Structure, tautomerism, spectroscopic and DFT study of o-vanillin derived Schiff bases containing thiophene ring

Article abstract of DOI:10.1016/j.molstruc.2018.03.120

Two Schiff bases derived from o-vanillin (o-HVA), a well-known antioxidant hydroxo aldehyde, have been obtained from condensation with 2-thiophenecarboxilic acid hydrazide (TPNNH) and 2-thiophenemethylamine (TPNH2), respectively. The inclusion of thiophen

Full text of DOI:10.1016/j.molstruc.2018.03.120

Accepted Manuscript
Structure, tautomerism, spectroscopic and DFT study of o-vanillin derived Schiff
bases containing thiophene ring
María R. Rodríguez, Julián Del Plá, Oscar E. Piro, Gustavo A. Echeverría, Gustavo
Espino, Reinaldo Pis-Diez, Beatriz S. Parajón-Costa, Ana C. González-Baró
PII:
S0022-2860(18)30417-4
10.1016/j.molstruc.2018.03.120
MOLSTR 25059
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 16 February 2018
Revised Date: 26 March 2018
Accepted Date: 27 March 2018
Please cite this article as: Marí.R. Rodríguez, Juliá. Del Plá, O.E. Piro, G.A. Echeverría, G. Espino, R.
Pis-Diez, B.S. Parajón-Costa, A.C. González-Baró, Structure, tautomerism, spectroscopic and DFT
study of o-vanillin derived Schiff bases containing thiophene ring, Journal of Molecular Structure (2018),
doi: 10.1016/j.molstruc.2018.03.120.
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ACCEPTED MANUSCRIPT
Structure, tautomerism, spectroscopic and DFT study of o-vanillin derived Schiff bases
containing thiophene ring.
María R. Rodrígueza, Julián Del Pláa, Oscar E. Pirob, Gustavo A. Echeverríab, Gustavo Espinoc,
Reinaldo Pis-Dieza, Beatriz S. Parajón-Costaa and Ana C. González-Baróa *
a CEQUINOR (CONICET-CCT La Plata, UNLP), Bvd. 120 N°1465, 1900 La Plata, Argentina.
b IFLP (CONICET-CCT La Plata, UNLP), CC 67, B1900AVV, La Plata, Argentina.
c
Departmento de Química, Universidad de Burgos, Pza. Misael Bañuelos s/n, E-09001 Burgos,
España.
Abstract
Two Schiff bases derived from o-vanillin (o-HVA), a well-known antioxidant hydroxo aldehyde, have
been obtained from condensation with 2-thiophenecarboxilic acid hydrazide (TPNNH) and 2-
thiophenemethylamine (TPNH2), respectively. The inclusion of thiophene is based on its significance in
the development of effective therapeutic agents. The study of the compounds oVATPNNH and
oVATPNH2 includes solid state structural and spectroscopic analysis by single-crystal X-ray diffraction
and vibrational spectroscopy (FTIR and Raman). The crystal structure of oVATPNH2 shows a peculiar
rotational disorder in the heterocycle. Tautomeric equilibria in solution, which depends on the molecule
1
structure and the nature of the solvent, were analysed by means of H and 13C{1H} NMR along with
electronic spectroscopy. Tautomerism plays an important role not only in the molecular interactions but
also in the behaviour of the Schiff base when acting as a ligand in coordination compounds. Results
obtained from DFT calculations were used in the interpretation of the experimental data and in the
spectral assignments.
Keywords: Thiophene, o-vanillin, X-ray crystal structure, tautomerism, spectroscopy, DFT.
1. Introduction
Condensation reaction of carbonylic compounds with amine derivatives leads to the formation of the
well-known Schiff bases family of compounds. The characteristic azomethine group (-HC=N-) plays an
important role in the broad variety of properties that those compounds have shown. Due to their
biological and pharmacological activity, Schiff bases are of continuous interest as antifungal, antitumor
and antibacterial agents and they have been used as herbicides, pesticides and insecticides, too [1,2].
In particular, the electrophilic C and nucleophilic N atoms in the azomethine moiety provide exceptional
synthetic effectiveness and excellent binding abilities to Schiff bases [3]. Thus, they can interact either
with nucleophiles or electrophiles, including DNA, enzymes as well as with other biological targets.
Besides the biological and pharmacological activities and due to their characteristic solid-state thermo-
and photo-chromism, these compounds have application in various areas of materials science, such as
display systems and optical memory devices [4].

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Schiff bases involving heterocycles have received special attention because of their important
properties [1,5]. Those containing thiophene are of interest as sulphur is a widely distributed element,
present not only in natural but also in synthetic products. Thiophene is relevant because of its
significance in drug discovery and development of effective therapeutic agents against cancer [6].
In particular, Schiff bases derived from o-hydroxyaromatic aldehydes and ketones are excellent models
for the study of keto-enol tautomerism, both in solution and in the solid state [4]. This property is greatly
influenced by the topochemistry of the molecule, which is determined by the nature of the precursors
and the position of the substituents. Tautomerism plays an important role not only in the interactions
within the crystal lattice but also in the behaviour of the Schiff base when acting as a ligand. Among the
o-hydroxyaromatic aldehydes, o-vanillin has been widely employed because its relevant properties. In
particular, together with its isomer vanillin, it is a well-known antioxidant agent [7]. Their low toxicity
and therapeutic properties make them good candidates to be considered in the search of compounds
with improved pharmacological profile.
Due to the versatility and variety of potential applications of this kind of compounds, we have prepared
and studied two Schiff bases containing thiophene. They were obtained from the condensation reaction
of 2-hydroxy-3-methoxy-benzaldehyde (o-vanillin, o-HVA) with the respective thiophene amino-
compound, namely 2-thiophenecarboxilic acid hydrazid (TPNNH) and 2-thiophenemethylamine
(TPNH2).
The molecules are depicted in Scheme 1 and they will be referred from now on as oVATPNNH (1) and
oVATPNH2 (2).
oVATPNNH, (1)
oVATPNH2 (2)
Sheme 1: Schiff bases containing thiophene: N'-(2-hydroxy-3-methoxybenzylidene)thiophene-2-
carbohydrazide (oVaTPNNH, 1) and 2-methoxy-6-{(E)-[(thiophen-2-ylmethyl)imino]methyl}phenol
(oVaTPNH2, 2).
Even though the crystal structure of the oVATPNNH has been reported in the literature [8], it has been
only scarcely characterized despite the remarkable potential of this kind of Schiff bases.
In this work, a solid-state structural study of the compounds, including single-crystal X-ray diffraction
and vibrational spectroscopy (FTIR and Raman) is presented. Their behaviour in solution, paying
special attention to the tautomeric equilibria, was analysed by UV-Vis and NMR spectroscopy. Results
were complemented with calculations based on DFT that were of help in the spectral assignment.
2. Experimental
2.1. Materials and Instrumentation

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Reactants and solvents were used as provided with no further purification. 2-hydroxy-3-methoxy-
benzaldehyde (o-HVA) 2-thiophenecarboxilic acid hydrazide (TPNNH) and 2-thiophenemethylamine
(TPNH2) were p.a. grade and purchased from Aldrich. Hydrochloric acid (36%) and ethanol (EtOH)
was from Carlo Erba, methanol (MeOH) from Carlo Erba or Merck and dimethylsulphoxide (DMSO)
from J.T. Baker.
X-ray diffraction measurements were performed on an Oxford Xcalibur Gemini, Eos CCD diffractometer
with graphite-monochromated CuKα (λ=1.54178 Å) radiation. Infrared spectra were recorded with a
Bruker Equinox 55 instrument, Raman spectra were measured with a WITEC alpha 300 RA
spectrophotometer, electronic spectra were registered in a Thermo-Nicolet 6700 spectrophotometer
and NMR spectra were recorded on a Varian Unity Inova-400 instrument (399.94 MHz for 1H and 100.6
MHz for 13C). Elemental analyses were performed in an Exeter CE 440 analyser and melting points
were determined in a Bock monoscop “M”instrument.
2.2. Syntheses
oVATPNNH (1): This compound was prepared by a procedure simpler and faster than that previously
reported [8], as follows: a solution of o-HVA (1.5 mmol, 0.2280 g) in methanol (10mL) was drop-wise
added to a solution of 1.5 mmol (0.2132 g) of TPNNH in 15 mL of the same solvent, under stirring and
mild heating conditions. The pH of the resulting solution was decreased to a value of 3 by the careful
addition of concentrated HCl drops. The system was kept under the same conditions during 30
minutes. Upon reaching room temperature and leaving the solution for one week, it was observed the
precipitation of dark yellow needle-shaped crystals. The solid was filtered out and washed with cold
methanol. [Yield: 85% (0.7510g); m.p. 108-109°C. An al. Calcd. for C13H12N2O3S.H2O: C 53.05%; H
4.80%; N 9.52%. Found: C 52.65%; H 5.08%; N 9.83%].
oVATPNH2 (2): The procedure was analogous to the one described for oVATPNNH, using also 1,5
mmol of o-HVA (0,2284 g) and TPNH2 (155 µl, δ=1.103 g/ml) and finally obtaining a crystalline
precipitate after two weeks. This precipitate was filtered out and then recrystallized from ethanol to
obtain orange needle-shaped crystals. [Yield: 52% (0.386g); m.p: 71-72°C; Anal. Calcd. for
C13H13NO2S: C 63.13%; H 5.30%; N 5.66%. Found: C 62.66%; H 5.54%; N 5.97%]. The yield of this
synthesis, significantly lower than that obtained in Schiff bases preparation, is due to the co-
precipitation of a sub-product that is removed by the recrystallization procedure.
2.3. X-ray diffraction data
X-ray diffraction intensities were collected (ω scans with ϑ and κ-offsets), integrated and scaled with
CrysAlisPro [9] suite of programs.
The unit cell parameters were obtained by least-squares refinement (based on the angular setting for
all collected reflections with intensities larger than seven times the standard deviation of measurement
errors) using CrysAlisPro. Data were corrected empirically for absorption employing the multi-scan
method implemented in CrysAlisPro. The structure was solved by intrinsic phasing with SHELXT [10]

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and refined by full-matrix least-squares with SHELXL of the SHELX suite of programs [11]. There are
two molecules per asymmetric unit, one of them showing rotational disorder of the five-member ring.
The disorder was modelled in term of two rings rotated from each other in 180º around the linking C-C
σ-bond and refined with anisotropic displacement parameters such that their occupancies summed up
to one. Disorder of this kind was already reported by P. Battaglia et al. [12] to occur in related
C10H8N2OS2 compound.
Most H-atoms were located in a difference Fourier map phased on the heavier atoms. However, all but
the methylene group of the disordered molecule were positioned on stereo-chemical basis and refined
with the riding model. The H-atoms in the C-OH groups were refined treating these as rigid groups
allowed to rotate around the corresponding O-C bond such as to maximize the electron density at the
calculated positions. A similar procedure was followed to refine the methyl groups, which converged to
staggered conformations. The methylene H-atoms of the disordered moiety were refined at their found
positions with C-H and H···H distances restrained to target values of 0.97(1) and 1.53(1) Å,
respectively, and with isotropic displacement parameters equal to 1.2 times the value corresponding to
the C-atom. Crystal data and structure refinement results are summarized in Table 1.
2.4. Spectroscopy
Infrared spectra of solid samples (KBr pellets) were recorded in the 4000-400 cm-1 region. Raman
spectra were measured using laser excitation wavelength of 532 nm and a 20x objective lens. Laser
power was 0.229 mW for oVATPNNH and 0.323 mW for oVATPNH2.
Electronic spectra of the compounds and reactants in solution of dimethyl sulfoxide (DMSO), ethanol
(EtOH) and methanol (MeOH) were recorded using 10 mm quartz cells in the spectral range from 190
to 800 nm.
NMR samples were prepared under a nitrogen atmosphere by dissolving the suitable amount of the
respective compound in 0.5 mL of pre-dried (Molecular Sieves 4Å) oxygen-free CD3)2SO and the
spectra were recorded at 298 K. Typically, 1H NMR spectra were acquired with 32 scans into 32 k data
1
13
points over a spectral width of 16 ppm. H and C chemical shifts were internally referenced to TMS
1
via the residual H signal of CHD2SOCD3 (δ = 2.50 ppm) and the 13C signal of (CD3)2SO (δ = 39.52
ppm), according to the values reported by Fulmer et al. [13]. Chemical shifts (δ) are reported in ppm
and coupling constants (J) in Hertz. The splitting of proton resonances in the reported 1H NMR data is
defined as s = singlet, d = doublet, t = triplet, st = pseudotriplet, q = quartet, sept = septet, m =
1
1
multiplet, bs = broad singlet. 2D NMR spectra such as H-1H gCOSY, H-1H NOESY were recorded
using standard pulse sequences. The probe temperature (±1 K) was controlled by a standard unit
calibrated with methanol as a reference. All NMR data processing was carried out using MestReNova
version 10.0.2.

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1
oVATPNNH: H NMR (400 MHz, CD3SOCD3, 25 ⁰C) Tautomer A (keto-amine/enol-imine): δ 12.10 (s,
1H, N-H, H9), 10.76 (s, 1H, -OH, H2), 8.65 (s, 1H, H7), 7.92 (m, 1H, Hb), 7.89 (d, J = 5.0 Hz, 1H, Hd),
7.23 (m, 1H, Hc), 7.17 (d, J = 7.8 Hz, 1H, H6), 7.02 (m, 1H, H4), 6.86 (m, 1H, H5), 3.82 (s, 3H, OMe).
1H NMR (400 MHz, CD3SOCD3, 25 ⁰C) Tautomer D (iminol/enol-imine): δ 11.78 (s, 1H, -OH, H10’), 9.34
(s, 1H, -OH, H2’), 8.48 (s, 1H, H7’), 8.04 (m, 1H, Hb’), 7.95 (m, 1H, Hd’), 7.51 (d, J = 7.9 Hz, 1H, H6’), 7.23
(m, 1H, Hc’), 7.02 (m, 1H, H4’), 6.86 (m, 1H, H5’), 3.82 (s, 3H, OMe’).
13C NMR (101 MHz, CD3SOCD3, 25 ⁰C) Tautomers A and D: δ 161.20, 157.53, 148.11, 147.98, 147.54,
147.03, 146.11, 140.74, 137.74, 134.87, 134.63, 133.16, 132.17, 129.21, 128.26, 126.67, 120.92,
120.47, 119.37, 117.54, 113.75, 112.86, 55.85.
oVATPNH2: 1H NMR (400 MHz, CD3SOCD3, 25 ⁰C) Tautomer A (enol-imine) δ 13.35 (s, 1H, OH, H2),
8.68 (s, 1H, H7), 7.47 (dd, J = 5.0, 1.1 Hz, 1H, Hd), 7.06 (m, 3H, Hb, H6, H4), 7.03 (dd, J = 5.0, 3.5 Hz,
1H, Hc), 6.84 (dd, J = 8.3, 7.5 Hz, 1H, H5), 4.99 (s, 2H, H9), 3.78 (s, 3H, OMe).
13C NMR (101 MHz, CD3SOCD3, 25 ⁰C) Tautomer A (enol-imine) δ 166.78 (s, 1C, C7), 150.83 (s, 1C,
C2), 147.90 (s, 1C, C3), 141.31 (s, 1C, Ca), 127.13 (s, 1C, Cc), 125.48 (s, 1C, Cd), 125.45 (s, 1C, Cb),
123.22 (s, 1C, C6), 118.43 (s, 1C, C1), 118.18 (s, 1C, C5), 114.99 (s, 1C, C4), 56.26 (s, 1C, C9), 55.74
(s, 1C, COMe).
2.5. Computational methods.
The experimental structures of oVATPNNH and oVATPNH2 obtained from X-ray diffraction were
optimized using the Becke's three parameters hybrid density functional [14] with the gradient-corrected
correlation functional due to Lee, Yang, and Parr [15] as implemented in version 3.0.3 of the ORCA
program [16]. The Def2-TZVP basis set of triple-zeta quality was used for all the atoms [17].
Optimizations were conducted both in the gas phase and including solvent effects through the
Conductor-like Screening Model (COSMO) [18].
To verify whether the optimized geometries are local minima or saddle points on the potential energy
surface of the molecules the eigenvalues of the Hessian matrix of the total energy with respect to the
nuclear coordinates were calculated. Those eigenvalues were then transformed to harmonic vibrational
frequencies, which were further used to aid in the assignment of the experimental vibrational
frequencies. The calculated frequencies were not scaled.
The electronic spectra of both ligands were calculated using the hybrid PBE0 functional [19] as
implemented in version 3.0.3 of the ORCA program. The Def2-TZVP basis sets were also used for
those calculations.
3. Results and discussion
3.1. Crystal Structure
The solid state structures of both compounds were determined by X-ray diffraction methods. The
crystal structure of oVATPNNH.H2O has been previously published [9] but no further characterization
has been reported. Present results obtained for this compound affords a more detailed analysis, which
is presented herein. Furthermore, those results have been useful to discard the presence of both
tautomers in the crystal sample, as it occurs in solution (see below).

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The compound crystallizes in the orthorhombic space group P212121 with four molecules per unit cell, in
coincidence with the reported data. The nearly planar molecular shape is favoured by an intra-
molecular O-H···N bond. The water molecule bridges three neighbouring molecules in the lattice
through one N-H···Ow, one Ow-H···O=C- and another Ow-H···OH intermolecular bonds.
Figure 1 shows the ORTEP [20] drawing of both Schiff bases. Crystal data and structure refinement
results for the new oVATPNH2 compound are summarized in Table 1 and a complete list of
geometrical parameters is available as supplementary material (Tables S1-S5). The compound
crystallizes in the monoclinic space group P21/n with Z=8 molecules per unit cell. The structure hosts
two molecules (hereafter labelled I and II) per asymmetric unit, one of them showing rotational disorder
of the heterocycle moiety. Intramolecular bond distances, angles and torsion angles for the two
independent molecules are compared with calculated results in the following section.
(I)
(II)
Figure 1. View of oVATPHNNH.H2O (left). Part of the H-bonding pattern is drawn by dashed lines. Plot
of the asymmetric unit content of oVATPNH2 (right) showing the labeling of the non-H atoms and their
displacement ellipsoids at the 30% probability level for each independent molecule (I and II). The graph
depicts only one of the two conformations exhibited by the rotationally disordered thiophene ring of
molecule (II). Intra-molecular H-bonds are indicated by dashed lines.
Table 1. Crystal data and structure refinement for oVATPNH2.
Empirical formula
Formula weight
Temperature
C13H13NO2S
247.30
297(2) K
Wavelength
Crystal system
Space group
1.54184 Å
Monoclinic
P 21/n
Unit cell dimensions
a = 19.768(3) Å
b = 5.6818(4) Å
c = 22.364(2) Å
ß = 94.21(1)°
2505.1(5) Å3
8
Volume
Z
Density (calculated)
Absorption coefficient
1.311 Mg/m3
2.213 mm-1

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1040
F(000)
θ-range for data collection
Index ranges
Reflections collected
Independent reflections
3.964 to 71.995°.
-24 ≤ h ≤ 24, -6 ≤ k ≤ 3, -27 ≤ l ≤ 25
9846
4843 [R(int) = 0.0287]
Observed reflections [I>2σ(I)] 3364
Completeness to θ = 67.684° 100.0 %
Refinement method
Full-matrix least-squares on F2
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2 σ(I)]
4843 / 5 / 340
1.116
R1 = 0.0828, wR2 = 0.2573
R indices (all data)
Largest diff. peak and hole
R1 = 0.1054, wR2 = 0.3016
1.196 and -0.758 e.Å-3
Molecules I and II are structurally closely related to each other. In fact, the rms deviation of
corresponding atoms from the best least-squares superposition, calculated by the Kabsh’s procedure
[21], is 0.166 Å. Because of π-bond delocalization, both the arylmethylidenemethanamine and the
thiophene fragments are planar [rms deviation of atoms from the corresponding best least-squares
planes less than 0.050 and 0.016 Å, respectively]. Planarity in the arylmethylidenemethanamine
molecular skeleton is further stabilized by an intra-molecular OH···N bond [H···N bond lengths of 1.91
Å (I) and 1.90 Å (II) and O-H···O bond angles of 144º (I) and 146º (II)].
Imine C-N=C bond lengths are 1.456(5) and 1.283(5) Å (I) and 1.443(5) and 1.265(5) Å (II) in
agreement with the formal single-double bond system expected for these links. In the benzene ring of
the oVA fragment of the molecule, C-C bond distances are in the range from 1.361(6) to 1.420(5) Å for
I and in the 1.348(8)-1.409(5) Å range for II, as expected for a resonant-bond structure. C-OH bond
distances are 1.351(4) Å (I) and 1.347(4) Å (II) and C-OCH3 lengths are 1.357(5) Å (I) and 1.372(5) Å
(II). Bond distances and angle for the C-S-C linking in the thiophene ring of molecule (I) are 1.681(4)
and 1.663(6) Å and (C-S-S) = 93.3(3)º.
3.2. Optimized geometries and their comparison with experimental data
Selected calculated geometric parameters of both compounds were compared with experimental ones
as a test of the computational methodology used throughout. It is important to remember that
calculations were carried out in the gas phase, thus lattice effects are completely ignored. As can be
seen in Table 2, bond distances are well described in general for oVATPNNH. Notably, the larger
discrepancies are observed for the N2-C8 and the C1-O1 bonds, for which errors are about 0.03 Å.
Also of interest is the O1-H···N1 hydrogen bond, for which the experimental O1-H is appreciably
shorter than usual O-H bond distances in alcohols. Calculated value for O1-H is 0.984 Å.
Consequently, the H···N1 distance obtained from calculations is significantly shorter than the
experimental value of 2.033 Å. On the other hand, calculated and experimental values for the O1···N1
bond are in very good agreement. Experimental bond angles are very well described by calculated

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parameters in the case of oVATPNNH, even the O1-H···N1 angle. Calculated and experimental
dihedral angles are in excellent agreement indicating that the oVATPNNH ligand undergoes small
changes due to crystal packing interactions, as calculated gas phase and experimental solid state
structures exhibit similar conformations.
For oVATPNH2 selected geometric parameters of the two molecules found in the unit cell are
compared with calculated values, see Table 3. It is interesting to mention that after geometry
optimization molecule (I) becomes 0.4 kcal mol-1 more stable than molecule (II), a difference that
suggests that about 66% of the sample exists as molecule (I). Calculated bond distances exhibit a
good agreement with the values reported for molecule (I), except for the C5-C1 and C8-O1 bonds, for
which the errors are 0.019 and 0.015 Å, respectively. For molecule (II) the agreement is slightly better
as the larger errors are 0.014 and 0.013 Å, for C9-O2 and C6-N, respectively. As in the case of
oVATPNNH, the O1-H and H···N bond distances of the O1-H···N hydrogen bond are predicted to be
larger and shorter than experimental values, respectively, both for molecule (I) and molecule (II). The
O1···N bond distance, on the other hand, is well described by the calculations. Contrary to the findings
in bond distances, the bond angles of the two experimental structures agree very well with calculated
values. Finally, calculated torsion angles are in very good agreement with experimental values of the
two molecules forming the asymmetric unit cell. The only exception is the N-C5-C1-C2 dihedral angle,
whose experimental values differ even in sign from calculated ones. This fact clearly suggests the
presence of non-negligible lattice effects in the solid state that allow the thiophene ring to adopt an
orientation with respect to the C6-N-C5 moiety that becomes a higher energy conformation in the gas
phase.
Table 2. Selected experimental and calculated geometric parameters of oVATPNNH. Bond distances
are in Å and bond and dihedral angles are in degrees. See Fig. 1 for labels.
Exp.
Calc.
Exp.
Calc.
C6-C7
C7-N1
N1-N2
N2-C8
C8-O3
C8-C9
C1-O1
O1-H
1.451(4) 1.448 C6-C7-N1
1.280(4) 1.284 C7-N1-N2
1.368(3) 1.354 N1-N2-C8
1.349(4) 1.382 N2-C8-C9
1.229(3) 1.214 O1-H···N1
1.465(4) 1.478 C5-C6-C7-N1
1.364(3) 1.339 C7-N1-N2-C8
0.755 0.984 N1-N2-C8-C9
2.033 1.805 N2-C8-C9-C10
2.683 2.659
123.1(3) 122.3
116.0(2) 118.7
120.8(2) 120.6
116.0(2) 114.4
144.3
143.2
176.8 -179.4
175.5
178.9
-8.3
177.3
178.9
-11.3
H···N1
O1···N1

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Table 3. Selected experimental and calculated geometric parameters for oVATPNH2. Bond distances
are in Å and bond and dihedral angles are in degrees. Both experimental and calculated data are given
for the two molecules (I and II) in the asymmetric unit cell. See Fig. F1 for labels.
Exp. I Calc. I Exp. II Calc. II
Exp. I Calc. I Exp. II Calc.II
2.615 2.628 2.614 2.627
C9-O2 1.357(5) 1.358 1.372(5) 1.358 O1···N
O2-C13 1.420(5) 1.416 1.408(6) 1.416 C7-C6-N
C7-C6 1.449(5) 1.452 1.449(6) 1.452 C6-N-C5
122.8(3) 123.2 122.6(3) 123.2
117.2(3) 119.1 119.5(3) 119.0
111.4(3) 112.8 112.5(3) 111.8
C6-N
N-C5
1.283(5) 1.278 1.265(5) 1.278 N-C5-C1
1.456(5) 1.456 1.443(5) 1.449 O1-H···N
143.9 147.6 145.5
147.7
179.9
-0.2
C5-C1 1.482(5) 1.501 1.503(4) 1.506 C8-C9-O2-C13 174.6 -179.6 177.3
C8-O1 1.351(4) 1.336 1.347(4) 1.337 C8-C7-C6-N 1.5 0.2 0.2
O1-H
H···N
0.820
0.996 0.820
0.996 C6-N-C5-C1
-120.4 -124.4 118.4
157.6 -113.8 138.8
119.0
-17.9
1.908 1.732 1.896 1.730 N-C5-C1-C2
3.3. Vibrational Spectroscopy
IR and Raman spectra of both compounds were recorded and analysed. Reactants employed in each
synthesis were included in order to stablish a correlation of the results. Even though data related to o-
HVA has been already reported [22] calculations obtained with the same level of theory that the
employed for compounds 1 and 2 are included in the present work. It is worth mentioning that the
results are in excellent agreement with the previously published data. Assignments were done based
on reported data and previous results on related species [23-26]. DFT calculations were also used to
assist in the assignment of experimental vibrational frequencies.
Selected frequencies and their assignments are listed for each compound in Tables 4 and 5. Complete
spectral data and assignment are available as supplementary material (Tables S6 and S7). For
oVATPNH2, calculations were performed both for molecule I and II. Calculated frequencies are almost
identical for both molecules, except for some differences in the deformation modes involving the
thiophene ring. Thus, only calculated frequencies for conformer I are included in Table 3 and further
considered for discussion. Calculated frequencies for molecule II are included for completeness in
Table S7. Figure 2 depicts the more relevant spectral region of IR and Raman signals for
oVATPHNNH.H2O (1) and oVATPHNH2 (2).

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Figure 2. IR and Raman spectra of a) oVATPNNH.H2O (1) and b) oVATPNH2 (2) in the more relevant
spectral region.
Table 4. Assignment, experimental and calculated frequencies (in cm-1) of selected bands in the IR and
Raman spectra of oVATPNNH.H2O (1). Data of o-HVA and TPNNH precursors are included for
comparison.
oHVA
Assignment
TPNNH
IR exp Calc. Assignment
oVATPNNH
Raman Calc.
IR exp Calc
IR Exp
Assignment
3553 s
3345 m
νasH2O
νsH2O
3312 m
3258 sh
3236 m-w 3583
3557
3471
νasNH2
νsimNH2
νN-H
3219 m, b
2995 mw
2975 sh
2940 w
2867 w
2840 vw
3518
3394
3052
3030
2999
νN-H
νO-H
νasC-H (CH3)
νC-H (ArCH)
νs C-H (CH3)
νC-H (ArCH)
3014 vw 3318
νO-H
2973 w
2939 w
2884 w
2839 w
1645 vs
3095
νasC-H (CH3)
νC-H (ArCOH)
νsC-H (CH3)
νC-H (ArCOH)
νC=O
3016
2943
1704
1646 w
1627 s, b 1693
1640 vs
1737
1650
1610
νC=O + δNH2 + δN-H
νC=O (Tph) + δN-H
νring (oVA) + δO-H
1649*
1622
1591 m
1582 s, b 1577 vs
1517 vw
νring (oHVA) + δO-H
νring (oHVA) + δO-H
δN-H + δsCH3 + δC-H (oVA) +
δO-H
1512 sh 1516
1512
1479 m
1473 sh
1471 m
1455 s
1510
1489
1475 s,b
1505
1493
1491
1478
1452
1432
δasCH3
δasCH3
δasCH3
δasCH3
1480 δsCH3 + δO-H
1472
δsCH3 + νring (oVA) + δO-H
δsCH3
νring (Tph)
1433 sh
1439 vw
δsCH3 + νring (oHVA)
δO-H
1421 vs
1420 m
1450
1316 ρrNH2
1416 m
1369 m
νring (Tph) + δN-H
1388 s
1422
δO-H + νring (oVA)
1330 m
1246 m
1215
νN-N
1146 m
843 w
1146 m
1168
νN-N
838 m
827
ρwNH2
838 m
737 m
717 s
534 m-w 536
515 vvw
822
752
709
841 m
749
733
744
594
555
489
456
428
γO-H
γO-H
γC-H (oVA) + γO-H
δring (oVA)
γring (oVA)
γring (oVA)
733 vs
722 sh
530 sh
517 w, b
460 vvw
γC-H (oHVA)
δring (oHVA)
γring (oHVA)
γring (oHVA)
515 vvw
439 vw
460 vw
447 w
472
599
γring (Tph)
γN-H
γring (Tph) + γN-H
478 vw
483 vvw
γN-H
vs: very strong, s: strong, : m: medium, w: weak, vw: very weak, b: broad, sh: shoulder: Tph: thiophene ring.

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Table 5. Assignment, experimental and calculated frequencies (in cm-1) of selected bands in the IR and
Raman spectra of oVATPNH2 (2). Data of o-HVA and TPNH2 precursors are included for comparison.
oHVA
TPNH2
Assignment
oHVATPNH2
Calc.
IR exp. Calc.
Assignment
IR exp.
Calc.
IR exp.
Raman
Assignment
3369 vs 3551
νasNH2
νsNH2
3293 s
2919 s
3476
3071
3014 vw 3318
2939 w
3003vw
2937vw
2923sh
2888vw
3005 w
3153
νO-H
νC-H (ArCOH)
νO-H
νC-H (ArCH)
νasCH2
νsC-H (CH3)* + νC-H (ArCH)
νs CH2
νC-H (ArCH)
2928 m
2892 w
3045
2998
2965
3000
νasCH2
νsCH2
2884 w
2839 w
3016
2943
νsC-H (CH3)
2852 vs 3036
2834w
1631vs
2838 w
1635 vs
νC-H (ArCOH)
νC=O
1645 vs 1704
1685
νC=N
1598 vs 1665
δNH2
1591 m
1649
1622
1510
1489
1583 sh
1462 vs
1433 sh
1587 m
1472 m
1440 m
1660
1618
1505
1493
1497
1460
νring (oHVA) + δO-H
νring (oVA) + δO-H
1471 m
1455 s
1433 sh 1480
1472
δasCH3
δasCH3
δsCH3+ δO-H
δsCH3 + νring (oHVA)
δasCH3
δasCH3
δsCH3 + δO-H + νring (oVA)
δO-H + δC-H (oVA) ip + δs
CH3
1439 s
1381 s
1483
1377
1415 m,b
1378 w
1361 m
1333 m-w
1269 s
1480
1394
1370
1355
1282
δCH2
δC-H (Tph) + ρrNH2
δCH2
δCH (Tph)
δO-H + νring (oVA)
ρwCH2
νC-OCH3 + δC-H (oVA)
1388 s
1422
1365 w
1337 s
δO-H
1330 w
1362
ρwCH2
1270 sh 1284
1257 s
νC-OCH3 + δC-H
(oHVA)
1255 vs
1242 sh
1258 vw
1229 m
1232 m,b 1193
1168
νC-CH2 + ρr[CH2 +
NH2] op
νC-CH2
826 m
747 sh
850
749
ρwNH2
838 m
822
832 ms,b
750 mw
736 s
725 s
704 sh
615 vw
838 w
757 w
735 m
851
762
740
742
710
627
γO-H
γO-H
νS-CH + δC-C-C(CH2)
νS-CH + δC-C-C(CH2)
γC-H (oVA)
δring (oVA)
γC-H (Tph)
δring [oHVA + Tph]
737 m
717 s
752
709
γC-H (oHVA)
δring (oHVA)
698 s,b
616 w
707
628
γC-H (Tph) ip
δring (Tph)
620 m
vs: very strong, s: strong, : m: medium, w: weak, vw: very weak, b: broad, sh: shoulder: Tph: thiophene ring.
Characteristic asymmetric and symmetric stretching signals of crystallization water are observed at
3553 and 3345 cm-1 in the IR spectrum of (1). As expected for both Schiff bases, bands related to NH2
group in the TPNNH and TPNH2 and to C=O stretching in o-HVA are absent after condensation.
Consequently, a strong band assigned to the C=N bond appears in each IR and Raman spectra. This
band appears at higher frequencies in (2) (IR: 1631cm-1, Ra: 1635 cm-1) than in those of (1) (IR: 1605
cm-1, Ra: 1603 cm-1), probably due to the charge delocalization arising from the presence of the
hydrazone C=O group in the latest compound. Another effect of hydrazone formation is the red-shift of
the N-N stretching band as compared with the hydrazide precursor. This change is also described by
the calculated frequencies and the assigned band, at 1146 cm-1 in the spectra (IR, Ra) of (1).
Calculations predict a strong coupling among several modes in many bands. Also, stretching
frequencies of N-H and O-H groups involved in H-bond interactions are overestimated by the
calculations.
Phenolic O-H stretching band appear at lower frequencies in the IR spectra of (1) and (2) (2995 and
3003 cm-1, respectively) in comparison to the o-HVA spectrum (3014 cm-1) denoting a stronger intra
molecular H-bond interaction with the N atom in the Schiff bases. Bending modes are also at lower

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frequencies and calculations describe that they are coupled with ring stretchings, in both studied
compounds. The N-H stretching band at 3236 cm-1 in the IR spectrum of TPNNH is also shifted to
lower frequencies (3219 cm-1) in compound (1). Bands assigned to the in-plane and out-of-plane
bending modes are not easily discernible because of the overlapping with bands due to ring modes.
Characteristic bands of methoxy group in oVA fragment appear at the expected region in the spectra of
both molecules. In contrast, the bands assigned to the CH2 moiety in (2) show some differences from
those in the TPNH2 precursor, probably as a consequence of the location of this group, closer to the
C=N bond in the Schiff base.
Although the bands assigned to ring modes have not remarkable changes after condensation, the
observed behaviour in each compound can be attributed to the difference in the functional group that
connects both rings, namely – C(O)-N(H)-N=C(H)- in (1) and –CH2-N=C(H) in (2).
3.4. NMR Spectroscopy. Tautomeric equilibria analysis.
The tautomeric forms conceivable for oVATPNNH and oVATPNH2 are depicted in Figure 3. Full NMR
characterization of these compounds was carried out in order to identify the dominant tautomers for
both compounds in solution.
1
The H and 13C{1H} NMR spectra of both compounds were recorded in CD3SOCD3 at 25 ºC. All the
peaks in the 1H NMR spectra of both compounds were assigned on the basis of 1H-1H COSY and 1H-1H
NOESY experiments. (See ESI- figures S1-S4).
Figure 3. General outline showing all the possible tautomers for: a) oVATPNNH and b) oVATPNH2.

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1
The H NMR spectrum of oVATPNH2 exhibits only one set of signals attributed to the enol-imine form
(A) (Figure 4) Hence, the formation of the keto-enamine form through a tautomeric equilibrium is ruled
1
out in DMSO solution. On the other hand, the H NMR spectrum of oVATPNNH shows two sets of
resonances reflecting a 2:1 integration ratio in agreement with a slow dynamic equilibrium between two
tautomers, presumably the keto-amine/enol-imine form (A) and the iminol/enol-imine form (D) (Figure
5). Key cross-peaks in the 2D NOESY spectrum for the assignation of the signals are those between N-
H9↔C-H7 and O-H10’↔C-H7’. Moreover, the NOE interactions observed for tautomer D suggest that
tautomerism is followed by a conformational change favoring rotamer (D)2 versus rotamer (D)1 (see
Figure S1). On the other hand, exchange cross-peaks are observed between pairs of peaks belonging
to both tautomers as a result of this chemical process. Again, tautomerism does not affect the o-vanillin
ring in oVATPNNH. Nevertheless, when comparing tautomers A and D, the chemical environment of
the vanillin O-H group is considerably modified by the presence of either a keto or a hydroxyl group on
C10 and C10’, respectively, and as a result its chemical shift is notably displaced, δ 10.76 ppm (H2 in
tautomer A) and δ 9.34 ppm (H2’ in tautomer D). The 13C{1H} NMR spectra of both compounds confirm
the features deduced by 1H NMR (See ESI).
Figure 4. 1H NMR spectrum recorded for oVATPNH2 in CD3SOCD3 at 25 ⁰C, showing only one set of
resonances in agreement with the presence of one tautomer (A). Two cuts have been applied for the
sake of clarity.

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1
Figure 5. Possible tautomeric equilibria for oVATPNNH. Low field region of the H NMR spectrum
recorded in CD3SOCD3 at 25 ⁰C, showing two sets of resonances with an integral ratio (2:1) in
agreement with a slow dynamic equilibrium between two tautomers. The OMe signals of both
tautomers are accidentally isochronous.
3.5. Electronic Spectroscopy
The electronic spectra of compounds (1) and (2) were registered in different solvents (DMSO, EtOH
and MeOH) and in the 190-800 nm spectral region. The spectra are shown in Figure 6. Because
spectra of compound (1) in MeOH and EtOH are coincident only the spectrum in EtOH is presented.
Calculations were used to assist in the assignment of the absorption bands. Maxima of experimental
bands and calculated transition energies in EtOH are listed in Tables 6 and 7 for (1) and (2),
respectively. The spectra of both compounds are compared to those of the respective precursors in the
same solvent and the results obtained in EtOH are depicted in Figure S5 (ESI).

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Figure 6 Electronic spectra of both compounds in the 190-600 nm range. Left: oVATPNNH in solution
of DMSO (- ꢀ - ꢀ -), EtOH (ꢀꢀꢀꢀꢀꢀ); Right: oVATPNH2 in DMSO (- ꢀ - ꢀ -), EtOH (ꢀꢀꢀꢀꢀꢀ) and MeOH (- - -)
Table 6. Electronic spectra of oVATPNNH (1) and its precursors in EtOH. Calculated transition
energies for tautomers A and D and the corresponding assignment are also given. Absorption maxima
and transition energies are in nm, ε (M-1.cm-1) in brackets.
oHVATPNNH
Exp.
201* (1.8x104)
223 (2.0x104)
252 (sh)
TPNNH oHVA
Calc. A
207
Calc. D
204
Assignment
Exp.
Exp.
HOMO → LUMO + 2
HOMO – 5 → LUMO
HOMO – 2 → LUMO
HOMO – 1 → LUMO
HOMO – 1 → LUMO
HOMO → LUMO
204 (*)
221
224
221
263
266
252
268
306 (2.6 x104)
309
264
341
313 (sh)
317
378
343 (sh)
370
(*) Ill-defined maximum due to solvent cut-off
Table 7 Electronic spectra of oVATPNH2 (2) and its precursors in EtOH. Calculated transition energies
for tautomers A and B and the corresponding assignment are also given. Absorption maxima in nm, ε
(M-1.cm-1) in brackets.
oHVATPNH2
Exp.
TPNH2 oHVA
Calc. A Calc. B Assignment
213 HOMO – 2 → LUMO + 1
Exp.
Exp.
221
264
223 (2.4 x104)
234
227
261
314
HOMO → LUMO + 2
HOMO – 2 → LUMO
HOMO – 1 → LUMO
HOMO → LUMO
263 (1.2 x104) 247
303 (sh) 299
331 (2.2 x103) 320
424 (0.5 x103)
286
383
HOMO → LUMO
341

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Due to the higher energy cut-off of EtOH, the discussion will be focused in the spectra of solutions in
this solvent. Calculation of transition energies was performed considering EtOH as solvent. Regarding
the reactants, the three of them have absorption bands in the 200-290 nm spectral region. The
spectrum of o-HVA has an additional band of lower intensity at 340 nm. As a consequence of
condensation, new bands arise in the spectra of both Schiff bases and, moreover, those bands present
in the precursors are shifted.
The electronic spectra in EtOH of all the tautomers found in the present work were calculated and their
transition energies are used to discuss the differences observed in the experimental spectra in different
solvents, see Figure 6. Figure 7 shows calculated spectra for both tautomers in each molecule and the
respective experimental one.
Figure 7. Electronic spectra of oVATPNNH (left panel) and oVATPNH2 (molecule I, right panel) in
EtOH. Experimental (—), and calculated for tautomers A (······) and D or B ( ), respectively.
The frequency red-shift observed in the spectrum of (1) in DMSO compared to the spectrum obtained
in EtOH can be attributed to expected solvent effects, as it is also predicted by calculations considering
DMSO solvent (data not shown).
It can be seen in Table 6 that there is a very good agreement between observed band positions and
calculated transition energies for compound (1). It is worth mentioning that oscillator strengths, which
are taken as a measure of band intensities, are much lower for tautomer D than for tautomer A for
transitions around 221 and 266 nm. The HOMO – 5, HOMO and LUMO + 2 are localized at the oVa
moiety as can be observed in Figure S6 of ESI. The HOMO – 2 is localized at the TPNNH moiety,
whereas the HOMO – 1 is mainly located at the o-Va with non-negligible contributions from the C=N-N-
C group. The LUMO is strongly delocalized at the two moieties forming the oVATPNNH compound.
There are no appreciable differences in the localization pattern of the MO’s when the two tautomers are
compared. Interestingly, present calculations suggest that the experimental band at 306 nm and its
shoulder at 313 nm can be assigned to the same electronic transition originated in tautomers A and D,
respectively. Thus, the slight differences observed in the alcoholic solutions compared with the DMSO

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one can be attributed to an increasing fraction of tautomer D, as a consequence of the higher dielectric
constant of the solvent. The maximum of absorption at 316 nm with a shoulder at 309 in DMSO
changes to a maximum at 306 nm with a shoulder at 313 nm in EtOH.
It is also worth mentioning that the HOMO → LUMO + 2 transition is the only one that can be assigned
to an intraligand (oVA) band. The other transitions listed in Table 6, on the other hand, can be assigned
both to intraligand and to interligand transitions as the LUMO is delocalized at oVA and TPNNH.
Table 7 shows the calculated transition energies of both tautomeric forms for conformer I of
oVATPNNH2 (2). Preliminary results (not shown) indicate that spectra of conformers I and II of
compound (2) are almost identical and no absorptions can be specifically assigned to molecule II.
Thus, the differences in the experimental spectra cannot be attributed to the simultaneous presence of
conformers I and II in solution. On the other hand, results, are in agreement with the presence of the
enol-imine tautomer (A) in DMSO, as has been determined by NMR measurements, and with the
presence of the keto-enamine tautomer (B) in alcoholic solutions, as a consequence of the increasing
dielectric constant of the solvent. The HOMO and the LUMO + 2 are located at the oVA fragment of
OVATPNH2 (see Figure S7 of the Supplementary Material). On the other hand, the LUMO + 1 is
located at the TPNH2 moiety. The LUMO is mainly located at oHVA with non-negligible contributions
from the N atom of TPNH2. Both the HOMO – 1 and the HOMO – 2 are delocalized over the two
moieties that form OVATPNH2. As in the case of compound (1), no appreciable differences in the
shape of MO’s are observed when the two tautomers are compared to each other. Calculated results
obtained suggest that the experimental bands at 424 and 331 nm can be assigned to a HOMO →
LUMO transition originated in different tautomers. It is interesting to note that the experimental band at
223 nm can be assigned to two intraligand (oVA → oVA and TPNH2 → TPNH2) transitions, whereas
the other experimental bands involve delocalized MO’s indicating that the assignment corresponds to
interligand transitions.
4. Conclusions
Two Schiff bases derived from the well-known o-vanillin (o-HVA) aldehyde and containing thiophene
ring have been synthetized with good yield and crystals suitable for x-ray structural determination were
obtained.
The compound oVATPNNH, derived from 2-thiophenecarboxilic acid hydrazide, has been prepared by
a procedure simpler than the one reported previously. The second compound, oVATPNH2, derived
from 2-thiophenemthylamine, shows structural peculiarities, including rotational disorder of the
thiophene ring in one of the two independent molecules present in the crystal. This characteristic
enhances the chelating versatility of this compound as a ligand. Besides the N and O donor atoms, the
tiophene S atom can also be involved in the interaction with metal centres. In the solid state,
oVATPNNH and oVATPNH2 are present in the keto-amine/enol-imine and enol-imine tautomeric forms,
respectively.

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Computational studies based on DFT assisted the interpretation of the experimental results. Calculated
geometrical parameters were in very good agreement with experimental data.
Characterization of the solids was complemented with a detailed spectroscopic study, including FTIR
absorption and Raman dispersion analysis. Spectra were compared with those obtained for the
reactants and characteristic modes assigned to Schiff base formation were observed. Changes in
those modes related to atomic groups involved in the condensation reaction were detected.
Calculations predicted strong coupling of several vibrational modes in many frequencies.
Tautomeric equilibria in solution were analyzed by means of NMR and electronic spectroscopy. The
presence of two tautomeric forms for oVATPNNH and only one for oVATPNNH2 in DMSO, as
determined by NMR, reveals that the keto-amine function in the first compound is prone to
tautomerism, whereas the enol-imine function, present in both compounds, does not display any itrend
towards the keto-enamine tautomer.
Electronic spectra show the influence of the nature of the solvent in the displacement of the equilibria
towards the iminol/enol-imine tautomer in oVATPNNH and to the keto-enamine form in oVATPNNH2.
Again, calculations supported the assignment of the changes observed in the experimental absorption
spectra.
Apendix A. Supplementary data
Crystallographic structural data have been deposited at the Cambridge Crystallographic Data Centre
(CCDC). Enquiries for data can be direct to: Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, UK, CB2 1EZ or (e-mail) deposit@ccdc.cam.ac.uk or (fax) +44 (0) 1223 336033. Any
request to the Cambridge Crystallographic Data Centre for this material should quote the full literature
citation and the reference number CCDC 1576831, CIF file is available as Supplementary information.
Geometrical parameters of oVATPNH2 (Tables S1-S5). complete vibration spectral data and
assignment for both compounds (Tables S6 and S7), 1H-1H NOESY and COSY NMR spectra (Figures
S1-S4), UV-vis spectra of compounds and their precursors in EtOH (figure S5) and MOs involved in
relevant electronic transitions (Figure S6,S7) are available as Supplementary Material.
Acknowledgments
This work was supported by CONICET (CCT-La Plata) and UNLP, Argentina and by Ministerio de
Economía y Competitividad Español (CTQ2014-58812-C2-1-R, CTQ2015-70371-REDT). B.P.C,
G.A.E., O.E.P., R.P.D. and A.C.G.B. are members of the Researcher Career of CONICET. M.R.R. and
J.D.P. are Doctoral Fellows of CONICET. The authors thank Dr. David Ibáñez Martínez (Department of
Chemistry, Universidad de Burgos, Spain) for Raman spectra.

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ACCEPTED MANUSCRIPT
Highlights
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o-vanillin derived Schiff bases obtained by condensation with thiophene
compounds.
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Structural crystallographic and solid state spectroscopic (FTIR and Raman) study.
Spectroscopic study in solution by means of NMR and electronic spectroscopies.
Tautomeric equilibria analysis reveals dependence on structural and solvent nature.
Assignment of vibrational and electronic spectra supported by DFT calculations.