Research Goals: We are generally interested in applying the powerful tools of modern organic synthesis to solve important problems in the design of organic materials and their understanding. A large part of our research aims at the use of the chemical and physical properties of fullerenes to design functional systems derived from these three-dimensional entities. We have also a strong interest in understanding the functions of biological systems by probing receptor sites with novel scaffolds, for example those based on combinatorial libraries built from the 3-dimensional buckyball (C₆₀). In this regard, a better understanding of the chemistry of C₆₀ plays a major role in developing such scaffolds.

An important goal of the group is to introduce transition metals within the empty cavity of C₆₀. Empty C₆₀ displays a surprising array of physical properties of major importance (superconductivity, ferromagnetism, nonlinear optical activity). C₆₀'s high symmetry seems to be at the origin of its unique physical properties compared to the less symmetrical, larger fullerenes (C70, C76, C84, etc.). Some fullerenes with metals inside have been obtained (e.g. La@C76, La@C78, Ln@C82 (Ln = La, Y, Sc, Gd, Tm), Sc2@C84,Sc3@C82), but they have been prepared in very limited quantities by evaporation of graphite rods filled with the metal oxides. This method fails to give the C₆₀ endohedrals and synthesis appears to be best way to obtain these promising compounds.

We are investigating two main approaches to the synthesis of endohedral metallofullerenes (Fig. 1): (a) One approach aims at the preparation of spherically-shaped acetylenic macrocycles which are expected to rearrange to endohedral metal complexes of fullerenes in a controlled process analogous to the gas-phase coalescence of mono- and polycyclic polyynes during fullerene formation by the graphite evaporation method (Fig. 2). (b) The second approach considers chemical transformations to open an orifice on the framework of C60. From our functionalization studies on C60, a recent achievement was gained by the formation of a metal complex having cobalt attached right on top of the opening (see below). We are actively pursuing this approach by combining this methodology to form two adjacent modification sites on C60, thus greatly enhancing the potential size of the cavity. We have also recently obtained very exciting results with the opening of a real orifice on a substituted fullerene though a series of computationally designed reactions.

Accomplishments and Prospects:

1. Total Synthesis of Endohedral Metallofullerenes:

(a) Trialkynyl-benzene Precursors: The synthesis of fullerenes represents a formidable challenge if they are to be built piece by piece by a linear synthesis. We are basing our strategy on the current picture of fullerene formation in the gas phase, in which mono- and polycyclic polyines coalesce to fullerenes (Fig. 2). We have shown that suitable acetylenic spherical macrocyclic precursors can be prepared in as little as 4 steps.

Recently, we have obtained a major and critical result in our study of alkynylated C60 precursors: Macrocycle 1 was prepared as a precursor of the highly unsaturated system 2. Macrocycle 2 is the penultimate precursor of C60 in our rearrangement hypothesis. Even though compound 1 is much more unstable than other compounds we have prepared, we were able to obtain beautiful mass spectroscopic data by ion cyclotron resonance laser desorption studies in collaboration with Charles Wilkins at U.C. Riverside. These studies confirm for the first time that a designed precursor of C60 indeed can form this molecule by spontaneous rearrangement. The ions corresponding to C60 are very likely fullerenes because they show a very characteristic fragmentation to C58 and C56 with C2-loss, a pattern not observed for the C60H6 ion. The latter is most likely the cyclophane depicted in the mechanistic scheme of Figure 3. We are now directing our efforts to tame the instability of compound 1 to undertake preparative isolation studies, either in low-temperature matrix photolysis, or by flash vacuum pyrolysis. Complexation of a metal with this or similar macrocycles prior to rearrangement are under study to obtain the endohedral complexes.

(b) Hexaalkynylbenzene Precursors: The synthesis of hexalinked cyclophanes such as 3a and 3b is one of our best approaches to achieve a preparative synthesis of C60 because such compact ball-shaped precursors would permit complexation of an array of transition metals in their rigid preorganized cavity. We have studied ways to link the two hexaalkynylbenzene moieties 4a in a highly efficient manner to minimize the number of synthetic operations. We have found a very convenient and practical way to link the three alkynyl groups of the model system 1,3,5-triethynylbenzene with silicon-based "protecting" groups of varying lengths (see substituents X in compound 4b). We are studying the similar linking of hexaalkynylbenzene moieties 4a as a preliminary step to the cyclophanes 3a and 3b.

(c) Decaalkynylmetallocene Precursors: We have been investigating ways to incorporate the metal earlier in the synthesis of the fullerene precursor in the form of the decaethynylmetallocenes 5a, leading to the 60-carbon precursors 5b with molecular formula M·C60H20X10. Precursors 5b are likely to lead to endohedral metallofullerenes (M@C60) in flash vacuum pyrolytic or even in solution-phase rearrangements induced by metal catalysis or radical or ionic processes.

We have accomplished the first steps in the synthesis of 5b from an easily available ketal. We also have verified the validity of this approach by reacting anion 6 with BrMn(CO)5 to afford half-sandwich complex 7 in good yield. Interestingly, the surprisingly stable radical 8 (R = TIPS, chromatographed in air!) was formed in an attempt to prepare the corresponding decaalkynylferrocene from 6. Radical 8 undergoes remarkably facile oxidation to the cation (Eox1/2 = 0.15 V vs Fc/Fc+, CH2Cl2), which may have an antiaromatic triplet ground state. 

The synthesis of precursors 5a and 5b has high priority. Alkynylmetallocenes will be very interesting compounds in their own right, for example in the formation of transition metal complexes of fullereneynes (Fig. 4).

The preparation of planar fragments of 2-dimensional carbon allotropes in which the graphitic texture is extended by acetylene or butadiyne units (graphynes) has recently become possible by application of the methodology leading to the cyclopentadienones shown on the previous page. The recent preparation of differentially protected hexaalkynylbenzenes (HEBs, e.g. 9),which are otherwise not accessible by other methods, has allowed the synthesis of the interesting and stable graphyne fragment 10. The trimer also formed is a piece of the 2D-carbon network shown at left.

2. Fullerene Functionalization: (a) Metal Insertion into Fullerenes. We have been exploring the possibility of opening a temporary orifice within a fullerene framework to form endohedral complexes by metal insertion.  We have discovered the unprecedented formation of the cobalt(III) complex 12 from bis-fulleroid 11 (Scheme left and Fig. 5). It is the product of an overall sequential triple scission of a 6-membered ring on C60 affording a 15-membered ring. The opening is the largest one created so far on a fullerene. This type of complex is one of the most promising candidates for the introduction of a metal into the C60 framework.

We are investigating ways to force the cobalt atom of 12 inside the cage using thermal activation or pressure, provided that the cyclopentadienyl, or a much less strongly bound ligand, can be removed in the process. Vibrational analysis at the PM3 level on the hypothetical Cd-complex 13 gives a low-frequency A’-mode which deforms the C-Cd-C angle in an insertion motion (Fig. 6). It shows nicely that a vibrational mode can expand the orifice to a point that should allow the metal to slip inside the fullerene under proper thermal activation or pressure.

(b) Novel Carbon Allotropes. Derivatives of C60 have a tremendous potential in the preparation of new materials due to the rich chemical and physical properties displayed by C60 itself. We have been pursuing the difficult synthesis of carbon allotropes such as 15 (C260) by oxidative coupling of the monomer 14. These macrocycles may ultimately lead to single-sized giant fullerenes by coalescence reactions. Oxidative coupling of 14 necessitated the development of solubilizing methodologies since 15 will be a poorly soluble material. Our latest progress in this area takes advantage of a reversible Diels-Alder reaction to keep the products of oxidative coupling of 14 in solution. We are currently characterizing the cycles obtained in 1,2-dichlorobenzene (LD-MS) by STM.

(c) C60 and Singlet Oxygen Reactivity. A variety of interesting allylic alcohols have been prepared by self-sensitized ¹O2 ene-reaction of cyclohexene-fused C60-derivatives. This efficient functionalization method was used e.g. in one preparative method of bis-fulleroid 11. The photophysics of a C60-derivative was studied in detail in collaboration with the group of Prof. Christopher S. Foote at UCLA.

More recently, site-specific cleavage of DNA by a C60-linked oligonucleotide (16) was carried out with remarkable efficiency. We have found that the mechanism of base modification involves direct electron transfer between the fullerene and proximate guanosines, rather than through the intermediacy of photogenerated ¹O2. We are interested to further explore the potential of this system as a versatile DNA cleaving agent.

(d) C60-Based HIV-protease Inhibitors.We have been interested in increasing the efficiency of C60-based inhibitors of HIV-1 protease following Wudl and Kenyon’s publication on this topic. A fruitful collaboration with the group of Kenyon (UCSF) has led to the synthesis of alcohol 17 showing substantially higher binding affinity (140 nM) to this enzyme than that of Wudl (~50 times). The correct enantiomer of the all-cis-diastereomer is our next target, since it was calculated to have even higher affinity to HIV-protease than 17. Combinatorial libraries of bisadducts are also being targeted.

(f) Other C60-Reactivity. Recent papers report on the tandemreaction of C60 with reagents having both diene and Michael-donor centers, as well as the formation of a strained Fe(CO)3-complex of cyclohexadieno-C60.We have also prepared the crystallographically characterized hexakis-(2,2,5,5-tetramethylpyrrolidine) adduct 19 as a precursor of the corresponding hexanitroxide (R2N-O·), a highly symmetrical building block for organic ferrimagnets which will be complexed with Mn(II)hexafluoro-acetylacetonate to obtain spin ordering in the crystalline solid.