calc. / mg mmꢀ3
1.230
0.179
384
0.35 x 0.29 x 0.27
3.30 to 27.62°
ꢀ9<=h<=9, ꢀ12<=k<=13, ꢀ17<=l<=17
18032
4399 [R(int) = 0.061]
4399/0/238
ꢁ / mmꢀ1
F(000)
Crystal size / mm3
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Data/restraints/parameters
Goodnessꢀofꢀfit on F2
Final R indexes [I >2σ (I)]
Final R indexes [all data]
Largest diff. peak/hole / e Åꢀ3
1.054
R1 = 0.0409, wR2 = 0.1064
R1 = 0.0434, wR2 = 0.1084
0.316 / ꢀ0.290
2.5ꢀHirshfeld surface computational method. Hirshfeld surfaces and their associated twoꢀ
dimensional fingerprint plots62ꢀ65 are generated using CrystalExplorer3.1 software.66 The dnorm
(normalized contact distance) surface and the breakdown of twoꢀdimensional fingerprint plots are
used for decoding and quantifying intermolecular interactions in the crystal lattice.67ꢀ69 The dnorm is
a symmetric function of distances to the surface from nuclei inside and outside the Hirshfeld surface
(di and de, respectively), relative to their respective van der Waals radii. A color scale of red
(shorter than vdW separation)—white (equal to vdW separation)—blue (longer than vdW
separation) is used to visualize the intermolecular contacts. The 3D dnorm surfaces are mapped over
a fixed color scale of ꢀ0.24 (red) to 0.93 Å (blue), shapeꢀindex mapped in the color range of ꢀ1.0 au
(concave) –1.0 au (convex) Å, and curvedness in the range of ꢀ4.0 au (flat) – 0.01 au (singular) Å.
The 2D fingerprint plots are displayed by using the translated 0.6–2.6 Å range, and including
reciprocal contacts.
3ꢀResults and Discussion
3.1ꢀ Conformational properties
Previous structural studies on 1ꢀ(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀmono substituted thioureas have
shown that a local planar structure of the acylꢀthiourea group is preferred, with opposite orientation
42, 70
between the C=O and C=S double bonds (“Sꢀshape”).41,
In the present case, a similar
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conformational behaviour has been computationally determined for 1ꢀ(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀ
(2,4,6ꢀtriꢀmethylphenyl)thiourea, with the 1ꢀacyl thiourea group adopting the Sꢀshape and the
substituted phenyl ring nearly perpendicular to the mean plane defined by the 1ꢀacyl thiourea group.
It is worthy to notice that the molecule isolated in vacuum displays nearlyꢀperfect CS symmetry.
For comparison purposes, similar calculations have been done for the related 1ꢀ
(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀ(phenyl)thiourea. For this species, the most stable form displays the
same Sꢀshape conformation, but on the contrary, the phenyl ring coplanar with the 1ꢀacyl thiourea
group. Thus, it becomes apparent that the conformation adopted by the 2,4,6ꢀtriꢀmethyl group is
determined by strong steric impedance caused by the interaction between the C=S bond with the
methyl groups occupying the 2,6ꢀpositions. The computed molecular structure is in very good
agreement with the experimental one (see Section 3.3).
3.2ꢀ Vibrational properties
The determination of the vibrational properties of 1ꢀacyl thioureas has showed to be a
powerful tool for analyzing conformational and structural features in the solid state.36 The FTIR
spectrum of (1) have been measured and compared with the calculated [B3LYP/6ꢀ311++G(d,p)]
harmonic frequencies. The experimental and simulated spectra are shown in Figure 1. Two wellꢀ
defined absorptions are observed in the infrared spectrum at 3426 and 3231 cm–1, the last one with
higher intensity, which can be associated with the ν(N–H) stretching modes.71 This spectral region
is well reproduced by quantum chemical calculations with the corresponding harmonic frequencies
computed at 3613 (56.6) and 3393 (366.5) cmꢀ1 (computed intensities, in Km/mol, are given). The
formation of the intramolecular N1–H···O1=C hydrogen bond is responsible for the impressive redꢀ
shift and a strong intensification of the ν(N1–H) normal mode as compared with the second ν(N2–
H) stretching, in agreement with previous data for related species.72 This interaction also affect the
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force constant of the ν(C=O) stretching mode,73 which is observed as an intense and symmetric
band at 1674 cmꢀ1 in the infrared spectrum in good agreement with the computed value (1707 cm–1).
The most intense absorption is observed as a rather broad band at 1511 cm–1 in the infrared
spectrum, which can be assigned to the δ(N–H) deformation modes, in agreement with previous
reported values for 1ꢀacylꢀ3ꢀmonoꢀsubstituted thioureas.74, 75 The computed spectrum shows two
intense absorptions at similar frequencies values [1567 (350.9 Km/mol) and 1546 (628.6 Km/mol)
cm–1] that are associated with the δ(N1–H) and δ(N2–H) normal modes, respectively.
The medium intensity absorptions observed at 772 and 751 cm–1 are assigned to the
76
characteristic “breathing mode” of the adamantane group and to the ν(C=S) stretching mode,
75, 77
respectively. The last assignment is in agreement with previously studied thiourea derivatives
and suggest that the C=S group is acting as a H bondꢀacceptor . It is wellꢀknown that the formation
of C=S···H–X intermolecular hydrogen bonds effect the frequency of the ν(C=S) mode.78
Thus, based on the analysis of the main features of the infrared spectra it is concluded that
compound (1) forms strong intraꢀ and interꢀmolecular interactions in the solid, most probably due
to the formation of hydrogen bonds involving the N1–H group as a donor and carbonyl and
thiocarbonyl groups as acceptors.
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δ(NH)s
ν
(N2C1)
ν(N1H)
ν(C=O)
ρ(NH)s
ν(C=S)
ν
(N=C)
ν
(N2H)
Experimental
Computed
3600 3400 3200 3000 28001800 1600 1400 1200 1000 800 600 400
Wavenumber (cm-1)
Figure 1. Computed [B3LYP/6ꢀ311++G(d,p)] and experimental (FTIR) infrared spectra of 1.
3.3ꢀCrystal Structure Determination
The Xꢀray geometrical parameters around the central 1ꢀacyl thiourea moiety of compound 1,
together with the computed [B3LYP/6ꢀ311++G(d,p)] values are listed in Table S1 in the electronic
supplementary information (ESI). The ORTEP view of the Xꢀray structure ꢀwith atomic labelingꢀ is
shown in Figure 2, together with the computed molecular structure. The geometric parameters of
hydrogen bonds for compound 1 are shown in Table 2. An intramolecular
N–H· · · O hydrogen bond
(H···O = 2.08(2) Å, N· · · O = 2.723(2) Å, ∠N–H· · · O
= 134o) is present, forming a sixꢀmembered
ring commonly observed in this type of compounds,79 which confirms the results of the vibrational
data. The central ꢀC(O)ꢀNHꢀC(S)ꢀNHꢀ fragment is planar, with the C=O and C=S bonds in opposite
orientation, adopting a ‘‘Sꢀshape’’ in agreement with close structures of 1ꢀacylꢀ3ꢀmonoꢀsubstitued
thioureas.32 The observed C=S and C=O double bonds, as well as the shortened C–N bond lengths
(Table S1), are typical of thiourea compounds.80 The dihedral angle between the best planes through
the thiourea moiety CNC(S)N and the 2,4,6ꢀtriꢀmethyl group is 89.56(5)o, in agreement with the
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theoretical calculations (see section 3.1). This value is also similar for related structures with the
same nature of substituents on the 2,4,6ꢀtriꢀsubstituted group.81 The ring puckering parameters 82 for
the cyclohexane rings of the adamantane group are given in Table S2 in the electronic
supplementary information (ESI). The q(3) puckering amplitude values are very longer than the
corresponding q(2) amplitude values, which are very close to zero. The q(3) values are also very
similar to the total puckering amplitudes QT with average value of 0.625
Å, which lies only slightly
under the QT value of 0.63
Å
for ideal cyclohexane chair.82 These results indicate that all
cyclohexane rings in the adamantane group adopt a very slightly distorted chair conformation.
Figure 2. Computed (left) and Xꢀray (right) molecular structure of 1 with displacement ellipsoids
plotted at 50% probability level. Intramolecular N–H…O hydrogen bond is shown as dashed lines.
In the crystal packing of 1, intermolecular N–H·· O and nonꢀconventional C–H···S
hydrogen bonds link the molecules into centrosymmetric dimers stacked along the direction of the b
axis (Figure 3), giving
and
graphꢀset motifs, respectively.
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Figure 3. A packing diagram of compound 1 showing centrosymmetric dimers stacked along bꢀ
axis. Intraꢀ and intermolecular hydrogen bonds are shown as dashed lines.
Table 2. Hydrogen bonding geometry for compounds 1ꢀ6 (Å, o).
Label
(Fig. 3)
∠
(D
—
H· · ·
A)
Compound
1
D
—
H· · ·
A
d
(
D
—
H)
d
(H· ··
A
)
d(D· ··A)
N1
C27
—
—
H1· ··O1i
0.83(2)
0.99
2.40(2)
3.041(2)
3.916(1)
132
157
1
6
H27B· · ·S1ii
2.986(1)
2
N102
C110
—
—
H102· · ·S2i
H11B· ··S2i
0.83
0.99
ꢀ
2.77(2)
2.7031(5)
2.7110(5)a
2.75(2)a
3.576(2)
3.652(2)
ꢀ
162
161
ꢀ
1
2
3
S1· ··H21Ji
S1· ··H202i
ꢀ
ꢀ
ꢀ
4
C105
C112
C106
—
—
—
H10B· ··O202ii
H11E· ··O203iii
H10C· ··C112iv
0.99
0.99
0.95
2.544(1)
2.404(1)
2.843(2)
3.412(2)
3.380(2)
3.649(2)
152
169
143
5
9
10
3
4
N2
C14
—
—
H2· ··S1i
0.89
0.99
0.95
0.99
2.66(1)
2.7829(4)
2.482(2)
2.646(1)
3.499(1)
3.710(1)
3.077(2)
3.526(2)
157
156
121
148
1
2
3
4
H14A· ··S1i
H6A· · ·O2ii
C6
—
C14
—
H14B· · ·O3iii
N2
—
—
—
—
—
H2· ··S1i
0.80
0.99
0.99
0.99
0.99
2.84(2)
2.7744(5)
2.9861(4)
2.834(1)
2.895(2)
3.592(1)
3.704(2)
3.865(2)
3.715(2)
3.812(3)
155
157
148
149
154
1
2
3
4
5
C22
C26
C29
C22
H22B· · ·S1i
H26A· ··S1i
H29A· ··Cl2ii
H22A· ··C16iii
5
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N1
—
—
—
—
—
H1· ··O1i
0.88
ꢀ
1.00
0.99
0.99
2.30(3)
2.380(2)
2.661(2)
2.9123(9)
2.9650(9)
3.038(4)
ꢀ
3.624(4)
3.830(3)
3.867(3)
141
ꢀ
161
154
152
1
2
3
4
5
C13
C23
C26
C27
H13· · ·F2ii
H23· · ·F1iii
H26A· ··S1iv
H27A· ··S1iv
6
N1
O1
C14
—
H1· ··O2i
0.79(3)
0.86(3)
0.97
0.93
0.97
2.52(3)
2.36(3)
2.8411(7)
2.628(2)
2.449(2)
3.184(3)
3.212(2)
3.761(2)
3.504(3)
3.354(3)
142
169
159
157
155
1
3
4
5
6
—
—
H10· · ·S1ii
H14A· ··S1iii
H3· ··O1iv
C3
—
C14
—
H14B· · ·F1v
Symmetry codes for (1): (i) 1ꢀx,ꢀy,1ꢀz; (ii) 1ꢀx,1ꢀy,1ꢀz; for (2): (i) x,y,z; (ii) ꢀ½+x,½ꢀy,ꢀ½+z; (iii) 3ꢀx,1ꢀy,1ꢀz;
(iv) 2.5ꢀx,ꢀ½+y,½ꢀz; for (3): (i) 1ꢀx,1ꢀy,ꢀz; (ii) x,1.5ꢀy,ꢀ½+z; (iii) ꢀx,½+y,ꢀ½ꢀz; (iv) ꢀx,1ꢀy,ꢀz; for (4): (i) 1ꢀx,1ꢀ
y,2ꢀz; (ii) ꢀ1+x,y,1+z; (iii) 1ꢀx,1ꢀy,1ꢀz; (iv) x,1.5ꢀy,ꢀ½+z; for (5): (i) 1ꢀx,y,½ꢀz; (ii) x,1+y,z; (iii) 1+x,y,z; (iv) 1ꢀ
a
x,ꢀy,1ꢀz; for (6): (i) 2ꢀx,1ꢀy,1ꢀz; (ii) 1ꢀx,ꢀy,2ꢀz; (iii) 2ꢀx,ꢀy,1ꢀz; (iv) 3ꢀx,ꢀy,2ꢀz; (v) ꢀ1+x,y,z; The
A· · ·H
reciprocal interaction.
3.4ꢀ Hirshfeld surface analysis
Hirshfeld surface analysis was carried out for the purpose to study the nature of
intermolecular contacts and theirs quantitative contributions to the supramolecular assembly of 1, as
well as on other five monoꢀsubstituted adamantyl phenylthiourea derivatives recently reported.41, 42,
83
The selected structures are labelled here as 2: 1ꢀ(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀ(3ꢀ
nitrophenyl)thiourea, 3: 1ꢀ(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀ(4ꢀnitrophenyl)thiourea, 4: 1ꢀ(adamantaneꢀ1ꢀ
carbonyl)ꢀ3ꢀ(2,4ꢀdichlorophenyl)thiourea,
difluorophenyl)thiourea, and
5:
1ꢀ(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀ(2ꢀbromoꢀ4,6ꢀ
1ꢀ(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀ(2,6ꢀdifluoroꢀ4ꢀ
6:
hydroxyphenyl)thiourea. The geometric parameters of hydrogen bonds for compounds 1ꢀ6 are
shown in Table 2.
The Hirshfeld surfaces of the compounds 1ꢀ6 are shown in Figure 4. The dnorm map of
compound 1 indicates that H···O reciprocal contacts are distinguished relative to the other
interactions by a pair of adjacent deepꢀred regions, labelled 1, attributed to strong N—H···O
hydrogen bonds (Table 2) forming
dimers as described in Figure 3. The same type of
interaction was only observed (labelled 1) for the structures 5 and 6. A pair of pale blue to white
spots for structures 1 (labelled 6), 5 (labelled 4) and 6 (labelled 4) represent H···S contacts that
indicate C· · ·H contacts associated to two Tꢀshaped C—H· · ·π interactions as described in Table 3.
The distances between the involved Hꢀatoms (H13 and H22A) and the nearest carbon atom in the
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corresponding benzene ring are in agreement with theoretical calculatons for related compounds.84
For structures 2, 3 and 4 (labelled 1) this motif is combined with N—H···S hydrogen bonds
forming typical centrosymmetric
loops. It is worthwhile to highlight here that the dihedral
angles of 65.22(2) and 71.61(3)o between the plane of central thiourea grouping and the plane of the
2,4,6ꢀtrisubstituted phenyl ring for structures 5 and 6, respectively, are the closest to the one
obtained for structure 1. The corresponding angles for structures 2, 3 and 4 measure 51.15(1),
37.22(2) and 39.38(1)o, respectively. The differences in the dihedral angle for structures 5 and 6
related to structure 1 could be attributed to the presence of two types of substituents in the phenyl
ring. For compound 1, the supramolecular arrangement is further controlled by two Tꢀshaped
C—
H· · ·π interactions involving the H26B and H29B atoms of adamantane group, and C11ꢀC16
bencene ring [centroid Cg(1); symmetry: 1ꢀx,ꢀy,1ꢀz]. The shorter interaction85 is found with H26B· ·
·Cg(1) as described in Table 4. The distance of 2.820(1) Å between H26B atom and the nearest
carbon atom in the benzene ring is in agreement with theoretical calculations.84
Table 3. Geometrical parameters for the πꢀstacking moieties involved in the π· ··π interactions for
compounds 2, 3 and 6 (Å, o)
rings IꢀJa
Rcb
R1vc
R2vd
αe
β f
γg
symmetry
Compound
2
Cg(1)· · ·Cg(2)
Cg(1)· · ·Cg(2)
3.656(1) 3.291(1) 3.317(1)
3.784(1) 3.371(1) 3.332(1)
2.03 24.9 25.8 1.5ꢀx, ꢀ½+y, ½ꢀz
2.03 28.3 27.0 2.5ꢀx, ꢀ½+y, ½ꢀz
Compound 3
4.670(1) 3.324(2) 3.324(2)
Compound
Cg(1)· · ·Cg(2) 4.101(2) 3.371(2) 3.371(2)
Cg(1)· · ·Cg(2)
0.00 44.6 44.6 ꢀx, 1ꢀy, ꢀz
6
0.00 18.3 18.3 2ꢀx, ꢀy, 2ꢀz
a Cg(1) and Cg(2) are the centroids of the rings C102ꢀC107 and C202ꢀC207 for (2), respectively,
b
c
and C1ꢀC6 for (3) and (6). Centroid distance between ring I and ring J. Vertical distance from
d
e
ring centroid I to ring J. Vertical distance from ring centroid J to ring I. Dihedral angle between
mean planes I and J. fAngle between the centroid vector Cg(I)· · ·Cg(J) and the normal to the plane (I).
gAngle between the centroid vector Cg(I)· · ·Cg(J) and the normal to the plane (J).
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Figure 4. Views of the Hirshfeld surfaces in two orientations for compounds 1ꢀ6. Thermal
ellipsoids at 50% probability level. Surface in column 3 rotated by 180 around the horizontal axis
of the plot; Hꢀatoms are omitted; numbered arrows are described either in Table 2 or in text.
Compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Table 4. Geometrical parameters of CꢀH· · ·π interactions* for compounds 1 and 4 (Å, o)
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CꢀH•••Cg(J)a
H•••Cg1 Hꢀperpb
compound 1
H•••Cd
symmetry
γc ∠CꢀH•••Cg(J)
C26ꢀH26B· · ·Cg(1)
2.70
2.66
10.7
162
2.820(1) 1ꢀx,ꢀy,1ꢀz
compound 4
(R1)C13ꢀH13· · ·Cg(1)
(R2)C22ꢀH22A· · ·Cg(1)
2.85
2.87
2.84
2.80
3.50
14.72
135
127
3.090(2) x,1.5ꢀy,ꢀ½+z
2.895(2) 1ꢀx,1ꢀy,1ꢀz
* (H•••Cg1 < 3.0 Å, γ < 30.0o). a Centroid of benzene ring. Perpendicular distance of H to ring plane J.
b
cAngle between the CgꢀH vector and ring J normal. Distance between Hꢀatom and the nearest carbon
d
atom in the benzene ring. R1 denotes a puckered ring of adamantane group, and R2 of benzene ring.
The N—H·· ·S, C—H···S and C—H···O hydrogen bonds are present in the structures 2 and
3, and can be seen as deepꢀred spots labelled 1, 2 and 5, respectively, with similar values for the
corresponding H···A distances (Table 2). However, when the nitro group is at meta position on the
phenyl ring (structure 2), the dnorm map shows H···C contacts (labelled 10) attributed to C—H···C
hydrogen bond, involving the hydrogen at position 5 on the phenyl ring. In addition, this hydrogen
atom form H···O and H···H contacts which are not visible in the two selected orientations of dnorm
map. These interactions are responsible for the increase of the dihedral angle between the plane of
thiourea fragment and the plane of 3ꢀnitroꢀphenyl ring in comparison to that for 4ꢀnitroꢀphenyl
conformation in the structure 3 (values are given above).
In the halophenylthioureas 4 and 5, X—H···S (X = N, C) contacts are manifested as deepꢀ
red spots (labelled 1 and 2) for the former, whereas deepꢀred regions (labelled 1) are attributed to
the presence of N—H·· ·O hydrogen bonds for the structure 5. The H·· ·D (D = Cl, F) contacts are
visible as small red spots, labelled 3 and 2, associated to
respectively. Unlike the structure 5, the dnorm map for structure 4 shows a red spot (labelled 5)
associated to · · · hydrogen bond It is common for all the six compounds the existence of H··
C—H· · ·Cl and C—H· · ·F hydrogen bonds,
C
—H
C
.
·H contacts with red to white regions in the Hirshfeld surfaces. In the case of structure 6 two deepꢀ
red regions (labelled 3) correspond to strong O–H···S hydrogen bonds associated with the presence
of hydroxyl groups. In the dnorm surfaces of 1, 2, 3 and 4 there are red to white spots labelled 5, 8, 5
and 6, respectively, due to H· · · H contacts with distances ranging from 2.325 to 2.391 Å, according
to the structural determinations.
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The red to white areas marked as 6 and 7 for surface of 2, and 7 for surface of 6 are C· · ·
C
contacts representative of π· · ·π stacking interactions (Table 3). The pattern of adjacent red and blue
triangles that appears on the shape index surfaces of 2 and 6, as well as a relative large and flat
green region at the same side of the molecule on the corresponding curvedness surfaces confirm the
presence of π· · ·π interactions (Figure 5). The largest region of flat curvedness appears for
compound 2. This type of intermolecular contact is also evident by using of these properties
mapped on the surface of 3 as showed in Figure 5, but its geometric parameters given in Table 3,
particularly Rc,
β and γ indicate a weaker interaction, in comparison with those on the surfaces 2
and 6. In addition, a relative smaller region of flat curvedness on the surface of 3 allows us estimate
the existence of π· · ·π stacking with a minor overlapping of the adjacent molecules.
Figure 5. Hirshfeld surfaces mapped with shapeꢀindex and curvedness for compounds 2, 3 and 6.
Compound 2
Compound 3
Compound 6
Fingerprint plots for the main intermolecular contacts for all the six structures are shown in
Figure 6. For structure 1 the shortest contacts correspond to the very close
a sharp spike centred (labelled 1) near a (de + di) sum of 2.1 Å. The · · ·
H
· · ·
H
contacts, showing
· · ·H
O
H
(labelled 2) and
C
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contacts (labelled 3), with sharp pairs of spikes centered near a (de + di) sum of 2.3 and 2.9Å,
correspond to · · · and · · · hydrogen bonds, respectively. In addition, we observe · ·
contacts (labelled 4) with less sharper spikes centered around (de + di) of 2.8 Å, attributed to
· · · hydrogen bonding (Table 2). The H···H contacts are shortest for each of the compounds, and
· · · H, S· · · H and C· · · intermolecular contacts are present in all the structures. In the case of
· · ·H and O· · · contacts, respectively, are longer than the sum
of van der Walls radii. Unlike the compound 1, there are
asymmetric pair of spikes for structure 2, indicating · · · and
different (de + di) distances, near of 2.3 and 2.5 Å, respectively.
N—H
O
C—H
C
S
·H
C—
H
O
S
H
structures 3 and 4, the distances of
C
H
O
· · ·
H
reciprocal contacts with
contacts with significantly
H
O
O· · ·
H
C
· · ·C
contacts (labelled 5)
attributed to π· ··π interactions between phenyl rings were observed for the structures 2 and 6, with
centroidꢀtoꢀcentroid distances of 3.656(2) and 4.101(3)Å, respectively. The corresponding
fingerprint plots clearly depicts a green area on the diagonal at approximately 1.8 Å, which is
characteristic of π· · ·π interactions. The pairs of spikes (labelled 6 and 7) in the halophenylthioureas
4 and 5 correspond to Cl· · ·H and F· · ·H contacts, respectively. Fingerprint of structure 5 reveals the
occurrence of weak Br·· H interactions (labelled 8), which are not visible in the Hirshfeld surfaces
due to the distances are longer that sum of van der Waals cutoff radii.
Figure 6. Fingerprint plots for compounds 1ꢀ6. Close contacts are labelled as: (1) H…H, (2) O…H,
(3) C…H, (4) S…H, (5) C…C, (6) Cl…H, (7) F…H, (8) Br…H.
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The relative contributions to the Hirshfeld surface area due to main intermolecular contacts
for the compounds 1ꢀ6 are shown as a histogram in Figure 7. It is clear that the nature, number and
position of the substituents on the phenyl ring play a key role in the participation of each type of
contact. For all the structures the
contribution to the total Hirshfeld surface. In the structure 1, the major presence of eleven hydrogen
atoms on the phenyl group, notably increases the contribution from · · ·H over the Hirshfeld surface
(72.0 %) regarding the other five structures. However, according to crystal structure determination
the lowest percentage of · · · contacts for structure 5 (33.9 %) is a result of interactions involving
the adamantane and phenyl groups. For the contacts associated to hydrogen bonds the contributions
of · · ·H contacts are very similar (9.5ꢀ12.8 %) due to all the six structures contain only one sulfur
atom involved in the formation of dimers through · · · hydrogen bonds. The percentages of
· · · contacts present less close interval of (8.3ꢀ14.2 %). In the case of structures 2 and 3 the · ·
H interactions show the highest Hirshfeld contact surfaces of 26.4 and 17.9 %, respectively, The · · ·
H· · ·H interactions (labelled 1) have the most important
H
H
H
S
C—H
S
C
H
O
·
N
H
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contacts are only visible for compounds
3.6 %, respectively Other types of intermolecular contacts with the most important percentages
such as · · · (3.4 %) occur for compound 2, and · · · (3.0 %), · · · (2.2 %) and · · · (2.4
%) for compound 3.
2 and 3, with the smallest fingerprint contributions of 4.6 and
.
C
C
C
O
N
O
O
O
Figure 7. Relative contributions of intermolecular contacts to the Hirshfeld surface area for
compounds 1ꢀ6.
In this study, we have calculated the enrichment ratios86 of the main intermolecular contacts
for compounds 1ꢀ6 in order to analyze the propensity of two chemical species (X,Y) to be in
contact. The enrichment ratio EXY is a descriptor derived from the Hirshfeld surface analysis, and
defined as the ratio between the proportion of actual contacts CXY in the crystal, and the theoretical
proportion of random contacts RXY. The percentages of Hirshfeld surface contacts CXY are given by
CrystalExplorer3.1.66 The proportion SX of different chemical species on the molecular surface is
obtained from CXX and CXY values. The random contacts RXY values are calculated from the
corresponding SX and SY proportions by using of probability products. The value of EXY is expected
to be generally larger than unity for pairs of elements with high propensity to form contacts in
crystals, while pairs that tend to avoid contacts are associated with EXY values lower than unity.
Table 5 shows the enrichment ratios of the main intermolecular interactions for compounds
1ꢀ6 (the whole information is provided in Table S3). The
H· ··
H
contacts can be considered as
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favoured in all structures due to enrichment ratios are very close to unity (EHH = 0.90ꢀ0.98), and
constitute most of the interaction surface (33.9ꢀ72.0 %). The ESH values are larger than unity (1.12ꢀ
1.49) for all the structures, indicating that
crystal packing, with similar random contacts ranging from 8.1 to 9.4 %. The ECH ratios ranging
from 1.10 to 1.37 (except structure 2) indicate that · ·· contacts have a high propensity to form in
crystal packing, as result of abundant SH proportion of hydrogen atoms (61.4ꢀ85.6%) at the
molecular surfaces. The · ·· contacts of all the structures are much enriched (except structure 3),
with the highest propensity for structures 2 and 6. Despite the contribution of · ·· contacts to the
S· ··H contacts have an increased likelihood to form in the
C
H
O
H
O
H
Hirshfeld surface (COH = 11.9 %) for compound 6 is lower than that for structure 3 (COH = 17.9 %),
the proportion of oxygen atoms on the molecular surface of the former is significantly smaller (SO =
6.5%), decreasing the value of the random contacts (ROH = 8.7%). This allows to explain the higher
propensity of the
O· ··H contacts for structure 6 (EOH = 1.37) in comparison with that of the
structure 3.
Table 5. Enrichment ratios EXY of the main intermolecular
interactions for compounds 1ꢀ6.
Interaction
1
0.98
1.17
0.83
1.15
1.12
2
0.91
0.73
1.21
1.35
1.44
ꢀ
3
0.97
1.10
0.90
0.93
1.46
ꢀ
4
0.98
1.12
0.19
1.02
1.14
ꢀ
1.07
ꢀ
1.00
ꢀ
5
0.90
1.37
6
0.84
1.20
1.15
1.37
1.49
1.35
H· · ·
H
C
N
O
· · ·
· · ·
· · ·
H
H
H
/
1.16
1.19
1.44
S
F
· · ·
· · ·
H
H
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Cl· · ·
H
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
/
ꢀ
ꢀ
ꢀ
Br· · ·H
0.77
C
C
· · ·
· · ·
C
O
4.86
0.58
1.00
ꢀ
0.71
1.30
2.72
1.20
ꢀ
ꢀ
ꢀ
ꢀ
N
O
· · ·
· · ·
O
O
ꢀ
ꢀ
EXY for random contacts RXY lower than 0.7% were not calculated
.
The EFH values of 1.44 and 1.35 in the halophenylthioureas 5 and 6, respectively, as well as
the EClH value of 1.07 for structure reveal that · ·· a nd Cl· ·· contacts are highly favoured, with
4
F
H
H
the highest proportion of SF (10.3 and 10.8%) and SCl(14.2%), respectively, apart from the SH
values. This indicates that the weak fluorine and chlorine hydrogen bonding interactions are
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comparable in importance to the characteristic strong
N
—
H
· · ·O hydrogen bonds 86ꢀ88 in acylthiourea
derivatives. Other types of contacts that appear in structure 6 involving fluorine atoms, such as
C· ·
·
F, N· · ·F and O· · · contacts are very impoverished. The · ·· contacts are highly favoured for
F
N
H
structures 2 and 6 (ENH = 1.21 and 1.15), slightly favoured for structures 1 (ENH = 0.83) and 3 (ENH
= 0.90), and impoverished for compounds 4 and 5, with ENH ratios of 0.19 and 0.06, respectively.
There are no correlation between ENH ratios and the corresponding random contacts.
Although the random contacts with values lower than 0.9 % are considered insignificant, we
have computed the enrichment ratio of
C
· ··C, N· ··
O
and
O
· ··
C
short contacts for compounds 1ꢀ4.
· ·· contacts are highly enriched
It is interesting to observe in this type of compounds that the
C
C
(ECC = 4.86) for compound 2, enriched for structure 4 (ECC = 1.00), and slightly impoverished for
structure 3 (ECC = 0.71), being 0.7 the percentage of RCC for the three compounds. This indicates
that ECC and Sc values show no correlation for structures 2, 3 and 4. On the other hand, the high
value of ECC for structure 2 helps to explain the exceptional low propensity of the
(ECH = 0.73) due to both · ·· and · ·· contacts are presumably in competition. In the case of
structure 3 the high probability to form · · ·O, C· · ·O and N· · · short contacts with enrichment
ratios ranging from 1.20 to 2.72, is another reason to explain the reduced value of EOH (0.93), in
comparison with the other structures. The · · · intermolecular contacts which are completely
C· ··H contacts
C
C
C
H
O
O
X
Y
avoided with EXY = 0.00, are not included in Table 5.
4ꢀConclusions
The molecular structure of 1ꢀ(adamantaneꢀ1ꢀcarbonyl)ꢀ3ꢀ(2,4,6ꢀtrimethylphenyl)thiourea
has been determined by singleꢀcrystal Xꢀray diffraction. The dihedral angle between the plane of
2,4,6ꢀtriꢀmethylphenyl fragment and the plane of thiourea moiety is 92.6º for the vacuum isolated
molecule, a value very similar to that of 89.56(5)o obtained in the crystal structure determination.
All the cyclohexane rings in the adamantane group adopt a very slightly distorted chair
conformation as reflected by q(3) value of 0.625Å. The Hirshfeld surfaces, fingerprint plots and
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enrichment ratios were found to be very useful in the study of the intermolecular interactions, and
their quantitative contributions towards the crystal packing of a series of six 1ꢀ(adamantaneꢀ1ꢀ
carbonyl)ꢀ3ꢀsubstitutedꢀphenyl thioureas. The results revealed remarkable relative contributions in
H
· ··H interactions more than other contacts. There are structural similarities for the compounds 1, 5
and 6, such as the presence of N–H···O and C–H···S hydrogen bonds forming centrosymmetric
and dimers, respectively, related with the nature of substituents on the triꢀ
substitutedꢀphenyl ring. According to the enrichment ratios the · ··H contacts are favoured, and the
· ·· contacts have high propensity to form in crystals for all the structures The · ·· and · ··
H
S
H
.
O
H
C
H
contacts displayed high propensity to occur in five structures. The presence of the less common C–
H···F and C–H···Cl hydrogen bonds, as well as π· · ·π and C–H···π contacts, showed be as
important as the conventional interactions to direct the packing of molecules. These results could be
applied in crystal engineering for the design of supramolecular arrangements using the 1ꢀ
(adamantaneꢀ1ꢀcarbonyl)ꢀthiourea synton.
5ꢀAcknowledgments
MFE is a member of the Carrera del Investigador of CONICET (República Argentina). The
Argentinean author thanks to the Consejo Nacional de Investigaciones Científicas y Técnicas
(CONICET), the ANPCYT and to the Facultad de Ciencias Exactas, Universidad Nacional de La
Plata for financial support.
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