Synthesis and determination of pKa values of some new 3,4-disubstituted-4,5-dihydro-1H-1,2,4-triazol-5-one derivatives in non-aqueous solvents.

Article abstract of DOI:10.3390/90400232

3-Alkyl(Aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones (2) reacted with 2-furoyl chloride and thiophene-2-carbonyl chloride to afford the corresponding 3- alkyl(aryl)-4-(2-furoylamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (3) and 3-alkyl(aryl)- 4-(2-thi

Full text of DOI:10.3390/90400232

Molecules 2004, 9, 232-240
molecules
ISSN 1420-3049
http://www.mdpi.org/
Synthesis and Determination of pKa Values of Some New 3,4-
Disubstituted-4,5-Dihydro-1H-1,2,4-triazol-5-one Derivatives in
Non-aqueous Solvents
*
Haydar Yüksek 1, , Zafer Ocak 1, Muzaffer Alkan 1, Şule Bahçeci 3 and Mustafa Özdemir 2
1 Department of Chemistry, Kafkas University, 36100 Kars, Turkey; Fax (+90)-474-2121185.
2 Department of Chemistry, Karadeniz Technical University, 61080 Trabzon, Turkey.
3 Fatih Education Faculty, Karadeniz Technical University, 61335 Trabzon, Turkey.
*Author to whom correspondence should be addressed; e-mail: hyuksek98@yahoo.com
Received: 12 June 2002; in revised from: /Accepted: 11 March 2004 / Published: 31 March 2004
Abstract: 3-Alkyl(Aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones (2) reacted with
2-furoyl chloride and thiophene-2-carbonyl chloride to afford the corresponding 3-
alkyl(aryl)-4-(2-furoylamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (3) and 3-alkyl(aryl)-
4-(2-thienylcarbonylamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (4), respectively. The
1
new compounds synthesized were characterized by using IR, H-NMR, 13C-NMR and
UV spectral data together with elemental analysis. In addition, to investigate the effects
of solvents and molecular structure upon acidity, compounds 3 and 4 were titrated
potentiometrically with tetrabutylammonium hydroxide in four non-aqueous solvents
(isopropyl alcohol, tert-butyl alcohol, N,N-dimethylformamide and acetonitrile). The
half-neutralization potential values and the corresponding pKa values were determined for
all cases.
Keywords: 4,5-Dihydro-1H-1,2,4-triazol-5-ones; acylation; acidity; potentiometric
titration; syntheses.

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Molecules 2004, 9
Introduction
1,2,4-Triazole and 4,5-dihydro-1H-1,2,4-triazol-5-one derivatives are reported to show a broad
spectrum of biological activities such as antifungal, antimicrobial, hypoglycemic, antihypertensive,
analgesic, antiparasitic, hypocholesteremic, antiviral, anti-inflammatory, antitumor and anti-HIV
properties [1-14]. These observations prompted us to synthesize some new 4,5-dihydro-1H-1,2,4-
triazol-5-one derivatives with potential biological activity. In addition, several articles, involving the
acylation of 4,5-dihydro-1H-1,2,4-triazol-5-one derivatives, have also been published up to date [11,
12,15,16].
On the other hand, it is known that 1,2,4-triazole and 4,5-dihydro-1H-1,2,4-triazol-5-one rings have
weak acidic properties, so some 1,2,4-triazole and 4,5-dihydro-1H-1,2,4-triazol-5-one derivatives were
titrated potentiometrically with tetrabutylammonium hydroxide in non-aqueous solvents, and the pKa
values of the compounds were determined [11, 17-20]. We have previously described the synthesis and
potentiometric titrations of some new 4,5-dihydro-1H-1,2,4-triazol-5-one derivatives in different non-
aqueous medium [21, 22], where we determined the pKa values of these compounds for each non-
aqueous solvent.
The aim of this work is to synthesize a series of 3-alkyl(aryl)-4-(2-furoylamino)-4,5-dihydro-1H-
1,2,4-triazol-5-ones (3) and 3-alkyl(aryl)-4-(2-thienylcarbonylamino)-4,5-dihydro-1H-1,2,4-triazol-5-
ones (4) from the reactions of 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones (2) with 2-
furoyl chloride and thiophene-2-carbonyl chloride, respectively (Scheme 1). Moreover, the synthesized
compounds 3 and 4 were titrated potentiometrically with tetrabutylammonium hydroxide (TBAH) in
four non-aqueous solvents, including isopropyl alcohol, tert-butyl alcohol, N,N-dimethylformamide
and acetonitrile to determine their pKa values. For each new compound synthesized, the half-
neutralization potential (HNP) and the corresponding pKa value were determined in the four mentioned
non-aqueous solvents. The data obtained from the potentiometric titrations were interpreted, and the
effect of the C-3 substituent and solvent effects were studied [17-22]. Determination of pKa values of
active constituents of certain pharmaceutical preparations is important, because their distribution,
transport behavior, bonding to receptors, and contributions to metabolic behavior depend on the
ionization constant [23].
Scheme 1
O
C Cl
1-4
a
R
N
NH
NNHCO2Et
OEt
N
NH
CH
3
H2NNH2
X
R
C
b
c
d
e
f
CH CH
CH C H
2
3
R
O
R
N
O
O
NH C
3,4
N
2 6 5
NH2
CH C H .CH (4-)
2 6 4
3
CH C H .Cl (4-)
X
2 6 4
2
1
C H
6 5
X=O ,S

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Molecules 2004, 9
Results and Discussion
In this study, the structures of the newly synthesized 3-alkyl(aryl)-4-(2-furoylamino)-4,5-dihydro-
1H-1,2,4-triazol-5-ones (3) and 3-alkyl(aryl)-4-(2-thienyl-carbonylamino)-4,5-dihydro-1H-1,2,4-
1
triazol-5-ones (4) were identified using elemental analysis and IR, H-NMR, 13C-NMR and UV
spectral data, and these obtained spectral values were seen to be compatible with literature reports [24,
25]. In addition, these newly synthesized compounds 3 and 4 were titrated potentiometrically with
tetrabutyl-ammonium hydroxide (TBAH) in non-aqueous solvents such as isopropyl alcohol (ε=19.4),
tert-butyl alcohol (ε=12), N,N-dimethylformamide (ε=37) and acetonitrile (ε=36).
The mV values were plotted versus TBAH volumes (mL) added, and thus potentiometric titration
curve was formed for all the cases. From these curves, the HNP values were measured, and the
corresponding pKa values were calculated.
As an example, the potentiometric titration curves for 0.001 M 3-Benzyl-4-(2-furoylamino)-4,5-
dihydro-1H-1,2,4-triazol-5-one (3c) solutions titrated with 0.05 M TBAH in isopropyl alcohol, tert-
butyl alcohol, N,N-dimethylformamide and acetonitrile are given in Figure 1. As it is clearly seen in
Figure 1, a typical S-shaped titration curve was obtained.
Figure 1. Potentiometric titration curves of 10-3 M 3-Benzyl-4-(2-furoylamino)-4,5-
dihydro-1H-1,2,4-triazol-5-one (3c) solutions titrated with 0.05 M TBAH in isopropyl
alcohol (●), tert-butyl alcohol (▲), N,N-dimethylformamide ( ) and acetonitrile (▼) at
25 °C.
-157
-314
mV
-471
-628
mL
0.0
0.3
0.6
0.9
The half-neutralization potentials (HNP) and the corresponding pKa values for compounds 3 and 4,
obtained from the potentiometric titrations with 0.05 M TBAH in isopropyl alcohol, tert-butyl alcohol,
N,N-dimethylformamide and acetonitrile, are given in Table 1.

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Molecules 2004, 9
Table 1. The half-neutralization potentials (HNP) and the corresponding pKa values of
compounds 3 and 4 in isopropyl alcohol, tert-butyl alcohol, N,N-dimethylformamide and
acetonitrile.
Compd.
no
Isopropyl
alcohol
Tert-butyl
alcohol
N,N-Dimethyl
formamide
Acetonitrile
pKa
pKa
pKa
pKa
HNP
(mV)
HNP
(mV)
HNP
(mV)
-447
HNP
(mV)
-430
3a
3b
3c
3e
3f
-292
11.63
11.69
8.79
-206
9.84
14.56
15.69
10.38
15.30
15.26
14.37
12.39
12.42
12.82
14.23
13.17
14.57
13.69
8.48
-298
-111
-290
-312
-275
-297
-291
-214
-286
-293
-260
-162
-248
-186
-273
-254
-175
-285
-277
-291
11.01
9.49
-459
-172
-443
-491
-450
-324
-347
-320
-436
-388
-388
-96
11.52
11.97
11.07
11.87
11.42
10.66
11.48
11.47
10.76
9.52
-409
-329
-374
-333
-352
-227
-284
-333
14.10
12.48
13.38
12.54
12.91
11.52
11.60
12.51
4a
4b
4c
4d
4e
4f
11.10
10.86
11.63
11.84
11.26
11.40
As it is well known, the acidity of a compound depends on some factors. The two most important
factors are the solvent effect and molecular structure [18-22, 26-28]. Table 1 shows that the HNP
values and the corresponding pKa values obtained from potentiometric titrations depend on the non-
aqueous solvents used. The results obtained illustrate that tert-butyl alcohol is the best solvent. As can
be observed in Figure 1, for example, the potential jump of compound 3c in the end-point is very large
for tert-butyl alcohol ranging from –266 mV to –599 mV. In addition, Table 1 shows that the
molecular structure of titrated compounds affects the HNP and corresponding pKa values depending on
the substituents at C-3 in the same solvent.

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Molecules 2004, 9
Experimental
General
Melting points were taken on a Electrothermal digital melting point apparatus and are uncorrected.
1
IR spectra were registered using KBr disks on a Perkin-Elmer 1600 FTIR spectrometer. H-NMR and
13C-NMR spectra were recorded in DMSO-d6 with TMS as internal standard on a Varian Mercury
spectrometer at 200 MHz and 50 MHz, respectively. UV absorption spectra were measured for ethanol
solutions in 10 mm quartz cells between 200 and 400 nm using a Shimadzu UV-1201
spectrophotometer. For potentiometric titrations, a Jenway 3040 ion analyser pH meter (calibrated
according to the instructions of the manufacturer) equipped with an Ingold pH electrode were used.
During the titrations, the titrant was added in increments of 0.05 mL after each stable reading, and the
corresponding mV values were recorded. Chemicals were supplied from Fluka and Merck. After
purification, isopropyl alcohol was used to prepare 0.05 M tetrabutylammonium hydroxide (TBAH).
For all potentiometric titrations, 0.05 M TBAH in isopropyl alcohol was used. The starting compounds
2a-e were prepared from the reactions of the corresponding ester ethoxycarbonylhydrazones (1a-e)
with hydrazine hydrate according to literature [16,29].
General Method for the Preparation of 3-alkyl(aryl)-4-[2-furoylamino]-4,5-dihydro-1H-1,2,4-triazol-
5-ones (3) or 3-alkyl(aryl)-4-[2-thienylcarbonyamino]-4,5-dihydro-1H-1,2,4-triazol-5-ones (4):
3-Alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-one (2) (0.01 mol) was refluxed with a
solution of the appropriate heteroaroyl chloride (2-furoyl chloride or 2-thiophenecarbonyl chloride)
(0.01 mol) in n-butyl acetate (40 mL) for 6 hours and then allowed to cool. The product was
recrystallized from an appropriate solvent to give 3 or 4. The following compounds were prepared
applying this procedure:
3-Methyl-4-(2-furoylamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (3a). Yield 90%; m.p. 83 °C (H2O);
Calculated for C8H8N4O3 (208.18): 46.16% C, 3.87% H, 26.91% N; found: 46.70% C, 4.18% H,
1
26.79% N. H-NMR: δ 2.06 (s, 3H, CH3), 6.76 (s, 1H, Ar-H), 7.40 (s, 1H, Ar-H), 8.02 (s, 1H, Ar-H),
11.38 (s, 1H, NH); 11.73 (s, 1H, NH); 13C-NMR: δ 10.72 (aliphatic carbon), 112.65, 116.87, 145.05,
147.07 (aromatic carbons), 145.36 (triazole C3), 152.89 (triazole C5), 157.24 (C=O); IR: 3500, 3170
(NH), 1715, 1680 (C=O), 1596 (C=N) cm-1; UV λmax nm, (ε, L·mol-1·cm-1): 253 (26350), 212
(16510) nm.
3-Ethyl-4-(2-furoylamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (3b). Yield 87%; m.p. 111-112 °C
(EtOH-toluene, 1:3); Calculated for C9H10N4O3 (222.20): 48.65% C, 4.54% H, 25.21% N; found:
48.35% C, 4.74% H, 24.93% N. 1H-NMR: δ 1.11 (t, 3H, CH3), 2.33 (q, 2H, CH2), 6.70 (s, 1H, Ar-H),
7.33 (s, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 11.33 (s, 1H, NH); 11.70 (s, 1H, NH); 13C-NMR: δ 9.88, 18.17

237
Molecules 2004, 9
(aliphatic carbons), 112.57, 116.74, 145.00, 149.10 (aromatic carbons), 147.00 (triazole C3), 152.96
(triazole C5), 157.14 (C=O); IR: 3450, 3260 (NH), 1715, 1695 (C=O), 1595 (C=N) cm-1; UV λmax nm,
(ε, L·mol-1·cm-1): 211 (11390) nm.
3-Benzyl-4-(2-furoylamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (3c). Yield 82%; m.p. 160-162 °C
(EtOH); Calculated for C14H12N4O3 (284.27): 59.15% C, 4.25% H, 19.71% N; found: 59.48% C,
1
4.18% H, 18.79% N. H-NMR: δ 3.72 (s, 2H, CH2), 6.74 (s, 1H, Ar-H), 7.20-7.36 (m, 7H, Ar-H),
11.71 (s, 1H, NH); 11.90 (s, 1H, NH); 13C NMR: δ 30.40 (aliphatic carbon), 112.80, 117.10, 126.89,
128.47 (3C), 128.63 (3C), 134.60 (aromatic carbons), 146.20 (triazole C3), 152.00 (triazole C5), 163.30
(C=O); IR: 3450, 3230 (NH), 1746, 1715 (C=O), 1590 (C=N), 770, 705 (monosubstituted benzenoid
ring) cm-1; UV λmax nm, (ε, L·mol-1·cm-1): 246 (28720), 221 (23950) nm.
3-(4-Chlorobenzyl)-4-(2-furoylamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (3e). Yield 90%; m.p. 177-
178 °C (EtOH-H2O, 1:3); Calculated for C14H11N4O3Cl (318.72): 52.76% C, 3.48% H, 17.58% N;
1
found: 52.45% C, 3.87% H, 17.56% N. H-NMR: δ 3.82 (s, 2H, CH2), 6.75 (s, 1H, Ar-H), 7.25-7.38
(m, 5H, Ar-H), 8.02 (s, 1H, Ar-H), 11.36 (s, 1H, NH); 11.92 (s, 1H, NH); 13C-NMR: δ 30.30 (aliphatic
carbon), 112.40, 117.10, 128.58 (3C), 130.96 (2C), 131.90, 134.10, 147.03 (aromatic carbons), 145.00
(triazole C3), 153.00 (triazole C5), 157.30 (C=O); IR: 3400, 3210 (NH), 1725, 1688 (C=O), 1595
(C=N), 810 (1,4-disubstituted benzenoid ring) cm-1; UV λmax nm, (ε, L·mol-1·cm-1): 256 (14340), 221
(16830) nm.
3-Phenyl-4-(2-furoylamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (3f). Yield 79%; m.p. 278-239 °C
(H2O); Calculated for C13H16N4O3 (270.25): 57.78% C, 3.73% H, 20.73% N; found: 58.02% C, 3.50%
H, 20.43% N. 1H-NMR: δ 6.75 (s, 1H, Ar-H), 7.47-7.52 (m, 4H, Ar-H), 7.85-7.86 (m, 2H, Ar-H), 8.03
(s, 1H, Ar-H), 11.82 (s, 1H, NH); 12.49 (s, 1H, NH); 13C-NMR: δ 112.80, 117.20, 126.25, 127.14
(2C), 129.30 (2C), 130.91, 146.53, 147.17 (aromatic carbons), 145.21 (triazole C3), 153.62 (triazole
C5), 157.45 (C=O); IR: 3450, 3150 (NH), 1713, 1670 (C=O), 1590 (C=N), 760, 695 (monosubstituted
benzenoid ring) cm-1; UV λmax nm, (ε, L·mol-1·cm-1): 246 (29600), 216 (22900) nm.
3-Methyl-4-(2-thienylcarbonylamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (4a). Yield 83%; m.p. 255-
256 °C (EtOH); Calculated for C8H8N4O2S (224.24): 42.85% C, 3.60% H, 24.99% N; found: 43.26%
1
C, 3.45% H, 24.98% N. H-NMR: δ 1.99 (s, 3H, CH3), 7.06-7.29 (m, 1H, Ar-H), 7.45-8.22 (m, 2H,
Ar-H), 11.46 (s, 1H, NH); 11.70 (s, 1H, NH); 13C-NMR: δ 11.87 (aliphatic carbon), 129.30, 131.56,
134.00, 135.84 (aromatic carbons), 146.21 (triazole C3), 153.82 (triazole C5), 161.84 (C=O); IR: 3300,
3150 (NH), 1720, 1660 (C=O), 1610 (C=N) cm-1; UV λmax nm, (ε, L·mol-1·cm-1): 248 (29140), 212
(19790) nm.
3-Ethyl-4-(2-thienylcarbonylamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (4b). Yield 82%; m.p. 202-
203 °C (EtOH-H2O, 1:3); Calculated for C9H10N4O2S (238.26): 45.37% C, 4.23% H, 23.51% N;

238
Molecules 2004, 9
1
found: 45.03% C, 4.18% H, 23.57% N. H-NMR: δ 1.14 (t, 3H, CH3), 2.41 (q, 2H, CH2), 7.27-7.29
(m, 1H, Ar-H), 7.97-7.99 (m, 2H, Ar-H), 11.47 (s, 1H, NH); 11.79 (s, 1H, NH); 13C-NMR: δ 10.11,
18.34 (aliphatic carbons), 128.79, 130.76, 133.47, 135.40 (aromatic carbons), 149.26 (triazole C3),
153.19 (triazole C5), 161.05 (C=O); IR: 3500, 3175 (NH), 1720, 1675 (C=O), 1600 (C=N) cm-1; UV
λmax nm, (ε, L·mol-1·cm-1): 250 (22220), 207 (16500) nm.
3-Benzyl-4-(2-thienylcarbonylamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (4c). Yield 86%; m.p. 220-
222 °C (EtOH-H2O, 1:3); Calculated for C14H12N4O2S (300.33): 55.99% C, 4.03% H, 18.65% N;
found: 55.73% C, 3.73% H, 18.38% N. 1H-NMR: δ 3.82 (s, 2H, CH2), 7.26 (s, 6H, Ar-H), 7.95 (s, 2H,
Ar-H), 11.46 (s, 1H, NH); 11.94 (s, 1H, NH); 13C-NMR: δ 31.10 (aliphatic carbon), 127.18, 128.76
(3C), 129.08 (2C), 131.10, 133.90, 135.40, 135.90 (aromatic carbons), 147.90 (triazole C3), 153.40
(triazole C5), 161.20 (C=O); IR: 3250, 3100 (NH), 1725, 1660 (C=O), 1600 (C=N), 770, 705
(monosubstituted benzenoid ring) cm-1; UV λmax nm, (ε, L·mol-1·cm-1): 251 (22220), 210 (30440) nm.
3-(4-Methylbenzyl)-4-(2-thienylcarbonylamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (4d). Yield 77%;
m.p. 167-168 °C (EtOH-H2O, 1:3); Calculated for C15H14N4O2S (314.36): 57.31% C, 4.48% H,
1
17.82% N; found: 57.10% C, 4.27% H, 17.93% N. H-NMR: δ 2.27 (s, 3H, CH3), 3.95 (s, 2H, CH2),
7.11-7.27 (m, 5H, Ar-H), 7.95-8.00 (m, 2H, Ar-H), 11.43 (s, 1H, NH); 11.89 (s, 1H, NH); IR: 3250,
3120 (NH), 1760, 1670 (C=O), 1615 (C=N), 790 (1,4-disubstituted benzenoid ring) cm-1; UV λmax
nm, (ε, L·mol-1·cm-1): 269 (23580), 211 (24660) nm.
3-(4-Chlorobenzyl)-4-(2-thienylcarbonylamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (4e). Yield 90%;
m.p. 190-191 °C (EtOH-H2O, 1:3); Calculated for C14H11N4O2SCl (334.78): 50.23% C, 3.31% H,
1
16.74% N; found: 50.55% C, 2.99% H, 16.50% N. H-NMR: δ 3.82 (s, 2H, CH2), 7.24-7.37 (m, 5H,
Ar-H), 7.93-7.97 (m, 2H, Ar-H), 11.41 (s, 1H, NH); 11.93 (s, 1H, NH); 13C-NMR: δ 29.00 (aliphatic
carbon), 127.25 (3C), 129.39, 129.57 (2C), 130.90, 131.99, 132.63, 134.30 (aromatic carbons), 145.90
(triazole C3), 152.90 (triazole C5), 159.80 (C=O); IR: 3220, 3100 (NH), 1730, 1665 (C=O), 1595
(C=N), 805 (1,4-disubstituted benzenoid ring) cm-1; UV λmax nm, (ε, L·mol-1·cm-1): 251 (15100), 222
(24400) nm.
3-Phenyl-4-(2-thienylcarbonylamino)-4,5-dihydro-1H-1,2,4-triazol-5-one (4f). Yield 85%; m.p. 160-
161 °C (EtOH-H2O, 1:3); Calculated for C13H10N4O2S (286.31): 55.54% C, 3.52% H, 19.57% N;
found: 55.16% C, 3.52% H, 19.43% N. 1H-NMR: δ 7.29-8.05 (m, 8H, Ar-H), 11.85 (s, 1H, NH); 12.46
(s, 1H, NH); 13C-NMR: δ 126.10, 126.98 (2C), 127.10, 129.25 (2C), 130.90 (2C), 133.80, 135.50
(aromatic carbons), 146.20 (triazole C3), 153.70 (triazole C5), 161.10 (C=O); IR: 3250 (NH), 1730,
1675 (C=O), 1610 (C=N), 770, 700 (monosubstituted benzenoid ring) cm-1; UV λmax nm, (ε, L·mol-
1·cm-1): 253 (25710), 210 (16990) nm.

239
Molecules 2004, 9
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