Water-soluble fullerenes for medical applications

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1 1,3,5-Cyclohexatriene and [5]radialene sub-units, as found in C₆₀ (double bonds are emitted for clarity)

2 ¹³C nuclear magnetic resonance (NMR) spectra of C₆₀ a and C₇₀ b. Every carbon environment in C₆₀ is identical (all are equally strained in the spherical structure), while there are five environments in C₇₀, corresponding to each successive, increasingly strained ‘layer’ of carbon atoms away from the equatorial plane c. NMR spectra were taken in carbon disulphide (CS₂) on a Bruker AVIII 400MHz machine

3 The absorption spectra of the fullerenes change as the size of the conjugated system increases: with slight variations depending on solvent, solutions of C₆₀ are an intense purple colour a, C₇₀ red like wine b and C₈₄ a green-yellow. (All above solutions in toluene). Generally speaking, the gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital decreases with increasing cage size leading to optical absorptions of lower energy, i.e. longer wavelength⁷

4 Amination mechanism of C₆₀. The first step is single-electron transfer (a fast process) to produce the C₆₀ anion radical which has a characteristic green colour.²³ Radical recombination gives a zwitterion which can be stabilised by proton transfer to give the final product (a slow process giving a brown solution)

5 Prato reaction mechanism (after Scarel²⁹). Initial attack of the aldehyde/ketone's polar carbonyl group by the nitrogen lone pair of the amino acid leads to the expulsion of water, before decarboxylation gives the reactive ylide intermediate

6 Possible second addend addition sites (adapted after ³¹). There are three sites in the same hemisphere as the initial site of addition, giving rise to cis-regioisomers , and ; two equatorial sites, e' and e”; and four addition sites in the other hemisphere, giving trans-regioisomers , , and

7 Bingel reaction mechanism. Deprotonation by the strong base gives the nucleophilic malonate anion which then attacks the [6,6] bond. Bromine is then expelled as cyclisation is completed

8 C₆₀ diethyl malonate tris-adducts. Addition at the trans-3 positions imparts symmetry and produces a red solution; at the equatorial positions, symmetry and an intense orange solution

9 tert-Butyl(trialkoxy)silane-tethered cyclopropanation e,e,e tris-adduct (2<n<4)

10 C₆₀ Bingel reaction in the presence of dimethyl sulphoxide (DMSO), with basic catalyst replaced by amino acid (adapted from Jin et al.⁴²). DMSO facilitates single-electron transfer from the amino acid to the fullerene to give the radical cation and radical anion respectively. The fullerene anion then attacks a brominated active methylene, expelling the bromine and forming a fullerenyl radical. Interaction between this and the amino acid radical cation from the first step then finalises cyclisation to give the desired methanofullerene

11 C₆₀–N-vinylpyrrolidine (C₆₀–NVP) derivative

12 Dendro[60]fullerene mono-adduct

13 C₆₀ mono-adduct bis-carboxylic acid building block for water-soluble derivatives

14 C₆₀-(Gd-DOTA)_n (n=4 or 5)

15 Highly iodinated and water-soluble C₆₀ derivative for X-ray imaging

16 First generation water-soluble dendro[60]fullerene

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