Molecular surgery

The next big step in fullerene chemistry:  Opening up fullerene cages and inserting a transition metal

With their inner void of ≥3.5 Å, fullerenes have enough space inside them to accommodate any single atom of the periodic table (N, He, Ne, Ar, Kr, Xe, the lanthanide3+ cations)[1],[2] or a small molecule (H2, H2O, CO, NH3, Sc3N).[3],[4],[5],[6] Endohedral metallofullerenes encapsulating transition metals are the most exciting targets that have so far eluded three decades of attempted preparation. The various oxidation and spin states of these metals, coupled with the potentially strong electronic interaction with the carbon cage, make them ideal targets for synthesis. It is easily conceivable that these complexes will display a large array of electronic, magnetic, and photo-chemical properties that could be quite different from the currently known empty fullerenes or the lanthanide endohedral complexes (e.g. La@C82, Sc3N@C80). The potential for real-life applications for any of these compounds is very high. For example, gadolinium metal complexes (e.g. Gd3N@C80) are close to receiving approval for use as MRI contrast agents – they are non-toxic (including no leaching out of Gd3+) and display higher NMR relaxivities than the commercial Gd-DOTA MRI agent.[7]

We reported the first open fullerene (1) and demonstrated that small gaseous atoms (He) or molecules (H2) can be incorporated under high pressure.iv While we and others have developed synthetic methods to open fullerenes with a larger orifice using complex reaction mechanisms, all known open fullerenes have resulted from unanticipated bond scission and fragmentation reactions. Currently, four known classes of open fullerenes are known. None has an orifice that is wide enough for transition metal insertion.

A potentially highly efficient approach to obtain a large orifice in fullerenes has been based on the concerted triple scission of a six-membered ring on the fullerene surface via [2+2+2] ring opening (Fig. 2, top).[8],[9] This model system relies on the formation of a closed 1,2,3,4,5,6-hexaadduct that has proven extremely challenging to synthesize.ix The prototypical model we have used so far is shown in Figure 2 (lower). The tris(isobenzofuran)-18-crown-6 macrocycle (2) may react three times with C60 by Diels-Alder reaction to give a closed fullerene, which opens via a concerted [2+2+2] ring opening mechanism to give 3. The space-filling model of 3 shows that its orifice is large enough to allow passage of most transition metal cations – the distance between the three C=C constricting units to the center of the “neck” is similar to the C=C bond distances in tris(ethylene)Pt (2.25(4) Å).[10] We discovered a stepwise approach for this model by using tethered bisisobenzofurans.[11],[12] Isobenzofurans have become reactants of choice in this particularly demanding cis-1 functionalization because of their high reactivity and their ease of generation from the benzyne adducts of substituted furans.xi,xii

The first 1,2,3,4,5,6-hexaadduct we synthesized is compound 4, formed in 20-25% isolated yield from diol 5a through an unusual double radical addition.ix However, here the hexasubstituted 6-membered ring remains closed and does not show a propensity to undergo [2+2+2] ring opening. What prevents the opening reaction is that the oxa-bridges in 4 would introduce too much strain upon formation of two norbornadiene-type bonds.ix If the oxygens of the oxa-bridges can be removed from 4 to give antiaromatic ortho-quinodimethane intermediates,[13] the opening reaction calculates to be strongly exothermic (–90.3 kcal/mol).ix

We found that the opening of the oxa-bridges was only possible under reductive hydrogenation conditions with low-valent titanium. The reaction with model compound 5c gives diol 6 as a 2:1 pair of diastereomers (syn H-addition as shown, or anti) where the hydrogens are provided by the toluene solvent. However, this reaction does not proceed with hexaadduct 4. It is likely that the inherently strained nature of 4 leads to reversal of the two oxygen additions under the reducing conditions of this reaction.

More recently, we have examined several approaches utilizing cycloaddition reactions. An example is the 1,3-dipolar cycloaddition of a reactive azomethine ylide tethered by a two-carbon bridge to the original addend bisisobenzofuran, which adds at the least torsionally demanding C=C bond (Figure 3). Thus, condensation of aldehyde 6 with N-methylglycine gives the pyrrolidine 7 as a major diastereo-mer with endo-H configuration, as demonstrated by a single crystal X-ray structure.

While azomethine ylides are some of the most reactive 1,3-dipoles available,[14] their steric requirement makes them unsuitable to add at the highly congested C=C bond of our cis-1 bisisobenzofuran derivatives (5a,b), and presumably other 1,2,3,4-tetraadducts. We found that two key factors critically influence the outcome of tethered additions, the first being the requirement for a 1-atom tether and the second the nature of the 1,3-dipole. The requirement for the short (CH2) tether was already observed in the formation of bis-oxyl radical addition product 4. Five-membered tetrahydrofuran rings are formed in the reaction from 5a to 4, but if the homologous (R-CH2CH2OH) diol is used, no cyclization and only polymerization takes place.[15]

Nitrile-oxides have proven exquisitely suited for this purpose, resulting in the highest yield (80%) of formation of a 1,2,3,4,5,6-hexaadduct (10). With a longer 2-atom bridging group, the nitrile oxide dipole generated from 6 adds at the same relative cis-2 position (i.e. exocyclic 1,3 positions of a pentagon) to give the adduct 8, characterized by an X-ray structure. Interestingly, formation of a nitrile oxide proceeds smoothly in good yields via a a-chloro oxime followed by dehydrochlorination.[16] Application of this strategy to the shorter CH2 tether using this method afforded the desired 1,2,3,4,5,6-hexa-adduct 10, but in low yield (25%). However, the alternate nitrile oxide generation methodxvi involving dehydration of nitroalkyl precursor 9 proceeded in high yield (80%) to give 1,2,3,4,5,6-hexaadduct 10. Its bridgehead methine proton is unusually deshielded by 1.15 ppm (close presence of oxygen lone pairs) is a clear indication of the identity of this product.

We are currently pursuing cis-1 bisadducts with tethered Diels-Alder or 1,3-cycloaddition components other than isobenzofurans.

[1] a) “Stable Compounds of Helium and Neon: He@C60 and Ne@C60” Saunders, M.; Jiménez-Vázquez, H. A.; Cross, R. J.; Poreda, R. J. Science 1993, 259, 1428-1430. b) “Enrichment and Characterization of a Noble Gas Fullerene: Ar@C60” DiCamillo, B. A.; Hettich, R. L.; Guiochon, G., Compton, R. N.; Saunders, M.; Jiménez-Vázquez, H. A.; Khong, A.; Cross, R. J. J. Phys. Chem. 1996, 100, 9197-9201. c) “Observation of Atomlike Nitrogen in Nitrogen-Implanted Solid C60” Murphy, T. A.; Pawlik, T.; Weidinger, A.; Höhne, M.; Alcala, R.; Spaeth J.-M. Phys. Rev. Lett. 1996, 77, 1075-1078. d) “Isolation and Spectral Properties of Kr@C60, a Stable van der Waals Molecule” Yamamoto, K.; Saunders, M.; Khong, A.; Cross, R. J.; Grayson, M.; Gross, M. L.; Benedetto, A. F.; Weisman, R. B. J. Am. Chem. Soc. 1999, 121, 1591-1596. e) “Do Nitrogen-Atom-Containing Endohedral Fullerenes Undergo the Shrink-Wrap Mechanism?” Cao, B.; Peres, T.; Cross, R. J.; Saunders, M.; Lifshitz, C. J. Phys. Chem. A 2001, 105, 2142-2146. f) “129Xe NMR Spectrum of Xenon Inside C60” Syamala, M. S.; Cross, R. J.; Saunders, M. J. Am. Chem. Soc. 2002, 124, 6216-6219.

[2] a) “Endofullerenes: A New Family of Carbon Cluster”; Akasaka, T., Nagase, S., Eds.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 2002. b) “Endohedral Clusterfullerenes—Playing with Cluster and Cage Sizes” Dunsch, L.; Yang, S. Phys. Chem. Chem. Phys. 2007, 9, 3067-3081.

[3] a) “Organic Approaches to Endohedral Metallofullerenes: Cracking Open or Zipping Up Carbon Shells?” Rubin, Y. Chem. Eur. J. 1997, 3, 1009-1016. b) “Ring Opening Reactions of Fullerenes: Designed Approaches to Endohedral Metal Complexes”; Rubin, Y. Top. Curr. Chem. 1999, 199, 67-91.

[4] “Insertion of Helium and Molecular Hydrogen Through the Orifice of an Open Fullerene”; Rubin, Y.; Jarrosson, T.; Wang, G.-W.; Bartberger, M. D.; Schick, G.; Saunders, M.; Cross, R. J.; Houk, K. N. Angew. Chem. Int. Ed. Engl. 2001, 40, 1543-1546.

[5] a) “100% Encapsulation of a Hydrogen Molecule into an Open-Cage Fullerene Derivative and Gas-Phase Generation of H2@C60” Y. Murata, M. Murata, and K. Komatsu, J. Am. Chem. Soc., 2003, 125, 7152-7153. b) “Synthesis, Structure, and Properties of Novel Open-Cage Fullerenes Having Heteroatom(s) on the Rim of the Orifice” Y. Murata, M. Murata, and K. Komatsu, Chem. Eur. J. 2003, 9, 1600-1609. c) “The Reaction of Fullerene C60 with 4,6-Dimethyl-1,2,3-Triazine: Formation of an Open-Cage Fullerene Derivative” Y. Murata, M. Murata, and K. Komatsu, J. Org. Chem. 2001, 66, 8187-8191. d) “Encapsulation of Molecular Hydrogen in Fullerene C60 by Organic Synthesis” K. Komatsu, M. Murata, Y. Murata, Science 2005, 307, 238-240.

[6] a) “A Bowl-Shaped Fullerene Encapsulates a Water into the Cage” Iwamatsu, S.-I.; Uozaki, T.; Kobayashi, K.; Re, S.; Nagase, S.; Murata, S.; J. Am. Chem. Soc. 2004, 126, 2668-2669. b) “Putting Ammonia into a Chemically Opened Fullerene”, Whitener Jr., K. E.; Frunzi, M.; Iwamatsu, S.; Murata, S. R.; Cross, J.; Saunders, M. J. Am. Chem. Soc. 2008, 130, 13996-13999.

[7] a) “Paramagnetic Water-Soluble Metallofullerenes Having the Highest Relaxivity for MRI Contrast Agents” Mikawa, M.; Kato, H.; Okumura, M.; Narazaki, M.; Kanazawa, Y.; Miwa, N.; Shinohara H. Bioconjugate Chem. 2001, 12, 510-514. b) “First Soluble M@C60 Derivatives Provide Enhanced Access to Metallofullerenes and Permit in Vivo Evaluation of Gd@C60[C(COOH)2]10 as a MRI Contrast Agent” Bolskar, R. D.; Benedetto, A. F.; Husebo, L. O.; Price, R. E.; Jackson, E. F.; Wallace, S.; Wilson, L. J.; Alford, J. M. J. Am. Chem. Soc. 2003, 125, 5471-5478. c) “Gd@C60[C(COOH)2]10 and Gd@C60(OH)x: Nanoscale Aggregation Studies of Two Metallofullerene MRI Contrast Agents in Aqueous Solution” Sitharaman, B.; Bolskar, R. D.; Rusakova, I.; Wilson, L. J. Nano Lett. 2004, 4, 2373-2378. d) “Understanding Paramagnetic Relaxation Phenomena for Water-Soluble Gadofullerenes” Laus, S.; Sitharaman, B.; Tóth, É.; Bolskar, R. D.; Helm, L.; Wilson, L. J.; Merbach, A. E. J. Phys. Chem. C 2007, 111, 5633-5639. e) “Conjugation of a Water-Soluble Gadolinium Endohedral Fulleride with an Antibody as a Magnetic Resonance Imaging Contrast Agent” Shu, C.-Y.; Ma, X.-Y.; Zhang, J.-F.; Corwin, F. D.; Sim, J. H.; Zhang, E.-Y.; Dorn, H. C.; Gibson, H. W.; Fatouros, P. P.; Wang, C.-R.; Fang, X.-H. Bioconjugate Chem. 2008, 19, 651-655.

[8] “Surgery of Fullerenes”, Murata, M.; Murata, Y.; Komatsu, K. Chem. Commun. 2008, 6083–6094.

[9] “Approaches to Open Fullerenes: A 1,2,3,4,5,6-Hexaadduct of C60”, Chuang, S.-C.; Clemente, F. R.; Khan, S. I.; Houk, K. N.; Rubin, Y. Org. Lett. 2006, 8, 4525-4528.

[10] “X-ray and Neutron Diffraction Studies of the Crystal and Molecular Structures of Tris(ethylene)platinum and Bis(ethylene)(tetrafluoroethylene)platinum”, Howard, J. A. K.; Spencer, J. L.; Mason, S. A., Proc. R. Soc. Lond. A 1983, 386, 145-161.

[11] “Approaches to Open Fullerenes: Synthesis and Kinetic Stability of Diels-Alder Adducts of Substituted Isobenzofurans and C60”, Chuang, S.-C.; Sander, M. Jarrosson, T.; James, S.; Rozumov, E. Khan, S. I.; Rubin, Y. J. Org. Chem. 2007, 72, 2716 -2723.

[12] “Approaches to Open Fullerenes: Synthesis and Thermal Stability of cis-1 Bis(isobenzofuran) Diels-Alder Adducts of C60”, Sander, M. Jarrosson, T.; Chuang, S.-C.; Khan, S. I.; Rubin, Y. J. Org. Chem. 2007, 72, 2724-2731.

[13] a) “o-Quinodimethanes: Efficient Intermediates in Organic Synthesis”; Segura, J. L.; Martin, N. Chem. Rev. 1999, 99, 3199-3246. b) “o-Quinodimethanes”; Charlton, J. L.; Alauddin, M. M. Tetrahedron 1987, 43, 2873-2889.

[14] “Highly Efficient Retro-cycloaddition Reaction of Isoxazolino[4,5:1,2][60] and [70]fullerenes”, Martín, N.; Altable, M.; Filippone, S.; Martín-Domenech, A.; Martínez-Álvarez, R.; Suarez, M.; Plonska-Brzezinska, M. E.; Lukoyanova, O.; Echegoyen, L. J. Org. Chem. 2007, 72, 3840–3846.

[15] Huang, S.; Rubin, Y., work in progress.

[16] “Recent Advances on the Synthesis and Reactivity of Isoxazoles”, Pinho e Melo, T. M.V.D. Curr. Org. Chem. 2005, 9, 925-958.

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