Copper conjugates of Knoevenagel condensates of curcumin and their Schiff base derivatives: Synthesis, spectroscopy, magnetism, ESR, and electrochemistry

Article abstract of DOI:10.1080/15533170601172385

Novel copper(II) complexes of curcumin Knoevenagel condensates and their Schiff bases have been synthesized and characterized. All copper complexes possess distorted square-planar geometries with 1:1 metal to ligand stoichiometry capable of stabilizing Cu

Full text of DOI:10.1080/15533170601172385

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Copper Conjugates of Knoevenagel Condensates of
Curcumin and their Schiff Base Derivatives: Synthesis,
Spectroscopy, Magnetism, ESR, and Electrochemistry
Ajit P. Zambre a b , Abeda Jamadar b , Subhash Padhye a & V. M. Kulkarni b
a Drug Design and Molecular Medicine Group, Department of Chemistry, University of Pune,
Pune, India
b Department of Medicinal Chemistry, Bharati Vidyapeeth University Poona College of
Pharmacy, Pune, India
Published online: 30 Mar 2007.
To cite this article: Ajit P. Zambre , Abeda Jamadar , Subhash Padhye & V. M. Kulkarni (2007) Copper Conjugates of
Knoevenagel Condensates of Curcumin and their Schiff Base Derivatives: Synthesis, Spectroscopy, Magnetism, ESR, and
Electrochemistry, Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 37:1, 19-27
To link to this article: http://dx.doi.org/10.1080/15533170601172385
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Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 37:19–27, 2007
Copyright # 2007 Taylor & Francis Group, LLC
ISSN: 1553-3174 print/1553-3182 online
DOI: 10.1080/15533170601172385
Copper Conjugates of Knoevenagel Condensates of Curcumin
and their Schiff Base Derivatives: Synthesis, Spectroscopy,
Magnetism, ESR, and Electrochemistry
Ajit P. Zambre
Drug Design and Molecular Medicine Group, Department of Chemistry, University of Pune, Pune, India
and Department of Medicinal Chemistry, Bharati Vidyapeeth University Poona College of Pharmacy,
Pune, India
Abeda Jamadar and Subhash Padhye
Drug Design and Molecular Medicine Group, Department of Chemistry, University of Pune, Pune, India
V. M. Kulkarni
Department of Medicinal Chemistry, Bharati Vidyapeeth University Poona College of Pharmacy, Pune,
India
to circumvent the problems associated with low bioavailability
Novel copper(II) complexes of curcumin Knoevenagel conden- extensive efforts have been made to evolve various drug
sates and their Schiff bases have been synthesized and character-
ized. All copper complexes possess distorted square-planar
geometries with 1:1 metal to ligand stoichiometry capable of
delivery strategies including structural modifications of 1. In
our laboratory, we have encapsulated curcumin with hydrophi-
stabilizing Cu21/Cu11 redox couples in the range 0.34 to 0.40 V.
ESR spectral features are consistent with g > g > 2.0 suggesting
lic jellose polymer, which leads considerable enhancement in
the bioactivity rather than the parent compound. This has
k
?
monomeric nature of copper complexes having dx2ꢀy2 ground state. encouraged us to undertake derivatization of diketo motif of
curcumin by employing hydrophilic metalloid scaffold. The
enolizable ketonic function of 1 has long been known to
Keywords curcumin, thiosemicarbazones, copper(II) complexes,
form complexes with various metal ions and metalloids.[7–10]
redox properties, Knoevenagel condensation
In order to impose some selectivity in these interactions
it is necessary to introduce different donor functionalities in
metal coordination other than oxygen by modifying the
INTRODUCTION
Curcumin, (1,7-bis(4-hydroxy-3-methoxy phenyl)-1,6-hep-
diketonic functions. This task can be facilitated by conden-
sation of its active methylene group with an aldehydic
tadiene-3,5-dione, 1) is an active principle of turmeric
(Curcuma Longa Linn.) which has a long history of medicinal
group giving a non-enolisable Knoevenagel condensate
use in the middle East and India. Extensive scientific research
that can then be effectively reacted with appropriate func-
tionality generating corresponding Schiff bases as shown
on 1 have demonstrated anti-inflammatory[1] anticancer,[2] and
potent antioxidant[3] activities apart from its promising role in
in Scheme 1.[10]
variety of disease conditions including AIDS, Alzheimer’s
In the present communication we describe synthesis,
disorders.[4] The polyphenolic compound is pharmacologically
molecular characterization and redox behavior of copper(II)
complexes of curcumin-thiosemicarbazone Schiff bases. Due
safe even when administered at doses up to 10 g/day[5] and
hence has enormous potential in the prevention and therapy
perhaps to sulphur-nitrogen donor functionalities in these
ligands they have preferential affinities for softer copper
metal ions yielding very stable metal conjugates. In most
of variety of acute diseases and chronic disorders.
However, it exhibits low oral bioavailability and undergoes
rapid first-pass metabolism and excretion in the bile.[6] In order
cases the compounds possess distorted square planar geome-
tries with facile Cu2þ/Cuþ redox couples functionally useful
and adaptable under biological systems. The redox behavior
is found to be dependent on coordination geometry and
donor atoms set around the central metal ion[11,12] and good
Received 29 September 2006; accepted 14 November 2006.
Address correspondence to Subhash Padhye, Drug Design and
Molecular Medicine Group, Department of Chemistry, University of
Pune, Pune 411 007, India. E-mail: sbpadhye@chem.unipune.ernet.in
19

20
A. P. ZAMBRE ET AL.
SCH. 1. Synthetic steps used in the preparation of copper conjugates of Knoevenagel condensates and Schiff bases of 1. Specific conditions followed for various
.
steps include: (a) piperidine, 48 hrs, methanol; (b) H2NCSNHNH2 HCl, 24 hrs, piperidine, methanol, room temp. (1:2); (c) CuCl2 2H2O, methanol, piperidine (1:1).
.
structure-activity relationship is observed between ESR conductivity (9-42 mV21 cm2 mole21) in DMSO solvent indi-
parameters and the distortion factor calculated.
cating their non-electrolyte nature.[14]
NMR Studies
In the NMR spectrum of 1 the strong signal at d 5.7 ppm due
to methylenic protons is lost upon Knoevenagel condensation
RESULTS AND DISCUSSION
Synthesis
1
Curcumin (1) is available commercially as a mixture of three (2–4). As anticipated H-NMR spectra of Schiff bases 5–7
curcuminoids and hence was separated from its demethoxy and do not show any resonance attributable to the S-H proton at
bis-demethoxy analogs by column chromatography over silica d 4.0 ppm,[15] but instead show a singlet at d 13.70 ppm due
gel using chloroform:methanol (9:1) as eluting solvent. The to the intramolecular hydrogen-bonded thiohydrazinic (N-H)
intramolecular hydrogen bonding in 1 restricts the diketone proton indicating existence of the thione form in DMSO
moiety to take part in derivatization with condensable amines. solvent.[16,17] This absorption is absent in the spectra of the
It can, however, be carried out by condensing its active methyl- complexes consistent with deprotonation of the thiosemicarba-
ene group with aldehydes to yield non-enolisable b-diketone by zide chain confirming coordination through the thiolate form.
a reaction known as Knoevenagel condensation.[10,13]
A broad singlet appearing at ꢀd 3.0 ppm is ascribed to the
In the present work methylenic proton of the b-diketone terminal NH2 group suggesting their involvement in hydrogen
moiety was replaced by various hydroxy aromatic aldehydes bonding interactions. The partial double bond character for the
with good yields. The condensates were reacted with C-NH2 linkage restricts free rotation and makes the two
thiosemicarbazide side chains in the molar ratio of 1:2 to protons magnetically inequivalent resulting in broadening of
yield bis-Schiff base ligands. Interactions of these Schiff base the signal.[18] In the spectra of the corresponding metal com-
ligands with copper chloride resulted in mono-ligand plexes the singlets are shifted downfield implying lowering of
copper complexes having a general molecular formula the bond order as a consequence of thione ) thiol tautomeriza-
C30H30CuN6O5-6S2. They exhibit negligible solution tion during complexation.[19]

COPPER(II) COMPLEXES OF NEW CURCUMIN ANALOGS
21
Infrared Spectra
energy side indicating enolisation of the thiocarbonyl group
which is commonly observed in the thiolato binding of thiose-
micarbazone complexes.
IR spectrum of 1 in its stable enolisable form exhibits the
carbonyl stretching frequency at 1620 cm21 and an intramolecu-
larly hydrogen bonded hydroxyl absorption at 3379 cm21. In the
Knoevenagel condensates (2–4) the carbonyl stretch appears at
1655–1633 cm21 while the hydroxyl absorption is found to be
absent. Introduction of thiosemicarbazone side chains into
the Knoevenagel condensates (5–7) is best diagnosed from the
disappearance of carbonyl frequency and occurrence of
additional bands at 1595 and 870 cm21 ascribed to azomethine
and thiocarbonyl stretching frequencies, respectively.
For square-planar copper complexes with a dx2ꢀy2 ground
state, three spin-allowed transitions are expected, viz.,
2
2
2
2B1g ! A2g (dx2ꢀy2 ! dz2 ), B1g ! B2g (dx2ꢀy2 ! dxy) and
2
2B1g ! Eg (dx2ꢀy2 ! dxy,yz) respectively, which, however,
are difficult to resolve due to their comparable energies and
difficulties in distinguishing individual transfers.[25,26] In case
of present copper complexes of the Knoevenagel condensates
8–10, the absorption in the region 17,000–20,000 cm21 is
assigned to dx2ꢀy2 ! dz2 transition which is shifted towards
lower energy in the bis-thiosemicarbazonate metal conjugates.
The absorption between 21,000–25,000 cm21 corresponds to
the intense LMCT charge transfer band, which is characteristic
feature commonly associated with metal-thiosemicarbazone
complexes.[27,28] Room temperature magnetic moments (meff)
of all copper(II) complexes described presently fall in the
range of 1.76–1.82 B.M. corresponding to the spin only value
for monomeric square planar complexes.[36]
The bisthiosemicarbazone derivatives are known to exhibit
thione N thiol tautmerism due to the presence of a thioamide
group. The absence of the n(S-H) band near 2750 cm21 and
presence of n(N-H) stretching frequency between 3751–
3349 cm21 indicate that ligands 5–7 exist as thione tautomers
in the solid state.[20] The thiolic absorption is found to be
absent in the IR spectra of metal complexes indicating depro-
tonation of the thiosemicarbazide side chain and subsequent
coordination through thiolate anion.[21]
The absorptions at 3250 and 3150 cm21 are attributed to the
asymmetric and symmetric stretching frequencies of the
terminal NH2 group which exhibit appreciable changes upon
metal coordination due to involvement of the thioamide
sulfur in complexation.[22] Similarly the imino frequency of
the thiosemicarbazide side chains is shifted to lower frequency
upon metal coordination indicating involvement of imine
nitrogen in metal coordination.[23] The bands in the region
448–435 and 352–345 cm21 are ascribed to Cu-N and Cu-S
stretches respectively.
Electrochemistry
The electrochemical profile of 1 shows a quasi-reversible
peak centered at 20.84 V ascribed to the reduction of its
carbonyl functions.[7] On Knoevenagel condensation, this
peak is shifted to positive side and an additional peak is
observed at 21.6 V due to reduction of azomethine function-
ality.[29] Analysis of the cyclic voltammetric profiles of all
copper conjugates indicates ipa/ipc ratio approximately equal
to unity for the well-defined Cu2þ/Cuþ redox couple
centered between þ0.33 to þ0.40 V.
Electronic Spectra and Magnetic Studies
The scan rate dependence of this peak is shown in the inset of
Present curcumin derivatives exhibit strong absorptions Figure 1, which confirms its reversible nature. In the absence of
around ꢀ30800 cm21 and 24000 cm21 attributed to the intra- either uncompensated solution resistance or anomalous electrode
ligand p-pꢁ and n-pꢁ transitions respectively.[24] For the surface effects, the departure of DEp from 0.059 V observed in
copper conjugates 11–13, the former were shifted to lower some of the present copper complexes is indicative of significant
FIG. 1. Cyclic voltammogram of 8 and 11 (v ¼ 100 mV/s) in DMSO where Inset shows scan rate dependence of the copper redox couple.

22
A. P. ZAMBRE ET AL.
FIG. 2. Cyclic voltammogram of 11 in DMSO with TEAP as supporting electrolyte at 100–500 mV s21. Inset plot of square root of scan rate versus cathodic
current.
geometrical reorganization accompanying the redox changes.[30] 8–10 may probably originate due to the presence of a thione/
It is known that the Cu(II)/Cu(I) couple experiences some thiol sulfur center and redox active diketone moiety. Since
structural reorganization barrier in view of the rearrangement both the diketone moiety and the thiosemicarbazide side chain
from square-planar Cu(II) to pseudo-tetrahedral Cu(I) are flexible, the ligand can adopt different conformations so as
geometries. The effects of stereochemical changes on redox to fit the smaller sized Cu(II) ions, thus favoring the oxidation
potentials are directly correlated to conversion of square-planar process appreciably.
copper(II) species to tetrahedral Cu(I) products.
Moreover, this oxidation step results in the formation of
The redox potentials observed for the present series of com- Cu(II) with a preference for a square-planar geometry. The
plexes indicate a moderate strength for bis-thiosemicarbazonates extent of electrochemical stability may be assessed from the
to sustain these changes. It implies that greater deformation in the correlation (Figure 3) between the E1/2 values with that of
chelate rings of a coordinated thiosemicarbazone ligand induces the degree of tetrahedral distortion (F) for the Cu(II)/Cu(I)
substantial departure from square-planar geometry with more redox couples. A linear relationship observed for these
difficulty in stabilizing the Cu(I) state. The potentials of copper compounds indicates that departure from a square-
Cu(II)/Cu(I) couple of the present series of complexes are planar stereochemistry leads to destabilization of the
notably shifted than expected may be due to the difference in copper(I) species formed in the solution.
the chemical environment and the chromophore around the
Cu(II) ions.
ESR Studies
The X-band EPR spectra of all copper conjugates were
Nevertheless, it is likely attributable not only to inductive
electronic factors of the redox active diketone moiety but also
recorded in DMSO glass at 77K (see Figure 4) and the spin
because of columbic effects such as formation of charged or
neutral sulfur donor sites. However, the anodic (Epa) peak
potentials of copper complexes (8–10 and 11–13) in the
positive region are comparable with copper complex of natu-
rally occurring curcumin and synthetic models containing
S-donor ligands.[7] The cathodic peak current was found to be
proportional to the square root of the scan rates indicates that
the charge transfer process are diffusion controlled, which is
confirmed by the observed linear plot of (Figure 2) square
root of the scan rate versus cathodic peak current.
The ligand system with extended p orbitals and the distor-
tions in the copper geometry might have forced the central
copper to reduce at a positive reduction potential. The redox
process associated with oxidation of Cu(I) to Cu(II) for 11–13
seems to be more significant (E1/2 ¼ 0.4–0.3625 V) than
FIG. 3. Correlation of degree of tetrahedral distortion (F in cm21) against
Cu2þ/Cu1þ redox potentials (E1/2 in volts). The straight line represents the
best-fit curve.

COPPER(II) COMPLEXES OF NEW CURCUMIN ANALOGS
23
which is regarded as an index of deviation from idealized
geometry. The values of 110–120 cm21 are typical for
square planar complexes, while the range of 130–150 cm21
is characteristic of slight to moderate distortion and 180–
250 cm21 indicate considerable distortion.[32,33] The values
observed for the present series of compounds (117–
156 cm21) suggest a moderate distortion.
Figure 5 depicts the correlationship between g , A and F, as
k
k
a consequence of the destabilization of the square-planar
geometry. Moreover, this tetrahedral distortion influences the
copper hyperfine structure, suggesting that the unpaired
electron is asymmetrically delocalized along the chelate
rings. Thione sulfur binding probably induces more structural
deformations leading to substantial departure from the planar
geometry. While on the other hand, the thiol sulfur enforces
the structure to remain in a nearly square-planar geometry[34]
Such a difference may originate from the fact that thiolato
sulfur binding incorporates greater covalency in the metal-
ligand bonding through delocalized dp-pp in-plane
p-bonding as well as s-bonding interactions.
EXPERIMENTAL
FIG. 4. EPR spectrum of compound 8 in DMSO at 77 K.
Materials
Hamiltonian parameters calculated for these are summarized in
Table 1. All compounds exhibit a well-resolved four-line
copper hyperfine pattern and follow the relationship
g . g . 2.0 characteristic of monomeric planar copper
All reagents and solvents were of reagent grade or were
purified by standard methods prior to use.[35] Curcumin was
a commercial product Sigma (St. Louis, MO), which also con-
tained demethoxycurcumin, and bisdemethoxycurcumin,
respectively. Curcumin was separated and isolated from it by
column chromatography using silica gel 60 (Merck 60-120
mesh) monitored through thin layer chromatography (TLC)
on pre-coated silica gel plates (Merck) using chloroform:
methanol (9:1) as developing system.
k
?
complexes. Kivelson and Niemen have pointed out that com-
pounds having g ꢂ 2.3 are ionic while those with g , 2.3
k
k
are covalent in character.[31]
The g values for the present series of complexes reveal
k
appreciable covalency with dx2ꢀy2 as the ground state. EPR par-
ameters also reflect the degree of tetrahedral distortion for
square-planar copper(II) complexes. It has been observed that
increase in g values with concomitant decrease in A com- Physical Measurements
k
ponents leads to an increase in the tetrahedral distortion and
k
1H-NMR spectra were recorded on a FT-NMR Varian
Mercury YH-300 Spectrometer. Unless otherwise specified
the degree of distortion defined by the parameter F ¼ g /A ,
k
k
TABLE 1
Magnetic, ESR and electrochemical data on copper conjugates of Knoevenagel condensates and Schiff bases
Parameter
8
9
10
11
12
13
meff. (B.M.)
Epc (V)
Epa (V)
E1/2 (Cu2þ/Cuþ)
DEp
1.76
1.79
1.82
1.80
1.77
1.80
0.200
0.475
0.3375
0.275
0.125
0.550
0.3375
0.425
0.125
0.600
0.3625
0.475
0.250
0.475
0.3625
0.225
0.075
0.725
0.4000
0.655
0.250
0.550
0.4000
0.300
%ipc/ipa
90
80
95
77
96
88
g
2.212
2.069
2.232
2.073
2.260
2.077
2.280
2.066
2.291
2.070
2.294
2.072
k
?
k
g
A (G)
F(cm21
188
117
175
127
170
132
157
145
156
146
147
156
)

24
A. P. ZAMBRE ET AL.
of aromatic aldehyde (1 mmol) in a dropwise manner with con-
tinuous stirring and catalytic amount of piperidine (0.05 cm3).
The reaction mixture was stirred for 48 hr and set aside for the
product separation. The compounds were washed with excess
of petroleum ether-hexane and were recrystallized from chloro-
form-hexane mixture to give pure dark brown Knoevenagel
condensates.
4-Salicylidene-1,7-bis (4-hydroxy, 3-methoxyphenyl)-1,6-
heptadiene-3,5-dione (2). Yield: 76%, mp: 96–98 8C, 1H-
NMR (CDCl3): d 3.73 (s, 6H, OCH3), 6.66 (s, 2H, ArH),
6.71 (dd, 4H, J ¼ 7.8, 7.8 Hz, ArH), 7.1 (d, 2H, J ¼ 15.6 Hz,
55C-H), 7.6 (d, 2H, J¼15.6 Hz, H-C55), 7.49 (m, 4H, ArH),
7.98 (s, 1H, 55CH-Ar); IR (KBr, cm21): ꢀ3400 (nO-H br.),
ꢀ3012, 2945 (n
C-H), ꢀ1633(nC¼O), ꢀ1508 (nC¼C),
¼C-H,
ꢀ1388, 1029 (nC-H), ꢀ975 (nH-C¼C-Htrans), ꢀ821 (nC-H aro.);
UV-Vis: lmax (nm, DMSO): 327; MS (þES-MS): m/z ¼
472.48 (475) (M þ 2); Anal. Calc. (Found): C28H24O7; C,
71.18 (71.07); H, 5.12 (5.20%).
FIG. 5. Variation of g with A and degree of tetrahedral distortion (F). The
k
straight lines represents the best-fit curve.
k
4-(2,3-dihydroxy benzyl)-1,7-bis (4-hydroxy, 3-methoxyphe-
nyl)-1,6-heptadiene-3,5-dione (3). Yield: 63%, mp: 79–818C,
1H-NMR (CDCl3): d 3.82 (s, 6H, OCH3), 6.97 (m, 2H, ArH),
6.80 (m, 6H, J ¼ 8.62 Hz, ArH), 6.42 (d, 2H, J ¼ 15.6 Hz,
55C-H), 7.54 (d, 2H, J¼15.4 Hz, H-C55), 7.34 (d, 1H,
J ¼ 8.62 Hz, ArH), 7.98 (s, 1H, 55CH-Ar); IR (KBr, cm21):
ꢀ3417 (nO-H br.), ꢀ3050, 2947 (n¼C-H, C-H), ꢀ1655 (nC¼O),
ꢀ1514 (nC¼C), ꢀ1382, 1029 (nC-H), ꢀ977 (nH-C¼C-Htrans),
ꢀ819 (nC-H aro.); UV-Vis: lmax (nm, DMSO): 329, 428; MS
(þES-MS): m/z ¼ 488.48 (490) (M þ 1); Anal. Calc.
(Found): C28H24O8; C, 68.85 (68.78); H, 4.95 (4.82%).
all NMR spectra were obtained in deuterated chloroform
(CDCl3) and referenced to the residual solvent peak. In order
to examine thione N thiol tautomerism of thiosemicarbazide
ligands and their copper complexes 1H-NMR spectra were
also recorded in polar solvent like D6-DMSO. IR spectra
were recorded using KBr pellet on FTIR-8400 Schimadzu
spectrophotometer. Electronic spectra were recorded between
200 to 1000 nm (cm21) in DMSO solvent using identical
quartz cuvettes on double beam UV-1601 Spectronic
Genesys 2 UV-Vis spectrophotometer.
All electrochemical measurements were made in 10 mM
DMSO solvent using 0.1 M tetraethyl ammonium perchlorate
(TEAP) as a supporting electrolyte on BAS cyclic voltam-
metric model CV-27 with automatic system under dry and
pure nitrogen atmosphere. The three-electrode system
employed consisted of platinum as working electrode,
platinum wire as auxiliary electrode and standard calomel
electrode (SCE) as a reference electrode. The SCE was cali-
brated with the ferricinium/ferrocene redox couple located at
E1/2 ¼ þ0.40 V (DEp ¼ 0.06 V).
4-(3,4-dihydroxy benzyl)-1,7-bis (4-hydroxy, 3-methoxy-
phenyl)-1,6-heptadiene-3,5-dione (4). Yield: 80%, mp:
1
104–1068C, H-NMR (CDCl3): d 3.83 (s, 6H, OCH3), 6.80
(m, 6H, ArH), 7.38 (m, 3H, ArH), 7.98 (s, 1H, 55CH-Ar),
6.43 (d, 2H, J¼14.85 Hz, 55C-H), 7.54 (d, 2H, J¼15.68 Hz,
H-C55); IR (KBr, cm21): ꢀ3500 (nO-H br.), ꢀ2929, 2856
(n
C-H), ꢀ1633 (nC¼O), ꢀ1521 (nC¼C), ꢀ1382, 1028
¼C-H,
(nC-H), ꢀ954 (nH-C¼C-Htrans), ꢀ823 (nC-H aro.); UV-Vis: lmax
(nm, DMSO): 341, 420; MS (þES-MS): m/z ¼ 488.48 (512)
(M þ Na)þ; Anal. Calc. (Found): C28H24O8; C, 68.85
(68.88); H, 4.95 (4.91%).
The X-band ESR spectra were recorded on a Varian ESR
spectrometer with 100 KHz field modulation frequency and
the instrument was calibrated with DPPH standard. Elemental
analyses were performed on Hosli Holland CHN analyzer. The
magnetic susceptibility was measured at room temperature on a
Faraday type magnetic balance with a permanent magnetic
field of 7000 G and the instrument was calibrated with
Hg[Co(SCN)4] standard compound.
General Procedure for Preparation of Various Hydroxy
Substituted 1,7-bis(4-hydroxy, 3-methoxyphenyl)-1,6-
heptadiene-3,5-bis-thiosemicarbazones (5,6,7)
The methanolic solutions of Knoevenagel condensates (2–4)
(1 mmol) were reacted with thiosemicarbazide (2 mmol) with
continuous stirring and addition of catalytic amounts of piper-
General Procedure for Preparation of Various
Knoevenagel Condensates (2–4)
To the purified curcumin (368 mg, 1 mmol) dissolved in idine (0.05 cm3) over 5–10 min. The reaction mixture was
minimum amount of chloroform:methanol (9:1) mixture in a further stirred for 24 hrs and set aside when a dark brown
round bottom flask (RBF) was added a methanolic solution solid precipitated out. The compound was purified by

COPPER(II) COMPLEXES OF NEW CURCUMIN ANALOGS
25
recrystallization from chloroform-methanol to yield pure dark [4-Salicylidene-1,7-bis(4-hydroxy, 3-methoxyphenyl)-1,6-
brown thiosemicarbazonates of Knoevenagel condensates.
heptadiene-3,5-dione] copper(II) (8). Yield: 82%, IR (KBr,
cm21): ꢀ3453 (nO-H br.), ꢀ3110, 2949 (n¼C-H, C-H), ꢀ1614
4-Salicylidene-1,7-bis(4-hydroxy, 3-methoxyphenyl)-1,6- (nC¼O), ꢀ1589 (nC¼C), ꢀ1390, 1031 (nC-H), ꢀ829 (nC-H aro.),
heptadiene-3,5-dithiosemicarbazone (5). Yield: 82%, mp: ꢀ551 (nCu-O), ꢀ332 (nCu-Cl); UV-Vis: lmax (nm, DMSO):
1
108–1108C, H-NMR (CDCl3): d 2.63 (s, 4H, NH2 br), 3.78 353, 465; Anal. Calc. (Found): C28H24Cl2CuO7; C, 55.41
(s, 6H, OCH3), 6.6 (s, 2H, NH br), 6.84 (m, 14H, ArH), 8.00 (55.62); H, 3.99 (4.12); Cu, 10.47 (10.38%).
(s, 1H, 55CH-Ar); IR (KBr, cm21): ꢀ3500 (nO-H br.), ꢀ3349
(nN-H), ꢀ3244, 3156 (nC-NH2), ꢀ3035, 2949 (n
C-H), [4-(2,3-dihydroxy benzyl)-1,7-bis(4-hydroxy, 3-methoxy-
¼C-H,
ꢀ1610 (nC¼N), ꢀ1502 (nC¼C), ꢀ1367, 1028 (nC-H), ꢀ943 phenyl)-1,6-heptadiene-3,5-dione] copper(II) (9). Yield:
(nH-C¼C-Htrans), ꢀ823.5 (nC-H aro.), ꢀ870 (nC¼S); UV-Vis: 87%, IR (KBr, cm21): ꢀ3479 (nO-H br.), ꢀ3018, 2945 (n
¼C-H,
lmax (nm, DMSO): 332, 410; MS (þES-MS): m/z ¼ 618.72 C-H), ꢀ1591 (nC¼O), ꢀ1506 (nC¼C), ꢀ1406, 1028 (nC-H),
(620) (M þ 1); Anal. Calc. (Found): C30H30N6O5S2; C, 58.24 ꢀ827 (nC-H aro.), ꢀ559 (nCu-O), ꢀ336 (nCu-Cl); UV-Vis: lmax
(58.29); H, 4.89 (4.84); N, 13.58 (13.52%).
(nm, DMSO): 335, 476, 506 (ddtrans.); Anal. Calc. (Found):
C28H24Cl2CuO8; C, 53.99 (54.12); H, 3.88 (3.96); Cu, 10.20
4-(2,3-dihydroxy benzyl)-1,7-bis(4-hydroxy, 3-methoxyphe- (10.34%).
nyl)-1,6-heptadiene-3,5-dithiosemicarbazone (6). Yield:
1
68%, mp: 127–1298C, H-NMR (CDCl3): d 3.14 (s, 4H, NH2 [4-(3,4-dihydroxy benzyl)-1,7-bis(4-hydroxy, 3-methoxy-
br), 3.85 (s, 6H, OCH3), 6.8 (s, 2H, ArH), 7.1 (s, 2H, NH br), phenyl)-1,6-heptadiene-3,5-dione] copper(II) (10). Yield:
7.4 (m, 7H, ArH), 7.99 (s, 1H, 55CH-Ar), 6.33 (d, 2H, 81%, IR (KBr, cm21): ꢀ3544 (nO-H br.), ꢀ3026, 2941 (n
¼C-H,
J¼15.61 Hz, 55C-H), 7.6 (2H, d, J¼15.5 Hz, H-C55); IR C-H), ꢀ1587 (nC¼O), ꢀ1525 (nC¼C), ꢀ1357, 1026 (nC-H),
(KBr, cm21): ꢀ3751 (nN-H), ꢀ3553 (nO-H br.), ꢀ3289, 3164 ꢀ823 (nC-H aro.), ꢀ555 (nCu-O), ꢀ331 (nCu-Cl); UV-Vis: lmax
(nC-NH2), ꢀ3009, 2943 (n¼C-H, C-H), ꢀ1596 (nC¼N), ꢀ1514 (nm, DMSO): 398, 509 (ddtrans.); Anal. Calc. (Found):
(nC¼C), ꢀ1379, 1028 (nC-H), ꢀ945 (nH-C¼C-Htrans), ꢀ817 C28H24Cl2CuO8; C, 53.99 (54.21); H, 3.88 (4.07); Cu, 10.20
(nC-H aro.), ꢀ874 (nC¼S); UV-Vis: lmax (nm, DMSO): 322, (10.11%).
403; MS (þES-MS): m/z ¼ 634.72 (636) (M þ 1); Anal.
Calc. (Found): C30H30N6O6S2; C, 56.77 (56.81); H, 4.76
(4.73); N, 13.24 (13.30%).
General Procedure for Preparation of Copper(II)
Conjugates of Hydroxy Substituted 1,7-Bis-(4-hydroxy,3-
methoxyphenyl)-1,6-heptadiene-3,5-
4-(3,4-dihydroxy benzyl)-1,7-bis(4-hydroxy, 3-methoxyphe-
nyl)-1,6-heptadiene-3,5-dithiosemicarbazone (7). Yield:
79%, mp: 132–1348C, H-NMR (CDCl3): d 2.96 (s, 4H, NH2
dithiosemicarbazones (11,12,13)
The copper(II) conjugates were prepared by interaction of
the methanolic solutions of Schiff bases of Knoevenagel con-
1
.
br), 3.87 (s, 6H, OCH3), 6.56 (s, 2H, NH br), 6.88 (dd, 4H,
J ¼ 8.2 Hz, ArH, J ¼ 16.01 Hz, H-C55), 7.04 (s, 2H, ArH),
7.49 (m, 5H, ArH), 6.2 (d, 2H, J ¼ 15.67 Hz, 55C-H), 8.0
(s, 1H, 55CH-Ar); IR (KBr, cm21): ꢀ3683 (nN-H), ꢀ3617
(nO-H br.), ꢀ3262, 3155 (nC-NH2), ꢀ3012, 2949 (n¼C-H, C-H),
ꢀ1610 (nC¼N), ꢀ1517 (nC¼C), ꢀ1380, 1026 (nC-H), ꢀ945
(nH-C¼C-Htrans), ꢀ844 (nC-H aro.), ꢀ869 (nC¼S); UV-Vis: lmax
(nm, DMSO): 326, 404; MS (þES-MS): m/z ¼ 634.72
(635.5) (M þ 1); Anal. Calc. (Found): C30H30N6O6S2; C,
56.77 (56.73); H, 4.76 (4.72); N, 13.24 (13.28%).
densate (8–10) (1 mmol) with CuCl2 2H2O (1 mmol) in
presence of catalytic amount of piperidine (0.05 cm3). The sep-
arated light brown precipitates were isolated after 3 hr of con-
tinuous stirring and washed with cold methanol. They were
dried overnight in vacuo at ambient temperature.
[4-Salicylidene-1,7-bis(4-hydroxy, 3-methoxyphenyl)-1,6-
heptadiene-3,5-dithiosemicarbazone]
copper(II)
(11).
Yield: 78%, IR (KBr, cm21): ꢀ3575 (nO-H br.), ꢀ3215, 3126
(nC-NH2), ꢀ3012, 2941 (n¼C-H, C-H), ꢀ1593 (nC¼N), ꢀ1508
(nC¼C), ꢀ1360, 1028 (nC-H), ꢀ815 (nC-H aro.), ꢀ856 (nC¼S),
ꢀ435 (nCu-N), ꢀ350 (nCu-S); UV-Vis: lmax (nm, DMSO):
306, 459; Anal. Calc. (Found): C30H30CuN6O5S2; C, 52.81
(53.13); H, 4.43 (4.27); N, 12.32 (12.48), Cu, 9.31 (9.54%).
General Procedure for Preparation of Copper(II)
Conjugates of Hydroxy Substituted 1,7-Bis(4-hydroxy,
3-methoxyphenyl)-1,6-heptadiene-3,5-diones (8,9,10)
Copper(II) conjugates were prepared in situ by dissolving
the Knoevenagel condensates (2–4) in methanol with [4-(2,3-dihydroxy benzyl)-1,7-bis(4-hydroxy, 3-methoxy-
dropwise addition of piperidine (0.05 cm3) and methanolic phenyl)-1,6-heptadiene-3,5-dithiosemicarbazone]
solution of CuCl22 H2O (1 mmol). The reaction mixture copper(II) (12). Yield: 83%, IR (KBr, cm21): ꢀ3607 (nO-H
.
was stirred for the period of 3 hr. The light brown precipitate br.), ꢀ3264, 3154 (nC-NH2), ꢀ3030, 2947 (n¼C-H, C-H), ꢀ1575
separated out was isolated by vaccum filtration, washed with (nC¼N), ꢀ1514 (nC¼C), ꢀ1369, 1028 (nC-H), ꢀ817 (nC-H
cold methanol and dried overnight in vacuo at ambient aro.), ꢀ867 (nC¼S), ꢀ441 (nCu-N), ꢀ345 (nCu-S); UV-Vis:
temperature.
lmax (nm, DMSO): 329, 395, 515 (ddtrans.); Anal. Calc.

26
A. P. ZAMBRE ET AL.
14. Geary, W. The use of conductivity measurements in organic
solvents for the characterization of coordination compounds.
Coord. Chem. Rev. 1971, 7, 81–122.
(Found): C30H30CuN6O6S2; C, 51.60 (51.09); H, 4.33 (4.78);
N, 12.04 (12.18), Cu, 9.10 (9.22%).
15. Ali, M. A.; Mirza, A. H.; Butcher, R. J.; Rahman, A. Nickel(II),
copper(II), palladium(II) and platinum(II) complexes of bidentate
SN ligands derived from S-alkyldithiocarbazates and the X-ray
[4-(3,4-dihydroxy benzyl)-1,7-bis(4-hydroxy, 3-methoxy-
phenyl)-1,6-heptadiene-3,5-dithiosemicarbazone]
copper(II) (13). Yield: 79%, IR (KBr, cm21): ꢀ3692 (nO-H
br.), ꢀ3249, 3077 (nC-NH2), ꢀ3019, 2943 (n¼C-H, C-H), ꢀ1600
(nC¼N), ꢀ1517 (nC¼C), ꢀ1359, 1026 (nC-H), ꢀ814 (nC-H
aro.), ꢀ856 (nC¼S), ꢀ448 (nCu-N), ꢀ352 (nCu-S); UV-Vis:
lmax (nm, DMSO): 395, 473, 557 (ddtrans.); Anal. Calc.
(Found): C30H30CuN6O6S2; C, 51.60 (51.78); H, 4.33 (4.51);
N, 12.04 (12.26), Cu, 9.10 (9.28%).
.
crystal structures of the [Ni(tasbz)2] and [Cu(tasbz)2] CHCl3
complexes. Transition Met. Chem. 2000, 25, 430–436.
16. Rodriguez-Arguelles, M. C.; Ferrari, M. B.; Fava, G. G.;
Pelizzi, C.; Pelosi, G.; Albertini, R.; Bonati, A.;
Dall’Aglio, P. P.; Lunghi, P.; Pinelli, S. Acenaphthenequinone
thiosemicarbazone and its transition metal complexes: Synthesis,
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17. Casas, J. S.; Castineiras, A.; Rodriguez-Arguelles, M. C.;
Sanchez, A.; Sordo, J.; Vazquez-Lopez, A.; Vazquez-
Lopez, E. M. Reactions of diorganotin(IV) oxides with isatin
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