Organoantimony(III/V) as Prospective
Antileishmanial and Anticancer Drugs: Synthesis and Characterization
Islamabad
A dissertation submitted to the Department of Chemistry, Quaid-i-Azam
University, Islamabad, in partial fulfilment of the requirements for the degree
of
Doctor of Philosophy
In
Inorganic/Analytical Chemistry
By
Rabia Mushtaq Department of Chemistry
Quaid-i-Azam University Islamabad
2018
CONTENTS
Acknowledgements III
Abstract V
Chapter -1 Introduction 1-27
1.1 Organometallics 2
1.2 Antimony(V) Complexes 3
1.2.1 Pentavalent Antimonials With Oxygen Donor Ligands 5
1.2.2 Pentavalent Antimonials With Carbohydrates as Ligands 7
1.2.3 Pentavalent Antimonials With Nucleosides as Ligands 7
1.2.4 Pentavalent Antimonials With Porphyrins as Ligands 8
1.2.5 Pentavalent Antimonials With Dioxygen as Bridging Ligands 8
1.3 Antimonials As Drugs: Merits and Demerits 9
1.4 Biological applications of antimony (V) complexes 11
1.5 Some Important Antimony Based Therapeutic drugs 11
1.6 Structure Activity Relationship 16
1.7 Aims and Objectives 17
1.8 Plan of Work 18
1.8.1 Choice of Ligands 18
1.8.2 Choice of Metal and Targets for Biological Studies 19
References 20 Chapter -2 Experimental and Characterization 28-53
2.1 Chemicals and Reagents 28
2.2 Software and Instrumentation 28
2.3 General Methodology for Synthesis 29
2.3.1 Synthesis of Organo-antimony (III) (a-g) & (V) (A-G) Precursors 29
2.3.2 Synthesis of Triphenylantimony(V) Dicarboxylates (1A-18A) 30
2.3.2.1 Synthesis and Characterization (1A-18A) 31
2.3.3 Synthesis of Tris(p-tolyl)antimony(V) dicarboxylates (1B-10B) 38
2.3.3.1 Synthesis and characterization data of (1B-10B) 38
2.3.4 Synthesis of Tris(2,5-dimethylphenyl) antimony(V) Dicarboxylates 43
(1C-20C)
2.3.4.1 Synthesis and characterization data of (1C-20C) 43
2.3.5 Synthesis of Organoantimony(V) Dicarboxylates (1D-10D), (1E-
52
10E), (1F-10F) and (1G-10G).
References 53
Chapter -3 Biological Studies 54-68
3.1 Biological Screening of Some Selected Pentavalent Antimonials 54
3.1.1 Antileishmanial Screening 54
3.1.2 Anti-promastigotes assays on (1A-9A) 56
3.1.3 Anti-promastigotes and anti-amastigotes assays on 10A-18A 57
(labelled in graphs as 1-9) and their parent acids (L1-L9)
3.1.4 Anti-promastigotes and Cytotoxicity assays on (1B-8B) and (1C- 60
20C)
3.1.5 Cell Viability Assay Cell Culture 64
3.1.6 In vitro Cytotoxicity Screenings of Pentavalent Antimonials (1C- 65
20C)
References 67
Chapter -4 Results and Discussion 69-99
4.1 Infrared Spectroscopy 69
4.2 1H and 13C NMR Spectroscopy 74
4.3 Single Crystal XRD Analysis 75
4.3.1 Crystal Structures of Bis(2-aminobenzoato)(triphenyl)antimony(V) 75
(1A) and Bis(3,5-dichlorobenzoato)(triphenyl)antimony (V) (4A)
4.3.2 Crystal Structures of Compounds (10A), (11A), (13A), (14A) and 81
(17A).CHCl3
4.3.3 Crystal Structures of Bis(4-methylbenzoato)tris(p-tolyl)antimony(V) 87
(1B), Bis(3,5-dichlorobenzoato)tris(p-tolyl)antimony(V) (3B) and
Bis(nicotinato)tris(p-tolyl)antimony(V) (5B)
References 96
List of Publications 98
ACKNOWLEDGEMENTS
All praises be to Almighty Allah, who is the most gracious, the most
compassionate and the kindest. Peace and blessing of Allah be upon the Holy
Prophet Muhammad (PBUH) and his pious progeny, who is the source of
knowledge and guidance for the entire human beings forever.
I am grateful to my supervisor and chairman, Prof. Dr. Amin Badshah,
Department of Chemistry, Quaid-i-Azam University, Islamabad, for his guidance,
invigorating encouragement and for providing all the necessary research facilities
throughout my research work.
A special word of thanks is due to my Co-supervisor Dr. Muhammad
Khawar Rauf, Director, Office of Research, Innovation and Commercialization,
Quaid-i-Azam University, Islamabad, for his help to carry out this research work
and valuable discussions received for Spectroscopic, Single Crystal X-Ray
Diffraction analysis and regarding biological studies. Without his generous help, the
timely completion of the work would have not been possible for me.
My cordial thanks and gratitude are due to my parents and My Husband Mr. M.
Tariq Bashir. It was their love and care that has brought me to this stage. Without
their encouragement, excessive generosity and patience, I would have not been able
to complete this task.
I am thankful to all of my friends Faiza, Saira, Shumaila and colleagues
at Quaid-i-Azam University, Islamabad. Special thanks are owned as well to my
laboratory fellows for the conversations we shared, both creative and hilarious. I am
also grateful to all supporting staff in the Department of Chemistry for the nice
cooperation.
Rabia Mushtaq
ABSTRACT
A variety of pentavalent antimonials have been synthesized from the triorganoantimony(V)
halides and a variety of carboxylic acids having known biological applications to better
understand the medicinal potential of the synthesized assemblies. The successful synthesis
of complexes 1A-18A, 1B-10B and 1C-20C was confirmed by melting points, elemental
analysis, FTIR, 1H & 13C NMR spectroscopy. The selected finely crystallized complexes
have also been analysized through single crystal X-ray diffraction technique. The
crystallographic analysis reveals that these complexes are mononuclear in solution as well
as in solid state. The carboxylate ligands bind to the antimony(V) atom through oxygen
atoms and occupy axial position adopting geometries between distorted trigonal
bipyramidal and square pyramidal. Main purpose objective of this study was to investigate
anti-leishmanial and cytotoxic/anticancer potential of the synthesized pentavalent
antimonials bearing carboxylic acids with a variety of pharmacophores. The activity of these
compounds was tested against Leishmanial tropica and human cell lines carcinomas A498
(renal), EVSA-T (breast), H226 (lung), IGROV (ovarian), M19 (melanoma-skin), MCF-7
(breast), WIDR (colon) and MDA-MB-231 and HeLa. Results of biological activities
including anti leishmanial and anti-cancer activity demonstrated that the compounds under
studies significantly inhibit Leishmania parasite and also showed promising anti-cancer
activity. The carboxylic acids showed no considerable results, while p-tolyl (1B-10B) and
2,5-dimethylphenyl (1C-20C) moieties bearing complexes exhibited potent activity
compared to the simple phenyl derivatives (1A-18A). The studies also reveal that these
compounds have considerable shelflife, reproducibility and stability in solution mediums as
used for testing of biological activities. Hence, it is suggested that reported pentavalent
antimonials, particularly with p-tolyl and 2,5-dimethylphenyl groups seem to be a safe,
reasonable and worthwhile option for the further investigations to hunt the lead therapeutic
agents for leishmaniasis and cancer.
c
Sayings of Holy Prophet (S.A.W.)
“The seeking of knowledge is obligatory for every
Muslim”
(Al-Tirmidhi)
1
Chapter-1
INTRODUCTION
The metal-organic compounds have been used for the treatement of various diseases
for many years. In the ancient periods of civilizations, the Egyptians used copper to
make germ-free water, gold products as medicine by Arabs, in China and the use of
silver metal as well as in its chelated forms is also in practices for the pathogenic
purification of water in the modern era. The introduction of inorganic compounds as
drugs was based on the pre- and post therapy conditions. Fromthe earliest inorganic
remedies, the inorganicsaltswere used as diuretics and iron compouds as dietary
supplements. Currently, many of the gold compounds were used as anti-bacterial,
anti-tuberculosis, as anti-arthritis and anti-rheumatoid drugs. Arsenic compound
(arsephenamine) have been used as to treat syphilis [1], Bismuth subsalicylateto treat
diahrrea in children [2] and antimony complexes for the treatment of parasiticand
protozoaldiseases [3], affecting more than 50 million persons per year. In this research
assignment, we have focused on the synthesis of pentavalent antimonials solely to
find out their potential as prospective antileishmanial drugs, and additionally for their
scope as anticancer and antidiabetes mellitus drugs. In continuation of the
introductory paragraph of this chapter, it is worth mentioning that the toxicity and the
therapeutic potential of organometallics have been well studied now a day. The
appearance of metalloenzymes in the human body is widespread and included iron in
transferrin and hemoglobin, zinc in carbonic anhydrase, molybdenum in xanthine
oxidase, copper in hepatocuprein and vanadium in hemovanadin. The use
oforganometallic drugs are very common now. Few examples take account of
merbromine and meralein as an anti-septic, silver complex of sulfadiazine for burns,
arsphenamine as antimalarial, carbarsone for parasitic ailments, and
dimercaptosuccinate antimony for the treatement of schistosomiasis [4].
2
1.1. Organometallics
The first organometallic compound was prepared by Danish chemist W. C. Zeise, in
1827 by the reaction of ethanol with a mixture of PtCl2 and PtCl4 in the presence of
KCl. This was about the time as the first successful synthesis of urea in 1828 by
Wohler and about the 40 years prior to the proposal of the Periodic Table by A. D.
Mendeleev in 1869. The compound prepared and formulated as PtCl2
(C2H4).KCl.H2O by Zeise [5]. Compound with organic groups bonded to metal
through hetero atom such as O, N and S should not be called organometallic
compound even though these compounds appear to be organometallic like metal
alkoxides, metal ß-diketones, metal thiocarbonate and thiocarbamate and amine
derivatives.
There are a lot of compounds in which carbon is bonded to another nonmetallic
carbon, oxygen, nitrogen, sulfur, halogens and hydrogen but all such type of
compounds are called organic compound are studied separately, such types of
compounds are generally very stable. This stability is due to several reason one of
them is very small electronegativity of carbon and the above elements. Compounds
in which carbon is directly bonded with metal atom are generally less stable and are
prepared under inert atmosphere at low temperature. In present, the Grinard reagents
are a very popular class of organometallics used for the derivation of other
organometallics and organic compounds.
Grignard reagentsare prepared by the reaction of alkyl halides with magnesium in
the presence of ether/THF under inert manipulations.
R and Ar are alkyl and aryl group respectively. In Grignard reagent carbon which is
attached to the magnesium atom directly, is nucleophilic in nature because the
electronegativity of carbon (2.5) is greater than magnesium (1.30) and the shared pair
3
of electron is attracted towards the carbon atom of alkyl or aryl group so this group
is capable of attacking on any electrophilic center. Grignard reagent is very reactive
compound and readily decomposed. But in ether it is stabilized as a tetrahedral
complex in two donors are solvent molecules, because ether molecules have and
unpaired electron present on oxygen atom are donated to RMgX and stabilizes it.
Where ‘S’ stands for solvent molecule. But in solution the following structures have
been proposed for Grignard reagents which are in dynamic equilibrium. Grignard
reagent was extensively used in synthetic chemistry [6].
1.2. Antimony(V) Complexes
The inorganic chemistry of antimony has been a subject of scientific interests. There
is a variety of versatile organic ligands for the preparation of metal-organic
compounds with a variety of metals and non-metals like Sn, Ge, Bi, Sb and As etc.
Organometal compounds have many advantages on the drugs purely of organic
nature in medicinal chemistry. The coordination of an organic molecule, preferably
bearing some pharmacophoric groups may change the metabolic path and helps to
the controled release and prolonged availability of the drug to the target centre i.e.,
the role of metal complexes as pro-drugs can not be over ruled. Although, there are
4
many serious objections over the toxicity of heavy metal-based drugs therapies but
the significance of metal-based medicines is undisputed as depicted by their
successful use as anti-protozoal, anti-ulcer, anti-arthritis, anti-malarial, anti-cancer
and santi-microbial drugs and for the treatment of various other diseases.
Potassium salt of antimony tartrate (I) was widely used for the treatement of
parasitic and cancerious diseases near 1900, despite of their toxic nature. Now a day,
many of the antimony complexes have been reported and known for their significant
anticancer activities [7, 8].
(I)
The use of antimonials as drugs has attracted a great attention as anti-protozoal drugs,
especially, for the treatment of leishmaniasis [9-12]. Leishmaniasis is a parasite
disease caused by sand-flies into mammals and is expressed as cutaneous and visceral
ulcerious lesions [13]. The antimony(V) drugs, Pentostam (sodium salt of
stibogluconate) (II) and Glucantine (meglumine antimonite) (III) are clinically used
as front line drugs for leishmaniasis. Recent studies revealed that antimony(V) is
transformed to antimony (III) in the biological system [14]. The exact molecular
structures pentostam and glucantine drugs are still not known.
5
(II) (III)
Keeping in view the medicinal importance of antimony compounds, here we are of
the interest to synthesis a number of antimony (V) compounds with ligands having
donor atoms like O, N, and S etc. Before proceeding to the synthesis of the
compounds of our interest, we wish to give a brief review of the research work carried
out in the recent years.
1.2.1. Pentavalent Antimonials With Oxygen Donor Ligands
The carboxylic acids are the ligands which have been extensively used for the
development of metal-organic assemblies and reported in the recent years. Among the
p-block elements, derivatives of organotin and antimony precursors with carboxylic
acidshave been studied in detail. Structural diversity revealed by these metal
carboxylates is remarkable which ranges from discrete molecules to macromolecules
[15]. Compounds having carboxylic group in their functionality may act as multi-
dentate ligands and may serve as an insertion site between metal and other auxillary
species [16].
A series of phenylacetic acids complexes with tri(phenyl)antimony(V) halides have
been synthesised by the reactions in 1:1 or 1:2 stoichiometric ratios, having distorted
squarpyramidal/trigonalbipyramidal or octahedral geometries. The pentavalent
antimonials exhibit significant activities as antimicrobial agents, fungicides, catalysts
and antioxidants [17]. The triphenylantimony (V) diiodide in moist acetonitrile give
(Ph3SbI)2O molecules with Sb-O bond lengths and Sb-O-Sb angle, 1.9410-
1.9437(6) A and 144.6(4) respectively [18]. New catecholate Sb(V) complexes
6
synthesized through oxidative addition of o-quinones inti tri(phenyl)antimony(V)
precursours have also been reported[19, 20].
A series of oxo-bridged antimonials like bis(triphenyl/methylantimony)oxo4-
acylpyrazol-5-ones have been reported. The fluoromethylbenzoate ligands containing
pentavalent antimonials have been synthesized by treating with
tris(phenyl)antimony(V) dihalide in 1:1 or 1:2 stoichiometries stabilized by
intermolecular interactions have also been documented in the recent years [21, 22].
Pd(PPh3)4 catalyzed base-free Suzuki-coupling reactions between triphenylantimony
(V)carboxylates and phenylboronic acids to produce biaryl derivatives are reported in
literature[23].
Tri- and tetraphenylantimony (V) derivatives containing carboxylate ligands
have been reported with coordination environment (ArCOO)2SbPh3 or
(ArCOO)SbPh4. Triorganoantimony(V) complex has been synthesized by reacting
Ph3SbCl2 with acetylferroceneoxime in 1:2 ratio [24-26].
Bis(triorganosiloxy)triphenylantimony complexes, oxobridged species like
[SbPh3X]2O and [SbMe3X]2O with alkali metal salts of carboxylic acids to lead
[R3Sb(OOCR)]2O and R3Sb(OOCR)2 derivatives, arylantimony(V)
tris(phenyl)germanylpropionates with the formula (Ph3GeCHR1CHR2CO2)nSbAr(5-n)
(R1=H, Ph, R2=H, CH3, n-1, 2), derivatives of demethylcantharimide with anticancer
activities have been reported [27-31]. The silver salts [AgO2CC(OH)R1R2] of
αhydroxy carboxylic acid react with SbPh3Cl2 to produce cyclometalled
complexes.The salts of N-heterocylic carboxylic acidsreact with Ph3/Me3SbBr2 to
gave compounds of the type [R3Sb(O2C–Ar)2] [32-33].
The triphenylantimony complexes of the type [(C8H4F3O2)2Sb(ph)3], found to
be in trigonal-bipyramidal geometries and the crystalshave been stabilized by the 3D
network stabilized by C-H...O H-bonds. Also some oxo-bridged binuclear
tri(phenyl)antimony(V) complexes with formulae [Sb2(C6H5)6(C6H3CINO2)2O], has
7
been reported with each antimony centerbearing five coordianted environment
resulting trigonal-bipyramidal geometry[34-39].
1.2.2. Pentavalent Antimonials With Carbohydrates as Ligands
Antimony(V) complex with a polysaccharide, named mannan, is widely used for
leishmaniasis therapy/treatment. Proposed mechanism describes the formation of
water soluble antimony-carbohydrate complex in the cells in which less toxic
antimony(V) serve as pro-drug which later converted into hazardous lower oxidation
state antimony ions in the cells. Activity of the drug may be enhanced due to
sulfhydryl-antimony exchange within the cell [40-42]. Antimony is transported to
macrophages only by interacting with carbohydrates and forming stable complex.
These macrophages are the site for division of leishmania parasite [43].
1.2.3. Pentavalent Antimonials With Nucleosides as Ligands
Researchers have explained that complex formation occurs between antimony(V) and
adenine ribonucleoside [44]. First investigation about formation of biologically active
and physically stable complex of biomolecules (ribonucleoside) hasstated that these
complexes of antimony(V)-adenine ribonucleoside can be formed in two ratios i.e. 1:1
or 1:2 [44,45]. 1H-NMR data showed that antimony(V) is attached to the
ribonucleoside through –OH functionality and ring formation occurs due to bonding
with –OH group of C2 and C3 of ligand ribose. It is proved that “antimony(V)adenine
ribonucleoside complex” is formed at greater rate in those biological system which
have acidic environment [46]. At pH=7 “antimony(V)-nucleoside complexes” show
one of the remarkable property i.e. very low dissociation rate [46a]. For example
dissociation rate for “antimony(V) guanidine monophosphate” is recorded as 1:1[46a]
and it remained as such in higher vertebrates like humans and other animals which
means, antimony is not stored in vertebrate’s body organs [47]. Two hypotheses are
given to explain the mechanism of “antimony (V)-ribonucleoside complexation [46a].
According to first hypothesis, these complexes inhibit the purine carriers of leishmania
8
parasite. Other one stated that like allopurinol i.e. a purine analog, “antimony (V)-
purine complex” impregnate within the parasitic cell and then degradation of purine
bases occur at pH=7.0 of the cell. It has been reported that the elimination of
nucleotides like GTP and ATP is accompanied by formation of these compounds [48].
1.2.4. Porphyrins containing Pentavalent Antimonials
Porphyrin exhibiting conjugates have high absorbance in visible region have been
broadly used as chemical and biological active functionalities [49]. Porphyrin based
compounds have property of a variety of catalytic processes via electron/energy
transfer by irradiating visible-light. Now a day, bio-active porphyrins have gained
interest in connection of photo inactivation [50] and photodynamic therapy (PDT)
[51]. Generally, the porphyrin complexes have tendency to form face-to-face clusters
which have low solubility even in the organic solvents. For the biological applications.
of porphyrins, water solubility is an important property in handling the porphyrins in
aqueous solution. Typically, water solubilization of metalloporphyrins is achieved by
the variation of porphyrin ring by an ionic group such as ammonium [52], pyridinium
[53], sulfonate [53e, 54], phosphonium [53a, 55]or amino carboxylate [53a]. But the
synthesis of these complexes is not an easy task. Recently water-solubilization of Sb-
porphyrins has been done by varying the axial ligands [56]. Tetraphenylporphyrin
(H2tpp) is a typical and commercially available porphyrin and can easily coordinateto
the antimony. Antimony porphyrins are able to connect covalently with axial ligands
through oxygen and nitrogen atoms, resulting in the highly stabilized complexes.
Therefore, the axial ligand ofSbporphyrins can appropriately provide a variety of
water-soluble porphyrins with bioactivity and bio affinity as well as high electron
accepting ability.
1.2.5. Pentavalent Antimonials With Dioxygen as Bridging Ligands
Dioxygen, a strong oxidizing agent, has many applications in biological systems. It is
usually inert and activated only after coordinating with metal center [57]. Several
types of biomolecules can interact with O2. For example, enzymes of biological
9
systems i.e. dioxygen enzymes necessary for cell reaction, require oxygen and many
other species act as oxygen storage and carriers. In some biological systems redox
reactions are catalyzed by coordination of metalloproteins with O2. These
metalloproteins activate the O2 and help in completion of cell reactions. There is need
to replace natural O2 with its synthetic form to enhance the rate of redox reactions in
biological systems. Researchers are in the quest of finding new, easy and ideal
biological systems for production of dioxygen.
There are a large number of metal complexes to which reversible binding of
O2 takes place [58]. Though, it is a unique process and requires special conditions for
recognition of this bonding mode. The conditions required to inhibit irreversible
oxidation of O2 species are: steric hindrance in metal complexes, low temperature and
immobilization [59]. Though, researchers are trying to find out replacement of O2 as
carriers and transporters but, dioxygen is still ranked first in the biological perspective.
Mechanism of “dioxygen and transition-metal complexes” involves the transfer of
electrons from the attached transition metal to the attached ligand antibonding p-
orbitals i.e. O2. It is investigated that O2-active species can be synthesized by using
antimony in complexation reaction with O2 instead of using any other transition-metal.
1.3. Antimonials As Drugs: Merits and Demerits
The therapeutic history of antimony based compounds/drugs is dates back to medieval
ages since Paracelsus (1493-1541) used antimony powder and its compounds for the
treatment of common diseases of the time. Later on this therapy was rejected by
medical practitioners due to toxic effects. In parallel, the efforts for the development
of safer antimony based drugs with minimum residual effects of antimony (III) were
made rapidly. Treatment of leishmaniasis with pentavalent antimony complexes has
been started since 1940s. These are the first line drugs to treat all types of
leishmaniasis. Antimony (III) / (V) compounds have also been known for their
potential biological activity against some microbial and parasitic infections [60-
65].Organoantimony (III) / (V) complex have alsoshown anti-tumor activities. These
10
compounds may be exploited for development of new drugs in order to treat different
types of tumor [60, 64, 66].Recent studies have revealed that like other organo
transition metal complexes, organoantimony (III) / (V) compounds have also known
for anticancer activities [60, 61, 66].Many Organoantimony (III) / (V) compounds
showed anti-bacterial activity against different bacterial strains[6766].Several reports
indicated the antifungal activity of antimony compounds against plants and animal
pathogenic fungi[70-72]. However, very few literature references have been found in
this regard so far [71]. Organoantimony (III) / (V) compounds are also known for their
anti feedant activities [65, 73].
Despite these applications, there are several limitations in clinical use of
pentavalent antimonials in therapy of leishmaniasis [74, 75]. Very careful medical
supervision is required for this therapy as administration of these compounds is only
done by intramuscular injections on daily basis, for at least three weeks. It often results
in local pain and certain side effects which typically include abdominal colic,
vomiting, diarrhea, nausea, skin rashes, weakness, myalgia, hepatotoxicity, along with
cardiotoxicity. Another main issue to cure this disease is the appearance of resistance
against drugs [76]. The reason behind that is improper use and incomplete treatment.
It has been observed that only few (26%) patients were given treatment as stated by
prescription. These mishandling of anti- leishmanial drugs in Bihar state of India was
a major cause of the drug resistance. “Pentamidine” and “amphotericin B” are the
drugs used in place of that described above. These are also limited due to parenteral
administration and by severe side effects. However, besides all the above mentioned
issues, antimonial drugs are still first choice for the medical practitioners worldwide.
So, there is need to develop new series of effective compounds similar to sodium
stibogluconate (SSG) and meglumine antimoniate with well-established physical and
structural chemistry [77-80].
11
1.4. Biological applications of Antimony (V) complexes
The uses of metal complexes (inorganic compounds) in medicines have been started
many centuries ago. Many metals and their complexes have significant medicinal
applications like Pt and Pd (anti-tumor agents), As (bactericides), Sb (anti protozoal),
Au (Arthritis, gout), Bi (skin injuries, diarrhea, alimentary diseases), Ag ( anti-septic
agent, Ga (antitumor agent), Co (vitamin B12), Li (manic depression),
Cu (algicide, fungicide, insecticide), Mn (anti-fungal, Parkinson’s disease), Ru, Rh
and Os (experimental antitumor agents), Os (anti-arthritis), Hg (anti-septic), Rb (an
alternative to potassium in muscular dystrophy, protects from side effects of heart
drugs), Zn (fungicide) and Sn (anti-microbial agents) [81].
Antimony has been used for several centuries for therapeutic purposes. During
ancient Egypt, antimony was used to treat fever and skin irritations. Antimony
compounds have well known anti-parasitic effects. The mode of action and
biochemistry of antimony compounds is not clear. It is believed that the proteins and
enzymes are major targets for antimony [82].
1.5. Some Important Antimony Based Therapeutic drugs
The use of antimony in medicinal treatment has been started since sixteenth century
owing to emetic effect. Antimony compounds have also found their role in medication
of ulcers. Wine slowly develops emetic properties when it is allowed to stand in
antimony goblets, due to formation of tartar emetic by interaction of tartaric acid with
antimony [83]. After sixteenth century, the crude antimony drugs were abandoned due
to toxicity issues. However in the early twentieth century, the use of antimony in
medicine regained importance on basis of its antiparasitic impact against
trypanosomiasis.
12
Anti-leishmanial Agents
Leishmania are the parasitic protozoan from the family Trypanosomatidae.
Leishmaniasis is transmitted through sandflies vector from Phlebotomus genus
initially and later on also from Lutzomyia. Different types of Leishmaniasis are
appeared as cutaneous which involve lesions, mucocutaneous and visceral damaging
the vital organs [84-86]. The Leishmania parasite has two stages, one is promastigote
(sandfly stage) and other is amastigote (mammalian stage). It reproduces in the
intestine of the sand fly and becomes infective in 1-3 weeks. The parasite is passed on
when the sandfly bites its next vertebrate victim. Sandflies turns to be more active
from dusk to dawn. About 20 species of Leishmania causes disease in humans, while
30 sandfly species act as vectors. Leishmania parasite has two modes of transmission:
(1) which involve transfer of parasite from animals to human is termed as zoonotic (2)
anthroponotic in which vector transmitted from human to other animals. However it
is mainly a zoonotic disease [87, 88].
Fig 1.1. Life Cycle of Leishmania Parasite [Center for Disease Control (US)] Leishmania is
a tropical parasitic disease, which is widespread in 98 countries, mainly among people of
under developed countries; about 1.5 million new cases per year with 90% of cases have
13
been reported from Bangladesh, Nepal, India, Ethiopia, Brazil and Sudan. 12 million people
around the world are affected by leishmaniasis, with approximately 70,000 deaths every
year. According to the WHO reports, Leishmaniasis is the 6th largest in the epidemic
diseases in the 3rd world. [89-91].
The potassium antimony (III) tartrate [tartar emetic] was the first antimonial
compound used against leishmaniasis in 1913. This compound was very poisonous,
as it contains antimony (III), a proven toxic form of antimony. In 1940s, antimony
(III) complexes were out classed by the more effective and safe antimony (V)
compounds, sodium stibogluconate and meglumine antimoniate marketed as
Pentostam and Glucantime, repectively. They are 10 times less harmful to vertebrates
than antimony (III) salts [92].
Mode of Action
As mentioned in the previous sections, the mode of action of antimony (V) compounds
in the treatment of leishmaniasis is not well understood. It is not obvious that which
form of antimony (III) or (V) is playing role in activity of such drugs. Previous studies
portray that Sb (V) act as a prodrug; it is supposed that reduction of pentavalent
antimony occurs into more active trivalent antimony. In vivo reduction of part of Sb
(V) into (III) is the evidence of this model [72]. Different thiols are involved in this
reduction. These include: Glutathione (GSH), a principal thiol in the cell cytosol of
mammals, trypanothione [T(SH)2], an essential thiol within leishmania parasite and
the lysosomes contains primary thiols cysteinyl-glycine (Cys-Gly) and cysteine (Cys)
[93-100]. The reduction is favoured at low pH and higher temperature. Within
leishmania parasite, reduction of Sb (V) occurs by T(SH)2, while in the acidic
environment of mammalian cells Sb (V) reduces by Cys or Cys-Gly. Reduction take
place favourably in amastigotes [95], having higher temperature and lower
intracellular pH.Furthermore it is proposed that Sb(V) undergoes reduction to Sb(III)
due to contribution of enzymes, thiol-dependent reductase or antimoniate
reductase[101,102].
14
It is supposed that mechanism of action may include the interaction of Sb(III)
with zinc-finger protein or trypanothione reductase (TR). The trypanothione causes
the reduction of T(SH)2 and protection of trypanosomatids from heavy metal toxicity
and oxidative stress. Antimony (III) complexes have been reported to inhibit
trypanothione reductase, causing interference with metabolism of trypanothione and
hence pumping out trypanothione and Glutathione from cells of parasite. Another
study reported that Sb(III) has the ability to eject the Zn(II) and involved in binding to
a CCHC zinc finger peptide mode. In zinc finger domain, a number of amino acid
residues, usually histidines and cysteines are coordinated to the zinc atom. This
framework is associated with interaction of protein-protein and protein with nucleic
acid as well as other variety of functions, such as recognition of DNA, packaging of
RNA, transcriptional activation, folding of protein, lipid binding, cell differentiation,
growth and regulation of apoptosis [103, 104]
On the other hand, direct involvement of Sb (V) in mechanism of action is
suggested due to the capability of the antimony drugs to interfere with the nucleoside
metabolism [105] and to inhibit a leishmania topoisomerase [106, 107]. It has been
reported that sodium stibogluconate inhibited type-I DNA topoisomerase from
Leishmania donovani [110, 111].These studies and the fact that nucleosides and
polynucleotides contains a large number of nitrogen and oxygen donor sites for metal
ions suggest that nucleosides might be a target for pentavalent antimonials.
As antimony has high affinity for sulphur and nitrogen containing ligands so,
mechanism of leishmanial inhibition is most likely due to coordination with molecules
containing -SH group, which includes proteins, peptides, enzymes and thiols.
Antimony (V) has also been reported to form complex with adenine ribonucleoside.
The effectiveness and 10 times less toxicity of the pentavalent antimony complexes
have make them the first choice for the therapy of leishmaniasis [108-112]. So far two
models have been suggested for the probable mode of action of antimonial drugs
against leishmaniasis are as follows [110].
15
Antiviral Agents
Hepatitis-C virus is among the most lethal viruses and is found in blood. Sodium
stibogluconate has been reported to suppress replication of HCV in a section of human
liver which was freshly taken from patient infected with HCV [111]. Later on this
impact of the drug was confirmed against cell line and was found to be suitable for
HCV infection.
Sodium Stibogluconate [Pentostam]
16
Anti-HIV Agents
In the treatment of AIDS, antimoniotungstate (HPA-23) with formula of
[(NH4)17Na(NaSb9W21O86).14H2O] has beenfound to be very effective.This
compound reduces HIV levels and inhibit several DNA and RNA viruses. After this
investigation, the survey for other polyoxometalates as an active anti-HIV agents has
been started [112].
Anticancer Agents
Antimony compounds also showed anti-cancer activities. In vitro cytotoxicity of
potassium antimony tartrate against lung cancer has been evaluated, having IC50 value
of 4.2-322 μg/ml. This complex was proved to be active as clinically available drugs
for the treatment of cancer e.g. doxorubicin and cisplatin [113]. Antimony has also
showed remarkable therapeutic behavior in patients suffering from acute
promyelocytic leukemia [114]. Sodium stibogluconate exhibited substantial
anticancer activity as well [115, 116] and appeared to inhibit tumors better than
suramin, a compound having its well-known anti-neoplastic activity [115].
Potassium Antimony Tartrate
1.6. STRUCTURE ACTIVITY RELATIONSHIP
The activity of organoantimony complexes is essentially dependent upon the nature
and number of alkyl/aryl moieties (R) attached with metal center. Anionic groups
17
(X) attached to the metal center have small influence on biological potential of
organoantimony compounds and are not as much important as that of cationic groups
[116].
Bioactivity potential of organoantimony derivatives is dependent on geometry
of the complex and number and nature of the alkyl/aryl groups. Trivalent complexes
are more active than their organotincongerers. However, there is not any
otheranticancer drug which is as widely used as cisplatin. Antimony(III) adopts a
geometry of distorted pseudo-trigonalbipyramidal and also hasa lone pair atequatorial
position. The preliminary results have shown that the coordination of antimony(III)
by the ligands such as polydentate carboxylic acid results in the compounds with
greater biological activity than displayed by the non-coordinated ligands [117].
The pentavalent complexes are normally trigonal bipyramidal but sometimes
adopt simple octahedral geometry. They are 10 times less poisonous and more
effective than antimony(III) equivalents. These pentavalent antimonials became first-
line therapeutic drugs for leishmaniasis therapies [118]. If carbohydrates are attached
ligands to antimony center then solubility of the drug is enhanced which leads to the
transfer of antimony to macrophages and finally metabolic conversion of less toxic
antimony (V) to highly active antimony (III) and this reduction takes place in the
parasitic cell. Structural comparison of the active and inactive compounds suggested
that the availability of coordination position at the metal center and the stability of
alkyl/aryl-metal bondsenhance the bioactivity.
1.7. AIMS AND OBJECTIVES
Antimony (V) complexes have gained a distinctive position among the current
antileishmanial drugs. It is necessary to find out new drugs having better
leishmanicidal properties than previously known organoantimony drugs which have
become resistant to the disease and parasite. In order to achieve these objectives, more
focus should be on the interdisciplinary research work involving synthesis of new
compounds along with diagnosis of biological properties, for better perception of this
research work. This project has been designed for thesynthesis, biological assessment
18
and characterization of organoantimony (V) complexes over here in Pakistan by using
existing research facilities.This research work is primarily based on applied chemistry
and biology. Financial and scholastic obligations were trailed firmly.
1.8. PLAN OF WORK
Synthesis of different types of commercially available oxygen donor ligands
(derivatives of cinnamic acid) and organoantimony (V) complexes will be done.
Synthesized cinnamic acid derivatives i.e. oxygen donor ligands will be reacted with
pentavalent organoantimony halides to assemble tris(organo)antimony (V)
carboxylates. Different stoichiometric amounts and solvents like THF, diethyl-ether
and toluene were tested to ensure the maximum Final yield. Principally, synthesized
organoantimony (V) complexes would be tested for leishmanicidal properties. Then,
other biological activities of these compounds will also be performed such as
anticancer, alpha amylase and antibacterial activities.
1.8.1. Choice of Ligands
Cinnamic acid and its derivatives (oxygen donor ligands) are naturally occurring
materials. These cinnamic acid derivatives have a common functionality i.e. “3phenyl
acrylic acid”. There are three attachment sites present i.e. phenyl ring, carboxylic
group, andα, β-unsaturated carbon atoms. Addition reactions occur at carboxylic
group whilephenyl ring and α, β-unsaturated carbon atoms are involved in substitution
reactions. These properties of cinnamic acid and its derivatives gained much
consideration in medicinal field for the synthesis of anti-cancer drugs. Before 1905,
these medicinal applications and anti-cancer potential of cinnamic acid and their
derivatives was not reported. More attention has been given to these compounds in
the last twenty years to find out their anti-cancer ability and other potential biological
properties. We have synthesized different antimony(V) complexes [R3Sb(OOCR')2],
with R=phenyl and p-tolyl and R'=derivatives of cinnamic acids and also investigated
their various biological applications.
19
1.8.2. Choice of Metal and Targets for Biological Studies
First introduction of antimony in medical science was reported in ancient Egyptians
age. It gained huge importance because of its emetic properties. During the ancient
Egyptians age, skin diseases and different types of fevers were treated by using
antimony [119]. In past, various types of ulcers were treated with antimony containing
compounds. But, in the modern world researchers are interested in antiparasitic
properties of antimony against trypanosome infection i.e. leishmaniasis which were
reported in 1930’s after the discovery of urea stibamine (an antimony containing
compound). Antimony based drugs have a modest role in the prevailing anti-
leishmanial therapies. On the basis of biological potential of antimony it is emphasized
to synthesize new antimony based compounds and investigate their leishmanicidal as
well as other biological properties.
20
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113. Yi, T., Pathak, M. K., Lindner, D. J., Ketterer, M. E., Farver, C., Borden, E.C.,
The Journal of immunology, 2002, 169, 5978-5985.
114. Yeh, C.-T., Hwang, D.-R., Lai, H.-Y., Hsu, J. T., Biochemical and biophysical
research communications 2003, 310, 537-541.
115. Goodwin, L., Transactions of the Royal Society of Tropical Medicine and Hygiene
1995, 89, 339-341.
116. Hu, et. Al., Main Group Metal Chemistry. 1997, 20 (3), 169-180.
117. Venugopal, B., Luckey, T. D., Metal Toxicity in Mammals. Volume 2. “Chemical
toxicity of metals and metalloids”. Plenum Press.1978.
118. Solomon, E. I., Brunold, T. C., Davis, M. I., Kemsley, J. N., Lee, S.-K., Lehnert,
N., Neese, F., Skulan, A. J., Yang, Y.-S., Zhou, J., Chemical Reviews.2000, 100
(1), 235-350.
119. Harrison, P. M., Hoare, R. J., Metals in Biochemistry. Springer: 1980.
28
Chapter-2
EXPERIMENTAL & CHARACTERIZATION
2.1. Chemicals and Reagents
The carboxylic acids as mentioned with the relevant synthesized complexes for the
stoichiometric calculations and Bromobenzene, 4-Bromotoluene,
2,5dimethylbromobenzene, 2-chlorobenzene, 4-chlorobenzene, 2-fluorobenzene,
4fluororobenzene, 2-trifluororomethylbenzene and magnesium turnings were
purchased from well reputed vendors and used as obtained. All solvents and reagents
were purchased from daejung S. Korea. The deutrated solvents used for multinuclear
NMR studies were purchased from Sigma-Aldrich. The solvents were distilled and
dried where deemed necessary, and stored under saturated environment of nitrogen
[1, 2].
2.2. Software and Instrumentation
The rough melting points of the synthesized compounds were determined in capillary
tubes as sample holders on MPD Mitamura apparatus, Riken Kogyo, Japan. Reported
values were used as a tool to differentiate between the starting materials and final
products.
Bruker Avance 300 MHz spectrometer was used for NMR (1H & 13C) studies
using distilled deuterated solvents. Tetramethylsilane (TMS) were used as reference
standard for chemical shift scaling at 300 and 75.5 MHz for 1H and 13C NMR
measurements, respectively. The abbreviations used for representation of the splitting
of proton resonances in 1H NMR spectra are defined as s = singlet, d = doublet and m
= multiplet pattern.
Perkin-Elmer-2000 Infrared spectrometer was used for recording of all the
FTIR spectra at 250-4000cm-1. The CHNS analysis was conducted by using LECO183
elemental analyzer.
29
Single crystal XRD analysis were carried out by using diffractometers like Rigaku
AFC7R with Mercury CCD, Bruker SMART-CCD area-detector with graphite
monochromatic (MoKα) radiation source (λ = 0.71073Å). The structures were solved
by direct methods like Sir 97 [3], and refined with Shelxl 97 [4].
2.3. General Methodology for Synthesis
2.3.1. Preparation of Organo-antimony (III) (a-f) & (V) (A-G) Precursors
To a three necks reaction flask, 0.12mol of magnesium chips/ turnings was stirred in
100 ml ether with few crystals of iodine as an activator under inert conditions. The
temperature of reaction flask was maintained at 0 to -5 °C by using a cooling mixture
and afterwards 0.12 mol of the respective aryl halide was added slowly. After attaining
the exothermic conditions and cooling, a solution of 0.02 mol of SbCl3 in ether was
added drop wise with continuos stirring for one hours. After two hours stirring, the
ether was removed under reduced pressure and triarylantimony was isolated by
solvent extraction technique by using CH2Cl2/CHCl3 and then washed the organic
layer with 1M HCl and separated the organic layer and separated the product by
removing the solvent. Dissolved the impure triarylantimony(III) in ether and treated
with liquid bromine (Scheme 1). Removed the solvent to get product and dissolved
the dibromotriaryl antimony(V) in a minimum volume of dichloromethane and kept
under slow evaporation for for the isolation of product[5-9].
Ether
Mg + RX RMgX
3RMgX + M(III)X'3 M(III)R3 + 3MgXX'
(a-g) Ether
M(III)R3 + Br2 R3M(III)Br2
(a-g) (A-G)
Where
R= -C6H5 (a, A), p-CH3C6H4 (b, B), 2,5-(CH3)2C6H3(c, C), p-ClC6H4 (d, D), o-
CF3C6H4(e, E), p-FC6H4 (f, F), o-ClC6H4 (g, G) M= Sb X= Halogens
Scheme 1. Synthesis of Organo-antimony (III) (a-g) & Organo-antimony (V) (A-G)
Precursors.
E t h e r
30
2.3.2. Synthesis of Triphenylantimony(V) Dicarboxylates (1A-18A)
The sodium/potassium salt of the carboxylic acid (0.01mol) and organo-antimony (V)
(0.005mol) were added in 75 ml of toluene, and stirred for 10 h. The sodium/potassium
salt and solvent was removed by filtering it under low pressure. The residue obtained
was dissolved in dichloromethane and kept under slow evaporation in semi sealed
bottles for crystallization. Toluene was distilled over sodiumbenzophenone ketyl and
used fresh when required.
Scheme 2. Synthesis of tri(phenyl)antimony(V) dicarboxylates (1A-18A)
31
2.3.2.1. Synthesis and Characterization (1A-18A)
Bis(2-aminobenzoato)(triphenyl)antimony(V) (1A)
The stoichiometric quantities was 1.59g (0.01 mol) potassium salt of o-aminobenzoic
acid and 2.51g (0.005 mol) tris(phenyl)antimony(V) dibromide precursor. Colourless
solid, Final yield 83%, m.p.211-212 ˚C, FTIR(cm-1) 3094 (C-Haromatic ), 3455, 3345
(C-NH2), 1663 (C=O), 1253 (C-O), 562 (Sb-C), 463 (Sb-O), 1HNMR (CDCl3) δ 5.61
(sbroad, 4H,-NH2), 6.58 (d, 2Hf, J=8.1 Hz), 6.64 (t,dds appeared as t, 2Hd, 3J=7.2 Hz),
7.22 (td,dds appeared as td, 2He, 3J=8.4Hz, 4J=1.5Hz), 7.49-7.55 (m, 9Hb, b´, j), 7.94
(dd, 4Hc, 3J= 7.8Hz, 4J=1.5Hz), 8.13 (dd, 6Ha,a´, 3J=7.2Hz, 4J=2.1Hz), 13C MR
(CDCl3) δ 113.2 (2C, C-C=O), 115.9 (2Cf), 116.4 (2Cd), 129.4 (6Cb, b´), 130.9
(3Cj),132.3 (2Cc), 133.4 (2Ce), 133.7 (6Ca, a´), 139.2(3C, ipso-C), 150.4(2C, C-NH2),
172.5 (2C, carbonyl), Anal. calcd. C32H27N2O4Sb: C, 61.46, H, 4.35, N, 4.48 Found:
C, 61.40, H, 4.33, N, 4.51.
Bis(4-methylbenzoato)(triphenyl)antimony(V) (2A)
Stoichiometric amounts were calculated as for 1A. Colourless solid, Final yield 86%,
m.p.233-235˚C, FTIR(cm-1) 3054 (C-Haromatic), 2920 (C-Haliphatic), 1611 (C=O), 1265
(C-O), 550 (Sb-C), 457 (Sb-O), 1HNMR (CDCl3) δ 2.39 (s, 6H, -CH3), 7.18 (d,
4Hd,d´,3J=7.8Hz), 7.49-7.54 (m, 9Hb, b´, j), 7.88 (d, 4Hc, c´,3J= 8.1Hz), 8.16 (dd, 6Ha,
a´,3J=7.5Hz, 4J=2.1Hz), 13CNMR (CDCl3) δ 21.6 (2C, -CH3), 128.8 (4Cd, d´), 129.4
(6Cb, b´), 129.9(2C, C-C=O), 130.0(4Cc, c´), 131.1(3Cj), 133.9(6Ca, a´), 138.6(3C,
ipsoC), 142.7(2C, CH3-), 170.4 (2C, carbonyl), Anal. calcd. for C34H29O4Sb: C,
65.51, H, 4.69 Found: C, 65.46, H, 4.65.
Bis[2-(phenylamino)benzoato](triphenyl)antimony(V)(3A)
Stoichiometric amounts were calculated as for 2A. Colourless solid, Final yield 85%,
m.p.155-156 ˚C, FTIR(cm-1) 3265 (-NH),3026 (C-Haromatic), 1629 (C=O), 1260 (CO),
564 (Sb-C), 448 (Sb-O), 1HNMR (CDCl3) δ 6.74 (td, 2He,3J=7.2Hz, 4J=1.8Hz), 7.07
(t, dds appeared as t,2Hh,3J=7.2Hz), 7.16-7.18 (m, 4Hg, f), 7.23-7.35 (m, 8Hc, c´, d, d´),
7.51-7.54 (m, 9Hb, b´, j), 8.04 (d, 2Hi, 3J=8.1Hz), 8.16 (dd, 6Ha, a´,3J= 7.2Hz, 4J=2.4Hz)
9.54 (s, 2H, -NH-), 13CNMR (CDCl3) δ 113.7 (2C, carbonyl), 114.7 (4Cc, c´), 116.8
32
(2Cg), 122.2 (6Cb, b´), 122.9 (2Ce), 129.2 (4Cd, d´), 129.6 (6Ca, a´), 131.3 (2Ci), 132.7
(2Cf), 133.4 2(Ch), 133.8 (3Cj),138.5 (2C, ipso-C), 141.2 (2C, C6H4-NHC), 147.5
(3C,C-NH-C6H6), 172.3 (2C, carbonyl), Anal. calcd. for C44H35N2O4Sb: C,
67.97, H, 4.54, N, 3.60 Found: C, 67.95, H, 4.49, N, 3.64. Bis(3,
5-dichlorobenzoato)(triphenyl)antimony(V)(4A)
Stoichiometric amounts were calculated as for 3A. Colourless solid, Final yield 84%,
m.p.145-146 ˚C, FTIR (Powder, cm-1) 3068 (C-Haromatic), 1647 (C=O), 1258 (C-O),
740 (C-Cl), 579 (Sb-C), 444 (Sb-O), 1HNMR (CDCl3) δ7.44 (st, 3He,4J=2.1Hz), 7.56-
7.59 (m, 9Hb, b´, j), 7.80 (sd, 4Hc, c´,4J=2.1Hz), 8.12 (dd, 6Ha, a´,3J= 7.2Hz,
4J=2.4Hz), 13CNMR (CDCl3) δ 128.3 (4Cc, c´), 129.7 (6Cb, b´), 131.6 (3Cj), 131.8 (2C,
C-C=O), 133.7 (6Ca, a´), 134.8 (4C, C-Cl), 135.5 (2Ce), 136.9 (3C, ipso-C), 167.5 (2C,
carbonyl), Anal. calcd. for C32H21Cl4O4Sb: C, 52.43, H, 2.89, Found: C, 52.40, H,
2.85.
Bis(propanoato)(triphenyl)antimony(V)(5A)
Stoichiometric amounts were calculated as for 4A. Colourless solid, Final yield 85%,
m.p.121-123 ˚C, FTIR(cm-1) 3057 (C-Haromatic), 2974-2937 (C-Haliphatic), 1647 (C=O),
1278 (C-O), 555 (Sb-C), 458 (Sb-O), 1HNMR (CDCl3) δ 0.93 (t, 6Hb, CH3b-CH2
a-,
3J=7.5Hz), 2.13 (q, 4Ha, CH3b-CH2
a-,3J=7.5Hz), 7.48-7.52 (m, 9Hb, b´, j), 8.03
(dd,6Ha, a´,3J=6.0Hz, 4J=2.7Hz), 13CNMR (CDCl3) δ 9.7 (2C, -CH3), 28.9 (2C, -CH2),
129.1 (6Ca, a´), 130.8 (3Cj), 133.8 (6Cb, b´), 139.0 (3C, ipso-C), 178.8 (2C, carbonyl),
Anal. calcd. for C24H25O4Sb: C, 57.74, H, 5.05, Found: C, 57.70, H, 5.01.
Bis(nicotinato)(triphenyl)antimony(V) (6A)
Stoichiometric amounts were calculated as for 5A. Colourless solid, Final yield 82%,
m.p.180-182 ˚C, FTIR(cm-1) 3054 (C-Haromatic),1654 (C=O),1587(C-N), 1269 (C-O),
562 (Sb-C),447 (Sb-O), 1HNMR (CDCl3) δ 7.28-7.32 (m, 2He), 7.50-7.56 (m, 9Hb, b´,
j), 8.12-8.18 (m,8Ha, a´, d), 8.68 (dd, 2Hf,3J=4.8Hz, 4J=1.5 Hz), 9.15 (sd, 2Hc,4J=1.5
Hz), 13CNMR (CDCl3) δ 123.1(2Ce), 128.3 (2C, C-C=O), 129.7 (6Cb, b´), 131.6 (4Cj),
33
133.8 (6Ca, a´), 136.9 (3C, ipso-C),137.4 (2Cd), 151.2 (2Cc), 152.4 (2Cf), 168.3 (2C,
carbonyl), Anal. calcd. for C30H23N2O4Sb: C, 60.33, H, 3.88, N, 4.69, Found: C,
60.29, H, 3.85, N, 4.72.
Bis(2-methoxyphenylacetato)(triphenyl)antimony(V) (7A)
Stoichiometric amounts were calculated as for 6A. Colourless solid, Final yield
85%, m.p.168-170 ˚C, FTIR(cm-1) 3018(C-Haromatic), 2926 (C-Haliphatic), 1657 (C=O),
1259 (C-O), 582 (Sb-C), 484 (Sb-O), 1HNMR (CDCl3) δ 3.39(s, 4H, -CH2-), 3.88 (s,
6H, -OCH3), 6.75 (d, 2Hf, 3J=8.1 Hz), 6.84 (t, 2Hd, 3J=7.2 Hz), 7.24 (td, dds appeared
as td, 2He,3J=7.2Hz, 4J=1.5Hz), 7.42-7.52 (m, 9Hb, b´, j), 7.91 (d, 4Hc,3J=7.8 Hz), 8.11
(dd,6Ha, a´, 3J=8.1Hz, 4J=1.2Hz), 13CNMR (CDCl3) δ 45.0 (2C, -CH2-), 55.2(2C,-
OCH3), 110.2(2C, C-CH2-), 120.6(2Cf), 123.3(2Cd), 128.2(6Cb, b´),
129.6(3Cj), 129.8(2Cc), 131.1(6Ca, a´), 135.0(2Ce), 136.1(3C, ipso-C), 157.4(2C,
COCH3), 177.3 (2C, carbonyl), Anal. calcd. for C36H33O6Sb: C, 63.27, H, 4.87,
Found: C, 63.24, H, 4.83.
Bis(4-methoxyphenylacetato)(triphenyl)antimony(V) (8A)
Stoichiometric amounts were calculated as for 7A. Colourless solid, Final yield 84%,
m.p.171-172 ˚C, FTIR(cm-1) 2936(C-Haromatic), 2840 (C-Haliphatic), 1652 (C=O), 1265
(C-O), 548 (Sb-C), 484 (Sb-O), 1HNMR (CDCl3) δ3.37 (s, 4H, -CH2-), 3.81 (s, 6H, -
OCH3), 6.75 (d(skewed), 4Hc, c´,3J=8.7Hz), 6.95 (d(skewed), 4Hd, d´, 3J=8.4Hz), 7.39
(t(skewed), 6Hb, b´, 3J=7.5Hz), 7.47 (tt(skewed), 3Hj, 3J=7.5Hz, 4J=1.2Hz ), 7.79 (dd, 6Ha, a´,
3J=8.1Hz, 4J=1.2Hz), 13CNMR (CDCl3) δ 42.3 (2C, -CH2-), 55.3 (2C, -OCH3), 113.6
(4Cd, d´), 127.7(2C, C-CH2-), 129.1(6Cb, b´), 130.2 (4Cc, c´), 130.9(3Cj), 133.8 (6Ca, a´),
137.4 (3C, ipso-C), 158.2(2C, C-OCH3), 175.2 (2C, carbonyl), Anal. calcd.
for C36H33O6Sb: C, 63.27, H, 4.87, Found: C, 63.24, H, 4.84.
Bis(p-chlorophenylacetato)(triphenyl)anitmony(V)(9A)
Stoichiometric amounts were calculated as for 8A. white crystalline solid, Final
yield 83%, m.p, 143-144 ˚C, FT-IR (cm-1) 3050(C-Haromatic), 2929 (C-Haliphatic),
1642(COOasym), 1262 (C-O), 737(C-Cl), 563(Sb-C), 453(Sb-O), 1HNMR
34
(CDCl3) δ3.39 (s, 4H, -CH2-), 6.82 (d(skewed), 4Hc, c´,3J=8.7Hz), 7.12 (d(skewed), 4Hd, d´,
3J=8.4Hz), 7.36 (t(skewed), 6Hb, b´, 3J=7.5Hz), 7.43 (tt(skewed), 3Hj,
3J=7.5Hz, 4J=1.2Hz),
7.72 (dd, 6Ha, a´, 3J=8.1Hz, 4J=1.2Hz),13C NMR (CDCl3) δ 42.5 (2C, CH2-), 113.8
(4Cd, d´), 127.8 (2C, C-CH2-), 129.7 (6Cb, b´), 131.2 (4Cc, c´), 132.5 (3Cj), 133.7 (6Ca,
a´), 138.9 (3C, ipso-C), 156.8(2C, C-Cl), 175.7 (2C, cabonyl), Anal.calcd.
C34H27Cl2O4Sb: C, 58.99, H, 3.93, Found: C, 58.92, H, 3.94.
Bis (o-formylbenzoato)(triphenyl)antimony(V) (10A)
Stoichiometric amounts were calculated as for 9A. Final yield 81%, white crystalline
solid, m.p.=147˚C. FTIR(cm-1) 3096(m) & 3079(m) (C-Haromatic), 2992(m) & 2972(m)
(C-Haliphatic), 1671(m) & 1674(s) (C=O), 1431(s), 1394(s), 1332(m), 1303(s),
1294(s)(C-O), 1267(m), 1206(m), 1127(s), 1111(m), 931(m), 859(m), 852(m), 791(s),
762(s), 687(m), 623(m), 561(m)(Sb-C), 526(m), 516(m),
456(m), 448(m)(Sb-O). 1HNMR (CDCl3) δ 7.46 (d, 2H, 3J=7.2Hz, ArH), 7.50-7.57
(m, 13H, ArH), 7.71(d, 2H, ArH, 3J=7.2Hz,), 8.14 (dd, 6H, 3J=7.2 Hz, 4J=2.4Hz,
ArH), 10.17 (s, 2H, H-C=OPh). 13CNMR (CDCl3) δ125.3 (2C), 127.6 (3C), 128.2
(6C), 129.6 (2C), 131.3 (3C), 131.6 (6C), 132.7 (2C), 134.3 (2C), 135.2 (2C), 136.8
(3C, ipso-C), 170.2 (2C, >=O), 192.7 (2C, >=O). Anal.calc. for C34H25O6Sb: C,
62.70, H, 3.87, Found: C, 62.68, H, 3.85.
Bis (4-oxo-4-p-tolylbutanoato)(triphenyl)antimony(V) (11A)
Stoichiometric amounts were calculated as for 10A. White crystalline solid, Final
yield. 76%, m.p.=128-130˚C. FTIR(cm-1) 3028(m) (C-Haromatic), 2968(m), 2844(m) &
2715(w) (C-Haliphatic), 1688(s, broad) (C=O), 1629(s), 1622(s) 1611(s), 1601(s),
1599(s), 1450(m), 1423(s), 1379(s), 1328(m), 1315(m), 1284(m), 1255(s)(C-O),
1216(s), 1175(m), 979(m), 831(m), 799(m), 693(m), 626(m), 564(m)(Sb-C),
551(m), 526(m), 516(m), 456(m), 451(m)(Sb-O). 1HNMR (CDCl3) δ 2.40 (s, 6H,
CH3), 2.58(t, 4H, 3J=5.4Hz, -CH2- ), 3.06 (t, 4H, 3J=5.4Hz, -CH2-), 7.23(d, 4H,
3J=7.2Hz, ArH), 7.43-7.51(m, 9H, ArH), 7.79 (d, 4H, 3J=7.2Hz, ArH), 7.87 (dd, 6H,
3J=7.2Hz, 4J=2.4Hz, ArH). 13CNMR (CDCl3) δ 21.6 (2C, -CH3), 34.0 (2C, -CH2-),
35
45.5 (2C, -CH2-), 129.2 (2C), 129.5 (4C), 130.9 (6C), 133.8 (6C), 134.1 (3C), 135.3
(2C), 137.7 (4C), 143.6 (3C, ipso-C), 177.3 (2C, >=O), 195.3 (2C, >=O). Anal.calc.
for C40H37O6Sb: C, 65.32, H, 5.07, Found: C, 65.30, H, 5.06.
Bis (3-(2, 3-dimethoxyphenyl)acrylato)(triphenyl)antimony(V) (12A)
Stoichiometric amounts were calculated as for 11A. White crystalline solid, Final
yield 82%, m.p=156˚C. FTIR(cm-1) 3021(m) (C-Haromatic), 2983(m), 2944(m) &
2888(m) (C-Haliphatic), 1699(s, broad) (C=O), 1597(m) 1581(m), 1483(s), 1464(m),
1456(m), 1442(m), 1426(s), 1320(s), 1298(m), 1267(s)(C-O), 1232(m), 1200(s),
1172(m), 1089(m), 1056(s), 1003(s), 972(s), 940(m), 898(m), 821(m), 807(m), 760(s),
732(m), 569(m)(Sb-C), 550(m), 522(m), 519(m), 459(m), 448(m)(Sb-O).
1HNMR (CDCl3) δ 3.87 (s, 6H, -OCH3), 3.89 (s, 6H, -OCH3), 6.36 (d, 2H, 3J=12Hz,
-CH=CH-Ph), 6.89 (d, 2H, 3J=8.1Hz, ArH), 7.04 (t, 2H, 3J=8.1Hz, ArH), 7.12 (d, 2H,
3J=8.1Hz, ArH), 7.51-7.56 (m, 9H, ArH), 7.85 (d, 2H, 3J=12Hz, -CH=CH-Ph),
8.12 (dd, 6H, 3J=7.8Hz, 4J=2.4Hz, ArH). 13CNMR (CDCl3) δ 55.8 (2C, -OCH3), 61.2
(2C, -OCH3), 113.4(2C), 119.1(2C), 122.3(2C), 124.1(3C), 128.1(2C), 129.3(6C),
131.2(3C), 134.2(6C), 137.7(2C), 38.2(3C, ipso-C), 148.2(2C), 153.2(2C), 171.0 (2C,
>=O). Anal.calc. for C40H37O8Sb: C, 62.60, H, 4.86, Found:
C, 62.58, H, 4.85.
Bis (2, 6-difluorobenzoato)(triphenyl)antimony(V) (13A)
Stoichiometric amounts were calculated as for 12A. Colourless solid, Final yield
84%, m.p.145-146 ˚C, FTIR (cm-1) 3120 (w) & 2930(s) (C-Haromatic), 1630(s) (C=O),
1560(w), 1490(s), 1420(m),1370(w), 1310(m), 1288(s)(C-O), 1270(w), 1140(m),
1020(m), 920(m), 810(m), 770(m), 740(m), 690(m), 570(w)(Sb-C). 526(m), 510(m),
447(m)(Sb-O), 1HNMR(CDCl3) δ 7.44 (t, 3H, ArH, 3J=7.2Hz), 7.56-7.59 (m, 8H,
ArH), 7.80 (d, 4H, ArH,3J=7.2Hz), 8.12 (dd, 6H, ArH,3J=7.2Hz, 4J=2.4Hz), 13CNMR
(CDCl3) δ 128.3 (4C), 129.7 (6C), 132.1 (2C), 131.7 (2C), 133.7 (6C), 134.8 (4C),
135.5 (2C), 136.9 (3C, ipso-C), 167.5 (2C, Carbonyl), Anal. calcd. for C32H21F4O4Sb
(667.26): C, 57.60, H, 3.17, Found: C, 57.57, H, 3.16.
36
Bis (2, 5-dichlorobenzoato)(triphenyl)antimony(V) (14A)
Stoichiometric amounts were calculated as for 13A. White crystalline solid, Final
yield 84%, m.p.=160-165˚C. FTIR(cm-1) 3092(m) & 3078(m) (C-Haromatic), 1675(s)
(C=O), 1583(m), 1565(m), 1464(m), 1436(m), 1409(m), 1372(m), 1295(s)(C-O),
1272(m), 1264(m), 1216(m), 1182(m), 1153(m), 1112(s), 1052(m), 901(m), 856(s),
825(s), 784(m), 737(m), 666(m), 616(m), 583(m)(Sb-C), 529(m), 512(m), 444(m)
(Sb-O), 1HNMR (CDCl3) δ 7.46 (t, 3H, ArH, 3J=7.8Hz), 7.54-7.61 (m, 8H, ArH), 7.78
(m, 4H, ArH, 3J=7.2Hz), 8.10 (dd, 6H, ArH, 3J=7.2Hz, 4J=2.4Hz), 13CNMR (CDCl3)
δ 128.3 (3C), 129.7 (6C), 130.4(2C), 131.6 (2C), 131.8 (2C), 132.3(2C), 133.7 (6C),
134.8 (2C), 135.5 (2C), 136.9 (3C, ipso-C), 167.5 (2C, 2C, carbonyl),
Anal. calcd. for C32H21Cl4O4Sb: C, 52.43, H, 2.89, Found: C, 52.40, H, 2.87,
Bis(4-ethoxybenzoato)(triphenyl) antimony(V) (15A)
Stoichiometric amounts were calculated as for 14A. White crystalline solid, Final
yield 82%, m.p.=156˚C. FTIR (cm-1) 3264(m), 2984(m) & 3080(m) (C-Haromatic),
2941(m)& 2902(m) (C-Haliphatic), 1738(s) (C=O), 1604(s), 1582(s), 1488(s),1474(s)
1460(s), 1401(s), 1363(s), 1298(s)(C-O), 1239(s), 1226(s), 1164(s), 1128(s), 1113(m),
1089(m), 1076(m), 1039(s), 1030(s), 924(m), 904(m), 864(m), 817(m),
756(s), 687(m), 666(m), 642(m), 613(w), 607(m), 578(m)(Sb-C), 568(m), 548(m),
518(m), 514(m), 455(m), 458(m)(Sb-O). 1HNMR (CDCl3) δ 1.45 (t, 6H, 3J=12Hz, O-
CH2-CH3), 3.98(q, 4H, 3J=20Hz, -O-CH2-CH3), 6.79 (d, 4H, 3J=7.5Hz, ArH), 7.36-
7.42(m, 9H, ArH), 7.88 (d, 4H, 3J=8.1Hz, ArH), 8.04 (dd, 6H, 3J=8.1Hz,
4J=2.4Hz, ArH). 13CNMR(CDCl3) δ 14.5 (2C, -O-CH2-CH3), 63.5 (2C,-O-CH2CH3),
113.7(4C), 129.4(2C), 129.4(6C), 130.9(3C), 131.2(4C), 131.8(6C), 138.4(3C, ipso-
C), 162.1 (2C, C-O-CH2-CH3), 170.1(2C, >=O). Anal.calc. for
C36H33O6Sb: C, 63.27, H, 4.87, Found: C, 63.26, H, 4.85
Bis (3-acetoxybenzoato)(triphenyl)antimony(V) (16A)
Stoichiometric amounts were calculated as for 15A. white crystalline solid, Final yield
84%, m.p.=137˚C. FTIR (cm-1)3005(m) (C-Haromatic), 2891(m) & 2836(m) (CHaliphatic),
37
1685(s) (C=O), 1601(s), 1504(m), 1432(s), 1379(m), 1318(m), 1290(s)(CO), 1221(s),
1202(s), 1168(s), 1123(m), 1104(m), 1098(w), 1017(m), 921(s), 860(s),
825(s), 793(w), 757(s), 701(s), 671(m), 581(w)(Sb-C), 547(m), 501(m), 455(m)(Sb-
O). 1HNMR (CDCl3) δ 2.29 (s, 6H, -C=O-CH3), 7.20 (d, 2H, 3J=7.2Hz, ArH), 7.37 (t,
2H, 3J=7.2Hz, ArH), 7.41-7.44 (m, 9H, ArH), 7.59 (s, 2H, ArH), 7.76 (d, 2H,
3J=7.2Hz, ArH), 8.03 (dd, 6H, 3J=7.2Hz, 4J=1.2Hz, ArH). 13CNMR (CDCl3)δ
21.1(2C, -CH3), 125.4(2C), 127.4(2C), 128.9(2C), 130.0(6C), 132.0(3C), 133.8(6C),
134.0(2C), 134.4(2C), 137.6(3C, ipso-C), 150.4(2C), 169.0 (2C, >=O), 169.4 (2C,
>=O). Anal.calc. for C36H29O8Sb: C, 60.78, H, 4.11, Found: C, 60.74, H, 4.09.
Bis (4-methoxycinnamato)(triphenyl)antimony(V) (17A)
Stoichiometric amounts were calculated as for 16A. White crystalline solid, Final
yield 79%, m.p.=147˚C. FTIR (cm-1) 3057(m) (C-Haromatic), 2902(m) & 2844(m)
(CHaliphatic), 1664(s, broad) (C=O), 1629(s), 1614(m), 1584(m), 1512(m),
1464(m),1444(m) 1358(m), 1318(m), 1313(m), 1265(s)(C-O), 1244(s), 1209(m),
1160(m), 1136(s), 1026(s), 979(m), 950(m), 939(m), 866(m), 858(m), 818(m),
762(m), 691(m), 611(m), 605(m), 571(m)(Sb-C), 558(m), 506(m), 502(m),
450(m)(Sb-O). 1HNMR (CDCl3) δ 3.80 (s, 6H, -OCH3), 6.14(d, 2H, 3J=15.6Hz,
CH=CH-), 6.77 (d, 4H, 3J=8.1Hz, ArH), 7.29(d, 4H, 3J=8.4Hz, ArH), 7.33-7.49(m,
11H, ArH, -CH=CH-Ph), 8.01(dd, 6H, 3J=8.1Hz, 4J=2.4Hz, ArH). 13CNMR (CDCl3)δ
55.3(2C, -OCH3), 114.1(6C), 125.3(2C, -CH=CH-), 127.6 (2C, -CH=CH), 128.2(4C),
129.0(6C), 131.1(4C), 137.8(2C), 138.4(2C), 139.0(3C, ipso-C), 143.1(3C),
171.2(2C, >=O). Anal.calc. for C38H33O6Sb: C, 64.52, H, 4.70, Found:
C, 64.49, H, 4.69.
Bis (2-ethoxybenzoato)(triphenyl)antimony(V) (18A)
Stoichiometric amounts were calculated as for 17A. White crystalline solid, Final
yield 82%, m.p.=156-157˚C. FTIR (cm-1) 3261(m) & 3078(m) (C-Haromatic), 2980(m)
& 2942(m) (C-Haliphatic), 1739(s) (C=O), 1601(s), 1578(s), 1484(s), 1478(s) 1460(s),
1405(s), 1359(s), 1294(s) (C-O), 1239(s), 1221(s), 1162(s), 1125(s), 1109(m),
38
1088(m), 1075(m), 1030(m), 928(m), 905(m), 868(m), 813(m), 751(s), 681(m),
666(m), 640(m), 610(w), 605(m), 576(m), 569(m) (Sb-C), 545(m), 513(m), 512(m),
456(m)(Sb-O). 1HNMR (CDCl3) δ 1.45 (t, 6H, 3J=12Hz, -O-CH2-CH3), 3.98(q, 4H,
3J=20Hz, -O-CH2-CH3), 6.79 (d, 4H, 3J=7.5Hz, ArH), 7.36-7.42(m, 9H, ArH), 7.88
(d, 4H, 3J=8.1Hz, ArH), 8.04 (dd, 6H, 3J=8.1Hz, 4J=1.2Hz, ArH). 13CNMR (CDCl3)
δ 13.9 (2C, -O-CH2-CH3), 66.5 (2C, -O-CH2-CH3), 113.7(4C), 129.4(2C), 129.4(6C),
131.1(3C), 131.2(4C), 131.8(6C), 133.8(2C), 138.4(3C, ipso-C), 162.1 (2C),
170.1(2C, >=O). Anal.calc. for C36H33O6Sb: C, 63.27, H, 4.87, Found: C,
63.26, H, 4.85
2.3.3. Synthesis of Tris(p-tolyl)antimony(V) dicarboxylates (1B-10B)
The sodium/potassium salt of the carboxylic acid (0.01mol) and organoantimony(V)
(0.005mol) were added in 75 ml of toluene, and stirred for 8-10 hours. The
sodium/potassium halide salt formed was removed by filtration and solvent was
removed under low pressure. The product obtained was dissolved in dichloromethane
and kept under slow evaporation in semi sealed bottles for crystallization. Toluene
was distilled over sodiumbenzophenone ketyl and used fresh when required.
2.3.3.1 Synthesis and characterization data of (1B-10B)
Tris(p-tolyl)bis(4-methylbenzoato)antimony(V) (1B)
The stoichiometric quantities used was 1.59g (0.01 mol) potassium salt of
4methylbenzoic acid and 2.75g (0.005 mol) tris(p-tolyl)antimony(V)dibromide.
Colourless solid, Final yield 82%, m.p.214-215˚C, FTIR(cm-1) 3023 (C-Haromatic) ),
2920 (C-Haliphatic), 1632 (C=O), 551 (Sb-C), 481 (Sb-O), 1HNMR (CDCl3) δ 2.45(s,
15H, -CH3), 7.22(d, 4H, ArHd=d', 3J=8.1Hz), 7.36(d, 6H, ArHb=b',
3J=8.1Hz), 7.95
(d, 4H, ArHc=c', 3J=8.1Hz), 8.11 (d, 6H, ArHa=a',
3J=8.1Hz), 13CNMR(CDCl3) δ
21.6(2C, -CH3), 128.8(4C), 130.0(4C), 130.3(6C), 130.4(2C), 133.7(6C), 134.8(3C),
141.5(3C), 141.5(3C, ipso-C), 142.6(2C), 170.1 (2C, carbonyl C); Anal. calcd. for
C37H35O4Sb: C, 66.78, H, 5.30, Found: C, 66.74, H, 5.26
39
Scheme 3. Synthesis of Tris(p-tolyl)antimony(V) dicarboxylates (1B-10B)
Bis(2-(phenylamino)benzoato)tris(p-tolyl)antimony(V) (2B)
Stoichiometric amounts were calculated as for 1B. Final yield 83%, Colourless solid,
m.p.165-166˚C, FTIR(cm-1) 3250 (-NH),3210 (C-Haromatic), 2921 (C-Haliphatic),
1635(C=O), 562 (Sb-C), 484 (Sb-O), 1H NMR (CDCl3) δ 2.44 (s, 9H, -CH3), 6.78(t,
40
2H, ArHe, J=7.2Hz), 7.09 (t, 2H, ArHg, J=7.2Hz), 7.19 (d, 4H, ArHc=c’, J=7.8Hz),
7.29-7.39 (m,16H, ArHb=b’, d=d’, f,h,i), 8.08 (d, 6H, ArHa=a', J=7.8Hz), 9.57(s, 2H, -NH-
), 13C NMR (CDCl3) δ 21.6 (3C, -CH3), 113.8 (2C), 115.3 (2C), 116.9(2C), 121.9(4C),
122.8(3C), 129.1(4C), 131.0(6C), 132.7(2C), 133.2(2C), 133.8(6C),134.6(2C).141.4
(2C), 141.5(3C), 144.4 (3C, ipso-C), 172.0 (2C, 2C, carbonyl), Anal. calcd. for
C47H41N2O4Sb: C, 68.88, H, 5.04, N, 3.42 Found: C, 68.84, H, 5.01, N, 3.45
Bis(3,5-dichlorobenzoato)tris(p-tolyl)antimony(V) (3B)
Stoichiometric amounts were calculated as for 2B. Final yield 83%,Colourless solid,
m.p.151-153˚C, FTIR(cm-1) 3070 (C-Haromatic), 2910 (C-Haliphatic), 1638 (C=O),740
(C-Cl), 579 (Sb-C), 485 (Sb-O), 1H NMR (CDCl3) δ 2.437 (s, 9H, -CH3), 7.38 (d,
6H, ArHb=b’,J= 8.1Hz), 7.44 (s, 2H, ArHe), 7.80 (s, 4H, ArHc=c’), 7.99 (d, 6H, ArHa=a’,
J=8.1Hz), 13C NMR (CDCl3) δ 21.6 (3C, -CH3), 128.3 (4C), 130.4 (6C), 131.7(2C),
133.2(2C), 133.6(6C), 134.7(4C), 135.9(2C), 142.0 (3C, ipso-C), 167.2 (2C, 2C,
carbonyl), Anal. calcd. for C35H27Cl4O4Sb: C, 54.23, H, 3.51, Cl,
18.29Found: C, 54.20, H, 3.48, Cl, 18.25
Bis(propanoato)tris(p-tolyl)antimony(V) (4B)
Stoichiometric amounts were calculated as for 3B. Final yield 82%, Colourless solid,
m.p.145-146˚C, FTIR(cm-1) 3024 (C-Haromatic), 2937 (C-Haliphatic), 1647 (C=O), 571
(Sb-C), 485 (Sb-O), 1H NMR (CDCl3) δ 2.40 (s, 9H, -CH3), 0.94 (t, 6H, CH3β-CH2-,
ArH, J=7.5Hz), 2.12 (q, 4H, CH3-CH2α-, J=7.5Hz), 7.29 (d, 6H, ArHb=b’, J=7.8Hz),
7.86 (d, 6H, ArHa=a’, J=8.4Hz), 13C NMR (CDCl3) δ 9.82 (2C, -CH2-CH3), 21.5 (3C,
-CH3), 29.1 (2C, CH3-CH2-), 129.8 (6C), 133.7(6C), 135.2(3C), 141.1 (3C, ipso-C),
178.3 (2C, 2C, carbonyl) Anal. calcd. for C27H31O4Sb: C, 59.91, H, 5.77, Found: C,
59.88, H, 5.72
Bis(nicotinato)tris(p-tolyl)antimony(V) (5B)
Stoichiometric amounts were calculated as for 4B. Final yield 84%, Colourless solid,
m.p.181-183˚C, FTIR(cm-1) 3035, 3025(C-Haromatic), 2919(C-Haliphatic),
1638(C=O),1587(C-N), 557(Sb-C), 484(Sb-O), 1H NMR (CDCl3) δ 2.39 (s, 9H,
41
CH3), 7.27(t, 2H, pyridyl He, J=5.1Hz), 7.35(d, 6H, ArHb=b', J=8.1Hz), 8.02 (d, 6H,
ArHa=a', J =8.1Hz), 8.16 (dt, 2H, pyridylHf, 1J=8.1Hz, 2J=1.8Hz), 8.66 (dd, 2H,
pyridylHd, 1J=6.6Hz, 2J=1.8Hz), 9.16(sd, 2H, pyridylHc,
2J=1.2Hz,), 13C NMR
(CDCl3) δ 21.6 (3C, -CH3), 123.0, 128.6, 130.4 (4C), 133.2, 133.6 (6C), 137.5, 141.9
(3C, ipso-C), 151.3 (N-C), 152.4 (N-C), 168.2 (2C, 2C, carbonyl), Anal. calcd. for
C33H29N2O4Sb: C, 61.99, H, 4.57, N, 4.38 Found: C, 61.65, H, 4.48, N, 4.51
Bis((S)-2-Amino-3-(4-imidazolyl)propionato)tris(p-tolyl)antimony(V) (6B)
Stoichiometric amounts were calculated as for 5B. Final yield 83%, Colourless solid,
m.p.211-212˚C, FTIR(cm-1) 3438, 3412 (C-NH2, -NH-), 3100 & 3082 (C-Haromatic),
3020 & 2939 (C-Haliphatic), 1646 (C=O), 564(Sb-C), 475 (Sb-O), 1H NMR (CDCl3) δ
2.39 (s, 9H, -CH3), 2.82(m, broad, -CH2-), 4.20(t, 1H, -CH-), 5.11(s, 2H, -NH2),
7.66(s, 1H, -CHc-), 7.34(d, 6H, ArH), 7.74 (d, 6H, ArH),8.33(s, 1H, -CHd-), 12.68 (s,
1H, -NH-), 13C NMR (CDCl3) δ 21.5 (3C, -CH3), 29.0(2C, -CH2-), 57.1(2C, -CH-),
110.3(6C), 119.9(2C), 120.7(6C), 128.9(3C), 133.2(2C), 138.1(2C), 157.5 (3C,
ipsoC), 176.6 (2C, 2C, carbonyl), Anal. calcd. for C33H37N6O4Sb: C, 56.34, H, 5.30,
N, 11.95 Found: C, 56.31, H, 5.29, N, 11.97
Bis(o-methoxyphenylacetato)tris(p-tolyl)antimony(V) (7B)
Stoichiometric amounts were calculated as for 6B. Final yield 83%, Colourless solid,
m.p.172-173˚C, FTIR(cm-1) 3013 (C-Haromatic), 2916 (C-Haliphatic), 1652 (C=O), 584
(Sb-C), 480 (Sb-O), 1H NMR (CDCl3) δ 2.39 (s, 9H, CH3), 3.67(s, 4H, -CH2-),
3.84 (s, 6H, -OCH3), 6.90-6.99 (m, 4H, ArHc,f), 7.21- 7.33(m, 4H, ArHd,e), 7.17(d, 6H,
ArHb=b', J =8.1Hz), 7.39 (d, 6H, ArHa=a', J =8.1Hz), 13C NMR (CDCl3) δ 21.6 (3C, -
CH3), 45.1 (2C, -CH2-), 55.4 (2C, -OCH3), 110.1(6C), 120.5(6C), 123.3, 128.6(3C),
129.6, 129.7, 131.1(3C), 134.0, 136.2, 157.6 (3C, ipso-C), 178.0 (2C, carbonyl), Anal.
calcd. for C39H39O6Sb: C, 64.57, H, 5.42, Found: C, 64.53, H, 5.39
Bis(p-methoxyphenylacetato)tris(p-tolyl)antimony(V) (8B)
Stoichiometric amounts were calculated as for 7B. Final yield 82%, Colourless solid,
m.p.91-92˚C, FTIR(cm-1) 2930 (C-Haromatic), 2835 (C-Haliphatic), 1640 (C=O), 545 (Sb-
42
C), 486 (Sb-O), 1H NMR (CDCl3) δ 2.41 (s, 9H, CH3), 3.39(s, 4H, -CH2-), 3.84 (s,
6H, -OCH3), 6.79 (d, 4H, ArH, J=9.0Hz), 7.05 (d, 4H, ArH, J=8.7Hz), 7.22 (d, 6H,
ArH, J=9.0Hz), 7.71(d, 6H, ArH, J=8.1Hz), 13C NMR (CDCl3) δ 21.5 (3C, CH3), 42.5
(2C, -CH2-), 55.3 (2C, -OCH3), 113.5(4C), 113.9(2C), 127.8(3C), 129.9(6C),
130.3(4C), 133.7(6C), 141.2 (3C, ipso-C), 158.2(2C, -OCH3), 175.1 (2C, carbonyl
C), Anal. calcd. for C39H39O6Sb: C, 64.57, H, 5.42, Found: C, 64.52, H, 5.39
Tris(p-tolyl)bis(m-chlorophenylacetato) anitmony(V) (9B)
Stoichiometric amounts were calculated as for 8B. White solid, Final yield 90%,
m.p, 152-153 ˚C, FTIR(cm-1) 3050(C-Haromatic), 2928(C-H aliphatic), 1635(COOasym),
562(Sb-C), 477(Sb-O), 1HNMR(CDCl3) δ 2.43(s, 9H,-CH3), 3.35(s, 4H, -CH2-),
7.11(dd, 2H, 3J=7.5Hz, 4J=3.1Hz, ArH), 7.28-7.34(m, 2H, ArH), 7.38(d, 6H,
3J=7.5Hz, ArH), 7.45-7.54(m, 2H, ArH), 7.58(d, 2H,
3J=7.5Hz, ArH), 8.10(d, 6H, 3J=7.1Hz, ArH), 13CNMR(CDCl3) δ 21.8(3C, CH3),
43.5(2C, -CH2-), 114.2(2C), 117.3(2C), 123.2(2C), 130.2(2C), 130.4(6C),
130.6(6C), 135.1(2C), 135.4(2C), 142.6(3C), 146.2(3C, ipso-C), 170.0(2C,
>C=O), Anal.calcd. C37H33Cl2O4Sb: C, 60.52, H, 4.53, Found: C, 60.50, H, 4.52.
Tris(p-tolyl)bis(m-bromophenylacetato) anitmony(V)(10B)
Stoichiometric amounts were calculated as for 9B. Final yield 87%, m.p, 158-159
˚C, FTIR(cm-1) 3046 (C-Haromatic), 2926 (C-H aliphatic), 1634 (COOasym), 565 (SbC), 476
(Sb-O), 1HNMR(CDCl3) δ 2.43(s, 9H,-CH3), 3.36(s, 4H, -CH2-), 7.12(dd,
2H, 3J=7.5Hz, 4J=3.1Hz, ArH), 7.32-7.35(m, 2H, ArH), 7.38(d, 6H, 3J=7.5Hz, ArH),
7.49-7.54(m, 2H, ArH), 7.62(d, 2H, 3J=7.5Hz, ArH), 8.14(d, 6H,
3J=7.1Hz, ArH), 13CNMR(CDCl3) δ 21.6(3C, -CH3), 43.6(2C, -CH2-), 114.4(2C),
115.8(2C), 124.4(2C), 128.2(2C), 132.2(6C), 132.8(6C), 134.0(2C), 136.8(2C),
142.8(3C), 144.6(3C, ipso-C), 170.0(2C, >C=O), Anal.calcd. C37H33Br2O4Sb: C,
53.98, H, 4.04, Found: C, 53.97, H, 4.01.
43
2.3.4. Synthesis of Tris(2,5-dimethylphenyl) antimony(V)dicarboxylates (1C20C)
The sodium/potassium salt of the carboxylic acid (0.01mol) and organo-antimony (V)
(0.005mol) were added in 75 ml of toluene, and stirred for 8-10 hours. The
sodium/potassium halide salt formed was removed by filtration and solvent was
removed under low pressure. The product obtained was dissolved in dichloromethane
and kept under slow evaporation in semi sealed bottles for crystallization. Toluene
was distilled over sodiumbenzophenone ketyl and used fresh when required.
2.3.4.1 Synthesis and characterization data of (1C-20C)
Bis(o-methoxybenzoato)tris(2,5-dimethylphenyl) antimony (V) (1C)
Quantities used were 1.90 g (0.01 mol) potassium salt of o-methoxy benzoic acid and
2.98 g (0.005 mol) tris(2,5-dimethylphenyl)antimony (V) dibromide. White
crystalline solid, Final yield 86%, m.p.=112-114˚C. FTIR(cm-1) 3143(w), 3080(w),
2923(m), 2860(m), 1661(s), 1597(m), 1485(w), 1243(s), 1105(m), 1080(m),
1018(m), 850(w), 753(s), 700(w), 657(m), 563(m), 440(s), 316(w), 290(s), 3143 (C-
Haromatic), 2923, 2860 (C-Haliphatic), 1661(C=O), 563(Sb-C), 440(Sb-O), 1HNMR
(CDCl3) δ 2.34 (s, 9H, -CH3), 2.54(s, 9H, -CH3), 3.64(s, 6H. -OCH3), 6.79-6.84(m,
4H, ArH), 7.21-7.24(m, 6H, ArH), 7.25(d, 2H, 3J=4.5Hz, ArH), 7.47(dd, 2H,
3J=7.8Hz, 4J=1.8Hz, ArH), 8.26(s, 3H, ArH), 13CNMR (CDCl3) δ 21.2 (3C, -CH3),
22.9(3C, -CH3), 55.4(2C, -OCH3), 131.2(3C), 131.3(2C), 131.7(2C), 132.2(3C),
133.7(2C), 134.7(2C), 135.5(3C), 135.9(3C), 138.9(2c), 139.1(3C), 139.3(3C),
158.4(2C, >C-O-CH3), 168.4(2C, >=O). Anal.calc. for C40H41O6Sb: C, 64.97, H,
5.59, Found: C, 64.95, H, 5.57.
45
Tris(2,5-dimethylphenyl)bis(3-methoxybenzoato) antimony (V) (2C)
Stoichiometric amounts were calculated as for 1C. White crystalline solid, Final
yield 81%, m.p.=145-146°C. FTIR(Powder cm-1) 3228 (w), 2926(m), 1651(s),
1588(m), 1459(m), 1292(s), 1109(m), 1035(m), 907(w), 761(s), 600(m), 550(m),
445(s), 294(s), 3228 (C-Haromatic), 2929(C-Haliphatic), 1651 (C=O), 550(Sb-C),
445(Sb-O). 1HNMR (300MHz, CDCl3) δ 2.38(s, 9H, -CH3), 2.54(s, 9H, -CH3),
3.75(s, 6H, -OCH3), 6.98(dd, 2H, 3J=8.1Hz, 4J=2.7Hz, ArH), 7.22(t, 2H, 3J=7.8Hz,
ArH), 7.26(s, 6H, ArH), 7.36-7.41(m, 4H, ArH), 8.25(s, 3H, ArH). 13CNMR
(75MHz, CDCl3) δ 21.1(3C, -CH3), 21.2(3C, -CH3), 55.2(2C, -OCH3 ), 114.0(2C),
118.2(2C), 122.3(2C), 128.8(3C), 131.4(3C), 132.1(3C), 135.4(3C), 135.5(2C),
136.2(3C), 138.6(2C), 138.8(3C), 159.2(2C, >C -OCH3), 168.1 (2C, >=O).
Anal.calc. for C40H41O6Sb: C, 64.97, H, 5.59, Found: C, 64.95, H, 5.57.
Tris(2,5-dimethylphenyl) bis(4-methoxybenzoato) antimony (V) (3C)
Stoichiometric amounts were calculated as for 2C. White crystalline solid, Final yield
78%, m.p.=114-118˚C. FTIR(cm-1) 3048(w), 2924(s), 2675(w), 1645(s),
1603(s), 1497(m), 1294(s), 1252(s), 1160(s), 1123(w), 1025(s), 845(m), 776(m),
694(m), 617(s), 600(w), 442(m), 289(s), 3048 (C-Haromatic), 2924(C-Haliphatic), 1645
(C=O), 600(Sb-C), 442(Sb-O). 1HNMR (CDCl3) δ 2.38 (s, 9H, -CH3), 2.53(s, 9H,
CH3), 3.82(s, 6H, -OCH3), 6.79(d, 4H, 3J=8.7Hz, ArH), 6.97(d, 3H,3J=8.7Hz, ArH),
7.78(d, 4H, 3J=8.7Hz, ArH), 8.10(d, 3H, 3J=8.7Hz, ArH), 8.26(s, 3H, ArH).
13CNMR (CDCl3) δ21.2 (3C, -CH3), 22.9(3C, -CH3), 55.3(2C, -OCH3), 113.0(4C),
126.6(2C), 131.3(3C), 131.6(4C), 131.9(3C), 135.5(3C), 136.1(3C), 138.8(3C),
138.9(3C), 163.8(2C, CH3-O-Ph), 168.5(2C, >=O). Anal.calc. for C40H41O6Sb: C,
64.97, H, 5.59, Found: C, 64.96, H, 5.58.
Tris(2, 5-dimethylphenyl) Bis(3, 4, 5-trimethoxy benzoato) antimony (V) (4C)
Stoichiometric amounts were calculated as for 3C. Colorless solid, Final yield 78%,
m.p.=168-170°C. FTIR(cm-1) 3042(m), 2934(m), 2910(w), 1653(s), 1585(s),
1497(m), 1460(m), 1411(s), 1328(s), 1226(s), 1123(s), 1006(m), 940(m), 818(w),
46
4(m), 727(m), 540(m), 440(m), 319(s), 285(s), 3042 (C-Haromatic), 2934 & 2910(C-
Haliphatic), 1653 (C=O), 550(Sb-C) 440(Sb-O). 1HNMR(CDCl3) δ 2.37 (s,
9H, -CH3), 2.56(s, 9H, - CH3), 3.78(s, 12H, -OCH3), 3.84(s, 6H, -OCH3), 7.09(s, 4H,
ArH), 7.26(s, 6H, ArH), 8.22(s, 3H, ArH). 13CNMR(CDCl3) δ21.2(3C, -CH3),
22.9(3C, -CH3), 55.9(4C, -OCH3), 60.8(2C, -OCH3), 106.8(4C), 131.3(3C),
132.2(3C), 133.4(3C), 135.3(3C), 136.3(3C), 138.4(3C), 140.8(2C), 152.5(4C, -
COCH3), 152.9(2C, -C-OCH3), 167.6 (2C, >=O). Anal.calc. for C44H49O10Sb: C,
61.48, H, 5.75, Found: C, 61.46, H, 5.74
Tris(2,5-dimethylphenyl)bis(phenyl acetato) antimony (V) (5C)
Stoichiometric amounts were calculated as for 4C. White crystalline solid, Final yield
86%, m.p=110-112˚C. FTIR(cm-1) 3030(m), 2921(m), 2360(m), 1665(s), 1490(m),
1447(m), 12168(s), 1441(s), 1029(m), 931(m), 813(s), 718(s), 643(s),
561(m), 438(s), 289(s), 3030 (C-Haromatic), 2921(C-Haliphatic), 1665 (C=O), 561(SbC),
438(Sb-O). 1HNMR (CDCl3) δ 2.31 (s, 9H, -CH3), 2.32(s, 9H,-CH3), 3.33(s, 4H, -
CH2-), 6.97(dd, 4H, 3J=5.7Hz, 4J=2.1Hz, ArH), 7.13-7.25(m, 12H, ArH), 7.81(s,
3H, ArH). 13CNMR (CDCl3) δ21.1 (3C, -CH3), 22.7(3C, -CH3), 44.1(2C, -CH2-),
126.2(3C), 128.1(4C), 129.2(4C), 131.3 (3C), 131.7(3C), 135.0(3C), 135.7(3C),
135.9(2C), 138.8(3C), 138.9(2C), 173.4 (2C,>=O). Anal.calc. for C40H41O4Sb: C,
67.90, H, 5.84, Found: C, 67.88, H, 5.85
Tris(2,5-dimethylphenyl)bis(Phenoxyacetato) antimony (V) (6C)
Stoichiometric amounts were calculated as for 5C. Final yield 82%, white crystalline
solid, m.p.=142˚C. FTIR(cm-1) 3029(w), 2926(m), 1637(s), 1447(s), 1035(m), 808(s),
556(m), 435(s), 320(s), 286(s), 3029 (C-Haromatic), 2926 (C-Haliphatic), 1637, (C=O),
556(Sb-C), 435(Sb-O).1HNMR (CDCl3) δ 2.31(s, 9H, CH3), 2.37(s, 9H, -CH3), 4.38(s,
4H,-OCH2-), 6.93(dd, 4H, 3J=5.7Hz, 4J=1.8Hz, ArH), 7.09-7.24(m, 12H, ArH),
7.78(s, 3H, ArH). 13CNMR (CDCl3) δ21.1 (3C, CH3), 22.7(3C, -CH3), 66.3(2C, -
CH2-), 125.9(3C), 127.8(4C), 128.4(4C), 131.1(3C), 132.1(3C), 134.8(3C),
47
134.9(3C), 135.7(2C), 138.7(3C), 156.4(2C, -OCPh), 170.0(2C, >=O). Anal.calc. for
C40H41O6Sb: C, 64.97, H, 5.59, Found: C, 64.96, H, 5.58.
Tris(2,5-dimethylphenyl)bis(dimethylphenylaminobenzoato) antimony (V) (7C)
Stoichiometric amounts were calculated as for 6C. Final yield 78%, Colorless solid,
m.p.=156-157˚C. FTIR(cm-1) 3259(m), 3010(m), 2922(m), 2359(m), 1631(s),
1578(s), 1499(s), 1448(m), 1329(m), 1252(s), 1147(m), 1010(w), 750(m), 561 (m),
435(s), 322(s), 286(s), 3259(-NH-), 3010 (C-Haromatic), 2922(C-H aliphatic), 1631 (C=O),
561(Sb-C), 435(Sb-O). 1HNMR (CDCl3) δ 1.98 (s, 6H, -CH3), 2.31(s, 6H, CH3), 2.36
(s, 9H. -CH3), 2.59(s, 9H, -CH3), 6.56(t, 2H, 3J=8.1Hz, ArH), 6.67(d, 2H, 3J=7.8Hz,
ArH), 6.97-7.15(m, 8H, ArH), 7.16-7.25(m, 6H, ArH), 7.76(dd,
2H,3J=8.1Hz,4J=1.8Hz, ArH), 8.23(s, 3H, ArH), 9.29(s, 2H, -NH-), 13CNMR (CDCl3)
δ13.8 (2C, -CH3), 20.6(2C, -CH3), 21.3(3C, -CH3 ), 23.0(3C, -CH3), 112.9(2C),
114.8(2C), 115.4(2C), 123.4(2C), 125.6(2C), 126.2(2C), 131.5(3C), 131.9(3C),
132.3(2C), 132.5(2C), 132.7(2C), 135.5(3C), 136.2(3C), 137.8(2C), 138.8(3C),
138.9(2C), 139.4(2C), 148.9(3C), 170.6 (2C, >=O). Anal.calc. for C54H55N2O4Sb: C,
70.67, H, 6.04, N, 3.05, Found: C, 70.66, H, 6.03, N, 3.06.
Tris(2,5-dimethylphenyl)bis(o-methylbenzoato) antimony (V) (8C)
Stoichiometric amounts were calculated as for 7C. White solid, Final yield 81%,
m.p.=175-176˚C. FTIR(cm-1) 3029(w), 2921(m), 1654(s), 1489(m), 1440(m),
1400(m), 1299(s), 1269(s), 1144(m), 1088(s), 1040(w), 819(m), 745(s), 720(w),
660(m), 557(m), 439(s), 400(m), 345(s), 277(s), 3029 (C-Haromatic), 2921(C-Haliphatic),
1654 (C=O), 557(Sb-C), 439(Sb-O), 1HNMR (CDCl3) δ 2.31 (s, 6H, CH3), 2. 41 (s,
9H, -CH3), 2.55 (s, 9H, -CH3), 6.73-6.85 (m, 4H. ArH), 7.20-7.25(m, 6H, ArH),
7.26(d, 2H, 3J=7.5Hz, ArH), 7.53(dd, 2H, 3J=7.5Hz, 4J=1.8Hz ArH), 8.25(s, 3H,
ArH). 13CNMR (CDCl3) δ21.2 (2C, -CH3), 21.3(3C, -CH3), 22.7(3C, CH3), 125.9(2C),
126.7(2C), 130.2(2C), 132.1(3C), 132.2(2C), 132.8(3C), 133.9(2C), 135.2(3C),
135.8(3C), 136.8(2C), 137.6(3C), 138.4(3C), 167.7 (2C, >=O). Anal.calc. for
C40H41O4Sb: C, 67.90, H, 5.84, Found: C, 67.87, H, 5.83.
Bis(3-methyl benzoato)tris(2,5-dimethylphenyl) antimony (V) (9C)
Stoichiometric amounts were calculated as for 8C. Final yield 76%, white crystalline
material, m.p.=181-183˚C. FTIR(cm-1) 3028(w), 2922(s), 2360(m), 1650(s), 1601(m),
1442(m), 1305(s), 1209(s), 1109(m), 1036(w), 901(w), 790(w),
48
7478(s), 674(m), 568(m), 517(m), 433(s), 323(s), 286(s), 3028 (C-Haromatic), 2922(C-
Haliphatic), 1650 (C=O), 568(Sb-C), 433(Sb-O), 1HNMR (CDCl3) δ 2.32 (s, 6H, CH3),
2.41(s, 9H, -CH3), 2.55(s, 9H, -CH3), 7.17-7.22 (m, 4H. ArH), 7.26(s, 6H, ArH),
7.63(d, 2H, 3J=7.2Hz, ArH), 7.61(s, 2H, ArH), 8.27(s, 3H, ArH). 13CNMR
(CDCl3) δ21.2 (2C, -CH3), 21.3(3C, -CH3), 22.9(3C, -CH3), 126.8(2C), 127.8(2C),
130.5(2C), 130.4(3C), 132.0(3C), 132.2(2C), 133.9(2C), 135.5(3C), 136.1(3C),
137.5(2C), 138.8(3C), 138.9(3C), 168.4(2C, >=O). Anal.calc. for C40H41O4Sb: C,
67.90, H, 5.84, Found: C, 67.92, H, 5.82
Tris(2,5-dimethylphenyl)bis(furoato) antimony (V) (10C)
Stoichiometric amounts were calculated as for 9C. Final yield 77%, white solid,
m.p=144146˚C. FTIR(Powder cm-1) 3137(w), 2922(w), 2360(m), 1642(s), 1571(m),
1476(s), 1389(m), 1312(s), 1225(w), 1177(s), 1122(s), 1006(m), 927(m), 771(s),
563(m), 439(s), 298(s), 279(m), 3137 (C-Haromatic), 2922 (C-Haliphatic), 1642 (C=O),
1177(C-O-C), 563(Sb-C), 439(Sb-O). 1HNMR (CDCl3) δ 2.38 (s, 9H, -CH3), 2.56(s,
9H, -CH3), 6.35(dd, 2H, 3J=3.3Hz, 4J=1.5Hz, Furyl-H), 6.77(dd, 2H, 3J=3.3Hz,
4J=1.6Hz, Furyl-H), 7.18-7.26(m, 8H, ArH+Furyl-H), 8.18(s, 3H, ArH). 13CNMR
(CDCl3) δ 21.2(3C, -CH3), 22.9(3C, -CH3), 11.2(2C), 115.7(2C), 125.3(2C),
128.2(2C), 129.5(3C), 131.4(3C), 135.3(3C), 136.2(3C), 138.3(3C), 144.8(3C),
160.3(2C, >=O). Anal.calc. for C34H33O6Sb: C, 61.93, H, 5.04, Found: C, 61.90, H,
5.04.
Bis(2-thiophene carboxylato)tris(2,5-dimethylphenyl) antimony (V) (11C)
Stoichiometric amounts were calculated as for 10C. Final yield 86%, yellowish
crystalline material, m.p.=165-166˚C. FTIR(cm-1) 3025(w), 2923(m), 2674(m),
1038(s), 1639(s), 1521(m), 1487(m0, 1417(s), 1357(m), 1283(s), 1096(s), 1029(m),
857(m), 758(m), 718(s), 651(m), 532(m), 441(s), 326(m), 292(s), 3025 (C-Haromatic),
2923(C-Haliphatic), 1639 (C=O), 718(C-S), 532(Sb-C), 441(Sb-O). 1HNMR (CDCl3) δ
2.39 (s, 9H, -CH3), 2.56(s, 9H, -CH3), 6.95 (t, 2H, 3J=5.1Hz, Thiophene-H),
7.227.30(m, 6H, ArH), 7.34 (d, 2H,3J=5.1Hz, Thiophene-H),7.47(d, 2H, 3J=3.6Hz,
49
Thiophene), 8.20(s, 3H, ArH). 13CNMR (CDCl3) δ21.1 (3C, -CH3), 22.9(3C, -CH3),
127.4(3C), 130.6(2C), 131.4(3C), 131.8(2C), 132.2(3C), 135.4(3C), 136.3(3C),
138.2(2C), 138.9(3C), 140.5(2C), 164.4(2C, >=O). Anal.calc. for C34H33O4S2Sb: C,
59.05, H, 4.81, S, 9.27, Found: C, 57.00, H, 4.79, S, 9.26
Bis(benzenepropenoato)tris(2,5-dimethylphenyl) antimony (V) (12C)
Stoichiometric amounts were calculated as for 11C. Final yield 74%, White crystalline
solid, m.p.=146-148˚C. FTIR(cm-1) 3027(w), 2922(m), 2360(m), 1647(s),
1610(w), 1500(w), 1480(w), 1279(s), 1205(m), 750(m), 705(m), 567(m), 441(m),
340(w), 293(s), 3027 (C-Haromatic), 2922(C-Haliphatic), 1647 (C=O), 1610(-HC=HC-),
567(Sb-C), 441(Sb-O). 1HNMR (CDCl3) δ 2.31 (s, 9H, -CH3), 2.33(s, 9H, -CH3),
6.37 (d, 2H, 3J=15.9Hz, -CH=CH-Ph), 6.87(dd, 4H, 3J=7.5Hz, 4J=2.5Hz, Ar-H),
7.06-7.24 (m, 14H, Ar-H+CH=CH), 7.78(s, 3H, Ar-H). 13CNMR (CDCl3) δ21.6 (3C,
CH3), 22.3(3C, -CH3), 121.5(2C), 127.8(3C), 128.6(4C), 129.7(2C), 130.1(3C),
130.9(3C), 132.4(3C), 133.5(3C), 134.8(3C), 135.1(2C), 141.4(4C), 143.1(2C),
169.3(2C, >=O) Anal.calc. For C42H41O4Sb: C, 68.96, H, 5.65, Found: C, 68.94, H,
5.64.
. Tris(2,5-dimethylphenyl) bis(2-acetoxybenzoato) antimony (V) (13C)
Stoichiometric amounts were calculated as for 12C. Colorless solid, Final yield
78%, m.p.=120˚C, FTIR(cm-1) 3012 (C-Haromatic), 2923(C-H aliphatic), 1638 (C=O),
561(Sb-C), 451(Sb-O). 1HNMR (CDCl3) δ 2.39(s, 9H, -CH3), 2.56(s, 9H, -CH3),
3.12(s, 6H, -CH3), 6.73(t, 2H, 3J=7.8Hz, Ar-H), 6.84(d, 2H, 3J=8.4Hz, ArH),
7.247.33(m, 8H, Ar-H), 7.55 (d, 2H, 3J=6.3Hz, Ar-H), 8.18(s, 3H, Ar-H). 13CNMR
(CDCl3) δ21.0(2C, -CH3CO-), 21.2(3C,-CH3), 22.8(3C,-CH3), 115.6(2C), 116.5(2C),
118.4(3C), 130.5(2C), 131.7(2C), 132.2(3C), 134.3(3C), 134.9(2C), 135.3(3C),
136.6(3C), 137.7(2C), 138.8(3C), 161.6(2C, >=O), 171.9(2C, >=O) Anal.calc. For
C42H41O8Sb: C, 63.41, H, 5.19, Found: C, 63.40, H, 5.18.
50
Tris(2,5-dimethylphenyl)bis(cyanoacetato) antimony (V) (14C)
Stoichiometric amounts were calculated as for 13C. Final yield 78%, white material,
m.p.=210-211˚C, FTIR(cm-1) 3015(w), 2919(m), 1640(m), 1582(m), 1485(s),
1200(w), 1035(w), 811(s), 790(s), 563(m), 439(s), 285(s), 3015 (C-Haromatic), 2911(C-
Haliphatic), 1640 (C=O), 1582(-CN), 563(Sb-C), 439(Sb-O), 1HNMR (CDCl3) δ 2.31(s,
4H, -CH2-), 2.41(s, 9H, -CH3), 2.53 (s, 9H. -CH3), 7.11-7.24(m, 6H, Ar-H ) 8.11(s,
3H, Ar-H), 11CNMR (CDCl3) δ 21.2 (3C, -CH3), 22.9 (3C, -CH3), 42.7(2C, CH2-),
121.7(2C,-CN), 127.4(3C), 131.7(3C), 132.2(3C), 135.4(3C), 136.3(3C), 138.7(3C),
169.3 (2C, >=O), Anal.calc. C30H31N2O4Sb: C, 59.52, H, 5.16, N, 4.63, Found: C,
59.50, H, 5.15, N, 3.64.
Tris(2,5-dimethylphenyl)bis(oxonato) antimony (V) (15C)
Stoichiometric amounts were calculated as for 14C. Colorless solid, Final yield
78%, m.p.=230-232˚C. FT-IR(cm-1) 3410(s, br), 3019(w), 2919(m), 1637(s), 1488(s),
1470(m), 1382(m), 1035(m), 813(s), 561(m), 458(s), 270(s), 3410(s, br)(OH), 3019
(C-Haromatic), 2919(C-Haliphatic), 1637 (C=O), 561(Sb-C), 458(Sb-O). 1HNMR (CDCl3)
δ 2.30(s, 9H, -CH3), 2.33(s, 9H, -CH3), 7.08-7.24(m, 6H, ArH), 7.95 (s, 4H.-OH),
8.06(s, 3H, ArH). 13CNMR (CDCl3) δ22.1 (3C, -CH3), 23.4(3C, CH3), 126.4(3C),
129.1(3C), 131.6(3C), 132.8(3C), 133.4(3C), 135.7(3C), 161.7(2C), 168.9(2C),
170.4(2C), 173.9(2C, >=O). Anal.calc. for C32H31N6O8Sb: C, 51.29, H, 4.17, N,
11.21, Found: C, 51.29, H, 4.18, N, 11.23.
Tris(2, 5-dimethylphenyl)bis(2-phenylglycinato) antimony (V) (16C)
Stoichiometric amounts were calculated as for 15C. Final yield 76%, Colorless solid,
m.p.=197-198˚C. FTIR(cm-1) 3368(s, br), 3022(w), 2920(m), 1639(m), 1530(m),
1027(m), 809(s), 568 (m), 440(s), 295(s), 3368(-NH2), 3022(C-Haromatic), 2920(C-
Haliphatic), 1639(C=O), 568(Sb-C), 440(Sb-O). 1HNMR (CDCl3) δ 2.38 (s, 9H, -CH3),
6(s, 9H, -CH3), 3.98 (s, 2H, -CH-), 5.09 (s, 4H, -NH-), 7.19(d, 4H, 135.9(2C),
51
136.4(3C), 138.9(3C), 173.5(2C, >=O) Anal.calc. For C40H43N2O4Sb: C, 65.14, H, 5.88,
N, 3.80, Found: C, 65.13, H, 5.87, N, 3.81.
Tris(2,5-dimethylphenyl)bis(indazole-3-carboxylato) antimony (V) (17C)
Stoichiometric amounts were calculated as for 16C. Colorless solid, Final yield 74%,
m.p.=212-214˚C. FTIR(cm-1) 3464 (s,br), 3232(s,br), 3025(w), 2918(m), 2360(m),
1639(s), 1487(m), 1404(m), 1292(m), 1232(m), 1143(m), 1032(m), 811(s), 749(s),
694(m), 435(s), 339(m), 315(m), 278(s), 3232(N-H), 3047(C-H aromatic), 2918 (C-H
aliphatic), 1639 (C=O), 565 (Sb-C), 457(Sb-O). 1HNMR (CDCl3) δ 2.38 (s, 9H, -
CH3), 2.61(s, 9H, -CH3), 6.86 (t, 2H, 3J=6.9Hz, ArH), 7.10-7.34 (m, 10H, ArH),
7.60(t, 2H, 3J=6.9Hz, ArH), 8.01(s, 3H, ArH), 8.28(s, 2H, -NH-). 13CNMR
(CDCl3) δ21.1 (3C, -CH3), 21.2(3C, -CH3), 120.2(2C), 122.6(2C), 124.3(2C),
131.0(2C), 131.8(3C), 132.4(3C), 134.8(3C), 135.4(3C), 136.3(3C), 138.2(2C),
138.4(3C), 138.9(2C), 163.9(2C, -NC), 164.0(2C, >=O). Anal.calc. for
C40H37N4O4Sb: C, 63.26, H, 4.91, N, 7.38, Found: C, 63.23, H, 4.92, N, 7.41.
Bis(indole-2-carboxylato)tris(2,5-dimethylphenyl) antimony (V) (18C)
Stoichiometric amounts were calculated as for 17C. Final yield 79%, Colorless solid,
m.p.=186-188˚C. FTIR(cm-1) 3286(s, br), 3029(w), 2921(m), 1631(s), 1521(m),
1500(w), 1381(m), 1310(m), 1258(s), 1015(m), 780(m), 743(m), 589(m),
561(m), 441(s), 343(s), 291(s), 3286(NH), 3029(C-Haromatic), 2921(C-Haliphatic), 1631
(C=O), 561 (Sb-C), 441(Sb-O). 1HNMR (CDCl3) δ 2.39 (s, 9H, -CH3), 2.63(s, 9H,
CH3), 7.06-7.21 (m, 6H, ArH), 7.31-7.43(m, 6H, ArH), 7.65(d, 2H,3J=7.5Hz, ArH),
7.97(d, 2H, 3J=7.8Hz, ArH), 8.09(s, 3H, ArH), 8.51(s, 2H, -NH-). 13CNMR (CDCl3)
δ21.1 (3C, -CH3), 21.4(3C, -CH3), 120.2(2C), 122.6(2C), 124.3(2C), 131.2(2C),
131.8(3C), 132.4(3C), 134.8(3C), 135.4(3C), 136.3(3C), 136.8(2C), 138.4(2C),
138.7(3C), 139.1(2C), 141.2(2C), 169.2(2C, >=O). Anal.calc. for C42H39N2O4Sb:
C, 66.59, H, 5.19, N, 3.70, Found: C, 66.49, H, 5.17, N, 3.72.
52
Tris(2,5-dimethylphenyl) bis(5-methyl-2-pyrazine carboxylato) antimony (V) (19C)
Stoichiometric amounts were calculated as for 18C. Colorless solid, Final yield 80%,
m.p.=182-184˚C. FTIR(cm-1) 3434(s, br), 2928(w), 2919(m), 1651(s),
1487(s), 1447(w), 1278(s), 1149(s), 1032(s), 812(s), 571(m), 437(s), 292(s),
3028(C-Haromatic), 2919 (C-H aliphatic), 1651 (C=O), 1032(-CN), 571(Sb-C), 437(SbO).
1HNMR (CDCl3) δ 2.36 (s, 6H, -CH3), 2.39(s, 9H, -CH3), 2.67 (s, 9H, -CH3), 7.27 (s,
6H, ArH), 7.75 (s, 3H, ArH), 7.98 (s, 2H, pyrazine-H), 8.45 (s, 2H, pyrazine-H),
13CNMR (CDCl3) δ21.1 (3C, -CH3), 23.4(2C, -CH3), 23.8(3C, -CH3), 131.6(3C),
131.9(3C), 132.4(3C), 133.4(3C), 134.6(2C), 134.8(2C), 136.3(3C), 136.4(3C),
137.5(2C), 140.8(2C), 165.4(2C, >=O), Anal.calc. for C36H37N4O4Sb:
C, 60.77, H, 5.24, N, 7.87, Found: C, 60.73, H, 5.23, N, 7.88.
Tris(2,5-dimethylphenyl) bis((methylthionicotinato) antimony (V) (20C)
Stoichiometric amounts were calculated as for 19C. Final yield 80%, Colorless Solid,
m.p.=174-176˚C. FTIR(cm-1) 3026(w), 2921(m), 2360(m), 1646(s), 1550(m),
1510(m), 1389(s), 1291(s), 1231(w), 1143(m), 1063(m), 813(m), 766(m), 575(m),
450(m), 410(s), 310(s), 299(s), 278(s), 3026(C-Haromatic), 2921 (C-Haliphatic), 1646
(C=O), 766(-C-S), 575(Sb-C), 451(Sb-O). 1HNMR (CDCl3) δ 2.39 (s, 9H, -CH3),
2.41(s, 9H, -CH3), 2.51 (s, 6H, -SCH3), 6.86-6.91 (m, 2H, pyridinyl-H), 7.21-7.27 (m,
6H, ArH), 7.84 (dd, 2H, 3J=7.8Hz, 4J=1.8Hz, pyridinyl-H), 8.28 (s, 3H, ArH), 8.43
(dd, 2H,3J=4.8Hz, 4J=1.8Hz, Pyridinyl-H). 13CNMR (CDCl3) δ13.9 (3C, SCH3),
21.2(3C, -CH3), 23.0(3C, -CH3), 117.8(2C), 127.2(2C), 131.8(3C), 132.3(3C),
134.8(2C), 135.6(3C), 136.3(3C), 138.4(3C), 138.8(3C), 150.5(2C), 161.7(2C),
167.4(2C, >=O). Anal.calc. C38H39N2S2O4Sb: C, 59.00, H, 5.08, N, 3.62, S, 8.29
Found: C, 58.97, H, 5.91, N, 3.63, S, 8.28.
2.3.5. Synthesis of Organoantimony(V) Dicarboxylates (1D-10D), (1E-10E), (1F-10F)
and (1G-10G).
The synthesis of antimonials (1D-10D), (1E-10E), (1F-10F) and (1G-10G) has been
accomplished by using the same methodology as mentioned in 2.3.1 to 2.3.4. The
53
characterization and biological activities data is included as a supplementary material
withis dissertation.
REFERENCES
1. (a)Perrin D. D., Armarego, W. L. F. “Purification of Laboratory Chemicals”, Ed.,
6th, Amsterdam Elsevier/Butterworth-Heinemann 2009, London, New York,
ISBN: 9781856175678. (b) Armarego, W.L.F and Chai, C.L.L., “Purification of
Laboratory Chemicals”, Ed., 5th, Butterworth Heinemann, London, New York,
2003.
2. Altomare et al., J. Appl. Crystallogr., (1999) 32, 115.
3. Sheldrick, G.M., SHELXL97 (1997) University of Göttingen, Germany.
4. Ali, M.I., Rauf, M.K., Badshah, A., Kumar, I., Forsyth, C.M., Junk, P.C.,
Kedzierski, L., Andrews, P.C. Dalton Trans. 2013, 42, 16733-16741.
5. Asghar F., Badshah A., Shah A., M Rauf.K., Ali M.I., Tahir M.N., Nosheen E.,
Zia, R., Qureshi, R., J. Organomet. Chem. 2012, 717, 1-8.
6. Mushtaq, R., Rauf, M.K., Bond, M., Badshah, A., Ali M.I., Nadhman, A.,
Yasinzai, M., Tahir, M.N. Appl. Organometal. Chem. 2016, 30, 465–472.
7. Mushtaq, R., Rauf, M.K., Bolte, M., Nadhman, A., Badshah, A., Tahir, M.N.,
Yasinzai, M., Khan, K.M., Appl. Organometal. Chem.2017, 31, e3606.
8. Rauf, M.K., Shaheen, U., Asghar, F., Badshah, A., Nadhman, A., Azam, S., Ali,
M. I., Shahnaz, G., Yasinzai, M., Arch. Pharm. Chem. Life Sci. 2015, 348, 1-
13.
54
Chapter-1
BIOLOGICAL STUDIES
For the rapid development of drugs, new methodologies have been established to
determine the bioactivities of natural and synthesized compounds. In the field of drug
discovery preliminary screening is very crucial to select the lead candidates and for
further pharmacological evaluation, initial screenings to identify the drug candidates
for secondary and tertiary trials. To cure human, animals and plants from harm full
effects of micro-organism, these screening act as a tool to identify the bioactive
compounds.
3.1. Biological Screening of Some Selected Pentavalent Antimonials
Metal containing compounds have been extensively used in medicine, mainly in the
cure of carcinomas, parasitic diseases; micronutrients based desfunctionings and
inflammatory disorders. The increased progress in modern inorganic based medicinal
chemistry is owing to the redox-active nature of metal and inductive effect of
coordinating ligands. The biomolecules like proteins, DNA and RNA facilitate
binding to metal atoms in inorganic compounds. Due to the diverse bioactivity
potential, significance of metal based drug is increasing [1-3]. Pentavalent antimonials
1 .1.1 Antileishmanial Screening
From the very beginning, antimony based compounds have been practiced clinically
about a 100 years ago for the treatment of parasitic diseases like trypanosomiasis,
schistomiasis and various type of leishmaniasis [4]. In 1913, potassium antimony (III)
tartrate and other antimony III based drugs were baned for the time being due to their
toxic nature and lethal side effects. Potassium antimony (III) tartrate was the
55
have well known therapeutic behaviour. So in this work, we have investigated the anti-
leishmanial and anti-cancer potential of the synthesized pentavalent antimonials.
A very first antimonial drug used against parasitc diseases especially against
leishmaniasis. In 1940s, antimony III drugs were substituted by antimony (V)
compounds like sodium stibogluconate and meglumine antimoniate commercially
known as Pentostam and Glucantime respectively. These antimonials were found to
more active and 10 times less poisonous to humans and animals than trivalent
analogues. The safest nature of pentavalent antimonial chemotherapy is obvious from
the upturn survival rate as reported above 90% [5]. Promastigote stage is considered
best for the initial screening owing to its easy cultivation and for in vitro determination
of anti-leishmanial impact of tested drugs [6]. The leishmanicidal potency of the tested
pentavalent antimonials was assessed by MTT colorimetric assay following
previously described protocols [7] and also delineated below as a reference
“Leishmania tropicakwh 23 promastigotes were cultured in medium-199 along with
culture media of 10% FBS, 100 µg/mL streptomycin. sulphate and 100 IU/mL
penicillin G at ambient temperature. An fraction of 180 µL of promastigotes at
cellularity of 1×106 promastigotes/mL was incubated with 20 µl (20 µg/ml) of tested
drugs (having ≤ 1% DMSO in phosphate buffer saline) in 96 well plate at 24°C for 72
h. 1% DMSO as negative and Amphotericin. B (1 µg/mL) was taken as positive
controls. Before and after the addition of MTT solution (4 mg/mL), incubation is done
at 24°C. The floating was decant off cautiously and then formazan. product was
solubilized in 100 µL of DMSO. Spectral peak was noticed at 541 nm employing plate
photoreader. Three fold dilutions of compounds were used for IC50 determination.
Antileishmanial data of antimonials (V) and their acids-products are described in
Table 4.1. The viability was evaluated by MTT assay whose yellow tetrazolium salt
is reduces to give dark purple-blue formazan assay by mitochondrial enzyme of
targeted cells. Because of formazan cell impermeability, viable cells look purple-blue.
The selected free acids presented lower potency then Sb (V) scaffolds. Activity
meaningfully improved on coordination with aromatic groups bearing antimony (III)
56
precursors.” The increase in population of lipophilic groups around the antimony
centre increases the lipophilicity of the pentavalent. Results of complexes were
insignificantly different from Glucantime/amphotericin B signifying their efficiency
comparable to Glucantime/amphotericin B. Antileishmanial assay results indicated
that a strong association exists between the structural features and the potency of
complexes having variety of substituents at various positions of antimonials exhibited
better antileishmanial activity[8-10].
3.1.2. Anti-promastigotes assays on (1A-9A)
The potential of the pentavalent antimonials (1A-9A) to inhibit Leishmania growth
was evaluated using the Leishmania tropica KWH23 strain promastigotes. All
scaffolds have shown good to significant antileishmanial activity. Based on the
significant IC50 values (Table 1), the metal-scaffolds were classified in the way:
1A>3A>5A>6A>4A>2A>7A>9A>8A (Figure 6) as compared with the standard
glucantime (5.21µg/ml±1.29).Concentration-dependent anti-promastigotes test
displayed that these prepared antimonials annihilate Leishmania tropica and thus
exhibited antileishmanial activities. It is found that all the complexes are more potent
against promastigotes. Among them, complexes (1A) and (3A) exhibit excellent IC50
against promastigotes. Thesignificant activity of the complex (1A) assumes that
presence of inter- and intramolecular interactions make the carboxylate ligands more
interactive and thereby increases of the hydrophilic character of the metal complex
which also favours its absorption in the biological fluids [11].
57
Table 1.Concentration dependent activity of the synthesized antimonials against anti-
promastigotes (1A-9A) Conc
(µg/ml)
Con
trol 1A 2A 3A 4A 5A 6A 7A 8A 9A
Glucanti
me
100 100 0 0 0 0 0 0 0 0 0 0
10 100 0 33.3333 0 0 0 0 0 10 15 40
1 100 36.5853 41.6666 38.4615 38.2352 35 36.8421 38.3333 41 32 72
0.1 100 51.2195 58.3333 48.7179 52.9411 52.5 55.2631 60.6666 63.7692 61.7692 92
0.01 100 56.0975 66.6666 56.4102 64.7058 57.5 65.7894 73.3333 72.3076 68.3076 100
0.001 100 63.4146 75 69.2307 82.3529 62.5 73.6842 80 85.3846 77.3846 100
0.0001 100 87.8048 88.3333 87.1794 91.1764 87.5 89.4736 86.6666 93.6153 90.6153 100
0.00001 100 100 100 100 100 100 100 100 100 100 100
IC50 in (µg/ml)
0.1 0.48 0.077 0.26 0.23 0.4 0.58 0.67 0.38 6.4
Figure 1. Concentration dependent activity of the synthesized antimonials (1A-9A).
3.1.3. Anti-promastigotes and anti-amastigotes assays on 10A-18A (labelled in graphs
as 1-9) and their parent acids (L1-L9)
Complexes 10A-18A (labelled in graphs as 1-9 in Figure 2) and their parent acids L1-
L9 (Figure 2) were tested for their activity against the Leishmania major
58
promastigotes and human primary fibroblasts. DMSO and Amphotericin B were used
as the reference antileishmanial reagents under the same experimental conditions. The
DMSO control was set-up across the same range of concentrations as that of the
complexes and showed no adverse effects on parasites or mammalian cells even at the
highest concentrations. After 48 hours, the parent acids had little to no effect against
both the human fibroblasts and L. major promastigotes, even at the highest tested
concentrations of 100 µM. The fibroblast cells showed at most a <5% decrease in
viability, whereas the promastigotes were unaffected.
In contrast, the antimony complexes are moderately toxic, showing incomplete
promastigote elimination of 12.5% -19.8% at 100 µM. Compared to Amphotericin B
which gives complete elimination of parasites at 50 µM, and 4% at 25 µM, the
complexes did not perform as well. In general, they followed a similar trend across
the different concentrations against the promastigotes. Complex 10A (1),
incorporating 2-formylbenzoic acid, is significantly more selective as compared to the
rest of the complexes at the concentration of 50 µM, with a percentage viability of
16.7% for the promastigotes and 97.9% for the fibroblasts (Table 2).
However, this is not reflected when we look at the IC50 values for all the
complexes. Instead, Complex 11A (2), with its SI value of 2.49e33, stands out as
having the greatest selectivity amongst the complexes based on the IC50 values against
the promastigotes and fibroblasts. Previously, there were two studies by Ali et. al.,
[12] and Mushtaq et. al., [11] which had also looked at similar antimony(V) tris-aryl
dicarboxylate complexes [SbR3(O2CR)2] (R = phenyl, o-, m-, p-tolyl).
59
Figure 2. Dose response curves for complexes 10A-18A (labelled as 1-9) and their
parent acids L1-L9 for their activity against the Leishmania major promastigotes and
human primary fibroblasts.
60
Table 2. IC50 values, with standard error of the mean (SEM) from duplicate
experiments, of the complexes 10A–18A against Leishmania major promastigotes and
human fibroblasts at t = 48 h
IC50 (SEM) Selectivity Index
Sb(V)
complexes
Parent acids of
[SbPh3(O2CR)2]
R=
L. major
promastigote
Human
fibroblasts
IC50 fibroblasts/
IC50
promastigote
10A (1) (o-HCO)C6H4 11.50 (1.639) 280.2 (78.83) 24.37
11A (2) (p-CH3)C6H4COCH2CH2 14.25 (2.318) 349 (126.2) 24.49
12A (3) 2,3-(OCH3)2C6H3CH=CH 14.63 (1.768) 200.2 (58) 13.68
13A (4) 2,6-F2C6H3 9.879 (1.754) 78.11 (19.12) 7.91
14A (5) 2,5-Cl2C6H3 20.66 (2.072) 81.55 (29.37) 3.95
15A (6) (p-OC2H5)C6H4 18.88 (2.081) 206.5 (130.8) 10.94
16A (7) (m-OCOCH3) 19.26 (2.072) 74.87 (34.2) 3.89
17A (8) (p-OCH3)6H4CH=CH 14.56 (1.455) 132.3 (48.36) 9.09
18A (9) (o-OC2H5)C6H4 21.68 (2.879) 339.4 (65.8) 15.65
aNC indicates non-toxicity as graphs were non-converged
3.1.4. Anti-promastigotes and Cytotoxicity assays on (1B-8B) and (1C-20C)
Newly synthesized pentavalent antimonials (1B-8B) were assessed for their anti-
leishmaniali potency against Leishmaniai. tropica KWH23. All scaffolds presented
significant in vitro anti-leishmanial potency for varying concentration range against
Leishmania tropica KWH23. Based on significant IC50 (p < 0.01) values, the activity
profile of the compounds (1B-8B) were categorized as following:
1B>2B>3B>6B>4B>7B>8B>5B upon comparison with the standard drug glucantime
(4.4µg/ml ±0.17) (Figure 3). Concentration dependent antipromastigotes assay
displayed that studied scaffolds effectively annihilated Leishmaniatropica and
therefore showed anti-leishmanial potency.
61
Figure 3. Concentration dependent activity of the synthesized antimonials (1B-8B).
Cytotoxicity of the synthesized antimonials (1B-8B) was examined on .macrophages
extracted from human blood stream by ficoll-gastrografin method for
cytotoxicityevaluation [13, 14]. Leishmania has the capability to attack and proliferate
in the macrophages thus, these cells were used for cytotoxicity. The percentage
mortality of all the drugs was calculated. It was detected that the survival rate was
depending on the drug concentration. The results were directly associated to drug
concentrations e.g. more macrophages were viable at lower concentrations and death
percentage was higher upon increasing the dosage. The LD50values presented that the
compounds (1B-8B) were biologically active and biocompatible (Table 3).
Comparison of the IC50 of the compounds (1C-20C) against the cell culture MDA-
MB-231 and HeLa as well as against the Leishmania tropica (Table 4) has shown a
clear difference that the current compounds can be good alternative to the currently
available antimonial drugs. The antileishmanial potential of the pentavalent
antimonials (1C-20C) was evaluated using the Leishmania tropica kwh23 strain and
their cytotoxic potency against the cell culture MDA-MB-231 and HeLa. Almost all
62
scaffolds exhibited impressive antileishmanial activity and promising cytotoxicity.
Based on the significant
IC50 values of metal complexes in comparison to standard Amphotericin B
(0.36±0.04μg ml-1). The significant potency of the scaffolds can be ascribed with the
presence of lipophilic methyl groups and, also inter- and intermolecular interactions
makes the carboxylate ligands more interactive and thereby increases the absorption
of these compounds in the biological fluids.
Table 3 Antileishmanial activity (IC50) and cytotoxicity (LD50) of the synthesized
antimonials (1B-8B).
Cytotoxicity Anti-leishmanial
Compound LD50 IC50
1B 21.38 ±1.99 0.0001849 ±0.00006
2B 27.9 ±2.82 0.001346 ±0.0002
3B 12.89 ±2.2 0.00817 ±0.0003
4B 21.19 ±1.91 0.2203 ±0.00011
5B 17.8 ±2.2 1.9 ±0.00031
6B 35.9 ±3.07 0.007513 ±0.00010
7B 22.9 ±2.98 1.377 ±0.0030
8B 18.05 ±3.04 1.8 ±0.00100
Glucantime - 4.4±0.17
63
Table 4. Antileishmanial activity (IC50) against Leishmania tropica and cytotoxicity
(LD50) against MDA-MB-231andHeLaof the synthesized antimonials (1C-20C)
Codes MDA-MB-231 HeLa Leishmania tropica
IC50 ± SEM (µM)
1C 0.91 ± 0.09 1.54 ± 0.11 3.40 ± 0.15
2C 1.09 ± 0.03 18.9 ± 1.28 1.13 ± 0.04
3C 0.65 ± 0.04 3.38 ± 0.17 4.22 ± 0.07
5C 0.78 ± 0.02 0.75 ± 0.01 22.6 ± 1.12
6C 1.43 ± 0.01 8.33 ± 0.65 3.68 ± 0.09
7C 1.80 ± 0.09 4.35 ± 0.14 3.39 ± 0.04
8C 0.83 ± 0.08 11.8 ± 0.32 4.29 ± 0.02
9C 5.71 ± 0.06 4.15 ± 0.26 23.3 ± 1.09
10C 0.37 ± 0.01 0.53 ± 0.01 6.60 ± 0.26
11C 0.72 ± 0.03 0.69 ± 0.02 5.08 ± 0.03
12C 0.37 ± 0.04 4.18 ± 0.37 14.3 ± 0.18
13C 0.37 ± 0.02 0.93 ± 0.08 2.13 ± 0.07
14C 2.61 ± 0.11 3.93 ± 0.05 2.38 ± 0.02
15C 1.64 ± 0.09 5.52 ± 0.09 0.27 ± 0.05
16C 10.2 ± 0.23 5.37 ± 0.17 2.39 ± 0.06
17C 10.3 ± 0.14 5.01 ± 0.12 6.78 ± 0.04
18C 4.90 ± 0.05 0.23 ± 0.01 2.25 ± 0.10
19C 2.70 ± 0.08 3.13 ± 0.18 18.5 ± 0.33
20C 1.10 ± 0.06 7.88 ± 0.19 0.23 ± 0.05
Cisplatin 1.12 ± 0.09 17.6 ± 1.94 -
Amphotericin B - - 0.47 ± 0.09
64
3.1.5. Celltiter Blue Cell Viability Assay
The cell vialbility test was performed as reported in literature [15-18]. As a reference
the salient features of this assay have delineated below “The celltiter blue cell viability
assay (Promega, Madison, WI, USA) was employed for testing antileishmanial
potency and cytotoxicity. Tested compounds were solubilized in DMSO to make stock
solution of 20 mg/mL and diluted out in suitable culturei media. The assay was
arranged in duplicates in 96-well plates as per manufacturer’s guidlines. 106
promastigotes/mL and 105/mL J774 macrophages or primary human fibroblasts were
used. Cell viability was evaluated spectrophotometrically at 550 nm with the reference
wavelength of 630 nm [15]. The Celltiter Blue was added to samples at the time of
setting up the assay and T = 0 value was deducted from all successive readingsi as a
background value. All readings were compared to the no drug control and the percent
growth inhibition was calculated. DMSO controls were included. All plates were
assessed microscopically [16]. Under certain conditions percentage of positive control
is higher than 100% in comparison to initial percentage and this displays that there is
a growth of the species being considered. L. major V1211 was kept at 26 °C in M199
medium (Invitrogen) augmented with 10% heat inactivated fetal bovine serum (HI-
FBS). The murine macrophage J774 cell line (ATCC, Rockville, MD, USA) and
human prime fibroblast were cultivate in DMEM (Life Technologies) augmented with
10% HI-FBS at 37°C in 5% CO2. Numerous features of the Sb (V) agents have been
recommended to contribute to their potency. Carbohydrates formulate water-soluble
scaffolds with Sb and may aid to bring antimonial drug to targeted macrophages.
Comparatively nontoxic Sb(V) may be a prodrug that is converted to more lethal
Sb(III) at or around the sitei of action. Interactions of Sb with major sulfhydryl
functionality may be a key mode of action and/or toxicity. The upgrading of
procedures for assessing intracellular Sb along with an better knowledge of the
structure of sodium stibogluconate and our synthesis of chemically analogous tri- and
65
and pentavalent antimony complexes have allowed further investigations of the significance
of these hypotheses”[17, 18].
3.1.6. Cytotoxicity Assays of Compounds (1C-20C)
In vitro cytotoxicity assays of compounds (1C-20C) have been performed using SRB
cell viability test as reported in literature [13-19]. “In vitro cytotoxicity tests with cell
lines (mentioned below) were performed with the help of our collaborators (Table 5).
The ID50 values (ng/ mL) of seven reference drugs in vitro employing *SRB as cell
viability assessment is given in Table 6. The following human tumour cell lines were
used: MCFT breast cancer, EVSA-T breast cancer, WIDR colon cancer, IGROV
ovarian cancer, M19 MEL melanoma, A498 renal cancer, and H226 non-small cell lung
cancer. Cell lines WIDR, M19 MEL, 4498, IGROV and H226 belong to the currently
used anticancer screening panel of the National Cancer Institute, USA. The MCFT cell
line is estrogen receptor (ER) +/ progesterone receptor (PgR) + and the cell line EVSA-
T is (ER) -/ (PgR)”.
Table 5. Cytotoxicity (anti-cancer activity) ID50 values (ng/ml) pentavalent
antimonials (1C-20C).
Test
Compounds
Cell lines
A498 EVSA-T H226 IGROV M19 MCF-7 WIDR
1C 1543 3755 2005 2400 2045 2135 1800
2C 1200 3520 500 1005 1085 1815 2520
3C 1000 3005 400 650 460 2054 1650
4C 1705 2555 2050 3005 2030 3012 1058
5C 1805 2528 1275 2500 1200 2560 3020
6C 1525 2535 1009 1580 1200 2565 2545
66
…………………………………………………………………………………………………..Table 5 continued
8C 1525 2000 1005 1095 1210 2424 3565
9C 1015 2063 850 1006 1025 2125 2052
10C 1029 2263 1159 1327 1036 2361 2331
11C 1013 2233 788 1132 1025 2330 2157
12C 1053 2135 700 1055 1025 1459 1523
13C 1250 1980 1045 1907 2400 2132 2201
14C 950 850 1508 1695 1152 2209 2196
15C 895 1555 905 903 1033 1855 1720
16C 1265 1872 955 1163 1152 2199 2366
17C 1025 2120 850 1410 1099 2230 2205
18C 931 1902 1300 13315 1150 2202 2005
19C 950 1653 1250 1650 1050 2055 1822
20C 1051 1320 1020 1011 1500 1853 2150
Table 6. ID50 (ng/ mL) of standard compounds evaluted in vitro using SRB cell
viability test
67
REFERENCES
1. Feng, S.-S., Chien, S., Chemical Engineering Science. 2003, 58, 4087.
2. Farrell, N., “Bioorganometallics”, Jaouen, G., Ed, Wiley-VCH: Weinheim, 2005.
3. Schabel, F.M., Cancer, 1977, 40, 558-568.
4. Duffin, J., René, P., Journal of the history of medicine and allied sciences, 1991,
46, 440-456.
5. Berman, J.D., Review of Infectious Diseases, 1988, 10, 560-586.
6. Baiocco, P., Colotti, G., Franceschini, S., Ilari, A., Journal of medicinal chemistry,
2009, 52, 2603-2612.
7. Khan, H. Fatima, M.M. Taqi, M. Zia, B. Mirza, Journal of Applied Research on
Medicinal and Aromatic Plants, 2015, 2, 77-86.
8. Sadeghi-Nejad, B., Saki, J., Khademvatan, S., Nanaei, S., Journal of Medicinal
Plants Research, 2011, 5, 5912-5915.
9. Shah, N.A., Khan, M.R., Nadhman, A., BioMed research international, 2014,
2014.
10. Frézard F., Demicheli, C., Ribeiro, R.R., Molecules 2009,14, 2317-2336.
11. Mushtaq, R., Rauf, M.K., Bolte, M., Nadhman, A., Badshah, A., Tahir, M.N.,
Yasinzai, M., Khan, K.M., Appl. Organometal. Chem. 2017, 31, 3606.
12. Mushtaq, R., Rauf, M.K., Bond, M., Badshah, A., Ali, M. I., Nadhman, A.,
Yasinzai, M., M.N. Tahir. Appl. Organometal. Chem. 2016, 30, 465–472.
13. Rauf, M. K., Imtiaz-ud-Din, Badshah, A., Gielen, M., Ebihara, M., de Vos, M. D.,
Ahmed, S., J. Inorg. Biochem.,2009, 103, 1135.
14. Hu, G. F. J.,Cell Biochem.,1998, 69, 326.
15. Linder, M., Hazegh-Azam, M., Am. J. Clin. Nutr.,1996, 63,797S.
16. Coates, R. J., Weiss, N. S., Daling, J. R., Rettmer, R. L., Warnick, G. R., Cancer
Res., 1989,49, 4353.
17. Hu, G.F.J., Cell Biochem, 1998, 69, 326–335.
68
18. Apelgot, S., Coppey, J., Fromentin, A., Anticancer Res. 1986, 6, 159–164.
19. Coates, R.J., Weiss, N.S., Daling, J.R., Rettmer, R.L., Warnick, G.R., Cancer
Res. 49 (1989) 4353–4356.
69
Chapter-4
RESULTS & DISCUSSION
4.1. Infrared Spectroscopy
The modern version of Infrared spectroscopy termed as FT-IR spectroscopy is a power
mean for a chemist to readily access the main/desired functionalities in the prepared
sample. This is a simple, cheaper and rapid way to analyze and entering into the next
step synthesis. This technique is very helpful in elucidating the carboxylate bearing
organo-antimony assemblies. The characteristic IR bands of organoantimony(V)
carboxylates (1A-18A) Table 1, (1B-10B) Table 2 and (1C20C) Table 3,
functionalities appeared between/near to 3470-3310(-NH2), 32653250(-NH), 3210-
2930 (C-H)aromatic., 3032-2835 (C-H)aliphatic, 1739-1619(C=O), 1587-1582 & 1331-
1228(C-N), 735-740(C-Cl), 584-545 (Sb-C), 486-441 (Sb-O). All the the absorptions
associated with (C=O) stretching frequencies appeared within the normal ranges as
reported in literature [1].
For better and clear explaination of the peak shifts here the comparison
between the spectra of a free acid i.e., 3,5-dichlorobenzoic acid and its complex with
tris(p-tolyl)antimony(V) (3B) is being carried out. The clear demarcation between C-
H and aromatic OH stretching of acids in most of the cases at 3150-2850 cm-1 is not
possible because of the overlapping of the two bands of very near frequencies as earlier
reported in the plethora of literature on synthesis and characterization aromatic
carboxylic acids and other similar type of compounds bearing the identical
functionalities. The C=O stretching at 1695 cm-1 followed by nodes at 1615 and
1565cm-1 due to the aromatic ring. Then in plane bending of O-H acid group gives
vibration at 1425 cm-1, C-O stretching vibrations at 1280 cm-1, C-C-O at 1235 cm-1,
O-C-O at 1097 cm-1 and the O-H bending out of plane of acid at 907 cm-1 and the out
of plane aromatic CH band at 768 cm-1. The infrared spectrum of the complex (3B) of
the above described acid with organoantimony(V) is given chapter-2 and also in Table
70
2 of this chapter. “The attention is focused to the symmetric and asymmetric carbonyl
bands near 1657cm-1 and 1300 cm-1, respectively. The shift from 1694cm-1(C=O) to
1652 cm-1 is attributing to converting the COO into the carboxylates with
rearrangement of bonds into one and half linkage. The appearance of new band in the
lower infra-red region (584-545cm-1) and 486-441cm-1 are for SbC deformations and
Sb-O stretching which are not present in the case of free ligands and on agreement
with literature”[2-9].
71
Table 1.Characteristic FTIRabsorptions (cm-1) for complexes (1A-18A)
Complexes C-Haromatic C-Haliphatic C=O C-O Sb-C Sb-O Miscellaneous
1A 3094 1663 1253 562 463 3455-3345
(-NH2)
2A 3054 2920 1619 1265 550 457
3A 3026 1629 1260 564 448 3265(-NH)
4A 3068 1647 1258 583 444 739(C-Cl)
5A 3057 2978, 2937 1647 1278 555 458
6A 3054 1654 1269 562 447 1587(CN)
7A 3018 2926 1657 1259 582 484
8A 2936 2840 1652 1265 548 448
9A 3048 2928 1641 1262 563 452 737(C-Cl)
10A 3096, 3079 2992, 2972 1671,
1674
1294 561 448
11A 3028 2968, 2844 1668 1255 564 451
12A 3021 2983, 2944,
2888
1699 1267 569 448
13A 3120, 2930 1630 1288 570 447
14A 3092, 3082 1675 1295 583 444
15A 3264, 3080 2941, 2902 1738 1298 578 458
16A 2930 2891, 2836 1685 1290 581 455
17A 3057 2902, 2844 1664 1265 571 450
18A 3261, 3078 2980, 2942 1739 1294 569 456
Range obs.
(cm-1)
3261-2930 2992-2836 1739-
1619
1298-
1253
583-
550
463-
444
-
72
Table 2.Characteristic FTIRabsorptions (cm-1) for complexes (1B-10B)
Complexes C-Haromatic C-Haliphatic C=O C-O Sb-C Sb-O Miscellaneous
1B 3023 2920 1632 1327 551 481
2B 3210 2921 1635 1256 562 484 3250(-NH)
3B 3070 2910 1638 1319 579 485 740(C-Cl)
4B 3024 2937 1647 1244 571 485
5B 3035, 3025 2919 1638 1331 557 484 1583 (C-N)
6B 3100, 3082 3020, 2939 1646 1258 564 475 3444,3334
(-NH2)
7B 3010 2916 1652 1239 584 480
8B 2930 2835 1640 1243 545 486
9B 3048 2928 1635 1258 562 477
10B 3046 2926 1634 1248 565 476
Range obs.
(cm-1)
3210-2930 3020-2835 1653-
1632
1331-
1243
584-
545
486-
476
-
73
Table 3.Characteristic FTIRabsorptions (cm-1) for complexes (1C-20C)
Complexes C-Haromatic C-Haliphatic C=O C-O Sb-C Sb-O Miscellaneous
1C 3143 2923,
2860
1661 1316 563 440
2C 3228 2929 1651 1263 550 445
3C 3048 2924 1645 1300 600 442
4C 3042 2934,
2910
1653 1239 555 458
5C 3030 2921 1665 1313 561 438
6C 3029 2926 1637 1255 556 435
7C 3010 2922 1631 1256 561 435
8C 3029 2921 1654 1266 557 439
9C 3028 2922 1650 1328 568 433
10C 3137 2922 1645 1266 563 439
11C 3025 2923 1639 1308 532 441 718 (C-S)
12C 3027 2922 1647 1255 567 441 1610 (-
CH=CH-)
13C 3012 2923 1638 1321 561 451
14C 3015 2911 1640 1268 563 439 1582 (C-N)
15C 3019 2919 1637 1236 561 458 3410 (O-H)
16C 3022 2920 1639 1240 568 440 3368, 3310
(-NH2)
17C 3047 2918 1639 1306 565 457 3232 (-NH)
18C 3029 2921 1631 1234 561 441 3286(-NH)
19C 3028 2919 1651 1328 571 437 1579 (-CN)
20C 3026 2921 1646 1260 575 451 766 (C-S)
Range obs.
(cm-1)
3228-
3010
2934-
2860
1665-
1631
1328-
1228
584-
545
486-
441
-
74
4.2. Multi-nuclear (1H, 13C) NMR Spectroscopy
The magnetically distinct hydrogen and carbon atoms of a molecule can be distinguish
by their chemical shift values (δ), referring to molecular symmetry and the expected
impacts of neighboring electronegative atoms and unsaturated groups. It is necessary
to understand the general pattern of chemical shifts (δ) for the elucidation of NMR
spectra. The chemical shift values of 1H and 13C signals are influenced by the vicinity
of electronegative atoms (O, N, F, Cl, etc.) in the bonding linkage and by the vicinity
to π-bonded groups (C=C, C=O, aromatic) directly through space. Electronegative
atoms drift the resonances frequency to the left (higher chemical shift, downfield
shift), whereas unsaturation shift to the left (higher chemical shift, downfield) when
the pretentious nucleus is in the plane of the unsaturated group, but have the reverse
effect (lower chemical shift to the right or “upfield”) in the region of above and below
this plane [10].
The 1H NMR data for the synthesized organoantimony(V) complexes
(1A18A), (1B-10B) & (1C-20C) delineated in chapter-2, shows that the 1H NMR
spctra for the organoantimony(V) scaffolds depict the presence of aromatic protons at
7.23-8.59 ppm as earlier given in literature[9, 10]. The other resonances around 2.37-
2.40, 3.40-3.35 and 3.85-3.80 ppm are assigned to –CH3, –CH2-, –OCH3 groups
respectively. The –NH2 and –NH– protons of the ligands around 5.60 and 9.55 ppm,
respectively. 1H NMR spectra of the free ligands reveal that the singles resonating at
10.85 ppm are due to the –COOH group [7, 9]. “The 13C-NMR spectra depict all the
signals owing to the chemically distinct carbon atoms existent in these complexes. The
chemical shift values of aromatic carbon of the synthesized pentavalent antimonials
are designated on the reference of signal intensities and then equating with the
literature. The 13C NMR data of all compounds display a notable downfield shift of
all carbons resonant frequencies with comparison to the free ligand since an electronic
cloud relocate from the ligand to the metal. The 13C signal for -CH3 ariesd at 9.5–22.5
75
ppm. The 13C signals attributing to aryl group appeared at 110.0– 160.0 ppm and the
signals for carbonyl carbon gave signal at 167.0–180.0 ppm” [7, 11].
4.3. Single Crystal XRD Analysis
The synthesized organoantimony(V) complexes have been crystallized in suitable
solvent and selected for the single crystal X-ray diffraction analysis.
4.3.1. Bis(2-aminobenzoato)(triphenyl)antimony(V) (1A) and Bis(3,5dichlorobenzoato)
(triphenyl)antimony (V) (4A)
The antimony(V) complexes in (1A) and (4A) are five-coordinate with geometries in
between the trigonal bipyramidal. and square pyramidal. In the trigonal bipyramidal
consideration, the monodentate carboxylate ligands occupy axial position with a syn
conformation and the phenyl moieties rest at equatorial position, while in the square
pyramidal extreme the C7-C12 (for 1A) or C13a-C18a (for 4A) phenyl group is apical.
A molecular arrangement of the complex in (1A) is presented in Figure 1 and of the
complex in (4A) in Figure 2.
The geometries in these complexes closely conform to the typical geometry
found for complexes with essentially synmonodentate carboxylate ligands in
approximately 53 similar compounds listed in the Cambridge Structural Database
(four additional compounds listed in the database are with carboxylate ligands serving
as bidentate and monodentate as well). The 2-aminobenzoato- (1A) and
3,5dichlorobenzoato- (4A) ligands show average C-O bond length of 1.271(3) and
1.261(3) Å, respectively. The Sb-O bond lengths for these complexes cluster
atcomparatively longer values 2.1286(18) and 2.1134(15)Å. The non-ligating Sb…O
contacts, involving O atoms is in the range of 2.726-3.010 Å, a contact range that has
beenmost frequently found for similar complexes [12, 16]. Particulars of the data
collection and structure refinement parameters are summarized in Table 4.
76
Figure 1.Molecular structure of (1A) with labels for the core atoms only. H-atoms
are drawn as circles of arbitrary radii.
Figure 2.Molecular structure of (4A) with labels for the core atoms only. H-atoms
are drawn as circles of arbitrary radii.
78
The benzoato- ligands are almost coplanar in all two complexes (angle between mean
plane normals of 10.50(5) and 3.77(5)º for (1A) and (4A)respectively. O-SbC(7) (for
1A) or O-Sb-C(13a) (for 4A) angles <90 between the apical phenyl and basal
carboxylate ligands indicate that the carboxylate ligands are distorted above the basal
plane. Similar distortions are found for the related complexes in the CSD. Sb-C bond
lengths average 2.122(3) and 2.134(3) Å for structures (1A) and (4A), respectively.
The average Sb-C bond lengths for these two structures fall within the range 2.089-
2.130 Å, most frequently observed for similar complexes [15]. Selected geometrical
parameters are listed in Table 5.
79
Table 6.The intermolecular and intramolecular hydrogen bonds for compound
The crystal packing in (1A) (orthorhombic Pccn) compared to (4A) (triclinic P ̅) bears
more complicated unit cell packing in which double layers of Sb(V) complexes are
stacked along c(Figure 3).
Figure 3: Unit cell packing for (1A) in which double layers of Sb(V) complexes are
stacked along c.
80
Figure 4. Supramolecular structure of complex (1A) showing 3D network of short
contacts and H-bonds are stabilizing crystal structure.
In the crystal structure (1A), molecules are connected through C-H…N and N-H…O
intermolecular and N-H…O and C-H…O intramolecular interactions forming a 3D
network extended throughout the crystal system (Figure 4) Table 6. The molecular
structures with greater multitude of interactions are considered to be very potent
regarding biological activities as evident from (1A) and (4A) (Figure 4). The crystal
structure of (4A) is stabilized via C-H…Cl and Cl…Cl interactions along c-axis forming
a type motifs (Figure 5) [15].
Figure 5.One-dimensionalview of molecules (4A) along c-axis forming a
type motifs stabilized by alternate Cl…Cl and C-H…Cl short contacts.
81
4.3.2. Crystal Structures of Compounds (10A), (11A), (13A), (14A) and (17A).CHCl3
The molecular structures of compounds (10A), (11A), (13A), (14A) and (17A).
CHCl3 were determined by single crystal X-ray diffraction methods (Figure 6).
82
Figure 6. Molecular diagrams of SbPh3L2: (10A), (11A), (13A), (14A)
and(17A).CHCl3. Solvate (CHCl3) part in 17A have been omitted.
Details of the data collection and structure refinement parameters are summarized in
Table 7(a & b). Each complex is monomeric and the coordination geometry of the
83
Sb(V) center is approximately trigonal bi-pyramidal with the three phenyl rings
equatorial and an oxygen atom of the two carboxylate ligands in the axial positions.
The coordination geometries of (10A), (11A), (14A) and (17A).CHCl3 are distorted
from a regular polyhedron as indicated by the significant deviations of the C-Sb-C
angles from 120° (Table 8) with notably one larger angle of 143.75(7) (10A), 154.9(1)
(11A), 152.1(1) (14A) and 137.61(8) (17A.CHCl3) Å. In each of these complexes, the
axial carboxylate groups are approximately coplanar (C-O-O-C torsion angles 3.3-
21.9°) with the second oxygen atom of each group bisecting the larger C-Sb-C angle.
The exception is compound 13A in which the axial carboxylate groups are twisted
relative to each other (C-O-O-C torsion angle 116.0°) and the second oxygen atom of
each carboxylate group bisects opposing C-Sb-C angles, resulting in a more regular
trigonal geometry (Table 8). In all complexes, the Sb-C distances fall in a narrow
range (2.096(1)-2.118(1) Å) whereas there are some differences in the Sb-O distances
2.1035(9)-2.157(2) Å, with longer values observed for complexes 11A and 14A and
which are associated with corresponding closer non-bonded Sb...O distances (2.63-
2.69 Å, cf 2.96-3.14 Å for 10A, 13A and 17A) to the second of the carboxylate oxygen
atoms.
87
4.3.3. Crystal Structures of Bis(4-methylbenzoato)tris(p-tolyl)antimony(V) (1B), Bis(3,5-
dichlorobenzoato)tris(p-tolyl)antimony(V) (3B) and
Bis(nicotinato)tris(ptolyl)antimony(V)(5B)
The structures of 1B, 3B and 5B are depicted in Figs.7-9, respectively and data
collection and refinement parameters are delineated in Table 9. Selected bond lengths
and bond angles appear in Table 10. The complex shows two ligand molecules
covalently bond through the oxygen atom with antimony atom, and three p-tolyl
groups originating three Sb–C bonds.
The antimony(V) complexes 1B, 3B, and 5B are five-coordinated with
geometries intermediate between trigonal bipyramidal and square pyramidal. In the
trigonal bipyramidal extreme, the monodentate carboxylate ligands are axial with a
syn conformation and the tolyl ligands occupy equatorial position, while in the square
pyramidal extreme the C4X (for 1B and 5B) or C1-C7 (for 3B) tolyl ligand is apical.
The thermal ellipsoid plots of the complexes 1B, 3B and 5B are presented in Figures
7, 8 & 9 respectively.
Figure 7. ORTEP plot (50% ellipsoids) for the coordination complex in 1B with labels
for the core atoms only. H-atoms are drawn as circles of arbitrary radii.
88
Figure 8. ORTEP plot (50% ellipsoids) for the coordination complex in 3B with labels
for the core atoms only. H-atoms are drawn as circles of arbitrary radii.
Figure 9.ORTEP plot (50% ellipsoids) for the coordination complex in 5B with labels
for the core and N-atoms only.
The geometries in these complexes closely conform to the typical geometry found for
complexes with essentially syn monodentate carboxylate ligands in 50 similar
89
compounds listed in the Cambridge Structural Database (four additional compounds
listed in the database with bidentate carboxylate ligands are, arguably, monodentate
as well). In contrast, complexes with a pronounced twist of the carboxylate groups
toward an anti-arrangement exhibit five-coordinate geometries far closer to trigonal
bipyramidal, as shown by C-Sb-C angle values clustered about 120º. So, for example,
the 4-methylbenzoato- (1B), 3,5-dichlorobenzoato- (3B), or nictinato- (5B) ligands
show average C-O bond lengths of 2.1251(12), 2.1257(120, and 2.1176(13) Å,
respectively, while Sb-O bond lengths for similar complexes cluster most frequently
in a slightly longer length range 2.122 to 2.137 Å. The Sb…O contacts involving non-
ligating O atoms are in the range of 2.8-3.0 Å, a range that corresponds to the most
frequently found contact distance for similar complexes. Details of the crystal data,
data collection, structure determination conditions and parameters are summarized in
Table 9. The benzoato- or nicotinato- ligands are almost coplanar in all three
complexes (angle between mean plane normals are of 5.10(6) and 4.45(5)º for 1B and
5B respectively) with ring N-atoms anti in 5B. The O-Sb-C(41) (for 1B and 5B) or
O-Sb-C(1) (for 3B) angles <90 between the basal carboxylate and apical tolyl ligands
indicate that the carboxylate ligands are distorted above the basal plane (Table 10).
Similar distortions are found for all but one of the related complexes in the CSD. The
Sb-C bond lengths average are 2.107(1), 2.110(2), and 2.113(2) Å for structures 1B,
3B, and 5B, respectively, with the apical C4X ligand in structure 5B showing small,
but significant, elongation relative to the basal C3X and C5X ligands (Average Sb-C
bond lengths for these three structures fall within the range 2.105-2.115 Å most
frequently found for similar complexes.). Among metrical parameters, the C31-Sb1-
C51 angle exhibits the strongest distortion from a trigonal bipyramidal geometry
(143.32(9)º for 1B, 145.92(11)º for 3B,and 145.84(11)º for 5B). The apical C4X
ligand is twisted relative to the basal C1X and C2X ligands in 1B (14.75(5) and
15.19(5)º, respectively between mean plane normals), while almost coplanar with the
same ligands in 5B (5.90(9) and 4.51(7) º respectively) and in 3B. The trans C3X and
C5X tolyl groups exhibit a slight twist about the Sb-C axis in structure 1B, and the
90
C3X group is slightly bent toward the O11 ligand in 5B, so that these groups are not
coplanar (angles between mean plane normals are 10.71(8)º for 1B and 11.17(2)º for
5B), although they are essentially coplanar in 3B [14].The selected geometrical
parameters are presented in Table 10 .
93
The disparate crystal packing in 1B (orthorhombic Pbca) compared to 3B and 5B
(triclinic P ̅) bears comment. The structure of 1B displays a more complicated unit cell
packing in which double layers of Sb(V) complexes are stacked along c-axis. The
double layers are composed, in turn, of distorted orthohexagonal packed (b/a=
1.87410(2) compared to the ideal ratio of 1.73205) layers of complexes in which
phenyl ring 4 projects along positive (or negative for the neighboring layer) c-axis to
nest into a cavity formed by the other four phenyl rings of the neighboring layer, The
cavity walls are formed by vertical phenyl rings arranged in a square with the plane of
projecting phenyl ring 4 approximately parallel to the planes of phenyl rings numbers
3 and 5, and approximately perpendicular to the planes of phenyl rings 1 and 2 (of the
carboxylate ligands). Within the double layers there are voids formed between the
projecting phenyl rings (53 Å3 with a probe radius of 1.2 Å and a grid spacing of 0.2
Å), shown in the packing diagram of Figure 10, that are large enough to accommodate
a water molecule but too small for other common solvents.
Figure 10. Packing diagram for 1B with atoms plotted as spheres of arbitrary radii
and with axis labels (a horizontal and c vertical). The voids between projecting phenyl
rings of the double layers are depicted.
However, water was scrupulously avoided in preparation of the compound, no
significant residual electron density is observed in the voids, and application of the
94
SQUEEZE algorithm to the structure leads to deterioration of every measure of
structure refinement quality-hence we conclude that the voids are empty.
Unit cell parameters for 5B are consistent with distorted hcp layers of complexes in
the ab-plane stacked along c with phenyl ring 4 projecting above (or below for the
neighboring) layer. However, the complexes are rotated out of the layer to produce
ribbons two complexes wide directed along a with ribbons aggregated in (012) lattice
plane as the more prominent packing feature. Here complexes on opposite sides of
the ribbon have phenyl ring 4 projected in opposite directions away from the ribbon
plane. Rotation of the complexes out of the layer provides a more efficient packing
than 1B, with a calculated density almost 0.1 g/cm3 higher than 1B at ambient
temperature and no calculated voids found under the same conditions as stated above.
A packing diagram for 5B viewed down the ribbon axis is presented in Figure 11.
Figure 11. Packing diagram for 5B, viewed parallel to a, with atoms drawn as spheres
of arbitrary radii and with unit cell axis labels. The layers of ribbons in (012) are
viewed end-on.
The packing in 3B is distinctly different: chains of complexes parallel to [101]
(formed by face-to face overlap of carboxylate- ligand aromatic rings) assemble into
layers coincident with (1 ̅1), as shown in Figure 12. Phenyl rings of the apical tolyl
95
complexes project outward both above, and below the layer, to nest into voids formed
between chains of complexes in the neighboring layers. These voids are readily
apparent as the empty spaces visible in the layer packing diagram in Figure 12.
Figure 12. View of the layer packing in 3 viewed perpendicular to the (1 ̅1) plane with
[101], the direction of the chains of complexes formed by face-to-face overlap of
benzoate- phenyl rings, horizontal. The position of one of the voids, as discussed in
the text, is marked with an X.
Less apparent are the small voids offset from a large void, one such small void is
marked with an X in Figure 12, that each remain as an unfilled void with a volume of
23 Å3. Thus the three structures exhibit a range of packing behavior with, in the case
of 1B and 3B, the presence of voids that could indicate the possibility of
polymorphism or favorable conditions for co-crystal formation [16].
96
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LIST OF PUBLICATIONS
1. R. Mushtaq, M. Khawar Rauf, M.Bolte, A. Nadhman, A.Badshah, M. N. Tahir,
M. Yasinzai, K. M. Khan. (2017) Synthesis, characterization and antileishmanial
studies of some bioactive heteroleptic pentavalent antimonials. Appl.
Organometal. Chem. 31, 3606-3613.
2. R. Mushtaq, M. Khawar Rauf, M. Bond, A.Badshah, M. I. Ali, A. Nadhman, M.
Yasinzai and M. N. Tahir. (2016) A structural investigation of heteroleptic
pentavalent antimonials and their leishmanicidal activity. Applied Organometallic
Chemistry. 30 (2016) 465–472.
3. M. Khawar Rauf, R. Mushtaq, A. Badshah, R. Kingsford-Adaboh, J. J. E. K.
Harrison and H.Ishida. (2013) Synthesis and Crystal Structure Studies of Three N-
Phenylphthalimide Derivatives. Journal of Chemical Crystallography, 43:144–150