Triorganotin(IV) derivatives of umbelliferone (7-hydroxycoumarin) and their adducts with 1,10-phenanthroline: Synthesis, structural and biological studies

Article abstract of DOI:10.1016/j.jorganchem.2004.08.043

New triorganotin(IV) derivatives of the general formula R ₃Sn(Umb) (where, R = Me, n-Bu and Ph; Umb = umbelliferone anion) have been synthesized using sodium salt method. Further, the adducts of the general formula R₃Sn(Umb)·phen (where R = Me and Ph; phen = 1,10-phenanthroline) have also been synthesized by the interaction of the triorganotin(IV) derivatives of umbelliferone with 1,10-phenanthroline. The bonding and coordination behavior of these derivatives are discussed on the basis of IR, NMR (¹H, ¹³C and ¹¹⁹Sn), and ¹¹⁹Sn Mo?ssbauer spectroscopic studies. These investigations indicate that umbelliferone acts as a monoanionic bidentate ligand in R ₃Sn(Umb) coordinating through O(7) and O(1) in the solid-state. These polymeric R₃Sn(Umb) derivatives (where R = Me and n-Bu) have been proposed to have a trans-trigonal bipyramidal geometry with the three R groups in equatorial positions, while the axial positions are occupied by a phenolic oxygen and the O(1) atom from the adjacent molecule. A pseudotetrahedral geometry has been suggested for Ph₃Sn(Umb). A distorted octahedral geometry around tin has been proposed for R₃Sn(Umb)·phen, in which umbelliferone anion acts as a monodentate ligand coordinating through phenolic oxygen O(7). The newly synthesized derivatives have been assayed for their anti-inflammatory, cardiovascular and anti-microbial activities. The average LD₅₀ values >1000 mg kg^-1 of these derivatives indicate their safety margin. Among all the compounds tested, Ph ₃Sn(Umb)·phen has been found to show potent anti-inflammatory activity with low mammalian toxicity and mild hypotensive activity.

Full text of DOI:10.1016/j.jorganchem.2004.08.043

Journal of Organometallic Chemistry 690 (2005) 134–144
www.elsevier.com/locate/jorganchem
Triorganotin(IV) derivatives of umbelliferone
(7-hydroxycoumarin) and their adducts with 1,10-phenanthroline:
synthesis, structural and biological studies
a,
a
b
b
c
Mala Nath *, Ruchi Jairath , George Eng , Xueqing Song , Ashok Kumar
a
Department of Chemistry, Indian Institute of Technology-Roorkee, Roorkee 247 667, India
Department of Chemistry and Physics, University of The District of Columbia, Washington, DC 20008, USA
b
c
Department of Pharmacology, LLRM Medical College, Meerut 250 004, India
Received 8 June 2004; accepted 31 August 2004
Available online 28 September 2004
Abstract
New triorganotin(IV) derivatives of the general formula R3Sn(Umb) (where, R = Me, n-Bu and Ph; Umb = umbelliferone anion)
have been synthesized using sodium salt method. Further, the adducts of the general formula R3Sn(Umb) Æ phen (where R = Me and
Ph; phen = 1,10-phenanthroline) have also been synthesized by the interaction of the triorganotin(IV) derivatives of umbelliferone
with 1,10-phenanthroline. The bonding and coordination behavior of these derivatives are discussed on the basis of IR, NMR (1H,
13C and 119Sn), and 119Sn Mo¨ssbauer spectroscopic studies. These investigations indicate that umbelliferone acts as a monoanionic
bidentate ligand in R3Sn(Umb) coordinating through O(7) and O(1) in the solid-state. These polymeric R3Sn(Umb) derivatives
(where R = Me and n-Bu) have been proposed to have a trans-trigonal bipyramidal geometry with the three R groups in equatorial
positions, while the axial positions are occupied by a phenolic oxygen and the O(1) atom from the adjacent molecule. A pseudotet-
rahedral geometry has been suggested for Ph3Sn(Umb). A distorted octahedral geometry around tin has been proposed for
R3Sn(Umb) Æ phen, in which umbelliferone anion acts as a monodentate ligand coordinating through phenolic oxygen O(7). The
newly synthesized derivatives have been assayed for their anti-inflammatory, cardiovascular and anti-microbial activities. The aver-
age LD50 values >1000 mg kgꢀ1 of these derivatives indicate their safety margin. Among all the compounds tested, Ph3Sn(Umb) Æ
phen has been found to show potent anti-inflammatory activity with low mammalian toxicity and mild hypotensive activity.
ꢀ 2004 Elsevier B.V. All rights reserved.
Keywords: Triorganotin(IV); Umbelliferone; 7-Hydroxycoumarin; 1,10-Phenanthroline; 119Sn Mo¨ssbauer; Biological activity
1. Introduction
umbelliferone, is an active drug. It is used as a fixative
and enhancing agent in perfumes and is added to toilet
soaps and detergents, toothpaste, tobacco products
and some alcoholic beverages [5].
Coumarin and its derivatives have a wide spectrum
of bioactivities including anticoagulant, estrogenic,
dermal photosensitizing, vasodilator, molluscacidal,
anthelmintic, sedative, hypnotic, analgesic, hypother-
mic [6], antimicrobial [7], anti-inflammatory [8], anti-
fungal [9] and antiulcer [10] activities. In vitro,
coumarin and its derivatives inhibit the proliferation
of several human tumor cell lines, viz., coumarin
Coumarin (1, 2-benzopyrone) is a widely distributed
natural product [1] with low human toxicity [2] and
short half-life (1–1.5 h) [3]. It has been suggested [4] that
coumarin may be a pro-drug and its major biotrans-
formed product 7-hydroxycoumarin, also known as
*
Corresponding author. Tel.: +91 1332 285797; fax: +91 1332
73560.
E-mail address: malanfcy@iitr.ernet.in (M. Nath).
0022-328X/$ - see front matter ꢀ 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2004.08.043

M. Nath et al. / Journal of Organometallic Chemistry 690 (2005) 134–144
135
retards the development of renal [11] and prostate car-
cinoma [12,13], and prevents the recurrence of mel-
anoma [14]; coumarins and 7-hydroxycoumarins
exhibit cytotoxic effects against the lung adenocarci-
noma cell lines KB [9], A549 [15], SK-LU-1, 1.3.15,
3A5A and A-427 [16]. Coumarin has undergone clini-
cal trials for the treatment of the lymphoedema fol-
lowing breast cancer treatment and in the treatment
of lung and kidney carcinoma, having been used both
in isolation [17] and in combination with cimetidene,
as an antineoplastic treatment [2,11,18].
In view of the wide biological importance of the
coumarins, it is worthwhile to synthesize and charac-
terize their metal complexes, which may be explored
as potentially active metallopharmaceuticals. Despite
of the good complexing ability of 7-hydroxycoumarin,
limited studies on the transition metals and lantha-
nides with 7-hydroxy- and dihydroxycoumarin
derivatives [19–28] have been carried out. The study
of the interaction of coumarin derivatives with
organometallic compounds of group IV is, therefore,
indispensable.
2.1.1. Synthesis of triorganotin(IV) derivatives of
umbelliferone
Umbelliferone (0.98 g; 6.0 mmol) was dissolved in the
minimum amount (35 ml) of dry methanol. To this was
added sodium methoxide, prepared by dissolving so-
dium (0.14 g; 6.0 mmol) in methanol (10 ml). The result-
ing solution was refluxed for 2–3 h with constant
stirring. A hot methanolic solution of tri-n-butyltin(IV)
chloride (1.96 g; 6.0 mmol)/trimethyltin(IV) chloride
(1.20 g; 6.0 mmol)/triphenyltin(IV) chloride (2.20 g; 6
mmol) in a 1:1 molar ratio was added to the solution
of the preformed sodium salt of umbelliferone. The
resulting mixture was further refluxed with constant stir-
ring for another 9–10 h, and was then centrifuged and
filtered in order to remove the sodium chloride formed.
The excess of solvent was removed under reduced pres-
sure. The semi-solid mass thus obtained was solidified
by trituration with hexane and recrystallized from meth-
anol–hexane (1:2 v/v) mixture.
2.1.2. Synthesis of 1,10-phenanthroline adducts of trior-
ganotin(IV) derivatives of umbelliferone
Among non-platinum chemotherapeutic metallo-
pharmaceuticals, organotin(IV) compounds have
emerged as potential biologically active compounds in
the last two decades [29,30]. The present study aims to
find out coordination behavior of umbelliferone with tri-
organotin(IV) compounds, and to screen their biological
activity with the final goal to synthesize potential
metallopharmaceuticals.
In view of this, here we report the synthesis and struc-
tural studies of some triorganotin(IV) derivatives of
umbelliferone or 7-hydroxycoumarin. In order to see
their interaction with nitrogen-donor ligands, 1,10-
phenanthroline adducts of these triorganotin(IV) deriv-
atives have also been synthesized. The newly synthesized
compounds have been assayed for per oral toxicity, anti-
inflammatory, cardiovascular and anti-microbial
activities.
1,10-Phenanthroline (0.60 g; 3.0 mmol) and the trior-
ganotin(IV) derivative of umbelliferone (3.0 mmol) were
dissolved separately in the minimum amount of metha-
nol and then mixed. The resulting mixture was refluxed
for 20 h. The excess of solvent was removed under re-
duced pressure. The crude product thus obtained was
solidified by trituration with petroleum ether and recrys-
tallized with methanol–petroleum ether (1:2 v/v)
mixture.
2.2. Measurements and biological studies
The melting points of the synthesized compounds
were determined on a Toshniwal capillary melting point
apparatus and are uncorrected. Carbon, hydrogen,
nitrogen and tin analysis and conductance measure-
ments were carried out as reported previously [32]. IR
and Far IR spectra of the solid compounds were re-
corded on the same instrument [32] as reported previ-
2. Experimental
1
ously. H and 13C NMR spectra were recorded on a
Bruker DRX-300 (300 MHz) FT NMR spectrometer
at the Central Drug Research Institute, Lucknow, India,
using DMSO-d6 or CDCl3 or CD3OD as solvent and
TMS as the internal standard. 119Sn NMR spectra were
recorded in CD3OD on a Bruker Avance (500 MHz) FT
NMR spectrometer using tetramethyltin as the internal
reference at the Tata Institute of Fundamental Re-
search, Mumbai, India. 119Sn Mo¨ssbauer spectra were
recorded on Mo¨ssbauer spectrometer model MS-900
(Ranger Scientific Co., Burelson, TX) according to the
procedure reported previously [32], at the Department
of Chemistry and Physics, University of The District
of Columbia, Washington, DC. Anti-inflammatory,
2.1. Materials
All the reactions were carried out under an anhy-
drous nitrogen atmosphere. Methanol, petroleum ether
(b.p. 40–60 ꢁC) and hexane (b.p. 60–80 ꢁC, fraction
from petroleum) (E. Merck) were dried and distilled
before use. Tri-n-butyltin(IV) chloride, trimethyltin(IV)
chloride, triphenyltin(IV) chloride (Merck–Schu-
chardt), and 1,10-phenanthroline (Sigma–Aldrich)
were used as received. Umbelliferone was synthesized
by the reported method [31] using malic acid (Sisco
Chem.), resorcinol (E. Merck) and conc. sulphuric
acid (E. Merck).

136
M. Nath et al. / Journal of Organometallic Chemistry 690 (2005) 134–144
cardiovascular and acute toxicity studies were carried
out according to the previously reported methods [32].
with nitrogen-donors is rather difficult. The reaction be-
tween triorganotin(IV) derivatives of umbelliferone and
2,20-bipyridyl did not take place, and the reactants were
recovered even after refluxing them for 30 h. However,
the adducts of 1,10-phenanthroline with triorgano-
tin(IV) derivatives of umbelliferone have been isolated
(Table 1), but n-Bu3Sn(Umb) did not form the adduct
with 1,10-phenanthroline under similar reaction condi-
tions (see Scheme 1).
All of the synthesized compounds are brown colored
powders (except n-Bu3Sn(Umb) which is semi-solid and
Ph3Sn(Umb) Æ phen which is yellow colored solid), and
obtained in good yields (70–80%). The compounds are
stable towards air and moisture, and are soluble in
dimethylsulphoxide and methanol, but sparingly soluble
in chloroform and other organic solvents. The analytical
data of the compounds are presented in Table 1 and cor-
respond to the proposed stoichiometry. The molar con-
ductance of 10ꢀ3 M solution of the compounds in
methanol lie in the range 0.00–0.20 Xꢀ1 cm2 molꢀ1, indi-
cating their non-electrolytic nature.
2.2.1. Anti-microbial activity
The compounds were tested in vitro for their anti-mi-
crobial activity against Gram-positive (Staphylococcus
aureus Mau 29/58, Staphylococcus aureus Mau 78/71,
Bacillus subtilis 18/64) and Gram-negative (Escherichia
coli 326/71, Escherichia coli) bacteria as well as the yeast
(Candida albicans Pn-10) and the mould (Microsporum
gypseum) by the standard dilution method in sabouraud
agar medium [33]. The minimum inhibitory concentra-
tion (MIC) values in lg/ml were reported. The anti-mi-
crobial activities were also tested by the standard plate
diffusion method using Muller–Hinton and sabouraud
agar (Imuna, Sarisske Michalany, Slovak Republic)
for the Gram-positive bacteria Bacillus polymyxa and
Gram-negative bacteria Salmonella typhii.
3. Results and discussion
The reactions of triorganotin(IV) chloride with the
sodium salt of umbelliferone (formed according to Eq.
(1a)) in a 1:1 molar ratio led to the formation of the
compounds according to Eq. (1b). Triorganotin(IV)
derivatives of umbelliferone, on reaction with 1,10-
phenanthroline in a 1:1 molar ratio (Eq. (2)) afforded
the corresponding adducts:
3.1. Infrared spectral studies
The characteristic infrared absorption frequencies (in
cmꢀ1) and their assignments are presented in Table 2.
The infrared spectrum of umbelliferone exhibits two
strong bands at 1682 and 1233 cmꢀ1, which may be as-
signed to mas(C@O) and ms(C@O), respectively. The low
carbonyl frequency (1682 cmꢀ1) is presumably due to
intermolecular hydrogen bonding of the 7-hydroxyl
ðUmbÞH þ NaOMe ! NaðUmbÞ þ MeOH
ð1aÞ
ð1bÞ
NaðUmbÞ þ R3SnCl ! R3SnðUmbÞ þ NaCl
(where, R = Me, n-Bu and Ph),
5'
5'
5
4
6'
6'
4'
1:1
R3SnðUmbÞ þ phen ! R3SnðUmbÞ ꢁ phen
(where, R = Me and Ph).
4a
8a
4'
2'
6
3
ð2Þ
2
3'
3'
7
7'
7'
HO
O
O
8
The reaction between triorganotin(IV) chloride and
umbelliferone (Eq. (1b)) was found to be quite feasible
and required 9–10 h of reflux. The adduct formation
of these triorganotin(IV) derivatives of umbelliferone
N
N
1
2'
1'
1'
(Umb)H: Umbelliferone
phen : 1,10-Phenanthroline
Scheme 1.
Table 1
Characteristic properties of triorganotin(IV) derivatives of umbelliferone and their 1,10-phenanthroline adducts
Compound number
Compound (empirical formula)
Yield (%)
Melting point (ꢁC)
Analysis (%): found (calculated)
Sn
C
H
N
–
1
2
3
4
5
Me3Sn(Umb)
[C12H14O3Sn]
72
75
80
74
78
80–82
36.22
(36.53)
25.98
44.11
(44.36)
55.99
4.11
(4.34)
7.11
n-Bu3Sn(Umb)
[C21H32O3Sn]
Ph3Sn(Umb)
Semi-solid
208–210d
55–57
–
–
(26.31)
23.11
(55.90)
63.80
(7.15)
3.79
[C27H20O3Sn]
(23.22)
23.20
(63.44)
56.80
(3.94)
4.42
Me3Sn(Umb) Æ phen
[C24H22O3N2Sn]
Ph3Sn(Umb) Æ phen
[C39H28O3N2Sn]
5.60
(23.50)
16.80
(17.17)
(57.06)
67.89
(67.75)
(4.39)
4.00
(4.08)
(5.55)
4.01
(4.05)
67–68

M. Nath et al. / Journal of Organometallic Chemistry 690 (2005) 134–144
137
Table 2
Characteristic IR frequenciesa,b (in cmꢀ1) of umbelliferone, triorganotin(IV) derivatives of umbelliferone and their 1,10-phenanthroline adducts
Assignments
UmbH
1
2
3
4
5
mas(C@O)
ms(C@O)
mas(C–O) (phenolic)
ms(C–O) (phenolic)
mas(Sn–C)
ms(Sn–C)
1682vs
1233vs
1561vs
1318vs
–
1697vs
1235s
1598vs
1334s
620w
–
1688s
1237s
1601vs
1341s
599
1686s
1233s
1599vs
1319s
286m
228m
615w
560w
–
1704vs
1233s
1593vs
1336s
620m
543w
585m
–
1720vs
1233s
1592vs
1336s
281m
217s
–
m(Sn–O)
–
–
548m
490m
–
564m
538m
–
578w
–
451s
m(Sn O)
m(Sn N)
a
464m
vs, Very strong; s, strong; m, medium; w, weak.
Complex number as indicated in Table 1.
b
hydrogen either with O(1) or with O(2). The mas(C–O)
(phenolic) has been assigned at 1561 cmꢀ1 as a very
strong band in umbelliferone. In the IR spectra of trior-
ganotin(IV) derivatives of umbelliferone, there is a sig-
nificant shift in mas(C–O) (phenolic) (by 38 1 cmꢀ1),
which clearly indicates the participation of the phenolic
oxygen (after its deprotonation) in bonding with the tri-
organotin moiety. The coordination by O(2) should sig-
nificantly shift the carbonyl stretching frequency to
lower wave numbers. In triorganotin derivatives studied,
coordination by O(2) is ruled out as mas(C@O) under-
goes a small shift to higher wave numbers (1686–1697
cmꢀ1) whereas the ms(C@O) remains almost unaffected.
The small shift in mas(C@O) to higher wave numbers in
compounds 1, 2 and 3 is also indicating the absence of
intermolecular hydrogen bonding (as observed in
umbelliferone) as well as participation of O(1) in coordi-
nation. Appearance of new bands due to m(Sn–O) and
m(Sn O) (Table 2) also confirms the bonding of tin
with phenolic oxygen and O(1), respectively, in the trior-
ganotin(IV) derivatives.
anthroline to tin is supported by the appearance of a
new band near 450 cmꢀ1 in compounds 4 and 5, which
may be assigned to m(Sn N).
3.2. 119Sn Mo¨ssbauer spectral studies
119Sn Mo¨ssbauer spectral data of compounds 1–5 are
given in Table 3. Mo¨ssbauer spectra of all the triorgan-
otin(IV) derivatives exhibit a doublet centered in the iso-
mer shift (IS) value range 1.25–1.42 mm sꢀ1 and the
quadrupole splitting (QS) values in the range 2.62–3.17
mm sꢀ1 show that the electric field gradient around tin
nucleus is generated by the inequalities in the tin–oxygen
r bonds and is also due to geometric distortions. A pos-
sible geometry around the tin atom in R3Sn(Umb)
(where R = Me and n-Bu) is a distorted trigonal bipy-
ramidal in which umbelliferone anion acts as bidentate
ligand coordinating through O(7) and O(1). A possibil-
ity of intermolecular coordination of O(2) with central
tin atom of adjacent molecule is ruled out on the basis
of IR spectra as mas(C@O) is shifted to higher wave num-
bers in these compounds. Further, Me3Sn(Umb) and n-
Bu3Sn(Umb) have q values of 2.5 and 2.8, respectively,
which also suggest the coordination number of tin either
5 or 6. The three possible isomers (Fig. 1) of R3SnOX
(where, X = O/N; OX are the donor sites of the ligands)
have been reported [34] to have different QS values: QS
In the IR spectra of the adducts, mas(C@O) is further
shifted to higher wave numbers (1704–1720 cmꢀ1),
whereas ms(C@O) does not change. Furthermore, the
m(Sn O) in the region 550–500 cmꢀ1 is not observed
in compounds 4 and 5. These changes in the IR spectra
may be due to non-coordination of O(2) and O(1) as
well as absence of intermolecular hydrogen bonding in
compounds 4 and 5. Further, the bonding of 1,10-phen-
for isomer (a) 1.7–2.3 mm sꢀ1; for (b) 3.0–3.9 mm sꢀ1
for (c) 3.5–4.1 mm sꢀ1
;
.
Table 3
119Sn Mo¨ssbauer data (at 80 K) of the triorganotin(IV) derivatives of umbelliferone and their 1,10-phenanthroline adductsa
Compound number
QS (mm sꢀ1
)
IS (mm sꢀ1
)
q (QS/IS)
s1(L)
s2(R)
1
2
3
4
5
3.17
3.31
2.62
3.27
2.81
1.25
1.42
1.29
1.26
1.20
2.5
2.8
2.0
2.6
2.3
1.08
1.03
1.06
1.20
1.09
1.38
1.12
1.21
1.46
1.82
QS, quadrupole splitting; IS: isomeric shift relative to BaSnO3 and tin foil (splitting 2.52 mm sꢀ1); s1(L), half line-width left doublet component;
s2(R): half line-width right doublet component.
Complex number as indicated in Table 1.
a

138
M. Nath et al. / Journal of Organometallic Chemistry 690 (2005) 134–144
In the trialkyltin(IV) derivatives of umbelliferone
studied, the observed values of IS (1.25–1.42 mm sꢀ1
ture may be responsible for low solubility of these deriv-
atives in non-polar solvents. On the other hand,
Ph3Sn(Umb) has q value of 2.0, which is a borderline
case, and its QS (2.62 mm sꢀ1) value is slightly lower
than those typical for trans-trigonal bipyramidal (3.0–
3.9 mm sꢀ1), but substantially higher than those for
cis-trigonal bipyramidal (1.7–2.3 mm sꢀ1) (Fig. 1(a))
and pseudotetrahedral (1.00–2.41 mm sꢀ1) arrange-
ments [35]. These results are readily rationalized if
compound 3 has either structure (a) of Fig. 1 or pseudo-
tetrahedral as shown in Fig. 3. Because of the bigger size
of phenyl groups and steric strain introduced in the mol-
ecule, a pseudotetrahedral structure with very weak Sn–
O(1) interactions has been proposed for Ph3Sn(Umb)
(Fig. 3).
)
and QS (3.17–3.31 mm sꢀ1) lie in the range typical of
trans-trigonal bipyramidal coordination (Fig. 1(b)) of
tin as found in R3SnO2 fragments of triorganotin(IV)
carboxylates [35]. The QS value in the range of 3.0–3.1
mm sꢀ1 were also found in the trimethyltin(IV) deriva-
tives of amino acids with trans-trigonal bipyramidal
geometry and the tin atom with amino-bridged intermo-
lecular interactions [36]. Thus, the tin atom configura-
tion as shown in Fig. 2 in which three organic groups
are in the equatorial positions and the phenolic oxygen
and O(1) from an adjacent molecule are axial, can be
proposed for compounds 1 and 2. This polymeric struc-
The possible geometry around tin in the adducts with
1,10-phenanthroline is distorted octahedral in which
umbelliferone anion acts as monodentate ligand coordi-
nating through the phenolic oxygen, and strong nitro-
gen-donor, 1,10-phenanthroline (as revealed from the
IR spectra), occupies two coordinating sites around
tin. The q values of the adducts also indicate the coordi-
nation number of tin greater than four. R3Sn(Umb) Æ -
phen may have either fac- or mer-octahedral
environment consisting of three organic groups, phe-
nolic oxygen and two phenanthroline nitrogen atoms
around tin (Fig. 4(a) and (b)).
R
Sn
R
O
Sn
R
O
Sn
X
O
R
R
R
X
R
X
R
R
(a)
(b)
(c)
Fig. 1. Structures of possible isomers for R3Sn(OX) (OX = donor sites
of the ligand).
3.3. Solution NMR spectral studies
1H, 13C and 119Sn NMR chemical shifts along with
coupling constants obtained from solutions of com-
pounds 1–5 are summarized in Tables 4–6, respectively.
The chemical shifts of umbelliferone and 1,10-phen-
anthroline [37] are also given in the tables for compari-
son. The assignments of 1H and 13C resonances are
based on 1H–13C HMBC experiment. The 1H–13C
HMBC spectrum of Ph3Sn(Umb) (in CD3OD) is given
in Fig. 5, which shows correlations between the carbon
atoms and protons of the umbelliferone residue as well
as those of the organotin moiety.
R
O
R
Sn
O
R
O
R
R
O
Sn
R
O
R
O
The assignment of resonances is difficult in 1D NMR
spectra of the compounds due to double ring structure
of umbelliferone, which can be interpreted with the help
of a 2D NMR spectrum. In addition, there is a complex
overlapping pattern in the aromatic region in the triphe-
nyltin(IV) derivative as both phenyl groups and umbel-
liferone moiety give resonances in this region, which can
be distinctly identified with the help of a HMBC
spectrum.
Sn
R
R
Fig. 2. Proposed structure of the R3Sn(Umb) derivatives (where
R = Me or n-Bu).
1
Sn
In H NMR spectra of the triorganotin(IV) deriva-
O
O
O
tives, all the characteristic resonances of umbelliferone
are slightly shifted upfield (lower d values). The reso-
nances of C-7 in the triorganotin(IV) derivatives of
umbelliferone shift slightly (d 162.1–157.0 ppm) com-
pared to the ligand (d 160.3 ppm). All the magnetically
Fig. 3. Proposed structure of Ph3Sn(Umb).

M. Nath et al. / Journal of Organometallic Chemistry 690 (2005) 134–144
139
R
N
N
R
R
R
Sn
R
Sn
O
N
N
R
O
O
O
O
O
(a)
(b)
Fig. 4. Octahedral structures of R3Sn(Umb) Æ phen (where R = Me and Ph).
Table 4
1H NMR spectral dataa,b of umbelliferone, its triorganotin(IV) derivatives, and 1,10-phenanthroline and its adducts with triorganotin(IV) derivatives
of umbelliferone
Atom
number
UmbHc
Phenc
1 (DMSO-d6)
2 (CDCl3)
3 (DMSO-d6)
3 (CD3OD)
4 (DMSO-d6)
5 (DMSO-d6)
H-3
H-4
H-5
H-6
H-8
H-20
H-30
H-40
H-50
H-a
6.22d [9.5]
7.95d [9.5]
–
6.00d [9.0]
7.80d [9.0]
6.12d [9.0]
7.63d [9.0]
5.89d [9.6]
7.63d [9.0]
5.93d [9.6]
7.62 [9.0]
5.99d [9.3]
7.80m
6.17d [5.7]
8.06d [7.0]
7.95d [6.6]
6.7dbr
–
7.55d [9.0]
6.82d [9.0]
6.75s
–
7.35d [9.0]
6.54d [9.0]
7.27d [9.0]
6.64d [6.0]
7.11d
6.74d
6.18s
7.20d
6.62d
6.50s
7.35d [8.4]
6.54d [8.1]
6.42sbr
–
–
6.44s
–
6.57s
–
6.77dbr
–
–
–
–
–
9.35d
8.25dd
9.12d
8.35s
–
–
–
–
–
–
–
–
–
–
–
9.09d [3.0]
7.80m
9.09d [3.0]
7.79, 7.77dd [4.2, 4.5]
8.50d [8.1]
7.99s
–
–
–
–
8.50d [8.1]
8.00s
0.47s [70.0]d
–
–
1.32mbr
0.47s [72.0]d,
–
0.02s [35.1]d
H-b
H-c
H-d
–
–
–
–
–
–
–
–
–
1.61mbr
1.32mbr
0.89t
7.90d [7.0] [72.0]e
7.34d [9.0]
7.38d
7.70d [7.0] [72.0]e
7.28d [9.0]
7.34d
–
–
–
7.48–7.32mf
s, Singlet; d, doublet; dd, doublet doublet; dbr, doublet broad; m, multiplet; mbr, multiplet broad.
a
Complex number as indicated in Table 1.
The values of coupling constants in Hz are given in square brackets.
b
c
Ref. [37].
2J(1H–119/117Sn).
3J(1H–119/117Sn).
Strongly overlapping multiplets.
d
e
f
non-equivalent alkyl/phenyl carbons of the organic
groups attached to tin, and those of the ligands (umbel-
liferone and 1,10-phenanthroline) have also been suc-
cessfully identified and are given in Table 5.
sion of Eq. (3) is very less. Me4Sn appears at d 0.02 ppm
2
as suggested by its low J(1H–119Sn) value (35.1 Hz),
which corresponds well to a tetrahedral structure
[37,38]. In the solid-state, umbelliferone anion in Me3S-
n(Umb) acts as a monoanionic bidentate ligand coordi-
nating through O(7) and O(1) of umbelliferone, but in
the presence of strongly coordinating solvent DMSO,
weak interaction of C(1)O disrupts and now umbellifer-
one anion is coordinating through O(7) only, the fifth
coordinating site being occupied by the solvent mole-
cule. The 1J(13C–119Sn) (498.0 Hz) and 2J(1H–119Sn)
(72.0 Hz) values as well as calculated \Me–Sn–Me
(120.4ꢁ) using the equation given by Lockart and Mand-
ers [38] correspond to a pentacoordinate trigonal bipy-
ramidal geometry for Me3Sn(Umb) Æ solvent with three
methyl groups in equatorial plane and oxygen donor
atom of monodentate umbelliferone anion and solvent
Me3Sn(Umb) shows two signals for methyl groups in
2
1
its H (d 0.47 ppm; J (1H–119Sn) = 72.0 Hz and d 0.02
2
ppm; J(1H– 119Sn) = 35.1 Hz) as well as in 13C (d 3.3
1
ppm; J(13C–119Sn) = 498.0 Hz and d ꢀ8.9 ppm) NMR
spectra which could be due to the decomposition of
Me3Sn(Umb) in DMSO-d6 according to the following
reaction:
Solvent
2Me3SnðUmbÞ ! Me4Sn þ Me2SnðUmbÞ ꢁ solvent
2
ð3Þ
The ratio of mutual integral intensities of H NMR
1
signal is 12:1 for signals at d 0.47 ppm and at d 0.02
ppm, respectively, suggesting that the degree of conver-

140
M. Nath et al. / Journal of Organometallic Chemistry 690 (2005) 134–144
Table 5
13C NMR spectral dataa of umbelliferone, its triorganotin(IV) derivatives, 1,10-phenanthroline and its adducts with triorganotin(IV) derivatives of
umbelliferone in DMSO-d6
Carbon number
UmbHb
Phenb
1
2 [in CDCl3]
3
3 [in CD3OD]
4
5
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-4a
C-8a
C-20
C-30
C-40
C-50
C-60
C-70
C-a
C-b
C-c
C-d
161.2
111.2
–
166.5
108.9
166.7
110.7
144.0
128.6
117.3
162.1
105.8
112.4
156.1
–
161.0
112.0
163.9
111.0
161.2
108.6
145.4
129.3
116.2
161.2
103.6
108.6
156.4
150.2
126.9
144.9
123.7
128.6
136.7
2.5 [n.o.]c
–
162.0
111.3
–
144.3
129.5
–
144.9
129.3
144.8
127.5
146.2
129.9
144.8
128.5
–
113.0
160.3
–
115.9
161.1
114.0
158.0
115.6
157.0
113.3
157.0
–
102.1
111.2
155.4
–
103.5
109.3
103.0
112.0
104.2
112.6
102.2
111.3
–
–
156.2
–
151.0
–
146.2
–
145.3
150.0
–
–
–
–
–
–
–
–
–
–
147.7
127.3
141.4
125.4
129.2
137.4
–
–
–
–
–
127.9
144.6
–
–
–
–
–
–
–
–
123.5
128.4
–
–
–
–
–
–
–
–
136.5
3.3 [498]c, ꢀ8.9
16.8 [453]c
27.6 [20]d
26.9 [66]e
13.4
144.8 [n.o.]c
136.4 [45]d
128.0 [n.o.]e
128.5
142.5 [750]c
137.3 [45]d
129.6 [75]e
130.4
144.8f [n.o.]c
136.3f [45]d
128.9f [76]e
129.7f
–
–
–
–
–
–
–
–
a
Complex number as indicated in Table 1.
Ref. [37].
b
c
d
e
f
1J(13C–119/117Sn).
2J(13C–119/117Sn).
3J(13C–119/117Sn).
Strongly overlapping signals.
Table 6
119Sn NMR spectral data of the synthesized compoundsa
redistribution. The additional signal at d 2.05 ppm is
attributed to Me4Sn and the very low intensity signal
at d ꢀ140.0 ppm may be due to pentacoordinate trigonal
bipyramidal Me2Sn(Umb)2 Æ solvent in solution. Re-
cently, some pentacoordinate trimethyltin(IV) deriva-
tives of dipeptides have also been reported to undergo
similar type of decomposition in solution [40]. n-Bu3S-
n(Umb) shows a sharp signal in its 119Sn NMR spec-
trum at d ꢀ11.3 ppm (Table 6), which is indicative of
its pentacoordinate trigonal bipyramidal structure.
Ph3Sn(Umb) exhibits a broadened signal at d ꢀ176.9
ppm in its 119Sn NMR in CD3OD. This value is very
close to the value reported for Ph3Sn(IV)–Gly–Leu
(ꢀ170 ppm), which has been assigned a pseudotetrahe-
dral structure [32]. Therefore, a pseudotetrahedral struc-
ture can be proposed for Ph3Sn(Umb) in solution.
In 119Sn NMR spectrum of Me3Sn(Umb) Æ phen, a
single resonance at d 24.0 ppm is observed, which is in
the range of pentacoordinate trimethyltin(IV) com-
Compound number
Solvent
d (in ppm)
1
2
3
4
5
a
CD3OD
CDCl3
43.6 (2.0,ꢀ140.0)
ꢀ11.3
ꢀ176.9
25.3
CD3OD
CDCl3
CD3OD
ꢀ475.2
Compound number as indicated in Table 1.
molecule in axial positions. A similar 1J(13C–119Sn) cou-
pling constant of about 500 Hz was observed in metha-
nol-d4 solutions of the trimethyltin derivative of
N-benzoyl-gylcylglycine [39] where a five-coordinated
trialkyltin moiety in a trigonal plane is proposed as
structural motif. Further, the 119Sn NMR spectrum of
Me3Sn(Umb) recorded in CD3OD also shows two sig-
nals at d 43.64 ppm (broad) and d 2.05 ppm (sharp)
and a very weak signal at d ꢀ140.0 ppm (Table 6).
The presence of additional 119Sn resonances is also in
accordance with the decomposition reaction (Eq. (3)),
a process which is favoured by the nucleophilic complex-
ation by the solvent molecule, which weakens one of the
Sn–CH3 bond which becomes prone to methyl group
1
pounds. The H NMR spectrum of compound 4 also
shows a single signal at d 0.47 ppm for all the methyl
2
groups with J(1H–119Sn) value of 70.0 Hz, which also
supports the presence of pentacoordinate trimethyltin
moiety with three methyl groups in equatorial plane in

M. Nath et al. / Journal of Organometallic Chemistry 690 (2005) 134–144
141
Fig. 5. HMBC (1H–13C) spectrum of Ph3Sn(Umb).
solution. It seems that the hexacoordinated Me3Sn(Um-
b) Æ phen dissociates in solution giving the pentacoordi-
nate trimethyltin(IV) derivative of umbelliferone. On
the other hand, Ph3Sn(Umb) Æ phen does not show any
chemical shift in the region of Ph3Sn(Umb) (ꢂꢀ200
ppm), clearly indicating change of structure upon ad-
duct formation and preventing the decomposition of
the adduct in solution. The tin shielding in 119Sn
NMR spectra increases markedly with increase in coor-
dination number and tin shifts are normally higher with
phenyl compared to alkyl substituents [41]. Therefore, a
six-coordinated octahedral structure may be retained in
solution for Ph3Sn(Umb) Æ phen considering its higher
119Sn chemical shift (d = ꢀ475.2 ppm) in CD3OD. Due
and 13C NMR spectra, it could not be possible to resolve
and assign the signals of two types of phenyl groups at-
tached to tin in fac- or mer-octahedral structure. This
observation may be due to almost similar electron den-
sity around each phenyl group in the octahedral com-
plex as umbelliferone and 1,10-phenanthroline both
have heteroaromatic rings.
50.8% inhibition). Trimethyltin(IV) derivative of
umbelliferone is more active than the phenyl ana-
logue. The activity increases upon adduct formation
with 1,10-phenanthroline. Among tested compounds,
Ph3Sn(Umb) Æ phen has been found to possess the most
potent activity (50.8% inhibition), which has been found
to be more potent than that of the reference drug,
phenylbutazone (38.4% inhibition).
A number of studies [42,43] of the triorganotin com-
pounds, R3SnX and diorganotin compounds, R2SnXY
indicated that the marked biological activity of the
organotins may be due to the transport of either more
active species (RnSn(4 ꢀ n)+, where n = 2 or 3) or the mol-
ecule as a whole across the cellular membrane, and X or
XY group influences only the readiness of delivery of the
active part R3Sn+/R2Sn++ into the cell [42]. Further, the
studies on structure-activity correlation of organo-
tin(IV) compounds reveal that the biologically active
compounds should have available coordination posi-
tions at tin and relatively stable ligand–tin bonds, viz.,
1
to strongly overlapping pattern of the signals in its H
˚
Sn–N [44] (bond length >2.39 A) and Sn–S bonds. These
bonds should have low hydrolytic decomposition. Thus,
it can be proposed that the same mechanism may be in-
volved in the observed activity of the studied organo-
tin(IV) derivatives.
3.4. Biological studies
3.4.1. Anti-inflammatory activity
The analysis of the data of Table 7 indicates that the
anti-inflammatory activity of the studied compounds is
influenced by the nature of ligand environment and or-
ganic groups attached to tin. The least activity of
Ph3Sn(Umb) (9.2% inhibition) may be due to the differ-
ent geometry (pseudotetrahedral) of this compound as
compared to other trialkyltin(Umb) which have trigonal
bipyramidal structure. Further, the activity of the trior-
ganotin(IV) derivatives of umbelliferone is enhanced
The anti-inflammatory activity (% inhibition) of the
synthesized compounds was conducted on adult albino
rats (body weight 120–160 g) of Froster Charles species
against carrageenan induced edema in the doses of 50
mg kgꢀ1 given orally. The results are presented in Table
7. The activity of the standard drug phenylbutazone is
included for the comparison. The compounds exhibit
anti-inflammatory activity of varying degree (9.2–

142
M. Nath et al. / Journal of Organometallic Chemistry 690 (2005) 134–144
upon the adduct formation with 1,10-phenanthroline.
This may be due to the presence of Sn–N bonds which
tend to dissociate relatively more easily as compared
to Sn–O bonds in R3Sn(Umb) as a part of the mecha-
nism for inhibition.
3.4.2. Acute toxicity studies
The acute toxicity (LD50) was studied on albino mice
(body weight 20–25 g) of either sex. The LD50 values of
the studied compounds are given in Table 7. All of the
compounds have LD50 values greater than 1000
mg kgꢀ1 suggesting the safety margin of these deriva-
tives. Further, Ph3Sn(Umb) Æ phen shows LD50 value
even greater than 1600 mg kgꢀ1. It has been observed
that the organotin(IV) derivatives of umbelliferone and
their adducts with 1,10-phenanthroline are much less
toxic than the organotin(IV) derivatives of simple a-
amino acids [45] (<50 mg kgꢀ1) and peptides [32,46]
(>500–800 mg kgꢀ1), indicating that umbelliferone and
1,10-phenanthroline lower the toxicities but enhance
the activities of the resulting organotin(IV) derivatives.
3.4.3. Blood-pressure lowering (cardiovascular) activity
The blood pressure lowering activity of the synthe-
sized compounds was carried out on either adult dogs
(body weight 10–20 kg) or on cats (body weight 3–4
kg) of either sex. The results are presented in Table 7.
The trialkyltin(IV) derivatives of umbelliferone exhib-
ited mild hypotensive activity of varying degree (10–20
mm Hg) and duration (5–15 min) without affecting the
carotid occlusion (CO) and noradrenaline (NA) re-
sponse. Such a profile of pharmacological effect is indic-
ative of direct vasodilator action of these compounds.
Ph3Sn(Umb) Æ phen showed hypotensive activity (23
mm Hg) which lasted for about 15 min. This compound
inhibited the NA response without affecting CO re-
sponse. Me3Sn(Umb) Æ phen showed mild blood pres-
sure lowering activity, with inhibition of both CO and
NA responses.
The results suggest that Ph3Sn(Umb) Æ phen can act
as an effective anti-inflammatory agent (50.8% inhibi-
tion) as it is least toxic (LD50 > 1600 mg kgꢀ1) and has
mild hypotensive activity (23 mm Hg that lasted for
ꢂ15 min).
3.4.4. Anti-microbial activity
Minimum inhibitory concentrations (MIC in
lg mlꢀ1) determined by the standard dilution method
are given in Table 8. The studied compounds showed
mild activities against different microbes. Ph3Sn(Umb)
and Me3Sn(Umb) show good activity against Staplylo-
coccus aureus (strains 1 and 2) and Bacillus subtilis, Can-
dida albicans and Microsporum gypseum, respectively.
However the anti-microbial activities of the triorgano-
tin(IV) derivatives of umbelliferone against certain mi-
crobes are slightly enhanced (Table 8) upon adduct

M. Nath et al. / Journal of Organometallic Chemistry 690 (2005) 134–144
143
Table 8
Anti-microbial activity data (by standard dilution method)
Compound
MIC (in lg/ml)
1
2
3
4
5
6
7
Me3Sn(Umb)
Ph3Sn(Umb)
>25.0
10.0
2.0
>25.0
2.0
2.0
2.0
>25.0
>25.0
>25.0
10.0
>25.0
>25.0
10.0
5.0
5.0
>25.0
>25.0
>25.0
>25.0
5.0
5.0
>30.0
5.0
>30.0
Me3Sn(Umb) Æ phen
Ph3Sn(Umb) Æ phen
>25.0
2.0
10.0
1, Staphylococcus aureus Mau 29/58; 2, Staphylococcus aureus Mau 78/71; 3, Bacillus subtilis 18/6; 4, Escherichia coli 326/71; 5, Escherichia coli; 6,
Candida albicans Pn-10; 7, Microsporum gypseum.
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Daneshtalab, Bioorg. Med. Chem. 7 (1999) 1933.
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mild activity against Bacillus polymyxa and Salmonella
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Acknowledgements
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This work is part of a major research project spon-
sored by the UPCST, Lucknow (Grant No. CST/
SERC/D-1909, 26.10.1998). M. Nath is thankful to the
UPCST, Lucknow, India, for sanctioning the project
and R. Jairath is thankful to the UPCST, Lucknow
for Junior Research Fellowship. Thanks are also due
to the Director, Central Drug Research Institute, Luc-
know, India, for carrying out elemental analysis and
1H/13C NMR spectral measurements and to the Head,
NMR division, Tata Institute of Fundamental Re-
search, Mumbai for carrying out 2D-HMBC and 119Sn
NMR measurements. Financial support for Mo¨ssbauer
work from the National Institute of Health Minority
Biomedical Research Support Program (MBRS/
SCORE, GM08005) is gratefully acknowledged. R. Jai-
rath is also thankful to MHRD, India, for providing
Institute Assistantship during the writing of this
manuscript.
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