Retro-cycloaddition reaction of pyrrolidinofullerenes

Article abstract of DOI:10.1002/anie.200502556

(Chemical Equation Presented) All things retro: Pyrrolidinofullerenes undergo a retro-cycloaddition reaction to afford the corresponding fullerene (C₆₀, C₇₀, or an endohedral C₈₀ metallofullerene; see scheme) in quantitative yield upon treatment with an excess of a dipolarophile (maleic anhydride or N-phenyl-maleimide) in o-dichlorobenzene. The reaction works efficiently with higher fullerenes and has allowed the isolation of one of the constitutional isomers of Sc ₃N@C₈₀.

Full text of DOI:10.1002/anie.200502556

Communications
Fullerene Chemistry
DOI: 10.1002/anie.200502556
Retro-Cycloaddition Reaction of
Pyrrolidinofullerenes**
Nazario Martín,* Margarita Altable,
Salvatore Filippone, Angel Martín-Domenech,
Luis Echegoyen,* andClaudia M. Cardona
Dedicated to Professor David Schuster
on the occasion of his 70th birthday
The 1,3-dipolar cycloaddition reaction of azomethine ylides to
alkenes is one of the most important and elegant methods for
the construction of nitrogen-containing five-membered ring
compounds. This reaction has been successfully conducted
with fullerenes and it is considered one of the most
straightforward procedures for their functionalization.[1] The
resulting C60-fused pyrrolidines (pyrrolidino[3,4:1,2][60]full-
erenes or simply pyrrolidinofullerenes) are easily prepared by
reaction of the in situ generated azomethine ylides to
[60]fullerene. Although azomethine ylides are reactive inter-
mediates which can be generated in several ways by following
efficient synthetic protocols, the decarboxylation of immi-
nium salts, derived from condensation of a-amino acids with
aldehydes or ketones, is the easiest and most general
procedure commonly followed.[2] Other convenient methods
for the synthesis of pyrrolidinofullerenes are based on the
thermal ring opening of aziridines, acid-catalyzed or thermal
desililation of trimethylsilylamino derivatives, or photochem-
ical treatment of tertiary amines with C60.[3] The isolation and
characterization of all eight possible regioisomers of bis-
adducts of pyrrolidinofullerene derivatives have also been
reported.[4]
Pyrrolidinofullerene cycloadducts have proven to be
chemically stable species and, therefore, they typically do
[*] Prof. Dr. N. Martín, M. Altable, Dr. S. Filippone,
Dr. A. Martín-Domenech
Departamento de Química Orgµnica I
Facultad de Ciencias Químicas
Universidad Complutense de Madrid
Ciudad Universitaria s/n, 28040 Madrid (Spain)
Fax: (+34)91-394-4103
E-mail: nazmar@quim.ucm.es
Prof. Dr. L. Echegoyen, Dr. C. M. Cardona
Department of Chemistry
Clemson University
219 Hunter Laboratories, Clemson, SC 29634-0973 (USA)
Fax: (+1)864-656-6613
E-mail: luis@clemson.edu
[**] These investigations were financially supported by the MEC of Spain
(Project BQU2002-00855). S.F. thanks the CAM for a postdoctoral
contract, and M.A. thanks the MEC for a research grant. L.E. and
C.C. thank the US NSF(CHE-0509989) for generous financial
support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
110
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not undergo further chemical transformations. In contrast to
other well-known fullerene derivatives, such as Diels–Alder
cycloadducts[5] or Bingelꢀs methanofullerenes,[6] which can
undergo their corresponding retro-cycloaddition reactions,
pyrrolidinofullerenes are considered to be very stable cyclo-
adducts. Herein, we describe the first highly efficient retro-
cycloaddition reactions of differently substituted pyrrolidino-
fullerenes which quantitatively afford the parent unsubsti-
tuted fullerene.
indicate that the retro-cycloaddition reaction is strongly
dependent on the nature of the substituents on the pyrrolidine
ring which influence the stability of the thermally generated
1,3-dipole.
To improve the efficiency of the removal of the pyrroli-
dine ring from the carbon sphere to yield pristine C60, we
carried out the thermal reaction in the presence of a metal
Lewis acid to see if a possible coordination with the nitrogen
atom could activate the retro-reaction. When compounds 1a–
d were heated at reflux in o-DCB for a variable time (8–18 h)
in the presence of maleic anhydride (30 equiv) and copper(ii)
triflate (1 equiv), the reaction led in all cases (entries 7–10,
Table 1) to the quantitative formation of the parent unsub-
stituted C60 (determined by HPLC), solutions of which were
the typical magenta color. Interestingly, the reaction also
proved to be highly efficient with the mono-adduct mixture of
the three isomers of [70]pyrrolidinofullerene (2),[10] which
afforded under these conditions pristine C70 in 95% yield (by
HPLC; see entry 11 in Table 1 and Scheme 2).
It was previously reported that pyrrolidines undergo a
retro-cycloaddition reaction which leads to the alkene and the
azomethine ylide.[7] Although it is well-known that pyrrolidi-
nofullerenes exhibit a much lower basic and nucleophilic
character than pyrrolidines owing to the electronegative
character of the fullerene core,[8] we decided to investigate the
retro-cycloaddition reaction of pyrrolidinofullerenes under
thermal and catalytic conditions.
Following previously reported standard procedures,[9]
pyrrolidinofullerenes 1a–e were initially synthesized
(Scheme 1). Compound 1a (R1 = R2 = H) was heated at
reflux in o-dicholorobenzene (o-DCB) for 24 h in the
Scheme 2. Retro-cycloaddition reaction of C70 derivative 2 catalyzed by
a metal Lewis acid. Tf=CF3SO2.
The 1,3-dipolar retro-cycloaddition reaction appears to be
quite general in terms of substitution on the pyrrolidine ring
(unsubstituted 1a, monosubstituted 1b,c,e, and disubstituted
1d) as well as with higher fullerenes, such as C70 and C80.
Scheme 1. Retro-cycloaddition reaction of pyrrolidinofullerenes 1a–e.
presence of an excess of a highly efficient
Table 1: Experimental conditions of the retro-cycloaddition reaction.[a]
dipolarophile, such as maleic anhydride, in
order to trap the corresponding ylide that
results from the thermal retro-cycloaddition
reaction. However, under these conditions
the reaction proceeded with a very low yield
(Table 1, entry 1: 4.9% of recovered C60 as
determined by HPLC). When compounds
1b–d were treated under similar reaction
conditions, significantly better yields were
obtained (entries 2–4). Surprisingly, when
compound 1e was heated at reflux in o-
DCB for 12 h under the same experimental
conditions (entry 6), C60 was recovered
quantitatively. In fact, the initial brown
solution of the pyrrolidinofullerene 1e
recovered the magenta color typical of
solutions of [60]fullerene. Furthermore, 1e
led to pristine C60 in 96.5% yield (deter-
mined by HPLC) after only 4 h at reflux in o-
DCB (entry 5, Table 1). These results clearly
Entry
Compound
Dipolarophile[b]
Catalyst
t [h]
Conv. [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
1d
1e
1e
1a
1b
1c
1d
2
1e
1e
1e
1e
3
maleic anhydride
maleic anhydride
maleic anhydride
maleic anhydride
maleic anhydride
maleic anhydride
maleic anhydride
maleic anhydride
maleic anhydride
maleic anhydride
maleic anhydride
N-phenylmaleimide
maleic anhydride
1,4-benzoquinone
diethyl maleate
–
–
–
–
–
–
24
24
12
24
4
12
8
8
4.9
43.5
35.0
15.3
96.5
100.0
100.0
99.3
100.0
100.0
95.0
100.0
97.2
79.9
[d]
CuTf2
CuTf2
CuTf2
CuTf2
[d]
[d]
18
8
[d]
[d]
CuTf2
18
18
18
18
18
18
(Ph3P)3RhCl[e]
(Ph3P)3RhCl[e]
(Ph3P)3RhCl[e]
(Ph3P)3RhCl[e]
–
60.9
100.0
C60 (4 equiv)
[a] All the reactions were carried out in o-DCB at reflux (4–24 h); [b] 30 equiv dipolarophile used unless
otherwise stated. [c] Conversion determined by HPLC. [d] 1 equiv CuTf2 (copper(ii) trifluoromethylsul-
fonate) used. [e] 0.1 equiv Wilkinson’s catalyst ((Ph3P)3RhCl) used.
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Communications
To explore the use of other metals as well as the influence
ethylpyrrolidinofullerene.[13] 1H, 13C, and 2D NMR experi-
ments of this mono-adduct confirmed that the cycloaddition
occurred selectively at a corannulene-type site (a double bond
at a [5,6] ring junction abutted by two hexagons) of the
icosahedral (Ih) C80 cage, in the same position as that
described previously for a Diels–Alder mono-adduct of the
same compound.[14] In our synthesis, the 1,3-dipolar cyclo-
addition reaction was very selective, and only one regioisomer
product of the Ih constitutional isomer of Sc3N@C80 was
isolated, even when the reaction was conducted in the
presence of Sc3N@C78 (and presumably D5h Sc3N@C80).[12]
Therefore, the cycloaddition selectively extracts the Ih
constitutional isomer from the product mixture, and the
subsequent retro-cycloaddition constitutes an efficient puri-
fication method for Ih-symmetric Sc3N@C80 by its separation
from other endohedral metallofullerenes and other constitu-
tional isomers.
of the trapping dipolarophile on the reaction outcome, we
carried out the thermal retro-cycloaddition reaction of 1e in
the presence of catalytic amounts of Wilkinsonꢀs catalyst
(0.1 equiv) and using a variety of different efficient dipolar-
ophiles (entries 12–15, Table 1). After heating at reflux in o-
DCB for 18 h, the reaction gave good yields of C60 when N-
phenylmaleimide (100%) or maleic anhydride (97.2%) was
used as dipolarophiles. However, lower yields were observed
when either 1,4-benzoquinone (79.9%) or diethyl maleate
(60.9%) was used as the trapping dipolarophile (entries 14
and 15).
It is well-known that [60]fullerene is a very efficient
dipolarophile, and, therefore, we decided to evaluate its
effectiveness in the present reaction. To test this, a mixture of
bis-cycloadducts 3 was heated at reflux in o-DCB for 18 h in
the presence of an excess (4 equiv) of pristine C60 (Scheme 3).
The 1,3-dipolar retro-cycloaddition reaction was success-
fully carried out with N-ethylpyrrolidino-Sc3N@C80 (with a
13Clabel incorporated in the pyrrolidine ring) by heating at
reflux in o-dichlorobenzene (20–24 h) in the presence of
maleic anhydride (30 equiv) in sealed NMR tubes in the dark
(Scheme 4). The retro-cycloaddition reaction of this endohe-
Scheme 3. Reaction of a mixture of bis-adducts 3 in the presence of
C60 as dipolarophile.
The mono-adduct was recovered quantitatively (100% by
HPLC) together with unreacted C60 (entry 16). This finding
confirms the general scope of this thermal retro-cycloaddition
reaction and opens new avenues for improving the yields of
mono-adduct formation from the usually undesired bis-cyclo-
adducts in many 1,3-dipolar cycloaddition reactions of differ-
ently substituted azomethine ylides.
Scheme 4. 1,3-Dipolar retro-cycloaddition of N-ethylpyrrolidino-Sc3N@
C80.
Depending on the substitution pattern on the pyrrolidi-
nofullerene moiety, we can use different protocols to quanti-
tatively remove the pyrrolidine ring from the carbon sphere to
recover the parent fullerene. This new reaction significantly
enhances the utility of one of the most important and
successful reactions in the chemistry of fullerenes, as it can
now be used as a highly efficient protection/deprotection
protocol. This new strategy will enable the preparation of
unusual addition patterns on different fullerenes. Just as the
cyclopropanation/retro-cyclopropanation protocol has been
successfully used in the purification of higher fullerenes and
their enantiomers,[11] the pyrrolidine/retro-pyrrolidine strat-
egy described here has the potential for similar applications.
We thus decided to apply this thermal retro-cycloaddition
reaction to the separation of pyrrolidine derivatives of
trimetallic nitride endohedral metallofullerenes, whose con-
stitutional isomers are difficult to separate.[12]
dral metallofullerene was followed by TLC, HPLC, and NMR
spectroscopy. The heteronuclear multiple quantum coherence
(HMQC) NMR spectrum of the derivative (Figure 1) clearly
shows that the starting compound is a pure pyrrolidine mono-
adduct derivative of Sc3N@C80. The 13CNMR spectrum
exhibits a single signal at d = 69.56 ppm in [D4]-o-dichloro-
benzene, indicating that both the methylene carbon atoms of
the five-membered ring are equivalent. The complete dis-
appearance of the single 13Csignal after heating this deriva-
tive at 1808Cin the presence of maleic anhydride for 22 h
indicates that retro-cycloaddition occurred in high yield as the
pyrrolidine adduct is no longer present (Figure 1).
The reaction proved to be quantitative upon analysis by
TLC(93% recovered after column chromatography on SiO 2),
and only Sc3N@C80 was isolated and characterized by HPLC
(Figure 2, peak at 6.16 min) and MALDI mass spectrometry.
We believe that the product must be the Ih isomer, as this was
the only isomer of the pyrrolidine derivative present initially.
Recently, some of us reported the synthesis and character-
ization of a mono-adduct derivative of Sc3N@C80, an N-
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Angewandte
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The retro-cycloaddition proceeded in the presence of
maleic anhydride as the dipolarophile in both dark aerobic
and anaerobic conditions. 12C- and 13C-enriched formalde-
hyde was a noticeable by-product of the retro-cycloaddition
reaction under oxygenated conditions when 13C-labeled N-
ethylpyrrolidinofullerene was employed, as shown by the
1H NMR spectra (Figure 3) recorded before and after retro-
Figure 3. 1H NMR spectrum of 13C-enriched Ih-symmetric N-ethylpyr-
rolidino-Sc3N@C80 a) before the reaction and b) after 22 h at 1808C in
the presence of maleic anhydride, showing signals for the azomethine
ylide product after retro-cycloaddition. c) 1H NMR spectrum of a
(control) solution of maleic anhydride and paraformaldehyde (both
12C- and 13C-enriched) in [D4]-o-dichlorobenzene after 22 h at 1808C.
Figure 1. a) HMQC NMR spectrum of 13C-labeled Ih-symmetric N-ethyl-
pyrrolidino-Sc3N@C80 mono-adduct in [D4]-o-dichlorobenzene, and
b,c) 13C NMR spectra recorded before (a) and after (b) heating the
adduct at reflux in the presence of maleic anhydride in o-dichloro-
benzene.
The asterisk ( ) denotes unknown products.
*
cycloaddition. Such a strategy also worked successfully and
quantitatively for the isolation of Ih-symmetric Y3N@C80
[15]
when N-ethylpyrrolidino-[5,6]-Y3N@C80 was subjected to
the retro-cycloaddition conditions described above. We are
currently analyzing the other by-products of the reaction and
investigating the roles of oxygen and light in the reaction in
order to elucidate the mechanism and compare it to the retro-
cycloaddition of fullerene derivatives with empty cages. Our
interest also lies in the isolation of other constitutional
isomers such as D5h-symmetric Sc3N@C80, which has eluded
isolation thus far.
Although the reaction mechanism of the retro-cycloaddi-
tion reaction is not yet clear, the above experiments suggest
that thermal treatment leads to the formation of the
azomethine ylide, which is efficiently trapped by the dipolar-
ophile that is present in the reaction medium. When
pyrrolidinofullerene 1c, which bears a fluorescent pyrene
unit as substituent at C2 of the pyrrolidine ring, was heated at
reflux in o-DCB under standard conditions (maleic anhydride
(30 equiv), 18 h), formation of the corresponding pyrene-
substituted pyrrolidine 4 was not observed. However, alde-
hyde 5 was isolated as the only characterizable compound
instead (Scheme 5) which thus suggests that oxygen could
play a role in the evolution of the 1,3-dipole, although the
influence of the trace amounts of water present in the solvent
cannot be ruled out. More studies are therefore required to
Figure 2. HPLC traces of a) the initial reaction mixture, b) the mixture
after completion of the reaction, and c) maleic anhydride under
identical conditions (Buckyclutcher column: 25 cm”10 mm (Regis
Chemical Company); toluene, flow rate: 4 mLminÀ1; detection at
l=310 nm).
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Communications
Monatsh. Chem. E 2001, 132, 63 – 70; d) Spectral data for 1d:
1H NMR (300 MHz, CDCl3/CS2): d = 1.71 (s, 6H, 2CH3), 2.56 (s,
3H, CH ), 4.23 ppm (s, 2H, CH2); 13C NMR (300 MHz, CDCl3/
3
CS2): d = 22.5, 33.9, 65.4, 68.6, 69.3, 79.1, 136.0, 136.4, 139.6,
140.0, 141.5, 141.7, 141.8, 141.9, 142.0, 142.2, 142.5, 143.0, 144.3,
144.4, 145.0, 145.1, 145.2, 145.5, 145.8, 145.9, 146.0, 146.1, 146.3,
147.2, 154.3, 156.0 ppm; MS (ESI): m/z: 805 [M]+; e) L.-B. Gan,
D.-J. Zhou, C.-P. Luo, H.-S. Tan, C.-H. Huang, M.-J. Lu, J.-Q.
Pan, Y. Wu, J. Org. Chem. 1996, 61, 1954 – 1961.
[10] S. R. Wilson, Q. J. Lu, J. Org. Chem. 1995, 60, 6496 – 6498.
[11] M. ꢁ. Herranz, F. Diederich, L. Echegoyen, Eur. J. Org. Chem.
2004, 2299 – 2316, and references therein.
[12] a) J. C. Duchamp, A. Demortier, K. R. Flrtche, D. Dorn, E. B.
Iezzi, T. Glass, H. C. Dorn, Chem. Phys. Lett. 2003, 375, 655 –
659; b) M. Krause, L. Dunsch, ChemPhysChem 2004, 5, 1445 –
1449.
Scheme 5. Retro-cycloaddition reaction of pyrene-substituted pyrrolidi-
nofullerene 1c.
[13] C. M. Cardona, A. Kitaygorodskiy, A. Ortiz, M. A. Herranz, L.
Echegoyen, J. Org. Chem. 2005, 70, 5092 – 5097.
determine if this is a simple thermal cycloreversion or a more-
complex oxidative process. In this regard, preliminary inves-
tigations using oxidative controlled-potential electrolysis
indicate that retro-cycloaddition is also efficiently obtained
under these conditions. These experiments are ongoing and
may shed additional information about the nature of the
mechanism.
[14] a) E. B. Iezzi, J. C. Duchamp, K. Harich, T. E. Glass, H. M. Lee,
M. M. Olmstead, A. L. Balch, H. C. Dorn, J. Am. Chem. Soc.
2002, 124, 524 – 525; b) H. M. Lee, M. M. Olmstead, E. Iezzi,
J. C. Duchamp, H. C. Dorn, A. L. Balch, J. Am. Chem. Soc. 2002,
124, 3494 – 3495.
[15] a) C. M. Cardona, A. Kitaygorodskiy, L. Echegoyen, J. Am.
Chem. Soc. 2005, 127, 10448 – 10453; b) C. M. Cardona, L.
Echegoyen, unpublished results.
Experimental Section
In a typical experiment, pyrrolidinofullerene (0.02 mmol), dipolar-
ophile (0.06 mmol), and metal catalyst (0.002 mmol) were heated at
reflux in o-DCB (6 mL). The reaction was monitored by HPLC
(Cosmosil Buckyprep column, 4.6 mm (i.d.) ” 250 mm; toluene, flow
rate: 1 mLminÀ1). Retention times: 5.8–6.2 min for the pyrrolidino-
fullerenes; 8.0 min for C60.
Received: July 21, 2005
Published online: October 20, 2005
Keywords: azomethine ylides · cycloaddition · fullerenes ·
.
nitrogen heterocycles · retro reactions
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