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ISSN 2348-7410
PRAJNAN O SADHONA – A SCIENCE ANNUAL
VOL 1, 2014
DEPARTMENT OF CHEMISTRY
FAKIR CHAND COLLEGE
1 | Prajnan O Sadhona ……
Prajnan O Sadhona – a Science Annual
Volume 1, 2014
Published by:
The Principal
Fakir Chand College
Diamond Harbour, West Bengal
Ph.: 03174-255230
Email: [email protected]
Web: www.fakirchandcollege.org
January, 2014
Cover Design:
Prajnamoy Pal, Rana Karmakar
Moumita Sen Sarma, Tapas Kumar Mandal
Printed by:
Adhunik Press, Diamond Harbour
24 Parganas (S)
Mob: 9800415767
ISSN 2348–7410
vol 1, 2014 2
EDITORIAL ADVISORY COMMITTEE
1. Dr. Subires Bhattacharyya
Principal
Fakir Chand College, Diamond Harbour, South 24 Parganas, W.B.
2. Dr. Kalyan K. Mukherjea
Professor in Chemistry
Jadavpur University, Jadavpur, Kolkata-700032
3. Dr. Debprasad Chattopadhyay
Deputy Director, ICMR Virus Unit
ID & BG Hospital, Beliaghata, Kolkata-700010
4. Dr. Debashis Bandyopadhyay
Principal Scientist
Programme Management Division (CSIR)
Central Glass & Ceramic Research Institute
Jadavpur, Kolkata-700032
5. Dr. Pralay Das
Assistant Professor & Scientist
Institute of Himalayan Bioresource Technology.
Palampur, Himachal Pradesh
6. Dr. Prajnamoy Pal
Associate Professor, Department of Chemistry
Fakir Chand College, Diamond Harbour, South 24 Parganas, W.B.
7. Dr. Rana Karmakar
Assistant Professor, Department of Chemistry
Fakir Chand College, Diamond Harbour, South 24 Parganas, W.B.
8. Dr. Moumita Sen Sarma
Assistant Professor, Department of Chemistry
Fakir Chand College, Diamond Harbour, South 24 Parganas, W.B.
9. Dr. Tapas Kumar Mandal
Assistant Professor, Department of Chemistry
Fakir Chand College, Diamond Harbour, South 24 Parganas, W.B.
3 | Prajnan O Sadhona ……
Preface
For an all-round development of one‟s thoughts and intellect the
customary bookish learning is not only insufficient but also harmful as it
prevents the development of a complete mind. A good journal/periodical
is such a device through which one can express and nurture one‟s thoughts
and intellect that significantly assist to comprehend the self-potentiality.
College/departmental journal is an important torch in this direction. Here
the views and knowledge are communicated in a common platform and
thus offers a successful surge and transaction of knowledge benefiting the
whole community. With this in mind the Department of Chemistry has
developed its brain child „Spandan‟ which was first formally published in
January 2013, as a departmental journal. „Prajnan O Sadhona – a Science
Annual‟ is an upgraded version of „Spandan‟, which is a peer-reviewed
journal with ISSN no. where a large arena of science has been covered
with an aim to significantly widen our knowledge spectrum in the area of
current trends in science.
sd/-
EDITORS
vol 1, 2014 4
Contents
Pages
1. Basic Ideas of Supramolecular Chemistry
Debabrata Pal
2. Organotin Compounds – A Short Review on the
Nature of Bonding and Other Related Properties
Moumita Sen Sarma
3. Formula for the Wiener Index of n-polyphenacene
systems
Piyali Ghosh
4. Nanotechnology in medicine
Prajnamoy Pal
5. Solvation Dynamics
Rana Karmakar
6. Chemistry of the Brain in Depression and its relation
to the Immune system
Sanjukta Chaudhuri
7. Controlled Drug Delivery in Chemotherapy using
Polymeric Drug Carriers
Suchandra Biswas
8. Recent applications of iodine in organic synthesis
Tapas Kumar Mandal
9. Stabilization of Lipophilic Drug, Curcumin within
Micelles
Ummul Liha Khatun
05-10
11-19
20-24
25-33
34-41
42-59
60-70
71-86
87-89
5 | Prajnan O Sadhona ……
Basic Ideas of Supramolecular Chemistry
Debabrata Pal *
Science encompasses everything around us. We want justification of our
every instant. The moment we fail to logically follow a situation from our
existing knowledge, there comes a stage of generation of newer ideas,
with an aim to explain the facts, thus newer theories are developed and
science proceeds in its own way towards better and better apprehension.
The different branches of science have been ascribed own territories
regarding the field of application. In the early days, the boundary was
quite rigid among the different branches, but with the development of
science which is essentially the growth and spreading out of various
interdisciplinary subjects such that the initial delineation is largely
scrambled. In this context the range of a subject is interpreted solely in
view of its relevance to the area of basic sciences. In the field of
Chemistry, “Supramolecular Chemistry”, not necessarily a newer branch,
is expanding immensely in view of the development of theories and
methodologies, characterization of newer systems and owing to the
increasing area of applicability in diversified fields.
* Assistant Professor, Department of Chemistry, Sreegopal Banerjee
College, Bagati, Magra, Hooghly, West Bengal, Pin - 712148
Email: [email protected]
vol 1, 2014 6
Supramolecular chemistry refers to the area of chemistry beyond the
molecules and focuses on the chemical systems made up of a discrete
number of assembled molecular subunits or components. This is the
branch of chemistry that describes self-organization or self-assembly of
systems to well defined molecular architectures. It refers to the area that
focuses on the noncovalent bonding interactions of molecules. While
traditional chemistry focuses on the covalent bond, supramolecular
chemistry examines the weaker and reversible noncovalent interactions
between molecules. These forces include hydrogen bonding, metal
coordination, hydrophobic forces, van der Waals forces, pi-pi interactions
and electrostatic effects. Important concepts that have been demonstrated
by supramolecular chemistry include molecular self-assembly, folding,
molecular recognition, host-guest chemistry, mechanically-interlocked
molecular architectures and dynamic covalent chemistry. The study of
non-covalent interactions is crucial to understanding many biological
processes from cell structure to vision that rely on these forces for
structure and function. Biological systems are often the inspiration for
supramolecular research.
The supramolecular chemistry has its origin long before. Johannes Diderik
van der Waals first postulated the existence of intermolecular forces in
1873. However, it is with nobel lauriate Hermann Emil Fischer that
supramolecular chemistry has its philosophical roots. In 1890, Fischer
suggested that enzyme-substrate interactions take the form of a "lock and
key", pre-empting the concepts of molecular recognition and host-guest
chemistry. In 1891 Villers isolated „cellulosine‟, followed by preparation
of cyclodextrin-iodine complexes by Schradinger in 1903. In the early
twentieth century non covalent bonds were understood in gradually more
7 | Prajnan O Sadhona ……
detail, with the hydrogen bond being described by Latimer and Rodebush
in 1920. And thus led to the understanding of the principles towards
elucidation of structures of DNA and functioning of various biological
processes. In 1954 Cramer published Einschiussverbindungen (Inclusion
Compounds). The breakthrough came in the 1960s with the synthesis of
the crown ethers by Charles J. Pedersen. The field exploded when three of
the pioneers, namely, Jean-Marie Lehn, Donald Cram and Charles
Pedersen won the 1987 Nobel Prize in chemistry for synthesizing
molecules and compounds with cavities and cages within which metal ions
and other molecules could be bound. The words of J. M. Lehn in defining
the term are still noteworthy. “Just as there is a field of molecular
chemistry based on the covalent bond, there is a field of supramolecular
chemistry, the chemistry of molecular assemblies and of the
intermolecular bond.”
In the 1990s, supramolecular chemistry became even more sophisticated,
with researchers such as James Fraser Stoddart developing molecular
machinery and highly complex self-assembled structures, and Itamar
Willner developing sensors and methods of electronic and biological
interfacing. During this period, electrochemical and photochemical motifs
became integrated into supramolecular systems in order to increase
functionality, research into synthetic self-replicating system began, and
work on molecular information processing devices began. The emerging
science of nanotechnology also had a strong influence on the subject, with
building blocks such as fullerenes, nanoparticles, and dendrimers
becoming involved in synthetic systems.
The two major principles involved in supramolecular chemistry are
namely molecular recognition and self-assembly. Supramolecular
vol 1, 2014 8
chemistry is essentially termed as “Host-Guest Chemistry”, where a
molecule "host" combines with a molecule "guest", where the bonding
interactions prevail through non covalent bonding. The host component is
defined as an organic molecule or ion, whose binding sites converge in the
complex and the guest component, is defined as any molecule or ion
whose binding sites diverge in the complex. Non covalent bonding is
critical in maintaining the three-dimensional structure of large molecules,
such as proteins and is involved in many biological processes in which
large molecules bind specifically but transiently to one another. Here the
host and guest involved exhibit molecular complementarity. However
when the interaction between the host and the guest becomes so specific,
such that the discrimination of a particular guest molecule among a
number of guest molecules is achieved by the host molecule, it is the case
of „molecular recognition‟. Crown ethers, cyclodextrins, calixarenes,
porphyrins etc are different macrocyclic host molecules or receptors that
can bind different guest molecules in different cases, such as the cations,
anions and also neutral molecules. Inclusion phenomenon chiefly
describes the type of interaction whereby some large guest is embodied
within the cavity of the host molecule, examples can be cited of the
complexation of fullerenes by means of bisporphyrins or calixarenes.
In self-assembly, molecular structures of a defined geometry add
complementary molecular components, becoming ever-larger arrays
without guidance or management from an outside source (other than to
provide a suitable environment). The molecules are directed to assemble
through non covalent interactions. Self-assembly may be subdivided into
intermolecular self-assembly (to form a supramolecular assembly), and
intramolecular self-assembly (or folding as demonstrated by foldamers
9 | Prajnan O Sadhona ……
and polypeptides). Molecular self-assembly also allows the construction of
larger structures such as micelles, membranes, vesicles, liquid crystals,
and is important to crystal engineering.
The interactions involved in supramolecular chemistry are predominantly
intermolecular where the different type of interactions such as H-bonding,
pi-pi stacking, hydrophobic interactions etc play their part with their
effects varying from system to system. Though each interaction is very
weak, yet their combination produces thermodynamically stable
structures, which is the essence of Supramolecular chemistry.
Supramolecular chemistry continues its expansion to include
understanding and mimicking biological processes, molecular recognition,
molecular self-assembly, catalysis, materials and medicinal chemistries,
but also dynamic covalent chemistry. In particular, efforts are recently
devoted to the synthesis of molecular machines that function through
host–guest recognition. Such systems are designed to achieve a specific
function and considerable efforts are currently focused on the construction
of molecular switches and devices in which external stimuli are used to
induce molecular motion. Therefore, the design of molecular systems
capable of controlled molecular-level motion has become an area of
growing interest, and a key issue in this field concerns the so-called
molecular tweezers, clips and clefts. The application of the underlying
principles of supramolecular chemistry is envisazed in various fields,
starting from sensors, biosensors to optoelectronics, drug delivery and
many others. In a word, it is sufficient to mention that the field of
Supramolecular chemistry will be not only promising but also extensively
challenging in the coming days. The words of J. M .Lehn seem
particularly apt for conclusion. “Supramolecular chemistry embodies the
vol 1, 2014 10
creative power of chemistry. By its very essence, by its ability to create
and through the beauty of its objects, chemistry is an art as well as a
science. Indeed, it fashions entire new worlds that do not exist before they
are shaped by the hand of the chemist, just as matter, shaped by the hand
of the sculptor, becomes a work of art”.
11 | Prajnan O Sadhona ……
Organotin Compounds – A Short Review on the Nature of
Bonding and Other Related Properties
Moumita Sen Sarma *
Introduction
The Chemistry of tin has been the subject of extensive research in the last
few decades. Tin in the form of a metal and its alloys were known to the
ancient people and have greatly affected the course of human history. Tin
(atomic number, 50; relative atomic mass 118.70) is an element of group
14 of the periodic table, together with C, Si, Ge and Pb. Tin exists in three
allotropic modifications and it can form a variety of inorganic and
organometallic compounds. These two classes of compounds have
different chemical and physical properties, which make them suitable for
different applications in industry, agriculture and elsewhere. Tin as a
metal, either as such, or in the form of its alloys and chemical compounds,
has an astonishing amount of usefulness. Characteristically, in majority of
its applications, only small amount of tin is needed to see its effect. This is
generally true for organotin compounds, which during the past few
decades have developed into extremely useful industrial commodities. Tin
is unsurpassed by any other metal in the multiplicity of its applications.
These involve such widely divergent fields as stabilizers for polyvinyl
chlorides, industrial catalysts, industrial and agricultural biocides, wood
preservatives and anti-fouling agents to mention only the most important
applications.
* Assistant Professor, Department of Chemistry, Fakir Chand College,
Diamond Harbour, South 24 Parganas, Pin- 743331
Email: [email protected]
vol 1, 2014 12
Organotin compounds are defined as those that contain at least one
carbon-tin covalent bond, the carbon atom being part of an organic group.
The compounds contain tetravalent tin centres and are classified as mono-,
di-, tri- and tetraorganotin (IV)s, depending on the number of alkyl (R) or
aryl (Ar) moieties. The anion is usually a chloride, fluoride, oxide,
hydroxide, a carboxylate or thiolate.
The first chemist to report the existence of “organic bodies of tin” as they
were then known seems to have been E. Frankland. This paper was
devoted largely to the reaction which occurred when ethyl iodide and zinc
were heated together in a sealed tube. The behaviour of ethyl iodide in
contact with metallic tin, at elevated temperatures (150 to 200oC) was also
studied. Frankland later showed that the crystals obtained by the reaction
of EtI with Sn at elevated temperatures (Eq.1) were of diethyltin diiodide.
2EtI + Sn Et2SnI2 ………… (1)
Bonding in organotin compounds
Tin has 5s2, 5p
2 electronic configuration in its valence shell and therefore,
two oxidation states i.e., +2 and +4 (due to „inert s-pair effect‟) are
possible. The ground state for tin is a 3P state, derived from s
2p
2
configuration. In this state, there are only two unpaired electrons and a
covalence of two would be expected. But the tetra-covalent state occurs
much more frequently than the divalent state. The four-covalent state is
derived from the sp3,
5S state of the tin, which is not the ground state but
the first excited state.
13 | Prajnan O Sadhona ……
Essentially, most of the organometallic tin compounds are of the Sn(IV)
type . The marked increase in the stability of R4Sn compounds over R2Sn
compounds demonstrates the effect of increased hybridization. The
stability (to heat & oxygen) of organotin derivatives in tetravalent states is
reflected in the vast amount of growing literature about them. By contrast,
their bivalent derivatives are much less stable, but these are also beginning
to attract attention particularly with sterically demanding ligands {e.g.
CH(SiMe3)2} and -bonding ligands. These bulky ligands stabilize the
compounds in low-coordination geometry, as the congested environment
around the metal hinders polymerization due to steric factors. For
example, tin(II) cyclopentadienyl, (C5H5)2Sn is a well-established
compound with tin in the (+2) oxidation state.
Reactivity of organotin compounds
The tetraalkyl and aryl compounds of main group 14 elements differ from
the corresponding derivatives of these elements in neighbouring groups
because of their relatively low reactivity. This difference in behaviour is
more because of kinetic than thermodynamic factors.
Within group 14, the reactivity of M-C bond in tetra- alkyl and aryl
increases progressively from Si to Pb as
bond energy decreases in the same sequence
expansion of the coordination number of the metal (M) becomes
easier with increasing atomic size and decreasing difference
between np and nd orbitals.
Si(C2H5)4 Ge(C2H5)4 Sn(C2H5)4 Pb(C2H5)4
Decreasing M-C bond energy
Decreasing thermal stability
vol 1, 2014 14
The electronegativity of tin change with its oxidation number. Tin(II)
compounds are generally more ionic than tin(IV) compounds .
The general characteristic pertaining to increase in electropositive
character with increase in atomic number in a group is also strikingly
pronounced among the metals of group 14. Therefore, the Sn-C bond
should be polar since tin is electropositive with respect to carbon and is
represented by Cδ-
-Snδ+
. The polarization of Cδ-
-Snδ+
bond makes tin atom
more electrophilic and carbon atom attached to tin more nucleophilic. This
enhances the reactivity of organotin moieties both towards electrophiles as
well as nucleophiles. Reaction of alkyltin chlorides with the appropriate
nucleophiles gives the alkyltin alkoxides, amides, thioalkoxides,
carboxylates etc. The presence of these electronegative groups on tin
renders the metal susceptible to coordination by Lewis bases and simple
tetrahedral four-coordination is an exception rather than the rule in such
cases.
Organotin compounds can undergo Grignard type reactions particularly
with carbonyl containing substrates. For instance, allyltin compounds will
add across the C=O bond of aldehydes in a manner analogous to that of
Grignard reagent.
Et3SnCH2CH=CH2 + RCHO RCH(OSnEt3)CH2CH=CH2 …….(2)
Due to low polarity of C-Sn bond, as in tetraalkyl and aryl derivatives of
tin, these are not actually hydrolyzed by water. Hydrolysis however, may
be brought about by increasing pressure and temperature and using
catalysts such as acid or alkalis which attack „C‟ or „Sn‟. A rather unusual
feature of the organotin compounds is the ionization of some of the R3SnX
and R2SnX2 compounds in water .The extremely ready hydrolysis of a
15 | Prajnan O Sadhona ……
fluorocarbon-tin bond in perfluorophenyl trimethyltin has been partly
ascribed to the increased susceptibility of tin to nucleophilic attack. The
hydrolysis is catalyzed by halide ion.
There is substantial evidence that the d orbitals of the elements of group
14, other than carbon are used in dπ-pπ bonding. A simple example
illustrates this phenomenon. With the four acids of the type p-
R3MC6H4COOH, where M=C, Si, Ge or Sn, C is the most electronegative
and should enhance the acid strength to the greatest extent. But, it is found
that M=C compound shows the lowest acid strength, indicating that dπ-pπ
bonding is operative in the other three metal compounds. The tendency to
use„d‟ orbitals in bonding decreases from Si to Sn, since in (GeH3)2S and
(GeH3)2O, the Ge-S-Ge and Ge-O-Ge appear to be highly bent whereas in
(SiH3)2O, the Si-O-Si bond angle is around 150oC. However, the
possibility of dπ-pπ bonding in Sn cannot be completely ignored, atleast
with elements of higher atomic numbers, e.g., Cl, Br, I, etc. This is
supported by the higher values of Sn-Cl stretching frequencies in certain
tin compounds and Sn–O frequency in (Ph3Sn)2O.
Reactions of the general type:
Sn-C Sn-A C-BA B
are of utmost significance in both theoretical and practical studies in
organotin chemistry. Although the reactivity of tin-carbon bonds depends
on molecular environment, they are susceptible to attack by a wide variety
of reagents so that A-B in the above equation may be a halogen, mineral
acid, carboxylic acid, thiol, phenol, alcohol, metallic or non-metallic
halide, alkali & alkali metal etc. Tin-carbon bond cleavage not only
vol 1, 2014 16
involves electrophilic attack at „C‟ but also nucleophilic assistance at the
Sn atom.
Among organometallic main group compounds, organotin compounds are
quite unique in possessing reasonably labile tin-carbon bonds. While
compounds containing Sn-allyl bonds are the most labile, those containing
Sn-benzyl and Sn-phenyl substituents are sufficiently reactive. The Sn-
alkyl bond cleavage is the most difficult to accomplish and occurs under
relatively harsh conditions. Even among Sn-alkyl compounds those
containing Sn-methyl cleavage are the most documented. In contrast,
those involving Sn-butyl cleavage are very few. The current state of
knowledge of these Sn-C cleavage reactions allow these compounds to be
utilized extensively as synthons. In view of this, it is expected that in
addition to organotin halides, oxides and hydroxide compounds containing
Sn-alkyl, Sn-benzyl, Sn-phenyl or Sn-allyl bonds will also be very useful
as reactants in synthetic procedures for the construction of rings, cages and
clusters.
Structure of organotin compounds
Tin(II) compounds are mostly bent, pyramidal or distorted (due to the
presence of a stereochemically active lone pair of electrons which does not
participate in bonding and occupies a position directed away from the
strongly bonded coordination sites). The structural chemistry of tin(IV)
compounds reflects the relative simplicity of the electronic configuration
in this oxidation state and is dominated by regular bond arrangements:
tetrahedral, trigonal bipyramidal and octahedral depending on the
coordination number. Tin(IV) is remarkable in its capacity to expand its
17 | Prajnan O Sadhona ……
coordination number from four (which is found in most simple organotin
compounds like the simple tetraalkyls and tetraaryls) to five, six or seven .
In organotin derivatives of the type RnSnX4-n (n = 1 to3), where X is an
electronegative group (e.g. halide or carboxylate etc.), the Lewis acid
strength of tin is increased and subsequently the Lewis bases form
complexes with higher coordination number. The compounds R3SnX
usually yield five-coordinate complexes R3SnXL which are approximately
trigonal bipyramidal, and the compounds R2SnX2 and RSnX3 usually form
six-coordinate complexes R2SnX2L2 and RSnX3L2 which areapproximately
octahedral. The groups X, however, by virtue of the unshared electron
pairs which they carry, can themselves act as Lewis bases resulting in
intermolecular self-association to give dimers, oligomers, or polymers.
Nature of the ligands and the steric demands of R, X and L are the factors
influencing the self-association. If R or X carries a functional substituent
Y beyond the -position, intramolecular coordination can occur leading to
the formation of monomers with 5-, 6-, 7-, or 8- coordinated tin . In fact,
even, coordination number 7 which was once regarded an oddity no longer
remains to be so given the appropriate type of ligand to interact with the
metal; double-armed bis(semicarbazone) and bis(thiosemicarbazone)
ligands derived from pyridine belong to this class .
Applications of organotin compound
Non-biological applications
A major development in recent years has been the increasing use of
organotin reagents and intermediates in organic synthesis, exploiting both
their homolytic and heterolytic reactivity. Another important use of
organotin compounds is in the stabilization of PVC. Many organotin
vol 1, 2014 18
compounds are used as homogeneous catalysts in industry. Also, several
organostannosiloxanes have been shown to be extremely versatile
catalysts for transesterification reactions.
Biological applications
Organotin compounds have found a variety of applications in agriculture
and medicine. The first organotin compounds to reach commercialization
in agriculture (in the early 1960s) were triphenyltin acetate (Brestan*,
Hoechst A.G.) and triphenyltin hydroxide (Duter*, Philips Duphar, N.V.)
both of which are used widely. Aquatic organisms such as algae,
crustaceans, fish and mollusks are sensitive to tri-n-butyltin, triphenyl and
tricyclohexyltin compounds leading to the incorporation of these
triorganotin units in anti-fouling paints for marine transport vessels.
Organotin compounds are also used extensively as preservatives of wood
and as agricultural fungicides and insecticides, and in medicine they are
showing promise in cancer therapy and in the treatment of fungal
infections. Organotin compounds with coordination number greater than
four are significant for their biological activity and interesting structures.
Along with this their potent antitumour activity has led many researchers
to investigate them as effective antitumour agents. A large body of
literatures is now available.
References
1. Encyclopedia Britannica, 15th
Ed., 1974, Vol.18, 426.
2. Frankland, E. J. Chem. Soc., 1849, 2 , 263.
3. Frankland, E. Phil. Trans. 1852, 142, 417.
4. Frankland, E. Liebigs Ann. Chem. 1853, 85, 329.
19 | Prajnan O Sadhona ……
5. Weiss, R. W. (Ed.) Organometallic compounds, 2nd
Ed.,
Springer-Verlag, New York, 1967, Vol. 2, 158.
6. Cotton, F. A. Wilkinson, G. Advanced Inorganic Chemistry, 2nd
Ed., Inter Science Publishers, New York, 1967.
7. Poller, R. C. The Chemistry of Organotin Compounds, Logos
Press, London, 1970.
8. Neumann, W. P. The Organic Chemistry of Tin, Wiley, London,
1970.
9. Sawyer, A. K. (Ed.) Organotin Compounds, Marcel Dekker Inc.,
New York, 1971; 1972, Vols.1&2; Vol.3.
10. Zuckerman, J. J. (Ed.) Organotin Compounds: New Chemistry and
Applications, ACS, Washington, D.C. 1976.
11. Davies, A. G.; Smith, P. J. ‘Tin’, in: Comprehensive
Organometallic Chemistry, Wilkinson, G. (Ed.), Pergamon Press,
Oxford, 1982, Vol. 2, 519.
12. Blunden, S. J.; Cusack, P.A.; Hill, R. The Industrial Use of Tin
Compounds, Royal Society of Chemistry, London, 1985.
13. Evans, C. J.; Karpel, S. Organotin Compounds in Modern
Technology, Elsevier, Amsterdam, 1985.
14. Evans, C. J. in: Smith, P. J. (Ed.) Chemistry of Tin, Blackie
Academic and Professional, London, 1998, 442.
15. Molloy, K. C. Bioorganotin Compounds, in: F.R. Hartley (Ed.),
The Chemistry of Metal-Carbon Bond, John Wiley and Sons,
London, 1989, Vol.5, 46.
16. Mehrotra, R. C. ; Singh, A. Organometallic Chemistry-A unified
Approach, 2nd
Ed., New Age International (P) Ltd. Publishers,
New Delhi, 2000.
17. Davies, A. G. Organotin Chemistry, Wiley-VCH, Verlag, GmbH
& Co., KGaA, Weinhem, 2003.
18. Crowe, A. J. Appl. Organomet. Chem. 1987, 1, 143.
19. Crowe, A. J. Appl. Organomet. Chem. 1987, 1, 331.
20. Saxena, A. K.; Huber, F. Coord. Chem. Rev. 1989, 95, 109.
21. Gielen, M. Coord. Chem. Rev. 1996, 151, 41.
22. Nath, M.; Pokharia, S.; Yadav, R. Coord. Chem. Rev. 2001, 215,
99
23. Beckman, J.; Jurkschat, K. Coord. Chem. Rev. 2001, 215, 267
vol 1, 2014 20
24. Chandrasekhar, V.; Nagendran, S.; Baskar, V. Coord. Chem. Rev.
2002, 235, 1.
25. Pellerito, L.; Nagy, L. Coord. Chem. Rev. 2002, 224, 111.
26. Chandrasekhar, V.; Gopal, K.; Sasikumar, P.; Thirumoortii, R. L.;
Pellerito, L.; Nagy, L. Coord. Chem. Rev. 2005, 249, 1745.
21 | Prajnan O Sadhona ……
Formula for the Wiener Index of n-polyphenacene Systems
Piyali Ghosh *
Abstract
Formula for the determination of Wiener Index of n-polyphenacene
systems where n numbers of phenyl rings are attached in linear fashion is
derived. The formula so developed has been expressed in matrix product
form and in analytical form also. The analytical formula requires only the
value of n i.e. the number of phenyl rings present in polyphenacene
systems. Such formula has general applicability for the calculation of
Wiener Index for a large number of polyphenacene systems for any n
value.
Key Words
Wiener Index; n-polyphenacene; analytical formula
Introduction
Quantitative Structure-Activity Relationship (QSAR) and Quantitative
Structure-Property Relationship (QSPR) studies [1-3] are active areas of
chemical research that focus Structure-dependant chemical behavior of
molecules. Topological indices [4,5] are graph invariants and are found to
be very useful for searching molecular database, selecting compounds for
molecular drug screening and drug designing, modeling drug receptor sites
[6] and also predicting the properties like toxicities of chemical
compounds etc.
* Department of Chemistry, M.U.C. Women’s College, Burdwan-713104
Email: [email protected]
vol 1, 2014 22
2n+1 2n+1
3 4 4 4 4 4 3
3 4 4 4 4 4 3
Wiener Index of Graph
Wiener index (W) is one of the oldest and also common topological
descriptor of molecular structure and is based on the distance matrix; for a
graph G it is equal to the sum of the shortest distances between all pairs of
vertices of G and is expressed [7] as
jiji vv
i
vv
ji vDvvdw )(2
1),(
,
(1)
Method of determination for the Wiener Index of n-polyphenacene
Figure-1: Fragmentation of n-polyphencene using symmetry planes
Fragmentation of n-polyphencene using plane of symmetry is shown in
Figure-1. In this figure only four phenyl rings are shown but actually „n‟
numbers of phenyl rings are present here. According to graph theoretical
method we obtain three fragments which are given below
Figure-2
23 | Prajnan O Sadhona ……
When n-phenacene is fragmented using horizontal plane as shown in
Figure-3 two linear chains are obtained each consists of (2n+1) vertices if
n number of phenyl rings are present. Similarly considering the
fragmentations by other symmetry planes we obtain the last two linear
graphs as shown in Figure-2.
Figure-3
Thus using graph theoretical approach we can write the expression of
Wiener index (W) for n-phenacene as follows
2n+1
2n+1
vol 1, 2014 24
2
1
(2 1) 2 [3 ( 1)4][3 ( )]n
r
W n r n r
.......... (2)
Equation (2) can be written in matrix product form also and it is given
below
TABnW 2)12( 2 , T stands for transpose .......... (3)
In above equation (3) A and B are the two matrices of the form given
below
A ]4)1(3[ r and B )](3[ rn
Equation (2) can be farther calculated (replacing r by 1, 2, 3…n.) to obtain
the analytical formula
24 4 1 2[16 ( 1) / 2 16 ( 1)(2 1) / 6
16 ( 1) / 2 4 3]
W n n n n n n n
n n n
.......... (4)
After simplification of equation (4) we obtain the following form
15206016 23 nnnW .......... (5)
The formula to determine the Wiener index for n-polyphenacene is given
in above equation (5).
Conclusion
The formula has been used to generate the Wiener index for any poly-
phenacene systems. This index can be correlated to some important
physic-chemical properties of polyphenacene compounds. The Wiener
indices of thorn trees, stars, rings and rods have been presented by
Bonchev and Klein [8].
25 | Prajnan O Sadhona ……
References
1. Randić, M. J. Am. Chem. Soc. 1975, 97, 6609.
2. Randić, M. J. Am. Chem. Soc. 1992, 9, 97.
3. Balaban, A. T. (Eds.), Topological Indices and Related
Descriptors in QSAR and QSPR, Gordon and Breach Science
Publishers, The Netherlands, 1999.
4. Klein, D. J.; Randić, M. (Eds.), Mathematical Chemistry, VCH,
Weinheim, 1990.
5. Gutman, I.; Polansky, O. E. Mathematical Concepts in Organic
Chemistry, Springer-Verlag, New York, 1986.
6. Johnson, M. A.; Maggiora, G. M., Concepts and Applications of
Molecular Similarity, Wiley Interscience, New York, 1990.
7. Wiener, H. J. Am. Chem. Soc. 1947, 69, 17.; J. Phys. Chem. 1948,
52, 1082.
8. Bonchev, D.; Klein, D. J. Croat. Chem. Acta. 2002, 75, 613.
vol 1, 2014 26
Nanotechnology in Medicine
Prajnamoy Pal *
Nanomedicine involves utilization of nanotechnology for the benefit of
human health and well-being. The use of nanotechnology in various
sectors of therapeutics has revolutionized the field of medicine where
nanoparticles of dimensions ranging between 1-100nm are designed and
used for diagnostics, therapeutics and as biomedical tools. Conventional
drugs suffer from major limitations of adverse effects occurring as a result
of non-specificity of drug action and lack of efficacy due to improper or
ineffective dosage formulation. Designing of drugs with greater degree of
cell specificity improves efficacy and minimizes adverse effects.
Nanotechnology is being applied extensively to provide targeted drug
therapy, diagnostics, tissue regeneration, cell culture, biosensors and other
tools in the field of molecular biology. Various nanotechnology platforms
like fullerenes, nanotubes, quantum dots, nanopores, dendrimers,
liposomes, magnetic nanoprobes and radio controlled nanoparticles are
being developed.
The major factors influencing the treatment outcome in a patient are the
efficacy and safety profile of the drug more so when used for cancer
chemotherapy. These drugs have poor cell specificity and high toxicity
like bone marrow suppression, gastric erosion, hair loss, renal toxicity,
* Associate Professor, Department of Chemistry, Fakir Chand
College, Diamond Harbour, South 24 Parganas, Pin- 743331
Email: [email protected]
27 | Prajnan O Sadhona ……
Cardiomyopathy and several effects on other systems. Similarly treatment
for diabetes faces challenges with the route of delivery and inadequate
glycaemic control.
Development of newer drug delivery systems based on nanotechnology
methods is being tried for conditions like cancer, diabetes, fungal
infections, viral infections and in gene therapy. The main advantages of
this modality of treatment are targeting of the drug and enhanced safety
profile. Nanotechnology has also found its use in diagnostic medicine as
contrast agents, fluorescent dyes and magnetic nanoparticles.
Liposomes discovered in mid 1960s were the original models of
nanoscaled drug delivery devices. They are spherical nanoparticles made
of lipid bilayer membranes with an aqueous interior but can be unilamellar
with a single lamella of membrane or multilamellar with multiple
membranes. They can be used as effective drug delivery systems. Cancer
chemotherapeutic drugs and other toxic drugs like amphotericin and
hamycin, when used as liposomal drugs produce much better efficacy and
safety as compared to conventional preparations. Immunoliposomes are
liposomes conjugated with an antibody directed towards the tumour
antigen. The antibody can be conjugated to the surface of a stealth
liposome, the polyoxyethylene coating of a stealth liposome or on the
surface of a non-stealth liposome. These immunoliposomes when injected
into the body, reaches the target tissue and gets accumulated in its site of
action. This reduces unwanted effects and also increases the drug delivery
to the target tissue, thus enhancing its safety and efficacy.
vol 1, 2014 28
Nanopores consist of wafers with high density of pores (20 nm in
diameter). The pores allow entry of oxygen, glucose and other products
like insulin to pass through. However, it does not allow immunoglobulin
and cells to pass through them. Nanopores can be used as devices to
protect transplanted tissues from the host immune system, at the same
time, utilizing the benefit of transplantation.
Fullerenes, a carbon allotrope, also called as “bucky balls” were
discovered in 1985. The Buckminster fullerene is the most common form
of fullerene measuring about 7Å in diameter with 60 carbon atoms
arranged in a shape known as truncated icosahedrons. It resembles a
soccer ball with 20 hexagons and 12 pentagons and is highly symmetrical.
Fullerenes have the potential to stimulate host immune response and
production of fullerene specific antibodies. Animal studies with C60
fullerene conjugated.
Carbon nanotubes discovered in 1991 are tubular structures like a sheet of
graphite rolled into a cylinder capped at one or both ends by a buckyball.
Single walled nanotube has an internal diameter of 1-2 nm and multi-
walled nanotube has a diameter of 2-25 nm. Cell specificity can be
achieved by conjugating antibodies to carbon nanotubes with fluorescent
or radiolabelling. Entry of nanotubes into the cell may be mediated by
endocytosis or by insertion through the cell membrane. Amphotericin B
nanotubes have shown increased drug delivery to the interior of cells
compared to amphotericin B administration without nanotubes. The
efficacy of amphotericin B nanotubes was greater as an antifungal agent
compared to amphotericin B alone and it was effective on strains of fungi
which are usually resistant to amphotericin B alone. Further, there was
29 | Prajnan O Sadhona ……
reduced toxicity to mammalian cells with amphotericin B nanotubes. The
ability of nanotubes to transport DNA across cell membrane is used in
studies involving gene therapy. It was observed that carbon nanotubes,
except acetylated ones, when bonded with a peptide produce a higher
immunological response compared to free peptides. This property can be
used in vaccine production to enhance the efficacy of vaccines. Further, it
was also found that compounds bound to nanotubes increase the efficacy
of diagnostic methods like ELISA. These can also be used for designing of
biosensors owing to property of functionalization and high length to
diameter aspect ratio which provides a high surface to volume ratio.
Quantum dots are nanocrystals measuring around 2-10nm which can be
made to fluorescence when stimulated by light. Their structure consists of
an inorganic core, the size of which determines the colour emitted, an
inorganic shell and an aqueous organic coating to which biomolecules are
conjugated. The biomolecule conjugation of the quantum dots can be
modulated to target various biomarkers. Quantum dots can be used for
biomedical purposes as a diagnostic as well as therapeutic tool. These can
be tagged with biomolecules and used as highly sensitive probes.
Quantum dots can also be used for imaging of sentinel node in cancer
patients for tumour staging and planning of therapy. This method can be
adopted for various malignancies like melanoma, breast, lung and
gastrointestinal tumours.
Nanoshells were developed by West and Halas at Rice University as a new
modality of targeted therapy. Nanoshells consist of nanoparticles with a
core of silica and a coating of thin metallic shell. These can be targeted to
desired tissue by using immunological methods. This technology is being
vol 1, 2014 30
evaluated for cancer therapy. Nanoshells were developed by West and
Halas at Rice University as a new modality of targeted therapy.
Nanoshells consist of nanoparticles with a core of silica and a coating of
thin metallic shell. These can be targeted to desired tissue by using
immunological methods. This technology is being evaluated for cancer
therapy. Nanoshells can also be embedded in a hydrogel polymer
containing the drug. After directing the
nanoshells to the tumour tissue by immunological methods, with an
infrared laser, these can be made to get heated up, melting the polymer
and releasing the drug at the tumour tissue. Targeting the drug release
avoids the toxicity of cancer chemotherapy drugs. Nanoshells are currently
being investigated for micro metastasis of tumours and also for treatment
of diabetes.
Cancer therapeutic drugs can be incorporated into nanoscaled bubble like
structures called as nanobubbles. These nanobubbles remain stable at
room temperature and when heated to physiological temperature within
the body coalesce to form microbubbles. These have the advantages of
targeting the tumour tissue and delivering the drug selectively under the
influence of ultrasound exposure. This results in increased intracellular
uptake of the drug by the tumour cells. It also provides an additional
advantage of enabling visualisation of the tumour by means of ultrasound
methods. Liposomal nanobubbles and microbubbles are also being
investigated for their role as effective non-viral vectors for gene therapy.
Nanobubbles are also being tried as a therapeutic measure for removal of
clot in vascular system in combination with ultrasound, a process called as
sonothrombolysis. This method has advantages of being non-invasive and
causing less damage to endothelium.
31 | Prajnan O Sadhona ……
Paramagnetic nanoparticles are being tried for both diagnostic and
therapeutic purposes. Diagnostically, paramagnetic iron oxide
nanoparticles are used as contrast agents in magnetic resonance imaging.
These have a greater magnetic susceptibility than conventional contrast
agents. Targeting of these nanoparticles enables identification of specific
organs and tissues. Magnetic microparticle probes with nanoparticle
probes have been used for identification of proteins like prostate specific
antigen. Magnetic nanoprobes are used for cancer therapy. Iron
nanoparticles coated with monoclonal antibodies directed to tumour cells
can be made to generate high levels of heat after these accumulate in their
target site by means of an alternating magnetic field applied externally.
This heat kills the cancer cells selectively.
Nanosomes are being developed for treatment of various tumours, in
particular CNS tumours. Silica coated iron oxide nanoparticles coated with
polyethylene glycol and affixed with targeting antibody and contrast
elements like gadolinium are used to access specific areas of brain
involved with tumour. Targeting aids in binding the nanoparticle
specifically to the tumour cells and the contrast elements helps in better
detection with magnetic resonance imaging. Subsequent treatment with
laser can destroy the cells loaded with these nanoparticles by the heat
generated by iron oxide particles by absorbing the infrared light.
Nanosomes can also be integrated with a photocatalyst which produces
reactive oxygen species when stimulated by light and destroy the target
tissue. This method has advantage over conventional drugs in being much
safer without the adverse effects of cancer chemotherapy drugs and also
the absence of development of drug resistance. Nanosomes are being
vol 1, 2014 32
developed to integrate more and more components in it for flexibility of its
applications.
Dendrimers are nanomolecules with regular branching structures. The
number of branching determines the size of the dendrimer which can be
controlled. The branches arise from the core in shape of a spherical
structure by means of polymerisation. This results in formation of cavities
within the dendrimer molecule which can be used for drug transport. The
ends of the dendrimer molecule can be attached with other molecules for
transport. These molecules give the dendrimers various functional
applications. This extended nanodevice has potential applications in
cancer chemotherapy as a mode of targeted drug therapy. Dendrimers can
be used for gene therapy where these can replace conventional viral
vectors. Dendrimer based drugs are being tried for antiretroviral therapy.
Respirocytes are hypothetical artificial red blood cells are nanodevices
which can function as red blood cells but with greater efficacy. These have
higher capacity to deliver oxygen to tissues, supplying 236 times more
oxygen per unit volume than natural red blood cells. These devices have
sensors on the surface which can detect changes in the environment and
the onboard nanocomputer will regulate the intake and output of the
oxygen and carbon dioxide molecules.
Microbivores83 are hypothetical structures which function as white blood
cells in the blood stream designed to trap circulating microbes. They are
expected to have greater efficacy than cellular blood cells in phagocytosis.
The microbivores surface is arranged with processes which can extend in
length and secure the microbe which gets in contact with it. The microbe
33 | Prajnan O Sadhona ……
will be gradually maneuvered to the ingestion port and undergoes the
process of morcellization and enzymatic degradation.
Regulatory issues play a major role in the development of
nanoformulation drugs. These include, the type of nanodrug produced and
the various regulatory requirements that the manufacturers must follow
during the manufacturing of nanodrugs. A nanoformulation of a drug
which is based on a previously approved drug in microformulation can
undergo a shorter approval pathway by means of abbreviated new drug
application if bioequivalence can be demonstrated to its microformulation
drug. However, if bioequivalence cannot be demonstrated, it would
necessitate approval of all the stages of new drug application. Further,
when a nanodrug is designed as a new chemical entity, the evaluation
procedure becomes more stringent.
Nanoparticles, as a result of their extreme microscopic dimension, which
gives unique advantage, have potential hazards similar to particulate
matter. These particles have the potential to cause varied pathologies of
respiratory, cardiovascular and gastrointestinal system. Intratracheal
instillation of carbon nanotube particles in mice, has shown that carbon
nanotubes have the potential to cause varied lung pathologies like
epitheloid granuloma, interstitial inflammation, peribronchial
inflammation and necrosis of lung. The toxicity produced by carbon
nanotube was found to be greater than that produced by carbon black and
quartz. Nanoparticles can enter the central nervous system either directly
through axons of olfactory pathway or through systemic circulation that
C60 fullerene can cause oxidative stress and depletion of GSH in brain in
fishes by entering through the olfactory bulb. Involvement of olfactory
vol 1, 2014 34
bulb in humans is possible in case of inhalational exposure. Nanoparticle
mediated delivery can in future provide a means of alternate route,
circumventing the blood brain barrier. However, this can also result in the
inflammatory reactions in the brain which needs to be evaluated. The
toxicity of nanoparticles can also be extrapolated to gastrointestinal
system, resulting in inflammatory bowel diseases. The toxicity of
nanoparticles may be related to its ability to induce release of pro-
inflammatory mediators resulting in inflammatory response and organ
damage. If ingested, the nanoparticles can reach the circulation and reach
different organs and systems and possibly result in toxicity. These have
been studied in vitro and in animal models and the effect on human system
is difficult to extrapolate from such studies. Their use in humans require
further research and much needed caution.
Reference
1. Surendiran A.; Sandhiya S.; Pradhan S. C.; Adithan C. Novel
applications of nanotechnology in medicine. Ind. J. Med. Res.
2009, 130, 689, and references therein.
35 | Prajnan O Sadhona ……
Solvation Dynamics
Rana Karmakar *
Solvation dynamics generally refers to the reorientation of the solvent
molecules around a solute dipole instantly created in a polar solvent. In the
fluorescence study the solute refers to the fluorescence probe molecules
that are weekly polar or nonpolar in the ground state but become highly
dipolar upon excitation. Some typical fluorophores normally used for the
study of solvation dynamics are shown in Fig. 1. Instantaneous excitation
of the probe molecule with an ultra-short laser pulse disturbs the
equilibrium arrangement of solvent dipoles around the probe molecule.
The solvent molecules reorient themselves around the newly created
dipole and the time taken for the rearrangement of the solvent molecules
to form a new equilibrium configuration around the excited probe
molecule is referred to as the relaxation time of the solvent. This
relaxation time obviously depends on the viscosity, the molecular structure
of the solvent and the temperature of the medium. In conventional solvents
at room temperature the excited state equilibrium is reached prior to
emission because the solvent relaxation times are typically less than 100
ps whereas the emission decay times are of the order of a few
nanoseconds.
* Assistant Professor, Department of Chemistry, Fakir Chand College,
Diamond Harbour, South 24 Parganas, Pin- 743331
Email: [email protected]
vol 1, 2014 36
Fig. 1. Typical fluorescence probe molecules used for the study of
solvation dynamics
However, the relaxation times become much slower in a viscous solvent
and in proteins or in membranes. In these cases, the emission occurs
during the solvent relaxation and this results in a time-dependent shift in
the emission spectra. This phenomenon is pictorially shown in Fig. 2.
37 | Prajnan O Sadhona ……
Fig. 2. Time-dependent Stokes shift
Time-dependent Stokes shifts are measured from the time-resolved
emission spectra (TRES), which are usually constructed by an indirect
procedure starting with the measurement of a series of time-resolved
decays monitoring 15 – 20 wavelengths across the entire steady state
emission spectrum. A wavelength dependent intensity decays are
observed as a general case. The solvation dynamics is evaluated by
monitoring the time dependence of the solvation correlation function,
C(t), defined as1
0
ttC
where, )0( , )(t and )( are the peak frequencies of the TRES at
time zero, at an intermediate time (t) and at infinite time after excitation
respectively. The longitudinal relaxation time of the solvent, L, is an
exponential decay function of C(t) with time, so that C(t) = exp(-t/L).
However, experimentally found C(t) functions are multi-exponential in
nature and hence, an average solvation time <L> is reported, where
n
i
iiL a1
. The simple continuum theory equates the
vol 1, 2014 38
longitudinal relaxation time, L, with much slower Debye relaxation
time, D according to the following equation.
DDD
c
cL
nn
22
0 12
12
2
2
where,
and 0 (<0) are the infinite-frequency and low-frequency
dielectric constant of the solvent. c is the dielectric constant of the
cavity containing the probe molecule. The equation is often simplified
assuming = n2, where n is the refractive index & replacing 0 by
static dielectric constant, .
Relaxation processes in polar and nonpolar solvents
The relaxation processes in conventional solvents are usually faster due
to very fast reorientation of the solvent molecules. Using ultrafast time
resolution of the order of few femto-seconds and exact time zero
calculation, Maroncelli and coworkers2 showed that in major class of
solvents where specific interaction like hydrogen bonding is
unimportant, the solvation times are in the sub picosecond time scale at
room temperature. The result can be well explained using non-specific
theories of solvation dynamics. The linear correlation between
experimentally observed average relaxation time and longitudinal
relaxation time, L as predicted by simple continuum theory, depends
primarily on the nature of solute-solvent interaction and temperature of
the medium. Deviation from the above can be accounted for
considering molecular nature of the solvent, translational contribution
to the solvent relaxation and specific hydrogen bonding ability of the
protic solvents.
39 | Prajnan O Sadhona ……
High pressure solvation dynamics
The effect of enhanced pressure on solvation dynamics of coumarin
153 in different alcohol has been studied by Hara and coworkers.3 They
observed a good correlation between the average solvation time and the
longest longitudinal relaxation time of the alcohol used as the solvent.
A similar observation was made by Huppert and coworkers while
studying the solvation dynamics of coumarin 480 in ethanol at much
higher pressure.4 In atmospheric pressure ethanol shows usual
monomeric relaxation process with a relaxation time of 35 ps. With
gradual increase in pressure (> 0.5 Gpa) the solvation becomes
biexponential in nature. A typical biphasic solvation time of 110 ps and
500 ps, with an average relaxation time of 410 ps was observed at a
pressure of 1.55 Gpa. This slow dynamics has been explained on the
basis of liquid-solid phase transition of ethanol in this high pressure.
On the contrary, in solid phase, relaxation occurs at a relatively faster
rate with an average time of 360 ps. The faster relaxation process in
solid crystalline alcohol is ascribed to rapid reorientation of the ethanol
molecule in vicinity of the fluorescence probe.
Hara and coworkers observed a faster solvation rate of C153 in aqueous
Triton X-100 micelle with increase in pressure.5 At enhanced pressure,
a weakening of hydrogen bonding interaction at the Stern layer of the
micelle is believed to result in an increased mobility of the water
molecules, resulting a shorter relaxation time.
Solvation dynamics in confined environment
The relaxation in pure water is biexponential nature with an ultrafast
relaxation time of 126 fs and a relatively slower one, 880 fs.6
vol 1, 2014 40
According to Fleming et al., the faster component arises due to
intramolecular vibration of the water molecule and the slower one for
the librational motion. Interestingly, the presence of a slow component
(of few nanoseconds) with significant amplitude has been reported by
Bhattacharyya et al. for water present in a confined environment such
as in micelles, cyclodextrin, polymer-surfactant aggregates, protein and
DNA. In all cases, two types of water molecules have been assigned,
unbound or free and bound with the macromolecules by strong
electrostatic interaction or hydrogen bonding. The former one is
responsible for the faster component whereas the slow relaxation time
arises due to the latter.7
Solvation dynamics in ionic salt solution
Chapman and Maroncelli uses large number of metal perchlorate and
halide salts and studied those in a number of non-aqueous solvents with
different polarity. Their observations suggest an excitation wavelength
dependent solvation rate. The solvent response functions could be
extracted either by single exponential or bi exponential decay function
depending on the salt concentration. The ionic solvation is rather slow
(few nanoseconds) when compared with that in conventional solvents.
A profound effect of the solvent polarity and charge to size ratio of the
cation has been observed. Considering the faster rotational rate of the
probe molecule relative to spectral relaxation, a slow activated
exchange between ions and solvent molecules in the first solvation
shell of the probes is attributed to the slow dynamics in these media.
41 | Prajnan O Sadhona ……
Solvation dynamics in high temperature molten salts
A slow solvation dynamics, similar to that in ionic salt solution, was
observed by Huppert and coworkers in several solids and in molten
tetra alkyl ammonium salts.8 In all cases, the solvation process occurred
in two different time scales (picosecond and nanosecond). The average
relaxation time in molten salt was found relatively slower than that
observed in pure solvent or electrolyte solutions. According to Huppert
et al., the fast component of the dynamics is due to the translational
motion of the smaller species, the anion and the slower one is due to the
larger cation. Both the solvation times were found to be dependent on
the cation size and the chosen probe molecule.
Solvation dynamics in room temperature ionic liquids
The solvation dynamics in these media are bi exponential in nature, in
all cases consisting of a short and a long component. The average
solvation time, which is found to depend on the probe molecule used
and viscosity of the medium, lies in the nanosecond time scale. Based
on the observed results, the fast initial response of the bi-phasic
dynamics is attributed to the motion of the relatively smaller species,
the anions, while the slow component originates from the collective
motion of the cations and the anions.9, 10
References
1. Bagchi, B.; Oxtoby, D. W.; Flemming, G. R. Chem. Phys.
1984, 86, 257.
2. Horng, M. L.; Gardecki, J. A.; Papazyan, A.; Maroncelli, M. J.
Phys. Chem. 1995, 99, 17311.
vol 1, 2014 42
3. Kometani, N.; Kajimoto, O.; Hara, K. J. Phys. Chem. A. 1997,
101, 4916.
4. Molotsky, T.; Koifman, N.; Huppert, D. J. Phys. Chem. A.
2002, 106, 12185.
5. Hara, K.; Kuwabara, H.; Kajimoto, O. J. Phys. Chem. A. 2001,
105, 7174.
6. Jimenez, R.; Fleming, G. R.; Kumar, P. V.; Maroncelli, M.
Nature 1994, 369, 471.
7. Bhattacharyya, K. Acc. Chem. Res. 2003, 36, 95.
8. Bart, E.; Meltsin, A.; Huppert, D. J. Phys. Chem. 1994, 98,
10819.
9. Karmakar, R.; Samanta, A. J. Phys. Chem. A 2002, 106, 4447.
10. Karmakar, R.; Samanta, A. J. Phys. Chem. A. 2002, 106, 6670.
43 | Prajnan O Sadhona ……
Chemistry of the Brain in Depression and its Relation to the
Immune System
Sanjukta Chaudhuri *
Abstract
The brain is the most mysterious and understudied part of human anatomy.
Ever since the evolution of the human race, it has been the prerogative of
the humans to find out everything they can about themselves and the
world around them. 20th and 21st century saw many breakthrough events
in brain research. It is now established that the brain functions by using
many charged particles, called neurotransmitters, whose presence or
absence or balance determines how a person perceives and thinks as well
as conducts and carries out all the voluntary and involuntary functions
throughout his lifetime. Depression is one of the leading causes of
disability nowadays and is mainly the outcome of chemical imbalance in
the brain. It has a close relationship with stress and immune system.
Key words
Depression, neurotransmitters, immunity, cytokines
Introduction
The World Health Organization (WHO), states that depressive disorder is
the fourth leading cause of disease and disability in the world, and is
expected to rank second by the year 2020.
* Assistant Professor, Department of Zoology, Fakir Chand College,
Diamond Harbour, South 24 Parganas, Pin- 743331
Email: [email protected]
vol 1, 2014 44
This disease however remains under-recognized and most of the time goes
untreated (WHO, 2000). For the affected person, it causes major
psychological setback that diminishes the quality of life. It is the second
leading cause of disability (Murray and Lopez, 1996). Depression is also
associated with an increased mortality in today‟s world due to suicide,
murders, accidents, and heart diseases. The symptoms of depression can
range from mild to severe, and can be associated with anxiety and
agitation. In the Diagnostic and Statistical Manual Of Mental Disorders,
(Fourth Edition, Text Revision), the diagnosis of depression or major
affective disorder (MAD), requires the experience of major depressive
episodes that are defined by at least five of the following symptoms for a
minimum of 2 weeks duration: loss of interest, depressed mood,
appetite/weight disturbance, sleep disturbance, psychomotor change, loss
of energy, worthlessness/guilt, difficulty in concentration, recurrent
thoughts of death/suicide (DSM-IV, 2000; ICD-10, 1992). The occurrence
of depression is double fold in relatives of depressed people; this suggests
a genetic basis of the disease (Nemeroff, 1998). From the initial idea that
depression was caused by „disturbances‟ in the „chemical equilibrium‟ of
the brain, the mass of research has developed into a complicated theory
which involves several neural networks, neuronal plasticity and
neurotransmitters (Castren, 2005).
What triggers depression?
Depression or Major Affective Disorder (MAD) affects the dynamic
connectivity among the neuroanatomical structures of brain that regulate
mood and stress response (FIG-1). Limbic structures like, hippocampus,
amygdala, and nucleus accumbens, have bidirectional connections with
cortical areas, anterior cingulated cortex and ventromedial prefrontal
45 | Prajnan O Sadhona ……
cortex (VMPFC). It is believed that disrupted connectivity between limbic
areas and rostral integrative prefrontal cortex (RIPFC), results in disturbed
and incomplete feedback regulation of limbic functions. As a result, dorsal
cognitive/executive network is hypoactive and on the other hand,
hyperactive limbic areas continuously stimulate the hypothalamus, finally
leading to neuroendocrine dysregulation and sympathetic hyperactivity
(Anand et al, 2005; Whittle et al, 2005). According to neurobiological
studies, anxiety is very closely associated with depression. This is
supported by the fact that stress hormone levels (cortisol in man and
corticosterone in rat), are elevated in depressed individuals. Stress induced
depression is caused by the Hypothalamic-Pituitary-Adrenal axis (HPA-
axis). Stress results in glucocorticoid release and corticotrophin releasing
hormones (CRH) and cytokines (TNF, IL-1, IL-6). In MAD, disruption of
serotonin (5-HT), dopamine (DA), and norepinephrine (NE) transmission
impair the regulatory feedback loops that seem to “turn off” the stress
response. Sympathetic over reactivity results in activation of immune
system and release of cytokines (Raison et al, 2006).
Depression and immunity in human beings
a) Occurrence of depression: Depression is one of the major disorders of
mood. With 21% women and 13% men suffering from major depression
worldwide, this is second leading basis for disability (Murray and Lopez,
1996). The interaction of genes with a given environment leads to
depression. Environmental stress, heredity and change in biological
rhythm can trigger depression in individuals who possess the genes for
depression (Nestler et al, 2002).
vol 1, 2014 46
b) Different types of depression and immunological changes: Psychiatrists
often encounter an unrepresentative sample of patients. Some patients are
severely ill and some may suffer from mild mood swings. That is the
reason why depressive disorders have been classified into different
categories, so that proper diagnosis and treatment could be done. Table-1
lists different types of depression along with their symptoms.
TABLE - 1
TYPE OF DEPRESSION SYMPTOMS
Recurrent Unipolar
depression or Major
Affective Disorder (MAD)
(DSM-IV, 2000; ICD-10,
1992)
Episodes of depression vary in length, severity,
impairment.
Depressed mood for more than 2 weeks.
All 7 symptoms of depression.
Often associated with anxiety.
Presence of somatic depressive symptoms like
feeling sick, weight loss, headache etc.
Dysthymia
(DSM-IV, 2000; ICD-10,
1992)
Mild depression, often more than 2 months but not
exceeding 2 years.
2 of the 7 general symptoms of major depression.
No evidence of unequivocal major depression
during 1st 2 years.
Recurrent brief depression
(DSM-IV, 2000; ICD-10,
1992)
Depression lasting for less than 2 weeks.
Similar to Recurrent unipolar depression.
Often occur every month.
Seasonal Affective
Disorder (SAD)
(DSM-IV, 2000)
3 episodes of mood disturbance in 3 separate years
with at least 2 or more episodes consecutive years.
Mixed Anxiety Depressive
Disorder (MADD)
( ICD-10, 1992)
Both anxiety and depression symptoms are present.
Bipolar Affective Disorder
(BAD)
(DSM-IV, 2000)
Distinct period of elation following depression.
7 symptoms of depression.
Symptoms of mania- Over activity, Talkativeness,
Flight of ideas, Inflated self-esteem, Decreased
sleep, Distractibility, Indiscreet behavior with poor
judgment (sexual, financial).
47 | Prajnan O Sadhona ……
In people suffering from depression or affective disorder, the cognitive
and emotional responses to any given stressful situation is exaggerated, so
these people are more stressed in comparison to their normal counterparts.
Chronic stress is encountered during depression and it brings about
simultaneous enhancement and suppression of the immune response by
modifying cytokine secretion patterns (Marshall et al, 1998). It has been
shown in many researches that depressed people are more susceptible to
infection than nondepressed ones (Herbert and Cohen, 1993; Miller et al,
1994; Bachen et al, 1995). Depression is associated with
immunodeficiency. Natural killer cell activity (NKCC) and number
seemed to decrease in patients suffering from depression (Adler et al,
2008). Reiche et al (2004) reported that decreased NKCC and cytotoxic T
cell, lead to tumor formation during depression. Mitogenic response to
Con-A and PHA is reduced in people suffering from depression. Increased
IL-1β and IL-6 secretion by blood mononuclear cells were also found to
be associated with depression (Maes, 1995). Mark et al (2003) reported
that hormone therapy, antidepressive drugs (AD), immunomodulators can
act on the depression-immune pathways to improve cellular immunity.
In Animals
a) Different animal models: There are many methods with which animals
are depressed under laboratory conditions; e.g., Forced Swim Test (FST) ,
Learned Helplessness (LH), Open Field (OF), and Conditioned Defensive
Burrowing (CDB) ( Pare et al.,1994), Tail Suspension (TST) (Porsolt et al,
2001). Genetically developed strains of rodents, such as Flinders Sensitive
Line (FSL) or Fawn Hooded (FH) are also used in laboratories (Braw et al,
2006; Simmons and Broderick, 2005). The most commonly used models
vol 1, 2014 48
are FST, OF, MS, and TST. Sometimes Olfactory Bulbectomised (OB)
rats are also used as animal model of depression, since OB rats exhibit
similar behavioral and immunological characteristics of depressed rats
(Song and Leonard, 2005). In his review article about FST and TST,
Porsolt et al (2001), stated how both the methods are useful in screening
depressed rats and how application of antidepressants can normalize the
behavioral changes due to depression. Cryan et al (2002) also gave useful
information regarding animal models of depression in their review article.
The affective symptoms in humans are not wholly reflected in rats, but
neuroendocrine responses, psychomotor activities, cognitive changes,
disturbances in sleep and appetite in rats are considered for depression
studies.
b) Physiological changes: There are marked physiological changes in
depressed rats as reported by many researchers. These changes include
behavioral changes like low intake of food and water resulting in weight
reduction (Dunn and Swiergiel, 2005), reduced psychomotor activity as
seen in FST, TST, OFT, etc. Sometimes fever is also associated with
depression (Levay et al, 2006). However, most of the physiological
changes are due to neural or endocrine dysfunction associated with
depressive disorders.
c) Immune changes:
i) Certain immune changes are associated with depression. The available
literature on depression induced immune changes in rat model is not
exhaustive. It shows that during depression few parameters of immunity
are suppressed while others are stimulated. Studies in cellular immunity,
as reported by many scientists, show that in depressed rats neutrophil
49 | Prajnan O Sadhona ……
percentage increases whereas lymphocyte percentage decreases (Connor et
al, 1998). Decrease in Neutrophil phagocytosis (Song et al, 1994) and
Natural Killer Cell Activity (NKCC) (Levay et al, 2006) was also
reported. Decrease in mitogen induced lymphocyte proliferation was
demonstrated by using Phytohemagglutinin or PHA (Connor et al, 1998)
and increase in lymphocyte proliferation was induced by using Concavalin
A or ConA (Levay et al, 2006). It was also found that the depressed rats
were susceptible to infection (Breveik et al, 2006). Change in humoral
immunity was also reported in depressed rats; cytokine transformation
factor or TNF levels were altered. Increased TNF-β and decreased TNF-α
levels were associated with depressed rats (Breveik et al, 2006). The level
of corticosterone (CORT) was elevated in all these experiments suggesting
the probable involvement of HPA-axis in bringing about those immune
and behavioral changes during depression. The immune changes are
confusing because PHA induced lymphocyte proliferation decreases while
that of ConA induced increases in rats in two different studies (Connor et
al, 1998; Levay et al, 2006). Similar experiments in humans showed that
in depression both PHA and ConA invoke reduced mitogenic response
(Herbert et al, 1994; Bachen et al, 1995).
ii) Over the years depression was treated by developing antidepressive
drugs (AD). In rats, application of AD, reduce and sometimes completely
recover the behavioral changes due to depression (Connor et al, 1998;
Song et al, 1994; Kitamura et al, 2002). Reduction or recovery of
depression is a good indicator of AD activity (as clearly reflected in
behavioral studies using FST, TST, OF etc.). The immune changes in
depression should, theoretically, be normalized along with the recovery of
behavioral parameters by the use of AD. So, efforts were also made to
vol 1, 2014 50
study AD induced immune recovery by some workers. The changes of
immune parameters during depression are recovered by the use of AD.
The following immune changes have been reported to be recovered: PHA
induced depressed lymphocyte proliferation (Connor et el, 1998, by
Desipramine), increased TNF-α levels (Breivik et al, 2006, by Tianeptine),
decrease of phagocytic activity of neutrophil (Song et al, 1994, by DMI
and lithium chloride), and decrease of T-lymphocyte (Basso et al, 1993, by
Imipramine). Depressed hypersensitivity type-IV, increased tumor
formation, and increased periodontal infection were also normalized
(Basso et al, 1993; Basso et al, 1992; Breivik et al, 2006). Some
parameters like percentage of neutrophill and lymphocyte remained
unchanged by AD administration (Connor et al, 1998). CORT level also
remained unaltered i.e. high in all the antidepressant treated groups, even
though the behavioral and immune changes are near normal. This data
points to the fact that there must be other factors responsible in depression
induced immune response apart from HPA-axis and stress hormone.
iii) The components of limbic system such as hippocampus, amygdala,
cingulate gyrus (Drevets, 1998; Davidson, 2003; Swanson, 1987) and
other areas such as the brain stem nuclei locus ceruleus (LC) (Bracha et
al, 2005) and Raphae nucleus (RN) (George J. Siegel, ed. 1999) are the
areas regulating depression. LC mediates sympathetic effects during stress
through release of NE and thereby stimulation of HPA-axis. Experiments
involving manipulation of different brain areas show that hippocampus,
amygdala (Brooks et al, 1982; Cross et al, 1982; Pan and Long, 1993),
hypothalamus (Carlson and Felten, 1989; Hass and Schauenstein,1997),
BNST (Jurkowski et al, 2001), medial septum (Labeur et al, 1991;Zach et
al, 1999) are primarily responsible for immune changes brought about by
51 | Prajnan O Sadhona ……
CNS. Some areas of brain involved in immunemodulation, therefore, are
common with the areas causing depressive behavior. Although, CORT
remains unaltered even after antidepressant use (Song et al, 1994; Connor
et al, 1998; Levay et al, 2006), some immune and behavioral changes are
normal.
Theories of Depression
There are mainly four basic hypotheses that are used to explain the neural
basis of depression.
a) Glucocorticoid hypothesis states that, HPA-axis is involved in
depression. Normal response to stress seems to activate hypothalamus to
secrete CRF, which in turn activates pituitary to secrete ACTH, and finally
ACTH causes adrenal cortex to secrete glucocorticoid. A long term high
levels of glucocorticoid during chronic stress can damage hippocampal
cells and normal feedback inhibition in the hippocampus is disrupted.
Thus some of the serotonergic neurons could be destroyed. (Arborelius et
al, 1999). Some serotonergic changes due to depression may be the result
of hypersecretion of cortisol, the stress hormone. Increased ACTH levels,
elevated plasma and urinary cortisol are indicators of depression.
Exogenous administration of ACTH leads to a greater release of cortisol in
depressed people, suggesting state-dependant oversensitive adrenal gland.
Treatment with CRF seems to correct the symptoms (Nemeroff, 1998).
b) Monoamine hypothesis proposes the interaction of monoamine (MA)
neurotransmitters such as serotonin (5-HT; 5 hydroxytryptamine),
dopamine (DA), and nor-epinephrine (NE; also known as nor adrenaline)
in the brain. Many reviews indicate that hypofunctioning of
vol 1, 2014 52
monoaminergic neurons in brain lead to depression (Caldecott-Hazard and
colleagues, 1991; Morgan et al., 1994; Willner, 1995). A close study by
Sulser (1989) has led to the discovery that, 5-HT and NE modulate each
other. This forms the basis of many antidepressant drugs. Antidepressants
are either Monoamine Oxidase Inhibitors (MAO-Is), which prevent the
monoamines from being destroyed, or, Monoamine Reuptake Inhibitors
(SSRIs and SNRIs), which prevent reuptake of monoamines by the
presynaptic neurons. Both types of drugs finally increase the amount of
monoamines available for the postsynaptic neurons. Depression seems to
be associated with decreased neurotransmission at post-synaptic receptors
and many antidepressants act on this site (Nemeroff, 1998; Nestler et al,
2002).
c) Neurotropic hypothesis implies that deficiency of neurotropic factors,
like Brain Derived Neurotropic Factor (BDNF), could be responsible for
loss of dendritic spines a well as branches. Chronic stress seems to reduce
BDNF and treatment with antidepressant can increase BDNF. (Vaidya et
al, 1999).
d) Immune hypothesis a current hypothesis states that cytokines like
Interleukin-1 might be involved in depression (Smith, 1991; Dantzer et al,
1999; Charlton, 2000). It was found that administration of IL-1 induces
sickness behavior very similar to depressive behavior (Kent et al, 1992;
Smith, 1991).
Most accepted theory of depression is, however, the monoamine theory.
During neurotransmission in brain monoamine neurotransmitters (NT)
such as serotonin (5-HT), dopamine (DA), and norepinephrine (NE), are
53 | Prajnan O Sadhona ……
released into the synaptic cleft from storage vesicles present in the pre-
synaptic neuron. The NTs then bind to their respective receptors on the
post-synaptic neuron, thereby transferring the signal. If the concentration
of NT available for the post-synaptic neuron is lower, then depression
occurs (Nestler et al, 2002). Some cytokines (e.g. IL-1, IL-6, TNF-α) are
also involved in the regulation of monoaminergic transmission during
depression (Berkenbosch et al, 1987; Sapolsky et al,1987; Adler et
al,2008). Immune system is altered in humans (Herbert et al, 1994;
Bachen et al, 1995; Reiche et al, 2004) and animals in depression (Song et
al, 1994; Connor et al, 1998; Levay et al, 2006; Breveik et al, 2006).
Immune system and depression are sometimes linked together via HPA-
axis. Hormones like glucocorticoids are increased in stressed animals and
in turn cause depression (Blalock, 1989; Haddad et al, 2002).
Glucocorticoids may influence immune system and is one of the causes of
immune changes in depression. Several areas of the brain are involved in
depression, such as, hippocampus (HPC), raphae nucleus (RN), locus
ceruleus (LC), limbic area (LA), etc (Anand et al, 2005; Whittle et al,
2005). All these areas have different monoaminergic transport systems.
The balance between different MAs and their receptors, together with the
endocrine system, determine normal psychomotor activity. The
monoamines, cortisol/corticosterone and cytokines may modulate each
other‟s function. The immune changes occurring during depression has
been explained on the basis of higher circulating levels of cortisol or
corticosterone. However, antidepressive drugs may ameliorate the
psychological component of depression along with the recovery of some
suppressed immune parameters, when the cortisol or corticosterone level
remains high (Connor et al, 1998 and 2000). Thus, it appears cortisol or
corticosterone may not be the only cause of immune suppression and
vol 1, 2014 54
higher sensitivity to inflammatory response in depression. There are
several reports that central neural areas such as hypothalamus (HPTH),
amygdala (AM), hippocampus (HPC), are able to modulate the immune
system through HPA-axis and autonomic activity in spleen and lymph
glands (Hori et al, 1995). Some of these areas are also considered as
neural centres involved in depression. However, the role of the central
neural areas affected in depression may be responsible for the immune
changes in depression.
Discussion
Depression induced immune changes may be mediated through several
neural centres of the brain which are common sites for regulation of
immune system and psychological state. These neural areas may regulate
the immune system through autonomic nervous system (ANS) and
neuroendocrine axis. Several works have reported that autonomic
innervation to spleen and lymph glands, is important for changes of
immune activity (Irwin, 1994). Hence, depression and immunity are
closely related due to their common biochemical pathway sharing.
Treatments of mental depression should be more non-invasive, so that any
chemical dysregulation in the immune system does not occur. Also,
similarly, while treating a physical ailment, utmost caution and a sound
knowledge of the patient‟s mental health is to be taken in account, so as to
avoid future complications.
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vol 1, 2014 62
Controlled Drug Delivery in Chemotherapy Using
Polymeric Drug Carriers
Suchandra Biswas *
Introduction
The problems of Chemotherapy and related toxic side effects cannot be
limited to any Nation. Intravenously administered chemotherapy have
limited effectiveness, since only a small amount of the systemic blood
flow is directed to the target (for example in cancerous tissues), only a
fraction of the total dose reaches the site [1]. The remainder of the dose is
distributed throughout healthy organs and tissues, leading to a variety of
undesirable side effects ranging from neutropenia to cardiomyopathy
[2,3]. Many chemotherapeutic drugs have also been reported to show very
rapid plasma clearance, leading to short target exposure times [4].
Using controlled drug delivery in a non-toxic biodegradable matrix, the
toxicity and side effects of the internationally accepted potent drugs can
be reduced to a great extent. Optimal therapy of a disease requires the
efficient delivery of active drugs to the tissues or organs that need
treatment. Pharmacological activity and therapeutic efficacy are known to
depend upon the concentration of the drug reaching the ailing tissue cells
at a constant level and within a therapeutically effective dose range for as
long as the treatment requires.
* Assistant Professor, Department of Chemistry, Bankim Sardar
College, P.O. – Tangrakhali, South 24 Parganas, Pin – 743329.
Email: [email protected]
63 | Prajnan O Sadhona ……
However, the availability of drug molecules to the cells is governed by a
sequence of Pharmacokinetic processes - release, absorption, distribution
and elimination. The potential benefits that a controlled release drug
delivery system may bring to us can be appreciated by a consideration of
prolonged and efficient delivery of therapeutically effective doses, patient
compliance and localization of therapy.
Polymeric drug carrier
A model for pharmacologically active polymer drug carriers has been
developed (Figure-1). Here, four different groups are attached to a
biodegradable polymer backbone. One group is the pharmacon or drug,
the second is a spacing group, the third is a transport system and the
fourth is a group to solubilize the entire biopolymer system. The transport
system for these soluble drug carriers can be made specific for certain
tissue/cells with targeting moieties such as pH sensitive group or receptor
active components such as antibody-antigen recognition [5-11]. They
afford a high degree of compatibility and stability to many drugs. A wide
variety of polymers are required to fit many applications. [12-15]
Figure -1: A Model for Polymeric drug carrier
vol 1, 2014 64
In the polymeric drug delivery system, three kinds of polymers are used
water soluble, biodegradable and non-water soluble-non biodegradable.
Water-soluble drugs are used for the short-term (Several hours to several
days) drug delivery. Polymers used are of different types like
polyethylene glycol, polyethylene imine, polyacrylic acid, chitosan.
Biodegradable polymers are used for long-term drug delivery. In the third
generation of polymeric drug delivery system, non-degradable polymers
are used. Hydro gels are used in oral delivery of drugs and as devices in
rectal, vaginal and buckle delivery of drugs.
Biodegradable polymers have been widely used in biomedical
applications because of their known biocompatibility and
biodegradability. Biodegradation is a natural process by which organic
chemicals in the environment are converted to simpler compounds,
mineralized and redistributed through elemental cycles such as carbon,
nitrogen and sulphur cycles. Polymers within this group retain their
properties for a limited period of time and then gradually degrade into
soluble molecules that can be excreted from the body. Biodegradable
polymers are preferred for drug delivery applications, since the need for
surgical removal of the depleted device is eliminated. Although the
number of biodegradable polymers is large, only a limited number of
polymers are suitable for drug delivery applications. Suitable candidates
must not only be biodegradable but also fit the high prerequisites of
biocompatibility. In addition, a polymer should ideally offer
processability, sterilizability, and storage stability if it is to be useful for
biomedical applications. The greatest advantage of degradable polymers
is that they are broken down into biologically acceptable molecules that
are metabolized and removed from the body via normal metabolic
pathways. However, biodegradable materials do produce degradation by-
65 | Prajnan O Sadhona ……
products that must be tolerated with little or no adverse reactions within
the biological environment. Some of the important biodegradable
polymers used in drug delivery are listed below in Table -1
Table -1: List of Polymers used in Drug Delivery
Polymers Structures
Polyesters
Polyanhydrides
Polyamides
Phosphorous based
polymers like
Polyphosphorazenes
Polycaprolactones
Polysaccharides like
chitosan
vol 1, 2014 66
Mechanism for controlled drug release
A diverse range of mechanisms [16] have been developed to achieve
controlled release of drugs using polymers. This diversity is a necessary
consequence of different drugs imposing various restrictions on the type of
delivery system employed. For example, a drug that is to be released over
an extended period in a patient‟s stomach where the pH is acidic and
environmental conditions fluctuate widely will require a controlled release
system very different from that of a drug that is to be delivered in a
pulsatile manner within the blood system. An important consideration in
designing polymers for any controlled release mechanism is the fate of the
polymer after drug release. Polymers that are naturally excreted from the
body are desirable for many controlled release applications. These
polymers may be excreted directly via the kidneys or may be biodegraded
into smaller molecules that are then excreted.
Most drug molecules need to be dissolved in the aqueous environment of
the patient and freely diffuse within that media before they can act on their
target receptors. Polymeric devices that achieve temporal controlled
release protect drug molecules from this aqueous living environment for
preprogrammed periods of time. This protection can involve delaying the
dissolution of drug molecules, inhibiting the diffusion of the drug out of
the device, or controlling the flow of drug solutions. Polymers employed
to delay drug dissolution aim to slow the rate at which drug molecules are
exposed to water from the aqueous environment surrounding the drug
delivery system. This may be achieved by a polymer coating or matrix that
dissolves at a slower rate than the drug. In diffusion-controlled release,
drug molecule diffusion within an aqueous solution is inhibited by the
insoluble polymer matrix in which drug molecules must travel through
67 | Prajnan O Sadhona ……
tortuous pathways to exit the device. Polymer chains such as those in a
cross-linked hydrogel form the diffusion barrier. The barrier to diffusion
can be decreased by swelling of the hydrogel, for example, which creates
voids in the gel structure. Such hydrogels may also benefit from
bioadhesive characteristics which allow them to reside within the
gastrointestinal tract for extended time periods. Polymers used for
diffusion-controlled release can be fabricated as either matrices in which
the drug is uniformly distributed or as a rate-limiting membrane that
protects the drug reservoir from the living environment. Devices that
control the flow of drug solutions sometimes utilize osmotic potential
gradients across semipermeable polymer barriers to generate pressurized
chambers containing aqueous solutions of the drug. This pressure is
relieved by the flow of the solution out of the delivery device. The rate of
flow is controlled because flow is restricted to fluid transport through a
micrometer scale to larger diameter pore or pores. Many temporal
controlled release devices use the above mechanisms to provide sustained
release of drug at a constant rate. Another form of temporal controlled
release is responsive drug delivery in which drug is released in a pulsatile
manner only when required by the body. Much work in this area has as its
eventual goal the delivery of insulin to diabetics. Insulin requirements
fluctuate throughout the day as patient food intake and activity change
blood glucose levels. Current insulin formulations require repeated
injections daily and careful control of glucose intake. Responsive drug
delivery hopes to revolutionize insulin therapy with the design of systems
that release insulin in response to increased blood glucose levels. In
general, responsive drug delivery systems have two components: a sensor
that detects the environmental parameter that stimulates drug release and a
delivery device that releases drug. For diabetes treatment, responsive drug
vol 1, 2014 68
delivery systems have been proposed that use the enzyme glucose oxidase
as the sensor. When blood sugar levels rise, glucose oxidase converts
glucose to gluconic acid resulting in lowered pH. This pH decrease is then
used as the signal for insulin release. Release is achieved by pH-sensitive
polymers that either swell or degrade in acidic environments. The concept
of responsive drug delivery can be used for any drug therapy in which a
sensor and delivery device can be coupled. Signals that have been
employed to trigger drug release include the following: magnetic signals
in which magnetic beads are distributed within a polymer matrix and
cause a rearrangement of that matrix when a magnetic field is applied;
electrical signals in which pore size, permeability, and other factors are
controlled by electrically stimulated polymer swelling; ultrasonic signals
in which the intensity, frequency, and duration of ultrasound increase for
both nondegradable and biodegradable polymeric systems; pH systems in
which ionizable groups within polymer gels control polymer chain
interactions; and temperature systems in which thermosensitive hydrogels
swell and collapse in response to temperature variations.
A review of different drug delivery systems developed
Delivery of drug by means of controlled release technology began in
1970 and has continued to expand so rapidly that there are now numerous
products in the market. Extensive research efforts are being made to
improve both the polymers and the processes as well as to apply them to
the controlled release of a wide variety of pharmaceutical products
[17,18]
Encapsulation of phthalocyanines in biodegradable polysebasic anhydride
nano particle has been developed by Ng and Wu et. al. for photo dynamic
69 | Prajnan O Sadhona ……
therapy (PDT) for cancer treatment. The treatment involves
administration of photosensitive drug, which has a high affinity to
malignant tissues. It unlashes singlet oxygen as the predominant
cytotoxic agent when excited by the light of appropriate wavelength and
power. Among the various photosensitizers, phthalocyanines have been
found to be highly promising. Owing to their strong Q-band absorption at
the red visible region (700 nm) these pigments can be excited at longer
wavelength than photofrin, which is the first clinically, approved
photosensitizer. This optical property allows a deeper penetration of the
light into tissues. A novel series of co-polymers of Zn (II) phthalocyanine
and sebasic anhydride which are common building block of
biocompatible and biodegradable polymers have been prepared. The
degradation pattern has been seen in alkaline pH. The result shows that
this biocompatible polymer based colloidal system is potentially useful
for delivery and release of photosensitizer in PDT [19-21].
Robert Lu developed phospho lipid-sub micro emulsion as carrier system
for new cholesterol based compounds for targeted delivery to cancer
cells. Low density lipoprotein (LDL) and high-density lipoprotein (HDL)
are the natural carriers of cholesteryl esters in the body. Certain human
and animal tumor has been shown to have elevated LDL receptor activity
primarily because the rapidly dividing cancer cells need higher amount of
cholesterol to build new cell membrane. The elevated LDL receptor has
also been used in colon, kidney and liver tumors. To utilize LDL as a
drug carrier for preferential drug delivery to cancer cells, cholesteryl
esters of carbonates has been synthesized by Lu. This compound mimics
the native cholesteryl ester present in the core of LDL for drug targeting
and can be potentially used for boron neutron capture therapy (BNCT) of
cancers. It is an important requirement to have about 20μg of 10
B per gm
vol 1, 2014 70
of cell to achieve successful BNCT. All the tests were carried on Rat 9L
glioma cell (cancer-infected cell) in vitro [22].
In number of publications chitosan has been used as polymer matrix for
control release of drug. Chitosan is polysaccharide derived from chitin by
alkaline deacetylation. Chitosan nano particles were first prepared in
1997 by Alonso et. al. and was used in nasal delivery of insulin in rabbits.
Lim et.al. reported the release of insulin from chitosan-insulin in presence
of different enzyme [23].
Several self-regulating insulin delivery devices have been coupled with
insulin release to construct artificial pancreas systems. One of the
approaches is based on immobilizing glucose oxidase (GOX) in a pH
sensitive hydrogel, which is used as the insulin-release controller. GOX
catalyses the oxidation of glucose to gluconic acid. This reaction
generates a localized pH change, which causes a volume change in the
pH-sensitive hydro gel, release of the entrapped insulin, GOX has been
immobilized on a wide variety of polymers and hydro gel [24-26].
Conclusion
Polymer drug targeting to a specific biological site is an enormous
advantage in drug delivery because only those sites involved are affected
by the drug. This precludes the transport throughout the body, which can
elicit serious side effects. Ideally, a targetable drug carrier is captured by
the target cell to achieve optimum drug delivery while minimizing the
exposure to the host. However, the ultimate fate of drugs and their
metabolites is a major concern. If they are not cleared in a reasonable
time, they could lead to undesirable side effects. If the sizes of polymeric
drug carriers are greater than 40,000 daltons, they could accumulate in
71 | Prajnan O Sadhona ……
the host with the potential of future unwanted effects. The future of
success of biodegradable polymer based formulation will primarily
depend on pledge of pharmaceutical and biotechnology industries to
development of this technology. Although many advances have been
made, much work still remains before proteins can be tamed as useful
molecules for efficient drug delivery systems
References
1. Dowell, J. A.; Sancho, A. R.; Anand, D.; Wolf. W.
Noninvasive measurements for studying the tumoral
pharmacokinetics of platinum anticancer drugs in solid tumors.
Adv. Drug Deliv. Rev. 2000, 41, 111.
2. Crawford, J.; Dale, D. C.; Lyman, G. H. Chemo-therapy-
induced neutropenia: Risks, consequences, and new directions
for its management. Cancer 2004, 100, 228.
3. Wallace, K. B. Doxorubicin-induced cardiac
mitochondrionopathy. Pharmacol Toxicol 2003, 93,105.
4. El-Kareh, A. W.; Secomb, T. W. A mathematical model for
comparison of bolus injection, continuous infusion, and
liposomal delivery of doxorubicin to tumor cells. Neoplasia,
2000, 2, 325.
5. Brand, C. et. Al. Bio act Comp. Polymer. 1989, 4, 269.
6. Muzzarelli, R. A. et. al. J. Bio act Comp. Polymer. 1990, 5,
396.
7. Dumitrin, S. et. al. J. Bio act Comp. Polymer. 1988, 3, 243.
8. Ringsdorf, H. J. Polymer Sc. 1975, 51, 135.
9. Larsen, C. Adv. Drug Delivery Rev. 1989, 3, 103.
10. Duncan, R. et. al. J. Bio act Comp. Polymer. 1988, 3, 4.
11. Flanagen, P. A. et. al. J. Bio act Comp. Polymer. 1990, 5, 151.
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12. Ganderton, D. in Drug Delivery Systems, Johnsten, P. et. al.
(Ed), Ellis Harwood Publisher, Chichester,UK, 1987.
13. Heller, J. Critical Reviews in Therapeutic Drug Carrier
Systems, S. D. Bruk (Ed) CRC Press, Fl, 1984 (Vol. I), 38.
14. Pitt, C. G. In Biodegradable Polymers as Drug Delivery
Systems, Longer, R. et. al. (Ed) MD, NY 1990, Vol. 45, 71.
15. Kormeyer, R. W. et. al. J. Control. Rel.1984, 1, 89.
16. Uhrich, K. E. Chem. Rev. 1999, 99, 3181.
17. Donaruma, L. G.; Vogl, O. (Eds.), Polymeric Drugs. AP NY,
1978.
18. Ottenbriten, R. M. in Anti-cancer and Interferon, MD NY,
1984.
19. Fu, J.; Li, X.; Ng, D. K. P.; Wu, C. Langmuir. 2002, 18(10),
3843.
20. Bonnet, R. Chemical Aspect of Photodynamics, Gordon and
breach, Amsterdam, 2000.
21. (a) Allen, C. M.; Sharman; van Lier, J. E. J. Porphyrins
Phthalocyanins. 2001, 5, 161.
(b) Urizzi, P.; Allen, C. M.; Langlois, R.; Ouellet, R.; La
Madeleine, C.; van Lier, J. E. J. Porphyrins Phthalocyanines.
2001, 5, 154.
22. Lu, D. R. J. Phamaceutical Sc. 2002, 91(6), 1405.
23. Lim, L. Y. et. al. J. Pharmaceutical Sc. 2002, 91(6), 1396.
24. Design and evaluation of polymeric ocular drug delivery
system for controlled release of tetracycline HCl, K.M.
College of Pharmacy, Department of Pharmaceutics,
Uthangudi, Madurai-525107.
25. Rajan, N. S. M. G.; Jayaprakash, S.; Somnath, S. Indian
Journal of Pharmaceutical Sciences. 2001, 63(6), 526.
26. Podual, K.; Doyle III, F. J.; Peppas, N. A. J. Controlled
Release. 2000, 67, 9.
73 | Prajnan O Sadhona ……
Recent Applications of Iodine in Organic Synthesis
Tapas Kumar Mandal *
Introduction
Iodine is shown to be an effective catalyst in organic synthesis. Last ten
years have witnessed a remarkable growth and development in the use of
iodine in organic synthesis, both as a Lewis acid catalyst and as a reagent.
Iodine has been explored as a powerful catalyst for various organic
transformations such as cross-Aldol condensation, conjugate addition
reaction, Hantzsch pyrimidine synthesis, Suzuki-Miyaro coupling,
esterification reaction, transesterification reaction, acetylation reaction,
protection and deprotection reaction, Diels-Alder reaction, Friedel-Crafts
reaction and various cyclization reactions. Besides its use due to its Lewis
acidity, it is also used as an electrophilic regents and mild oxidiging agent.
Iodine has been attracting much attention since its discovery1a
in 1811by
French chemist Bernard Courtois (1777-1838). The element occurs
primarily in sea water and in solids formed when seawater evaporates. It is
the heaviest of the commonly occurring halogens. Iodine‟s chemical
properties are similar to those of the lighter halogens above it, viz.,
fluorine, chlorine and bromine but its physical properties are very
different. It is one of the most striking and beautiful of all elements.
* Assistant Professor, Department of Chemistry, Fakir Chand College,
Diamond Harbour, South 24 Parganas, Pin- 743331
Email: [email protected]
vol 1, 2014 74
As a solid, it is a heavy, grayish-black, metallic-looking material. Iodine
dissolves only slightly in water (0.33gL-1
at 25ºC). But it dissolves in
many other liquids to give distinctive purple solutions. Iodine has several
advantages over the vast majority of the other Lewis-acid catalysts,
especially the metallic catalysts. Its catalytic potential is intriguingly
broad; it is a water-tolerant, relatively cheap and environmentally friendly
catalyst. Another distinctive feature of iodine is its high catalytic activity
in dilute solutions, under highly concentrated reaction conditions (HCRC)
as well as under solvent free reaction conditions (SFRC). The latter
reaction conditions are particularly important in terms of green chemistry;
they contribute to waste- and health-hazard minimization and cost
efficiency.
About two-thirds of all iodine and its compounds are used in sanitation
systems or in making various antiseptics and drugs. Iodine is also used to
make dye, photographic film and specialized soaps. But it is used as a
reagent and mostly as a catalyst in industry as well as in laboratory. The
Lewis acidity1b
of iodine comes from the consideration of the electronic
structure of this molecule. Iodine has the electronic structure
5σ25σ
2*5π
45σ
25π
4*5σ*. This shows iodine has an empty 5σ*orbital which
is anti-bonding. When iodine is dissolved in a solvent S having a lone pair
of electrons or when contact comes with molecules containing N, O, S,
etc. having lone pair of electrons, it forms a charge transfer complex (CT
complex) with donor molecules. This is accompanied by the partial
charge-transfer of an electron lone pair from the donor to iodine, resulting
the Lewis acidity of the molecules.
The Lewis acid promoted organic reactions were carried out as early as
1890, and they still play important roles in modern organic chemistry.
75 | Prajnan O Sadhona ……
O
+ ArCHO
O
ArArI2, CH2Cl2
( )n ( )n(Ref. 2a)
I2, No solvent
(Ref. 2b)
Molecular iodine has received considerable attention in organic synthesis
because of its low cost, non-toxicity and ready availability. The mild
Lewis acidity associated with iodine has enhanced its use in organic
synthesis. Owing to numerous advantages associated with this eco-
friendly element, iodine has been explored as a powerful catalyst for
various organic transformations. In the following Sections the author
presents some applications of iodine reported in the literature during last
ten years.
Result and Discussion
Cross-Aldol Condensation Reaction
Cross-Aldol condensation of aromatic aldehydes with cyclic ketones is an
important synthetic reaction for the preparation of α,α'-bis(benzylidene)-
cycloalkanones. These benzylidene derivatives are intermediates for
synthesis of various pharmaceuticals, agrochemicals and perfumes. Das et
al.2a
first reported that molecular iodine efficiently catalyses the two
component cross-aldol condensation of aromatic aldehyde and cyclic
ketones in CH2Cl2 at room temperature affording α,α'-
bis(substituted)benzylidene in high yield (Scheme 1). The same
observation was reported by Pasha et al.2b
under stirring in solvent free
condition in good to excellent yield (85-94%).
vol 1, 2014 76
Scheme 1
Dehydration of Alcohols
Iodine has been shown to be an efficient catalyst for transforming of
alcohols to alkenes under solvent free conditions. In presence of 5% of
iodine, tertiary alcohols underwent dehydration forming the corresponding
alkenes3. Secondary and primary alcohols under the same conditions gave
corresponding ethers.
Scheme 2
Ren et al.4a
converted benzylic and aliphatic alcohols into nitriles in
the presence of a twofold excess of iodine in aqueous NH4OAc. The
same transformation could also be accomplished in aqueous NH34b
using an excess of I2 or with TBHP4c
and a catalytic amount of I2.
Scheme 3
77 | Prajnan O Sadhona ……
Esterification Reaction
Transesterification of esters with alcohols have been accomplished
using molecular iodine. Ramalinga and co-workers5 reported that
iodine acts as a Lewis acid catalyst for transesterification of simple
esters with different alcohols including tertiary alcohols and sterically
hindered primary and secondary alcohols in refluxing condition
(Scheme 4). Simultaneous esterification and transesterification
reactions can also be reported using iodine.
Scheme 4
Etherification
Rostami et al. 6successfully converted primary, secondary, tertiary
aliphatic, benzylic alcohols and phenols into the corresponding
tetrahy-dropyranyl ethers by using iodine.
R1COOR2 + R3OHI2
RefluxR1COOR3 + R2OH
vol 1, 2014 78
Scheme 5
Cleavage of Ethers
Yadav et al.7
were cleaved ethers with iodine in the presence of
aromatic or aliphatic acyl chlorides, and the corresponding esters
(Scheme 6) were formed in high yield at ambient temperature;10
mol % of I2 and a nine-fold excess of ether relative to acyl chloride
were used. Later, it was found that much less iodine was necessary
and that the reaction time could be significantly reduced. Ring
opening of THF with benzoyl chloride was also very efficient with
iodine, below 1 mol
Scheme 6
Iodine was shown to catalyze the transformation of epoxides to
thiiranes8 using NH4SCN in MeCN; acid-sensitive protecting
groups, e.g., THP or TBDMS unaffected during the process.
OMeCOCl or PhCOCl
10 mol % of I2, ,rt, 120 min
R3
O
O
Cl
R3 = Me or Ph
(91-96 %)
O
Cl
MeCOCl
ClH2C CH2Cl
OAc
85 %
40mol % of I2, ,rt, 240min
Acetic acid 2-chloro-1-chloromethyl-ethyl ester
79 | Prajnan O Sadhona ……
Furthermore, iodine catalyzed the ring opening of epoxides in the
presence of nucleophiles to the corresponding hydroxy
derivativesb.
Scheme 7
Protection and Deprotection of Carbonyl Group
Banik et al.9 showed that several ketals were prepared using
carbonyl compounds and ethylene glycol in the presence of iodine
(5 mol%). Aliphatic aldehydes and ketones were extremely good
substrates for this purpose. The yields with the aromatic aldehydes
and benzylic ketones were satisfactory.
Scheme 8
O
R2
R1
NH4SCN in CH3CN
10 mol % I2
R1 = H, R
2 = CH2OPh
R1 = R
2 = Ph
S
R2R
1
I2, 1-1.7 mol %
R3OH
OR3
R2
R1
OH
R1 + R
2 = (CH2)3, (CH2)4
R1 = H, R
2 = aryl, alkyl
R3 = H, alkyl, Ac
b
Thiiranesa
vol 1, 2014 80
Hu et al 10
. An extremely convenient method for deprotection of
acetals and ketals catalyzed by molecular iodine (10 mol%) in
acetone reported. The protocol achieved the deprotection of acyclic
or cyclic O,O-acetals and O,O-ketals in excellent yields within a
few minutes under neutral conditions. The double bond, hydroxyl
group, and acetate group remained unchanged, and the highly acid-
sensitive furyl, tert-butyl ethers, and ketone-oxime stayed intact
under these conditions.
Scheme 9
Conjugate Addition
Singh et al.11
reported regioselective 1,2-reduction of conjugated
α,β-unsaturated aldehydes/ ketones by using I2 and NaBH4 (
Scheme 10).
Scheme 10
O
R2
R1 NaBH4 /I2
THF, 15oC, stirring OH
R2
R1
H
81 | Prajnan O Sadhona ……
R-OH + Ac2OI2, cat.
(1-10 min.)R-OAc
85-100%
Wang et al.12
reported that indole undergoes conjugate addition
with α,β-unsaturated carbonyl compounds (chalcones) by means of
alkylation of indoles in presence of catalytic amount of molecular
iodine in ethanol at room temperature to afford the corresponding
adduct in excellent yield (up to 96%) (Scheme 11). The same
observation was reported by B. K. Banik et al13
. under solvent free
condition in good yield.
Scheme 11
Acetylation Reaction
The acetylation of alcohols, phenols, amines and anilines is an important
and widely used transformation in organic synthesis. Phukan14
reported
that iodine acts as a Lewis acid catalyst for acetylation of alcohols and
phenols in a very short time by using an equivalent amount of acetic
anhydride under solvent free condition at room temperature (Scheme 12).
Scheme 12
NH
+
O
R2
R1
NH
R2
O
R1I2, EtOH
I2, Solvent
a)
b)
free
vol 1, 2014 82
Saini et al.15
also reported a one pot process for effective transformation of
aldoximes into nitriles using Zn/I2 system. Here, iodine acts as a Lewis
acid for the dehydration process (Scheme 13).
Scheme 13
Friedel–Crafts Reaction
Iodine is shown to be an efficient catalyst for the Friedel–Crafts
alkylation16
of arenes with a wide variety of aldehydes in toluene under
„open-flask‟ and mild conditions. In the presence of 10 mol % of iodine,
the reaction of arenes with aromatic aldehydes gives the corresponding
triarylmethane derivatives (TRAMs), regioselectively, in good to excellent
yields. On the other hand, a series of diarylalkane derivatives is
synthesized smoothly by reaction with aliphatic aldehydes (Scheme 14).
Scheme 14
RCH=N-OH RC NI2, Zn
CH3CN, r.t.
83 | Prajnan O Sadhona ……
O
OHPh
Ph
PhNH2
NH4OAc
ArCHO
N
NPh
Ph
Ar
Ph
+
+
+
I2
EtOH
wang et al17
developed a novel molecular iodine-catalyzed benzylation of
arenes with benzyl alcohols . The reaction can be carried out under mild
conditions to afford a series of diarymethane derivatives in high yields and
good regioselectivities (Scheme 15).
Scheme 15
Synthesis of Imidazole
Kidwai and Mothsra18
synthesized 1,2,4,5-tetraarylimidazoles using
benzoin, an aromatic aldehydes, aniline and ammonium acetate in
presence of molecular iodine in excellent yield (94-98%). The Lewis
acidity of iodine makes it capable of binding with the aldehyde carbonyl
oxygen increasing the reactivity of the parent carbonyl compounds.
Scheme 16
vol 1, 2014 84
NH
O
OO ArO
O
O
O
OArCHO
NH4OAC
I2
ethanol+ + +
Iodine reacts initially with aldehyde to produce a diamino intermediate
then it condenses with benzil which is produced in situ and subsequently
elimination of water affords 1,2,4,5-tetraarylimidazoles (Scheme 16).
Hantzsch Pyrimidine Synthesis
Hantzsch 1,4-dihydropyrimidines (1,4-DHPs) and their derivatives have
gained great importance in the field of organic and medicinal chemistry
since they display a fascinating array of pharmacological properties. A
variety of 4-substituted 1,4-dihydropyrimidines was synthesized by Ko et
al19
from the reaction of different aryl or alkyl aldehydes, 1,3-
cyclohexanone, ethyl acetoacetate and ammonium acetate in presence of
catalytic amount of iodine at room temperature in ethanol (Scheme 17).
Scheme 17
Domino/Domino Knoevenagel Reaction
2-Arylquinolines are biologically active and occur in the structures of a
number of antimalarial compounds and antitumor agents. Therefore, the
developement of new synthetic approaches leading to them remains an
active research area. Lin et al20
reported that a molecular iodine-catalysed
85 | Prajnan O Sadhona ……
N
R1
R2 HR3
O+
N
R3
R1
R2
I2
Benzene reflux
one pot domino reaction of imines with enolisable aldehydes afforded
various substituted quinoline in good yields (60-82%) (Scheme 18).
Scheme 18
Molecular iodine was used as a catalyst in the [3+3] cyclocoupling of
phenols and cinnamic acids which proceeds via a tandem esterification –
hydroarylation process at 120-130⁰C under solvent-free conditions.
Substituted 4-aryl-3, 4-dihydrobenzopyran-2-ones21
were obtained in good
yield (Scheme 19).
Scheme 19
Mallik et al.22
reported that cinnamylideneacetophenones underwent facile
cyclocondensation with thiophenol in dichloromethane under iodine
catalyzed condition yielding cis-2-(aroylmethyl)-4-phenylthiochromans in
very good to excellent yield. The structures of the products have been
OH
R
HO
Ar
O O O
Ar
+
20 mol % I2
120o-130oC
vol 1, 2014 86
established from their spectral data as well as X-ray crystallographic
studies on one of them (Scheme 20).
Scheme 20
Conclusion
This review focuses the versatile uses of iodine in different chemical
transformations. It specially concentrates on the utility of molecular iodine
as an effective Lewis acid catalyst, not only in performing selective
transformations but also in development of host of interesting and useful
reactions. The ever-growing relevance and concern of modern chemistry
chemistry is for the protection of the environment, solid-supported iodine
with unreduced activity could considerably contribute to green chemistry.
Although many interesting observations have not received application in
synthesis of natural products or complex molecules so far, it is expected
that in near future they will be useful in facile synthesis of many useful
target molecules.
Acknowledgements
The author takes this opportunity to express his sincere gratitude and deep
appreciation to Dr. A. K. Mallik, Professor and Former Head, Department
SH
+
Ph
OAr
H
S
PhH
HAr
O
I2
CH2Cl2, reflux
2.5-3.5 h
1 2
87 | Prajnan O Sadhona ……
of Chemistry, Jadavpur University, for constructive ideas, valuable
guidance throughout the progress of this work.
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89 | Prajnan O Sadhona ……
Stabilization of Lipophilic Drug, Curcumin within Micelles
Ummul Liha Khatun *
In recent year curcumin [having IUPAC nomenclature: 1,7-bis (4-
hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] has received
considerable attention due to its versatile medicinal properties. Curcumin
(structure is shown in figure 1) is the major ingredient of the yellow
pigments (curcuminoids) in the Indian spice plant turmeric. A large
number of studies have shown that curcumin possesses anti-cancer, anti-
oxidant, anti-mutagenic, antibiotic, anti-viral, anti-fungal, anti-amyloid,
anti-diabetic and anti-inflammatory properties. Because of its numerous
pharmaceutical effects without side effects unlike conventional
chemotherapy drugs and its inherent non-toxicity curcumin has been the
focus of many recent biochemical investigation.
Fig. 1. Structure of Curcumin
_______________________________________________________________
* Guest lecturer, Department of Chemistry, Fakir Chand College,
Diamond Harbour, South 24 Parganas, Pin- 743331
Email: [email protected]
vol 1, 2014 90
Two major problems regarding the application of curcumin as a drug are
the lack of bioavailability and limited stability in aqueous environments.
Low aqueous solubility of curcumin tends to aggregation and precipitation
in water, limiting its bioavailability. In addition, curcumin undergoes rapid
degradation in water and in buffer solutions due to deprotonation
producing the degradation products vanillin, ferulic acid and feruroyl
methane. Recent studies show that encapsulation of curcumin within
micelles improved clinical use of curcumin. Curcumin is intrinsically
fluorescent. The photo-physical properties and fluorescence spectra of
curcumin are very sensitive to the polarity of the medium/environment.
When free curcumin was excited at 420 nm it showed a low-intensity
broad steady-state fluorescence peak at 540 nm in aqueous solution.
When curcumin bound to micelles its steady-state fluorescence spectrum
was blue shifted to a well-defined peak at 500 nm and intensity sharply
increased. Such blue shift of the emission spectra indicates the binding of
curcumin to the hydrophobic core of the micelles. Stabilization of
curcumin within micelles was measured using the loss of the characteristic
absorption maximum at 424 nm as a marker for curcumin degradation.
Curcumin exists predominantly in keto-enol tautomeric form in a number
of solvants other than water. This keto-enol tautomeric form help
curcumin to execute excited state intramolecular hydrogen atom transfer
(ESIHT) due to the presence of strong intramolecular hydrogen bonding
between the proton donor and the acceptor atom i.e., ESIHT is a major
photophysical event of curcumin. It is also reported that the presence of
labile hydrogen as a result of ESIHT plays a role in the medicinal effects
of other naturally occurring pigments such as hypericin and hypocrellin
etc. Time-resolved fluorescence results demonstrate that ESIHT is a major
91 | Prajnan O Sadhona ……
photophysical event of curcumin within micelles. Micelles-encapsulated
curcumin is well-dispersed consequently preventing aggregate formation,
thereby increasing the bioavailability significantly. Moreover, curcumin is
trapped in the hydrophobic region of the micelles where the presence of
free water molecules is limited preventing alkaline hydrolysis which is the
major mechanism for degradation. It is therefore inferred that
encapsulation of curcumin within micelles enable curcumin to exhibit its
medicinal characteristics. Apart from preventing degradation, micelles
also serve as well-defined model systems for biomembranes as well as
drug-delivery vehicle.
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