Microwave-assisted synthesis of novel 2,4-dihydro-5-[4-(trifluoromethyl) phenyl]-3h-1,2,4-triazol-3-ones and potentiometric determination of their pKa in nonaqueous solvents

Article abstract of DOI:10.1002/hlca.201000002

The novel 4-amino- or 4-aryl-substituted 2,4-dihydro-5-[(4-trifluoromethyl) phenyl]-3H-1,2,4-triazol-3-ones 3a-3g were synthesized by reaction of N-(ethoxycarbonyl)-4-(trifluoromethyl)benzenehydrazonic acid ethyl ester (2) and primary amines or hydrazine

Full text of DOI:10.1002/hlca.201000002

Helvetica Chimica Acta – Vol. 93 (2010)
1967
Microwave-Assisted Synthesis of Novel 2,4-Dihydro-5-[4-
(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-ones and Potentiometric
Determination of Their pKa in Nonaqueous Solvents
˙
by Musa ꢀzil*, Fatih Islamog˘lu, Emre Mentes¸e, and Bahittin Kahveci
Department of Chemistry, Faculty of Art and Science, Rize University, Rize, 53100, Turkey
(phone: þ 904642235375; fax: þ 904642235376; e-mail: musa.ozil@rize.edu.tr)
The novel 4-amino- or 4-aryl-substituted 2,4-dihydro-5-[(4-trifluoromethyl)phenyl]-3H-1,2,4-tria-
zol-3-ones 3a – 3g were synthesized by reaction of N-(ethoxycarbonyl)-4-(trifluoromethyl)benzenehy-
drazonic acid ethyl ester (2) and primary amines or hydrazine by microwave irradiation. Compounds 3a –
3g were potentiometrically titrated with tetrabutylammonium hydroxide (Bu4NOH) in four nonaqueous
i
t
solvents, i.e., PrOH, BuOH, MeCN, and N,N-dimethylformamide (DMF). Also half-neutralization
potential values and the corresponding pKa values were determined in all cases.
Introduction. – Triazol compounds have been found to be associated with diverse
pharmacological activities such as antibacterial, antifungal, anticancer, and anticon-
vulsant [1 – 6]. In recent years, the synthesis of some 3H-1,2,4-triazol-3-one derivatives
from arenehydrazonic esters (compounds of type 2) has been reported [7]. However,
most of the conventional syntheses of such compounds are time-consuming and lack
high selectivity. On the other hand, in recent years, microwave-assisted reactions have
attracted much research interest because of the simplicity in operation, enhanced
reaction rates, and great selectivity [8]. Thus, microwave irradiation, which has become
a powerful synthetic tool for the rapid synthesis of a variety of compounds, is used to
enhance the rates of classical organic reactions [9]. In this study, we synthesized some
new 3H-1,2,4-triazol-3-one derivatives containing trifluoromethyl groups by the
reaction of 2 and primary amines under microwave irradiation for 10 min. We have
already previously synthesized triazole compounds by using the microwave-irradiation
method [10 – 12].
It is known that 2,4-dihydro-3H-1,2,4-triazol-3-ones are weakly acidic [13][14]. The
acidity of a compound in a given medium is influenced by both the electronic effects of
the substituents and the polarity of the solvent.
Results and Discussion. – The first step in our synthesis was the formation of the
hydrochloride of 4-(trifluoromethyl)benzenimidic acid ethyl ester (1; Scheme). Passing
HCl gas through solutions of 4-(trifluoromethyl)benzonitrile in dry EtOH, followed by
precipitation with Et2O, gave 1. Treatment of 1 with ethyl hydrazinecarboxylate
resulted in the formation of 2. Such compounds can be considered as useful
intermediates leading to the formation of heterocycles such as 3H-1,2,4-triazol-3-ones.
Therefore, treatment of compound 2 with primary amines or hydrazine under
microwave heating resulted in the formation of 3H-1,2,4-triazol-3-ones 3a – 3g
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

1968
Helvetica Chimica Acta – Vol. 93 (2010)
(Scheme). The reactions were performed in dry EtOH. The reaction time was as short
as 10 min, and 3a – 3g were isolated in up to 91% yield. Their structure was confirmed
by IR and 1H- and 13C-NMR spectroscopy and elemental analysis.
Scheme. Pathway for the Formation of the 3H-1,2,4-Triazol-3-ones
In the IR spectrum (KBr) of compound 1, the characteristic NHþ2 absorption bands
appeared at 2977, 2920, and 850 cmꢀ1 and the C¼N band at 1647 cmꢀ1. The IR spectrum
(KBr) of 2 showed the C¼O band at 1698 cmꢀ1 and the C¼N band at 1613 cmꢀ1. The
IR spectra (KBr) of 3a – 3g were characterized by absorption bands at 3160, 1699, and
1602 cmꢀ1 attributable to NH, C¼O, and C¼N functions, respectively. In addition,
observation of NH and aromatic H-atoms, as well as the lack of EtO signals in the
1H-NMR spectra of 3a – 3g and the triazolone C¼O signal at d(C) ca. 155, a C¼N
signal at d(C) ca. 150, as well as the CF3 signal in average at d(C) 122 in the 13C-NMR
spectra supported the proposed structures. Moreover, the elemental analyses of 3a – 3g
showed good agreement with the calculated values.
All compounds were potentiometrically titrated with Bu4NOH in four nonaqueous
i
t
solvents, namely PrOH, BuOH, MeCN, and DMF. The mV values read in each
titration were plotted against 0.05m Bu4NOH in iPrOH (in ml) yielding the
potentiometric titration curves for all 3H-1,2,4-triazol-3-ones (see Fig. 1 for 3d). From
these titration curves, the half-neutralization potential (HNP) values were determined
(see Fig. 2 for 3d), and the corresponding pKa values were calculated (see Table). Also
the derived potentiometric titration curves were plotted (Figs. 3 – 5 for 3d).
The pH of the weak acids are given by the pH ¼ pKa þ log[Aꢀ]/[HA], i.e., pH ¼ pKa
at [Aꢀ] ¼ [HA] at the half-neutralization point. Therefore, the pH values can be
regarded as pKa at the half-neutralization points (HNP). When the dielectric
permittivity of solvents is taken into consideration, the acidic sequence can be

Helvetica Chimica Acta – Vol. 93 (2010)
1969
Fig. 1. mV vs. ml Bu4NOH Potentiometric titration curves of 0.001m solutions of compound 3d titrated
with 0.05m Bu4NOH at 258
Fig. 2. pH vs. ml Bu4NOH Potentiometric titration curves of 0.001m solutions of 3d titrated with 0.05m
Bu4NOH at 258

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Helvetica Chimica Acta – Vol. 93 (2010)
Table. Half-Neutralization-Potential (HNP) Values and Corresponding pKa Values of 3a – 3g
iPrOH
DMF
tBuOH
MeCN
pKa
HNP [mV]
pKa
HNP [mV]
pKa
HNP [mV]
pKa
HNP [mV]
3a
3b
3c
3d
3e
3f
3g
10.68
12.49
12.64
12.55
12.36
12.05
11.21
ꢀ 212.3
ꢀ 324.9
ꢀ 334.2
ꢀ 328.0
ꢀ 316.9
ꢀ 298.9
ꢀ 247.7
15.18
15.03
14.40
14.63
14.59
14.84
14.27
ꢀ 484.0
ꢀ 474.9
ꢀ 437.7
ꢀ 451.8
ꢀ 448.0
ꢀ 456.2
ꢀ 421.6
12.69
14.48
14.36
14.30
14.84
9.85
ꢀ 337.4
ꢀ 442.5
ꢀ 435.6
ꢀ 431.7
ꢀ 463.9
ꢀ 166.6
ꢀ 233.9
15.22
14.89
14.99
14.90
14.06
8.67
ꢀ 487.0
ꢀ 467.1
ꢀ 472.9
ꢀ 467.8
ꢀ 417.8
ꢀ 98.1
9.68
15.98
ꢀ 514.8
Fig. 3. DE/DV vs. ml Bu4NOH Potentiometric titration curves of 0.001m solutions of compound 3d titrated
with 0.05m Bu4NOH at 258
expected as follows: DMF (e ¼ 36.7) > MeCN (e ¼ 36) > iPrOH (e ¼ 19.4) > tBuOH
i
(e ¼ 12). In PrOH, all these solvents show the strongest acidic properties. The degree
to which a pure solvent (SH) ionizes is represented by its autoprotolysis constant, KSH
.
For the above reaction, the constant is defined by KSH ¼ [H2Sþ] · [Sꢀ]. The importance
of the autoprotolysis constant in titrations lies in its effect on the completeness of a
titration reaction. As it is well known, the acidity of a compound depends on several
factors. The most important ones are solvent effect and molecular structure. The Table
shows that the HNP values and the corresponding pKa values obtained from
potentiometric titrations depend on the type of nonaqueous solvents used and the
molecular structure of the compound.

Helvetica Chimica Acta – Vol. 93 (2010)
1971
Fig. 4. DE2/DV2 vs. ml Bu4NOH Potentiometric titration curves of 0.001m solutions of compound 3d
titrated with 0.05m Bu4NOH at 258
Fig. 5. DV/DE vs. ml Bu4NOH Potentiometric titration curves of 0.001m solutions of compound 3d
titrated with 0.05m Bu4NOH at 258

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Helvetica Chimica Acta – Vol. 93 (2010)
As seen in the Table, the acidic sequence for compounds 3a, 3c, and 3d is iPrOH >
tBuOH > DMF > MeCN; for compound 3b, it is iPrOH > tBuOH > MeCN > DMF; for
i
compound 3e, it is PrOH > MeCN > DMF > tBuOH for compound 3f, it is MeCN >
t
tBuOH > iPrOH > DMF; and finally for 3g, it is BuOH > iPrOH > DMF > MeCN. In
i
another words, 3a – 3e show the strongest acidic properties in PrOH, and 3f and 3g
t
show the strongest acidic properties in MeCN and BuOH, respectively. On the other
hand, the order of the weakest acidic properties is as follows: 3a, 3c, 3d, and 3g in
t
MeCN, 3b and 3f in DMF, and 3e in BuOH. This situation may be attributed to H-
bonding between the formed anions and the solvent molecules in the amphiprotic
neutral solvents.
Experimental Part
General. M.p.: Bꢀchi melting-point apparatus, in open capillaries; uncorrected. IR Spectra: Perkin –
.
Elmer-100 FT-IR spectrophotometer; KBr pellets; ˜n in cmꢀ1 1H- and 13C-NMR Spectra: Varian-200
spectrometer; in (D6)DMSO; chemical shifts d in ppm rel. to Me4Si as internal standard and coupling
constants J in Hz. Elemental analyses: Carlo-Erba-1106-CHN analyzer; the measured percentages were
in agreement (ꢁ0.4%) with the calculated ones.
Microwave Experiments. A monomode CEM-Discover microwave apparatus was used in the
standard configuration as delivered, including its software. All experiments were carried out in
microwave process vials (30 ml) with control of the temp. by an IR sensor. The temp. was computer-
monitored and maintained constant by a discrete modulation of delivered microwave power. After
completion of the reaction, the vial was cooled to 608 by air-jet cooling (see also the General Procedure
below).
Potentiometric Titrations. For the potentiometric titrations, an Orion-720A pH/ion meter, equipped
with a combined pH electrode (in gold) and indicator electrode, were used (Fig. 6). Also, a magnetic
stirrer, a semi-microburette, and a 25 ml beaker were used in titrations. Before potentiometric titrations,
the pH meter was calibrated according to the instructions supplied by the manufacturers of the pH meter.
During the titrations, the titrant was added in increments of 0.05 ml after each stable reading, and mV
Fig. 6. Potentiometric-titration cell

Helvetica Chimica Acta – Vol. 93 (2010)
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values were recorded. The necessary chemicals were supplied by Fluka and Merck. After purifications,
iPrOH was used to prepare 0.05n Bu4NOH by dilution of 0.1n Bu4NOH. The 0.05m Bu4NOH in iPrOH,
which is widely used in the titration of acids, was used as titrant, and the mV values were recorded with
the pH meter. Finally, the HNP values were determined by plotting the mV/ml (Bu4NOH) graphics.
4-(Trifluoromethyl)benzenimidic Acid Ethyl Ester Hydrochloride (1:1) (1). To an ice-cooled soln. of
the 4-(trifluoromethyl)benzonitrile (1 mol) in dry EtOH (1.1 mol), dry HCl gas was added until 1.1 mol
had been absorbed. The resulting soln. was then allowed to stand at 08 in the refrigerator for 12 h, after
which cold Et2O was added. The precipitated crystals were filtered off immediately, washed with cold
Et2O, and dried in a dessicator: 87% of 1. White solid. M.p. 1318. IR: 2977, 2920, 850 (NHþ2 ), 1647
(C¼N), 850 (1,4-disubstituted benzene ring). 1H-NMR: 1.39 (t, 3J ¼ 7.1, 3 H); 4.32 (q, 3J ¼ 7.1, 2 H); 6.65
(br. s, 2 H); 7.53 – 7.64 (m, 4 H). 13C-NMR: 14.02; 68.12; 114.33 (CF3); 126.16; 128.04; 129.04; 136.60;
163.88 (C¼N). Anal. calc. for C10H11ClF3NO: C 47.35, H 4.37, N 5.52; found: C 47.21, H 4.30, N 5.44.
N-(Ethoxycarbonyl)-4-(trifluoromethyl)benzenehydrazonic Acid Ethyl Ester (2). In an ice bath, 1
(0.01 mol) was dissolved in dry EtOH (50 ml), and ethyl hydrazinecarboxylate (0.01 mol) in dry EtOH
(20 ml) was then added. After stirring for 6 h at 08, the mixture was filtered to remove NH4Cl which
separated from the soln., and the filtrate was concentrated at 35 – 408. The solid residue, after drying in a
dessicator, was recrystallized from petroleum ether: pure 2 (79%). White solid. M.p. 708. IR: 3257 (NH),
1698 (C¼O), 1613 (C¼N), 847 (1,4-disubstituted benzene ring). 1H-NMR: 1.19 (t, 3J ¼ 6.8, 3 H); 1.29 (t,
3J ¼ 7.3, 3 H); 4.09 (q, 3J ¼ 6.8, 2 H); 4.51 (q, 3J ¼ 7.3, 2 H); 7.94 (d-like, AA’ of AA’XX’, 3J ¼ 8.2, 2 arom.
3
H); 8.33 (d-like, XX’ of AA’XX’, J ¼ 8.2, 2 arom. H); 8.44 (br. s, 1 H). 13C-NMR: 14.16; 15.23; 62.14;
63.10; 115.39 (CF3); 126.51; 127.94; 128.88; 134.87; 153.82 (C¼O); 157.01 (C¼N). Anal. calc. for
C13H15F3N2O3: C 51.32, H 4.97, N 9.21; found: C 51.31, H 4.90, N 9.28.
3H-1,2,4-Triazol-3-ones 3: General Procedure. A mixture of 2 (0.01 mol) and amino compound
(0.01 mol) in EtOH (25 ml) was microwave-irradiated in closed vessels with pressure control at 1308 for
10 min (hold time) at 300 W maximum power. After the completion of the reaction (TLC monitoring
(AcOEt/hexane 3 :1)), the crude product was recrystallized from EtOH: pure 3.
4-Amino-2,4-dihydro-5-[4-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (3a): Yield 84%. M.p.
253 – 2548. IR: 3342, 3320 (NH2), 3194 (NH), 1698 (C¼O), 1601 (C¼N), 833 (1,4-disubstituted benzene
1
3
ring). H-NMR: 5.49 (s, 2 H); 7.87 (d-like, AA’ of AA’XX’, J ¼ 8.4, 2 arom. H); 8.24 (d-like, XX’ of
AA’XX’, J ¼ 8.4, 2 arom. H); 12.08 (s, 1 H). 13C-NMR: 120.13 (CF3); 124.97; 128.62; 132.75; 134.13;
3
146.29 (C¼N); 156.44 (C¼O). Anal. calc. for C9H7F3N4O: C 44.27, H 2.89, N 22.95; found: C 44.21, H
2.84, N 22.93.
2,4-Dihydro-4-phenyl-5-[4-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (3b): Yield 81%. M.p.
213 – 2148. IR: 3156 (NH), 1694 (C¼O), 1620 (C¼N), 837 (1,4-disubstituted benzene ring), 695, 750
(monosubstituted benzene ring). 1H-NMR: 7.24 – 7.58 (m, 9 H); 10.35 (s, 1 H). 13C-NMR: 119.41 (CF3);
121.22; 122.34; 124.75; 125.48; 126.50; 127.83; 128.65; 135.21; 148.04 (C¼N); 153.82 (C¼O). Anal. calc.
for C15H10F3N3O: C 59.02, H 3.30, N 13.77; found: C 59.09, H 3.27, N 13.81.
2,4-Dihydro-4-(4-methylphenyl)-5-[4-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (3c): Yield
87%. M.p. 193 – 1948. IR: 3160 (NH), 1699 (C¼O), 1620 (C¼N), 835, 847 (1,4-disubstituted benzene
ring). 1H-NMR: 2.31 (s, 3 H); 7.12 – 7.74 (m, 8 H); 10.42 (s, 1 H). 13C-NMR: 21.80; 120.13 (CF3); 121.87;
122.56; 123.05; 125.22; 126.13; 127.22; 129.05; 134.12; 147.84 (C¼N); 154.76 (C¼O). Anal. calc. for
C16H12F3N3O: C 60.19, H 3.79, N 13.15; found: C 60.17, H 3.77, N 13.19.
4-[4-(tert-Butyl)phenyl]-2,4-dihydro-5-[4-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (3d):
Yield 91%. M.p. 219 – 2208. IR: 3162 (NH), 1698 (C¼O), 1621 (C¼N), 833, 849 (1,4-disubstituted
benzene ring). 1H-NMR: 1.30 (s, 9 H); 7.21 – 7.77 (m, 8 H); 12.35 (s, 1 H). 13C-NMR: 31.70; 35.18; 126.18
(CF3); 126.26; 126.91; 127.84; 128.94; 130.05; 131.42; 131.69; 142.85; 150.02 (C¼N); 155.23 (C¼O). Anal.
calc. for C19H18F3N3O: C 63.15, H 5.02, N 11.63; found: C 63.17, H 5.04, N 11.60.
4-(4-Fluorophenyl)-2,4-dihydro-5-[4-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (3e): Yield
86%. M.p. 205 – 2068. IR: 3171 (NH), 1691 (C¼O), 1621 (C¼N), 833, 843 (1,4-disubstituted benzene
ring). 1H-NMR: 7.33 – 7.78 (m, 8 H); 12.39 (s, 1 H). 13C-NMR: 124.21 (CF3); 125.14; 126.21; 127.34;
128.37; 129.13; 131.87; 133.10; 143.23; 149.92 (C¼N); 155.14 (C¼O). Anal. calc. for C15H9F4N3O: C
55.73, H 2.81, N 13.00; found: C 55.70, H 2.84, N 13.02.

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Helvetica Chimica Acta – Vol. 93 (2010)
2,4-Dihydro-4-(4-hydroxyphenyl)-5-[4-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (3f): Yield
83%. M.p. 175 – 1768. IR: 3339 (OH), 3174 (NH), 1697 (C¼O), 1614 (C¼N), 824, 845 (1,4-disubstituted
benzene ring). 1H-NMR: 6.37 – 7.49 (m, 8 H); 8.36 (br. s, 1 H); 12.23 (s, 1 H). 13C-NMR: 123.14 (CF3);
125.32; 125.98; 126.67; 128.21; 129.61; 131.66; 132.73; 146.21 (C¼N); 147.23; 156.21 (C¼O). Anal. calc.
for C15H10F3N3O2: C 56.08, H 3.14, N 13.08; found: C 56.02, H 3.14, N 13.10.
2,4-Dihydro-4-(4-phenoxyphenyl)-5-[4-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (3g): Yield
85%. M.p. 183 – 1848. IR: 3195 (NH), 1683 (C¼O), 1602 (C¼N), 837, 852 (1,4-disubstituted benzene
ring), 688, 749 (monosubstituted benzene ring). 1H-NMR: 6.94 – 8.02 (m, 13 H); 11.97 (s, 1 H).
13C-NMR: 122.76 (CF3); 123.14; 124.22; 125.03; 125.87; 126.58; 127.21; 128.56; 129.44; 130.37; 131.62;
145.14 (C¼N); 146.44; 147.33; 155.53 (C¼O). Anal. calc. for C21H14F3N3O2: C 63.48, H 3.55, N 10.58;
found: C 63.42, H 3.54, N 10.51.
REFERENCES
[1] O. G. Todoulou, A. E. Papadaki-Valiraki, S. Ikeda, E. De Clercq, Eur. J. Med. Chem. 1994, 29, 611.
[2] S. Rollas, N. Kalyoncuoglu, D. Sꢁr-Altiner, Y. Yegenoglu, Pharmazie 1993, 48, 308.
[3] F. Malbec, R. Milcent, P. J. Vicart, A. M. Bure, J. Heterocycl. Chem. 1984, 21, 1769.
˙
[4] A. A. Ikizler, B. Kahveci, C. B. Johansson, C. C¸ elik, H. Yꢁksek, Acta Pol. Pharm. Drug Res. 1997, 54,
307.
:
[5] B. Kahveci, O. Bekircan, M. Serdar, A. A. Ikizler, Indian J. Chem., Sect. B 2003, 42, 1527.
[6] O. Bekircan, B. Kahveci, M. KꢁÅꢁk, Turk. J. Chem. 2006, 30, 29.
:
[7] R. ꢂn, A. Ikizler, Chim. Acta Turc. 1975, 3, 113.
[8] C. O. Kappe, D. Dallinger, S. Murphree, ꢃPractical Microwave Synthesis for Organic Chemistsꢄ,
Wiley-VCH, Weinheim, 2009.
[9] S. Caddick, Tetrahedron 1995, 51, 10403; R. S. Varma, Green Chem. 1999, 1, 43; R. S. Varma, J.
Heterocycl. Chem. 1999, 36, 1565; A. Loupy, A. Petit, J. Hamelin, F. Texier-Boullet, P. Jacquault, D.
Mathe, Synthesis 1998, 1213; A. de la Hoz, A. Dꢅaz-Ortis, A. Moreno, F. Langa, Eur. J. Org. Chem.
2000, 3659.
[10] B. Kahveci, M. ꢆzil, M. Serdar, Heteroatom Chem. 2008, 19, 38.
[11] B. Kahveci, M. ꢆzil, E. Mentes¸e, O. Bekircan, K. Buruk, Russ. J. Org. Chem. 2008, 44, 1816.
:
˘
˘
[12] M. ꢆzil, E. Agar, S. S¸as¸maz, B. Kahveci, N. Akdemir, I. E. GꢁmrꢁkÅꢁoglu, Dyes Pigm. 2007, 75, 732.
:
˘
[13] F. Islamoglu, B. Kahveci, M. ꢆzil, E. Akyꢁz, E. Mentes¸e, A. P. Ekinci, Asian J. Chem. 2009, 21, 1453.
[14] F. Islamoglu, B. Kahveci, M. ꢆzil, E. Akyꢁz, Asian J. Chem. 2008, 20, 3569.
:
˘
Received January 4, 2010