Research Article Received: 31 October 2014
Revised: 16 December 2014
Accepted: 20 December 2014
Published online in Wiley Online Library
Rapid Commun. Mass Spectrom. 2015, 29, 497–504 (wileyonlinelibrary.com) DOI: 10.1002/rcm.7131
Competitive retro-cycloaddition reactions in heterocyclic fullerene bis-adducts ions: selective removal of the heterocyclic moieties Margarita Suárez1, Enrique E. Maroto2, Salvatore Filippone2, Nazario Martín2,3 and Roberto Martínez-Álvarez2* 1
Laboratorio de Síntesis Orgánica, Facultad de Química, Universidad de La Habana, 10400, Ciudad Habana, Cuba Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Complutense, E-28040, Madrid, Spain 3 IMDEA-Nanociencia, Campus de Cantoblanco, E-28049, Madrid, Spain 2
RATIONALE: We have investigated the fragmentation reactions of ions from bis-adducts containing isoxazolino-,
pyrrolidino- and methanofullerene moieties. METHODS: The fragmentation reactions induced by collision-induced dissociation (CID) of ions generated under
electrospray ionization (ESI) in positive and negative modes of detection using an ion-trap spectrometer have been investigated. RESULTS: The competitive retro-cycloaddition process between isoxazoline and pyrrolidine rings fused to [60]fullerene reveals that it is strongly dependent on the experimental negative or positive ESI experimental conditions. Thus, whereas retro-cycloaddition reaction is favored in the pyrrolidine ring under negative conditions, the protonation occurring on the nitrogen atom of the pyrrolidine ring under positive conditions precludes its retro-cycloaddition and, therefore, only the isoxazoline ring undergoes the retro-cycloaddition process. The obtained experimental results are different from those reported when the reaction is carried out under thermal conditions. Competitive retro-cycloaddition reactions of isoxazolino- and methanofullerenes show that the heterocyclic ring undergoes cycloelimination, leaving the methanofullerene moiety unchanged. In this case, the same selectivity is observed under thermal and gas-phase conditions. CONCLUSIONS: The observed selectivity in the heterocyclic removal in these [60]fullerene derivatives is reversed from negative conditions (radical anions) to positive conditions (protonated molecules). Moreover, the retro-cycloaddition reaction behaves differently under spectrometric and thermal conditions. Copyright © 2015 John Wiley & Sons, Ltd.
Since the discovery of fullerenes, mass spectrometry (MS) has been a useful technique to determine the gas-phase chemistry of these compounds and also to characterize the huge number of chemically modified fullerenes that have been prepared so far.[1,2] Furthermore, fullerenes and other carbon nanoforms have been used as matrices in MS studies.[3,4] Although matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) are the most frequently used ionization methods for the analysis of fullerenes, new techniques such as atmospheric pressure photoionization (APPI) have also been successfully employed for the characterization of these carbon allotropes and their derivatives.[5] The electrochemical nature of the ESI process was used for the direct analysis of fullerene solutions providing evidence of the process occurring at the ES capillary tip.[6] On the other hand, the ion sources of electron impact (EI) and laser desorption/ionization (LDI) spectrometers have been used to study the reaction of C60 with aromatic compounds.[7] Some gas-phase reactions between fullerenes,
* Correspondence to: R. Martínez-Álvarez, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Complutense, E-28040 Madrid, Spain. E-mail: [email protected]
acting as starting materials, and diamines,[8] ketones,[9] or organomercurials,[10] have been investigated using MS techniques. Cycloaddition [3+2] and [4+2] reactions using a continuous-flow approach to prepare fullerene derivatives have been tested using MS.[11] 1,3-Dipolar cycloadditions of different dipoles to C60 are among the most useful reactions for the preparation of modified fullerenes,[12,13] for applications in fields such as medicinal chemistry[14] and materials science.[15–17] Stereocontrolled syntheses have been developed for the preparation of chiral fulleropyrrolidines by [3+2] cycloadditions.[18] The thermal reaction of isoxazolino[60]- and -[70]fullerenes,[19] pyrrolidino [60]- and -[70]fullerenes[20] and pyrazolino[60]fullerenes[21] results in pristine fullerene proving that the cycloaddition and retro-cycloaddition reactions can be used as a protectiondeprotection protocol. The thermal treatment of fullerene derivatives was carried out by heating at 150 °C in o-dichlorobenzene and in the presence of a dipolarophile in order to quench the corresponding 1,3-dipole formed during the reaction. Sometimes a catalytic process induced by copper triflate is required.[17–19] The retro-cycloaddition process can be also promoted under electrochemical conditions. Thus, controlled potential electrolysis (CPE) for the removal of pyrrolidine moieties from pyrrolidinofullerene derivatives has been reported.[22]
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M. Suárez et al. The retro-cycloaddition reaction of heterocyclic fullerene C60 and C70 derivatives is also easily promoted under MS conditions. Thus, when the radical anions (M•–) generated under ESI conditions from heterocyclic fullerene derivatives undergo collision-induced dissociation (CID), the corresponding [60]- and -[70]fullerene radical ions at m/z 720 and 840, respectively, were detected as main ion products (Scheme 1).[19,23] The exceptional stability of these ionic fullerene species stabilizing the unshared electron facilitates the reaction. The formation of fullerene ions was accounted for by the elimination of the corresponding 1,3- and 1,2-dipole fragments through a retro-cycloaddition reaction. The in situ generation of these ylides has been demonstrated by trapping this reactive intermediate under MS conditions with a fullerene monoadduct which acts as dipolarophile, leading to the formation of fullerene bis-adducts.[24] Under positive ESI conditions, pyrrolidinofullerenes provide protonated molecules [M+H]+.[25] It is well known that pyrrolidine is a weak base and theoretical calculations and experimental data reveal that the fullerene moiety reduces dramatically the basicity of the nitrogen atom of the pyrrolidine ring.[26] Values of proton affinity also indicate a reduced gas-phase basicity for this heterocyclic amine.[27,28] Despite these data, the reduced basicity seems to be enough to permit the protonation of the nitrogen atom resulting in the formation of the corresponding [M+H]+ ion. We have previously reported that the protonated molecules [M+H]+ of pyrrolidinofullerenes do not undergo the retro-cycloaddition reaction under CID conditions.[25] In this case, the protonation seems to avoid the loss of the corresponding azomethine ylide molecule. Instead, different fragmentations take place at the pyrrolidine ring depending on the nature of the substituents attached to the heterocyclic moiety. [25] Similarly, the protonation of isoxazolinofullerenes takes place at the nitrogen atom.[19,27–30] The protonated molecules from isoxazolinofullerenes do not undergo the corresponding cycloelimination and only a loss of a nitrile molecule is observed.[19] In this work we have investigated the MS behavior under ESI conditions of a series of bis-adducts containing isoxazolino, pyrrolidino and methanofullerene moieties in order to evaluate the structural requirements which control the competitive fragmentations of these compounds.
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Scheme 1. Negative ESI-CID-MS2 for heterocyclic fullerene monoadduct radical ions.
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EXPERIMENTAL Fullerene bis-adducts 1 and 2 (Scheme 2) were prepared according to previously reported methods.[19] ESI mass spectra were recorded in positive and negative mode of detection using an Esquire-LC ion-trap spectrometer (Bruker Daltonics, Bremen, Germany). The direct injection of samples was achieved using a syringe pump (Cole Palmer, Vernon Hills, IL, USA) through a short length of PEEK tubing of 254 μm i.d. (Upchurch Scientific, Oak Harbor, WA, USA) at a flow rate of 2 μL min–1. To prepare the samples, fullerene derivatives were dissolved in dichloromethane/ toluene/methanol (1:1:0.1, v/v/v). In the positive and negative modes of detection, the conditions were: capillary voltage 3 kV, nebulizing gas pressure 10 psi, drying gas flow 4 L min–1, drying gas temperature 350 °C. MSn spectra were obtained using collision-induced dissociation (CID) with helium after isolation of the appropriate precursor ions using the following fragmentation options: amplitude 0.60 V, time 40 ms, delay 0 μs and mass width of 5.00 m/z.
RESULTS AND DISCUSSION For a better understanding of the reactions involving a retro-cycloaddition process and in order to compare the reactivity of the ions generated from different heterocyclic fullerene derivatives, we have investigated the mass spectra of bis-adducts 1 and 2 under ESI conditions. Thus, the competitive retro-cycloadditions in bis-adducts could shed light on the factors that seem to control this process. Only one example concerning the competitive retro-cycloaddition reaction of [60]- and [70]fullerene homodimers and ([60]/ [70])heterodimers linked by a pyrazolinopyrrolidine bridge is reported in the literature. The thermal reaction of these compounds indicates that the retro-cycloaddition of pyrrolidinofullerenes is favored compared to the same process for pyrazolinofullerenes.[31] The occurrence of this process has also been observed in the corresponding MALDI mass spectra[31] and these findings are in agreement with those predicted by theoretical calculations.[31] Moreover, the observed relative highest thermal stability of pyrazolinofullerenes compared with pyrrolidinofullerenes is in agreement with the observed results for dimers under MALDI conditions.[31] Radical anions from compounds 1–2 are indicated within the text as a while even-electron protonated molecules are denoted as b. When bis-adduct 1 is ionized under negative
Scheme 2. Heterocyclic [60]fullerene bis-adducts 1 and 2 investigated.
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Selective retro-cycloaddition in [60]fullerene derivatives ESI conditions, a radical anion 1a (M•–) at m/z 1012 is observed. The isolation of this ion and subsequent induced fragmentation produced a MS2 spectrum (Fig. 1) with a main fragment 3 at m/z 835 and another product ion 4 at m/z 897 albeit of lower intensity. The fullerene radical ion was also observed at m/z 720 but with a low abundance. These results can be explained assuming that two retro-cycloaddition processes take place competitively producing the loss of both heterocyclic moieties as the corresponding 1,3- and 1,2-dipole neutral fragments (5 and 6, Scheme 3). Thus, the elimination of the azomethine ylide 5 (C10H11NO2, 177 u) corresponding to the pyrrolidine ring affords ion 3. On the other hand, the loss of the N-oxide of carbocyanidic acid ethyl ester 6 (C4H5NO3, 115 u) leads to the formation of 4. The ratio of the intensities of the peaks corresponding to 3 and 4 (83:17) clearly indicates that the retro-cycloaddition reaction is favored in the pyrrolidine ring compared with the isoxazoline ring. The MS3 spectra of fragments 3 and 4 show that both ions undergo a second cycloelimination process with exclusive formation of the corresponding fullerene radical ion product at m/z 720. These results, together with the low abundance of the fullerene radical ion at m/z 720 in the MS2 spectrum, indicate that the double retrocycloaddition from 1a does not take place directly from the molecular ion or is eventually produced in a very small extension. It is well established that heterocyclic fullerene derivatives also undergo retro-cycloaddition reactions under thermal conditions.[19,20] Thus, when a fullerene bis-adduct bearing isoxazoline and pyrrolidine rings was heated at 150 °C for 24 h in the presence of maleic anhydride, only a fulleropyrrolidine was obtained, indicating the selective
elimination of the isoxazoline moiety.[19] The double retrocycloaddition reaction which produces pristine fullerene takes place only when the temperature (180 °C) and heating time are increased. The selective chemical removal of the heterocyclic moieties was explained assuming the highest thermal stability of pyrrolidinofullerenes. Surprisingly, the reported selectivity in the thermal retro-cycloaddition reaction is reversed under negative ESI conditions (Table 1). The observed selectivity in the gas phase seems to be controlled by the relative stabilities of the eliminated dipoles (5 and 6) as well as by the stabilities of the formed radical anions 3 and 4. The electronic effects of the phenyl group and the methoxycarbonyl group stabilizing the positive and negative charges, respectively, increase the stability of 5 when compared to 6. On the other hand, the more electron-deficient isoxazoline ring produces a more stable radical anion 3 than 4. These two effects produce a remarkable selectivity favoring the cycloelimination reaction of the pyrrolidine ring. We report here, for the first time, how the retrocycloaddition reaction behaves differently under spectrometric and thermal conditions. We can conclude that the different selectivity observed in the retro-cycloaddition reactions for pyrrolidine and isoxazoline rings under thermal and spectrometric conditions reveals that each process follows a different mechanism pathway controlled by different factors. Different results were obtained from the study of the MSn spectra of compound 1 under positive ESI conditions (Fig. 2). The corresponding protonated molecule [M+H]+ (1b) was observed at m/z 1013 and the mass spectrum obtained by CID reveals a main fragment 7 at m/z 926
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Figure 1. MS2 spectrum of radical ion 1a under negative conditions.
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Scheme 3. Retro-cycloaddition reactions for heterocyclic fullerene bisadduct radical ion 1a under negative mass spectrometric conditions.
Table 1. Observed selectivities in the removal of the heterocyclic rings for bis-adducts 1 and 2
Compound
Conditions
1
ESI negative
1
ESI positive
1 2 2
Thermal (150 °C) ESI negative Thermal (150 °C)
Selectivity in the retro-cycloaddition reaction (% of eliminated ring) Pyrrolidine (83), Isoxazoline (17) Isoxazoline (25), pyrrolidine remains unchanged Isoxazoline (100) Isoxazoline (100) Isoxazoline (100)
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(75%). The formation of this ion can be explained by assuming a loss of a methyliminoacetate molecule (C3H5NO2, 87 u) (Scheme 4), similarly to the eliminations reported to explain the fragmentations of protonated fulleropyrrolidines.[25] The elimination of the pyrrolidine ring does not take place and the loss of the imino derivative molecule produces the formation of 7, while the isoxazoline ring remains attached to the C60 core. The differences observed between negative and positive conditions show that the protonation could play a controlling role in this process. It is known that pyrrolidine is several orders of magnitude a stronger base than isoxazoline.[27–30] Although the fullerene moiety reduces dramatically the basicity of the nitrogen atom of the pyrrolidinofullerenes,[26] the decreasing basicity can be assumed similar for both rings. The protonation of the bisadduct 1 takes place at the nitrogen atom of the pyrrolidine ring which is the more basic centre of the molecule.
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A peak of low intensity at m/z 898 (25%) (8) produced by elimination of the N-oxide of carbocyanidic acid ethyl ester is observed. This fragmentation produces the retrocycloaddition reaction of the isoxazoline ring. The direct retro-cycloaddition process from 1b only takes place at the isoxazoline ring because the protonation at the nitrogen atom of the pyrrolidine ring inhibits the process in this protonated ring. The total absence of a peak at m/z 836 (10) (Scheme 4), theoretically formed by cycloelimination reaction of the pyrrolidine ring, confirms that the retro-cycloaddition reaction does not take place at this ring. In consequence, the competitive retro-cycloaddition reaction is favored for the isoxazolinofullerenes compared to the same process for pyrrolidinofullerenes (Table 1). The facility of protonation of the pyrrolidine ring prevents the elimination of the corresponding azomethine ylide and only retro-cycloaddition is observed for isoxazolinofullerenes. The observed selectivity for the retro-cycloaddition reaction pyrrolidino- versus isoxazolinofullerenes changes from 83:17 under negative conditions to a total inhibition of the process for pyrrolidinofullerene derivatives under positive conditions (Table 1). The protonated isoxazoline ring of 7 does not undergo a further retro-cycloaddition process indicating that these ions are unable to evolve through a cycloelimination fragmentation (Fig. 3). We can conclude that the retro-cycloaddition reaction and the selectivity for the different heterocyclic ring eliminations under negative conditions seem to be controlled by the relative stability of the eliminated dipole molecules as well as the relative stability of the produced radical anion fragments taking place either from molecular or fragment ions. In contrast, the protonation that occurs under positive conditions inhibits the process in the protonated ring allowing the process in the unprotonated ring.
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Selective retro-cycloaddition in [60]fullerene derivatives
Figure 2. MS2 spectrum of protonated molecule 1b.
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Scheme 4. Proposed general fragmentation pathways for the protonated molecule 1b generated under positive ESI conditions.
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Figure 3. MS3 spectrum of fragment ion 7.
We have extended our investigation on the competitive retro-cycloaddition reactions under mass spectrometric conditions to bis-adduct 2 bearing both a methanofullerene moiety and an isoxazoline ring. The negative MS2 mass spectrum of radical ion 2a only shows a fragment 11 at m/z 878 generated as a consequence of a retro-cycloaddition process in the isoxazoline ring with elimination of the corresponding N-oxide of benzonitrile (Scheme 5 and Fig. 4). Although methanofullerene dicarboxylate esters have been reported to undergo unimolecular fragmentations with elimination of the alkoxy moieties and formation of a methanofullerene acid anhydride product ion under MALDI conditions, we have not observed a similar process for 2a.[32,33] Product ions bearing a methanofullerene moiety have been postulated as intermediates in the fragmentation pathway of fulleropyrrolidines with different arylpiperazine
groups.[34] These ions do not undergo further fragmentations similarly to the observed behavior of fragment 11. The same selectivity for the elimination occurs when bis-adduct 2 is heated in the presence of a quenching dipolarophile observing retro-cycloaddition in the isoxazoline ring while the methanofullerene remains unchanged.[19] In this case, the competitive retro-cycloaddition reactions of isoxazolino- and methanofullerenes show the same selectivity under thermal and mass spectrometric conditions. Unfortunately, it was not possible to record the mass spectrum of compound 2 under positive ESI conditions. Although removal of the methanofullerene moiety has not been possible under thermal or mass spectrometric conditions, these Bingel adducts undergo retro-cycloaddition reaction under reductive electrochemistry conditions.[35]
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Scheme 5. Proposed fragmentation pathway for radical ion 2a under negative ESI conditions.
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Selective retro-cycloaddition in [60]fullerene derivatives
Figure 4. MS2 spectrum of radical ion 2a under negative conditions.
CONCLUSIONS We have investigated the mass spectrometric behavior of bisadduct heterocycle-containing [60]fullerenes in order to determine the factors that control their retro-cycloaddition reactions. The experimental results indicate that the retrocycloaddition process is favored in pyrrolidinofullerenes when compared to isoxazolinofullerenes under negative ESI conditions. In contrast, under positive ESI conditions, protonation takes place at the nitrogen atom of the pyrrolidine ring, thus inhibiting the retro-cycloaddition reaction in this ring and, hence, allowing the retro-cycloaddition in the isoxazoline ring. On the other hand, the competitive retro-cycloaddition reaction between isoxazolino- and methanofullerene derivatives shows that this process takes place exclusively in isoxazolinofullerenes while the methanofullerene moiety remains unchanged. Table 1 shows a summary of the observed selectivities in the removal of the heterocyclic moieties.
Acknowledgements We thank the Servicio de Espectrometría de Masas of the UCM (Madrid, Spain) for recording the mass spectra. The authors acknowledge financial support for this work by the Ministerio de Economía y Competitividad (MINECO) of Spain (Project CTQ2011-24652), Marie Curie "Molesco" (FP7-PEOPLE-2012ITN) and the CAM PHOTOCARBON project S2013/MIT-2841.
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Copyright © 2015 John Wiley & Sons, Ltd.
Rapid Commun. Mass Spectrom. 2015, 29, 497–504
Revised: 16 December 2014
Accepted: 20 December 2014
Published online in Wiley Online Library
Rapid Commun. Mass Spectrom. 2015, 29, 497–504 (wileyonlinelibrary.com) DOI: 10.1002/rcm.7131
Competitive retro-cycloaddition reactions in heterocyclic fullerene bis-adducts ions: selective removal of the heterocyclic moieties Margarita Suárez1, Enrique E. Maroto2, Salvatore Filippone2, Nazario Martín2,3 and Roberto Martínez-Álvarez2* 1
Laboratorio de Síntesis Orgánica, Facultad de Química, Universidad de La Habana, 10400, Ciudad Habana, Cuba Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Complutense, E-28040, Madrid, Spain 3 IMDEA-Nanociencia, Campus de Cantoblanco, E-28049, Madrid, Spain 2
RATIONALE: We have investigated the fragmentation reactions of ions from bis-adducts containing isoxazolino-,
pyrrolidino- and methanofullerene moieties. METHODS: The fragmentation reactions induced by collision-induced dissociation (CID) of ions generated under
electrospray ionization (ESI) in positive and negative modes of detection using an ion-trap spectrometer have been investigated. RESULTS: The competitive retro-cycloaddition process between isoxazoline and pyrrolidine rings fused to [60]fullerene reveals that it is strongly dependent on the experimental negative or positive ESI experimental conditions. Thus, whereas retro-cycloaddition reaction is favored in the pyrrolidine ring under negative conditions, the protonation occurring on the nitrogen atom of the pyrrolidine ring under positive conditions precludes its retro-cycloaddition and, therefore, only the isoxazoline ring undergoes the retro-cycloaddition process. The obtained experimental results are different from those reported when the reaction is carried out under thermal conditions. Competitive retro-cycloaddition reactions of isoxazolino- and methanofullerenes show that the heterocyclic ring undergoes cycloelimination, leaving the methanofullerene moiety unchanged. In this case, the same selectivity is observed under thermal and gas-phase conditions. CONCLUSIONS: The observed selectivity in the heterocyclic removal in these [60]fullerene derivatives is reversed from negative conditions (radical anions) to positive conditions (protonated molecules). Moreover, the retro-cycloaddition reaction behaves differently under spectrometric and thermal conditions. Copyright © 2015 John Wiley & Sons, Ltd.
Since the discovery of fullerenes, mass spectrometry (MS) has been a useful technique to determine the gas-phase chemistry of these compounds and also to characterize the huge number of chemically modified fullerenes that have been prepared so far.[1,2] Furthermore, fullerenes and other carbon nanoforms have been used as matrices in MS studies.[3,4] Although matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) are the most frequently used ionization methods for the analysis of fullerenes, new techniques such as atmospheric pressure photoionization (APPI) have also been successfully employed for the characterization of these carbon allotropes and their derivatives.[5] The electrochemical nature of the ESI process was used for the direct analysis of fullerene solutions providing evidence of the process occurring at the ES capillary tip.[6] On the other hand, the ion sources of electron impact (EI) and laser desorption/ionization (LDI) spectrometers have been used to study the reaction of C60 with aromatic compounds.[7] Some gas-phase reactions between fullerenes,
* Correspondence to: R. Martínez-Álvarez, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Complutense, E-28040 Madrid, Spain. E-mail: [email protected]
acting as starting materials, and diamines,[8] ketones,[9] or organomercurials,[10] have been investigated using MS techniques. Cycloaddition [3+2] and [4+2] reactions using a continuous-flow approach to prepare fullerene derivatives have been tested using MS.[11] 1,3-Dipolar cycloadditions of different dipoles to C60 are among the most useful reactions for the preparation of modified fullerenes,[12,13] for applications in fields such as medicinal chemistry[14] and materials science.[15–17] Stereocontrolled syntheses have been developed for the preparation of chiral fulleropyrrolidines by [3+2] cycloadditions.[18] The thermal reaction of isoxazolino[60]- and -[70]fullerenes,[19] pyrrolidino [60]- and -[70]fullerenes[20] and pyrazolino[60]fullerenes[21] results in pristine fullerene proving that the cycloaddition and retro-cycloaddition reactions can be used as a protectiondeprotection protocol. The thermal treatment of fullerene derivatives was carried out by heating at 150 °C in o-dichlorobenzene and in the presence of a dipolarophile in order to quench the corresponding 1,3-dipole formed during the reaction. Sometimes a catalytic process induced by copper triflate is required.[17–19] The retro-cycloaddition process can be also promoted under electrochemical conditions. Thus, controlled potential electrolysis (CPE) for the removal of pyrrolidine moieties from pyrrolidinofullerene derivatives has been reported.[22]
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M. Suárez et al. The retro-cycloaddition reaction of heterocyclic fullerene C60 and C70 derivatives is also easily promoted under MS conditions. Thus, when the radical anions (M•–) generated under ESI conditions from heterocyclic fullerene derivatives undergo collision-induced dissociation (CID), the corresponding [60]- and -[70]fullerene radical ions at m/z 720 and 840, respectively, were detected as main ion products (Scheme 1).[19,23] The exceptional stability of these ionic fullerene species stabilizing the unshared electron facilitates the reaction. The formation of fullerene ions was accounted for by the elimination of the corresponding 1,3- and 1,2-dipole fragments through a retro-cycloaddition reaction. The in situ generation of these ylides has been demonstrated by trapping this reactive intermediate under MS conditions with a fullerene monoadduct which acts as dipolarophile, leading to the formation of fullerene bis-adducts.[24] Under positive ESI conditions, pyrrolidinofullerenes provide protonated molecules [M+H]+.[25] It is well known that pyrrolidine is a weak base and theoretical calculations and experimental data reveal that the fullerene moiety reduces dramatically the basicity of the nitrogen atom of the pyrrolidine ring.[26] Values of proton affinity also indicate a reduced gas-phase basicity for this heterocyclic amine.[27,28] Despite these data, the reduced basicity seems to be enough to permit the protonation of the nitrogen atom resulting in the formation of the corresponding [M+H]+ ion. We have previously reported that the protonated molecules [M+H]+ of pyrrolidinofullerenes do not undergo the retro-cycloaddition reaction under CID conditions.[25] In this case, the protonation seems to avoid the loss of the corresponding azomethine ylide molecule. Instead, different fragmentations take place at the pyrrolidine ring depending on the nature of the substituents attached to the heterocyclic moiety. [25] Similarly, the protonation of isoxazolinofullerenes takes place at the nitrogen atom.[19,27–30] The protonated molecules from isoxazolinofullerenes do not undergo the corresponding cycloelimination and only a loss of a nitrile molecule is observed.[19] In this work we have investigated the MS behavior under ESI conditions of a series of bis-adducts containing isoxazolino, pyrrolidino and methanofullerene moieties in order to evaluate the structural requirements which control the competitive fragmentations of these compounds.
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Scheme 1. Negative ESI-CID-MS2 for heterocyclic fullerene monoadduct radical ions.
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EXPERIMENTAL Fullerene bis-adducts 1 and 2 (Scheme 2) were prepared according to previously reported methods.[19] ESI mass spectra were recorded in positive and negative mode of detection using an Esquire-LC ion-trap spectrometer (Bruker Daltonics, Bremen, Germany). The direct injection of samples was achieved using a syringe pump (Cole Palmer, Vernon Hills, IL, USA) through a short length of PEEK tubing of 254 μm i.d. (Upchurch Scientific, Oak Harbor, WA, USA) at a flow rate of 2 μL min–1. To prepare the samples, fullerene derivatives were dissolved in dichloromethane/ toluene/methanol (1:1:0.1, v/v/v). In the positive and negative modes of detection, the conditions were: capillary voltage 3 kV, nebulizing gas pressure 10 psi, drying gas flow 4 L min–1, drying gas temperature 350 °C. MSn spectra were obtained using collision-induced dissociation (CID) with helium after isolation of the appropriate precursor ions using the following fragmentation options: amplitude 0.60 V, time 40 ms, delay 0 μs and mass width of 5.00 m/z.
RESULTS AND DISCUSSION For a better understanding of the reactions involving a retro-cycloaddition process and in order to compare the reactivity of the ions generated from different heterocyclic fullerene derivatives, we have investigated the mass spectra of bis-adducts 1 and 2 under ESI conditions. Thus, the competitive retro-cycloadditions in bis-adducts could shed light on the factors that seem to control this process. Only one example concerning the competitive retro-cycloaddition reaction of [60]- and [70]fullerene homodimers and ([60]/ [70])heterodimers linked by a pyrazolinopyrrolidine bridge is reported in the literature. The thermal reaction of these compounds indicates that the retro-cycloaddition of pyrrolidinofullerenes is favored compared to the same process for pyrazolinofullerenes.[31] The occurrence of this process has also been observed in the corresponding MALDI mass spectra[31] and these findings are in agreement with those predicted by theoretical calculations.[31] Moreover, the observed relative highest thermal stability of pyrazolinofullerenes compared with pyrrolidinofullerenes is in agreement with the observed results for dimers under MALDI conditions.[31] Radical anions from compounds 1–2 are indicated within the text as a while even-electron protonated molecules are denoted as b. When bis-adduct 1 is ionized under negative
Scheme 2. Heterocyclic [60]fullerene bis-adducts 1 and 2 investigated.
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Selective retro-cycloaddition in [60]fullerene derivatives ESI conditions, a radical anion 1a (M•–) at m/z 1012 is observed. The isolation of this ion and subsequent induced fragmentation produced a MS2 spectrum (Fig. 1) with a main fragment 3 at m/z 835 and another product ion 4 at m/z 897 albeit of lower intensity. The fullerene radical ion was also observed at m/z 720 but with a low abundance. These results can be explained assuming that two retro-cycloaddition processes take place competitively producing the loss of both heterocyclic moieties as the corresponding 1,3- and 1,2-dipole neutral fragments (5 and 6, Scheme 3). Thus, the elimination of the azomethine ylide 5 (C10H11NO2, 177 u) corresponding to the pyrrolidine ring affords ion 3. On the other hand, the loss of the N-oxide of carbocyanidic acid ethyl ester 6 (C4H5NO3, 115 u) leads to the formation of 4. The ratio of the intensities of the peaks corresponding to 3 and 4 (83:17) clearly indicates that the retro-cycloaddition reaction is favored in the pyrrolidine ring compared with the isoxazoline ring. The MS3 spectra of fragments 3 and 4 show that both ions undergo a second cycloelimination process with exclusive formation of the corresponding fullerene radical ion product at m/z 720. These results, together with the low abundance of the fullerene radical ion at m/z 720 in the MS2 spectrum, indicate that the double retrocycloaddition from 1a does not take place directly from the molecular ion or is eventually produced in a very small extension. It is well established that heterocyclic fullerene derivatives also undergo retro-cycloaddition reactions under thermal conditions.[19,20] Thus, when a fullerene bis-adduct bearing isoxazoline and pyrrolidine rings was heated at 150 °C for 24 h in the presence of maleic anhydride, only a fulleropyrrolidine was obtained, indicating the selective
elimination of the isoxazoline moiety.[19] The double retrocycloaddition reaction which produces pristine fullerene takes place only when the temperature (180 °C) and heating time are increased. The selective chemical removal of the heterocyclic moieties was explained assuming the highest thermal stability of pyrrolidinofullerenes. Surprisingly, the reported selectivity in the thermal retro-cycloaddition reaction is reversed under negative ESI conditions (Table 1). The observed selectivity in the gas phase seems to be controlled by the relative stabilities of the eliminated dipoles (5 and 6) as well as by the stabilities of the formed radical anions 3 and 4. The electronic effects of the phenyl group and the methoxycarbonyl group stabilizing the positive and negative charges, respectively, increase the stability of 5 when compared to 6. On the other hand, the more electron-deficient isoxazoline ring produces a more stable radical anion 3 than 4. These two effects produce a remarkable selectivity favoring the cycloelimination reaction of the pyrrolidine ring. We report here, for the first time, how the retrocycloaddition reaction behaves differently under spectrometric and thermal conditions. We can conclude that the different selectivity observed in the retro-cycloaddition reactions for pyrrolidine and isoxazoline rings under thermal and spectrometric conditions reveals that each process follows a different mechanism pathway controlled by different factors. Different results were obtained from the study of the MSn spectra of compound 1 under positive ESI conditions (Fig. 2). The corresponding protonated molecule [M+H]+ (1b) was observed at m/z 1013 and the mass spectrum obtained by CID reveals a main fragment 7 at m/z 926
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Figure 1. MS2 spectrum of radical ion 1a under negative conditions.
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Scheme 3. Retro-cycloaddition reactions for heterocyclic fullerene bisadduct radical ion 1a under negative mass spectrometric conditions.
Table 1. Observed selectivities in the removal of the heterocyclic rings for bis-adducts 1 and 2
Compound
Conditions
1
ESI negative
1
ESI positive
1 2 2
Thermal (150 °C) ESI negative Thermal (150 °C)
Selectivity in the retro-cycloaddition reaction (% of eliminated ring) Pyrrolidine (83), Isoxazoline (17) Isoxazoline (25), pyrrolidine remains unchanged Isoxazoline (100) Isoxazoline (100) Isoxazoline (100)
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(75%). The formation of this ion can be explained by assuming a loss of a methyliminoacetate molecule (C3H5NO2, 87 u) (Scheme 4), similarly to the eliminations reported to explain the fragmentations of protonated fulleropyrrolidines.[25] The elimination of the pyrrolidine ring does not take place and the loss of the imino derivative molecule produces the formation of 7, while the isoxazoline ring remains attached to the C60 core. The differences observed between negative and positive conditions show that the protonation could play a controlling role in this process. It is known that pyrrolidine is several orders of magnitude a stronger base than isoxazoline.[27–30] Although the fullerene moiety reduces dramatically the basicity of the nitrogen atom of the pyrrolidinofullerenes,[26] the decreasing basicity can be assumed similar for both rings. The protonation of the bisadduct 1 takes place at the nitrogen atom of the pyrrolidine ring which is the more basic centre of the molecule.
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A peak of low intensity at m/z 898 (25%) (8) produced by elimination of the N-oxide of carbocyanidic acid ethyl ester is observed. This fragmentation produces the retrocycloaddition reaction of the isoxazoline ring. The direct retro-cycloaddition process from 1b only takes place at the isoxazoline ring because the protonation at the nitrogen atom of the pyrrolidine ring inhibits the process in this protonated ring. The total absence of a peak at m/z 836 (10) (Scheme 4), theoretically formed by cycloelimination reaction of the pyrrolidine ring, confirms that the retro-cycloaddition reaction does not take place at this ring. In consequence, the competitive retro-cycloaddition reaction is favored for the isoxazolinofullerenes compared to the same process for pyrrolidinofullerenes (Table 1). The facility of protonation of the pyrrolidine ring prevents the elimination of the corresponding azomethine ylide and only retro-cycloaddition is observed for isoxazolinofullerenes. The observed selectivity for the retro-cycloaddition reaction pyrrolidino- versus isoxazolinofullerenes changes from 83:17 under negative conditions to a total inhibition of the process for pyrrolidinofullerene derivatives under positive conditions (Table 1). The protonated isoxazoline ring of 7 does not undergo a further retro-cycloaddition process indicating that these ions are unable to evolve through a cycloelimination fragmentation (Fig. 3). We can conclude that the retro-cycloaddition reaction and the selectivity for the different heterocyclic ring eliminations under negative conditions seem to be controlled by the relative stability of the eliminated dipole molecules as well as the relative stability of the produced radical anion fragments taking place either from molecular or fragment ions. In contrast, the protonation that occurs under positive conditions inhibits the process in the protonated ring allowing the process in the unprotonated ring.
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Selective retro-cycloaddition in [60]fullerene derivatives
Figure 2. MS2 spectrum of protonated molecule 1b.
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Scheme 4. Proposed general fragmentation pathways for the protonated molecule 1b generated under positive ESI conditions.
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Figure 3. MS3 spectrum of fragment ion 7.
We have extended our investigation on the competitive retro-cycloaddition reactions under mass spectrometric conditions to bis-adduct 2 bearing both a methanofullerene moiety and an isoxazoline ring. The negative MS2 mass spectrum of radical ion 2a only shows a fragment 11 at m/z 878 generated as a consequence of a retro-cycloaddition process in the isoxazoline ring with elimination of the corresponding N-oxide of benzonitrile (Scheme 5 and Fig. 4). Although methanofullerene dicarboxylate esters have been reported to undergo unimolecular fragmentations with elimination of the alkoxy moieties and formation of a methanofullerene acid anhydride product ion under MALDI conditions, we have not observed a similar process for 2a.[32,33] Product ions bearing a methanofullerene moiety have been postulated as intermediates in the fragmentation pathway of fulleropyrrolidines with different arylpiperazine
groups.[34] These ions do not undergo further fragmentations similarly to the observed behavior of fragment 11. The same selectivity for the elimination occurs when bis-adduct 2 is heated in the presence of a quenching dipolarophile observing retro-cycloaddition in the isoxazoline ring while the methanofullerene remains unchanged.[19] In this case, the competitive retro-cycloaddition reactions of isoxazolino- and methanofullerenes show the same selectivity under thermal and mass spectrometric conditions. Unfortunately, it was not possible to record the mass spectrum of compound 2 under positive ESI conditions. Although removal of the methanofullerene moiety has not been possible under thermal or mass spectrometric conditions, these Bingel adducts undergo retro-cycloaddition reaction under reductive electrochemistry conditions.[35]
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Scheme 5. Proposed fragmentation pathway for radical ion 2a under negative ESI conditions.
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Selective retro-cycloaddition in [60]fullerene derivatives
Figure 4. MS2 spectrum of radical ion 2a under negative conditions.
CONCLUSIONS We have investigated the mass spectrometric behavior of bisadduct heterocycle-containing [60]fullerenes in order to determine the factors that control their retro-cycloaddition reactions. The experimental results indicate that the retrocycloaddition process is favored in pyrrolidinofullerenes when compared to isoxazolinofullerenes under negative ESI conditions. In contrast, under positive ESI conditions, protonation takes place at the nitrogen atom of the pyrrolidine ring, thus inhibiting the retro-cycloaddition reaction in this ring and, hence, allowing the retro-cycloaddition in the isoxazoline ring. On the other hand, the competitive retro-cycloaddition reaction between isoxazolino- and methanofullerene derivatives shows that this process takes place exclusively in isoxazolinofullerenes while the methanofullerene moiety remains unchanged. Table 1 shows a summary of the observed selectivities in the removal of the heterocyclic moieties.
Acknowledgements We thank the Servicio de Espectrometría de Masas of the UCM (Madrid, Spain) for recording the mass spectra. The authors acknowledge financial support for this work by the Ministerio de Economía y Competitividad (MINECO) of Spain (Project CTQ2011-24652), Marie Curie "Molesco" (FP7-PEOPLE-2012ITN) and the CAM PHOTOCARBON project S2013/MIT-2841.
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