THE REACTIONS OF HYDRAZIDE (4-NITROIMIDAZOL-1

THE REACTIONS OF HYDRAZIDE (4-NITROIMIDAZOL-1

THE REACTIONS OF HYDRAZIDE (4-NITROIMIDAZOL-1-YL)
ACETIC ACID WITH ISOTHIOCYANATES
Monika Wujeca, Maciej Pisklakb, Monika Pituchaa, Maria Dobosza, Agata
Siweka
a
Department of Organic Chemistry, Faculty of Pharmacy, Medical University, Lublin,
6 Staszica Str. , [email protected]
b
Department of Physical Chemistry, Faculty of Pharmacy, Medical University,
Warszawa, 1 Banacha Str.
The biological activities of various triazoles [1-11] and imidazoles [12-13] have
been extensively studied. We observed from the literature that combination of two
heterocyclic moieties can enhances these activities [14]. In continuation of our work on
the synthesis of heterocycles of pharmaceutical interest [15-16] we report here synthesis
and characterisation of new derivatives of 3-[(4-nitroimidazol-1-yl) methyl]-1,2,4triazoline-5-thione.
The new obtained compounds can exist in two tautomeric forms: thione or thiole.
N
O2N
N
O2N
R
NCS
N
N
CH2 C NHNH C NH R
CH2 C NHNH2
O
O
S
2% NaOH
N
O2N
N
N
O2N
N
NH
CH2 C
N
N
N
CH2 C
N
C S
R
N
C SH
R
R = C6H5, 4-OCH3C6H4, CH2C6H5
Experimental
Melting points were determined in a Fisher-Johns block without corrections. The 1H
NMR spectra were recorded on a Brucker Avance 300 in DMSO-d6 with TMS as
internal standard. TLC was performed on commercial Merck SiO2 60 F254 plates with
chloroform-ethanol (10:1) eluent system, visualization: UV light λ 254 nm. Elemental
analyses were performed on a Perkin-Elmer analyzer and were in the range of ± 0.4%
for each element analyzed (C, H, N). Chemicals were purchased from Merck Co. or
Lancaster and used without purification.
(4-nitroimidazol-1-yl) acetic acid hydrazide (I)
Methyl (4-nitroimidazol-1-yl) acetate (0.01 mole), dry ethanol (5 cm3) and hydrazine
hydrate (80%, 0.02 mole) were mixed and kept for 24 h in room temperature. The
product was filtered, dried and crystallized from 95% ethanol.
C5H7N5O3 M.w 185.14. M.p. 110-1oC. Yield 86%.
Thiosemicarbazide derivatives of (4-nitroimidazol-1-yl) acetic acid (IIa-IIc)
Hydrazide I (0.01 mole) and isothiocyanates (0.01 mole) were mixed carefully and then
placed in a round bottom flask, and heated on oil bath at 70oC for 8 h. The reaction
product was washed with diethyl ether in order to remove the unreacted isothiocyanate
and then with water to remove the unreacted hydrazide. Next, the product was filtered,
dried and crystallized from 95% ethanol.
4-Phenyl-1-[(4-nitroimidazol-1-yl)acetyl]thiosemicarbazide (IIa)
C12H12N6O3S Mw:320.33. M.p. 140-2oC. Yield 88%. 1H NMR (δ, d6); 4.99 (s,1H,CH2);
6.90-7.43 (m, 5H,arom. benzene); 7.52 (s,1H,CH); 8.24 (s,1H,CH); 9.57, 9.88, 10.34
(3s,3H,3NH).
4-(4-Methoxyphenyl)- 1-[(4-nitroimidazol-1-yl)acetyl]thiosemicarbazide (IIb)
C13H14N6O4S Mw:350.36. M.p. 192-4 oC. Yield 93%. 1H NMR (δ, d6); 3.75 (s, 3H,CH3);
4.94 (s,1H,CH2); 6.88-7.40 (m, 4H,arom. benzene); 7.80 (s,1H,CH); 8.31 (s,1H,CH);
9.56, 9.65, 10.44 (3s,3H,3NH).
4-Benzyl-1-[(4-nitroimidazol-1-yl)acetyl]thiosemicarbazide (IIc)
C13H14N6O3S Mw:334.36. M.p. 149-150oC. Yield 90%. 1H NMR (δ, d6); 4.78
(s,1H,CH2); 4.91 (s,1H,CH2); 7.21-7.36 (m, 5H,arom. benzene); 7.80 (s,1H,CH); 8.30
(s,1H,CH); 8.59, 8.61, 10.33 (3s,3H,3NH).
3-[(4-Nitroimidazol-1-yl)methyl]-4-substituted-1,2,4-triazoline-5-thione (IIIa-IIIc):
thiosemicarbazide IIa-IIc (0.01 mole) and sodium hydroxide (2%, 20 cm3) were boiled
for 2 h. after cooling, the solution was neutrailed with diluted hydriochloric acid. The
precipitate was filtered and then crystallized from 95% ethanol.
3-[(4-Nitroimidazol-1-yl)methyl]-4-phenyl-1,2,4-triazoline-5-thione (IIIa)
C12H10N6O2S Mw:302.31. M.p. 309-310oC. Yield 89%. 1H NMR (δ, d6); 5.33
(s,1H,CH2); 7.40-7.59 (m, 5H,arom. benzene); 7.49 (s,1H,CH); 8.16 (s,1H,CH); 14.02
(s,1H,NH).
4-(4-Methoxyphenyl)-3-[(4-nitroimidazol-1-yl) methyl]-1,2,4-triazoline-5-thione (IIIb)
C13H12N6O3S Mw:332.34. M.p. 148-150oC. Yield 88%. 1H NMR (δ, d6); 3.83 (s,
3H,CH3); 4.95 (s,1H,CH2); 7.38-7.64 (m, 4H,arom. benzene); 7.76 (s,1H,CH); 7.93
(s,1H,CH); 13.85 (s,1H,NH).
4-Benzyl-3-[(4-nitroimidazol-1-yl) methyl]-1,2,4-triazoline-5-thione (IIIc)
C13H12N6O2S Mw:316.34. M.p. 120-2oC . Yield 78%. 1H NMR (δ, d6); 5.35 (s,1H,CH2);
5.57 (s,1H,CH2); 7.07-7.48 (m, 5H,arom. benzene); 7.84 (s,1H,CH); 8.19 (s,1H,CH);
14.05 (s,1H,NH).
Calculation
Theoretical quantum chemical calculations were performed for the thiole and thione
form of compounds IIIb and IIIc.
The molecular geometries were optimized by semi-empirical PM3 quantum chemical
method. Finally, B3LYP hybrid DFT potential with the 6-31G** functional base was
used to gain the single-point electronic energies. All of the quantum chemical
calculations were accomplished by Gaussian 98 package [17].
The results of calculations evidenced that the thione forms are more favourable for both
compounds. However, the energy difference between both tautomers is significanly
higher for compounds with the benzyl substituent IIIc(18.7 kcal/mol) then for IIIb
(14.7 kcal/mol).
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