Monatshefte f ur Chemie 133, 1089±1096 (2002)
Synthesis, Characterization, and Biological Activity of n-Tributyltin Derivatives of Pharmaceutically Active Carboxylates Saira Shahzadi1 , Moazzam H. Bhatti1 , Khadija Shahid1 , Saqib Ali1; , Saadia R. Tariq1 , Mohammad Mazhar1, and Khalid M. Khan2 1 2
Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan HEJ Research Institute of Chemistry, University of Karachi, Karachi, Pakistan
Summary. Tributyltin(IV) derivatives of six different pharmaceutically active carboxylates were synthesized. The complexes were characterized by different analytical techniques (elemental analysis; infrared, NMR, and mass spectroscopy). 119Sn NMR data were also recorded in six different coordinating and non-coordinating solvents. The antibacterial activities of the compounds were tested using ten different bacteria relative to the reference drugs ampicillin and cephalexin. Keywords. Tributyltin(IV) derivatives; Biological activity;
119
Sn NMR.
Introduction Although organotin compounds have achieved a wide range of commercial applications [1], few of these involve tributyltin derivatives. A number of such compounds have found application as biocidal constituents in marine antifouling paints and pesticides [2]. The increased commercial use of tributyltin compounds has stimulated research on the effects of acute or chronic exposure. In view of our continuous interest in the synthesis, characterization, biological applications, and crystal structure of organotin carboxylates [3±7], we have prepared a series of tributyltin derivatives starting from various pharmaceutically active carboxylates. These compounds have been characterized by elemental analysis as well as infrared, multinuclear NMR (1H, 13C, 119Sn), and mass spectroscopy. Their biological activities have been tested against various bacteria. From 119 Sn NMR in various coordinating and non-coordinating solvents it can be concluded that (119Sn) and 1J(119Sn, 13C) can be used to propose the geometry of coordination polyhedra around the Sn atom.
Corresponding author. E-mail:
[email protected]
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Results and Discussion The analytical results and certain physical properties of the complexes are reported in Table 1. The complexes are quite stable, show sharp melting points, and are soluble in common organic solvents. All drugs have anti-in¯ammatory and analgesic properties [8]. Infrared spectroscopy The infrared spectra of the complexes were recorded as KBr discs in the range from 4000 to 400 cm 1. The most important frequencies of the complexes are reported in Table 2. The complexation of tin with the ligands is con®rmed by the absence of the (OH) band in the products (2900±2600 cm 1). The difference between asym(COO) and sym(COO) () is important for the prediction of the nature of the ligand. In all complexes is less than 250 cm 1, indicating that the ligand is bidentate [9, 10]. Bands in the range of 560±520 and 480±450 cm 1 indicate the presence of Sn±C and Sn±O bonds. Mass spectroscopy The mass fragmentation pattern of triorganotin complexes is given in Scheme 1. A molecular ion peak of very low intensity was observed for all compounds. In triorganotin derivatives, the primary fragmentation is due to the loss of ±OOCR0 group, followed by successive cleavage of R groups and ending at Sn (m=z 120). Table 1. Physical parameters of compounds 1±6
1 2 3 4 5 6
Molecular formula
Molecular weight
Yield=%
m.p.= C
C27H39FO2Sn C26H38O2NCl2Sn C19H33O3Sn C28H41O3Sn C21H35O2Sn C25H45O2Sn
533 585 428 544 438 496
70 89 70 90 80 85
50±51 51±52 74±75 63±65 59±60 40±42
Table 2. Characteristic infrared bands of compounds 1±6
1 2 3 4 5 6
asym(COO)
sym(COO)
(Sn±C)
(Sn±O)
1569 s 1575 s 1569 s 1579 s 1580 s 1586 s
1390 s 1410 s 1394 s 1413 s 1383 s 1395 s
179 165 175 166 197 191
511 w 565 s 548 s 500 m 547 m 547 m
454 w 447 s 421 m 456 w 426 m 426 s
n-Tributyltin Complexes
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Scheme 1. General fragmentation pattern
A second fragmentation pathway is characterized by loss of all R groups by different routes, followed by liberation of CO2; this route is more probable than the ®rst one. The most common fragments together with their m=z-ratios and relative abundances are given in Table 3. Biological testing Biological activity tests for the complexes were carried out against various bacteria by the `agar well diffusion' method [11]. The results are given in Table 4. The screening tests show that tributyltin carboxylates are potent candidates against all types of bacteria tested. It is well established that tributyltin compounds are
Table 3. Mass spectroscopic data for compounds 1±6; n.o. not observed Fragment Ion
1 m=z (%)
2 m=z (%)
3 m=z (%)
4 m=z (%)
5 m=z (%)
6 m=z (%)
R3SnOCOR0 R2SnOCOR0 RSnOCOR0 SnOCOR0 R3Sn R2Sn RSn R3SnR0 OCOR0 R0 SnH Sn
533(2) 477(100) 419(n.o) 363(8) 291(10) 235(60) 177(4) 489(6) 243(4) 199(8) 121(2) 120(4)
585(9) 528(100) 471(n.o) 411(4) 291(3) 235(5) 177(47) 541(n.o) 295(20) 251(53) 121(12) 120(8)
428(6) 371(75) 314(12) 254(8) 291(64) 235(34) 177(100) 384(2) 135(7) 91(9) 121(42) 120(13)
544(8) 487(100) 430(32) 373(45) 291(12) 235(34) 177(23) 500(20) 254(50) 210(4) 121(10) 120(18)
438(15) 381(100) 324(10) 153(8) 291(12) 235(10) 177(40) 394(2) 148(22) 104(38) 121(18) 120(17)
496(n.o) 439(100) 382(n.o) 325(10) 291(22) 235(15) 177(15) 396(2) 206(20) 162(80) 121(8) 120(7)
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Table 4. Antibacterial activity of triorganotin carboxylates; 7 (ampicillin) and 8 (cephalexin): reference drugs; c 200 g in 100 mm3 of DMSO; zone of inhibition is given in mm B. cereus C. diph- E.C. ETEC K. Pneu- P. mira- P. aero- S. typhi S. boydii S. aureus S. pyotheria monia bilis ginosa genes 1 2 3 4 5 6 7 8
15 16 17 20 21 27.5 8.5 8
20 20 19 20 17 15 11 10
13.5 15 16 15 13.5 14 8 8
20 15 20 22 21 25 10 11
15.5 15 18 17.5 17 17 10 9.5
12.5 13.5 14 13 13.5 15 14 15
17.5 17 16 22 17.5 23 10 10
18 16 22 20 16 25 10 9.5
15 18 15 16 16 20 8.5 10.5
18 16 17.5 18 21 17 8 10
signi®cantly more biocidally active than other classes of alkyltin species [12]. Within the R3SnL unit, the nature of R determines the speci®city of the biocide. Apparently, the function of the ligand is to support the transport of the active organotin moiety to the site of action where it is released by hydrolysis [12]. To study this effect, we employed different donor ligands. The anionic ligands also play an important role in determining the degree of activity of R3SnL derivatives. The biocidal activity of triorganotin carboxylates is also related to their structure; species generating a tetrahedral structure in solution are more active [12]. The order of antibacterial activity for the synthesized organotin derivatives is 3>4, 5, 6>1, 2. In most of the cases, the activity of the organotin derivatives is greater than that of the reference drugs with the exception of P. aeroginosa where the reference drugs show more activity. The higher activity of compound 3 might be due the smaller size of the carboxylate group attached to the tributyltin(IV) moiety. NMR Spectroscopy 1
H NMR spectroscopy
1
H NMR spectra of the investigated compounds were recorded in CDCl3; the data are given in Table 5. The resonances are characterized by their multiplicity and coupling constants. The integration of the spectra showed good agreement with the expected composition. 13
C NMR spectroscopy
13
C NMR data are presented in Table 6. The aromatic resonances were assigned by comparison with values calculated from increments [13]. In case of n-tributyltin derivatives, nJ(119Sn, 1H) coupling constants were observed in most of the cases. Earlier data show that the size of 1J(119Sn, 13C) in R3SnL derivatives is usually less than 400 Hz, indicating tetrahedral geometry in non-coordinating solvents [14]. In
1 2 3 4 5 6
Table 7.
119
(m) (t) (s) (d) (d) (d,d) (s) (t), 54.0 (m), 68.0 (m), 3.66 (m), 7
3 4 5 6 7
± ± ± ±
6.50 6.41 7.40 7.32 6.32 1.28 1.64 1.34 0.88 ± ± ± ±
Proton 3 (d), 3.3 2 3.75 (q), 7.77 (dd), 1.7, 1.5 3 1.48 (d), 7.0 (d), 1.0 5 7.40 (t), 8.0, 8.0 (d), 15.7 6 7.35 (t), 7.6, 7.6 (d), 15.7 7 7.60 (t), 8.0, 8.0 (m), 54.1 9 7.74 (s) (m), 65.2 12, 120 7.74 (d), 7.40 (m), 2.7 13, 130 7.55 (d), 7.0 (t) 14 7.62 1.58±1.48 (m), 54.0 1.47±1.42 (m)
1.22 (m) 0.90 (t)
Proton 4 2 4=6 5 7 8 10
± ± ±
7.15 7.25 7.33 7.59 6.48 2.35 1.35 1.65 1.35 0.92 ± ± ±
Proton 5 (d), 7.3 (t), 8.1, 8.1 (d), 6.6 (d), 15.9 (d), 15.9 (s) (m), 53.9 (m), 68.0 (m), 3.4 (t), 7.0
115.72 (375) 119.11 109.42 (360) 114.76 (357) 110.29 (359) 110.1 (357)
CDCl3 105.42 (326) 111.1 97.74 104.14 (361) 97.70 (384) 99.5
C6D6 86.36 64.77 64.24 80.4 (400) 79.96 (382) 79.2 (400)
Acetone-d6
22.75 (478) 21.58 (474) 20.1 (460) 21.63 (462) 18.37 (477) 18.34
DMSO-d6
21.55 14.33 25.25 22.86 30.49 26.61
(430)
(427) (430) (437)
Pyridine
Sn NMR data for compounds 1±6 (=ppm relative to external Me4Sn, J=Hz; pyridine and DMF: not deuterated)
7.11 7.09 6.95 6.92 7.32 7.24 3.81 0.69 1.31 1.62 0.61 ± ±
2 3 4 5 9, 90 10 11
± ±
(q), 7.0 (d), 7.1 (d), 8.2 (m) (m) (m) (m) (m) (m), 54.5 (m) (m) (t), 11.9
2 3 5 9, 90 10, 100 11 12 13
±
3.81 1.58 7.21 7.56 7.45 7.45 7.43 7.20 1.58 1.38 1.31 0.92 ±
Proton 2
Proton 1
Table 5. 1H NMR data for compounds 1±6 (=ppm relative to internal TMS, J=Hz; - refer to the n-butyl moiety)
1, 10 2 3 5, 50 6, 60 8 9
± ±
9.94 (460) 21.21 (436) 22.47 (440) 28.47 12.45 39.78
DMF
0.89 (d), 7.2 1.46 (m) 2.36 (d), 7.2 7.14 (d), 8.0 7.20 (d), 8.0 3.61 (q), 7.0 1.65 (d), 7.1 1.2 (t), 59.6 1.67 (m), 54.6 1.38 (m) 0.82 (t) ± ±
Proton 6
n-Tributyltin Complexes 1093
179.5 46.3 19.4 144.0 144.1 115.4 115.8 158.1 162.0 127.5 127.7 136.2 129.4 128.8 127.9 130.9 124.0 16.9 28.2 27.4 14.1 ±
1 2 3 4
8 9, 90 10, 100 11 12 13
±
7
6
5
1
Carbon
(4) (3) (355)
(14) (1) (3)
(248)
(24)
(8) 129.5 130.8 128.8 125.9 38.8 177.9 16.4 (361.9) 27.8 (21.8) 27.0 13.6 ± ± ±
8, 80
9, 90 10 11 12
± ± ±
127.3
138.2 123.6 124.4 118
2
7
6
1 2 3, 5 4
Carbon
± ± ± ± ± ± ±
8
7
6
2 3 4 5
Carbon
16.51 (358.0) 27.8 (20.7) 26.9 (64.9) 13.6 ± ± ± ± ± ± ±
172.0
130.5
113.5
151.4 117.9 112.0 144.2
3
8 9 10 11 12, 120 13, 130 14
7
6
5
1 2 3 4
Carbon
142.4 130.0 196.6 137.6 129.3 128.3 131.8 17.52 (360) 28.1 (20.7) 27.3 (63.8) 14.1
128.5
128.2
131.6
179.1 26.91 19.30 132.3
4
8 9 10
± ± ± ±
7
6
5
1 2 3 4
Carbon
143.0 172.0 21.3 16.5 (362.0) 27.8 (21.8) 27.0 (68.0) 13.6 ± ± ± ±
119.0
125.1
128.5
134.9 130.4 138.3 128.6
5
C NMR data for compounds 1±6 (=ppm relative to internal TMS, J=Hz; - refer to the n-butyl moiety)
13
Table 6.
127.0 129.9
5, 50 6, 60
8 9 10
± ± ± ±
45.8 20.4 180.0 15.8 (319, 315.5) 29.1 (21.3) 28.5 (65.0) 14.2 ± ± ± ±
141.5
22.7 45.1 30.1 137.9
1, 10 2 3 4
7
6
Carbon
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n-Tributyltin Complexes
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the present series, these values are in the range of 320±370 Hz for all complexes, thus supporting earlier reports. 119
Sn NMR spectroscopy
It has been reported that in non-coordinating solvents tributyltin derivatives are present as simple isolated pseudotetrahedral molecules (coordination number of the central tin atom: 4) without any distinct side bonding interaction. 119 Sn NMR spectra were recorded in six different solvents of coordinating and non-coordinating nature; the corresponding 119Sn chemical shifts and 1J(119Sn, 13 C) values are reported in Table 7. The chemical shifts in CDCl3 and C6D6 range from 100±120 ppm, indicating four-coordination, whereas in acetone-d6 these values lie in the range of 65±90 ppm, pointing to a higher coordination number (probably ®ve). From the values of (119Sn) in DMSO-d6, pyridine, and DMF ( 20 to 30 ppm) it is concluded that hexacoordination is prefered. Thus, nBu3SnL derivatives are four-coordinated in non-coordinating solvents and ®veor six-coordinated in coordinating solvents. Experimental Most organotin halides and their carboxylate derivatives are air and moisture sensitive; hence all glassware was completely dried at 140 C. All reactions were carried out under Ar in dried solvents. All chemicals were of analytical grade and used without further puri®cation. General procedure for the synthesis of 1±6 Stoichiometric amounts of organic acid (0.01 mol) and bis-(tributyltin)-oxide (0.005 mol) were re¯uxed in acetone for 3 to 4 h (Scheme 2). After cooling, acetone was removed on a rotary evaporator. All complexes were recrystallized from CH2Cl2.
R3 Sn2 O 2R0 COOH
acetone
! 2R3 SnOCOR0 H2 O
R n C4 H9
Scheme 2
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S. Shahzadi et al.: n-Tributyltin Complexes
Instrumentation Melting points were determined on an electrothermal melting point apparatus model MP-D Mitamura Rikero Kogyo (Japan) and are uncorrected. Infrared spectra were recorded as KBr pellets on a Perkin Elmer 16FPC-IR instrument, mass spectra on a MAT 8500 Finnigan equipment. 1H and 13C NMR spectra were recorded on a Bruker AM 500 spectrometer at 500 and 125 MHz, respectively. 119Sn NMR spectra were obtained in CDCl3 on a Bruker AM 250 instrument at 93.2 MHz.
Acknowledgements S. Ali is grateful to the Quaid-i-Azam University for ®nancial support as URF. The pharmaceutical companies Wilson, Ferozsons Laboratories, and Upjohn are highly acknowledged for providing the pure drugs. Thanks are due to Prof. Dr. B. Wrackmeyer, University of Bayreuth, Germany, for providing facilities to record the spectra.
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