1.

THIOSEMICARBAZIDE AND COMPLEXES BASED ON

THIOSEMICARBAZONE
1.1. Thiosemicarbazide and thiosemicarbazone

Thiosemicarbazide is used to synthesis thiosemicarbazone. It is white

crystal solid having melting point of 181-183 0C. Structure of
thiosemicarzide is described as the following:

H S Bond angle Charge density

2
N N1 = -0.051
4
N1N2C = 122.50 N2 = 0.026
H N
1 N H N2CN4 = 118.80 C = -0.154
N2CS = 121.50 N4 = 0.138
H H
N4CS = 119.70 S = -0.306

where atoms N1, N2, N4, C, S lie in the same plane, two atoms S and N1
are at trans-position each other.
Because of containing group NH2, thiosemicarbazide easily reacts with
carbonyl compounds to form thiosemicarbazone. This is condensation
reaction where atom N1 plays the role as nucleophile, atom C of carbonyl
group is electrophile center. Catalyst of reaction is acid.
Mechanism of reaction:
R H
R
δ+ δ- ..
C O + H2N NH C NHR'' R' C N
+
NH C NHR''
R'
S O- H S

R R

R' C N NH C NHR'' R' C NH

N C NHR''
-H2O
S OH H S

Figure 1: Mechanism of condensation reaction forming thiosemicarbazone

1.2. Complex of thiosemicarbazone and their application

Forming-complex of thiosemicarbazide and thiosemicarbazone can be

explained by two phenomena: change from trans-position to cis-position of
two atoms N1, S and tautomerization.
 N N N
N
NH NH tautomerise N N
M

H2N S S NH2 HS NH S
NH2
Figure 2: Forming complex of thiosemicarbazone diagram

In the simple cases, thiosemicarbazones show to be bidentate-ligand,

coordination is performed by atom N of amine group and atom S of
thiosemicarbazide component (NS-ligand system).
In the case, carbonyl component contains hetero atom such as N, O, S…or
steric effect, complexing will become much more than complicated and
thiosemicarbazone show to be tri, tetra or even penta-dentate ligand but
monodentate in a few case.
Tri-dentate ligands of thiosemicarbazone usually have N2S- or NOS-
ligand system. Besides atoms N and S of thiosemicarbazide component,
third hetero atom which participates coordination is in carbonyl component.
Some ligands of this kind are thiosemicarbazone or derivative of
thiosemicarazone of salicylaldehyde, isatin, acetylaceton… Modeling of tri-
dentate complex is defined as the following:

Tetra-coordination is more than complicated. The ligand system is formed

by condensation two molecules thiosemicarbazones with carbonyl
compounds.

R1 O
NH NH2
HN N N NH
H2N
+ 2
S S + 2 H2O
S
R2 O NH2 H2N

Figure 3: Forming tetra-dentate thiosemicarbazone

 In this case, coordination can be formed by two atoms N of amine group
and two atoms S (N2S2-ligand system). However, in according to some
research [1,2], complexing could be formed by two atoms N of amine group
and two atoms N of thioamide group.

Ph Ph Ph Ph

N N N N
N N HN NH
Pd Cu
H2N NH2
S S S NH HN S

Figure 4: Some forms of coordination of tetra-dentate ligand

Specially, group of researchers explored structure of 2,6-diaxetyl; 2,6-

diformylpiridine Bis(thiosemicarbazone) and their complexes with Fe(II),
In(II), Sn(IV) to conclude that the thiosemicarbazones show penta-dentate
ability for N3S2-ligand system.

H3C CH3
N
N N
HN NH

S NH2 H2N S

Figure 5: 2,6-diacetylpyridine Bis(thiosemicarbazone) and their pentagonal

bipyramid complex with Fe(II), In(II), Sn(IV)

In a few case, thiosemicarbazone only show to be mono-dentate ligand

although it contains many hetero atoms having ability to form complex. A
typical example is complex of thiosemicarbazide with ion Hg2+: Hg(TSC)22+,
where coordination is formed by two atoms S.
Not only variety of structure, complex of thiosemicarbazone but also has
many application in the field of biochemistry. Bio-activity of
thiosemicarbazone is firstly discovered by Domagk. He recognized that
some thiosemicarbazones have antibacterial activity. After that there are
many studies of bio-activity of thiosemicarbazide , thiosemicarbazone as
well as their complex. Most important one is that p-acetaminobenzandehyde
thiosemicarbazone (thiacetazon-TB1) which is consider such as most
effective tubercular drug at present.

CH3 N
HN NH2
O N
H
S (TB1)

In addition, anticancer ability of thiosemicarbazone and their corresponding

complex also have attracted special interest. Complex based on
phenanthrenequinon have this activity because they have similar planar
structure of phenanthrolin-substance can interact with DNA to get inhibit
growth of cells. Complexes based on other dion such as benzoquinon,
napthaquinon are able to inhibit line of breast cancer cell MCF7.

1.3. Cu(II) thiosemicarbazone complexes and quantitative structure-

activity relationship (QSAR)