Synthesis, characterization, and in vitro cytotoxicity of triorganotin 3,5-di-tert-butyl-4-hydroxybenzoates

Article abstract of DOI:10.1080/15533174.2011.609233

The triorganotin 3,5-di-tert-butyl-4-hydroxybenzoates, 3,5-(t-Bu) ₂-4-HO-C₆H₂COOSnR₃ (R = c-C ₆H₁₁, 1; C₆H₅, 2; C ₆H₅CH₂, 3; C₆H₅C(CH ₃)₂CH₂, 4), have been synthesized and characterized by elemental analysis, IR, and ¹H and ¹³C NMR spectra. The crystal structures of 1 and 4 have been determined by X-ray single crystal diffraction and show that the tin atom possesses a distorted tetrahedral geometry. Intermolecular O-H...O hydrogen bond in 1 connects neighboring molecules into a cyclic tetramer. The in vitro cytotoxicity of the compounds against the human tumor cell lines A549 was found to be higher than that of cis-platin used clinically.

Full text of DOI:10.1080/15533174.2011.609233

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Synthesis, Characterization, and In Vitro Cytotoxicity
of Triorganotin 3,5-Di-tert-butyl-4-hydroxybenzoates
Wenchao Ding a , Zhi Liu a , Laijin Tian a & Xiangao Quan b
a Department of Chemistry , Qufu Normal University , Qufu , P. R. China
b School of Pharmaceutical Science , Jining Medical University , Rizhao , P. R. China
Published online: 31 Jan 2012.
To cite this article: Wenchao Ding , Zhi Liu , Laijin Tian & Xiangao Quan (2012) Synthesis, Characterization, and In Vitro
Cytotoxicity of Triorganotin 3,5-Di-tert-butyl-4-hydroxybenzoates, Synthesis and Reactivity in Inorganic, Metal-Organic, and
Nano-Metal Chemistry, 42:1, 82-87, DOI: 10.1080/15533174.2011.609233
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, 42:82–87, 2012
Copyright ꢀ Taylor & Francis Group, LLC
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ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2011.609233
Synthesis, Characterization, and In Vitro Cytotoxicity of
Triorganotin 3,5-Di-tert-butyl-4-hydroxybenzoates
Wenchao Ding,1 Zhi Liu,1 Laijin Tian,1 and Xiangao Quan2
1Department of Chemistry, Qufu Normal University, Qufu, P. R. China
2School of Pharmaceutical Science, Jining Medical University, Rizhao, P. R. China
acid, we have synthesized and characterized some triorganotin
3,5-di-tert-butyl-4-hydroxybenzoates (Scheme 1).
The triorganotin 3,5-di-tert-butyl-4-hydroxybenzoates, 3,5-(t-
Bu)2-4-HO-C6H2COOSnR3 (R = c-C6H11, 1; C6H5, 2; C6H5CH2,
3; C6H5C(CH3)2CH2, 4), have been synthesized and characterized
by elemental analysis, IR, and 1H and 13C NMR spectra. The crys-
tal structures of 1 and 4 have been determined by X-ray single
crystal diffraction and show that the tin atom possesses a distorted
tetrahedral geometry. Intermolecular O−H···O hydrogen bond in
1 connects neighboring molecules into a cyclic tetramer. The in vitro
cytotoxicity of the compounds against the human tumor cell lines
A549 was found to be higher than that of cis-platin used clinically.
EXPERIMENTAL
Materials and Physical Measurements
All chemicals were of reagent grade and were used without
further purification. Carbon and hydrogen analyses were deter-
mined using a Perkin-Elmer 2400 Series II elemental analyzer.
Melting points were measured on a WRS-1A digital melting
point. IR spectra were recorded on a Nicolet 470 FT-IR spec-
Keywords crystal structure, cytotoxicity, organotin carboxylate,
3, 5-di-tert-butyl-4-hydroxybenzoic acid
trophotometer using KBr discs in the range 4000–400 cm−1
.
1H and 13C NMR spectral data were collected using a Bruker
Avance DMX500 NMR spectrometer with CDCl3 as solvent
and TMS as internal standard.
INTRODUCTION
Organotin carboxylates have been receiving increasing atten-
tion, not only because of their structural interest but also because
of their varied applications.[1] Some examples find wide use as
catalysts and stabilizers, and certain derivatives are used as bio-
cides, antifouling agents, and wood preservatives.[2,3] In recent
years, investigations have been carried out to test their anti-
tumor activity and it has been observed that several triorganotin
species show potential as antineoplastic agents.[4,5] In general,
the organotin moiety, ligand (carboxylic acid), and coordina-
tion number of the tin atom appear to play an important role
in anti-tumor activity.[5] To synthesize new organotin esters of
carboxylic acid having biological activity is a optimized strat-
egy to find the organotin anti-tumor agents. 3,5-di-tert-butyl-4-
hydroxybenzoic acid is an important pharmaceutical intermedi-
ate,[6,7] and its organotin esters are not reported in the literature,
to our knowledge. In order to explore the chemistry and cytotoxi-
city of triorganotin esters of 3,5-di-tert-butyl-4-hydroxybenzoic
Synthesis of the Title Complexes 1–4
To a suspension of triorganotin hydroxide (2 mmol) in 50 ml
of toluene was added 3,5-di-tert-butyl-4-hydroxybenzolic acid
(0.50g, 2mmol). The reactionmixtures wereheatedunder reflux
for 5 h with a Dean–Stark separator, and then allowed to cool
to room temperature. The solution was filtered and the solvent
was removed under reduced pressure. The resulting white solid
was recrystallized from ethanol. The yield, m.p., and spectral
data for compounds 1–4 are as follows.
3,5-(t-Bu)2-4-HO-C6H2COOSnCy3 (1)
Yield 82%, m.p. 131–132◦C. Anal. Found: C, 66.06; H, 7.43.
Calcd. for C33H54O3Sn: C, 66.33; H, 7.65%. IR (KBr)
cm−1: 3600, 3367 (O-H), 3050 (Ar-H), 2921, 2848 (C-
H), 1620 [ν(COO−)as)], 1598, 1565, 1445, 1422 (Ar),
1332 (vs) (ν(COO−)s), 1257, 1230 (C-O). H NMR
1
(CDCl3) δ: 7.96 (2H, s, Ar-H), 5.56 (1H, s, OH), 1.46
(18H, s, 6CH3), 1.98–1.96 (9H, m), 1.75–1.63 (15H, m),
1.37–1.32 (9H, m) (Cy). 13C NMR (CDCl3) δ: 172.12
(C = O), 157.64, 135.84, 127.60, 124.22 (Ar), 34.66
(C(CH3)3), 33.89 (1J(13C-119Sn) = 336 Hz, C-α), 31.18
(2J(13C-119Sn) = 15 Hz, C-β), 30.48 (C(CH3)3), 29.02
(3J(13C-119Sn) = 64 Hz, C-γ ), 27.04 (C-δ).
Received 28 June 2011; accepted 26 July 2011.
This work was supported by Shandong Provincial Natural Sci-
ence Foundation, China (ZR2010BL012) and Post-Doctor Innovation
Project of Shandong Province (200702021).
Address correspondence to Laijin Tian, Department of Chemistry,
Qufu Normal University, Qufu 273165, P. R. China. E-mail: laijin-
tian@163.com
3,5-(t-Bu)2-4-HO-C6H2COOSnPh3 (2)
82

Triorganotin 3,5-Di-tert-butyl-4-hydroxybenzoates
83
SCH. 1. Preparation of triorganotin 3,5-di-tert-butyl-4-hydroxybenzoates 1–4.
Yield 78%, m.p. 178–179◦C. Anal. Found: C, 65.86; H, 5.89.
Calcd. for C33H36O3Sn: C, 66.13; H, 6.05%. IR (KBr)
cm−1: 3598 (O-H), 3067, 3056 (Ar-H), 2958, 2872 (C-
H), 1614 (ν(COO−)as), 1595, 1565, 1480, 1430 (Ar),
1337 (ν(COO−)s), 1262, 1239(C-O). 1H NMR (CDCl3)
δ: 8.00 (2H, s, Ar-H), 7.79 (6H, dd, J = 2.4, 7.4 Hz,
J(119Sn-H) = 65.5 Hz, H-2 in Ph), 7.47–7.44 (9H, m,
H-3 and H-4 in Ph), 5.63 (1H, s, OH), 1.45 (18H, s,
6CH3). 13C NMR (CDCl3) δ: 171.56 (C = O), 157.58,
135.87, 127.61, 124.34 (Ar), 137.84 (2J(13C-119Sn) = 47
Hz, o-C in Ph), 137.17 (1J(13C-119Sn) = 632 Hz, i-C in
Ph), 130.55 (4J(13C-119Sn) = 12 Hz, p-C in Ph), 128.86
(3J(13C-119Sn) = 62 Hz, m-C in Ph), 34.72 (C(CH3)3),
30.48 (C(CH3)3).
34.61 (C(CH3)3), 32.87 (3J(119Sn-13C) = 42 Hz, CH3),
30.49 (C(CH3)3).
Crystal Structure Determination of 1 and 4
The colorless single crystals of 1 and 4 were obtained from
dichloromethane-hexane (1:1, V/V) by slow evaporation at
room temperature. Diffractions measurements were performed
on a Bruker Smart Apex imaging-plate area detector fitted with
graphite monochromatized Mo-Kα radiation (0.71073 Å) using
the ϕ and ω scan technique. The data reductions were performed
using SAINT program and empirical corrections for absorption
effects were made using the SADABS program.[8] The struc-
tures were solved by direct methods and refined by a full-matrix
least squares procedure based on F2 using SHELXL-97.[8] The
non-hydrogen atoms were refined anisotropically and hydrogen
atoms were placed at calculated positions in the riding model
approximation, with C−H = 0.93 Å for aromatic H atoms, C−H
= 0.96 Å for methyl H atoms, C−H = 0.97 Å for methylene
H atoms, C−H = 0.98 Å for methine H atoms, and O−H =
0.82 Å for hydroxy H atoms. Crystallographic parameters and
refinements were listed in Table 1.
3,5-(t-Bu)2-4-HO-C6H2COOSn(CH2Ph)3 (3)
Yield 72%, m.p. 104–105◦C. Anal. Found: C, 67.56; H, 6.48.
Calcd. for C36H42O3Sn: C, 67.41; H, 6.60%. IR (KBr)
cm−1 3607 (O-H), 3057 (Ar-H), 2957, 2872 (C-H), 1624
(ν(COO−)as), 1596, 1492, 1452 (Ar), 1323 (ν(COO−)s),
1259, 1237(C-O) cm−1. 1H NMR (CDCl3) δ: 7.92 (2H,
s, Ar-H), 7.15 (6H, t, J = 7.6 Hz, H-3 in Ph), 7.04 (3H,
t, J = 7.3 Hz, H-4 in Ph), 6.82 (6H, d, J = 7.3 Hz,
H-2 in Ph), 5.66 (1H, s, OH), 2.68 (6H, s, J(119Sn-H)
= 71.0 Hz, CH2Sn) 1.49 (18H, s, 6CH3). 13C NMR
(CDCl3) δ: 171.96 (C = O), 157.88, 135.92, 127.66,
124.34 (Ar), 138.36, 129.32, 128.94, 124.88 (Ph), 34.74
(C(CH3)3), 30.46 (C(CH3)3), 24.49 (1J(13C-119Sn) =
366 Hz, CH2Sn).
In Vitro Cytotoxicity
Cytotoxic activity was assayed against the human tumor cell
lines (lung tumor cell). The samples were prepared by dissolving
compounds in C2H5OH and by diluting the solution obtained
with water. In the assays, the final concentration of C2H5OH
was less than 0.1% (the concentration used was found to be
non-cytotoxic against the tumor cell.). In vitro cytotoxicities of
the compounds were measured by the MTT assay according to
the literature.[9] The experiments were repeated three times for
each test. The dose causing 50% inhibition of cell growth (IC50)
was calculated by NDST software.[10]
3,5-(t-Bu)2-4-HO-C6H2COOSn(CH2C(CH3)2Ph)3 (4)
Yield 83%, m.p. 122–123◦C. Anal. Found: C, 70.66; H, 7.89.
Calcd. for C45H60O3Sn: C, 70.41; H, 7.88%. IR (KBr)
cm−1: 3623 (O-H), 3052 (Ar-H), 2959, 2926, 2873 (C-
H), 1642 (ν(COO−)as), 1599, 1497, 1443 (Ar), 1328
1
(ν(COO−)s), 1261, 1235(C-O). H NMR (CDCl3) δ:
7.98 (2H, s, Ar-H), 7.30 (6H, t, J = 7.4 Hz, H-3 in
Ph), 7.22 (3H, t, J = 7.3 Hz, H-4 in Ph), 7.17 (6H, d,
J = 7.4 Hz, H-2 in Ph), 5.61 (1H, s, OH), 1.51 (18H,
s, 6CH3), 1.28 (18H, s, 6CH3), 1.27 (6H, s, J(119Sn-
H) = 50.8 Hz, (CH2)3Sn).13C NMR (CDCl3) δ: 171.25
(C = O), 157.52, 135.46, 127.80, 124.24 (Ar), 151.27,
128.57, 126.02, 125.54 (Ph), 38.00 (2J(119Sn-13C) = 20
Hz, Ph-C), 37.53 (1J(119Sn-13C) = 352 Hz, CH2Sn),
RESULTS AND DISCUSSION
Four organotin compounds 1–4 were prepared by azeotropic
removal of water from the reaction between the triorganotin
hydroxide and 3,5-di-tert-butyl-4-hydroxybenzoic acid in the
molar ratio 1:1 in toluene (Scheme 1). The compounds are white
crystals, air stable and soluble in common organic solvents such
as benzene, trichloromethane, acetone, and methanol.

84
W. DING ET AL.
TABLE 1
Crystal data and structure refinement for 1 and 4
Compound
1
4
Formula
C33H54O3Sn
617.45
Tetragonal
I41/a
20.053(2)
20.053(2)
33.815(5)
90
C45H60O3Sn
767.62
Monoclinic
P21/c
14.920(3)
27.862(6)
19.950(4)
90.90(3)
8292(3)
8
Formula weight
Crystal system
Space group
a/Å
b/Å
c/Å
β/◦
V/Å−3
13598(3)
16
Z
Temperature/K
Crystal size /mm
Dc/g·cm−3
µ/mm−1
295(2)
295(2)
0.38 × 0.24 × 0.22
0.23 × 0.12 × 0.10
1.206
1.230
0.779
0.652
F(000)
θmax
5216
25.5
3232
25.5
Reflns meas.
Reflns unique, Rint
Reflns with I>2σ(I)
Weighting scheme
R indices [I>2σ(I)]
R indices (all data)
ꢀρmin, ꢀρmax/e Å−3
36988
6346, 0.074
3094
60936
14992, 0.048
12232
[σ2(F2) + (0.0948P)2]−1
R = 0.058, wR = 0.151
R = 0.129, wR = 0.183
–0.470, 0.405
[σ2(F2) + (0.0420P)2 + 3.4338P]−1
R = 0.045, wR = 0.095
R = 0.059, wR = 0.100
–0.528, 0.546
up the C(1)–Sn(1)–C(11) angle to 117.19(14) and 117.91(18)◦
and reducing the O(1)–Sn(1)–C(1) angle to 100.76(11) and
100.02(13)◦ for 4. The monodentate mode of coordination of
3,5-di-tert-butyl-4-hydroxybenzoate is reflected in the disparate
two C–O bond lengths of carboxylate (C(19)–O(1) 1.310(6) Å
Crystal Structure of Compounds 1 and 4
The molecular structures of 1 and 4 are shown in Figures 1
and 2, respectively. The selected bond lengths and bond angles
are listed in Tables 2 and 3. Compounds 1 and 4 crystallize in
tetragonal space group I41/a and monoclinic space group P21/c,
respectively. In 4, the asymmetric unit contains two independent
molecules which are labeled as molecules 4A and 4B, respec-
tively, and do not differ from each other significantly.
The tin atoms in 1 and 4 are both four-coordinate and
possess a distorted SnC3O tetrahedral geometry. The Sn–C
distances (the mean of 2.142(8) Å for 1 and 2.150(4) Å
for 4) are similar to those found in other reported tricy-
clohexyltin and tris(2-methyl-2-phenylpropyl)tin carboxylates,
such as tricyclohexyltin 3-indoleacetate[11] and tris(2-methyl-
2-phenylpropyl)tin acetate.[12] The bond length of Sn(1)–O(1)
in 1 and 4 is 2.051(4) and 2.054(2), 2.074(2)Å, respectively,
which lies in the range of the Sn–O covalent bond length
(2.038−2.115 Å)[13] and is consistent with that reported in re-
lated compounds.[11,12] The Sn(1)···O(2) separation of 2.963(4)
Å for 1 and 3.014(2), 3.002(2) Å for 4 is not indicative of a
significant interaction between these atoms. The major stereo-
chemical role of atom O(2) is to distort the tetrahedral geometry
by opening up the C(7)–Sn(1)–C(13) angle to 118.7(3)◦ and re-
ducing the O(1)–Sn(1)–C(1) angle to 97.9(3)◦ for 1, and opening
FIG. 1. Molecular structure of 1; hydrogen atoms are omitted for clarity.

Triorganotin 3,5-Di-tert-butyl-4-hydroxybenzoates
85
FIG. 2. Molecular structure of 4; hydrogen atoms are omitted for clarity.
ally, the difference between the νas(CO2) and νs(CO2) bands,
ꢀν(CO2), of bidentate carboxylate group is below 200 cm−1
and C(19)–O(2) 1.220(6) Å for 1, and the mean C(31)–O(1)
1.310(4) Å and C(31)–O(2) 1.219(4) Å for 4.
,
while unidentate carboxylate is above 200 cm .
−1 [14,15] The mag-
In the crystal structure of 1, neighboring molecules
are linked into a cyclic tetramer that is saddle-shaped
supramolecular structure by the hydrogen bond between phe-
nolic hydroxyl and adjacent carbonyl oxygen of carboxylate,
O(3)−H(3)···O(2) #1 [O(3)−H(3) 0.82 Å, H(3)···O(2)#1 2.02
Å, O(3)···O(2) #1 2.740(5) Å, O(3)−H(3)···O(2)#1 146.6◦, sym-
metry code #1: –x+5/4, y+3/4, –z+5/4] (Figure 3). How-
ever, the intermolecular hydrogen bond is not found in 4,
which is caused by the bulky 2-methyl-2-phenylpropyl on the
tin.
nitudes (277–314 cm−1) of ꢀν(CO2) in 1−4 indicate that the
carboxylate group is monodentate coordination to tin in the solid
state, which is agreement with the previous X-ray structures of
1 and 4.
1
The H NMR spectra of the compounds show the expected
integration and peak multiplicities. The singlet appeared
at ∼7.95, 5.60, and 1.50 ppm is assigned to proton res-
onance of phenyl ring, hydroxyl group and tert-butyl of
3,5-di-tert-butyl-4-hydroxybenzoate ligand, respectively. The
13C resonances of the phenyl of ligand lie in the range of
157.64–124.22 ppm. The 13C chemical shift the carboxyl
carbon is at ca. 172 ppm. The coordination number of the
Spectroscopic Analysis
The compounds 1–4 do not show the broad ν (OH) band
at 3600 ∼ 2500 cm−1 and the ν (C = O) strong band at
1690 cm−1, indicating the deprotonations of the carboxylic
group of the ligand due to the formation of the oxygen-tin bond.
The existence of stretching vibration absorption of the pheno-
lic hydroxyl group at ∼3600 cm−1 proves that the phenolic
hydroxyl groups remain intact in 1–4. In organotin carboxy-
lates, IR spectroscopy can provide useful information concern-
ing the coordination mode of the carboxylate group. Gener-
1
tin atom in organotins has been related to the J(119Sn-13C)
1
coupling constants.[16,17] The J(119Sn-13C) of the compounds
1–4 is 336, 632, 366, and 350 Hz, respectively, which is close
to that of the corresponding four-coordinate triorganotin car-
boxylates,[16,17] such as 2-HOC6H4N = NC6H4COOSnCy3,[18]
Ph3GeCH(o-C6H4Cl)CH2COOSn(CH2C(CH3)2Ph)3,[19] and
C6H5C6H4COOSnPh3,[20] suggesting that the tin atom in 1–4
is four-coordinated in CDCl3 solution.
TABLE 2
Selected bond lengths (Å) and angles (◦) for 1
Sn(1)-O(1)
Sn(1)-C(1)
O(1)-Sn(1)-C(1)
O(1)-Sn(1)-C(13)
2.051(4)
2.114(8)
97.9(3)
Sn(1)-C(7)
Sn(1)-C(13)
O(1)-Sn(1)-C(7)
C(1)-Sn(1)-C(13)
2.170(8)
2.132(7)
102.6(2)
110.3(5)
C(19)-O(1)
C(19)-O(2)
C(1)-Sn(1)-C(7)
C(13)-Sn(1)-C(7)
1.310(6)
1.220(6)
114.9(4)
118.7(3)
109.9(2)

86
W. DING ET AL.
TABLE 3
Selected bond lengths (Å) and angles (◦) for 4
4A
4B
4A
4B
Sn(1)-O(1)
Sn(1)-C(1)
2.074(2)
2.158(3)
2.054(2)
2.151(4)
Sn(1)-C(21)
C(31)-O(1)
2.157(4)
1.311(4)
2.151(4)
1.309(4)
Sn(1)-C(11)
2.142(3)
2.142(4)
C(31)-O(2)
1.220(4)
1.218(4)
O(1)-Sn(1)-C(11)
O(1)-Sn(1)-C(21)
C(11)-Sn(1)-C(21)
102.63(12)
103.58(12)
114.76(14)
102.06(12)
104.18(13)
113.71(18)
O(1)-Sn(1)-C(1)
C(1)-Sn(1)-C(11)
C(1)-Sn(1)-C(21)
100.76(11)
117.19(14)
114.78(14)
100.02(13)
117.91(18)
115.54(14)
In Vitro Cytotoxicity
SUPPLEMENTARY MATERIAL
Crystallographic data for the structural analysis have been
In order to evaluate the cytotoxicity of the synthesized organ-
otin carboxylates, we test their activity against a human tumor deposited with the Cambridge Crystallographic Data Cen-
cell lines A549. The IC50 of compounds 1-4 against A549 is 0.22 ter, CCDC Nos. 822995 and 822996. Copies of this infor-
0.03, 0.08 0.01, 0.46 0.03, and 3.24 0.12 µmol·l−1
,
mation may be obtained free of charge from The Director,
respectively, indicating that they are active against this tumor CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax:
cell, and their activity are higher than that of the reference 44–1223-336–033; email: deposit@ccdc.cam. ac.uk or www:
drug cis-platin (IC50 9.46
0.43 µmol·l−1). The activity of http://www.ccdc.cam.ac.uk).
the compounds decreased in the order 2>1>3>4. The activ-
ity of compounds 1–4 against the A549 is similar to that of
the reported analogues, 3,4-(H2N)2C6H3COOSnPh3 (IC50 0.30
µmol·l−1) and 3,4-(H2N)2C6H3COOSn(C4H9-n)3 (IC50 0.57
µmol·l−1).[21] As these results are preliminary, further study
on the anti-tumor effects of these compounds is highly recom-
mended.
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