Synthesis, physicochemical characterization, and TD–DFT calculations of monothiocarbohydrazone derivatives

Article abstract of DOI:10.1007/s11224-020-01700-y

Derivatives of thiocarbohydrazone studied so far have shown great biological activity such as antioxidant, antimicrobial, and anticancer. Most of these compounds are bis-substituted derivatives, while monothiocarbohydrazones are much less investigated. Еighteen monothiocarbohydrazones were synthesized and subjected to physicochemical characterization in order to facilitate the examination of their potential biological activity and application in future studies. The structure of synthesized derivatives was confirmed with NMR and FT–IR spectroscopy, and with elemental analysis. For one of the compounds, single-crystal X-ray diffraction analysis was performed. Specific and non-specific molecular interactions were interpreted by LSER principles, using Catalan’s model. For additional information about the dominance and influence of the interactions presented, correlations with Hansen’s solubility parameters were calculated. Influence of the type and position of the substituent on absorption maxima was determined with LFER (linear free-energy relationship) principles, using Hammett’s equation. Acidity constants of the synthesized compounds were theoretically calculated and experimentally determined. Moreover, the excitation of a molecule by a photon of UV–Vis light was interpreted by time-dependent density functional theory (TD–DFT) calculations of UV absorption bands, and intramolecular charge transfer (ICT) was quantified by calculations of the charge transfer distances (D_CT).

Full text of DOI:10.1007/s11224-020-01700-y

Structural Chemistry (2021) 32:1231–1245
https://doi.org/10.1007/s11224-020-01700-y
ORIGINAL RESEARCH
Synthesis, physicochemical characterization, and TD–DFT
calculations of monothiocarbohydrazone derivatives
Gorana S. Mrđan1 & Gyöngyi Gy. Vastag1 & Dušan Đ. Škorić1 & Mirjana M. Radanović1 & Tatjana Ž. Verbić2
Miloš K. Milčić2 & Ivana N. Stojiljković3 & Olivera S. Marković4 & Borko M. Matijević1
&
Received: 18 September 2020 /Accepted: 2 December 2020
/ Published online: 7 January 2021
#
The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021
Abstract
Derivatives of thiocarbohydrazone studied so far have shown great biological activity such as antioxidant, antimicrobial, and
anticancer. Most of these compounds are bis-substituted derivatives, while monothiocarbohydrazones are much less investigated.
Еighteen monothiocarbohydrazones were synthesized and subjected to physicochemical characterization in order to facilitate the
examination of their potential biological activity and application in future studies. The structure of synthesized derivatives was
confirmed with NMR and FT–IR spectroscopy, and with elemental analysis. For one of the compounds, single-crystal X-ray
diffraction analysis was performed. Specific and non-specific molecular interactions were interpreted by LSER principles, using
Catalan’s model. For additional information about the dominance and influence of the interactions presented, correlations with
Hansen’s solubility parameters were calculated. Influence of the type and position of the substituent on absorption maxima was
determined with LFER (linear free-energy relationship) principles, using Hammett’s equation. Acidity constants of the synthe-
sized compounds were theoretically calculated and experimentally determined. Moreover, the excitation of a molecule by a
photon of UV–Vis light was interpreted by time-dependent density functional theory (TD–DFT) calculations of UV absorption
bands, and intramolecular charge transfer (ICT) was quantified by calculations of the charge transfer distances (DCT).
.
.
.
.
.
Keywords Acidity constants LSER LFER Monothiocarbohydrazones TD–DFT X-ray
Introduction
[6, 7], and antitumor [8, 9] activity. Due to their structure,
more specifically to the presence of nitrogen and sulfur
atoms, they are easily coordinated and can build complexes
with many transition metals [10, 11]. Most of the derivatives
synthesized and investigated so far belong to bis-com-
pounds, while monothiocarbohydrazones (mTCHs) are less
investigated. Some studies have shown that mono-
derivatives can show better biological activity than bis-
compounds due to the contribution of existence of free hy-
drazineend(–NH–NH2 group)[1].Consideringallfactsstat-
ed above, the aim of this work was synthesis, physicochem-
ical characterization, and cognition of properties of
monothiocarbohydrazones in order to facilitate the examina-
tion of their potential biological activity and possible appli-
cation in future studies. Eighteen compounds of mTCHs
have been synthesized under controlled conditions in order
to avoid the formation of bis-compounds. Structure of the
compounds obtained has been confirmed by NMR and FT–
IR spectroscopy, as well as with elemental analysis. For one
of the synthesized compounds (17), single-crystal X-ray dif-
fraction analysis was also performed. Solvents’ effect on the
Derivatives of thiocarbohydrazone are synthesized by con-
densation of thiocarbohydrazide with appropriate aldehyde
or ketone. Depending on the molar ratio of the reactants (1:1
or1:2), mono-orbis-substitutedthiocarbohydrazonescanbe
obtained [1, 2]. Many of these compounds tested so far have
shown exceptionally good antimicrobial [3–5], antioxidant
* Gorana S. Mrđan
gorana.mrdjan@dh.uns.ac.rs
1
Faculty of Sciences, University of Novi Sad, Trg Dositeja
Obradovića 3, Novi Sad 21000, Serbia
2
Faculty of Chemistry, University of Belgrade, Studentski trg 12–16,
Belgrade 11000, Serbia
3
Faculty of Forestry, University of Belgrade, Kneza Višeslava 1,
Belgrade 11000, Serbia
4
Department of Chemistry, Institute of Chemistry, Technology and
Metallurgy – National Institute of the Republic of Serbia, University
of Belgrade, Njegoševa 12, Belgrade 11000, Serbia

1232
Struct Chem (2021) 32:1231–1245
UV–Vis absorption spectra was interpreted by LSER (linear
solvation energy relationship) principles with the use of
Catalan’s model. Also, for additional information about the
dominance and influence of the interactions presented, cor-
relationswith Hansen’ssolubilityparameterswereobtained.
Influence of the type and position of the substituent present
on the benzene ring on absorption maxima was determined
by LFER (linear free-energy relationship) principles, using
Hammett’s equation. Moreover, acidity constants—pKa
valuesof synthesizedcompounds—wereexperimentallyde-
termined and compared with values theoretically calculated.
In this research, the nature of the electronic transitions and
electronic structure of mTCHs have been investigated by
using computational theoretical methods which include
MP2 geometry optimizations and TD–DFT calculations.
heated under reflux for 3 h. The resulting products were
crystalized by cooling to the room temperature and then re-
crystallized from a suitable solvent, and the crystals were
washed and dried with ether and methanol. For the com-
pounds 4–9, 11, 12, 14, 16, and 17, there is no complete
literary characterization, so it is presented in the main text,
while the characterization of compounds 1–3, 10, 13, 15,
and 18 is given in Supplementary material.
4-hydroxydobenzaldehyde thiocarbohydrazone (4)
White substance, recrystallized from ethanol. Yield: 69%.
M.p. 203 °C. Elemental analysis: Calculated for C8H10ON4S
(Mw = 210.54 g mol−1): C, 45.34; H, 4.80; N, 26.73; O, 7.60;
S, 15.23%. Found: C, 45.42; H, 4.83; N, 26.27; O, 7.84; S,
15.64%. IR (KBr, cm−1): ν(OH): 3441s, ν(NH2): 3275s,
ν(NH): 3170s, ν(C=N): 1599s, ν(C=S): 1274s, ν(Ar-OH):
1
Experimental
1251s. H NMR (400 MHz, DMSO-d6, δ (ppm)): 4.80 (s,
2H, H2–N4), 6.76 (d, 2H, H–2, H–6), 7.63 (d, 2H, H–3, H–
5), 7.89 (s, 1H, H–7), 9.60 (s, 1H, H–OH), 9.83 (s, 1H, H–
N2), 11.21 (s, 1H, H–N3). 13C NMR (100 MHz, DMSO-d6, δ
(ppm)): 115.8 (C2; C6), 125.9 (C1), 129.6 (C5; C3), 143.2
(C7), 159.7 (C4), 176.3 (C8).
Materials and instruments
All chemicals used for synthesis were purchased from Sigma
Aldrich and with quality for synthesis. Thiocarbohydrazide
(dhS), basic compound for synthesis of mTCHs, was prepared
according to a known procedure [12]. Melting points of syn-
thesized mTCHs were determined with Kofler’s device. IR
spectra were recorded on a Nicolet Nexus 670 FTIR
(Thermo Fisher Scientific) spectrophotometer, in the 400–
4000 cm−1 range using the KBr pellet technique. NMR spectra
(1H and 13C) were recorded in DMSO-d6 on a Bruker
AVANCE III 400 spectrometer operating at 400 MHz (1H)
and 100 MHz (13C), and residual solvent signals were used
for the chemical shift (ppm; δ-scale) calibration. The elemen-
tal analysis was performed using a Vario El III elemental
analyzer. Diffraction experiments were performed on a
Gemini S goniometer (Oxford Diffraction) equipped with a
sealed X-ray tube (λ = 1.5418 Å) and a Sapphire CCD detec-
tor. UV–Vis absorption spectra were recorded on Shimadzu
UV–1800 spectrophotometer in 1.00 cm cells at 25.0 0.1 °C
with concentration of 4 × 10−5 mol dm−3. Solvents used were
also from Sigma-Aldrich, with quality for spectrophotometric
measurements. pH values were measured using Crison pH-
Burette 24 2S equipped with a micro-combined pH electrode
(Crison pH electrode 50 29). The electrode was calibrated by
standard Crison buffer solutions (pH 4.01, 7.00, and 9.21).
2-methylbenzaldehyde thiocarbohydrazone (5)
Pale yellow substance, recrystallized from ethanol. Yield:
66%. M.p. 192 °C. Elemental analysis: Calculated for
C9H12N4S (Mw = 208.57 g mol−1): C, 51.83; H, 5.81; N,
26.98; S, 15.38%. Found: C, 51.74; H, 5.87; N, 26.82; S,
15.57%. IR (KBr, cm−1): ν(NH2): 3296s, ν(NH): 3170s,
1
ν(C=N): 1538s, ν(C=S): 1254s. H NMR (400 MHz,
DMSO-d6, δ (ppm)): 2.35 (s, 3H, H–CH3), 4.85 (s, 2H, H2–
N4), 7.17–7.27 (m, 3H, H–C3, H–C4, H–C5), 8.11 (d, 1H, H–
C6), 8.34 (s, 1H, H–C7), 9.71 (s, 1H, H–N2), 11.32 (s, 1H, H–
N3). 13C NMR (100 MHz, DMSO-d6, δ (ppm)): 19.2 (C–
CH3), 126.4 (C4), 126.5 (C6), 129.9 (C5), 131.1 (C3), 132.6
(C2), 137.1 (C1), 141.2 (C7), 176.2 (C8).
3-methylbenzaldehyde thiocarbohydrazone (6)
White substance, recrystallized from ethanol. Yield: 77%.
M.p. 175 °C. Elemental analysis: Calculated for C9H12N4S
(Mw = 208.57 g mol−1): C, 51.83; H, 5.81; N, 26.98; S,
15.38%. Found: C, 51.77; H, 5.69; N, 27.11; S, 15.43%. IR
(KBr, cm−1): ν(NH2): 3274s, ν(NH): 2982m, ν(C=N): 1637s,
1
General procedure for synthesis of
monothiocarbohydrazones
ν(C=S): 1283s. H NMR (400 MHz, DMSO-d6, δ (ppm)):
2.31 (s, 3H, H–CH3), 4.82 (s, 2H, H2–N4), 7.18 (d, 1H, H–
C4), 7.26 (t, 1H, H–C3), 7.55 (d, 1H, H–C2), 7.69 (s, 1H, H–
C6), 7.96 (s, 1H, H–C7), 9.78 (s, 1H, H–N2), 11.38 (s, 1H, H–
N3). 13C NMR (100 MHz, DMSO-d6, δ (ppm)): 21.5 (C–
CH3), 125.3 (C2), 128.1 (C6), 129.0 (C3), 130.8 (C4), 134.7
(C5), 138.3 (C1), 142.7 (C7), 1766 (C8).
Thiocarbohydrazide (dhS) 1.0 mmol was dissolved in warm
70% ethanol (30 mL). After dissolution, the corresponding
benzaldehyde (0.5 mmol) and one drop of glacial acetic acid
were added to the solution, and the reaction mixture was

Struct Chem (2021) 32:1231–1245
1233
1
4-methylbenzaldehyde thiocarbohydrazone (7)
ν(C=N): 1604s, ν(C=S): 1251s. H NMR (400 MHz,
DMSO-d6, δ (ppm)): 3.82 (s, 3H, H–OCH3), 6.95 (t, 1H, H–
C5), 7.04 (d, 1H, H–C3), 7.36 (m, 1H, H–C4), 8.18 (dd, 1H,
H–C6), 8.36 (s, 1H, H–C7), 9.74 (s, 1H, H–N2), 11.40 (s, 1H,
H–N3). 13C NMR (100 MHz, DMSO-d6, δ (ppm)): 56.1 (C-
OCH3), 112.0 (C3), 121.0 (C6), 122.7 (C4), 126.8 (C5), 131.6
(C1), 138.1 (C7), 158.1 (C2), 176.2 (C8).
Yellow substance, recrystallized from ethanol. Yield: 59%.
M.p. 186 °C. Elemental analysis: Calculated for C9H12N4S
(Mw = 208.57 g mol−1): C, 51.83; H, 5.81; N, 26.98; S,
15.38%. Found: C, 51.28; H, 5.99; N, 26.64; S, 16.09%. IR
(KBr, cm−1): ν(NH2): 3283s, ν(NH): 3179s, ν(C=N): 1604s,
1
ν(C=S): 1237s. H NMR (400 MHz, DMSO-d6, δ (ppm)):
2.30 (s, 3H, H–CH3), 4.84 (s, 2H, H2–N4), 7.19 (d, 2H, H–
C5, H–C3), 7.70 (d, 2H, H–C2, H–C6), 7.96 (s, 1H, H–C7),
9.74 (s, 1H, H–N2), 11.34 (s, 1H, H–N3). 13C NMR
(100 MHz, DMSO-d6, δ (ppm)): 21.5 (C–CH3), 127.8 (C2;
C6), 129.7 (C5; C3), 132.0 (C4), 139.9 (C1), 142.7 (C7),
176.3 (C8).
3-metoxybenzaldehyde thiocarbohydrazone (12)
Pale yellow substance, recrystallized from ethanol. Yield:
91%. M.p. 204 °C. Elemental analysis: Calculated for
C9H12N4OS (Mw = 224.57 g mol−1): C, 48.14; H, 5.40; N,
25.06; O, 7.03; S, 14.32%. Found: C, 48.21; H, 5.36; N,
25.11; O, 7.02; S, 14.30%. IR (KBr, cm−1): ν(NH2): 3249s,
ν(NH): 3160m, ν(O-CH3): 2964m, 2832m, and 1429m,
2-nitrobenzaldehyde thiocarbohydrazone (8)
1
ν(C=N): 1579s, ν(C=S): 1279s. H NMR (400 MHz,
Yellow substance, recrystallized from ethanol. Yield: 68%.
M.p. 222 °C. Elemental analysis: Calculated for C8H9N5O2S
(Mw = 239.60 g mol−1): C, 40.11; H, 3.79; N, 29.36; O, 13.36;
S, 13.38%. Found: C, 39.98; H, 3.77; N, 29.64; O, 13.47; S,
13.14%. IR (KBr, cm−1): ν(NH2): 3296s, ν(NH): 3138m,
ν(C=N): 1610s, ν(NO): 1524s and 1346s, ν(C=S): 1272s.
1H NMR (400 MHz, DMSO-d6, δ (ppm)): 4.93 (s, 2H, H2–
N4), 7.61 (m, 1H, H–C4), 7.74 (m, 1H, H–C5), 8.02 (dd, 1H,
H–C6), 8.44 (s, 1H, H–C7), 8.56 (dd, 1H, H–C3), 10.03 (s,
1H, H–N2), 11.74 (s, 1H, H–N3). 13C NMR (100 MHz,
DMSO-d6, δ (ppm)): 124.9 (C3), 128.8 (C5), 129.0 (C4),
130.6 (C6), 133.7 (C1), 137.3 (C7), 148.7 (C2), 176.3 (C8).
DMSO-d6, δ (ppm)): 3.79 (s, 3H, H–OCH3), 4.86 (s, 2H,
H2–N4), 6.93 (m, 1H, H–C6), 7.20–7.33 (m, 2H, H–C4, H–
C5), 7.51 (s, 1H, H–C2), 7.96 (s, 1H, H–C7), 9.88 (s, 1H, H–
N2), 11.41 (s, 1H, H–N3). 13C NMR (100 MHz, DMSO-d6, δ
(ppm)): 56.0 (C-OCH3), 111.4 (C2), 117.2 (C6), 121.2 (C4),
130.3 (C5), 136.2 (C1), 142.5 (C7), 160.2 (C3), 176.6 (C8).
3-chlorobenzaldehyde thiocarbohydrazone (14)
White substance, recrystallized from ethanol. Yield: 66%.
M.p. 213 °C. Elemental analysis: Calculated for C8H9N4SCl
(Mw = 228.98 g mol−1): C, 41.96; H, 3.97; N, 24.58; S, 14.01;
Cl, 15.48%. Found: C, 41.77; H, 3.88; N, 24.66; S, 14.07; Cl,
15.62%. IR (KBr, cm−1): ν(NH2): 3235m, ν(NH): 3172m,
3-nitrobenzaldehyde thiocarbohydrazone (9)
1
ν(C=N): 1604s, ν(C=S):1279s, ν(C–Cl): 784m. H NMR
Yellow substance, recrystallized from ethanol. Yield: 54%.
M.p. 236 °C. Elemental analysis: Calculated for C8H9N5O2S
(Mw = 239.60 g mol−1): C, 40.11; H, 3.79; N, 29.36; O, 13.36;
S, 13.38%. Found: C, 40.12; H, 3.64; N, 29.57; O, 13.44; S,
13.23%. IR (KBr, cm−1): ν(NH2): 3282s, ν(NH): 3063m,
ν(C=N): 1606s, ν(NO): 1518s and 1347s, ν(C=S): 1248s.
1H NMR (400 MHz, DMSO-d6, δ (ppm)): 4.91 (s, 2H, H2–
N4), 7.66 (t, 1H, H–C5), 8.09 (s, 1H, H–C7), 8.17 (d, 1H, H–
C4), 8.22 (d, 1H, H–C6), 8.73 (s, 1H, H–C2), 10.17 (s, 1H, H–
N2), 11.60 (s, 1H, H–N3). 13C NMR (100 MHz, DMSO-d6, δ
(ppm)): 121.9 (C2), 124.5 (C4), 130.8 (C5), 134.3 (C6), 136.9
(C1), 140.4 (C7), 149.0 (C3), 176.6 (C8).
(400 MHz, DMSO-d6, δ (ppm)): 4.88 (s, 2H, H2–N4), 7.35–
7.43 (m, 2H, H–C4, H–C2), 7.63 (m, 1H, H–C3), 7.96 (s, 1H,
H–C6), 8.14 (s, 1H, H–C7), 10.02 (s, 1H, H–N2), 11.49 (s,
1H, H–N3). 13C NMR (100 MHz, DMSO-d6, δ (ppm)): 126.4
(C7), 127.2 (C3), 129.7 (C2), 130.8 (C4), 134.3 (C1), 137.1
(C5), 140.7 (C6), 176.3 (C8).
3-bromobenzaldehyde thiocarbohydrazone (16)
Yellow substance, recrystallized from ethanol. Yield: 61%.
M.p. 215 °C. Elemental analysis: Calculated for C8H9N4SBr
(Mw = 273.43 g mol−1): C, 35.14; H, 3.32; N, 20.58; S, 11.73;
Br, 29.22%. Found: C, 35.08; H, 3.37; N, 20.42; S, 11.64; Br,
29.46%. IR (KBr, cm−1): ν(NH2): 3282m, ν(NH): 3170m,
2-metoxybenzaldehyde thiocarbohydrazone (11)
1
ν(C=N): 1602s, ν(C=S): 1244s, ν(C-Br): 595m. H NMR
Pale yellow substance, recrystallized from ethanol. Yield:
85%. M.p. 184 °C. Elemental analysis: Calculated for
C9H12N4OS (Mw = 224.57 g mol−1): C, 48.14; H, 5.40; N,
25.06; O, 7.03; S, 14.32%. Found: C, 48.23; H, 5.31; N,
25.11; O, 7.03; S, 14.32%. IR (KBr, cm−1):ν(NH2): 3274s,
ν(NH): 3178s, ν(O-CH3): 2963m, 2837m and 1464m,
(400 MHz, DMSO-d6, δ (ppm)): 4.87 (s, 2H, H2–N4), 7.33
(t, 1H; H–C3), 7.53 (m, 1H; H–C4), 7.67 (d, 1H, H–C2), 7.94
(s, 1H, H–C7), 8.27 (s, 1H, H–C6), 10.03 (s, 1H, H–N2),
11.49 (s, 1H, H–N3). 13C NMR (100 MHz, DMSO-d6, δ
(ppm)): 122.8 (C1), 127.6 (C2), 129.3 (C6), 131.1 (C3),
132.6 (C4), 137.3 (C5), 140.7 (C7), 176.2 (C8).

1234
Struct Chem (2021) 32:1231–1245
4-bromobenzaldehyde thiocarbohydrazone (17)
pKa determination
Pale yellow substance, recrystallized from ethanol. Yield:
88%. M.p. 205 °C. Elemental analysis: Calculated for
C8H9N4SBr (Mw = 273.43 g mol−1): C, 35.14; H, 3.32; N,
20.58; S, 11.73; Br, 29.22%. Found: C, 35.11; H, 3.28; N,
20.39; S, 11.80; Br, 29.42%. IR (KBr, cm−1): ν(NH2):
3267 m, ν(NH): 3168 m, ν(C=N): 1590s, ν(C=S): 1246s,
Most of the synthesized compounds were sparingly soluble in
water; thus, the working solutions of mTCHs were prepared in
a methanol: water mixture (1:1, V:V) in the concentration
range (4.0024–6.3284) × 10−4 M. Investigated compounds
were dissolved in methanol, and solution was diluted with
aqueous NaCl (0.2 M) to maintain a constant ionic strength
(I = 0.1 M). Prior to titration, a certain volume of standard
0.09510 M HCl solution was added to 4.00 mL of every
working compound solution (nHCL: ncomp = 1.2:1) to reach
the full compound protonation. Titrations were performed
with 2.0 μL increments of standard 0.09720 M NaOH solu-
tion in 2.50–12.20 pH range in argon flow at t = 25 1 °C.
NaOH and HCl standard solutions were also prepared in a
methanol: water mixture (1:1, V:V) and standardized by po-
tentiometric titrations. For each compound, four titrations
were performed, and obtained results are shown as an average.
System calibration was performed according to Grann’s meth-
od, using the GLEE (Glass Electrode Evaluation) software
[17]. Experimentally obtained values were processed with
the software package HYPERQUAD 2008 [18].
1
ν(C-Br): 508m. H NMR (400 MHz, DMSO-d6, δ (ppm)):
4.86 (s, 2H, H2–N4), 7.57 (d, 2H, H–C2, H–C6), 7.79 (d,
2H, H–C3, H–C5) 7.95 (s, 1H, H–C7), 9.90 (s, 1H, H–N2),
11.46 (s, 1H, H–N3).13C NMR (100 MHz, DMSO-d6, δ
(ppm)): 123.3 (C4), 129.7 (C3; C5), 132.0 (C2; C6),
134.1(C1), 141.1 (C7), 176.2 (C8).
X–ray diffraction analysis
Single-crystal X-ray diffraction data for the compound 17
were collected on an Oxford Gemini S diffractometer
equipped with a CCD detector, using monochromatized
CuKα radiation (λ = 1.54184 Å). Data reduction and em-
pirical absorption correction were performed with
CrysAlisPRO [13]. The structure was solved by SHELXT
[14] and refined by using the full-matrix least-squares
method implemented in SHELXL [15]. The positions of
the nonhydrogen atoms were refined with anisotropic dis-
placement parameters. Hydrogen atoms were placed at
geometrically ideal distances (N–H = 0.86, O–H = 0.82,
C–H = 0.93, and 0.97 Å for CH3 and CH, respectively),
and their positions were refined using a riding atom mod-
el, with fixed isotropic displacement parameters. Images
of the obtained structures of monothiocarbohydrazone
were made using the Mercury program [16]. Table with
crystallographic data and some refinement parameters is
given in the supplementary material (Table S1).
Crystallographic and refinement details are deposited in
the Cambridge Crystallographic Data Centre under
CCDC 2031024, obtainable free of charge from https://
www.ccdc.cam.ac.uk//structures/.
Computational methods
The geometries of the E and Z isomers of all synthetized
compounds were fully optimized using the ab initio MP2 cal-
culations with a 6-311G(d,p) basis set in the gas phase. The
theoretical UV–Vis spectra were calculated on MP2/6-
311G(d,p) optimized geometries with a time-dependent (TD)
density functional theory (DFT) method. TD–DFT calcula-
tions were performed in DMSO with CAM-B3LYP function-
al and 6-311G(d,p) basis set. Solvent effects have been simu-
lated using the self-consistent reaction field (SCRF)/
isodensity surface polarized continuum model (IPCM).
Qualitative charge transfer index—the charge transfer dis-
tance (DCT) was estimated according to the method proposed
by Le Bahers et al. [19]. All quantum chemical calculations
were performed using the Gaussian 09 program package [20].
Results and discussion
UV–Vis measurements
Characterization of monothiocarbohydrazones
Solvents used for UV–Vis measurements were 2-
choloroethanol (2-ClEtOH), methanol, ethanol, n-propanol,
n-butanol, n-pentanol, i-propanol, i-butanol, t-butanol, acetic
acid, acetonitrile (ACN), dimethyl-sulfoxide (DMSO), N,N-
dimethylformamide (DMF), N,N-dimethylacetamide (DMA),
dichloromethane (DCM), chloroform, ethyl-acetate (EtAc),
tetrahydrofuran (THF), 1,4-dioxane, and diethyl-ether.
Obtained spectrophotometric data were processed with Excel
97–2003.
Purity of the obtained compound was checked by melting
point, NMR, FT–IR spectroscopy, and elemental analysis.
All synthesized compounds are already known except com-
pound 5. Compounds 1, 2, 3, 10, 13, 15, and 18 [21–24] are
known and partly characterized, while the rest are known but
uncharacterized. In this research, both previous and new re-
sults are systematically presented and thoroughly discussed.
Results obtained for partly characterized compounds are in

Struct Chem (2021) 32:1231–1245
1235
agreement with literature data. Chemical reaction used for
synthesis, the list of obtained compounds, and the numbering
of the atoms of interest are shown in Scheme 1.
Fig. 1, while Table 1 presents lengths of the selected bonds,
values of the angles formed between them, and torsion angles.
The length of the C7–N1 bond indicates the existence of a
localized double bond between these atoms, while the C8–N2
and C8–N3 bonds are, due to delocalization, longer than dou-
ble (1.29 Å) and shorter than single bonds (1.47 Å). Also, the
smallest angle with adjacent atoms is formed by the
unprotonated nitrogen atom N1, while the angles around the
protonated N2 and N3 are larger, around 120° and more.
Observing the values of the torsion angles shown in Table 1,
it can be seen that within the structure of compound 17, the
greatest torsion occurs at the free hydrazone end.
Since the optimization of the structures of all eighteen com-
pounds was performed, it is important to compare the exper-
imentally obtained results with the theoretically predicted
ones. Within the E isomer of compound 17, the dihedral angle
between the benzene ring and the thiocarbohydrazone moiety
is 7.57° (Table S2) and shows good agreement with the ex-
perimentally confirmed structure where this angle amounts
6.68°. The overlay of the two structures is shown in Fig. 2.
Results of the elemental analysis were within 0.5% of the
theoretical values. The FT–IR spectra of synthesized mTCHs
absorption between 3063 and 3188 cm−1 were assigned to N–
H vibrations. ν(C=N) for all compounds were in the range
from 1538 to 1637 cm−1, while signals recorded from 1237
to 1284 cm−1 were attributed to ν(C=S) band. One of the
proofs that all synthesized compounds belong to the deriva-
tives of monothiocarbohydrazones and that bis-compounds
were not formed is the existence of ν(NH2) vibrations that
1
were recorded in the range of 3235–3300 cm−1. H and 13C
NMR spectra of uncharacterized mTCHs showed a great
match with the signals expected for hydrogen and carbon
1
atoms. Also, H NMR spectra for partly characterized
mTCHs showed extraordinarily well superposition with the
literature data. Another proof that these compounds belong
to mono-derivatives is expressed through the existence of a
signal in the region between 4.70 and 4.91 ppm (1H NMR
spectra) for every synthesized compound, assigned to the
NH2 group.
Some previous studies have shown that mTCHs have sev-
eral possible solution structures including configurational (E
or Z) isomers around imine bond and thione/thiol tautomers
[25]. Careful analysis of the 1H NMR spectra of the mTCHs
concluded that all of the synthesized compounds in DMSO-d6
solution exist in thione form and that there is no mixture of
two isomers—E and Z.
Geometry optimization of monothiocarbohydrazones
All the isomers of mTCHs differing in configuration at the
C7=N1 double bond were optimized by quantum chemical
calculation at the second-order Møller–Plesset perturbation
theory (MP2) level using 6-311G(d,p) basis set in the gas
phase. The geometric structure of E isomers shows a nearly
planar configuration with the dihedral angles between phenyl
group and thiocarbohydrazone moiety from 5.77 to 9.12°
(Table S2), except for three compounds with ortho substitu-
ents: 2, 8, and 11 (18.14°–27.90°). In compound 2, intramo-
lecular hydrogen bond between –OH substituent in ortho po-
sition and N1 is formed inducing deviation from planarity.
Compounds 8 and 11 have bulky polar substituents present
in ortho position (–NO2 and –OCH3, respectively) and strong
repulsive electrostatic interaction with thiocarbohydrazone
X–ray structural analysis of
monothiocarbohydrazones
Compound 17 (4-bromobenzaldehyde thiocarbohydrazone)
was successfully obtained in the form of single crystals by
recrystallization in a suitable solvent and slow evaporation.
Molecular structure obtained for this compound is shown in
O
H
Scheme 1 Synthesis procedure
and numbering of atoms of
monothiocarbohydrazones
0.5 mmol
N2
N3
7
H
N
H
N
6
3
S
8
1
5
4
H2N
N4
N
NH2
R
+
H2O
N1
R
N
EtOH reflux, CH3COOH cat.
H2N
S
H
N
H
2
1.0 mmol
Compound
1
Reactant (R)
H
o/m/p - OH
2/3/4
o/m/p - CH3
o/m/p - NO2
o/m/p - OCH3
m/p - Cl
5/6/7
8/9/10
11/12/13
14/15
16/17
18
m/p - Br
p - F

1236
Struct Chem (2021) 32:1231–1245
Fig. 1 Molecular structure of the
compound 17
moiety. Thus, the most stable conformation for these com-
pounds is with substituent rotated away from
thiocarbohydrazone moiety, and the deviation from planarity
is a consequence of steric repulsion between hydrogen on C7
atom and substituent in ortho position (Fig. S1). In compound
5, nonpolar –CH3 group is in ortho position, so it can be
oriented towards thiocarbohydrazone moiety and retain planar
geometry (Table S2). On the other hand, Z isomers have much
larger deviations from planarity (52.28–70.70°) due to present
steric clash/hindrance between a hydrogen atom from N2 and
hydrogen atoms or substituents in ortho position from phenyl
group. Optimized structures of both isomers of all investigated
compounds are represented on Fig. S1.
coefficients a, b, c, and d describe the sensitivity of the ab-
sorption maxima to different types of solvent–solute
interactions.
UV–Vis absorption spectra of the synthesized
monothiocarbohydrazones were recorded within the 200–
400 nm range within twenty-one solvent of various properties.
As an example, spectrum of compound 5 in protic (a) and
aprotic (b) solvents is shown on Fig. 3. Similar spectra were
obtained for all other compounds.
After the deconvolution of the recorded spectra, maxima
that were considered in further analysis were in the 280–310-
nm range. The reason of this wide range of wavelengths is the
variety of substituents present, as well as the properties of the
solvents used. Absorption frequencies (wave numbers,
νmax·10−3, cm−1) and calculated values of molar absorptivity
of eighteen investigated monothiocarbohydrazones in all sol-
vents used are represented in Table S3.
Solvents’ effect on the absorption spectra of
monothiocarbohydrazones
Observing the values in Table S3, it can be seen that with
the increase of the solvent’s polarity absorption maxima of the
mTCHs shift hypsochromically, that is, the values of the ab-
sorption frequencies of the tested compounds increase. In or-
der to confirm this fact, correlations with empirical polarity
parameter (ETN [28], Table S4) of the solvents used have been
made. An example of the obtained linear dependencies is
shown in Fig. 4. For all other compounds tested, similar de-
pendencies were obtained.
Effects of specific and nonspecific solvent–solute interactions
on the absorption maxima of the mTCHs were studied by
multiple regression analysis (LSER principles) using
Catalan’s solvatochromic model [26, 27], described with
Eq. 1:
ν ¼ ν0 þ aSA þ bSB þ cSP þ dSdP
ð1Þ
Results of the quantitative analysis of specific and nonspe-
cific interactions represented between solvents used and in-
vestigated mTCHs obtained with Catalan’s solvatochromic
model are given in Table 2.
As can be seen from Table 2, the obtained correlation co-
efficients for each compound are high, in the range 0.902–
where ν is the frequency in a given solvent, ν0 is the solute
property of the reference system, cyclohexane, SA represents
the hydrogen bond donating ability (HBD, acidity of the sol-
vent), SB is a measure of the hydrogen bond accepting ability
(HBA, basicity of the solvent), SP describes the polarizability,
and SdP represents dipolarity of the solvent. Correlation
Table 1 Geometric parameters of
the compound 17
Bond
Bond lengths (Å)
Bond
Angle (°)
Bond
Torsion angle. τ (°)
C7–N1
N2–C8
C8–S1
C8–N3
C4–Br1
1.275 (3)
1.344 (3)
1.681 (2)
1.335 (3)
1.899 (2)
N4–N3–C8
N3–C8–S1
S1–C8–N2
C8–N2–N1
N2–N1–C7
C7–C1–C6
122.9 (2)
123.5 (2)
120.4 (1)
120.0 (2)
115.2 (2)
118.0 (2)
C7–N1–N2–C8
N2–C8–N3–N4
C6–C1–C7–N1
176.3 (2)
− 171.4 (2)
− 179.2 (2)

Struct Chem (2021) 32:1231–1245
1237
Fig. 2 Overlay of the optimized
structure (red) 17 with the struc-
ture obtained by single-crystal
XRD (green)
0.975, and it is assumed that the model used is suitable for
describing intermolecular interactions between the tested
compounds and the surrounding medium. Regression coeffi-
cient a has the biggest values, which means that the greatest
impact on spectral changes of the mTCHs has the acidity of
the solvent used (exceptions are compounds 2 and 10 where
polarizability of the solvent is the most dominant). Somewhat
smaller effects on maxima shifting have polarizability and
dipolarity of the solvent, presented with regression coeffi-
cients c and d, while basicity of the solvent has the slightest
impact on spectral changes of the investigated derivatives
(values of the regression coefficient b). A positive sign in front
of regression coefficients a, b, and d indicates that with in-
creasing of the solvent’s acidity, basicity, and dipolarity,
hypsochromic shifting of the maxima will occur. On the other
hand, the negative sign in front of the coefficient c indicates
that increasing solvent polarizability will result in a
bathochromic shifting of the investigated derivatives absorp-
tion maxima.
In addition to the solvent effect, correlations of the absorp-
tion maxima with Hansen’s solubility parameters [29] of the
solvents used were obtained by the Eq. 2.
νmax ¼ ν0 þ dδD þ pδP þ hδH
ð2Þ
where δD represents energy from dispersion forces, δP is en-
ergy from dipolar forces, and δH ability of building hydrogen
bonds, while d, p, and h are regression coefficients that show
measures of the impact of these forces on intermolecular in-
teractions that occur between the tested mTCHs and surround-
ing medium. Results obtained by correlations of absorption
frequencies of mTCHs (Table S3) and Hansen’s solubility
parameters (Table S4) are presented in Table 3.The highest
values were obtained for the regression coefficient d, which
means that the dispersion forces are the most dominant inter-
actions between the examined monothiocarbohydrazones and
the surrounding medium. They are followed by the influence
of hydrogen bond construction (regression coefficient h), and
finally, with the smallest impact, dipolar forces are present
(the coefficient p for all compounds has the smallest value).
A positive sign in front of the coefficients p and h indicates
that with the increase of the influence of dipolar forces and the
possibility of building a hydrogen bond, a hypsochromic shift
of absorption maxima will occur. A negative sign in front of
the coefficient d indicates a possible bathochromic shift with
an increase of the influence of dispersion forces.
In order to confirm the accuracy of the applied model,
correlations between the experimentally obtained and theoret-
ically calculated results were made. Obtained linear depen-
dence is presented in Fig. 5. Correlation coefficient is high
(0.979), leading to conclusion that the used model is suitable
for the interpretation of the interactions between investigated
mTCHs and surrounding medium.
1.4
Water
AcN
1.2
Methanol
DMSO
1.2
Ethanol
DMF
1.0
n-propanol
DMA
1.0
n-butanol
DCM
n-pentanol
Chloroform
EtAc
0.8
0.6
0.4
0.2
0.0
0.8
i-butanol
i-propanol
THF
1.4-dioxan
Diethyl-ether
0.6
0.4
0.2
0.0
t-butanol
Acetic acid
2-ClEtOH
250
300
350
400
300
350
400
, nm
, nm
Fig. 3 UV–Vis absorption spectra of compound 5, 2-methylbenzaldehyde thiocarbohydrazone, in protic (a) and aprotic (b) solvents

1238
Struct Chem (2021) 32:1231–1245
32,0
31,8
31,6
31,4
31,2
31,0
30,8
33
32
31
30
29
28
27
r2 = 0.979
27
28
29
30
31
32
33
0,0
0,2
0,4
0,6
0,8
1,0
calc10-3, cm-1
N
ET
Fig. 4 Correlation of absorption frequencies of compound 5 with ET
N
Fig. 5 Correlation of experimentally obtained with theoretical results of
Catalan’s model
The effect of substituent on UV–Vis absorption spec-
tra of monothiocarbohydrazones
solvent, and ρ is a proportionality constant reflecting the sen-
sitivity of the spectral data to the substituent effects, described
by the substituent constant, σm,p (Hammett’s constant). In
Fig. 6 spectra of all compounds recorded in water are
represented.
Observing Fig. 6 and Table S3, it can be noted that all
tested compounds have more or less bathochromic displace-
ment relative to the unsubstituted compound (1). The excep-
tions are compounds 8 and 18 where some hypsochromic
shifts have been reported. Table S5 shows the values of
Hammett’s substituent constants with exceptions for ortho-
The influence of the substituent on the appearance of the UV–
Vis absorption spectra is reflected in its type and position on
the benzene ring. Quantitative analysis of this impact was
determined with the help of Hammett’s equation [30], by ap-
plying LFER principles:
νmax ¼ ν0 þ ρσm;p
ð3Þ
where νmax is absorption frequency at the maximum absor-
bance, ν0 represents the wave number in the irrespective
Table 2 Values of the regression coefficients of Catalan’s solvatochromic model
Compound v0·10−3. (cm−1
)
a·10−3. (cm−1
)
b·10−3. (cm−1
)
c·10−3. (cm−1
)
d·10−3. (cm−1
)
r2
sd
F
Solvents
excluded
1
1
31.575 ( 0.154) 0.713 ( 0.046)
29.717 ( 0.265) 0.553 ( 0.073)
31.531 ( 0.361) 0.921 ( 0.092)
30.426 ( 0.142) 0.610 ( 0.039)
31.093 ( 0.245) 0.750 ( 0.073)
31.631 ( 0.173) 0.667 ( 0.048)
/
−0.305 ( 0.211)
−0.459 ( 0.444)
−0.988 ( 0.419)
−0.269 ( 0.185)
−0.482 ( 0.335)
−0.460 ( 0.225)
0.283 ( 0.059) 0.971 0.046
0.311 ( 0.062) 0.908 0.070
0.518 ( 0.118) 0.945 0.091
0.305 ( 0.039) 0.975 0.037
0.344 ( 0.094) 0.940 0.072
0.191 ( 0.062) 0.967 0.046
0.203 ( 0.088) 0.916 0.065
0.601 ( 0.127) 0.921 0.092
0.282 ( 0.083) 0.949 0.064
0.445 ( 0.120) 0.950 0.093
0.195 ( 0.053) 0.902 0.039
0.423 ( 0.098) 0.951 0.072
125
34
2
2
/
/
/
/
/
2, 3
2
3
64
4
134 2, 3
59
102 2, 3
5
2
6
7
31.236 ( 0.246) 0.584 ( 0.068) 0.103 ( 0.064) −0.355 ( 0.320)
38
38
70
72
32
69
2, 3
2, 3
2
8
32.240 ( 0.361) 1.039 ( 0.132)
31.403 ( 0.215) 0.746 ( 0.065)
27.488 ( 0.314) 1.098 ( 0.094)
30.226 ( 0.149) 0.244 ( 0.041)
/
/
/
/
− 0.702 ( 0.471)
− 0.384 ( 0.295)
− 0.583 ( 0.429)
− 0.573 ( 0.193)
9
10
11
12
13
14
15
16
17
18
2
2, 3
2, 3
2, 3
2
30.967 ( 0.274) 0.826 ( 0.076) 0.079 ( 0.072) − 0.601 ( 0.356)
30.795 ( 0.152) 0.575 ( 0.042)
31.261 ( 0.327) 0.943 ( 0.098)
31.004 ( 0.287) 0.920 ( 0.086)
31.246 ( 0.310) 0.813 ( 0.093)
30.945 ( 0.244) 0.772 ( 0.073)
31.388 ( 0.313) 0.801 ( 0.094)
/
/
/
/
/
/
− 0.234 ( 0.198)
− 0.734 ( 0.448)
− 0.702 ( 0.3939) 0.404 ( 0.110) 0.944 0.085
− 0.652 ( 0.424)
− 0.480 ( 0.333)
− 0.477 ( 0.429)
0.128 ( 0.054) 0.963 0.0470 90
0.347 ( 0.126) 0.930 0.097
50
63
42
61
43
2
0.303 ( 0.119) 0.918 0.092
0.306 ( 0.094) 0.942 0.072
0.475 ( 0.120) 0.919 0.093
2
2
2
The values in parentheses represent the determination error; r2 correlation coefficient, sd standard deviation, F Fischer’s coefficient; 1, error greater than
the value; 2, 2-ClEtOH; 3, diethyl-ether

Struct Chem (2021) 32:1231–1245
1239
Table 3 Results of correlations of absorption frequencies of monothiocarbohydrazones with Hansen’s parameters
Compound
ν0·10−3. cm−1
d·10−3. cm−1
p·10−3. cm−1
h·10−3. cm−1
r2
sd
F
Solvents
excluded
1
32.354 ( 0.347)
33.580 ( 0.141)
33.205 ( 0.494)
31.180 ( 0.289)
31.859 ( 0.285)
32.341 ( 0.308)
32.556 ( 0.314)
33.787 ( 0.440)
32.292 ( 0.338)
29.315 ( 0.511)
30.434 ( 0.164)
32.202 ( 0.384)
31.440 ( 0.291)
32.478 ( 0.455)
32.362 ( 0.439)
32.318 ( 0.371)
31.664 ( 0.350)
32.928 ( 0.410)
− 0.056 ( 0.020)
− 0.065 ( 0.008)
− 0.123 ( 0.028)
− 0.051 ( 0.016)
− 0.062 ( 0.016)
− 0.061 ( 0.017)
− 0.082 ( 0.017)
− 0.105 ( 0.023)
− 0.061 ( 0.019)
− 0.118 ( 0.028)
− 0.034 ( 0.009)
− 0.086 ( 0.022)
− 0.048 ( 0.016)
− 0.096 ( 0.026)
− 0.099 ( 0.025)
− 0.083 ( 0.021)
− 0.059 ( 0.020)
− 0.094 ( 0.023)
0.007 ( 0.005)
0.021 ( 0.003)
0.017 ( 0.001)
0.023 ( 0.004)
0.017 ( 0.002)
0.022 ( 0.002)
0.019 ( 0.003)
0.012 ( 0.003)
0.028 ( 0.006)
0.020 ( 0.003)
0.027 ( 0.004)
0.009 ( 0.001)
0.023 ( 0.003)
0.019 ( 0.003)
0.027 ( 0.004)
0.024 ( 0.004)
0.023 ( 0.003)
0.023 ( 0.003)
0.020 ( 0.003)
0.903
0.982
0.911
0.916
0.942
0.914
0.918
0.938
0.916
0.918
0.902
0.924
0.918
0.905
0.908
0.918
0.910
0.907
0.091
0.032
0.124
0.073
0.075
0.081
0.074
0.086
0.085
0.128
0.042
0.097
0.073
0.120
0.116
0.098
0.092
0.103
37
165
34
40
65
43
33
46
36
37
34
45
41
38
39
41
40
36
1
2
/
1, 2, 3
1, 2, 3
1, 2
1
3
/
4
0.007 ( 0.004)
5
0.008 ( 0.004)
6
0.005 ( 0.004)
1
7
/
1, 2, 3, 4
1, 2, 3, 5
1, 2, 3
1, 2, 3
1, 6
1, 2
1, 2
1
8
0.012 ( 0.005)
9
/
/
/
/
/
/
/
/
/
/
10
11
12
13
14
15
16
17
18
1
1, 3
1
1, 2
The values in parentheses represent the determination error; 1, diethyl-ether; 2, EtAc; 3, THF; 4, i-butanol; 5, water; 6, DCM
substituted compounds. They are excluded from these corre-
lations because of the steric interferences.
By correlating these values with absorption frequencies of
mTCHs, linear dependencies are obtained such as dependency
given in Fig. 7. For all other solvents used, similar results were
recorded.
As it can be seen, two separate dependencies are obtained.
The first, with a positive slope, belongs to electron-donor sub-
stituents (negative values of the Hammett’s constants), while
the second, with a negative slope, describes the electron-
acceptor substituents (positive values of the Hammett’s con-
stants) with deviation for compounds 9 (3-NO2), 14 (3-Cl),
and 16 (3-Br). Results of correlations for all solvents used are
given in Table 4.
The effect of substituent present is reflected through the
absolute value of proportionality constant ρ—the higher the
values, the bigger the influence on the change of electronic
density in the molecule. From Table 4, it can be seen that
greater impacts on spectral behavior of mTCHs have
electron-acceptor substituents. Negative sign in front of all
values of ρ for electron-acceptor substituents indicates a
1.5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1.0
0.5
0.0
3-Cl
3-NO2
32
31
30
29
3-Br
Electron-donor substituents
Electron-acceptor substituents
200
250
300
350
400
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
, nm
m,p
Fig. 6 UV–Vis Absorption spectra of all monothiocarbohydrazones
recorded in water
Fig. 7 Correlations of absorption frequencies of mTCHs in water with
Hammett’s constants

1240
Struct Chem (2021) 32:1231–1245
Table 4 Regression coefficients
of Hammett’s equation
Solvent/ parameter
ν0·10−3. cm−1
ρ·10−3. cm−1
r
sd
Electron-donors
Water
32.418 ( 0.050)
32.080 ( 0.073)
31.960 ( 0.045)
31.969 ( 0.071)
31.904 ( 0.068)
31.848 ( 0.072)
31.864 ( 0.054)
31.844 ( 0.041)
31.730 ( 0.095)
32.055 ( 0.065)
32.210 ( 0.046)
31.821 ( 0.069)
31.714 ( 0.060)
31.655 ( 0.069)
31.626 ( 0.057)
31.623 ( 0.028)
31.594 ( 0.040)
31.591 ( 0.048)
31.565 ( 0.057)
31.557 ( 0.064)
31.458 ( 0.025)
3.482 ( 0.226)
3.385 ( 0.331)
3.339 ( 0.203)
3.220 ( 0.320)
3.204 ( 0.309)
3.305 ( 0.328)
3.308 ( 0.247)
3.262 ( 0.187)
3.242 ( 0.431)
3.290 ( 0.294)
3.761 ( 0.207)
3.267 ( 0.311)
3.230 ( 0.272)
2.996 ( 0.313)
3.071 ( 0.258)
3.085 ( 0.126)
3.206 ( 0.183)
3.253 ( 0.216)
3.120 ( 0.258)
3.166 ( 0.283)
3.137 ( 0.114)
0.983
0.986
0.994
0.985
0.986
0.986
0.992
0.995
0.974
0.988
0.995
0.987
0.990
0.984
0.990
0.998
0.995
0.993
0.990
0.988
0.998
0.040
0.098
0.061
0.095
0.092
0.098
0.073
0.056
0.128
0.088
0.062
0.093
0.081
0.093
0.077
0.038
0.054
0.064
0.077
0.086
0.034
Methanol
Ethanol
n-Propanol
n-Butanol
n-Pentanol
i-Butanol
i-Propanol
t-Butanol
Acetic acid
2-ClEtOH
ACN
DMSO
DMF
DMA
DCM
Chloroform
EtAc
THF
1,4-dioxan
Diethyl-ether
Electron-acceptors
Water
32.727 ( 0.125)
32.352 ( 0.134)
32.192 ( 0.127)
32.094 ( 0.113)
32.073 ( 0.125)
31.999 ( 0.124)
32.147 ( 0.144)
32.178 ( 0.156)
31.898 ( 0.132)
32.244 ( 0.137)
32.393 ( 0.134)
32.022 ( 0.134)
31.882 ( 0.116)
31.843 ( 0.121)
31.771 ( 0.106)
31.827 ( 0.129)
31.768 ( 0.130)
31.703 ( 0.128)
31.690 ( 0.137)
31.649 ( 0.129)
31.580 ( 0.127)
− 5.025 ( 0.383)
− 5.140 ( 0.410)
− 5.284 ( 0.388)
− 5.039 ( 0.344)
− 5.259 ( 0.384)
− 5.204 ( 0.380)
− 5.339 ( 0.442)
− 5.479 ( 0.477)
− 5.318 ( 0.404)
− 5.109 ( 0.420)
− 5.129 ( 0.412)
− 5.322 ( 0.410)
− 5.425 ( 0.356)
− 5.392 ( 0.372)
− 5.349 ( 0.326)
− 5.426 ( 0.396)
− 5.422 ( 0.398)
− 5.293 ( 0.391)
− 5.521 ( 0.420)
− 5.432 ( 0.394)
− 5.480 ( 0.388)
− 0.966
− 0.985
− 0.987
− 0.989
− 0.987
− 0.987
− 0.983
− 0.982
− 0.986
− 0.983
− 0.984
− 0.986
− 0.989
− 0.988
− 0.991
− 0.987
− 0.987
− 0.987
− 0.986
− 0.987
− 0.988
0.245
0.262
0.248
0.220
0.245
0.243
0.282
0.305
0.258
0.268
0.263
0.262
0.228
0.238
0.208
0.253
0.254
0.250
0.268
0.252
0.248
Methanol
Ethanol
n-Propanol
n-Butanol
n-Pentanol
i-Butanol
i-Propanol
t-Butanol
Acetic acid
2-ClEtOH
ACN
DMSO
DMF
DMA
DCM
Chloroform
EtAc
THF
1,4-dioxan
Diethyl-ether
reduced electron density in the excited state related to the
ground. On the other hand, when proportionality constant
has a positive sign there will be an increased electron density
in the excited state in relation to the basic. In the end, observ-
ing values only within one type of substituents, it can be con-
cluded that properties of the solvents used have no significant

Struct Chem (2021) 32:1231–1245
1241
Table 5 Theoretically calculated (pKa calc) and experimentally
determined (pKa exp) pKa values of mTCHs
effect on the absorption changes caused by the nature of the
substituent (values of the proportionality constants for all sol-
vents used are very close).
Compound
pKa1 calc
pKa1 exp
pKa2 calc
pKa2 exp
The reason for the deviation of the three mentioned com-
pounds (9, 14, and 16) can be explained using resonant struc-
tures of the tested compounds presented on Scheme 2. А neg-
ative charge is clearly observed in the ortho and para posi-
tions, while meta positions are regions with a lack of electron
density. The nitro group, as the strongest electron-acceptor,
stabilizes ortho and para positions very well. For the same
reason, this group in the meta position cannot express its elec-
tronic effects at full capacity. This behavior is characteristic
for other meta-substituted derivatives with electron-acceptor
substituents (such as compound 14 and 16).
1
3.67
3.51
3.52
3.73
3.75
3.79
3.80
3.07
3.73
3.71
3.81
3.26
3.53
3.59
3.69
3.49 0.05
3.63 0.07
3.74 0.09
3.62 0.07
3.82 0.04
3.64 0.03
3.67 0.06
3.30 0.27
2.90 0.09
3.63 0.03
2.96 0.10
3.71 0.02
3.65 0.01
3.48 0.04
3.77 0.03
2
8.94
9.11
9.00
9.18 0.08
9.86 0.07
10.37 0.11
3
4
5
6
7
10
11
12
13
14
16
17
18
Determination of acidity constants (pKa) of
monothiocarbohydrazones
Determination of important physicochemical parameters such
as acidity constant (pKa value) is performed in early stage of
testing new potential drugs due to easier determination of their
further application. pKa of mTCHs was theoretically calculat-
ed using the ADMET predictor [31] and experimentally de-
termined by potentiometric titration. Compounds 9, 10, and
16 were not sufficiently soluble in methanol: water mixture, so
their acidity constants were not determined. For all other com-
pounds determinations were performed within the pH range
2.5–12.0. Possible protolytic equilibria present in studied so-
lutions is shown on Scheme 3, exemplified by compound 4.
pKa Value of terminal amino group was determined for all
compounds, while for compounds 2–4, containing hydroxyl
group as a substituent, pKa value of phenolic group was also
obtained. Obtained results are shown in Table 5.
As can be seen from Table 5, values of the experimentally
obtained acid constants of mTCHs showed good agreement
with the predicted pKa. For compounds 11 and 13 with -OCH3
substituent in ortho and para position obtained pKa have no-
ticeable lower values that the predicted. Similarity between
these two compounds is due to the same electronic effects of
–OCH3 group in mentioned positions. In general, by observ-
ing the results within Table 5, small differences between ex-
+
perimentally determined values of pKa1 (NH3 /NH2) can be
noted. This trend can be explained by the fact that due to the
large distance of the substituent present on the benzene ring
from the ionization center, its electronic effects cannot be
manifested.
Scheme 2 Resonant structures of
thiocarbohydrazone derivatives

1242
Struct Chem (2021) 32:1231–1245
H
N
H
N
H
N
H
N
Scheme 3 Possible equilibrium
in solution for compound 4
+
N
pK
a1
H N
2
N
H N
3
H4M+
H3M
S
S
OH
OH
H
N
H
N
H N
N
2
H2M-
S
-
O
TD–DFT calculations
induce a deformation in the molecular electronic cloud due to
appropriate partial shift of electrons from one moiety of a mole-
cule to another. In order to quantify this phenomenon known as
intramolecular charge transfer (ICT), charge transfer distance
(DCT) was calculated using the TD–DFT method. The results
of the calculations of the ICT index for E isomers of all investi-
gated compounds are shown in Table 6. On Fig. 9 the difference
between electronic densities in the ground and first excited state
(left picture) and positions of charge loss and charge gain
barycenters (right picture) are shown. In the nitro-substituted
compounds 8, 9, and 10, during excitations, the ICT process is
noticed from the nitro group to thiocarbohydrazide moiety. In
compound 10, charge is transferred across the longer distance
(4.051 Å) from nitro group in para position to the
thiocarbohydrazide part of the molecule. As can be seen in Fig.
9, the positions of barycenters confirm the ICT character of nitro-
substituted compounds (8, 9, and 10). In other compounds, the
degree of CT character of an electronic transition is low.
In order to further support experimental findings, theoretical
UV–Vis absorption spectra of E and Z isomers of all synthesized
monothiocarbohydrazones in DMSO were calculated from MP2
optimized structures by TD–DFT method using CAM–B3LYP
functional and 6-311G(d,p) basis set. Obtained results of TD–
DFT calculations, oscillator strength, vertical excitation energies,
and orbital decomposition of electronic transitions are presented
in Tables S6 and S7. A comparison of experimentally obtained
and theoretically calculated spectra of the E isomer of compound
17 in DMSO is shown in Fig. 8.
The obtained results of quantum chemical calculations are in
good qualitative agreement with the experimental data. Most of
the compounds have a bathochromic shift relative to
unsubstituted compound with the exception of compound 5
where small hypsochromic shifting was noted. TD–DFT calcu-
lations show that, due to its planar geometries, E isomers have
first absorption maxima at lower energies than Z isomers. For
most of the E isomers, the main contribution to the first excited
state comes from HOMO–LUMO single particle excitation. On
the other hand, in the case of Z isomers, for the first excited state,
the transition from HOMO to LUMO is expressed in a signifi-
cantly smaller percentage and is often coupled with other orbital
transitions. On Fig. S2 some orbitals included in electron excita-
tions for E isomers of mTCHs are shown. Photon absorption can
Conclusion
W i t h i n t h i s p a p e r , e i g h t e e n c o m p o u n d s o f
monothiocarbohydrazones were synthesized under controlled
conditions in order to avoid the formation of bis-compounds.
Table 6 Calculated values of DCT during electron excitation for E
isomer
Compound
es
DCT (Å)
Compound
es
DCT (Å)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1.118
0.464
0.541
0.287
1.012
0.961
0.581
10
11
12
13
14
15
16
17
1
1
1
1
1
1
1
1
4.051
0.642
0.346
0.411
1.466
1.018
1.453
0.908
1
2
2.127
1.133
Fig. 8 Theoretically calculated and experimentally determined UV–Vis
absorption spectra of the E isomer of compound 17 in DMSO
9
1
3.897
18
1
0.904

Struct Chem (2021) 32:1231–1245
1243
Fig. 9 ICT processes in E isomers
of monothiocarbohydrazones (1–
18). Left images, difference
between densities in first excited
and ground state (red and blue,
density increase and decrease
upon transition, respectively);
right images, positions of
barycenters for charge loss (cyan
circle) and charge gain (violet
circle) upon transition
Purity and structure of the synthesized compounds was con-
firmed by NMR and FT–IR spectroscopy and elemental anal-
ysis. A proof that all synthesized compounds belong to mono-
derivatives is given trough the existence of a signal in the region
between 4.70 and 4.91 ppm (1H NMR spectra) assigned to the
NH2 group, for all compounds. Optimized structures show that
E isomer is more stable for all derivatives and that most of the
synthesized compounds have planar structures (exceptions are
compounds with –OH, –NO2, and –OCH3 groups in ortho
positions). For compound 17 (4–Br), X-ray structural analysis
was performed, and obtained results are in agreement with the-
oretical calculations. The effect of specific and non-specific
solvent–solute interactions studied by Catalan’s model showed
that the greatest impact on spectral changes of the mTCHs has
the acidity of the solvent used (exceptions are compounds 2 and
10). Somewhat smaller effects on maxima shifting have polar-
izability and dipolarity of the solvent, while the basicity of the
solvent has the slightest impact on spectral changes of the in-
vestigated derivatives. In addition to the solvent effect, results
of the correlations of the absorption maxima with Hansen’s

1244
Struct Chem (2021) 32:1231–1245
Consent to participate This article does not contain any studies involv-
ing animals performed by any of the authors.
solubility parameters showed that the dispersion forces are the
most dominant interactions between the examined mTCHs and
the surrounding medium. They are followed by the influence of
hydrogen bond construction and finally, with the smallest im-
pact, dipolar forces. Results of the influence of the substituent
present on the UV–Vis absorption spectra of mTCHs deter-
mined using Hammett’s equation show that greater impact on
spectral behavior of mTCHs has electron-acceptor than
electron-donor substituents. Also, it has been concluded that
properties of the solvents used have no significant effect on
the absorption changes caused by the nature of the substituent.
Experimentally obtained pKa values of mTCHs showed good
agreement with the theoretically calculated ones and for amino
group were in the range from 2.90 to 3.77. For compounds 2–4,
pKa of the phenol group were also determined (9.18, 9.86 and
10.37, respectively). Theoretically predicted UV–Vis absorp-
tion spectra calculated in DMSO showed good agreement with
experimentally obtained spectra. TD–DFT calculations in
DMSO showed that for E isomers of the mTCHs the main
contribution to the first excited state comes from HOMO–
LUMO single particle excitation. In nitro-substituted com-
pounds (8, 9, and 10), the ICT process was noticed and electron
density was transferred from the nitro group to the
thiocarbohydrazide part of the molecule.
Consent to publish All the authors mentioned in the manuscript have
given consent for submission and subsequent publication of the
manuscript.
References
1. Božić A, Marinković A, Bjelogrlić S, Todorović TR, Cvijetić IN,
Novaković I, Muller CD, Filipović NR (2016) Quinoline based
mono- and bis-(thio)carbohydrazones: synthesis, anticancer activity
in 2D and 3D cancer and cancer stem cell models. RSC Adv 6:
10476–104781
2. Gangarapu K, Manda S, Jallapally A, Thota S, Karki SS, Balzarini
J, De Clercq E, Tokuda H (2014) Synthesis of thiocarbohydrazide
and carbohydrazide derivatives as possible biologically active
agents. Med Chem Res 23:1046–1056
3. Shebl M, Khalil SME, Al-Gohani FS (2010) Preparation, spectral
characterization and antimicrobial activity of binary and ternary
Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Ce(III) and UO (VI) com-
2
plexes of a thiocarbohydrazone ligand. J Mol Struct 980:78–87
4. Ebrahim Tehrani KHM, Kobarfard F, Azerang P, Mehravar M,
Soleimani Z, Ghavami G, Sardari S (2013) Synthesis and
antimycobacterial activity of symmetric thiocarbohydrazone deriv-
atives against mycobacterium bovis BCG. Iran J Pharm Res 12:
331–346
The obtained results gave insight into physicochemical
properties of monothiocarbohydrazones and opened the pos-
sibilities for the future examinations in the field of potential
biological activities and application of these compounds.
5. Božić A, Bjelogrlić S, Novaković I, Filipović N, Petrović P,
Marinković A, Todorović T, Cvijetić I (2018) Antimicrobial activ-
ity of thiocarbohydrazones: experimental studies and alignment-
independent 3D QSAR models. CHEMISTRYSELECT 3:2215–
2221
6. Muglu H, Cavus MS, Bakir T, Yakan H (2019) Synthesis, charac-
terization, quantum chemical calculation and antioxidant activity of
new bis-isatine carbohydrazone and thiocarbohydrazone deriva-
tives. J Mol Struct 1196:819–827
Supplementary Information The online version contains supplementary
material available at https://doi.org/10.1007/s11224-020-01700-y.
Author’s contribution All authors contributed to the study conception
and design. Material preparation, data collection, and synthesis of the
compounds were performed by G. Mrdjan. Structural characterization,
X-ray analysis, and interpretation of the specific and non-specific inter-
actions were performed and analyzed by G. Mrdjan, D. Škorić, M.
Radanović, Gy. Vastag, and B. Matijević. Determination of the pKa
was performed by T. Verbić, and O. Marković. TD–DFT calculations
were carried out by M. Milčić, and I. Stojiljković. The first draft of the
manuscript was written by G. Mrdjan, and all authors commented on
previous versions of the manuscript. All authors read and approved the
final manuscript.
7. Kaya Y, Erça A, Koca A (2015) Synthesis, structures, electro-
chemical studies and antioxidant activities of cis-
d i o x o m o l y b d e n u m ( V I ) c o m p l e x e s o f t h e n e w
bisthiocarbohydrazones. J Mol Struct 1102:117–126
8. Sathisha MP, Revankar VK, Pai KSR (2008, 2008) Synthesis,
structure, electrochemistry, and spectral characterization of bis-
isatin thiocarbohydrazone metal complexes and their antitumor ac-
tivity against Ehrlich ascites carcinoma in Swiss albino mice.
Metal-Based Drugs:article No. 362105
9. Sathisha MP, Shetti UN, Revankar VK, Pai KSR (2008) Synthesis
and antitumor studies on novel Co(II), Ni(II) and Cu(II) metal com-
plexes of bis(3-acetylcoumarin)thiocarbohydrazone. Eur J Med
Chem 43:2338–2346
10. Bagihalli GB, Avaji PG, Badami PS, Patil SA (2008) Synthesis,
spectral characterization, electrochemical and biological studies of
Co(II), Ni(II) and Cu(II) complexes with thiocarbohydrazone. J
Coord Chem 61:2793–2806
Funding The authors acknowledge financial support of the Ministry of
Education, Science and Technological Development of the Republic of
Serbia (Grants No. 451-03-68/2020-14/ 200125; 451-03-68/2020-14/
200026; 451-03-68/2020-14/200168).
11. Patil MV, Malve SP (2004) Synthesis, characterization and antimi-
crobial activity of ruthenium(III), rhodium(III), palladium(II) and
p l a t i n u m ( I I ) c o m p l e x e s w i t h b i s ( h y d r o x y -
isonitrosobenzoylacetone) thiocarbohydrazone. J Indian Chem
Soc 81:683–686
12. Kurzer F, Wilkinson M (1970) The chemistry of carbohydrazide
and thiocarbohydrazide. Chem Rev 70:111–149
13. Diffraction RO, System CAPS (2015) Rigaku corporation. United
Kingdom, Oxford
Data availability The datasets generated during and/or analyzed during
the current study are available from the corresponding author on reason-
able request.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.

Struct Chem (2021) 32:1231–1245
1245
14. Sheldrick GM (2015) SHELXT – integrated space–group and
crystal–structure determination. Acta Crystallogra A 71:3–8
15. Sheldrick GM (2015) Crystal structure refinement with SHELXL.
Acta Crystallogr C 71:3–8
16. Macrae CF, Edgington PR, McCabe P, Pidcock E, Shields GP,
Taylor R, Towler M, van de Streek J (2006) Mercury: visualization
and analysis of crystal structures. J Appl Crystallogr 39:453–457
17. Gans P, O’Sullivan B (2000) GLEE, a new computer program for
glass electrode calibration. TALANTA 51:33–37
18. Gans P, Sabatini A, Vacca A (1996) Investigation of equilibria in
solution. Determination of equilibrium constants with the
HYPERQUAD suite of programs. Talanta 43:1739–1753
19. Le Bahers T, Adamo C, Ciofini I (2011) A qualitative index of
spatial extent in charge-transfer excitations. J Chem Theory
Comput 7:2498–2506
22. Shi Z, Zhao Z, Liu X, Wu L (2011) Synthesis of new deoxycholic
acid bis thiocarbohydrazones under solvent-free conditions using
microwave irradiation. J Chem Res 35:198–201
23. Rajendran G, Jain SR (1984) Structural assignment of
monothiocarbohydrazones by 1H NMR spectroscopy. Organic
Magnetic Resonance 22:6–10
24. Han F, Bao Y, Yang Z, Fyles TM, Zhao J, Peng X, Fan J, Wu Y,
Sun S (2007) Simple bisthiocarbonohydrazones as sensitive, selec-
tive, colorimetric, and switch-on fluorescent chemosensors for fluo-
ride anions. Chem Eur J 13:2880–2892
25. Assaleh MH, Božić AR, Bjelogrlić S, Milošević M, Simić M,
Marinković AD, Cvijetić IN (2019) Water-induced isomerism of
salicylaldehyde and 2-acetylpyridine mono- and bis-
(thiocarbohydrazones) improves the antioxidant activity: spectro-
scopic and DFT study. Struct Chem 30:2447–2457
20. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA,
Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji
H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG,
Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF,
Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F,
Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D,
Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M,
Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima
T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K,
Montgomery JA, Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ,
Brothers EN, Kudin KN, Staroverov VN, Keith TA, Kobayashi
R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar
SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R,
Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB,
Fox DJ (2016) Gaussian 16. Revision B.01. Gaussian, Inc.,
Wallingford CT
26. Catalan J, Hopf H (2004) Empirical treatment of the inductive and
dispersive components of solute-solvent interactions: the solvent
polarizability (SP) scale. Eur J Org Chem 2004:4694–4702
27. Catalan J (2009) Toward a generalized treatment of the solvent
effect based on four empirical scales: dipolarity (SdP, a new scale),
polarizability (SP), acidity (SA) and basicity (SB) of the medium. J
Phys Chem B 113:5951–5960
28. Antić-Jovanović A (2006) Molekulska spektroskopija-
spektrohemijski aspekti. Fakultet za fizičku hemiju, Belgrade
29. Hansen CM (2007) Hansen solubility parameters, a user’s hand-
book. CRC Press, New York
30. Hammett LP (1937) The effect of structure upon the reactions of
organic compounds. Benzene derivatives. J Am Chem Soc 59:96–
103
31. ADMET Predictor (2016) Simulations Plus, Inc, Lancaster, CA,
USA, ver. 8.0
21. Li Z, Feng X, Zhao Y (2008) Microwave induced efficient synthe-
sis of (un)substituted benzaldehyde (5-aryl-1,3,4-thiadiazol-2-yl)
hydrazones using silica-supported dichlorophosphate as a recover-
able dehydrant. J Heterocyclic Chem 45:1489–1492
Publisher’s note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.