Nano Science….

Some Interesting Facts of Coinage Metals Tarasankar Pal Department of Chemistry, Indian Institute of Technology, Kharagpur, Kharagpur 712302

Email: [email protected]

Mendeleev designed the periodic table (1869) with a vision. His focus was very important that was supported by the discoveries of scientists in the later stage. He placed heavier nickel before lighter cobalt even though he was arranging the elements as per their increasing atomic weights (at. wt.). This apparent anomalous arrangement was justified by the discovery of atomic number (at. no.) of the elements at a later stage. Thus the position of cobalt (at. no. 27) and nickel (at. no. 28) was justified. Again, he did not place any element instead kept a void position in between manganese and rhenium in the manganese group. He himself realized that the element was not discovered by then. But below manganese, under the void place, he intelligently placed rhenium (Re). His realization gave birth to the first technically prepared element technetium (Tc). Thus manganese group was completed. Scientists realized that Tc, for its small half life, T1/2 (211,000 yrs) value, disappeared from earth’s crust and first man made element was born. This discovery filled a gap in the periodic table, and the fact that no stable isotopes of technetium exist. This explains its natural absence on Earth (and the gap). He also located the positions (one room for lanthanide and beneath that are actinide elements) of lanthanide and actinide elements below Sc and Y. In so doing he completed the group of alkaline earth metal with the representative element Sc. Like many other groups in his periodic table group 11 or one

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Pal, T.: Some Interesting Facts …. can say I B was reserved for copper, silver and gold and we call the elements in this group as coinage metals. These sub-grouping, i.e., B signify less electropositive character of these elements as compared to the alkali metal belonging to subgroup A. Thus sub-grouping ‘A’ (for more electropositive) and ‘B’ (for less electropositive) of group I is justified as is evident in recent times. The metallic colours of these three metals attracted the attention not only of the scientists but also for common mass. These metals in their bulk structure have distinctive colours: copper is reddish brown, silver metal is white and gold is fascinating yellow while viewed using visible light. Among them gold is most noble. Because of the nobility (corrosion resistance), availability and of the fascinating colour price of gold controls the market price. Thus people grab gold by fair means or foul. In Swiss Bank alone ~400, 000 tons of gold have been deposited by the people of different countries. Nobility of the metals can be described for their standard reduction potential value at room temperature. Thus metallic gold (AuIII/Au, E0, +1.50 V) can easily be found in Earth’s crust. Silver (AgI/Ag, E0, +0.79V) and copper (CuII/Cu, E0, +0.34V) are mainly present as compounds again because of there lower reduction potential values. The lower reduction potential values stand for their less noble character in comparison to gold. So one can easily reduce Au(III) ions in solution. The reduction reaction is progressively less facile for the other two coinage metal ions in solution. Gold is a metal that lures many. Primarily because of its easy liquidity, and is also used by women for adorning themselves. Now gold has become a symbol of perfection even in research. An interesting fact emerges out when you take a metal (bulk) to the nano (10-9 meter) meter size which is called a nanoparticle of the metal. So is true for any other object.

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Figure 1: Shape of nanoparticles

It can be a nanowire, nanosphere, nanoalloy etc. (Fig.1) if any constituent or dimension of the object lie in the ~10-9 nm range. Nanoparticle can be prepared by ‘Top Down’ or ‘Bottom Up’ approach. The physicists use the top down (i.e., physical) method but chemists mainly prefer bottom up technique. A nanoparticle of a metal comprises of many atoms. The assembly with lowest energy depicts a sphere. It has one atom in the centre and many atoms in the surface. (Fig.2).

Figure 2: Nanoparticle composed of many atoms

The central atom is co-ordinatively saturated (fully surrounded by other atoms from different sides) whereas the surface atoms are co- ordinatively unsaturated (partly surrounded). Thus the surface atoms become marginally electron deficient and find an avenue to get stabilized by negative ions/groups (Fig. 3). Now the negative ion-linked nanoparticles become a negatively charged assembly. Citrate stabilized gold nanoparticles are negatively charged and are known as gold hydrosol. Such negatively charged species in solution does not come closer to coalesce together because of

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Pal, T.: Some Interesting Facts …. electrostatic repulsion and get stabilized under dispersion (Fig. 4) in polar solvent.

Figure 3: Negatively charged nanoparticles

Figure 4: Electrostatic repulsion

Interestingly long chain polymer, surfactant (charged or uncharged), thiols amines etc. can bind with the nanoparticle surface thorough their charge re-distribution. This time also the particles get stabilized. Here the particles cannot coalesce together. This is due to long chain barrier related to steric factor. This type of nanoparticle stabilization is called steric stabilization (Fig. 5).

Figure 5: Steric stabilization This type of phenomenon is prevalent in colloid chemistry. The surface charge of particle with long chain molecule may not acquire any surface charge. So they easily dissolve in non-polar solvents. It is known

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Nano Science…. as ligand stabilized nanoparticle or organosol1 In this case, the long chain stabilized particles can be obtained as solid powder just evaporating the solvent. Again, the solid may be dissolved reversibly in non-polar solvents. Thus they find applications as reagent or catalyst. Coinage metal nanoparticles can easily be produced in solution as done by Michel Faraday2 with gold way back in 1857 and then in modern times Fren’s3 produced citrate stabilized gold in 1972. In the nanostage, gold, silver and copper may exhibit fascinating colour under dispersion. In the language of physics, it said that coinage metal nanoparticles (< 100 nm in size) has rich plasmon band (Fig. 6) and the peak position lies in the visible region.

Figure 6: Plasmon band of gold (A) and silver (B)

This band appears because of the resonance (excited) of all the conduction band electrons of the tiny particles with the incoming electromagnetic radiation. The electrons get excited all at a time. The excitation of all the electrons is believed to follow a gas model. Popularly it is known that gold depicts pink, and silver and copper nanoparticles are yellow in colour under dispersed condition. The colour shades differ with the change in size and shape of the particle as also the peak position. Solvent (dispersion medium) plays a dominant role for peak shifting thus

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Pal, T.: Some Interesting Facts …. solvent property can be evaluated using this solvent dependent peak shifting. Here we would confine our discussion to coinage metal nanoparticles only for a particular reaction which is hitherto unknown. Among the three different coinage metal nanoparticles gold deserves a special mention not because of its rich plasmon band but because of its novel applications in different fields. Innumerable papers are published each month involving gold nanoparticle. However, a small number of papers appear for silver. Copper nanoparticle work is very difficult to reproduce. This information relates to gradation in nobility of the coinage metals. It is important to discuss that the nobility of the metals can be altered by (i) down sizing a bulk metal to the atomic (size dependent redox potential) stage and (ii) inducting a strong nucleophile onto a metal surface. The latter case is the simplistic and over expressed idea of gold silver extraction by cyanide. Cyanide is a pseudo halide, a reducing agent and a strong complexing agent. But it is seldom uttered that cyanide is a strong nucleophile. In nanoparticle chemistry of metal, the density of states are well defined unlike the bulk metal (Fig.7). It is well described that a strong nucleophile shifts the Fermi level of metal to a more negative region.

Figure 7: Energy levels in metal particle

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It is analogous to the change in reduction potential value while one bulk metal enters successively into nanoparticle region which relates to the aggregation number of nanoparticle of metal (Fig. 8). Thus small metal particle together with a nucleophile induces much more pronounced Femi level shift of reduction potential value of metal particle.4

Figure 8: Reduction Potential of metallic silver with agglomeration number (Ref 4 and other cited reference therein)

Consequence is the facile oxidation of metal nanoparticle in the presence of a nucleophile like potassium cyanide or sodium borohydride 0 2- even by dissolved oxygen (E , O2/O =1.23 V, acidic pH). So one can reversibly dissolve gold, silver etc. metals in cyanide/borohydride solution under ambient condition.

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Figure 9: Reversible formation and dissolution of silver in aqueous surfactant solution (Ref. 4)

However, some surfactant has to be there in the aqueous medium to dissolve out the newly formed/wrappedoxide layer onto metal surface to make the surface fresh for further reaction in steps.4

References 1. Nath, S.; Jana, S.; Pradhan, M.; Pal, T. Journal of Colloid and Interface Science. 2009, 341(2), 333-352. 2. Faraday. M. Philosophical Transactions of the Royal Society of London, 1847, 147, 159. 3. Frens, G. Nature (London) Physical Science. 1973, 241(105), 20-22. 4. Pal, T.; Sau, T. K.; Jana, N. R. Langmuir 1997, 13(6), 1481-1485.

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Green Chemistry and Nanoscience Sanjay Bhar Department of Chemistry, Jadavpur University, Kolkata – 700 032 E-mail: [email protected] ; [email protected]

The art of performing efficient chemical transformations by identifying alternate reaction conditions avoiding toxic and costly reagents and minimizing the use of toxic solvents as the reaction medium constitutes an important tenet of Green Chemistry. According to Paul Anastas and John Warner, Green Chemistry is the utilization of a set of principles that reduces or eliminates the use or generation of hazardous substances in the design, manufacture and application of chemical products. Green Chemistry is about a) waste minimisation at source, b) use of catalysts in place of reagents, c) using non-toxic reagents, d) use of renewable resources, e) improved atom efficiency and f) use of solvent- free or recyclable environmentally benign solvent systems. One of the Twelve Principles1 of Green Chemistry includes the use of catalytic amount of reagents in place of stoichiometric amounts in order to prevent waste. The slogan for sustainability calls for “Reduce, Recover and Reuse”. Moreover, water is the most abundant and innocuous reaction medium. Therefore, in recent times, the development of efficient, cost- effective and easily recyclable catalytic systems for important chemical transformations in aqueous medium has come out as an indispensible area of contemporary chemical research all over the globe in order to minimize the dispersal of harmful chemicals in the environment and maximize the use of renewable resource.

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As an introduction to the catalytic organic reactions in aqueous medium, one can look at a cost-effective, operationally simple and eco- compatible protocol for the one-pot synthesis of photochromic pyrans by the reaction of propargyl alcohols as well as propargyl ethers with differently substituted phenols under ambient atmosphere in aqueous medium using β-cyclodextrin hydrate for the first time as an efficient, recyclable and stable catalyst.2 The method permits convenient access to a wide range of structurally novel and functionally important 2,2- disubstituted-2H-chromene skeletons (Scheme 1) with great potential for future applications. Moreover, this is the maiden report for the application of β-cyclodextrin hydrate (in contrary to β-cyclodextrin) as an efficient catalyst for an organic transformation.

R2 -cyclodextrin hydrate O R2 OH (4 mol%) R1 OX + o R1 water, 60 C R3 R3 X = H, Me, Et, i-Pr, n-Bu, Allyl, TBDMS, 70 - 85% Yield

Scheme 1: Synthesis of 2, 2-disubstituted-2H-chromenes from propargylic alcohols and ethers

Due to unique physicochemical properties3 of nanomaterials in general, and nanometals in particular, the field of nanoscience extends itself into the realm of Green Chemistry, specially, in terms of catalysis. As the heterogeneous catalysis by metal nanoparticles is a surface phenomenon, it critically depends on the fraction of atoms present at the surface, which in-turn, is reflected from the surface area-to-volume ratio of a cluster. It is estimated that this ratio decreases (92%, 76%, 63% and 52%) with increase in the number of atoms (13, 55, 147 and 309

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Nano Science…. respectively) in the cluster. Therefore, a cluster of smaller size has more number of surface atoms available for its catalytic activity. Therefore, in contrast to bulk, a metal cluster of nano-dimension bears immense promise to demonstrate important catalytic activity. A nano-size metal with high surface-to-volume ratio thus mimics a homogeneous catalyst due to increased contact between reactants and catalyst. But owing to its insolubility in the reaction medium it can also be identified with the heterogeneous catalyst. Thus a nanocatalyst can be considered as a bridge between homogeneous and heterogeneous catalysts. Elegant application of metal nanoparticles for organic transformation was aptly demonstrated during the reduction of aromatic 4 NO2 groups using iron nanoparticles generated in situ (Scheme 2). Enormous amount of the tin hydroxides is precipitated as the by-product after basification of the acidic reaction mixture during conventional reduction of aromatic NO2 groups using Sn/HCl, wherefrom isolation of the products often becomes tedious. The protocol described in Scheme 2 not only gets rid of this problem but also demonstrates excellent chemoselectivity where only the NO2 group is reduced leaving behind other reducible functional groups, e. g., CHO, CN, COOMe, N3 etc intact.

Fe- nanoparticles NO2 NH2 R R Water , rt, 2-3h

Scheme 2: Reduction of aromatic nitro group using iron nanoparticles

As a semiheterogeneous catalyst, nanocatalyst with a large surface- to-volume ratio, is an attractive alternative to conventional catalysts.

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Substantial enhancements in catalytic activity, selectivity, and stability are realized by tailoring their size, shape, composition, and electronic structure. Nanocatalysts are isolated and recovered through filtration or centrifugation methods. Often the inconvenience and inefficiency of tedious separation methods caused by the nano size of the catalyst particles hamper the sustainability and economics of the nanocatalytic strategy. Moreover, auxiliary compounds are often necessary to stabilize the nanoparticles. The use of these stabilizers leads to their contamination with the product and needs further purification. Due to their high chemical reactivity, it is often required to maintain inert atmosphere during generation and reaction of nanometals. All these aspects lead to decrement of greenness of a process. Therefore, new protocols are being developed where the separation of nanocatalyst is simplified without any compromise with its catalytic activity and contamination with the product. Under this direction, different nanocatalysts supported on chemically robust inorganic materials have been developed. Neither any auxiliary stabilizer nor inert atmosphere is needed in these protocols as the nanometals are stabilized through encapsulation inside the pores of the support as soon as they are formed. After the reaction, the supported catalyst can be easily separated by simple filtration due to its heterogeneity and recycled after proper washing and activation. The products are obtained from the mother liquor after proper manipulation. Gold is a good conductor of electricity but considered as a noble metal due to its lack of chemical reactivity. In the contrary, gold nanoparticles behave as insulator but demonstrate unique catalytic activity. Gold nanoparticles supported on TiO2 act as an efficient catalyst for the oxidative esterification of alkyl, allylic and benzylic alcohols in methanolic medium (Scheme 3) with high yield.5

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O

OH OMe O Au / TiO2 / MeOH OH OMe o O2 , 130 C , 10h

O

OH OMe

88 - 95% yield

Scheme 3: Oxidative esterification of 1o-alcohols using supported gold nanoparticles

A cost-effective, operationally simple and eco-friendly protocol for the O-arylation of phenols with aryl halides under ambient atmosphere in aqueous medium has been developed using alumina-supported nickel nanoparticles (to be called as Ni-alumina) as an efficient, recyclable and stable heterogeneous catalyst (Scheme 4).6 The reactions neither necessitate any additional stabilizer nor any inert environment. The present coupling protocol shows excellent chemoselectivity where more nucleophilc aromatic NH2 and alcoholic OH groups remain unaffected. Chemically susceptible motifs like allyl, alkoxycarbonyl, formyl, oxo and nitro are well tolerated during the reaction. Thus the present study has developed an eco-compatible method for chemoselective Ullmann coupling under aqueous medium using easily accessible, economically viable, highly stable and recyclable supported metal nanocatalyst with greater merits and wider applicability compared to many earlier reports. There was extremely marginal loss of Ni metal from the supported catalyst during the reaction. This was also confirmed from the atomic absorption spectroscopic analysis of the leftover reaction medium which was found to

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contain 0.935 ppm of nickel after the reaction. The occurrence of such a small amount of nickel in the reaction medium was due to its leaching from the supported catalyst which came out to be only 0.34% with respect to the nickel nanoparticles supported on alumina. So it can be concluded that in Ni- alumina, Ni atom remains encapsulated and firmly immobilized on the alumina support. Probably this is the reason why alumina-supported nickel nanoparticles are highly stable in air and resistant to oxidation which permits them to be used under normal atmospheric condition without any aid of inert environment. Excellent recyclability of the present catalyst is evident from the fact that after the 7th run the product yield of the reaction between p-cresol and iodobenzene varies a little.

G G 1 G2 Ni- alumina (6 mol%) 1 G2 H O + X 2 K CO (1eq.) OH Y 2 3 O Y SDS (8 mol%), 800C

X= I, Br, Cl; Y= CH, N

G1= H, 2-Me, 4-Me, 3,4-Me2, 4-Br, 4-Cl, 4-NO2, 2-NH2, 2-(CH2-CH=CH2), 4-CO2Me, 4-CHO

G2= H, 4-NO2, 4-COMe, 4-Me, 4-OMe, 3-CH2OH

Scheme 4: Ullmann coupling between substituted phenols with aryl and heteroaryl halides.

A cost–effective and operationally simple protocol for the chemoselective homocoupling of benzylic halides has been developed at room temperature under ambient atmosphere in aqueous medium using alumina–supported nickel nanoparticles as an efficient, recyclable and stable heterogeneous catalyst and hydrazine hydrate as the co-reductant (Scheme 5).7 The reactions neither necessitate high temperature nor any

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Nano Science…. other metal. Moreover, waste production is also minimized as no additional stablizer is necessary. No inert atmosphere is necessary for the aforesaid reaction. This homocoupling reaction does not occur with neutral alumina or with nickel nanopowder alone without any support. Thus the importance of alumina–supported nickel nanocatalyst in terms of its stability and catalytic activity is firmly established. Alkyl and allylic halides remain intact under the present protocol. Chemically susceptible motifs like alkoxycarbonyl, chloro, bromo, methoxy, benzyloxy and nitro are well tolerated during the reaction. Besides primary benzylic halides, secondary and tertiary benzyl halides react efficiently to furnish the homocoupling products without any elimination. Generally, halogen substituted benzyl halides are susceptible to sp2–sp2 homocoupling or cross coupling reaction in presence of various metals as evident in some literature reports. It is very important that only sp3–sp3 coupling takes place selectively with such substrates in the present reaction where aryl–Cl and aryl–Br bonds remain intact. So the greater merits and wider applicability of the present protocol can be well appreciated in comparison to many earlier reports. Thus, a sustainable catalytic system has been developed with specific features including low preparation cost, appreciable stability, high reactivity, excellent selectivity, efficient recovery and good recyclability. There are limited reports for the carcinogenic effects and toxicological data for Ni nanoparticles. Although nickel nanoparticles are firmly immobilized on the support of alumina and the leaching of Ni from the support during the reaction is very small, yet one should be cautious while handling the catalyst and disposing the leftover reaction medium avoiding inhalation, inadvertent swallowing and contact with skin.

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R1 2 R R2 R3 R3 X Ni - alumina (5 mol %) 2 3 NH2NH2 . H2O R R 1 30-40 mins R rt, R1 Yield= 80-90% 1 R = H, Me, OMe, O-CH2-O, OBn, Cl, Br, CO2Me, NO2 R2, R3= H, Me; X= Cl, Br

Scheme 5: Homocoupling between substituted benzyl halides using Ni– Alumina as catalyst

The aforesaid presentation, although brief, provides an overview about the basic facets of Green Chemistry and the strategy to accomplish important organic transformations identifying alternative reaction conditions with a view towards the improvement in environmental performance. The catalytic role of various nanometals paves the path for the discovery of important eco-compatible protocols in the days to come. To generate nanometals under ambient condition without any aid of stabilizer and inert atmosphere as well as to avoid the contamination of the metal nanoparticles with the product and to simplify the separation process, supported nanoparticles have been developed in recent times. This has simplified the generation, stabilization, storage, handling, separation and recycling procedures for important metal catalysts to a great extent.

References 1. a) Anastas P. T.; Warner, J. C. Green Chemistry- Theory and Practice, Oxford University Press, Oxford, 1998. b) Dicks, A. P. Green Chemistry Letters and Reviews, 2009, 2, 9-21.

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2. Ghatak, A.; Khan, S. Bhar, S. Adv. Synth. Catal. 2016, 358, 000. 3. Ghosh, S. K.; Pal, T. Chem. Rev. 2007, 107, 4797-4862. 4. Dey, R.; Mukherjee, N.; Ahammed, S.; Ranu, B. C. Chem. Commun. 2012, 48, 7982-7984. 5. Zhang, Y.; Cui, X.; Shi, F.; Deng, Y. Chem. Rev. 2012, 112, 2467– 2505. 6. Ghatak, A.; Khan, S.; Roy, R.; Bhar, S. Tetrahedron Lett. 2014, 55, 7082–7088. 7. Khan, S.; Ghatak, A.; Bhar, S. Tetrahedron Lett. 2015, 56, 2480-2487.

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Nanocomplexes and nanoparticles for delivery of therapeutic cargo to the skin

Manika Vij1 and Munia Ganguli* *Department of Structural Biology, RoomNo-225/Lab No-219, CSIR- Institute of Genomics and Integrative Biology, South Campus, Mathura Road, New Delhi, India - 110020.

Email: [email protected], [email protected]

1Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi, India - 110001.

Key word Skin penetration, Topical/Transdermal, Nanocomplexes, Nanoparticles, Nucleic acid delivery

Abstract Skin is a multifaceted organ that serves as a favourable site for topical/transdermal delivery of therapeutics owing to its large surface area, easy access, possible phenotypic monitoring and wide spectrum of associated disorders. Lipid-rich milieu of skin and its barrier properties vastly impede entry of hydrophilic macromolecules. Various physical, chemical and carrier-based methods have been devised to aid the process. However due to limitations like toxicity and invasive nature, nanoparticles and nanocomplexes have emerged as potential alternatives. We describe the different methods of delivery in skin and how nanoparticles and nanocomplexes can efficiently deliver cargoes to skin in a non-invasive manner.

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Introduction Skin is a multifunctional organ that acts as a communication interface between our body and the external environment. It not only has a well-established role in providing protection to our body against harmful external agents but is also involved in maintaining its insulation properties as well as the homeostasis within. Structurally skin is the largest organ of the human body covering an area of 1.2-1.3m2 and has a thickness of about 2mm. It contains multiple layers of cells (i.e. stratified epithelium) organized in a complex manner. The significant protection properties of skin is imparted by its topmost layer called stratum corneum (see Figure 1) which is 10-15 µm thick containing terminally differentiated keratin- containing cells termed as corneocytes. This keratin protein helps in better water retention inside skin and contributes to the skin moisture. Further, corneocytes are embedded within a multilamellar lipid matrix comprising ceramides, triglycerides, cholesterols and free fatty acids. The nature of the lipids and their exact organization varies depending upon the location in the skin. Underlying this superficial layer of stratum corneum is the epidermis. There are three major layers in the epidermis as shown in Figure 1 (from top to bottom), stratum granulosum, stratum spinosum and stratum basale, also called the basal layer. Epidermis contains two major type of cells namely, keratinocytes and melanocytes (pigment producing cells); along with the Langerhan cells (immune cells). The keratinocytes also contain keratin protein, but their forms are different from that present in the stratum corneum-depending upon which layer they are present in. As we go from top to bottom the keratinocytes in stratum granulosum possess active fillagrin and cross-linked keratin fibres. In the stratum spinosum, they primarily contain profilaggrin, intermediate filament and granules of keratinin. Lastly the basal layer contains keratin 5 and keratin

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14 variants. These cells in the epidermis are embedded in lipid matrix and connected together by tight junction proteins which are present between them. Additionally, this layer also has many antimicrobial peptides like defensins, LL-37 and enzymes like proteases which make it a metabolically active environment. Below the epidermis segment is the dermis that is rich in blood vessels and nerve endings and contains the openings of various appendages in skin such as hair follicles, sweat glands and sebaceous glands. Fibroblasts are its primary cell type that produce collagen and elastin fibres which help to keep the skin tight and wrinkle free. The fat tissue of skin resides in lowermost layer of hypodermis which provides the essential muscular support and insulation property to the organ1,2.

Figure 1: Skin architecture & barriers to topical delivery17(adapted from).

Delivery to and through the skin-what are the challenges? Skin serves as an organ for delivery of different kinds of molecules for both pharmaceutical (i.e. as a drug) and cosmeceutical (i.e. for skin beautification) purpose. The molecules delivered to skin largely comprise small molecule drugs, fusion proteins, bioactive peptides, nucleic acids

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Nano Science…. such as plasmids, siRNA, oligonucleotides and others. This delivery can be of two types either topical (to skin) or transdermal (through skin) - depending upon the final destination of these molecules. Topical delivery is required when one needs to treat skin diseases like psoriasis, atopic dermatitis, vitiligo or melanoma or for treatment of conditions like wounds or sunburns or for application of cosmetics. Transdermal delivery is required when one needs to send drugs through the skin into the dermis and hence into the circulation to reach some other affected organ. This is shown in Figure 2. Either way, skin is considered as an important organ as far as delivery of therapeutics is concerned. Its large surface area and easy accessibility allow easy intervention along with continuous visual monitoring of the after effects of treatments. In case of transdermal delivery, there are obvious advantages of sending the drug through the skin instead of the oral delivery because the drug can avoid the first pass metabolism in the liver. However, there are other major challenges presented by the nature of molecules delivered. Skin allows favorable entry of small molecules which are less than 500Da in size and lipophilic in nature that can passively diffuse whereas all others need active carriers for transport. The complex skin architecture described above makes it very difficult for large biomolecules to pass to or through the skin. Even after breaching the top layers of the skin using a carrier, additional cellular barriers are encountered. Apart from the topical delivery barriers such as overcoming the densely packed and thick stratum corneum with the rich lipid matrix and the corneodesmosomes connecting the corneocytes, the carrier and molecule to be delivered also have to adopt an appropriate route for further entry into the deeper skin layers. This can be achieved either through the protein or lipids present intercellularly, or utilizing transcellular pathways through one cell to another or through the follicular

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Vij, M. & Ganguli, M.: Nanocomplexes and nanoparticles …. pathways which are the sweat and sebaceous gland openings. Moreover, the molecules then have to target the cell type required, have to be efficiently internalized into cells, escape the acidic vesicles called endosomes inside cells, release the molecules at designated site within the cells and retain for long durations. Molecules meant for topical delivery need to reach some of the deeper layers of the epidermis - preferably up to the basal layer. Molecules for transdermal delivery not only need to overcome all these barriers mentioned above but has to reach the dermis and go into circulation3-5.

How are cargoes generally sent to the skin? The general methods of delivery of large cargoes like biomolecules to the skin are either harsh physical methods or chemical methods6,7 which also are either toxic or potential irritants. Some of the methods are listed below: a. Electroporation- This is a method in which short (< 0.5 s) and high intensity (< 100 V) electric pulses are given to the skin which allows permeation of the lipids in the epidermis and cell membrane resulting in delivery of the cargo. It is one of the most commonly used methods in the laboratory but for clinical applications it is poor in patient compliance, is costly and also can be applied only in small surface areas. b. Iontophoresis: In this method, a continuous low intensity (< 10 V) electric field is applied on the skin at constant current in order to drive the transport of charged drug molecules to and through the skin. This primarily uses the shunt pathways involving the hair follicles and sweat glands. Charged small molecule drugs like calcitonin,

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luteinizing hormone-releasing hormone and large charged nucleic acids have both been sent through this pathway. c. Microneedles: This involves an array of sharp tip needles that are 100-700µm in length and insert only into the viable epidermis thereby avoiding any pain sensations arising due to nerve stimulations in the dermis as seen by conventional intradermal injections in skin. This method has been used to deliver wide number of nucleic acid cargos for immunization purpose but is potentially irritating and takes care of only small area applications in skin. d. Sonophoresis: Here low frequency ultrasound is used to create transient permeability within the lipid bilayers of the stratum corneum thereby allowing many macromolecules like insulin, bovine serum albumin and oligonulceotides to pass into the skin as well as through it. e. Chemical enhancers: Different azone-based, alcohols or surfactant compounds are used as pre-treatments on skin followed by application of biomolecules to increase their entry in skin. But these chemicals destroy the stratum corneum barrier of skin in permanent manner.

Figure 2: Methods of delivery in skin (Topical & Transdermal)6,17(adapted from).

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Although all these active methods have been used for delivery of large number of small molecules as well as macromolecules in skin, they still have some disadvantages like limited area of application, high cost, no effect on enhancing cellular entry and potentially irritating in some of the cases. Therefore, delivery of certain type of macromolecules like DNA using above methods is a problem. Moreover, properties of certain biomolecules, such as low skin penetration of bioactive peptides, blockage of nanoparticles in appendageal reservoirs thereby impeding there movement into skin, depth of entry and stability of cargos can be issues during delivery which make it necessary to develop more efficient and safe methods of delivery.

Nanoparticles and nanocomplexes-how and why are they applied to skin? In recent years nanocarriers, broadly of two types i.e. inorgainc nanoparticles and organic nanocomplexes, have both found application as important materials for both topical and transdermal delivery in skin8. Inorganic nanoparticle based systems have the ability to diffuse passively into skin owing to their small size and are readily taken up by the skin cells. They have high loading capacity, are non-immunogenic and help the cargo to escape enzymatic degradations in skin. This category of carriers includes gold nanoparticles (< 100nm in size) which have been coated with siRNA molecules or peptide based carriers to increase their uptake in the skin tissue and cells. Based on their shapes and sizes these particles show huge variations in terms of their efficiency to enter skin. Recently many cosmeceutical formulations have them as one of the constituents. Spherical nucleic acids are another set of inorganic nanoparticles with highly ordered complex of nucleic acids that can resist

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Nano Science…. nucleases mediated degradations in skin. It has been used to treat various skin disorders like psoriasis and aid in wound healing. The core of this structure may be hollow for encapsulation of drugs or may be formed of inorganic matter like gold. However as mentioned before many of these nanoparticles get engulfed in appendages of skin which slows down their entry and affects the overall effectiveness of delivery. Organic nanocomplex based systems are economical, multi- functional, cell specific and safe for delivery in skin. These include lipids, polymers and peptide based carriers that are covalently or non-covalently bounded to the cargos and protect them from degradation. These carriers have the ability to penetrate skin as well as increase complexes uptake by the cells. Liposomes are one such cationic lipid based carrier that have been largely used for siRNA and IL-4 plasmid delivery to treat psoriasis. Poly(ethylenimine) (PEI) or dendrimer-based polymeric carriers have been used to deliver antisense oligonucleotide targeting the anti-apoptotic protein, Bcl-2, to enhance apoptosis and significantly reduce tumor size in mice. But owing to their toxicity concerns much attention has been given to peptide based carrier systems which are relatively safe to use. In recent times, natural and synthetic peptides have emerged as potential transporters of large biomolecules like proteins and plasmid DNA to cells and organs of different origins. Peptides are easy to synthesize, diverse in chemistry, can be applied over a large surface area, are economical to use and can be modified for cellular targeting in skin. Many peptides like polyarginine, TAT, magainin and penetratin can cross the stratum corneum using some of the techniques mentioned earlier and have been used for efficient transdermal delivery of conjugated drug molecules in skin. Recently a phage display derived cyclic peptide SPACE has been used for siRNA delivery across intact skin9. Moreover a cyclic

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Vij, M. & Ganguli, M.: Nanocomplexes and nanoparticles …. peptide TD-1 is capable of transdermal delivery of an important hydrophilic macromolecular protein like insulin10. For plasmid DNA delivery, a cysteine flanked arginine-rich peptide has been shown to deliver a reporter luciferase plasmid through intradermal injection in the skin11 and in an independent report HIFα ODD plasmid DNA delivery has been done successfully to stimulate wound healing12. Also many fusion proteins made from peptide sequences and target protein such as TAT- epidermal growth factor, Chaperon-epidermal growth factor, TAT and R9 fused anti-oxidative enzymes, and few non-covalently associated cargo such as TAT-EGFP protein have been shown to enter skin in an efficient manner13-15. In many of these cases, nanocomplexes have been formed between the peptide and the cargo. We have also identified a novel peptide based carrier Mgpe9 that seems to be a promising, non-invasive and non- toxic topical delivery system for plasmid DNA as nanocomplexes to intact human skin in unaided manner16. We have also shown that plasmid delivered is functionally potent and shows efficient gene expression throughout the skin tissue for a long duration thereby indicating its usefulness for future clinical applications and as an upcoming genetic cosmetics formulation.

Conclusion Skin is a dynamic organ that has immense potential to be explored for biomolecule delivery to address various localized and systemic disorders. One of the significant challenges in skin biology has been to develop non-invasive, non-toxic and efficient methods for delivering macromolecules to and through the skin. Peptide based carriers have been used to deliver cargos such as proteins, plasmids, drugs into skin in efficient and safe manner-mostly in the form of nanocomplexes. Apart

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Nano Science…. from overcoming the limitations of existing methods these carriers possess clinical and cosmeceutical translation utilities which contribute to efficient strategies for skin penetration and delivery technologies.

Acknowledgement We acknowledge network project BSC-0302 Entitled “Towards Understanding Skin Cell Homeostasis (TOUCH)”, Council of Scientific and Industrial Research (CSIR), New Delhi, INDIA for financial support.

References 1. Kolarsick, P. A. J.; Kolarsick, M. A.; Goodwin, C. J. Dermatol Nurses Assoc. 2011, 3, 203-213. 2. Bouwstra, J. A.; Honeywell-Nguyen, P. L. ADDR 2002, 54, S41-S55. 3. Zakrewsky, M.; Kumar, S.; Mitragotri. S. J. Control Release 2015, 219, 445-456. 4. Barua, S.; Mitragotri, S. Nano Today 2014, 9, 223-243. 5. Prausnitz, M. R.; Langer, R. Nat. Biotechnol. 2008, 26, 1261-1268. 6. Mitragotri, S. Nat. Rev. Immunol. 2005, 5, 905-916. 7. Prausnitz, M. R.; Mitragotri, S.; Langer, R. Nat. Rev. Drug Discov. 2004, 3, 115-124. 8. Patlolla, R. R.; Desai, P. R.; Belay, K.; Singh, M. S. Biomaterials 2010, 31, 5598-5607. 9. Hsu, T.; Mitragotri, S. Proc. Natl. Acad. Sci. USA 2011, 108, 15816- 15821. 10. Chen, Y.; Shen, Y.; Guo, X.; Zhang, C.; Yang, W.; Ma, M.; Liu, S.; Zhang, M.; Wen, L. P. Nat. Biotechnol. 2006, 24, 455-460. 11. Siprashvili, Z.; Scholl, F. A.; Oliver, S. F.; Adams, A.; Contag, C. H.; Wender, P. A.; Khavari, P. A. Human Gene Ther. 2003, 14, 1225- 1233.

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12. Trentin, D.; Hall, H.; Wechsler, S.; Hubbell, J. A. Proc. Natl. Acad. Sci. USA 2006, 103, 2506-2511. 13. Ruan, R. Q.; Wang, S. S.; Wang, C. L.; Zhang, L.; Zhang, Y. J.; Zhou, W.; Ding, W. P.; Jin, P. P.; Wei, P. F.; Man, N.; Wen, L. P. Eur. J. Med. Chem. 2013, 62, 405-409. 14. Zhao, B.; Guo, Y.; Fu, A. Appl. Biochem. Biotechnol. 2012, 166, 463- 471. 15. Hou, Y. W.; Chan, M. H.; Hsu, H. R.; Liu, B. R.; Chen, C. P.; Chen, H. H.; Lee, H. J. Exp.Dermatol. 2007, 16, 999-1006. 16. Vij, M.; Natarajan, P.; Pattnaik, B. R.; Alam, S.; Gupta, N.; Santhiya, D.; Sharma, R.; Singh, A.; Ansari, K. M.; Gokhale, R. S.; Natarajan, V. T.; Ganguli, M. J. Control Release 2016, 222, 159-168. 17. Nestle, F. O.; Meglio1, P. D.; Qin, J.; Nickoloff, B. J. Nat. Rev. Immunol. 2009, 9, 679-691.

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Synthesis of Orthometalated Organosulfur Compounds of Rh and Ir: A Promising Organometallic Nanoparticle

Ujjwal Das Department of Chemistry, Sarsuna College, 4/HB/A, Ho-Chi-Minh Sarani, Kolkata-700061, West Bengal, India Email: [email protected]

Key words Organosulfur, metalloligand, sulfur- capped nanoparticle, CS cleavage, agglomerate

Abstract A novel route of synthesise the organosulfur thiolato and thiol incorporating heavier transition metal complexes are discussed. The hexacoordinated orthometalated organosulfur complexes of Rh(III) and Ir(III) has been synthesized and isolated from solution where the ligands having multidentate C^N^S coordinating site. Most of the cases organosulfur thiolato are generated via in situ C–H and C–S/C–hetero atom bond scissions in the presence of excess phosphines or any external simuly. The high electron density on the thiolato-S concerning superior nucleophilicity can be visualized through the formation of a number of S- centered derivatives in solution, such as the oxygenation to sulfenato or sulfinato, alkylation and metalation processes. This thiophenolato complex is redox-active in solution exhibiting facile oxidative response unlike the case of its thioether. The organosulfur compounds exhibit rich spectral properties including inherent physicochemical properties, luminescence and the origin of these transitions is analyse with theoretical methods. The enhanced electron density on thiolato-S in prompted us to explore the  43 

Das, U.: Synthesis of Orthometalated Organosulfur …. reactivity of potential thiolato metalloligand toward the aspiration of possible synthesize and exploration of chemistry of analogous supramolecules and nanoparticles. One of the approach using apposite S- centred reactivity of thiolato to a route to synthesize a several self- assembled monolayers of thiolate-protected capped hetero metallic (M = Ag+, Au+) nanoparticles, which are of greater concentration in view of their higher stability and applicability in biology and catalytic properties corresponding to the homogeneous catalysts.

Introduction In recent years nanoparticles and nanoscale materials has engendered an immense interest for scientists and chemical engineers of almost all disciplines. This interest has been generated in large part by reports that a number of physical properties including optical phenomenon, magnetic and size-dependent properties and functionalizing in catalysis and biology.1 The coordination and organometallic chemistry of platinum group metals is a field of current growing interest under various viewpoints are mention above. This studies not only provide an access to improvise the fundamental knowledge like synthesis of new types of organosulfur compounds; their spectral aspects, electrochemical behaviour in solution, molecular and electronic structural properties etc, but hold much promise also to create new research topics to conversion of these organometallic sulfur compounds to the corresponding organometallic nanoparticles2 with an applied character such as the development of medicinal drugs, catalysis used in different industrial process, different modern photochemical devises etc. So far, most of the studies have focused on using transition metal compounds to understand

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Nano Science…. the C–H and C–S bond activation of thiophenes, benzothiophenes, dibenzothiophenes, and their derivatives.3 A novel hexacoordinated orthometalated organosulfur complexes SR S of M(III) of type [M(L )Cl2P] and [M(L )ClP2] (M= Rh and Ir, P= PPh3) has been synthesized from multidentate ligand L, with C^N^S coordination and the analogous MCl33H2O in the presence of excess phosphines via C(sp2)-H and C(sp3)-S/C–hetero atom bond scissions.4,5 The aforementioned cleavage process in association with (arene)C–H activation furnishes a new class of organosulfur compounds of rhodium(III)/iridium(III). The coordinatively and electronically saturated S thiolato [M(L )ClP2] complexes are stable in the solid state. Again the thiolato-S vis-à-vis superior nucleophilicity due to the high electron density on it can be visualized through the formation of a number of S- centered derivatives in solution, such as the oxygenation to sulfenato or sulfinato,6 Alkylation7 and homo-metalation8 processes. These thiophenolato complexes are redox-active in solution exhibiting facile SR oxidative response unlike the case of its thioethers [M(L )Cl2P]. The organosulfur compounds exhibit rich spectral properties including inherent physicochemical properties,9 luminescence and the origin of these transitions is analyse with theoretical methods. This role of S-centre towards the other thiophillic species will be focused and presenting an overview of the synthetic methods used to prepare organometallic nanomaterials have potential applications in materials science and biology, an emerging area of biodirected syntheses is of extreme interest.10-15 From both the experimental and theoretical findings that of enhanced electron density on thiolato-S in prompted researchers to explore the reactivity of potential thiolato metalloligand toward soft thiophilic metal centers principally having closed-shell d10

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Das, U.: Synthesis of Orthometalated Organosulfur …. configuration (M = Ag+, Au+ and Hg2+)16 with the aspiration of possible formation of S-bridged heterometallic aggregates (hetero-metalation) and extend the study to synthesize and exploration of chemistry of analogous supramolecules and nanoparticles. One of the straightforward strategy using apposite S-centred reactivity of thiolato to a route to synthesize a several self-assembled monolayers of thiolate-protected17 capped hetero metallic (M = Ag+, Au+) nanoparticles, which are of greater concentration in view of their higher stability18 and applicability in biology and catalytic properties corresponding to the homogeneous catalysts. Here the synthesis and different chemical behaviour of the orthometalated organosulfur complexes of Rh(III) and Ir(III) with respect to their thiolato S centre, and a scope of preparation of heterometallic nanoparticles encrusted with transition-metal incorporating self-assembled monolayers and their possible reactivity including bioactivity and catalytic studies of mixed monolayers of alkanethiolates, benzylthiol19 and thiolates functionalized with rhodium and iridium-mono and diphosphine complexes are reported. This review presents a brief overview of C–S bond activation mediated by Rh and Ir metal compounds and summarizes the recent advances and scope of the synthesis of transition-metal incorporating nanoparticles and their application in catalytic bond activation and transformations in the organic compounds. This study not only provide an access to improvise the elementary facts like synthesis of Organosulfur compounds and transformed into corresponding organometallic nanoparticles but hold much promise also to create topics with an applied temperament such as the development of medicinal drugs, catalysis used in different industrial process, different modern photochemical devises etc.

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Synthesis and characterization details of organometallicsulfur complexes An interesting way to synthesize organosulfur compounds of Rh and Ir has been reported using C^N^S ligand and corresponding metal

4,5 analogues. Where the reaction of MCl33H2O and alkyl 2- SR SR (phenylazo)phenyl thioether HL (HL ; M= Rh, Ir; R = Me, CH2Ph) in the presence of excess of PPh3 in ethanol at reflux gave access to the desired organothioether, organothiolato complexes (as neutral compounds), incorporating the cyclometallated LSR and LS ligand chromophores in approximately 25 and 40 yield, respectively (Scheme 1).

(M= Rh, Ir) Cl R PPh3 H N PPh3 S Cl S excess PPh3 + MCl3 M M N EtOH + S N N R N N Cl PPh3

SR S (HL , R = CH , CH Ph) SR [ML ClP2] 3 2 [ML Cl2 P] Thiolato Thioether Scheme 1: Synthesis of Cyclometalated M(III) Thioether and Thiolato

Because of the inertness of the coordination sphere of the metal ion, these syntheses require drastic conditions with a harsh control of the reaction time. The CH bond was cleaved in situ during the course of the synthesis prior to the cleavage of CS bond. The general mechanism of formation of orthometalated azobenzene derivatives was described to proceed via initial coordination of azo-nitrogen followed by electrophilic substitution at the pendant phenyl ring.20 It is significance to noting that the CS bond scission was not observed when reactions were performed

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Das, U.: Synthesis of Orthometalated Organosulfur ….

SR with mono equivalent PPh3 relative to both ligand HL and MCl33H2O. In that case, organothioethers were obtained in excellent yield. Significantly, the thioether functions are converted to thiolato group in presence of excess PPh3 (Scheme 2) via in situ CS bond scission. In the CS bond scission process the oxidation state of metal

PPh Cl R 3

Cl S PPh3 S excess PPh M M 3 + R N N EtOH N N PPh Cl 3 [MLSRCl P] S 2 [ML ClP2 ] Thioether Thiolato Scheme 2: Convertion of M(III)Thioether to M(III)Thiolato [ M= Rh/ Ir] via activation of C-S bond

remains the same in both the starting material organothioether and cleavage product organothiolato and this appears peculiar in the sense that the involvement of metal atom in the cleavage process and the presence of

PPh3 molecule is necessary during the cleavage process. A plausible mechanism21,22 was represented by Das et al.4,5 which authenticated the single-electron transfer (SET) CS cleavage process by exclusion of alkyl radical (R). Infrared spectra of the complexes exhibit many sharp and strong vibrations within 1600-400 cm1. The thiolato and thioether compounds exhibited a sharp vibration near 1430 cm1 [for all Ir(III) analogues] and near 1400 cm1 [for all the Rh(III) analogues] relative to that of free

1 23 ligands (14501492 cm ) are assigned to the NN. The expected

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lowering of NN values in complexes is consistent with the Ir(III)-d  azo-* back-bonding and authenticating the azo coordination. Experimental strong features near 520 and 690 cm1 are indicative of metal-phosphine bonding. Alkyl proton signals of thioether compounds appear as a singlet at δ 2.2-3.2 (SCH3) and a doublet centred at δ 5.1-6.2 1 (SCH2Ph) resonances, respectively. Absence of alkyl resonance in the H NMR spectrum of thiolato compounds validates the occurrence of S- dealkylation. The 31P signals of the thioether complexes occur near δ ≈ 22 for Rh and δ ≈ -20 for Ir. Whereas the monomeric thiolato complexes containing two phosphine groups exhibit only single doublet resonances, indicating equivalent phosphine environment near δ ≈ 17 for Rh and δ ≈ - 18 for Ir. The lowest energy transitions in the visible region are observed near 700-733 nm as broad band for the organothiolato compounds can be ascribed as ILCT transition. Shoulder around 390 nm assigned to LLCT/ILCT transition. In the visible region, the lowest energy excitations of thioether complexes around 630 nm for Ir(III) is ascribed as MLCT admixed with LLCT and 470 nm for Rh(III) is ascribed as MLCT. Lowest energy transition in the UV region is observed as shoulder near 390 nm. The lowest energy electronic excitation of thioether complexes is shifted to higher energy that of thiolato compounds, indicating that facile CT transition occurs in S-dealkylated complexes. The emission spectral behaviour of the organoiridium(III) sulfur complexes at room temperature in dichloromethane solution exhibit broad luminescence maxima (Fig. 1) within the range 400–450 nm and these remain unaffected with the energy of excitation wavelengths. The complexes Ir(III)-thioether and Ir(III)- thiolato are found to be moderate to strong emitters (Φ = 0.31 × 10−1and 1.23 × 10−1). Interestingly the analogous Rh-complexes are not emissive.

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Das, U.: Synthesis of Orthometalated Organosulfur ….

Figure 1: Luminescence spectra of complexes Ir(III)-thioether (orange) and Ir(III)-thiolato (green)

24 Dimeric rhodiumthiolato [Rh2(dippe)2(µ-SC12H9)(µ-H)] complexes was prepared using rhodium(I) complex [Rh(dippe)(µ-H)]2 i i (dippe = Pr2P(CH2)2P Pr2) reacts with dibenzothiophene in benzene at 100ºC following C–S cleavage approach (Scheme 3).

Again, the treatment of [Cp*Rh(PMe3)(Ph)H] (Cp* = cyclopentadiene) with the 2/3-methylthiophene derivatives led to selective25 formation of substituted thiophene derivatives resulting from insertion of the Rh atom into the less or more hindered C–S bonds (Scheme 3) was reported.26

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Scheme 3: Substituted thiophene derivatives of Cp*Rh(PMe3)] via activation of C-S bond

Interestingly the metal- active material [MCl(PPh3)3] unaided is capable to furnish the related thiolato in the analogous conditions in low yield.4,5 Similarly the multitude of dialkyne-trithia ligand was reacted with the Wilkinson’s catalyst and its symmetrical other transition-metal complexes are known to form organothiolato and polythiamacrocyclic complexes via C–S cleavage (Scheme 4).27–29 Another potential ligand benzaldehyde thiosemicarbazone provided organorhodium(III)thiolato 30 with [Rh(PPh3)3Cl] was reported where the C–H bond activation is the main concern rather C-S bond scission. Here the thiosemicarbazone ligand and [Rh(PPh3)3Cl] was dissolved in ethanol and refluxed the solution to

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Das, U.: Synthesis of Orthometalated Organosulfur …. yield a yellow solution of organorhodium(III)thiolato complex (Scheme 4).

Scheme 4: Synthesis of organorhodium(III)thiolato via activation of C-S bond

Although the thiosemicarbazones are usually expected to coordinate metal ions, via dissociation of the hydrazinic proton, as bidentate N^S donors generating a five-membered chelate ring, in the article this particular rhodium starting material is used because of its demonstrated capability to accommodate a tridentate ligand via oxidative addition31 and, more importantly, its competence in successfully mediating C–H activation of organic phenyl ring through orthometallation. The organothiolato compounds are found to be highly keen to S-centered oxidation under normal aerobic conditions forming different corresponding derivatives. Facile S-centered oxidation of iridium thiolato relative to the rhodium analogue was reflected in the electrochemical study and superior back-donating efficacy of iridium (5d) compared to rhodium (4d) can attributable to more dilated d orbitals of former because of relativistic effects.32 The sulfur-centered reactivity of M(III) thiolate was also reflected via its reactivity in alkylation processes. The reaction of organothiolato complexes with RX (R = Me, allyl and nBu; X = Br and I)  52 

Nano Science…. in toluene afforded orange corresponding thioether complexes4,5 of type

III SR [M (L )ClX(PPh3)] at reflux in good yields.

PPh PPh3 3 R

Cl S Cl S M M N eqv. RX N Toluene N N X PPh3 S [ML ClP2 ] [MLSRClXP] R= CH , nBu, Allyl etc. Thiolato 3 Thioether Scheme 5: Convertion of M(III)Thiolato to M(III)Thioether [ M= Rh/ Ir] via C-S bond formation

While there have been a number of reports of alkylation for mono(thiolato)-and bis(thiolato)-type metal complexes,33,34 the first report of tris(thiolato) alkylation for tris(thiolato)-type rhodium(III) complex, where the stepwise alkylation of the fac(S)-[Rh(aet)3], applying 1,2- dibromoethane and methyl iodide, forming dialkylated mono(thiolato)- type rhodium(III) complexes, fac(S)-[Rh(aet)(baete)]2+ (baete = 1,2-bis(2- 2+ aminoethylthio)ethane) and fac(S)-[Rh(aet)-(mtea)2] (mtea = 2- methylthioethylamine). Further conversion of bis-thiolato to the 3+ 35 trialkylated fac(S)-[Rh(mtea)3] by reaction with dimethyl sulphate.

Organometallic Noble Metal Nanoparticles Synthesis and their Application / Scopes The main intention of the scientist to synthesise/ conversion of the organometallic transition metal compounds to organosulfur (thoilate or thiol) capped nanoparticle, since, thiolate-protected nanoclusters have now

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Das, U.: Synthesis of Orthometalated Organosulfur …. culminate in the discovery of a new form of matter composed of a few atoms, which exhibit molecular behaviour.36 Literature study revel that numerous methods to prepare the nano- construction are documented. The professed “top down” and “bottom up” methods to produce the nano-structured metal colloids are very widespread. A typical “top down” method for example involves the mechanical grinding of bulk metals and subsequent stabilization of the resulting nanosized metal particles (Scheme 6) by the addition of colloidal protecting agents37,38 Metal vapor techniques are also a very versatile route for the preparation of a wide range of nano-structured metal colloids in laboratory scale.39–43 Another way the embryonic stage of

Scheme 6: Schematic representation of the formation of organometallic nanoperticles

nucleation of is caused by the reduction of metal salt into zerovalent metal atoms44. These metal atoms can collide in solution with metal ions, metal atoms, or clusters repeatedly to form an irreversible seed of stable metal nuclei. The diameter of the seed nuclei are below 1 nm

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Nano Science…. depending on the difference of the Eº(red) potentials between the metal salt and the reducing agent used, and also the metal–metal bonds strength. Now the synthesized nanoparticles, since they are of fine particulates are caused to clump together into a flock. The flock may then float to the top of the liquid (creaming), settle to the bottom of the liquid (sedimentation), termed agglomerate45. It is a material formed by objects sticking together and forming clumps. The formation of agglomerate from the nanoparticles is the step of damage the nano-structured. Some protective agents are use to avert agglomeration of the nano-structured colloidal metals which provide stabilization. Other basic modes of stabilizations as for electrostatic stabilization and steric stabilization have been distinguished.46 The main classes of protective groups selected from the literature are commonly: polymers and block copolymers47–49 N, P, S donors (e.g., amines, phosphines, thioethers/ thiolates)50 –70 solvents such as THF50,71, THF/MeOH72, or propylene carbonate73, long chain alcohols74–79 surfactants50, 80–83 and organometallics84,85. In general, metal colloids are made soluble in organic media (“organosols”) using lipophilic protective agents while hydrophilic agents yield water-soluble colloids (“hydrosols”). A convenient mode of synthesis of silver and gold nanoparticles, having diameter in 15−30 nm via the chemical reduction86 of Au3+/ Ag+ with sodium citrate87–89 followed by a variety of alkyl chains possessing O, N, P and S linkers in their head group have been used as protective mediator for Ag and Au nanoparticles (particles of size >2−100 nm).90 The nanoparticle size can be measured and shown by TEM images. Unlike the plasmonic systems, TEM investigations have not been hugely successful for the nano clusters mainly due to too small size to be observed in standard TEM91 and electron-beam induced growth of clusters during microscopic

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Das, U.: Synthesis of Orthometalated Organosulfur …. examination, have frustrated TEM investigations. The other experimental techniques, used especially for characterizing such organic and inorganic nano molecules, such as UV/vis, mass spectrometry (ESI and MALDI MS), IR, 1H NMR, and so forth, can be used eminently for characterizing these clusters. In recent years, crystallographic data have helped in acquiring more knowledge about these systems. The high electron density on the thiolato-S vis-à-vis superior nucleophilicity can be visualized through the formation of a number of S- centered derivatives and these properties generate an idea to produce S- thiolato capped and stabilized organometallic nanoperticles (Scheme 7) incorporating Rh or Ir and /or other thiophillic metals.

Scheme 7: Possible route to synthesize the S-thiolato capped and stabilized organometallic nanoperticles

Rh(PVP) nanocolloidal solution was produced using the

RhCl33H2O and PVP[ polyvinylpyrrolidone] in a mixed solvent of distilled water and ethanol by the reflux-flow system at 353 K for 5 hours. The nanocolloidal solution was protected by using L-cysteine solution as stabilizing material. It seems that a thiolate species originated from the L- cysteine exist on the Rh nanoparticle surface, because the peak at around 2472 eV has been reported as the thiolate adsorbate on the Rh surface92

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The dimethyl sulphide dissociates to the methanethiolate on the surface of Rh has presented by T. Nomoto92,93 Another efficient reducing agent hydrogen has been used for the preparation of electrostatically stabilized metal sols and of polymer-stabilized hydrosols of Pd, Pt, Rh, and Ir94–97. In the case of other transition metal Mn, Pd, and Pt organosols are successfully stabilize applying the tetrahydrothiophene (THT); but the organosols with Ti and V capped by THT are less stable and led to decomposition (Fig. 2)80

Figure 2: Tetrahydrothiophene protected organosols

The stepwise reductive formation of Ag3+ and Ag4+ clusters by spectroscopic methods has been followed by Henglein’s group98. Badia et al. has reported in a detailed IR spectra analysis of a variety of -1 alkanethiolate: Au nanoparticle δ(CH2) positions around 1468 cm . Yee et al. found a clear band splitting of this mode with 1473 and 1463 cm-1 band maximum positions,99 due to presence of a hexagonal subcell packing or a “liquidlike” assembly. This strategy to construct the organosulfur protected organometallic nanoparticles are very important due to their innovative chemical behaviour and their selectivity and improved efficiency as

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Das, U.: Synthesis of Orthometalated Organosulfur …. catalyst100 for different organic molecule transformation in addition to its supremacy in the biofunctions as biomedicines. The number of potential applications for these colloidal nanoparticles is growing rapidly because of the unique electronic structure of the nanosized metal particles and their extremely large surface areas. A large variety of nanoparticles preparation modes and materials serve as supports or grafting cores, and numerous media compete for resourceful catalytic processes. Protected organometallic nanoparticles having mono disperse, small (1–10nm), including bi and trimetallic nanoparticle catalysts, most often more efficient compare to only one type of metal containing, are offered for many modern reactions with great catalytic efficiency due to the enhanced available nanoparticle surface. This evolution has significantly improved the selectivity of nanoparticle catalyzed reactions Gavia, D. J.; Shon, Y.-S. controlling surface ligand density and core size of alkanethiolate-capped Pd nanoparticle and their effects on catalysis.101 Especially the hydrogenation of unsaturated organic substrates that proceeds strictly heterogeneously and high enantioselectivity has been obtained. A major recent finding, that it remains a challenge is the removal of these catalysts by filtration, although recycling and professional re-use many times of supported nanoparticle catalysts. The gold sols, nanoparticle is extraordinarily interesting for their intensive colors, which enabled them to be used as pigments for glass or ceramics. However, there are a few reports about an influence of nanoparticles in vivo. Most of the studies which have reported about the nanoparticle and the biological molecule have been investigated for the bio-electronic applications and details have reported the nanoparticle- biomolecule reaction102,103 Therefore, it is a great important field to

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Nano Science…. disclose the mechanism of interaction between the metal nanoparticle surface and the biomolecule in vivo. Many researchers have investigated the reaction of biomolecule on Au surface and shown that the sulfur containing molecules decompose to thiolate on Au substrate.104-106 Recently a large compound nanoparticles [128 nm] composed of biodegradable nuclear targeting oligolysine and an anticancer iridium compound as potential nanomedicine is synthesized for cancer chemotherapy to inhibit drug resistance mechanisms is reported.107 The metal nanoparticle field is presently escalating, and it is anticipated that these key challenges will be met in the close future, and that this area of nanoscience will be much more applied in tomorrow’s laboratory and industry.

Conclusion A family of orthometalated rhodium(III) and iridium(III) organosulfur compounds has been reported with their synthesis by (aryl)CH and CS bond activation. The most significant aspect among the syntheses is the transition metal [Rh and Ir]-mediated cleavage product organothiolato, where PPh3 used as external stimuli, plays the vital role in the cleavage process. The underlying mechanistic pathway is fascinating in CS cleavage pathway via single-electron transfer (SET) process keeping the metal oxidation state same in both starting complex and product. While majority of platinum-metals thiolato compounds are achieved from thioethers by oxidative addition during CS bond scission. Electrochemical study reveals the facile oxidative nature of thiolato complexes in solution unlike other organoiridium(III) sulfur compounds and this event is associated with its remarkable nucleophilicity, which

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Das, U.: Synthesis of Orthometalated Organosulfur …. leads to a number of sulfur center derivatives, toward electrophiles like dioxygen, carbo cations and metal ions. Consequently, an easy thiolato- thioether conversion is achieved another isomeric form, from the precursor thiolato and alkyl halide. The SC bond formation is occurred with concomitant substitution of one PPh3 molecule of thiolato by halide. Thiolato complexes are very much prone to S-centered oxidation to furnish numerous S-centered derivatives. The high electron density on the thiolato-S vis-à-vis superior nucleophilicity can be visualized through the formation of a number of S-centered derivatives and these properties generate an idea to produce S-thiolato capped and stabilized organometallic nanoperticles incorporating Rh or Ir and /or other thiophillic metals. The synthesis of stable and isolable rhodium and iridium nanoparticles was accomplished by employing micelle or surfactant as a ligand precursor. In this review the techniques for producing stable alkane-sulfur protected especially alkanethiolate-capped Platinum metals nanoparticles using reducing agents were discussed. Finally, the produced Ir nanoparticles exhibited strong magnetic moments demonstrating the potential of these Ir nanoparticles for various technological applications. Benzylthiol-functionalized gold and silver nanoparticles were synthesized by a modified two-phase method. A new, facile, one-phase synthesis of thiolfunctionalized gold and silver and other thiophillic metals nanoparticles in THF /THT using reducing agents was also presented. A brief introduction of a novel application of thiolato/ thiol protected transition metal-nanoparticles as precious catalysts in organic transformation as well as it selective and precise bio-functions are pointed out.

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Acknowledgement The author is grateful to UGC, New Delhi and W.B. [Eastern Zone] for their financial support as Minor Research Project [PSW-049/ 11-12, Dated 3rd August, 2011] to carrying out the research. Author is also thankful to the authority of Sarsuna College for providing the necessary infrastructural facility. Author is grateful to the Jadavpur University, Kolkata for different infrastructural facility and instrumental support. Finally, thanks to the students of the Department of Chemistry, Sarsuna College, specifically Anup Parali for his assistance and support for the preparation and presentation of poster regarding this topic.

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Abstract

Exploring the Interaction of a Micelle Entrapped Biologically Important Proton Transfer Probe with the Model Transport Protein Bovine Serum Albumin

Debarati Ray, Ashis Kundu, Animesh Pramanik and Nikhil Guchhait*

Department of Chemistry, University of Calcutta, 92 A. P. C. Road, Kolkata-700009, India E-mail: [email protected]*, [email protected]

Abstract Serum albumins are the most widely studied proteins abundant in plasma and play a key role in the transport of various exogenous and endogenous compounds in the body. There are many reports on the nature and mechanism of interactions between the small molecules/drugs and proteins as these have a crucial relevance to the understanding of biochemical consequences of drug-protein interactions. The present work deals with the binding interaction of a biologically important hetero cyclic compound namely 1-(2-hydroxy-5methyl-phenyl)-3,5-dioxo-1H-imidazo- [3,4-b] isoindole (ADII), a drug template, with the target protein Bovine Serum Albumin (BSA) using different spectroscopic techniques such as steady state absorption, emission, circular dichroism, dynamic light scattering, etc. Mainly, the interaction of different micelles (here, three surfactants like sodium dodecyl sulfates (SDS), cetyl trimethyl ammonium bromide (CTAB) and triton X 100 (TX 100) are used) loaded drug template molecule with protein is focused along with the probe-protein interaction in aqueous buffer medium in order to understand how the binding interaction is influenced in presence of different types of surfactants. Because the surfactants are also known to interact with the

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Nano Science…. protein which causes modification of the structure of proteins, hence affect the drug–protein interactions. Binding of ADII with BSA is found to be enormously modified when it is released from the micellar environments than that in pure aqueous tris buffer (pH = 7.4). The binding constant of the ADII−BSA complex is reduced when the probe is released from anionic SDS micelle, whereas the binding is observed to be strengthened in presence of cationic CTAB surfactants due to the formation of a 1:2 (ADII−BSA) complex. Time-resolved studies also support our steady state findings that the released drug from the micellar environment is found to be strongly bound with the protein BSA. Circular dichroism (CD) and dynamic light scattering (DLS) study reveals that the secondary structure of BSA gets some stabilization in SDS medium after binding of drug template to protein. The probable binding location of the probe within the protein cavity (hydrophilic subdomain IA) has been explored from an AutoDock- based blind docking simulation study.

References 1. Ray, D.; Kundu, A.; Pramanik, A.; Guchhait, N. J. Phys. Chem. B. 2015, 119, 2168−2179. 2. Ray, D.; Pramanik, A.; Guchhait, N. J. Photochem. Photobiol. A. 2014, 274, 33−42.

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Abstract

Synthesis of silver nanoparticles from neem (Azadiracta indica) leaf extracts and its potentiality towards degradation of pesticides

Amita Hajra, Shreya Medda, Uttiya Dey and Naba Kumar Mondal* Department of Environmental Science, The University of Burdwan, Burdwan - 713104 Email: [email protected]*

Keywords AgNPs, Pesticide, Degradation, Carbaryl, Endosulfan

Abstract Present research highlighted the biogenic synthesis of silver nanoparticles (AgNPs) from neem leaf extracts. The synthesized AgNPs was characterized by UV-Vis spectra and Fluorescent microscope. The sharp peak at near 420 nm clearly indicate the formation of AgNPs. The synthesized AgNPs was subjected to degradation of pesticide carbaryl and endosulfan under visible and UV light exposure. The results suggest that maximum degradation was achieved 37% and 70 % of carbaryl and endosulfan, respectively. However, maximum 57% degradation of endosulfan was achieved under combined AgNPs and UV exposure.

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Optical and electrical transport properties of vanadyl phosphate —polyaniline nanocomposites Ashis Dey

Department of Chemistry, Sarsuna College, Kolkata - 700061, India Email: [email protected]

Abstract Inorganic layered compounds are most attractive host systems to synthesize molecules by intercalation method. Hydrated vanadyl phosphate, VOPO4-2H2O is an important layered solid to undergo intercalation reactions with different guest elements. The nanocomposites of conducting polyaniline and layered vanadyl phosphate, VOPO4-2H2O are synthesized by redox intercalation method. Water content decreases with insertion of polyaniline molecules. In scanning electron micrographs plate like structures are observed for both VOPO4-2H2O and intercalated nanocomposites. Protonation of polyaniline and interaction with vanadyl phosphate are observed in infrared and UV absorption spectroscopy. Intercalation improves conductivity of pristine vanadyl phosphate. The optical band gap of vanadyl phosphate decreases from 4.0 to 3.7 eV due to insertion of polyaniline.

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Abstract

A small Antimicrobial Protein from egg white of marine turtle Suranjana Chattopadhyay

Department of Chemistry, Maharaja Manindra Chandra College, Kolkata-700003 Email: [email protected]

Abstract Small cationic peptides are abundant in nature. Many of them have roles in host defenses against microbial agents. Egg White contains a large number of small oligomeric peptides of known and unknown physiological functions. Most of the studies have been made on those present in the avian species, particularly hen. In contrast very little information is available about proteins of reptilian egg white and of these, only lysozyme and protease inhibitors have been reported. During their course of examination of proteins in reptilian egg whites, years back Chakrabarti et. al. found a low molecular weight cationic protein in marine turtle (Caretta caretta Linn) commonly found in India1. It is found to bind DNA and stimulate ATPase activity. The molecular weight of this protein is around 4000 daltons1. It showed strong antibacterial activity against both gram – negative bacteria like Escherichia coli and Salmonella typhimurium as well as towards gram – positive bacteria like Staphylococcus aureus. The protein also showed significant antiviral activity against an enveloped rhabdovirus, Chandipura virus, which is an emerging human pathogen. This small cationic protein is part of the innate immunity. Comparing with large proteins, the relatively simple structure of such small peptide like protein makes it easy to bind to well-known nano  74 

Nano Science…. materials like Graphene oxide (GO) featuring carboxylic acid groups at the edges, phenol hydroxyl and epoxide groups mainly at the basal plane, and some intact carbon-carbon sp2 domains2. Owing to the large inflation of scientific research in the arena of drug delivery using nano-bio technologies in today’s times, it has the potential to be developed as a novel therapeutic agent.

References 1. Chakrabarti, S.; Sen, P.C.; Sinha, N.K. Arch. Biochem. Biophys. 1988, 262, 286-292. 2. Zhang, Y.; Wu, C.; Guo, S.; Zhang, J. Nanotechnol Rev. 2013, 2(1), 27–45.

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Abstract

Temperature Dependent Terahertz TDS Study of Graphene Oxide

Partha Dutta

Department of Chemistry, Maharaja Manindra Chandra College, 20, Ramkanto Bose Street, Kolkata - 700003

Email: [email protected]

Abstract Graphene Oxide (GO) nanocomposites have been studied by Terahertz Time Domain Spectroscopy (THz-TDS) method from 78 K to 293 K. With increase in temperature, GO shows increase in signal intensities of different physical parameters like refractive index, absorption coefficient, conductivity etc. We have introduced a new analytical model to reveal the physical understandings of the THz spectra. In this model, both the contribution of scattering of free electrons (Drude- Smith Term) and the oscillation of bound electron (Lorentz Term) have been incorporated to fit the experimental data. This work shows the usefulness of THz-TDS technique to probe the electron landscape along with the dynamics present in this kind of system which eventually helps to characterize the materials.

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Organometallic Gold (I) Propergylic Alcohol Complexes

Prithwiraj Byabartta

Departmento de Quimica Inorganica, ICMA, The Universidad de Zaragaza-CSIC, Zaragaza-50009, Spain Present Address: Department of Chemistry, Jogesh Chandra Chaudhuri College, 30- Prince Anwar Shah Road, Kolkata-700033

Email: [email protected]

Abstract Alkynyl complexes of gold(I) containing phosphine ligands have been known for many years and have been studied in great detail. Recent research efforts in this field have focused on studying luminescence, nonlinear optical properties, and the supramolecular chemistry of gold(I) acetylide complexes. The phosphine ligand in the majority of known alkynylgold(I) complexes is either an arylphosphine including PPh3, P(4-

MeOC6H4)3, PPh2Me, PPhMe2, diphosphine like, dppe, dppm, or, less frequently, PMe3 or PCy3 (Cy = cyclohexyl). The vast majority of gold(I) complexes are two-coordinate, linear, 14-electron species, whereas three- and especially four-coordinate species are less common. Linear gold(I) complexes can group by means of aurophilic interactions to give supramolecular structures, such as pairs, rings, chains or layers, which are not present for the higher coordination numbers. The aggregation of gold(I) monomers can also be based on hydrogen bonds or a combination of aurophilic and hydrogen bonds. Diphosphane ligands in gold(I) + derivatives can act in chelating mode, typically [Au(PR2ZPR2)2] (Z=CH2,

(CH2)n, NH ) or in bridging mode; the latter usually affords dinuclear 2+ derivatives, namely [(AuX)2(μ-PR2ZPR2)] and [Au2(μ-R2ZPR2)2] . Much

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Abstract

n+ less common is the formation of polymers [{Au(μ-PR2ZPR2)}n] or even + catenanes or metallocryptands. The replacement of a proton by an AuPR3 fragment is a well-established synthetic procedure, which has been 2+ thoroughly used in cluster chemistry. In the same way, [AuPR2ZPR2Au] fragments have been used, e.g., the [Au(dppa)Au]2+ unit (dppa=bis (diphenylphosphino)ammine) obtained from the chloro derivative.

References 1. Grohmann A.; Schmidbaur H., In Comprehensive Organometallic Chemistry II; Wardell, J., Eds.; Pergamon: Oxford, 1995. 2. Schmidbaur, H.; Grohmann, A.; Olmos, M. E. In Gold Progress in Chemistry, Biochemistry and Technology; Schmidbaur, H., Eds.; John Wiley & Sons: Chichester, 1999. 3. Che, C. M.; Chao, H. Y.; Miskowski, V. M.; Li, Y.; Cheung, K. K. J. Am. Chem. Soc. 2001, 123, 4985-4991.

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V Estimation of Vertical Ionization Potential (ID ) of a Bisporphyrin from charge-transfer transitions of the Bisporphyrin with various electron acceptors in toluene.

Debabrata Pal

Department of Chemistry, Sreegopal Banerjee College, Bagati, Hooghly

E-mail: [email protected]

Abstract The bisporphyrin (P) is found to be engaged in appreciable amount of ground state electronic interaction with fullerenes C60 and C70 and also with various other electron acceptors, viz., 2,3-dichloro-5,6-dicyano-p- benzoquinone, tetracyanoethylene, o-chloranil and p-chloranil in toluene as evidenced from the perturbation of the electronic spectra of P in presence of the acceptors present in the medium. The interaction is facilitated through charge transfer (CT) transition as evidenced from well- defined CT absorption bands in the visible region of the electronic spectra. Utilizing the CT transition energies for various electron donor–acceptor V complexes of P, vertical ionization potential (ID ) of P is determined according to Mullikan’s formula and estimated to be 6.37 eV in solution.

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Abstract

Natural Nanomaterials: An inspiring way to bring Nanoscience into the Classroom! Moumita Sen Sarma Department of Chemistry, Fakir Chand College, Diamond Harbour, South 24 Pgs.

Email: [email protected]

Abstract Nanoscience is the study of structures and materials on the scale of nanometres, conveniently defined as 1 to 100 nm. When structures are made small enough—in the nanometre size range—they can take on interesting and useful properties. So, nanoscience and technology deals with studying systems and manipulating matter on atomic, molecular and supramolecular scales (the nanometre scale). On such a length scale, quantum mechanical and surface boundary effects become relevant, conferring properties on materials that are not observable on larger, macroscopic length scales. All materials, can in principle, be described at the nanoscale. Nanomaterials can be found everywhere in nature and have been part of the environment since our planet was created about 4.5 billion years ago. Fullerenes or graphene, which are of nanosize, have even been found in space while they have been synthesized by man only recently. So, Nanoscience isn’t new! Technology is just beginning to help us see and understand it. ‘Natural nanomaterials’ are the materials that belong to the natural world, which, without human modification or processing have remarkable properties because of their inherent nanostructure. Wood is one of the most common natural nanomaterial. It has a hierarchical scale structure. At the largest scale, wood contains soft fibres with a diameter of

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Nano Science…. about 20-30 μm and a length typically between 2 and 5 mm. At an intermediate hierarchical scale, nanofibres are present with a diameter less than 100 nm and a length greater than 1 μm. The smallest scale contains crystallites with a width less than 5 nm and a length less than 300 nm. It turns out that mechanical properties improve as the size of the structure decreases. For example, the elasticity is multiplied by almost 12 and the strength by 100 as one goes from softwood structure to wood nanocrystals. The nanostructure of a biological material is due to its supramolecular organisation — the arrangement of tens to hundreds of molecules into shapes and forms in the nanoscale range. The interaction of light, water and other materials with these nanostructures gives the natural materials some remarkable properties which can be appreciated at the macroscale. So, it will be really fascinating to discover that common, natural materials, such as wood and spider silk, or materials that we use every day, such as paper and cotton, have properties that depend not only on their chemistry but also on their nanostructure.

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Abstract

Formation kinetics of silver nanoparticles adopting biogenic synthesis process Rana Karmakar Department of Chemistry, Fakir Chand College, Diamond Harbour, South 24 Pgs.

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Abstract Nanomaterials have of late attracted considerable attention due to their unique properties and wide range of applications. In general, nanoparticles are synthesized by using chemical methods which are not eco-friendly and during synthesis it generates toxic byproducts, hazardous to our environment. An alternate environment-friendly green method is developed where natural resources are used for preparation and stabilization of nanoparticles. In the last few years’ silver nano particles are become a favorable candidate for exploration, as they can easily be reduced at room temperature from aqueous silver nitrate solution and show visible colour change without much effort. In the present study, Patola (Trichosanthes dioica), a popular green vegetable and Terminalia arjuna, a well-known medicine for the treatment in heart diseases, are used to prepare silver nanoparticles at room temperature. The formation kinetics of silver nanoparticles are studied by monitoring the change in optical density at 435 nm wavelength in the absorption spectra of silver nanoparticles arises due to its surface plasmon resonance. The experimental results indicate a strong influence of the used bio materials in the formation process of silver nanoparticles.

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