Complexation versus thiadiazole formation for reactions of thiosemicarbazides with copper(II)

Article abstract of DOI:10.1039/b617186a

The reactions of N,N-substituted thiosemicarbazides with copper salts have been investigated and either copper(ii) thiosemicarbazide complexes, 1,3,4-thiadiazolium salts or 1,3,5-thiadiazoles are obtained depending on the Cu(ii) salt and solvent used. The Royal Society of Chemistry 2007.

Full text of DOI:10.1039/b617186a

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Complexation versus thiadiazole formation for reactions of
thiosemicarbazides with copper(II)
Elena Lo´pez-Torres, Andrew R. Cowley and Jonathan R. Dilworth*
Received 24th November 2006, Accepted 7th February 2007
First published as an Advance Article on the web 20th February 2007
DOI: 10.1039/b617186a
The reactions of N,N-substituted thiosemicarbazides with
copper salts have been investigated and either copper(II)
thiosemicarbazide complexes, 1,3,4-thiadiazolium salts or
1,3,5-thiadiazoles are obtained depending on the Cu(II) salt
and solvent used.
The coordination chemistry of copper with N,S-donor ligands
has been widely studied, as the complexes can serve as models
for enzymes such as galactose oxidase and superoxide dismutase.1
Fig.
2
Representation of the structure of [Cu(L1)2],1. Selected
◦
Copper complexes of N,S donors also have potential biomed-
ical applications and thiosemicarbazide and thiosemicarbazone
complexes have been investigated as antiviral, antibacterial and
anticancer chemotherapeutic agents.2 However it is their use as
ligands for radioactive copper complexes in hypoxic selective
radiopharmaceuticals that has created the most recent interest.3
Although many structures of thiosemicarbazone complexes have
been reported,4 there are few for complexes of the precursor
thiosemicarbazides. There is also a report of the use of Cu(II)
salts for the oxidation of thiosemicarbazones to thiazoles,5 but
the conditions which determine coordination versus oxidative
cyclisation have not yet been established.
Reaction of 1,1-dimethyl-4-phenyl-thiosemicarbazide (HL1,
Fig. 1) (synthesised from dimethylhydrazine and phenylisothio-
cyanate in diethyl ether6) with copper acetate (2 : 1) in methanol
leads to the formation of a red copper(II) complex (1) with two
monodeprotonated ligands in good yield. The mass spectrum
shows a peak at m/z 452.1 corresponding to the ion [Cu(L1)2 +
H]+, consistent with the loss of a proton from each ligand. This
peak has an appropriate isotope distribution pattern for the
proposed structure. Analytical data are also in agreement with this
formulation.† Recrystallisation from methanol gave single crystals
suitable for X-ray structure analysis. त
˚
bond distances (A) and angles ( ): C(2)–N(3) 1.416(3), N(3)–C(1)
1.381(3), C(1)–N(1) 1.284(3), N(1)–N(2) 1.454(2), C(1)–S(1) 1.753(2),
Cu(1)–S(1) 2.2419(6), Cu(1)–N(2) 2.0526(18). C(2)–N(3)–C(1) 127.6(2),
N(3)–C(1)–S(1) 114.33(16), N(3)–C(1)–N(1) 119.7(2), C(1)–S(1)–Cu(1)
96.14(7), C(1)–N(1)–N(2) 114.38(18), N(1)–N(2)–Cu(1) 116.53(13),
N(2)–Cu(1)–S(1) 85.41(5).
chain (dihedral angle 30.10◦) and they are parallel to each other.
Although the ligand is deprotonated there is not a great deal of
electronic delocalisation and this is reflected in the bond distances.5
The values of the C(1)–N(1) and C(1)–S(1) bonds lengths indicate
that the ligand is in its thiolic form. The ligand is close to planar, as
found with thiosemicarbazone complexes, although deprotonated
thiosemicarbazones are more extensively delocalised.4 There are
no hydrogen bonds and the molecules are held together in the
˚
crystal packing by p–p interactions with a distance of 3.521 A,
which leads to the formation of infinite chains running in the b
direction.
Complex 1 is sparingly soluble in water and hexane, but quite
soluble in a wide range of common solvents, such as methanol,
diethyl ether, toluene and acetonitrile giving red solutions. The
cyclic voltammogram measured in DMF (Pt working and aux-
iliary electrodes, standard calomel reference electrode, scan rate
100 mV s−1) shows one quasireversible process corresponding to
the oxidation of Cu(II) to Cu(III) at E1/2 = +0.213 V (vs SCE) and
another irreversible process attributable to the reduction of Cu(II)
to Cu(I) at −0.727 V.
Reaction of the same ligand with copper(II) chloride in methanol
(1 : 1) yields a green solution, the ESMS(+) of which shows four
peaks at m/z 192.1, 311.1, 353.2 and 453.1. These correspond
to the formation of three species: one copper complex and two
different new heterocycles identified below. The peak at m/z 453.1
corresponds to the Cu(I) species [Cu(L1H)2]+ with two neutral
thiosemicarbazide ligands. This shows the appropriate isotopic
pattern.
Fig. 1 Structure of thiosemicarbazide HL1.
The X-ray crystal structure shows the Cu(II) ion to be four-
coordinate with the two monodeprotonated ligands in a N2S2
trans square-planar arrangement (Fig. 2). The complex is cen-
trosymmetric with the inversion point located at the copper ion.
The phenyl rings are more or less coplanar to the rest of the ligand
If the reaction is carried out in THF the mass spectrum of
the solution displays only the peak at m/z 192.1. After one day
in the freezer, green crystals of 2 suitable for X-ray structure
determination were obtained from the mother liquor in good
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road,
Oxford, UK OX1 3TA. E-mail: jon.dilworth@chem.ox.ac.uk; Fax: +44
(0)1865-272690; Tel: +44 (0)1865-285151
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yield.† The paramagnetism of the complex precluded NMR
studies. Compound 2 consists of a copper(II) salt containing
one [CuCl4]2− anion and two positively charged 3-methyl-1,3,4-
thiadiazolium cations (Fig. 3), which are formed by the oxidation
and cyclisation of the thiosemicarbazide, via the formation of
a bond between sulfur and a deprotonated methyl group. The
asymmetric unit contains two independent molecules of the cation
and a single molecule of the anion, none of which have any
2−
crystallographic symmetry. The geometry of the CuCl4 ion is
intermediate between square planar and tetrahedral and all the
Cu–Cl distances are different. The cations are both linked to the
˚
anion by N–H · · · Cl hydrogen bonds (N(3) · · · Cl(1) 3.378(2) A,
˚
N(6) · · · Cl(6) 3.266(2) A). The hydrogen-bonded assembly has an
approximately twofold axis of rotation. Bond distances and angles
in both heterocyclic rings are not identical but are very similar.
The N(2)–C(8) and N(5)–C(17) and N(1)–C(1) and N(4)–C(10)
bond distances correspond to double bonds, while the remaining
C–N, the N–N and the C–S bond distances are close to the
value expected for single bonds.3 The thiadiazolium rings are
virtually planar and they are coplanar with the phenyl groups.
The molecules are linked together by p–p interactions involving
Fig. 4 Thiadiazoles and thiadiazolium salts.
with CuCl2 in THF exclusively gives the previously unreported
3-methyl-5-aminophenyl-1,3,4-thiadiazolium salt (E); the X-ray
crystal structure of which is outlined above.
˚
the phenyl groups with a distance between centroids of 3.645 A.
The use of THF as solvent permits the fully selective syn-
thesis of 2. However, if the filtrate from the synthesis of 2
in methanol is allowed to evaporate slowly white crystals of
3, are obtained. This was unambiguously identified by an X-
ray crystal structure determination. This species results from
another oxidative cyclisation reaction, but now involving linking
of two thiosemicarbazide ligands with elimination of elemen-
tal sulfur to give 2-dimethylhydrazido-3-phenyl-4-phenylimino-
5-dimethylamino-1,3,5-thiadiazole (3) (Fig. 3). The weak peak
described earlier at m/z 355.2 corresponds to the molecular ion
[C18H22N6S + H]+ and the most intense peak at m/z 311.1 is
assigned to the fragment [C16H16N5S]+, corresponding to the loss
1
of a NMe2 group. The H and 13C NMR spectra are consistent
with the determined structure. Further details of the X-ray crystal
structure of 3 will be reported elsewhere.
Fig. 3 Thermal ellipsoid plot (ORTEP-3) at 40% probability for
compound [(C9H10N3S)2]2+[CuCl4]2− 2. Selected bond distances and
angles: N(3)–C(1) 1.339(3), C(1)–N(1) 1.313(3), N(1)–N(2) 1.376(3),
N(2)–C(8) 1.466(3), C(8)–S(1) 1.694(3), S(1)–C(1) 1.759(2), C(10)–N(6)
1.341(3), C(10)–N(4) 1.317(3), N(4)–N(5) 1.374(3), N(5)–C(17) 1.303(3),
C(17)–S(2) 1.688(3), S(2)–C(10) 1.760(2). C(2)–N(3)–C(1) 128.9(2),
N(3)–C(1)–N(1) 126.2(2), N(3)–C(1)–S(1) 119.48(17), C(1)–N(1)–N(2)
108.13(19), N(1)–N(2)–C(8) 118.0(2), N(2)–C(8)–S(1) 111.64(18),
S(1)–C(1)–N(1) 114.36(18), C(11)–N(6)–C(10) 128.8(2), N(6)–C(10)–N(4)
126.4(2), N(6)–C(10)–S(2) 119.32(17), C(10)–N(4)–N(5) 108.28(19),
N(4)–N(5)–C(17) 117.6(2), N(5)–C(17)–S(2) 111.97(18), S(2)–C(10)–N(4)
114.25(17).
Thiadiazoles have attracted interest due to their wide spectra of
biological activities7 and have usually been prepared via oxidative
reactions. 3,5-Diamino-1,2,4-thiadiazoles (Fig. 4, structure A) can
be prepared by oxidative coupling of thioureas with reagents such
Fig. 5 Reaction scheme with proposed mechanism.
as acidic DMSO8 or bis(acyloxyiodo)arenes.9 Analogous oxida-
The formation of the Cu(II) complex 1 occurs with Cu(II)
acetate where acetate is sufficiently basic to deprotonate the
thiosemicarbazide to give a stable Cu(II) complex. When Cu(II)
chloride is used ligand deprotonation does not occur and an
internal redox process occurs for the dicationic complex to give
presumably Cu(I) and a diazenium cation which then cyclises to
give 2 or couples with elimination of sulfur to give 3 (see Fig. 5). As
ꢀ
=
tion of aldehyde thiosemicarbazones RCH NNHCSNHR using
Cu(II)(ClO4)2 is reported to give 1,3,4-thiadiazoles of structure
B below.5 Methylation of the 5-amino-1,3,4-thiadiazole C with
MeI gives the neutral methylated thiadiazole D.10 The oxidation
of alkylated thiosemicarbazides such as Me2NNHCSNHPh has
not previously been described, and we here report that reaction
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expected the reduction of the positively charged complex occurs
more readily than for neutral 1. The Cu(II) anion arises from
adventitious oxidation during crystallisation which was carried
out in air. The formation of 2 cannot occur while the copper is
bound as the N-methyl groups and sulfur atoms are held too far
apart.
These investigations show that the products of the reactions of
Cu(II) with this type of thiosemicarbazide can in part be controlled
by selection of the appropriate metal salt and reaction solvent. This
has permitted the isolation of a new Cu(II) complex together with
a previously unreported 3-methyl-1,3,4-thiadiazolium cation and
a very unusual 1,3,5-thiadiazole.
measured, 2578 unique (Rint = 0.040) which were used in all calculations.
The final wR(F2) was 0.0379. Crystal structure determination of complex
2 Crystal data. C18H20Cl4CuN6S2, M = 589.89, triclinic, a = 7.3900(2),
˚
b = 9.9448(2), c = 16.1842(3) A, a = 80.9969(10), b = 88.6086(10), c =
3
¯
˚
85.1073(9) U = 1170.40(5) A , T = 150 K, space group P1, Z = 2, l(Mo-
Ka) = 1.588 mm−1, 17872 reflections measured, 5319 unique (Rint = 0.039)
which were used in all calculations. The final wR(F2) was 0.0357.
§ CCDC reference numbers 623527 and 623528. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b617186a
1 Metal Ions in Proteins, Vol. 3. Copper Proteins, ed. T. G. SpiroWiley,
New York, 1981; The Biochemistry of Copper, ed. J. Peisach, W. E. Blum-
berg and P. Aisen, Academic Press, New York, 1966.
2 D. X. West, S. B. Padhye and P. B. Sonawane, Struct. Bonding, 1991,
76, 1–50; A. E. Liberta and D. X. West, Biometals, 1992, 5, 121–
126; International Encyclopedia of Pharmacology and Therapeutics, ed.
J. G. Cory and A. H. Cory, Pergamon Press, New York, 1989; D. X.
West, A. E. Liberta, S. B. Padhye, R. C. Chikate, P. B. Sonawane, A. S.
Kumbar and R. G. Yeranda, Coord. Chem. Rev., 1993, 123, 49–71 and
references therein.
3 P. J. Blower, T. C. Castle, A. R. Cowley, J. R. Dilworth, P. S. Donnelly,
E. Labisbal, F. E. Sowrey, S. J. Teat and M. J. Went, Dalton Trans.,
2003, 4416–4425; A. R. Cowley, J. R. Dilworth, P. S. Donnelly, A. D.
Gee and J. Heslop, Dalton Trans., 2004, 2404–2412; A. R. Cowley,
J. R. Dilworth, P. S. Donnelly, E. Labisbal and A. Sousa, J. Am. Chem.
Soc., 2002, 124, 5270–5271; A. Obata, S. Kasamatsu, J. S. Lewis, T.
Furucawa, T. Takamatsu, J. Toyohara, T. Asai, M. J. Welch, S. G.
Adams, H. Saji, Y. Yorekura and Y. Fujibayashi, Nucl. Med. Biol.,
2005, 32, 21–28.
4 M. J. M. Campbell, Coord. Chem. Rev., 1975, 15, 279; J. S. Casas, M. S.
Garcia-Tasende and J. Sordo, Coord. Chem. Rev., 2000, 209, 197.
5 P. Le Meo, R. Noto, M. Gruttadauria and G. Werber, J. Heterocycl.
Chem., 1999, 36, 667–674.
Notes and references
† Compound 1: Found: C, 47.35; H, 5.35; N, 18.65; S, 14.22; Cu, 14.09.
C18H24N6S2Cu requires C, 47.84; H, 5.31; N, 18.66; S, 14.17; Cu, 14.06.
HPLC: Rt 10.44 min. kmax(DMF)/nm 288 (e/dm3 mol−1 cm−1 4972), 353
(4674) and 394sh (4177). Compound 2: Found: C, 36.91; H, 3.58; N,
14.31; S, 10.94; Cl, 23.92; Cu, 10.71. C18H20N6S2CuCl4 requires C, 36.63;
H, 3.39; N, 14.25; S, 10.86; Cl, 24.06; Cu, 10.71. HPLC: Rt 11.15 min.
kmax(DMF)/nm 407sh (e/dm3 mol−1 cm−1 870), 640 (100). Compound 3:
dH(300 MHz; CDCl3; Me4Si) 2.2 (6H, s, Me), 2.5 (6H, s, Me), 6.79–6.84
(2H, t, Ph), 7.09–7.14 (2H, t, Ph), 7.39–7.48 (6H, m, Ph). dC(300 MHz,
CDCl3, Me4Si) 42.6 (Me), 47.2 (Me), 120.5 (Ph), 120.9 (Ph), 127.8 (Ph),
=
=
128.0 (Ph), 128.6 (Ph), 129.0 (Ph), 136.4 (NNC N), 149,2 (NSC N).
‡ X-Ray crystallography Crystals were mounted on a glass fibre using
perfluoropolyether oil and cooled rapidly to 150 K in a stream of
cold N2 using an Oxford Cryosystems CRYOSTREAM unit. Diffraction
data were measured using an Enraf-Nonius Kappa CCD diffractometer
6 K. A. Jensen, A. Uffe, C. Larsen and C. Pedersen, Acta Chem. Scand.,
1968, 22, 1–50.
7 A. Castro, T. Castan˜o, A. Encinas, W. Porcal and C. Gil, Bioorg. Med.
Chem., 2006, 14, 1644–1652.
8 L. Forlani and C. Boga, J. Chem. Soc., Perkin Trans. 2, 2002, 768–772.
9 E. A. Mamaeva and A. A. Bakibaev, Tetrahedron, 2003, 59, 7521–7525.
10 F. Buccheri, G. Cusmano, R. Noto, R. Rainieri and G. Werber,
J. Heterocycl. Chem., 1987, 24, 521–523.
˚
(graphite-monochromated Mo-Ka radiation, k = 0.71073 A). Intensity
data were processed using the DENZO-SMN package.11 The structures
were solved using the direct-methods program SIR92,12 which located
all non-hydrogen atoms. Subsequent full-matrix least-squares refinement
was carried out using the CRYSTALS program suite.13 Coordinates
and anisotropic thermal parameters of all non-hydrogen atoms were
refined. The NH hydrogen atoms were located in a difference Fourier
map and their coordinates and isotropic thermal parameters subsequently
refined. Other hydrogen atoms were positioned geometrically after each
cycle of refinement. A 3-term Chebychev polynomial weighting scheme
was applied. Representations of the structures were produced using
ORTEP-3.14 Crystal structure determination of complex 1 Crystal data.
11 Z. Otwinowski and W. Monor, Processing of X-ray Diffraction Data
Collected in Oscillating Mode, Methods Enzymol, ed. C. W. Carter and
R. M. Sweet, Academic Press, New York, 1997, vol. 276.
12 A. Altomare, C. Cascarano, G. Giacovasco, A. Guagliardi, M. C. Burla,
G. Polidari and M. Camalli, J. Appl. Crystallogr., 1994, 27, 435.
13 CRYSTALS issue 12,P. W. Betteridge, J. R. Cooper, R. I. Cooper, K.
Prout and D. J. Watkin, J. Appl. Crystallogr., 36, 1487.
C18H24CuN6S2, M = 452.11, monoclinic, a = 11.8923(4), b = 5.5608(2),
3
˚
˚
c = 15.7983(5) A, b = 99.3695(14), U = 1030.81(6) A , T = 150 K,
space group P 21/c, Z = 2, l(Mo-Ka) = 1.277 mm−1, 10012 reflections
14 ORTEP-3 v 1.02, C. K. Johnson and M. K. Burnett, 1998.
1196 | Dalton Trans., 2007, 1194–1196
This journal is
The Royal Society of Chemistry 2007
©