New high-yielding synthetic routes to the small-molecule endofullerenes H2O@C60, D2O@C60 and H2@C60 are described. The use of high temperatures and pressures for the endohedral molecule incorporation are avoided. A new partial closure step using PPh3, and final suturing using a novel Diels–Alder/retro-Diels–Alder sequence are amongst the advances reported

Krachmalnicoff, A.

Levitt, M.

Whitby, R.

English

New efficient and practical routes to H2O@C60, D2O@C60 and H2@C60 are described.</p

Andrea Krachmalnicoff

Malcolm H. Levitt

Richard J. Whitby

Crossref

Chemical Communications

An optimised scalable synthesis of H2O@C60 and a new synthesis of H2@C60

Southampton (e-Prints Soton)

This journal is©The Royal Society of Chemistry 2014 Chem. Commun.Cite this:DOI: 10.1039/c4cc06198eAn optimised scalable synthesis of H2O@C60 and anew synthesis of H2@C60†Andrea Krachmalnicoﬀ, Malcolm H. Levitt and Richard J. Whitby*New high-yielding synthetic routes to the small-molecule endo-fullerenes H2O@C60, D2O@C60 and H2@C60 are described. The useof high temperatures and pressures for the endohedral moleculeincorporation are avoided. A new partial closure step using PPh3,and final suturing using a novel Diels–Alder/retro-Diels–Aldersequence are amongst the advances reported.The molecular structure of C60 fullerene consists of a carboncage enclosing a spherical cavity with a diameter of approxi-mately 3.5 Å. Small-molecule endofullerenes encapsulate asingle small molecule such as H2 or H2O within the cavity.1,2The encapsulated molecule behaves as a confined quantumrotor, displaying a rich energy level structure,3 which may bestudied by neutron scattering,4,5 infrared spectroscopy5,6 andnuclear magnetic resonance (NMR).3,5,7 The stability and homo-geneity of endofullerenes such as H2@C60 and H2O@C60 allowsthe convenient and precise study of important physical pheno-mena such as nuclear spin isomer conversion.5,7,8 It is possibleto detect the endohedral interconversion of ortho and para-water,and to show that the conversion is a bimolecular process evenunder cryogenic conditions, with neighbouring pairs of ortho-water molecules interacting so as to generate a pair of para-watermolecules.7 Apart from their intrinsic interest, such observationsmay underpin new routes to the generation of nuclear hyper-polarization, analogous to the chemical reactions of para-enrichedhydrogen gas.9 The high demand for these unique substances hashighlighted limitations of the current methods for their prepara-tion. The synthetic route to endofullerenes has been described as‘‘molecular surgery’’10 and involves three stages; (i) opening andprogressive widening of an orifice in the C60 cage throughexohedral reactions, (ii) introduction of a small moleculethrough the orifice into the cavity, (iii) further reactions leadingto reclosure of the C60 cage and encapsulation of the endo-hedral molecule. The final (reclosure) stage is the most diﬃcultand has been accomplished only by Komatsu and Murata usingtwo diﬀerent routes leading to H2@C60 (8 steps, 8% overallyield),1 and H2O@C60 (6 steps, 5% yield) respectively.2 Bothsyntheses require specialised high pressure equipment for theendohedral molecule incorporation step. Herein we reportmore eﬃcient and practical routes to these important molec-ular systems.The key feature of the H2O@C60 synthesis is that theopen-cage derivative 1, having a 13-membered orifice, can beconverted in situ into its dehydrated form 2 that has a16-membered orifice. Compound 2 is able to incorporate awater molecule but is easily re-hydrated, reducing once againthe size of the orifice trapping the guest molecule inside thecage. Compound H2O@1 is then reduced with (iPrO)3P toH2O@3 which in turn is pyrolysed under vacuum to produceH2O@C60 (Scheme 1).The reported route2 to the open fullerene 1 worked wellbut we lacked the equipment to apply the very high pressures(9000 atm) used to eﬃciently encapsulate the water molecule.It was already known that compound 1 could incorporate water(8%) under atmospheric pressure2 and that higher fillingfactors could be achieved under similar conditions in otheropen fullerenes bearing larger orifices.11 Published studies onthe filling of hydrophobic cavities by water molecules suggestedthat an increased filling factor could be as well achieved bychanging variables other than pressure.12 On these premises weinvestigated the filling of 1 under low pressure conditions.Heating a solution of 1 in toluene in an NMR tube in the presenceof water (5.6 equiv.) at 120 1C reached amaximum of 23% incorpora-tion after 36 h reflecting the equilibrium situation. Increasing reac-tion time further gave substantial decomposition. Changing to asealed tubewhich could be uniformly heated to prevent condensationin cooler regions increased incorporation to 45%. Using a large excessof water did not significantly change incorporation. Changing to otheraromatic solvents demonstrated increased incorporation (benzene,39%; ortho-dichlorobenzene, 61%; 1-chloronapthalene, 67%).Chemistry, University of Southampton, Southampton SO17 1BJ, UK.E-mail: rjw1@soton.ac.uk† Electronic supplementary information (ESI) available: Experimental proce-dures, compound characterization data, and details of calculations. See DOI:10.1039/c4cc06198eReceived 7th August 2014,Accepted 9th September 2014DOI: 10.1039/c4cc06198ewww.rsc.org/chemcommChemCommCOMMUNICATIONPublished on 09 September 2014. Downloaded by University of Southampton on 17/09/2014 15:55:02. View Article OnlineView JournalChem. Commun. This journal is©The Royal Society of Chemistry 2014Using 1-chloronapthalene as the solvent and lowering the tem-perature to 100 1C gave 78% H2O incorporation after 48 hproviding a practical alternative to high pressure procedures.The same process can be extended to the synthesis of D2O@1but to avoid contamination with HDO@1 and H2O@1 it wasnecessary to pre-form the dehydrated compound 2 by refluxing atoluene solution of 1 for one hour, passing the condensed solventthrough a column of activated 3 Å molecular sieves. Subsequentremoval of solvent to give 2, dissolution in 1-chloronapthalene,addition of D2O and heating as above gave D2O@1 with noHOD@1 or H2O@1 visible by1H NMR spectroscopy. Compound2 was recently isolated using a diﬀerent protocol.13In an eﬀort to complete the synthesis of H2O@C60 ourattention turned to suturing H2O@1. Unfortunately when com-pound H2O@1 was reacted with (iPrO)3P the expected productH2O@3 was isolated in only 34% yield. The same reactionmixture yielded 31% of the novel compound H2O@4. Thestructure of the latter can be deduced from the appearance inthe 1H NMR spectrum of a singlet at d 7.80 ppm from theproton present on the rim of the orifice and a broad signal atd 5.21 attributable to the single hydroxyl group. The DFT-GIAOcalculated spectra suggest the formation of regioisomer 4.Compound 4 was the only product isolated (76% yield) when1 was reacted with (iPrO)3P at room temperature. Compound 4is inert to (iPrO)3P and H2O@4 does not lose its endohedralwater molecule upon heating. A somewhat similar reactivitytowards alkyl phosphites has been reported for another open-cage fullerene, and the mechanism of the reduction studiedtheoretically.14 Pre-formed 2 reacted with (iPrO)3P at roomtemperature to aﬀord compound 3 in 33% yield without con-tamination by 4. It is likely that under the reported closureconditions2 it is a mixture ofH2O@1 and H2O@2 formed in situwhich are reacting with (iPrO)3P to give varying mixtures ofH2O@4 and H2O@3 (Scheme 2).In order to overcome this side reactivity of H2O@1 towardsalkyl phosphites we looked at alternative reagents and found thatreaction with excess Ph3P at 120 1C cleanly gave compoundH2O@5, isolated in 84% yield. Compound H2O@4 was notformed and, even with longer reaction times, reduction tocompound H2O@3 was not observed. No endohedral water waslost in the formation of H2O@5 for which this reaction providesthe first synthesis. Compound H2O@5 could be reacted withexcess (iPrO)3P to giveH2O@3 which was isolated after chromato-graphy in 84% yield. In comparison with the reported directreaction with (iPrO)3P,2 the yield of H2O@3 aﬀorded in the twostep process, is higher overall (69%) (Scheme 3).Our attention finally turned to the last step of the closure –the conversion of H2O@3 into H2O@C60. The reported yield of29% was achieved by vacuum pyrolysis (360 1C) of H2O@3Scheme 1 H2O@C60 synthesis.2Scheme 2 Reactivity ofH2O@1 and H2O@2 towards triisopropyl phosphite.Scheme 3 Optimised suturing procedure of compound H2O@1 to giveH2O@C60.Communication ChemCommPublished on 09 September 2014. Downloaded by University of Southampton on 17/09/2014 15:55:02. View Article OnlineThis journal is©The Royal Society of Chemistry 2014 Chem. Commun.dispersed on dry neutral alumina.2 Unfortunately in our handswe could isolate only traces of the product. A reasonable mecha-nism involves an initial [4+2] intramolecular cycloaddition togive strained intermediate 6 which rearranges via radical clea-vage (formally a retro-[4+4] cycloaddition) of the strained C–Ccyclopropane bonds generating intermediate 7. Finally, a retro-[2+2+2] cycloaddition leads to the extrusion of the side aromaticgroups and formation of the C60 structure (Scheme 4).The last step (7 to C60) is likely to have the highest activationenergy. We postulated that a lower energy reaction profile couldbe followed in presence of N-phenylmaleimide, a strong die-nophile that was expected to react readily with the intermediate7 in a [4+2] cycloaddition to aﬀord adduct 8 which is a goodsubstrate for a retro [4+2] cycloaddition to regenerate the C60structure. These predictions were confirmed experimentallyby reacting compound H2O@3 with N-phenylmaleimide in1-chloronaphthalene under reflux conditions. After 20 hoursa clean conversion to H2O@C60, was observed and columnchromatography aﬀorded the product in 90% yield. Furtherpurification by sublimation gave pure H2O@C60 in 72% overallyield (Scheme 3). The same route has been followed to completethe synthesis of D2O@C60 in identical yield.Komatsu has reported the synthesis of H2@C60 in 8 stepsand 8% overall yield via insertion of H2 into a diﬀerent cage-opened fullerene at 800 atm and 200 1C.1 Given the eﬃciency ofthe opening/closure described above a more convenient synthesisseemed possible. Incorporation of molecular hydrogen into 2(formed in situ from 1 using 3 Å molecular sieves) at 120 1C and120 atm H2 for 20 h gave H2@1 after work-up with a 60% fillingfactor. The lower temperature (120 1C cf. 200 1C) allowed reasonableincorporation at moderate pressures. It is likely that we would obtaincomplete filling at the high pressures (800 atm) used previously.1In order to test if the system could be closed without the lossof the endohedral hydrogen molecule, a mixture of H2O@1 andH2@1 was reacted with (iPrO)3P in refluxing toluene. All theendohedral hydrogen was lost while all the water was retainedinside. The problem was overcome by carrying out the phos-phite reaction under hydrogen pressure. Thus compound 1 washeated to 120 1C in o-dichlorobenzene under hydrogen pressure(120 atm) in the presence of molecular sieves to give H2@2(60% H2 incorporation). The bomb was then depressurised and(iPrO)3P or Ph3P was added before pressurising with hydrogenagain and heating to 120 1C overnight. The reactions aﬀorded60% filled H2@3 in 50% yield and 60% filled H2@5 in 84%yield respectively. Both H2@3 and H2@5 can be reacted in ananalogous way as already described for H2O@3 and H2O@5 toisolate 60% filled H2@C60 (Scheme 5).In conclusion a systematic study of the H2O@C60 synthesisdeveloped by Murata2 has been carried out. It has been demon-strated that 78% incorporation of H2O and D2O into compound 1can be achieved without the need for high pressure equipment.Treatment of hemiacetal 1 with (iPrO)3P at room temperaturegave the reduced product 4 and H2O@4 was a major by productduring the (iPrO)3P induce closure of H2O@1 to give H2O@3.Dehydration of hemi-acetal 1 to give tetraketone 2 before reactionwith (iPrO)3P at room temperature gave 3 without formation of 4.A new partial closure procedure from H2O@1 using PPh3allowed H2O@5 to be isolated for the first time, and sub-sequent deoxygenation with (iPrO)3P gave H2O@3 in improvedoverall yield. A new method for closing the fullerene H2O@3 toaﬀord H2O@C60 was developed using a Diels–Alder/retro-Diels–Alder sequence which gave substantially higher yields than theknown pyrolysis method, and was readily scalable. Overall puresublimed H2O@C60 (78% H2O incorporation) was synthesisedin 15% yield from C60. D2O@C60 uncontaminated with HOD@C60was made in similar yield. The same synthetic route has beensuccessfully applied to the formation of H2@C60, the large sizeof the orifice of compound 2 enabling a 60% incorporation ofH2 at 120 1C and 120 atm. These advances will lead to a greatlyimproved availability of the important molecular endofullerenesH2O@C60 and H2@C60, and their isotopologues.Scheme 4 Proposed mechanism for the conversion of 3 into C60. TheC60 skeleton other than the orifice carbons (solid line) has been omittedfor clarity.Scheme 5 Synthesis of H2@C60 from 1.ChemComm CommunicationPublished on 09 September 2014. Downloaded by University of Southampton on 17/09/2014 15:55:02. View Article OnlineChem. Commun. This journal is©The Royal Society of Chemistry 2014We thank the EPSRC (EP/I029451/1) and ERDF (Interreg-IVB,MEET project) for funding, and acknowledge the use of theIRIDIS High Performance Computing Facility and associatedsupport services at the University of Southampton. We wish tothank Prof. Koichi Komatsu, Prof. Yasujiro Murata, Prof. NickTurro, Dr Lei Xuegong and Dr YongJun Li for sharing theirdetailed experimental procedures.Notes and references1 K. Komatsu, M. Murata and Y. Murata, Science, 2005, 307, 238–240.2 K. Kurotobi and Y. Murata, Science, 2011, 333, 613–616.3 M. H. Levitt, Philos. Trans. R. Soc., A, 2013, 371, 20120429.4 (a) A. J. Horsewill, K. Goh, S. Rols, J. Ollivier, M. R. Johnson, M. H.Levitt, M. Carravetta, S. Mamone, Y. Murata, J. Y.-C. Chen,J. A. Johnson, X. Lei and N. J. Turro, Philos. Trans. R. Soc., A, 2013,371, 20110627; (b) A. J. Horsewill, K. S. Panesar, S. Rols, M. R.Johnson, Y. Murata, K. Komatsu, S. Mamone, A. Danquigny,F. Cuda, S. Maltsev, M. C. Grossel, M. Carravetta and M. H. Levitt,Phys. Rev. Lett., 2009, 102, 013001.5 C. Beduz, M. Carravetta, J. Y.-C. Chen, M. Concistre´, M. Denning,M. Frunzi, A. J. Horsewill, O. G. Johannessen, R. Lawler, X. Lei,M. H. Levitt, Y. Li, S. Mamone, Y. Murata, U. Nagel, T. Nishida,J. Ollivier, S. Rols, T. Ro˜o˜m, R. Sarkar, N. J. Turro and Y. Yang, Proc.Natl. Acad. Sci. U. S. A., 2012, 109, 12894–12898.6 (a) S. Mamone, M. Ge, D. Hu¨vonen, U. Nagel, A. Danquigny, F. Cuda,M. C. Grossel, Y. Murata, K. Komatsu, M. H. Levitt, T. Ro˜o˜m andM. Carravetta, J. Chem. Phys., 2009, 130, 081103; (b) M. Ge, U. Nagel,D. Hu¨vonen, T. Ro˜o˜m, S. Mamone, M. H. Levitt, M. Carravetta,Y. Murata, K. Komatsu, X. Lei and N. J. Turro, J. Chem. Phys., 2011,135, 114511; (c) T. Ro˜o˜m, L. Peedu, M. Ge, D. Hu¨vonen, U. Nagel,S. Ye, M. Xu, Z. Bacˇic´, S. Mamone, M. H. Levitt, M. Carravetta, J. Y.-C.Chen, X. Lei, N. J. Turro, Y. Murata and K. Komatsu, Philos. Trans. R. Soc.,A, 2013, 371, 20110631.7 S. Mamone, M. Concistre`, E. Carignani, B. Meier, A. Krachmalnicoﬀ,O. G. Johannessen, X. Lei, Y. Li, M. Denning, M. Carravetta, K. Goh,A. J. Horsewill, R. J. Whitby and M. H. Levitt, J. Chem. Phys., 2014,140, 194306.8 (a) M. Frunzi, S. Jockusch, J. Y.-C. Chen, R. M. K. Calderon, X. Lei,Y. Murata, K. Komatsu, D. M. Guldi, R. G. Lawler and N. J. Turro, J. Am.Chem. Soc., 2011, 133, 14232–14235; (b) Y. Li, X. Lei, S. Jockusch, J. Y.-C.Chen, M. Frunzi, J. A. Johnson, R. G. Lawler, Y. Murata, M. Murata,K. Komatsu and N. J. Turro, J. Am. Chem. Soc., 2010, 132, 4042–4043.9 (a) C. R. Bowers and D. P. Weitekamp, J. Am. Chem. Soc., 1987, 109,5541–5542; (b) R. W. Adams, J. A. Aguilar, K. D. Atkinson, M. J.Cowley, P. I. P. Elliott, S. B. Duckett, G. G. R. Green, I. G. Khazal,J. Lo´pez-Serrano and D. C. Williamson, Science, 2009, 323,1708–1711.10 J. C. Hummelen, M. Prato and F. Wudl, J. Am. Chem. Soc., 1995, 117,7003–7004.11 (a) S. Iwamatsu, T. Uozaki, K. Kobayashi, S. Re, S. Nagase andS. Murata, J. Am. Chem. Soc., 2004, 126, 2668–2669; (b) Q. Zhang,Z. Jia, S. Liu, G. Zhang, Z. Xiao, D. Yang, L. Gan, Z. Wang and Y. Li,Org. Lett., 2009, 11, 2772–2774.12 J. C. Rasaiah, S. Garde and G. Hummer, Annu. Rev. Phys. Chem.,2008, 59, 713–740.13 T. Futagoishi, M. Murata, A. Wakamiya, T. Sasamori and Y. 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An optimised scalable synthesis of H2O@C60and a new synthesis of H2@C60

An optimised scalable synthesis of H2O@C60and a new synthesis of H2@C60

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