INTRODUCTION:

Carbon, the common element in organic compounds, is known to exit in two allotropic forms, viz, diamond and graphite. In 1985, a third form of carbon called fullerenes was discovered. Fullerenes generated so much interest and excitement among research scientists that the three scientists Smalley, Kroto and Curl who discovered fullerenes received Nobel Prize in chemistry in 1996¹.

STRUCTURE AND PROPERTIES:

Fullerenes are large carbon cage molecules considered to be 3-D analogues of benzene.

C₃v C₆₀H₁₈ made in near quantitative yield

The most abundant form of fullerenes is Buckminster fullerene (C₆₀) carbon atoms arrange in a spherical structure. The shape of the molecule, known as truncated icosahedrons, resembles that of a soccer ball, which contains 12 pentagons and 20 hexagons. An important property of C₆₀ molecule is its high symmetry. There are two types of bond length in the fullerene²:

1. C5-C5 single bond in the pentagons (1.45+/-0.015A)

2. C5-C6 double bond in the hexagons (1.40+/-0.015A)

Each carbon atom forms bond to three other adjacent atom with sp2 hybridization (bond angle-1200) Hence these delocalized pi electrons stabilize the spheroid structure by resonance. A C60 molecule, also known as Buckyball or Buckminsterfullerene, is about 7Å in diameter. Chemically the molecule is quite stable; breaking the balls requires temperature of over 10000. By heating fullerenes up to 15000 in absence of air, they transform to graphite. Other than C60 fullerenes can contain between 30 to 980 carbon atoms forming different structures with different properties and field of application. Fullerenes have low density relative to diamond (1.65g/cc compared to 3.15g/cc). Fullerenes are unstable in water.

Good solvents for fullerenes carbon disulphide, o-dichlorobenzene, toluene and xylene. Unlike aromatics, fullerenes have no hydrogen atoms or other groups attached, and so are unable to undergo substitution reaction.³ Substitution reactions can take place on derivatives, once these have been formed by addition. As cages consist entirely of sp2-hybridized carbons, which have electron-withdrawing –I inductive effects, the fullerenes are strongly electron-attracting. This affects their chemical behavior; for example they react readily with nucleophiles.

PHYSICAL PROPERTIES OF FULLERENES:

Pure fullerenes have better close packing than impure fullerenes, and are therefore slower to dissolve; the close packing evidently precludes their use as lubricants. C₆₀and C₇₀are decomposed by light, with oxygen and ozone playing a role. The resultant degradation provided the first example of fullerene cage-opening reaction. On heating in oxygen, C₆₀ is gradually oxidized: C-O adducts are formed at 200⁰C and at 400-500⁰C decomposition is substantial. Derivatives of C₆₀ show a wide range of solubility; the fluorinated derivatives are much more soluble than the parent molecule, whereas some bromo derivatives are much less soluble⁴.

CHEMICAL PROPERTIES OF FULLERENES:

In contrast to the preparation of covalent mono-adducts of C₆₀, the development of selective routes to isomerically pure multiple adducts of the fullerene is still in its infancy. Mono functionalized C₆₀ has nine different 6-6-bonds that can react in a second addition and reactions such as the bis-osmylation or the double Binge1 cyclopropanation, i.e. the addition of bromomalonates in the presence of base, yielded regioisomeric mixtures of bis-adducts which could only be separated by tedious, scale-limiting high-performance liquid chromatography (HPLC). As illustrated below, we introduced the concept of tether-directed remote fictionalization to prepare with high regioselectivity specific b is- through hexakisadducts of C₆₀. Since the beginning of bulk scale fullerene chemistry and the isolation and characterization of chiral D2-symmetrical C₇₆, prepared from achiral graphite, fullerene chirality has attracted great fascination. This article closes with an example for the chiral-tether-mediated enanantioselective synthesis of an optically active bi-adduct of C₆₀ whose chirality’s exclusively results from the specific chiral addition pattern⁵.

PREPERATION OF FULLERENES:

Fullerenes are formed when vaporized carbon condenses in an atmosphere of inert gas. The gaseous carbon is obtained e.g. by directing an intense pulse of laser light at a carbon surface. The released carbon atoms are mixed with a steam of helium gas and combined to form clusters of few up to hundreds of atoms. The gas is then led into a vacuum chamber where it expands and is cooled to some degree above absolute zero. The carbon clusters can then be analyzed with mass spectrometry⁶.Mass spectroscopy shows that the C₇₀ molecule is present at levels of a few per cent.⁷

SPECIES OF FULLERENCES:

Some times after discovery of fullerenes, many chemical modifications of fullerenes were discovered. Some of the important fullerenes species are as follows:

1. Alkali-doped fullerenes

2. Endohedral fullerenes

3. Exohedral fullerenes

4. Hetrofullerenes

Figure1

1. Alkali-doped fullerenes:

As fullerenes molecule is highly electronegative, it readily forms compounds with electron donating atoms, the most common examples being alkali metals⁸. This reaction leads to production of an interesting class of compounds known as alkali-doped fullerides, where in alkali metal atoms fill in the space between Buckyballs and donate valence electron to the neighboring C60 molecule. If alkali atoms are potassium or rubidium, the compounds are superconductors, and they conduct electric current without any resistance at temperatures below 20-40 K, e.g. K3C60, Rb3C60.

2. Endohedral fullerenes:

Science fullerenes are hollow with a closed shell of carbon atoms; it is possible to enclose another atom inside. This class of fullerene derivative is known as Endohedral fullerenes. When the atom trapped inside a metal, they are known as metallofullerenes⁹. The atom that form stable endohedral compounds include lanthanum, yttrium, scandium and some of the noble gases.¹⁰It is very difficult to open up carbon cage molecule to enclose a foreign atom inside, endohedral material must be synthesized while formation of cage itself. The accepted notation for endohedral material is to use the @ symbol to show that the first material is inside the second, e.g. La@C82 and Sc@C84. Endohedral can stabilize reactive species include the cage, can serve as nondissociating salt in electrochemistry, and offer other exciting properties.

3. Exohedral fullerenes:

The most important and most versatile of all species of fullerenes is Exohedral fullerenes or fullerene derivatives, which are molecules formed by a chemical reaction between fullerenes and other chemical groups. Fullerene derivative are also known as functionalized fullerenes. As fullerenes possess the conjugated π-system of electron, two main type of primary chemical transformations are possible on fullerene surface: addition reactions and redox reactions, which lead to covalent exohedral adduct and salts respectively¹¹. As fullerenes are insoluble in water, numerous derivatives of fullerenes have been synthesized with improved solubility profile.

4. Hetrofullerenes:

Heterofullerenes represent another fundamental group of modified fullerenes. They represent heteroanalougues of C₆₀ and higher fullerenes: one or more carbon atom of the cage is substituted by hetero-atoms, e.g., trivalent nitrogen or boron atom¹². The simplest derivatives of nitrogen fullerenes is aza (60) fullerenes C₅₉N and its dimmer (C₅₉N)_2.

SYNTHESIS OF FULLERENES SPECIES:

Functionalization of C₆₀ in our group has been done primarily by cycloaddition reactions; particularly the 1, 3-dipolar addition of diazoalkanes and alkyl azides. Unlike the addition of a second equivalent of diazoalkane to C₆₀, which does not show marked selectivity, the addition of azides to C₆₀ shows chemo and regio selectivity? Utilization of this unique selectivity, led us to addition reactions; particularly the 1, 3-dipolar addition of diazoalkanes and alkyl azides. Utilization of this unique selectivity, led us to the preparation of the first heterofullerene ‘C₅₉N’ in bulk quantity.

The azafullerene (C₅₉N)₂ can be synthesized from C₆₀ in three steps. The initial step in the formation of azafullerenes is the 1, 3-dipolar cycloaddition of 2- methoxyethoxymethyl azide (MEM-azide)¹³

Interestingly, when azide addition reactions are carried out at temperatures ranging from 60- 140°C, in addition to the formation of azafulleroid and fulleroaziridine a bisazafulleroid is formed and is the major product (Scheme 1).

Scheme 1

The self-sensitized photo-oxygenation of N-MEM azafulleroid afforded the cage-opened N-MEM ketolactam in high yield. (Scheme 2)

Scheme 2

The azafulleronium ion is formed first in a manner that mimics the gas-phase formation of azafulleronium, i.e. that the acid protonates the MEM moiety, inducing the loss of 2-methoxyethanol, followed by rearrangement to the azafulleronium ion. In the presence of the 2-methoxyethanol (or water) the azafulleronium ion can be reduced to the azafullerenyl radical. Finally, the radical dimerizes to yield (C₅₉N)₂ (Scheme 3). Scheme 3

Scheme 3

The proposed mechanism for the formation of the azafullerene (C₅₉N)₂, we carried out the reaction in the presence of nucleophiles to trap the proposed carbonium ion intermediates. This led to the isolation of new holey balls, fullerenes with a ring larger than a hexagon, as depicted in Scheme 4.

Scheme 4

(a) pTsOH H2O, Hexanoic acid, ODCB, 180 C, 35%

(b) pTsOH H2O, Hydroquinone, ODCB, 180 C, 50%

In the presence of excess p-toluenesolfonic acid monohydrate and hydroquinon, a stronger reducing agent than the 2-methoxy ethanol, in ODCB at 170-180°C, the ketolactam was converted to the desired hyroazafullerene as shown in Scheme 5.

Scheme 5

The above methodology is applicable to the conversion of C70 to C69N and found that three out of the five possible C₆₉N dimers can be formed selectively from their corresponding holey balls.

In particular, a novel functionalization of C60 has been developed via cycloaddition of azomethine ylides to fullerene. The azomethineylides are generated in situ by condensation of amino acids and aldehydes or ketones. In this way, fulleropyrrolidines are obtained with the

5-membered ring fused to a 6, 6 bond on the fullerene (Scheme 6).

Scheme 6.

This reaction is very useful because it is possible to introduce different substituents on nitrogen and on carbons 2 and 5 using different substituted reagents. This class of fullerene derivatives retains the main properties of the parent molecule, such as the ground state absorptions,

which extend throughout the visible region up to 700 nm, and the excited state properties.

APPLICATION OF FULLERENES:

Fullerenes are inert, hollow and indefinitely modified. When administered orally in the water soluble form, they are not absorbed; while on i.v. inj. They get rapidly distributed to various body tissues. They are excreted unchanged by kidney. Acute toxicity of water soluble fullerenes was found to be quite low. All these interesting properties offer possibilities of utilizing fullerenes in biology and medicinal chemistry and promise a bright future for fullerenes as medicinal agents. However, this possibility faces a significant problem i.e. natural repulsion of fullerenes to water. To overcome this limitation, synthesize fullerene derivative having modified solubility profile, encapsulation of C₆₀ in Cyclodextrins or in calixarenes or water suspension preparations.

C₆₀ can be encapsulated in water soluble host-guest complex C₆₀(γ-Cyclodextrin)₂. Co crystalization with ferrocene produces C₆₀(ferrocene)₂ a host-guest structure.

1. DIAGNOSTIC APPLICATION:

Endohedral metallofullerenes are the fullerenes with metal ion trapped inside fullerenes cage. These have shown potential application in diagnostic. As per examples, water solublised form like M@ C₈₂ (OH)₃₀ are being used as magnetic resonance imaging contrast agents (M=Gd3+), X-ray contrast agents (M=Ho3+) and radiopharmaceuticals (M=166Ho3+ and 170 Tm2+)^{14, 15} One of these derivatives, i.e., ¹⁶⁶Ho3+ @ C₈₂ (OH) 30 has been extensively studies as radioactive tracer for imaging of diseased organs and for killing cancerous tumors.

2. ANTI-HIV ACTIVITY:

The enzyme protease specific to HIV-I has been shown to be a viable target for antiviral therapy. C₆₀molecule has approximately same radius as the cylinder that describe the active side of HIV-P an opportunity exist for a strong hydrophobic interaction between C₆₀derivative and the active site surfaces. Molecular modeling studies on these derivatives showed that they could fit well inside the HIV-P cavity and can interact with carboxylic residue of aspartic acid¹⁶. (Figure2)

Figure2. Computer designed accommodation of C₆₀ in the HIV protease hydrophobic cavity.

The structural optimization of C60 derivatives for HIV-P interaction are the catalytic site of HIV-P contains two aspartic residues. A stable interaction with the aspartates could increase the efficiency of the potential inhibitions¹⁷. So an ideal inhibitor 24, in which two ammonium groups at 5.5 Å distance are directly linked to C₆₀ and 25 in which the distance between the two ammonium residues was 5.1 Å (Figure 3).

Figure3. PM3-minimized distances of the two ammonium groups (black) in the ideal inhibitor 24 and in fulleropyrrolidine 25.

The synthetic procedure is based on the cycloaddition of N,N'-Boc-1,3-diamino-2-propanone 26 with sarcosine 27 or N-(3,6,9-trioxadecyl)glycine 28 (Scheme 7).

Scheme: 7

These products (29 and 30), after deprotection by TFA, afford the final compounds 31 and 32, which are still under investigation for their biological profiles. Molecular modeling studies on derivatives 31 and 32 showed that they could fit very well inside the HIV-P cavity and the electrostatic interactions can take place between the carboxylic residues of aspartates and the ammonium groups.¹⁸

A new series of bis-functionalized fullerene C₆₀ derivatives bearing two or more solubilizing chains have been evaluated for their activity against HIV-1 and HIV-2 strains. Some of the compounds show activity against HIV-1 type in the low micro molar range. The effect of the positions of the addends on the C₆₀ nucleus has been investigated, indicating that only trans-2 isomers possess promising activity. The presence of quaternary pyrrolidinium nitrogen is essential to increase solubility.¹⁹

3. DNA PHOTOCLEAVAGE:

A water soluble fullerenes carboxylic derivative was found to be cytotoxic when exposed to visible light. Cytotoxicity of C₆₀ derivatives was mediated by its ability to cleavage DNA²⁰. Other potential application of fullerenes is related to the easy photo excitation of fullerenes on the basis of which fullerenes based photodynamic compounds are being developed for the treatment of cancer.

In fact, from the ground state, the fullerene can be excited to ¹C₆₀ by photoirradiation. In the presence of molecular oxygen, the fullerene can decay from its triplet to the ground state transferring its energy to O₂, generating ¹O₂, known to be a highly cytotoxic species. In addition, the high-energy species ¹C₆₀ and ³C₆₀ are excellent acceptors and, in the presence of a donor, can undergo a different process, being easily reduced to C₆₀ ^.– by electron transfer. Again, in the presence of oxygen, the fullerene radical anion can transfer one electron, producing O₂^.–. The excited fullerene can be reduced in the presence of the guanosine residue present into DNA. Hydrolysis of oxidized guanosines followed by DNA cleavage is a consequence of the electron transfer from G to C₆₀*.²¹

Scheme 8

In this field, many fullerene conjugates with different units possessing biological affinity to nucleic acids or proteins might be particularly interesting. In particular, conjugates between C₆₀ and specific agents that interact with nucleic acid, such as acridine, ²² netropsin or complementary oligonucleotides, ²³ have been synthesized with the aim to understand the mechanism of action of this class of conjugates and to increase both cytotoxicity and sequence selectivity. Many fullerene derivatives linked to an intercalator or a minor groove binder have been reported, however, DNA cleavage occurs at guanine residues without significant sequence selectivity. Only when C₆₀ was conjugate to an oligonucleotide, a good selectivity was observed.

The rational design of derivative of C₆₀ 33 is based on a reinforced effect due to the simultaneous presence of two different agents able to confer sequence selectivity, such as trimethoxyindole (TMI) and oligonucleotide. The TMI nucleus is characteristic of a class of natural compounds named duocarmycins (Figure 4), possessing high cytotoxicity (pM range, 72 h of incubation for Leukemia Cells L 1210), and high selectivity for AT rich regions of DNA (Figure 5).^24,
25

Figure 4: Structures and cytotoxicity value of (+)-Duocarmicin A and (+)-Duocarmicin SA.

Figure 5: Rational design, possible interaction and triplex helix formation of 33

On the other hand, the oligonucleotide chain could increase the sequence- selectivity and water solubility, the biggest problem of C60 derivatives for their biological use.

The synthesis of this derivative started from the ethyl diamine N-Boc-protected 34, which was reacted with benzyl bromoacetate 35 to afford compound 36, which after deprotection of the amino group 37, and subsequent condensation with trimethoxy indol 2-carboxilic acid 38 in the presence of EDC, gave derivative 39 (Scheme 9).

Scheme: 9

The latter 39, after catalytic hydrogenation, afforded the corresponding amino acid 40, which was allowed to react with fullerene 1 and the N-Boc 6-aminohexanal 41 (Scheme 10). Removal of the N-Boc protection led to compound 43, whose amino group could be used for the oligonucleotide coupling reaction.

Scheme: 10

4. FREE RADICAL SCAVENGER:

Fullerenes compounds with their unique cage structure combined with high no. of conjugated double bonds in the core interact with bimolecular and have avid reactivity with fee radicals.²⁶ Buckminster fullerenes, for example, are capable of adding multiple radicals per molecules; the addition of as many as 34 methyl radicals to a single C60 sphere has been reported. Hence they are regarded as “free radical sponge”²⁷ A water soluble C60 derivative, fullerenol, has been shown to scavenge free radical in-vitro²⁸and in-vivo.²⁹Water as well as lipid soluble derivative of C₆₀ are useful as antioxidant in health and personal care products, e.g., skin creams, burn creams and nutritional supplements.

5. ANTIMICROBIAL ACTIVITY:

Fullerenes were anticipated to possess antibacterial activity based on the hypothesis that C60 molecule when exposed to visible light, creates reactive oxygen species (ROS) could produce membrane disruption by insertion into phospholipids bilayers.³⁰The resulting membrane disorder, causing altered permeability leads to release of metabolites and cell death.³¹.

As for example, monomethoxy triethylene glycol (mTEG) substituted fulleropyrollidines showed complete inhibition of Mycobacterium avium at dose 260μg/ml and M. tuberculosis at dose≡ 50μg/ml.³² Corboxyfullerenes were found to inhibit E. coli induced meningitis by reducing the damage caused by infiltrating neutrophils on the BBB but not by direct inhibition of E. coli. These derivatives exhibited varying effects on Gram+ve and Gram-ve bacteria, further investigations led to the observations that carboxyfullerenes can insert into cell wall of Gram +ve cocci, dirupt the cell wall structure and cause bacterial death.

Scheme 11

To obtain water-soluble derivatives, different aldehydes (paraformaldehyde or 3, 6, 9- trioxadecane aldehyde, Scheme 11 to synthesize N-mTEG (mTEG = monomethoxy triethylene glycol) substituted fulleropyrrolidines 44–46. The latter were also alkylated with methyl iodide to afford the corresponding ammonium salts 47–49.^{33, 34}

The quaternization ammonium salts 47–49 show increased water solubility (DMSO/Water 1/9) compared to neutral compounds 44-46.

C₆₀molecules also use in photo-purification of dirty water. Fullerene is act as inexpensive and energy efficient method of water purification.³⁵

6. ANTIOXIDANT and BIOPHARMACEUTICALS:

Fullerenes are powerful antioxidants, reacting readily and at a high rate with free radicals, which are often the cause of cell damage or death. Fullerenes hold great promise in health and personal care applications where prevention of oxidative cell damage or death is desirable, as well as in non-physiological applications where oxidation and radical processes are destructive (food spoilage, plastics deterioration, metal corrosion).

The use of fullerenes in controlling the neurological damage of such diseases as Alzheimer's disease and Lou Gehrig's disease (ALS), which are a result of radical damage. Drugs for atherosclerosis, photodynamic therapy, and anti-viral agents are also in development.

7. OSTEOPOROSIS:

Biphosphonate compounds and fluoride anions are the drugs used in the treatment of osteoporosis and other bone disorder. For example, polyfluoro biphosphonated fullerenes derivative are being developed as bimodal drug for osteoporosis therapy³⁶.

8. Novel Topical Drug Delivery Systems:

Fullerenes are molecules composed entirely of carbon that resemble a hollow sphere. Rouse, et al., showed that once fullerenes come into contact with the skin, they migrate through the skin intercellularly, as opposed to moving through cells. Therefore; a fullerene could be used to “trap” active compounds and then release them into the epidermis once they are applied on the skin. Moreover, fullerenes, themselves, are thought to be potentially potent antioxidants.

So, fullerenes are capable of enhancing the efficacy, tolerability, and cosmetic acceptability of topical formulations.³⁷

Recent Advances in Molecular Chemistry of Fullerenes:

Unlike most organic molecules, the convex surface of fullerenes offers possibilities for the study of reactions and mechanisms under severe geometrical constraints. Although the chemistry of fullerenes is nowadays considered to be an established discipline, a wide variety of important reactions involving alkenes and alkynes have not been studied previously on the fullerene surface. One example of the most successful reactions in organic synthesis is the Pauson- Khand (PK) reaction which has been used extensively for the construction of biologically active five-member carbocycles in a convergent approach. It involves the [2+2+1] cycloaddition of an alkyne, an alkene, and carbon monoxide ediated or catalyzed by a transition metal. Recently, this reaction has been carried out on fullerene C₆₀ acting as the alkene component; a highly efficient and regioselective intramolecular PK reaction has afforded a type of fullerene derivative 51 showing three (or five) fused pentagonal rings on the same hexagon of the fullerene surface³⁸.

The transition metal catalyzed cyclization of enynes represents an active research area which has been studied extensively as a powerful method for the construction of carbon and heterocyclic molecules. The unique geometry of fullerenes has allowed us to observe a different chemical reactivity to that found for related 1, 6-enynes. Recently, it was reported that the thermal treatment of 1,6-fullerenynes 50 affords cyclobutene adducts 52 without the presence of a catalyst; in a reaction this is the first example of a thermal [2+2] cyclization involving a fullerene double bond as the alkene moiety of the reactive 1,6-enyne³⁹ (Fig: 6)

Figure6. 1, 6-Fullerenynes 50 are versatile building blocks

A recent example of an unknown chemical reactivity has been found in fulleropyrrolidines, which are among the most studied fullerene derivatives used for many applications in materials science as well as in the search for biological properties⁴⁰. In contrast to other labile fullerene cycloadducts such as those prepared from Diels-Alder or Bingel reactions, 50 fulleropyrrolidines have been considered to be stable fullerene derivatives. This reaction reveals that the understanding of the reactivity of fullerene derivatives is still far from the level where it is possible to predict the reaction pathway reliably. This reaction constitutes a protection- deprotection protocol which has allowed, for example, the efficient separation of two isomers (I h and D5h) of endohedral Sc3N@C80.

One of the most successful applications of fullerenes is related to electron/energy transfer processes. Photo induced electron transfer is a fundamental process in nature because it governs photosynthesis in plants and bacteria. This process occurs through rapid charge separation at the reaction centers with quantitative quantum yield, thus enabling the transformation of sunlight into chemical energy.

In contrast to other well known electron acceptors such as p-benzoquinone derivatives used by nature in the photosynthetic process, the C60 molecule accelerates charge separation during photo induced electron transfer processes to form a charge separated state and simultaneously slows the charge recombination process in the absence of light. This behavior has been rationalized by the smaller reorganization energy (λ) of C60 compared with other acceptors. These unique electrochemical and photo physical properties of fullerenes have allowed the design of a wide variety of donor-acceptor systems in which the electro active units are connected by covalent or supramolecular bonds.⁴¹

CONCLUSION:

The exponential increase in patient filing and publications indicate growing industrial interest that parallels academic interest. The hydrophobic spheroid structure and radical sponge character of the fullerene molecule is responsible for activities in many fields. In addition to some of the important medical applications as mentioned above, fullerenes are being intensively investigated for practical utilization in number of other field e.g. as room temperature superconductors, as component of solar batteries, for production of synthetic diamonds and as lubricants. However, there are two important facts that are considered to be barriers to fullerenes applications:

1. Relative solubility and instability of fullerenes to water

2. High cost of fullerenes.

One possible development that may take place in near future is creation of modest demand of fullerenes in medicine, as medicine is considered to be the cost-intensive application. Hence research efforts in both chemistry and biology should be to further investigate the potential applications of these interesting spherical molecules.

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Received on 10.11.2009 Modified on 05.01.2010

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