Effect of incarcerated HF on the exohedral chemical reactivity of HF@C60

The first chemical modification on the brand new endohedral HF@C60 is reported. In particular, the isomerization from optically pure (2S,5S)-cis-pyrrolidino[3,4:1,2][60]fullerene 2b to (2S,5R)-transpyrrolidino[3,4:1,2][60]fullerene 2b has been studied and compared with empty C60 (2a) and endohedral H2O@C60 (3). The comparative study shows a kinetic order for the isomerization process of H2O@C60 4 HF@C60 4 C60, thus confirming the effect of the incarcerated species on the zwitterionic intermediate stability.

Since the detection of endohedral fullerenes following the discovery of C 60 , 1 many species such as metals, noble gases, clusters, atoms or molecules, have been encapsulated in the hollow fullerene cage. The main method to achieve endohedral fullerenes is based on the arc discharge of graphite rods containing metals. However, controlling the size of the carbon cage or the product distribution by using this methodology is not possible. ''Molecular surgery'' emerged as an alternative and suitable methodology to synthesize endohedral fullerenes in a controlled manner, and paved the way toward atoms or small molecules encapsulation, namely H 2 @C 60 , 2 He@C 60 , 3 and H 2 O@C 60 4 ( Fig. 1).
Because of their size, diatomic guest molecules are ideal candidates to be encapsulated inside C 60 . Hydrogen fluoride (HF) is frequently used in a variety of organic synthetic protocols and has been extensively studied. 5 Recently, Krachmalnicoff et al., have successfully isolated the HF molecule inside C 60 fullerene, thus forming the new endohedral HF@C 60 molecule. 6 A single HF molecule trapped in a fullerene cage provides the opportunity to analyze its singular properties in an interaction free situation as well as in a well-defined environment. Furthermore, considering the polarity of the HF molecule, it is expected to have an impact on the exohedral reactivity of the [60]fullerene cage.
It is known that some encapsulated molecules in endofullerenes can affect the exohedral reactivity of the fullerenes carbon cage. 7 Dolgonos et al. reported a computational study of several diatomic molecules encapsulated into C 60 , including the HF molecule. 5b Some of us have demonstrated the interaction of polar molecules inside fullerenes by reporting the cis-trans isomerization of enantiomerically pure H 2 O@C 60 pyrrolidines, showing the existence of a hydrogen bonding assistance between the carbanion on the cage and the trapped water molecule. 8 Herein, we report the first exohedral functionalization on the novel HF@C 60 using an efficient methodology to obtain enantiomerically enriched HF@C 60 pyrrolidines. A comparative study between pristine C 60 , H 2 O@C 60 , and HF@C 60 on the cis-trans isomerization process is also discussed for a better understanding of the effect of the molecule inside on the isomerization reaction. Furthermore, DFT calculations at the M06-2X/6-311++G(d,p)// OLYP/TZP level of theory nicely underpin the experimental evidences. In contrast to that expected, the kinetics observed does not only depend on the inherent acidity of the incarcerated HF molecule.
The synthesis of new enantiomerically enriched fulleropyrrolidines was carried out using the reported methodology involving a 1,3-dipolar cycloaddition of N-metalated azomethine ylide. 9 In order to determine the difference in the chemical reactivity between empty C 60 and HF@C 60 , the reaction was carried out with a mixture of both fullerenes in a ratio 12 : 88 (C 60 : HF@C 60 ) under the same reaction crude, thus ensuring the same experimental conditions.
Following the Scheme 1, the mixture of fullerenes reacted with iminoester 1 in the presence of the corresponding metal salt/chiral ligand pair to yield each one of the four enantiomers of the respective pyrrolidino[60]fullerenes, namely the cis-2a and cis-2b and the trans-2a and trans-2b for the C 60 and HF@C 60 , respectively, in good enantiomeric excesses. It is important to note that the respective enantiomers shown in the Scheme 1 were obtained as a mixture of the respective empty and filled fullerene derivatives in the same ratio than the starting mixture.
Interestingly, despite the polarity of the HF molecule, we did not observe significant differences in terms of reactivity on the carbon cage of the HF@C 60 compared with C 60 . Indeed, the ratio of pristine cages before and after reacting remained unaltered, (C 60 : HF@C 60 = 12 : 88), as well as the ratio of pyrrolidine-C 60 and pyrrolidine-HF@C 60 . These experimental data, corroborated by theoretical calculations (see below), contradict a priori the expected higher reactivity for the HF@C 60 molecules as result of an acidic/electrophilic LUMO activation of the cage double bonds.
The four new enantiomers cis-2b and trans-2b were fully characterized by NMR spectroscopy and mass spectrometry (ESI †). The signal for the inner proton of pristine HF@C 60 in the 1 H-NMR spectrum appears at -2.65 ppm ( J = 505.6 Hz) as a doublet. However, if the carbon cage is functionalized that signal is shifted to -5.81 ppm ( J = 505.8 Hz) for cis-2b and to -5.88 ppm ( J = 506.0 Hz) for trans-2b ( Fig. 2 and ESI †).
In order to get a better understanding of the HF behavior inside the carbon cage, we moved our attention to the isomerization process that involves the exohedral [60]fullerene functionalization. In this regard, the easy availability of optically active derivatives enables the use of chiral information as a powerful tool to shed light into the mechanism involved. We now study the isomerization process from the optically pure (2S,5S)-cis-to the (2S,5R)-trans-pyrrolidino [3,4:1,2][60]fullerene that proceeds with an absolute enantiospecificity. This process can be accounted for by a stepwise mechanism with a configurational inversion at the pyrrolidine C5 carbon atom while the configuration at C2 is maintained without losing enantiomeric excess. This enantiospecificity is coherent with the formation of a zwitterionic intermediate by heterolytic pyrrolidine ring opening between the C5 and the cage (see Fig. 3) that gives rise to a stable benzylic cation and a negative charge on the [60]fullerene cage.
In addition to the study on the isomerization process from the optically pure (2S,5S)-cis-pyrrolidino[60]fullerene 2b to the (2S,5R)-trans-pyrrolidino[60]fullerene 2b, it has also been compared with those of the empty C 60 (2a) and endohedral H 2 O@C 60 (3) (Fig. S11, ESI †). Thus, we can explore the influence of the hydrogen bonding -generated by the carbanion on the fullerene sphere and the hydrogen of the inner molecule (H 2 O and HF)-on the isomerization process. The proposed mechanism for the isomerization (equilibrium reaction) follows a first-order rate law. However, competing reactions such as the previously reported retro-cycloaddition 10 and the racemization might be also involved. Therefore, moderate temperatures have been used in order to avoid those competitive reactions. In all cases, the enantiomeric excesses of the trans derivatives remained unaltered demonstrating the enantiospecificity of the isomerization process (see ESI †).   Comparing the experimental findings of the three systems, the two endohedral fullerenes show the highest isomerization rates k H 2 O@C 60 4 k HF@C 60 4 k C 60 (see Table S1, ESI †). This confirms that the encapsulated molecule plays a significant role in the zwitterionic intermediate stability. In view of the aforementioned results, the H-bonding assistance is stronger for the H 2 O@C 60 system according to the kinetic constants. These experimental results are in good agreement with that predicted by theoretical calculations (see below).
We have carried out density functional theory calculations at the M06-2X/6-311++G(d,p)//OLYP/TZP level of theory 11 including solvent effects to analyze the cis-trans isomerization in the HF@C 60 chiral pyrrolidino[60]fullerene (2S,5S)-cis-2b (see ESI † for a detailed description of the computational methods). Nitrogen inversion in pyrrolidino[60]fullerenes is fast 12 and consequently, for all computations, the most stable conformation of the pyrrolidino[60]fullerene was used. Moreover, different orientations of the HF unit inside C 60 for reactants, intermediates, and products have been studied and the most stable orientation has been considered in all cases (see ESI †). Fig. 4 provides the computed reaction path for the cis-trans isomerization and the retro-cycloaddition process for (2S,5S)cis-2b. For comparison purposes, it also includes the values for the analogous empty pyrrolidino[60]fullerene (2S,5S)-cis-2a and water-incarcerated endohedral pyrrolidino[60]fullerene (2S,5S)cis-3 taken from our previous study. 8 As found in 2a and 3 and in agreement with experimental observations, PROD-(2S,5S)-cis-2b is more stable by 1.6 kcal mol À1 than PROD-(2S,5R)-trans-2b. This value is not far from the experimental 0.7 kcal mol À1 determined from the observed 77 : 23 ratio of products at 25 1C. The cis-trans isomerization occurs through a stepwise mechanism with the formation of zwitterionic intermediates referred as INT-(2S,5S)-cis-2b and INT-(2S,5R)-trans-2b in Fig. 4. Zwitterionic intermediates of this type are not exceptional and, for instance, they were also found in 1,3-dipolar isomerizations on endohedral metallofullerenes. 13 The heterolytic dissociation of the C-C bond to form the zwitterionic intermediate is much easier at C5 (with an energy barrier lower by 10 kcal mol À1 ) than at C2 position because of the electron withdrawing character of the carboxylic group (see Fig. 3). 13 This result is in concordance with experimental observation that the C2 configuration is preserved along the whole isomerization process. After dissociation, the negative charge is located on the cage and the positive one in the benzylic cation. As compared to separated reactants, zwitterionic intermediates are about 1.5 kcal mol À1 more stable in HF@C 60 than in hollow C 60 . The reason of this stabilization is the formation of an interaction between the H of the HF unit and the negatively charged C atom on the fullerene cage. The distance between the H atom of HF and C5 in the zwitterionic intermediate is ca. 2.6 Å (see Fig. S31, ESI †). The H-F distance in cis and trans intermediates is 0.931 Å, somewhat elongated as compared to that of HF@C 60 (0.929 Å), but less than that found in the hydrogen bonded (HF) 2 dimer (0.937 Å). Therefore, this HÁ Á ÁC interaction in the zwitterionic intermediate can be classified as a weak hydrogen bond.
From the zwitterionic INT-(2S,5S)-cis-2b, the system can evolve through two different pathways: (i) cis-trans isomerization to produce INT-(2S,5R)-trans-2b or (ii) retro-cycloaddition reaction to recover the initial reactants. Isomerization occurs through rotation around the C2-N bond of INT-(2S,5S)-cis-2b to yield INT-(2S,5R)-trans-2b, which evolves to PROD-(2S,5R)-trans-2b in an almost barrierless process. The retro-cycloaddition reaction from INT-(2S,5S)-cis-2b is also possible, but it has a barrier that is about 3.7 kcal mol À1 higher than the cis-trans isomerization process. This difference between the activation barrier for the retro-cycloaddition and isomerization process is substantially larger in the case of HF, as compared to free C 60 and H 2 O@C 60 (ca. 2.3 and 3.5 kcal mol À1 , respectively). Therefore, especially in the case of C 60 , the retro-cycloaddition can compete with the isomerization process at high temperatures.
It is worth noting that the presence of the inner HF molecule does not affect the final relative stability of the cis and trans products. However, it has an important effect on the retroreaction pathway and, especially, it has a significant influence on the energy barrier of the cis-trans isomerization process. The activation barrier is considerably lower in 2b (32.7 kcal mol À1 with respect to the lowest energy cis product) as compared to 2a (33.6 kcal mol À1 ). This ca. 1 kcal mol À1 difference is in agreement with the improved stereochemical outcome observed experimentally for the HF@C 60 chiral pyrrolidino[60]fullerene. The encapsulated HF molecule assists the isomerization process by stabilizing the formed fullerene anion intermediate, where the hydrogen atom of HF is directly pointing to the negatively charged carbon atom on fullerene surface. This distance is ca. 2.6 Å in INT-(2S,5S)-cis-2b, and slightly longer in TS cis-trans (ca. 2.7 Å) (Fig. S31, ESI †), indicating a disruption of the H-bonding in the TS cis-trans due to a more delocalized negative charge on the pyrrolidino[60]fullerene in the TS structure. The slightly smaller energy barrier (by 0.4 kcal mol À1 ) for the (green values). The retro-cycloaddition process is also included (in grey). All energies are in kcal mol À1 .