Electronic effects on13C NMR chemical shifts of substituted 1,3,4-thiadiazolium salts

Article abstract of DOI:10.1002/mrc.812

A series of 3- and 4-X-cinnamoyl-1,3,4-thiadiazolium-2-phenylamine chlorides were prepared and fully characterized by spectroscopic techniques. The ¹³C NMR chemical shifts of the α and β side-chain carbons were compared with those of the corres

Full text of DOI:10.1002/mrc.812

MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2001; 39: 182–186
Electronic effects on 13C NMR chemical shifts of
substituted 1,3,4-thiadiazolium salts
Ana Cristina Souza dos Santos and Aurea Echevarria*
´
ˆ
´
Departamento de Quımica, Instituto de Ciencias Exatas, Universidade Federal Rural do Rio de Janeiro, 23851–970, Seropedica (RJ), Brazil
Received 29 August 2000; Accepted 15 November 2000
A series of 3- and 4-X-cinnamoyl-1,3,4-thiadiazolium-2-phenylamine chlorides were prepared and fully
characterized by spectroscopic techniques. The 13C NMR chemical shifts of the a and b side-chain carbons
were compared with those of the corresponding cinnamic acid precursors and more significant transmission
electronic effects were observed for mesoionic compounds. The ratio rR /rI for the a and b side-chain carbons
in mesoionic derivatives reflects a more important inductive contribution whereas the value of rR/rI for
the b side-chain carbons indicates a higher resonance contribution. The chemical shifts of C-2 and C-5
of the heterocyclic ring were correlated with substituent constants and showed that the more extensive
conjugation of the side-chain with an exocyclic moiety is favoured by electron-withdrawing groups. The
correlation analysis of chemical shifts with dual parameters indicated a significant contribution of a
resonance effect for C-2 (rR/rI = 1.70) when compared with C-5 (rR/rI = 1.03). Copyright  2001 John Wiley
& Sons, Ltd.
KEYWORDS: NMR; 13C NMR; 1,3,4-thiadiazolium salts; mesoionic compounds; electronic effects
The interesting and promising results11 of antitumor
activity obtained with a few hydrochlorides of the 1,3,4-
thiadiazolium-2-aminide 5-cinnamoyl derivatives led us to
synthesize and carefully study this series to collect data for
future studies of structure–activity relationships (SAR).
In the present work, we synthesized eight 4-phenyl-5-(4-
X-cinnamoyl)- and three 4-phenyl-5-(3-X-cinnamoyl)-1,3,4-
thiadiazolium-2-phenylamine chlorides (7), where X D H,
4-OCH3, 4-CH3, 4-Cl, 4-F, 4-CN, 4-NO2, 4-OH, 3-NO2, 3-OH,
3-OCH3 (Scheme 1), and we studied the linear free energy
relationships to examine the transmission of electronic
effects involving the 13C NMR chemical shift values against
Hammett constants and dual electronic parameters.
INTRODUCTION
Mesoionic compounds have received much attention and
have been extensively studied because of their unique struc-
tures, reaction behaviour and pharmaceutical activities.1,2
Mesoionic compounds can be represented by the general
formula 1, where a–f are suitably substituted carbons or
heteroatoms (Scheme 1). The general structure affords sev-
eral different classes of heterocyclic mesoionics. The 1,3,4-
thiadiazolium-2-aminide class has shown particular interest
and their rearrangement isomers have been studied struc-
turally using multinuclear NMR techniques in the solid state
or in solution.3–5 We have previously studied the SNAr
reactivity,6,7 structural and chemical properties5,8,9 and bio-
logical activity10,11 of several mesoionic compounds of the
1,3,4-thiadiazolium-2-aminide class.
RESULTS AND DISCUSSION
Linear free energy relationships have been of great
importance to physical organic chemists in the description
and rationalization of structural effects on chemical reactivity
and physical properties. They are now investigating their use
to predict biological activity. The treatment of substituent
parameters resulting from the separation of electrical effects
into field and/or inductive and resonance contributions gives
the best results.12
The use of NMR chemical shifts in examining electronic sub-
stituent effects has been particularly used in studying less
common molecules, and has contributed to the best under-
standing in recent years of several more important modes of
transmission of substituent effects.13,14 We synthesized 7a–k
(where 7c–f, i–k are new compounds) by the dehydroacyla-
tion reaction between thiosemicarbazide (6) and appropriate
4- or 3-substituted cinnamoyl chlorides (5) (Scheme 2). The
13C NMR data for the mesoionic salts 7a–k and precursor
cinnamic acids 4a–k are summarized in Table 1.
The assignments of the carbon NMR signals were made
using similar arguments to those used in earlier work3,5,15
for the C-2 and C-5 carbons in the heterocyclic ring. These
carbons appear at high frequencies compared with signals
from other carbon atoms (with the exception of C-13 and C-12
Ł
´
Correspondence to: A. Echevarria, Departamento de Quımica,
Instituto de Cieˆncias Exatas, Universidade Federal Rural do Rio de
Janeiro, 23851–970, Serope´dica (RJ), Brazil.
E-mail: echevarr@ufrrj.br
Contract/grant sponsor: Conselho Nacional de Desenvolvimento
´
Cientıfico e Tecnolo´gico (CNPq).
Contract/grant sponsor: Coordenac¸a˜o de Aperfeic¸oamento de
Pessoal Docente (CAPES).
DOI: 10.1002/mrc.812
Copyright  2001 John Wiley & Sons, Ltd.

13C NMR substituted 1,3,4-thiadiazolium salts
183
Table 1. 13C NMR data (υ, ppm) for the C-˛ and C-ˇ of the
mesoionic salts 7a–k and cinnamic acids 4a–k (in CDCl3)
16
17
15
14
Cl -
8
Cinnamic acids
υ(C-˛) υ(C-ˇ) υ(C-˛) υ(C-ˇ) υ(C-2) υ(C-5)
148.93 105.86 157.94 162.58
Mesoionic salts
7
9
a
b
N
N
+
11
α
+
2
6
X
e
c
10
12
f
N
H
d
5
S
4-OH
—
—
β
13
X
11'
4-OCH3 143.89 116.59 149.00 107.12 157.97 162.03
1
7
12'
4-CH3
H
4-Cl
140.20 118.70 149.24 108.63 158.36 162.02
144.02 119.29 149.10 109.86 158.62 161.73
142.56 120.06 147.25 110.48 158.75 161.38
142.85 119.22 147.56 109.85 158.50 161.65
H (7a), 4-OCH3 (7b), 4-CH3 (7c), 4-Cl (7d)
4-F (7e), 4-CN (7f), 4-NO2 (7g), 4-OH (7h),
3-NO2 (7i), 3-OH (7j) and 3-OCH3 (7k)
4-F
4-CN
4-NO2
3-OH
142.02 122.91 145.38 113.16
n.o.a
161.00
141.36 123.64 145.32 113.87 159.40 160.65
144.17 118.91 149.35 109.83 158.67 162.31
Scheme 1. Compounds studied.
3-OCH3 143.99 116.27 148.98 110.23 158.60 161.63
3-NO2 141.53 124.42 145.17 112.80 n.o. n.o.
for 7b, e, h and 7i, j, k, respectively, ipso to the substituent).
We found υ157.97–159.40 for C-2 and υ160.65–162.58 for C-5,
which are also consistent with the results of x-ray diffraction,
theoretical studies8 and 15N NMR experiments3 for other
derivatives.
The chemical shifts of the ethylenic carbons linked to C-5
were assigned on the basis of the data for their corresponding
cinnamic acids,16,17 showing lower frequencies for C-ˇ, due
to the greater electron-withdrawing and anisotropic effects
(š20 ppm) caused by the heterocyclic ring (ꢀ D 0.71,7
whereas ꢀ D 0.45 for the COOH moiety). The remaining
aromatic carbons in the rings attached to N-4 and N-
exocyclic were assigned using aniline and anilinium groups
as models.17
Ring styrene substituted derivatives have probably been
involved in more studies of side-chain chemical shifts
than any other class of compounds.18–21 Happer and co-
workers16,22–24 investigated the range of styrene derivatives,
including cinnamic acids, involving the measurement and
analysis of side-chain substituent data for a wide range of
meta- and para-substituted derivatives. Unfortunately, they
did not include ꢁ-acceptor substituents in their data set for
the DSP analysis25–27 and the correlations with C-ˇ chemical
shift values indicated a strong dependence on the vinyl
substituent groups, that is, when they are electron acceptors
the best correlation is with ꢀRC whereas if they are relatively
neutral the correlation is with ꢀR.
a n.o., peak was not observed.
In this work, to obtain a better comparison with mesoionic
salts, we correlated the chemical shift values of C-˛ and C-ˇ
in cinnamic acids with ꢀm, ꢀp and ꢀpC constants and dual
parameters, ꢀI and ꢀR.12 For para-substituted derivatives, the
ratio ꢂR/ꢂI obtained with dual parameters suggest a more
significant inductive effect for C-˛ chemical shift values (0.73)
whereas for C-ˇ chemical shifts (ꢂR/ꢂI D 1.33) the resonance
effect has a more significant contribution. These results were
consistent with Butt and Topsom’s analysis.27
The correlation analysis for mesoionic salts was made
with chemical shift for C-˛, C-ˇ and carbon atoms of the
heterocyclic ring, C-2 and C-5 (Table 2). We had started
studying the correlations of υC-˛ and C-ˇ with Hammett
constants, ꢀ, ꢀp and ꢀC, and observed the best relationship
for C-ˇ against ꢀC28 (ꢂ D 4.43, sd D 0.293, correlation
coefficient D 0.994, F D 694), in accordance with the study of
styrene derivatives by Brownlee and Craik.20
Thus, the bilinear correlations between C-˛, C-ˇ chem-
ical shifts with dual parameters12 showed good results,
indicating that the magnitude of the ꢂR component at C-
ˇ (ꢂR/ꢂI D 1.29) is greater than the corresponding at C-˛
(ꢂR/ꢂI D 0.49). The resonance effect reflects the electron
demand placed on the C-ˇ by the adjacent heterocyclic ring,
O
O
H
Piperidine
Pyridine
OH
OH
O
+
X
X
OH
O
2
3
4
SOCl2
-
Cl
Ph
1,4-dioxane
O
Ph-NH-CS-NHNH-Ph
+
N
N
X
+
S
X
Cl
7
6
N
5
Ph
H
Scheme 2. Reaction sequence used in this work.
Copyright  2001 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2001; 39: 182–186

184
A. C. Souza dos Santos and A. Echevarria
Table 2. Correlation analysis for 13C NMR chemical shifts of
C-˛ and C-ˇ of the mesoionic salts against ꢀ12, ꢀC28 and dual
parameters12 (ꢀI and ꢀR)
that the dielectric properties of the molecular framework can
modify the electric field transmission of polarization effects.
Finally, the comparison between cinnamic acids and
mesoionic salts showed that the better transmission of the
electronic effects is more efficient when the heterocyclic ring
is the substituent group in the vinyl moiety. This observation
reflects the increase in the extended ꢁ-polarization favoured
by the relative coplanarity of the rings and vinyl system in
the mesoionic derivatives.
Correlationa
ꢂb
rc
Sdd
Fe
υꢃC-˛ꢄ ð ꢀ
ꢀ3.90
ꢀ2.49
0.905
0.855
0.976
0.994
0.980
0.990
0.950
0.962
0.977i
0.772
0.949
0.562
0.293
0.092
0.070
0.183
0.167
0.412
40.8
21.7
182
694
172
303
74.8
87.3
52.8
υꢃC-˛ꢄ ð ꢀC
υꢃC-ˇꢄ ð ꢀ
6.02
υꢃC-ˇꢄ ð ꢀC
υꢃC-2ꢄ ð ꢀ
4.43
1.28
0.852
υꢃC-2ꢄ ð ꢀC
υꢃC-5ꢄ ð ꢀ
EXPERIMENTAL
ꢀ1.42
υꢃC-5ꢄ ð ꢀC
υꢃC-˛ꢄ ð ꢀI and ꢀRf
ꢀ0.969
Spectra
ꢂIg D ꢀ5.31
ꢂRh D ꢀ2.62
ꢂI D 5.93
ꢂR D 7.66
ꢂI D 1.03
ꢂR D 1.48
ꢂI D ꢀ1.52
ꢂR D ꢀ1.56
13C NMR spectra were run on a Bruker AC-200 spectrometer
operating at 50.3 MHz, with a 5 mm probe, using CDCl3
as solvent, and their signals were employed as standards
with TMS as internal standard. All 13C spectra were taken
with 16K data points and a digital resolution of 1.1 Hz for a
υꢃC-ˇꢄ ð ꢀI and ꢀR
υꢃC-2ꢄ ð ꢀI and ꢀR
υꢃC-5ꢄ ð ꢀI and ꢀR
0.986i
0.996i
0.983i
0.548
0.056
0.133
84.8
239
71.8
concentration of ca 0.5 mmol mlꢀ1 and a 90 pulse was used
°
with no relaxation delay.
Compounds
General synthetic procedure
4- and 3-X-cinnamic acids, 4: the preparation of compounds
4a–k was carried out by published procedures.29 The purity
of the compounds was checked by TLC.
a The general equations utilized in correlation analysis12,17 were
υꢃCꢄ D a C ꢂꢀ (or ꢀC) and υꢃCꢄ D a C ꢂIꢀI C ꢂRꢀR.
b Transmission coefficient.
c Correlation coefficient.
d Standard deviation.
5-Phenyl-4-(4- or 3-X-cinnamoyl)-1,3,4-thiadiazolium-2-
phenylamine chloride, 7a–k: a solution of the freshly
prepared30 appropriately substituted cinnamoyl chloride
(10 mmol) in 1,4-dioxane (5 ml) was added to a suspension
of 1,4-diphenylthiosemicarbazide (10 mmol) in 1,4-dioxane
(15 ml), and the mixture was stirred at room temperature
until complete solubilization and a yellow solution was
formed. The reaction mixture was left standing for 24–48 h
to give a very bright yellow solid, which was filtered off and
purified by recrystallization from dichoromethane–ethanol
(1 : 1). The 13C NMR data for all compounds are listed in
Table 3.
e F test for significance of correlation.
f Only para-substituted derivatives.
g The sensitivity of the substituent chemical shifts to resonance
effects.
h The sensitivity of the substituent chemical shifts to inductive
effects.
i Multiple correlation coefficient.
even though the ꢂI value at C-ˇ (5.93) is slightly greater than,
but with opposite sign to, the corresponding component at
C-˛ (ꢀ5.31). This reflects some additional polarization of the
C-ˇ site above seen at C-˛. This trend applies to the other
styrene series and Butt and Topsom27 rationalized it in terms
of ꢁ-polarization of the vinyl group. In comparison with the
cinnamic acid series, the ratio ꢂR/ꢂI D 0.73 for C-˛ against
0.49 for the mesoionic series reflected the higher efficiency in
the transmission of resonance effect across the vinyl group
into the heterocyclic moiety. Polar and resonance effects are
largest at the C-ˇ site. The preferred scale ꢀC reflects the elec-
tron demand placed on this site by the adjacent heterocyclic
group.
The chemical shifts of C-2 and C-5 were correlated
against Hammett constants and showed better results for the
ꢀC parameter with C-2, indicating extensive conjugation of
side-chain with the exocyclic moiety favoured by electronic-
withdrawing groups (Table 2). The bilinear correlations
between chemical shifts of C-2 and C-5 against resonance
and inductive parameters separately presented good results,
showing a more significant contribution of the resonance
effect for C-2, ꢂR/ꢂI D 1.70, and for C-5, ꢂR/ꢂI D 1.03,
suggesting that the ꢁ-polarization effects might therefore be
transmitted via molecular lines of force, that is, we envisage
Analytical data
Melting-points were determined with a Melt-Temp appa-
ratus and are uncorrected. IR spectra were taken for KBr
pellets with a Perkin-Elmer Model 1420 instrument. Ele-
mental analyses were performed on a Perkin-Elmer Model
2400 instrument and mass spectra were obtained with a
Hewlett-Packard Model 5987A spectrometer.
11
°
°
7a, X D H, yield 75%, m.p. 266–7 C (lit. 266–7 C);
ꢅmax (cmꢀ1), 3430, 3064, 2680, 1605, 1570, 1510 and 965;
m/z (%), MCž 356 (17), 355 (64), 206 (10), 147 (100), 103 (12),
°
135 (7), 77 (46). 7b, X D 4-OCH3, yield 70%, m.p. 195–6 C
(lit.11 195 C); ꢅmax (cmꢀ1), 3410, 3020, 2920, 2690, 1600, 1570,
°
1512 and 1260; m/z (%), MCž 386 (28), 385 (100), 236 (14),
177 (98), 134 (24), 135 (8), 77 (21). 7c, X D 4-CH3, yield 73%,
°
m.p. 195–6 C (Found: C, 68.1; H, 4.7; N, 10.1. C23H20ClN3S
requires C, 68.0; H, 5.0; N, 10.4%); ꢅmax (cmꢀ1), 3423, 3030,
2890, 2690, 1615, 1600, 1510, 1326 and 1175; m/z (%), MCž
370 (21), 369 (80), 220 (10), 161 (100), 135 (5), 117 (10), 77 (61).
°
7d, X D 4-Cl, yield 75%, m.p. 264–5 C (Found: C, 61.9; H,
4.1; N, 9.6. C22H17Cl2N3S requires C, 62.0; H, 4.0; N, 9.9%);
Copyright  2001 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2001; 39: 182–186

13C NMR substituted 1,3,4-thiadiazolium salts
185
Table 3. 13C NMR chemical shifts (υ, ppm) for 7a–k
Carbon
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
2
5
6
7
8
158.62
161.74
137.82
118.85
129.15
124.33
132.97
130.18
128.92
131.91
136.45
125.33
128.85
132.36
149.10
109.88
157.97
162.03
137.99
118.56
128.81
123.95
125.81
130.92
114.70
163.15
136.15
125.35
130.09
131.61
149.00
107.12
158.36
162.02
137.73
118.46
128.84
124.21
130.24
130.03
129.76
143.64
136.33
125.18
128.66
131.73
149.24
108.63
158.75
161.38
138.33
118.71
129.84
124.23
131.63
128.95
129.45
136.57
137.94
125.45
130.21
131.91
147.25
110.48
158.50
161.65
137.79
118.56
130.12
124.16
129.36
130.94
116.47
164.83
136.43
125.30
128.65
131.85
147.56
109.85
158.93
161.00
137.34
118.42
128.51
124.36
n.o.a
128.69
132.94
n.o.
137.00
124.92
129.61
131.54
145.38
113.16
159.40
160.65
137.62
118.70
129.29
124.54
138.94
130.22
124.06
148.86
136.38
125.33
128.97
132.15
145.32
113.87
157.94
162.58
139.49
118.85
130.18
124.24
124.72
131.45
116.42
159.00
138.07
125.42
129.00
132.67
148.93
105.86
n.o.a
n.o.
158.60
161.63
137.80
118.66
128.97
124.43
n.o.
119.62
157.86
115.00
125.24
130.12
131.85
n.o.
158.60
161.63
n.o.
137.40
118.44
124.63
124.36
134.50
125.21
n.o.
122.70
136.30
124.96
128.69
131.58
145.17
112.79
133.42
129.75
118.69
128.94
124.30
134.94
114.03
159.83
117.84
136.39
125.35
130.21
131.94
148.98
110.23
n.o.
9
10
110
120
13
14
15
16
17
˛
149.35
109.83
120.10
n.o.
ˇ
11
12
OCH3
CH3
CN
n.o.
55.34
55.32
21.07
117.30
a n.o., peak was not observed.
ꢅmax (cmꢀ1), 3423, 3040, 2650, 1625, 1600, 1570, 1510, 1450,
and 1326; m/z (%), MCž 390 (30), 389 (100), 240 (11), 181 (99),
de Aperfeic¸oamento de Pessoal Docente (CAPES), the Brazilian
Federal Government Granting Agencies.
°
134 (6), 135 (5), 77 (94). 7e, X D 4-F, yield 77%, m.p. 252–3 C
(Found: C, 64.4; H, 4.1; N, 10.1. C22H17ClFN3S requires C, 64.5;
H, 4.2; N, 10.3%); ꢅmax (cmꢀ1), 3442, 3007, 2669, 1618, 1570,
1512, 1448, 1315 and 1230; m/z (%), MCž 374 (28), 373 (98),
224 (12), 165 (100), 121 (7), 77 (55, 51 (19). 7f, X D 4-CN, yield
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°
80%, m.p. 185 C (Found: C, 66.3; H, 4.1; N, 13.1. C23H17ClN4S
requires C, 66.3; H, 4.1; N, 13.4%); ꢅmax (cmꢀ1), 3404, 3060,
2740, 2220, 1610, 1570, 1500, 1420 and 1310; m/z (%), MCž
381 (24), 380 (80), 231 (14), 17 (39), 135 (29), 128 (9), 77 (100),
11
°
51 (23). 7g, X D 4-NO2, yield 78%, m.p. 232–3 C (lit.
232–3 C); ꢅmax (cmꢀ1), 3410, 3090, 1600, 1570 and 1380; m/z
°
(%), MCž 401 (12), 400 (48), 251 (10), 192 (5), 135 (81), 91 (40),
11
°
77 (100), 51 (17). 7h, X D 4-OH, yield 65%, m.p. 282–4 C (lit.
282–3 C); ꢅmax (cmꢀ1), 3425, 3050, 1600, 1570, 1500 and 1270.
°
°
7i, X D 3-NO2, yield 73%, m.p. 270–1 C (Found: C, 60.5; H,
3.8; N, 12.5. C22H17ClN4O2S requires C, 60.5; H, 3.9; N, 12.8%);
ꢅmax (cmꢀ1), 3420, 3050, 1620, 1570 and 1335; m/z (%), MCž
401 (16), 400 (57), 251 (13), 208 (14), 135 (63), 91 (42), 77 (100),
°
51 (30). 7j, X D 3-OH, yield 58%, m.p. 284–5 C (Found: C,
64.7; H, 4.5; N, 10.0. C22H18ClN3OS requires C, 64.8; H, 4.5; N,
10.3%); ꢅmax (cmꢀ1), 3410, 3050, 2285, 1615, 1595, 1570, 1495
and 1290; m/z (%), MCž 372 (19), 371 (48), 354 (23), 353 (18),
222 (16), 163 (39), 135 (45), 118 (32), 91 (66), 77 (100), 65 (32),
°
51 (46). 7k, X D 3-OCH3, yield 62%, m.p. 243–5 C (Found:
16. Happer DAR, Steenson BE. J. Chem. Soc., Perkin Trans. 2 1983;
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