Regioselective intramolecular nucleophilic addition of alcohols to C 60: One-step formation of a cis-1 bicyclic-fused fullerene

Article abstract of DOI:10.1021/jo901171r

(Chemical Equation Presented) The first example of intramolecular nucleophilic addition of an alcohol to a fullerene double bond is described. In particular, the straightforward one-step reaction of commercially available sarcosine, hydroxyacetaldehyde, a

Full text of DOI:10.1021/jo901171r

pubs.acs.org/joc
Regioselective Intramolecular Nucleophilic Addition of Alcohols to C60:
One-Step Formation of a cis-1 Bicyclic-Fused Fullerene
Marta Izquierdo,† Silvia Osuna,‡ Salvatore Filippone,† Angel Martın-Domenech,†
´
,‡
Miquel Sola,* and Nazario Martı
´
n*,†
ꢀ
†
´
ꢁ
´
Departamento de Quımica Organica, Facultad de Quımica, Universidad Complutense, E-28040-Madrid,
´
‡
´
Spain, and Institut de Quımica Computacional and Departament de Quımica, Universidad de Girona,
E-17071 Girona, Catalonia, Spain
nazmar@quim.ucm.es
Received June 9, 2009
The first example of intramolecular nucleophilic addition of an alcohol to a fullerene double bond is
described. In particular, the straightforward one-step reaction of commercially available sarcosine,
hydroxyacetaldehyde, and [60]fullerene, in refluxing chlorobenzene, affords a structurally complex
novel pyrrolidinofullerene endowed with a furan ring simultaneously fused to both the pyrrolidine
and fullerene moieties, which has been spectroscopically and electrochemically characterized. The 2-
fold cyclization reaction occurs in a totally regioselective stepwise process leading exclusively to the
cis-1 isomer. Theoretical calculations (DFT and ONIOM approach) predict that, in contrast to the
previous examples with phenols, which require the existence of an intramolecular H-bond and the
presence of a methyl group on C-2 of the pyrrolidine ring to afford the cyclized pyran-fused
pyrrolidinofullerenes, the formation of the oxygen pentagonal ring is highly favored and does not
present such structural constrains. Actually, the 5-exo-trig cyclization reaction involving the
nucleophilic attack of the hydroxyl group to the fullerene surface is moderately exothermic although
it has a substantially high energy barrier in accordance with the fact that high temperatures have to be
reached to obtain the final product.
Introduction
for preparing tailor-made fullerenes are currently being
reported.3
Fullerenes, the first and best known molecular carbon
allotropes,1 are among the most studied systems in chem-
istry during the last two decades and, therefore, their
chemical reactivity is nowadays well established.2 However,
because of the interest of these carbon materials in the
search for practical applications, new reactions involving
different covalent and supramolecular chemical protocols
Fullerene derivatives endowed with oxygen through a direct
C-O bond are among the less explored and elusive com-
pounds. Thus, in contrast to some well-known oxygen-contain-
ing derivatives such as fullerene epoxides, other derivatives like
acetals, hemiketals, or ketals are clearly underdeveloped.4
(3) (a) For a general overview, see: Martı
2093–2104. (b) For a recent review on covalent modification, see: Martı
Altable, M.; Filippone, S.; Martın-Domenech, A. Synlett 2007, 20, 3077–
3095. (c) For some supramolecular ensembles involving fullerenes, see:
´
n, N. Chem. Commun. 2006,
´
n, N.;
(1) For a recent review on the nano-forms of carbon, see: Delgado, J. L.;
Herranz, M. A.; Martın, N. J. Mater. Chem. 2008, 18, 1417–1426.
´
´
ꢁ
Figueira-Duarte, T. M.; Gegout, A.; Nierengarten, J.-F. Chem. Commun.
2007, 109–119. Hahn, U.; Cardinali, F.; Nierengarten, J.-F. New J. Chem.
(2) For some recent books, see: (a) Hirsch, A. The Chemistry of Fullerenes;
Wiley-VCH: Weinheim, Germany, 2005. (b) Guldi, D. M.; Martín, N., Eds.
Fullerenes: From Synthesis to Optoelectronic Properties; Kluwer Academic
Publishers: Dordrecht, The Netherlands, 2002. (c) Taylor, R. Lecture Notes on
Fullerene Chemistry: A Handbook for Chemists; Imperial College Press:
London, UK, 1999. (d) Langa, F.; Nierengarten, J.-F., Eds. Fullerenes; RSC
Publishing: Cambridge, UK, 2007.
ꢁ
2007, 31, 1128–1138. Perez, E. M.; Martı
´
n, N. Chem. Soc. Rev. 2008, 37,
1512–1519. Perez, E. M.; Illescas, B.; Herranz, M. A.; Martın, N. New J.
Chem. 2009, 33, 228–234.
ꢁ
´
(4) Wang, G. W.; Li, F.-B.; Xu, Y. J. Org. Chem. 2007, 72, 4774-4778
and references cited therein.
DOI: 10.1021/jo901171r
r
Published on Web 07/17/2009
J. Org. Chem. 2009, 74, 6253–6259 6253
2009 American Chemical Society

Izquierdo et al.
JOCArticle
ing the geometry of approximation of the O;H group to the
fullerene CdC and for the success of the reaction.8
Interestingly, an hexagonal oxygen containing heterocyc-
lic ring (dihydropyran II) was obtained as a consequence of
the atoms chain length existing between the reactive OH
phenolic group and the fullerene double bond (I), through a
6-exo-trig cyclization process.9
In this paper we report on the straightforward 5-exo-trig
cyclization reaction carried out in a simple one-step synthesis
from commercially available starting materials affording a
new tetrahydrofuran-fused pyrrolidino[3,4:1,2][60]fullerene
(11). Interestingly, the nucleophilic addition of the noniso-
lated intermediate alcohol 10 to the fullerene double bond
forming a new pentagonal ring is highly favored, thus
avoiding the many structural and electronic requirements
(see above) needed to form the oxygen-containing hexagonal
heterocycle from phenols.
The reaction mechanism of the intramolecular nucleophi-
lic addition of the hydroxyl group to the fullerene double
bond has been theoretically investigated at the density func-
tional theory (DFT) level by using the two-layered ONIOM
approach. This study reveals a more favorable formation of
the pentagonal ring when compared to that of the previously
reported 6-membered oxygen-containing dihydropyran
ring.
FIGURE 1. Chemical structures of the open pyrrolidinofullerene
(I) bearing a 2,6-dihydroxyphenyl substituent and the dihydropyr-
an-fused pyrrolidinofullerene (II) formed by intramolecular nucleo-
philic addition of the hydroxyl group to the fullerene double bond.
Fullerene derivatives bearing oxygen-containing hetero-
cycles, such as isoxazolines and oxazolines, have also been
reported in the literature, in which the oxygen atom is
directly linked to the fullerene surface.5 Furthermore,
isoxazolino[4,5:1,2][60] and [70]fullerenes undergo a retro-
cycloaddition affording pristine fullerenes.5j
Polyhydroxylated fullerenes (the so-called fullerenols or
fullerols) are another group of oxygen-containing fullerene
derivatives that only recently have been synthesized in a
controlled way.6 Furthermore, as a singular case, the sim-
plest unsubstituted fullerene-fused dihydrofuran has not
been reported so far.
In a program directed to the synthesis of novel chemically
modified fullerenes from suitably functionalized pyrrol-
idino[3,4:1,2][60]fullerenes,7 we have recently reported the
first observation of an intramolecular nucleophilic addition
of the hydroxyl group of a phenol to a double bond of the C60
sphere assisted by the H-bond formed between the pyrroli-
dine nitrogen and a second hydroxyl group (Figure 1). This
intramolecular H-bond was considered to be an essential
requirement for achieving the favorable geometry and close
proximity of the second OH group to the reactive fullerene
double bond. Furthermore, the presence of a methyl group
on C-2 of the pyrrolidine ring (similarly to the Thorpe-
Ingold effect) was determined to be a key factor for optimiz-
Results and Discussion
Our first goal was directed to the preparation of new
pyrrolidino[3,4:1,2][60]fullerenes suitably functionalized
with a hydroxymethyl group able to further react with the
fullerene double bond. Therefore, the first chemical strategy
was to obtain compound 3 by refluxing in chlorobenzene the
commercially available methyl serinate hydrochloride 1
with formaldehyde 2 in the presence of C60. The design of
fulleropyrrolidine 3 was made considering the presence of
the ester group on C-2 of the pyrrolidine ring in order to
favor the subsequent cyclization process, as previously ob-
served in related systems (Thorpe-Ingold effect). Further-
more, it should be expected that spontaneously compound 3
could cyclize to compound 4 by further in situ intramolecular
nucleophilic addition of the OH group to the fullerene
double bond. However, the only compound obtained from
the reaction resulted in the unexpected fulleropyrrolidine
derivative 7 in which a new oxazolidine ring has been formed
(Scheme 1).
Formation of bicyclic compound 7 can be accounted for
by the condensation reaction of the amino of the glycine
moiety and the carbonyl group of formaldehyde to yield
intermediate 5, which spontaneously cyclizes to oxazolidine
6. Further reaction of 6 (bearing the glycine moiety) with
formaldehyde generates in situ the required azomethyne
ylide, which reacts as a 1,3-dipole with [60]fullerene to afford
fulleropyrrolidine derivative 7 in moderate yield (20%).
The chemical structure of fulleropyrrolidine 7 was con-
(5) (a) Meier, M. S.; Poplawska, M. J. Org. Chem. 1993, 58, 4524–4525.
€
€
(b) Irngartinger, H.; Kohler, C. M.; Huber-Patz, U.; Kratschmer, W. Chem.
Ber. 1994, 127, 581. (c) Meier, M. S.; Poplawska, M. Tetrahedron 1996, 52,
5043–5052. (d) Irngartinger, H.; Weber, A. Tetrahedron Lett. 1997, 38, 2075–
2076. (e) Da Ros, T.; Prato, M.; Novello, F.; Maggini, M.; de Amici, M.; de
Micheli, C. Chem. Commun. 1997, 59–60. (f) de la Cruz, P.; Espildora, E.;
ꢁ
a, J. J.; de la Hoz, A.; Langa, F.; Martın, N.; Sanchez, L. Tetrahedron
´ ´
Garcı
Lett. 1999, 40, 4889–4892. (g) Irngartinger, H.; Escher, T. Tetrahedron 1999,
55, 10753–10760. (h) Martın, N.; Illescas, B. J. Org. Chem. 2000, 65, 5986–
5995. (i) Martın, N.; Illescas, B. C. R. Chim. 2006, 9, 1038. (j) Martın, N.;
Altable, M.; Filippone, S.; Martı nez-Alvarez, R.;
´
´
´
ꢁ
´
n-Domenech, A.; Martı
´
Suarez, M.; Plonska-Brzezinska, M. E.; Lukoyanova, O.; Echegoyen, L.
J. Org. Chem. 2007, 72, 3840–3846. (k) Zheng, M.; Li, F.-F.; Yang, W.-W.;
Gao, X. J. Org. Chem. 2008, 73, 3159–3168. (l) Li, F.-B.; Liu, T.-X.; Wang,
G.-W. J. Org. Chem. 2008, 73, 6417–6420. (m) Li, F.-F.; Gao, X.; Zheng, M.
J. Org. Chem. 2009, 74, 82–87.
(6) (a) Husebo, L. O.; Sitharaman, B.; Furukawa, K.; Kato, T.; Wilson,
L. J. J. Am. Chem. Soc. 2004, 126, 12055–12064. (b) Tajima, Y.; Hara, T.;
Honma, T.; Matsumoto, S.; Takeuchi, K. Org. Lett. 2006, 8, 3203–3205.
(c) Meier, M. S.; Kiegiel, J. Org. Lett. 2001, 3, 1717–1719.
1
firmed by spectroscopic techniques. In particular, the H
(7) (a) Martı
´
n, N.; Altable, M.; Filippone, S.; Martı
n, N.; Altable, M.; Filippone, S.;
n-Domenech, A.; Poater, A.; Sola, M. Chem.;Eur. J. 2005, 11, 2716–
2729. (c) Martın, N.; Altable, M.; Filippone, S.; Martın-Domenech, A.;
´
n-Domenech, A.
Chem. Commun. 2004, 1338–1339. (b) Martı
´
NMR spectrum shows, in addition to the presence of the
methyl ester group, the presence of the methylene protons of
the pyrrolidine ring, which appear as two doublets centered
at 5.06 and 4.94 ppm. Furthermore, we have observed the
ꢀ
Martı
´
´
´
€
ꢀ
€
Guell, M.; Sola, M. Angew. Chem., Int. Ed. 2006, 45, 1439–1442. (d) Guell,
ꢀ
n-Domenech, A.; Sola, M.; Martın, N.
´ ´
M.; Altable, M.; Filippone, S.; Martı
J. Phys. Chem. A 2007, 111, 5253–5258.
(8) Izquierdo, M.; Osuna, S.; Filippone, S.; Martı
M.; Martın, N. J. Org. Chem. 2009, 74, 1480–1487.
ꢀ
n-Domenech, A.; Sola,
´
´
(9) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–735.
6254 J. Org. Chem. Vol. 74, No. 16, 2009

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SCHEME 1. Synthesis of Unexpected Oxazolidine-Containing
Fullerene 7 from Hydroxymethylglycine Hydrochloride (1) and
Formaldehyde in the Presence of [60]Fullerene
FIGURE 2. UV-vis spectrum of compound 11 in CH2Cl2.
the use of an aldehyde endowed with the hydroxymethyl
group as in compound 9.
SCHEME 2. Synthesis of Fulleropyrrolidine 11 from Nonisol-
ated Intermediate 10 through an Intramolecular Nucleophilic
Addition of the Hydroxyl Group to the Fullerene Double Bond
Thus, reaction of commercially available N-methylglycine
8 (sarcosine) with hydroxyacetaldehyde 9 and C60 in reflux-
ing chlorobenzene by following Prato’s procedure10 afforded
the desired cyclized compound 11 in 25% yield. Interest-
ingly, intermediate fulleropyrrolidine 10 bearing the hydro-
xymethyl group was not observed. This experimental finding
is a clear indication of the favorable geometrical approach
between the reactive O-H and fullerene double bond. A
favored 5-exo-trig cyclization9 by intramolecular nucleophi-
lic addition of the O-H group to the adjacent double bond of
the fullerene leads to the formation of the unprecedented
compound 11 in which a tetrahydrofuran ring is simulta-
neously fused to the pyrrolidine and fullerene moieties
(Scheme 2).
The structure of 11 was confirmed by spectroscopic and
analytical techniques. Thus, in addition to the signals corre-
sponding to the N-methyl (2.89 ppm) and two methylene
groups (3.99 and 4.69 ppm for CH2-N; 4.49 and 4.82 ppm
for CH2-O), the 1H NMR spectrum of this compound
showed the typical signature of the hydrogen on the fullerene
skeleton, which appears as a singlet at 6.34 ppm, in good
agreement with other related fullerenes bearing a hydrogen
atom on their surface.8,11
NOE effect between the proton at 4.94 ppm and the proton at
5.11 ppm. This observation indicates that the coupled signals
at 5.11 and 5.32 ppm correspond to the methylene group
simultaneously attached to the oxygen and nitrogen atoms;
in the HSQC this methylene group, as expected, is coupled
with the most deshielding sp3 at 87.2 ppm, due to the
presence of the two electronegative heteroatoms (see Figure
S3 in the Supporting Iinformation).
The electronic spectrum of compound 11 exibits the
typical features of a cis-1 regioisomer with an intense absorp-
tion at λ=428 nm (Figure 2).
Since the chemical approach in which the hydroxymethyl
group belongs to the starting aminoester 1 leads to the
undesired compound 7 in which the cyclization occurs with
the pyrrolidine ring rather than with the fullerene double
bond to form an oxazolidine ring, we turned our strategy to
To the best of our knowledge, this is the first example
reported on the addition of the O-H group of a neutral
alcohol to a double bond of the fullerene sphere, affording in
a totally regioselective and siteselective manner the cis-1
isomer12 in which the oxygen atom is linked to the fullerene
carbon adjacent to the pyrrolidine ring.
(10) (a) Prato, M.; Maggini, M. Acc. Chem. Res. 1998, 31, 519–526.
(b) Tagmatarchis, N.; Prato, M. Synlett 2003, 768–779. The retro-cycloaddi-
tion process has also recently been reported as a useful protection-deprotec-
´
€
n-Domenech, A.; Guell, M.;
n, N. Org. Lett. 2006, 8, 5959–5962. (b) Meier, M. S.;
(11) (a) Altable, M.; Filippone, S.; Martı
ꢀ
tion protocol in fullerenes as well as in carbon nanotubes, see: Martı
Altable, M.; Filippone, S.; Martın-Domenech, A.; Echegoyen, L.; Cardona,
C. M. Angew. Chem., Int. Ed. 2006, 45, 110–114. Lukoyanova, O.; Cardona,
C. M.; Altable, M.; Filippone, S.; Martın-Domenech, A.; Martın, N.;
Echegoyen, L. Angew. Chem., Int. Ed. 2006, 45, 7430–7433. Brunetti,
´
n, N.;
Sola, M.; Martı
´
´
Bergosh, R. C.; Gallagher, M. E.; Spielman, H. P.; Wang, Z. J. Org. Chem.
2002, 67, 5946–5952. (c) Murata, Y.; Ito, M.; Komatsu, K. J. Mater. Chem.
2002, 12, 2009–2020. (d) Komatsu, K.; Murata, Y.; Takimoto, N.; Mori, S.;
Sugita, N.; Wan, T. S. M. J. Org. Chem. 1994, 59, 6101–6102.
´
´
~
F. G.; Herrero, M. A.; Munoz, J. M.; Giordani, S.; Dı
S.; Ruaro, G.; Meneghetti, M.; Prato, M.; Vazquez, E. J. Am. Chem. Soc.
2007, 129, 14580–-14581.
´
az-Ortiz, A.; Filippone,
(12) For a systematic and simple system to indicate the relative positional
relationships of addends in fullerene derivatives, see: Hirsch, A.; Lamparth,
I.; Karfunkel, H. R. Angew. Chem., Int. Ed. 1994, 33, 437–438.
ꢁ
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FIGURE 3. ONIOM2(B3LYP/6-31G(d):SVWN/STO-3G) reaction energy profile (Gibbs free energies in square brackets and red color, and
the imaginary frequencies of the TSs in parentheses) for the reaction of azomethine ylide and C60
.
As is shown in Scheme 2, compound 11 is obtained
together with the parent unsubstituted fulleropyrrolidine
12,13 which is obtained as the main reaction product (40%
yield). Although the formation of this compound lacking the
hydroxymethyl moiety from 10 is not clear, other related
cases;probably involving a radical mechanism;have been
reported in the literature.14
The electrochemical properties of the novel compound 11
have been studied by cyclic voltammetry (CV) in o-DCB/
MeCN (4:1) as solvent at room temperature, using tetra-
butylammonium perchlorate as the supporting electrolyte
(see the Supporting Information).
As is well-known, saturation of a double bond of the
pristine fullerene core results in a raise of the LUMO energy
level and, therefore, the reduction waves are shifted toward
more negative potential values, thus slightly reducing the
accepting ability, as it occurs in fulleropyrrolidine 12 when
compared to pristine [60]fullerene.15
FIGURE 4. Optimized structures (ONIOM2(B3LYP/6-31G(d):
SVWN/STO-3G)) for TS1 with the most relevant distances and
angles (in A and in deg). The atoms treated at the high level in the
ONIOM approach are those colored and darkened.
Thus, as expected, furan-fused pyrrolidinofullerene 11
showed two reversible and a third quasireversible reduction
waves (E11/2=-0.81 V, E21/2=-1.21 V, and E3pc=-1.82 V)
at values more negative than those of pristine C60 (-0.70,
-1.11, and -1.57 V). However, these values are similar to
those of pyrrolidinofullerene 12 (-0.82, -1.19, and -1.71 V)
despite the saturation of a second fullerene double bond in
11, which should raise to still higher values the LUMO level,
thus cathodically shifting the reduction potential values. The
presence of the electronegative oxygen atom, however, com-
pensates to some extent for the saturation of the second
fullerene double bond in 11, resulting in reduction potential
(13) Maggini, M.; Scorrano, G.; Prato, M. J. Am. Chem. Soc. 1993, 115,
9798–9799.
€
(14) (a) Zhou, D.; Tan, H.; Luo, C.; Gan, L.; Huang, C.; Pan, J.; Lu, M.;
Wu, Y. Tetrahedron Lett. 1995, 36, 9169–9172. (b) Gan, L.; Zhou, D.; Luo,
€
C.; Tan, H.; Huang, C.; Lu, M.; Pan, J.; Wu, Y. J. Org. Chem. 1996, 61, 1954–
1961. (c) Lu, X.; He, X.; Feng, L.; Shi, Z.; Gu, Z. Tetrahedron 2004, 60, 3713–
3716.
(15) (a) Echegoyen, L.; Echegoyen, L. E. Acc. Chem. Res. 1998, 31, 593–
ꢁ ꢁ
´
60. (b) Martın, N.; Sanchez, L.; Illescas, B.; Perez, I. Chem. Rev. 1998, 98,
2527–2547.
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FIGURE 5. Optimized structures (ONIOM2(B3LYP/6-31G(d):SVWN/STO-3G)) for (a) Prod1, (b) TS3, and (c) Prod2 with the most relevant
distances and angles (in A and in deg). The atoms treated at the high level in the ONIOM approach are those colored and darkened.
values similar to those obtained for the related monoad-
ducts. This experimental finding has previously been ob-
served in similar examples in which the presence of
electronegative atoms or electron-withdrawing groups sig-
nificantly influences the reduction potential values deter-
mined for a variety of organofullerenes.16
ving the 1,3-dipolar cycloaddition (TS1) has been shown to lead
to cycloadduct Int2, which is 4.8 kcal mol-1 less stable than the
more favorable cycloaddition product for the 1,3-dipolar reac-
tion (Prod1). The highest stability of Prod1 with respect to Int2 is
basically due to the formation of a weak hydrogen bond between
the hydrogen atom of the hydroxyl group and the nitrogen atom
of the pyrrolidine ring (the H-N distance is 2.226 A, see
Figure 5). The TS converting Int2 to Prod1 presents an activa-
tion barrier of 3.6 kcal mol-1 (or 3.4 kcal mol-1 in Gibbs free
energies). The 5-exo-trig cyclization of the hydroxyl group to the
fullerene surface that transforms the product of the 1,3-dipolar
cycloaddition (Prod1) to the final adduct (Prod2) is exothermic
by 9.5 kcal mol-1 (7.8 kcal mol-1 in Gibbs free energies).
Figure 5 shows the optimized structures of Prod1, TS3, and
Prod2 where the most relevant distances and angles have been
marked. In TS3, the oxygen atom of the hydroxyl group and the
carbon atom of the fullerene surface that will be finally bound
are 1.579 A apart. The distance between the hydrogen atom of
the hydroxyl group and the carbon atom of C60 is 1.630 A.
Interestingly, in a previous paper the 6-exo-trig cyclization was
produced in an organofullerene bearing a phenyl substituent
with two hydroxyl groups in an ortho configuration.8 The TS
involving the nucleophilic attack of one of the hydroxyl groups
to the C60 surface presented considerably larger O-C and
shorter H-C distances (1.808 and 1.528 A for O-C and
H-C, respectively) as compared to the distances found for
the 5-exo-trig cyclization. This difference might be attributed
to the different nature of the 5- and 6-membered cycles formed.
The energy barriers for the 5- (ΔGq=42.3 kcal mol-1) and 6-exo-
trig cyclization (ΔGq=39.7 kcal mol-1) differ by only ca. 2.0 kcal
mol-1. Although the latter activation barriers are substantially
high, both reactions are experimentally feasible. Recently, it has
been found that a single point (SP) energy calculation using the
new DFT functional M06-2X17 at the optimized ONIOM-
(B3LYP/6-31G(d):SVWN/STO-3G) (i.e., M06-2X/6-31G(d)//
Theoretical Calculations
As shown above, the intramolecular nucleophilic addition of
the hydroxyl group of the 1,3-dipole substituent to the fullerene
surface is observed experimentally. The reaction mechanism of
the whole path has been theoretically described by means of the
ONIOM approach. Figure 3 shows the relative energies and
Gibbs free energies of the transition states (TSs), reaction
intermediates, and products found.
The first step of the reaction involves the 1,3-dipolar cycload-
dition of the 1,3-dipole to the fullerene surface, followed by the
intramolecular nucleophilic attack of the hydroxyl group of the
dipole substituent. The 1,3-dipolar cycloaddition reaction is
extremely favored;the reaction energy calculated with respect
to separated reactants is -48.3 kcal mol-1. The TS involving the
cycloaddition reaction present negative activation barriers as
compared to those involving isolated reactants (-5.3 kcal mol-1).
However, Gibbs free energies give an activation barrier of 7.2 kcal
mol-1. A reactant complex (Int1, see Figure 3) has been localized
that is -5.9 kcal mol-1 more stable than the corresponding isolated
C60 and 1,3-dipole although it is less stable in terms of Gibbs free
energies by 5.3 kcal mol-1. The activation barrier for the 1,3-
dipolar cycloaddition referred to the later reactant complex (Int1)
is 0.6 and 1.9 kcal mol-1 in electronic and Gibbs free energies,
respectively. Figure 4 shows the optimized structure for the TS
involving the 1,3-dipolar cycloaddition (TS1), where the most
relevant distances and angles have been represented. As can be
seen, a concerted but asynchronous TS is found.
ONIOM(B3LYP/6-31G(d):SVWN/STO-3G)) gives
a good
Full optimization of each TS has been done by slightly
shifting the geometry of the TS in either sense of reactants or
products following the direction of the transition vector (the
eigenvector corresponding to the negative eigenvalue).
Although this is not equivalent to performing an intrinsic
reaction coordinate (IRC), it gives a first idea of which reactants
and products are connected through a given TS. The TS invol-
approximation to the experimental activation barrier for the
Diels-Alder reaction of C60 with cyclopentadiene.18 So, we
have decided to perform a SP M06-2X/6-31G(d)//ONIOM-
(B3LYP/6-31G(d):SVWN/STO-3G) calculation for the present
reaction. Using this method we have obtained an activation
barrier for the 5-exo-trig cyclization reaction of 44.1 kcal mol-1
,
which is quite close to the ONIOM2(B3LYP/6-31G(d):SVWN/
(16) (a) Suzuki, T.; Maruyama, Y.; Akasaka, T.; Ando, W.; Kobayashi,
K.; Nagase, S. J. Am. Chem. Soc. 1994, 116, 1359–1363. (b) Illescas, B.;
(17) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215–241.
ꢀ
(18) Osuna, S.; Morera, J.; Cases, M.; Morokuma, K.; Sola, M. J. Phys.
Chem. A 2009, submitted for publication.
Martın, N. C. R. Chim. 2006, 9, 1038–1050. (c) Illescas, B.; Martı
´ ´
Chem. 2000, 65, 5986–5995.
n, N. J. Org.
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Izquierdo et al.
JOCArticle
STO-3G) value. So we conclude that the activation barrier for
the 5-exo-trig reaction is high, which is in line with the relatively
high temperatures used in experiment.
B3LYP method25-27 with the standard 6-31G(d) basis set28,29
was employed for the high-level system. All systems were treated
with the spin-restricted formalism. The choice of DFT methods
was based on previous studies which showed that DFT (and in
particular B3LYP together with the 6-31G(d) basis set) give
reasonable descriptions of the reaction mechanism of pericyclic
reactions.30-37 Hessians were computed to determine the nature
of stationary points (one or zero imaginary frequencies for
transition states and minima, respectively) and to calculate
unscaled zero-point energies (ZPEs) as well as thermal correc-
tions and entropy effects by using the standard statistical-
mechanics relationships for an ideal gas from which Gibbs free
energies have been calculated at 298 K.38
Summary and Conclusions
In summary, we report the first example of the intramo-
lecular nucleophilic addition of the hydroxyl group to the
fullerene double bond adjacent to the pyrrolidine ring, in a
totally regioselective process, affording the cis-1 isomer. In
contrast to the previous examples with phenols, which
require the existence of an intramolecular H-bond and the
presence of a methyl group on C-2 of the pyrrolidine ring to
afford the cyclized compound, the formation of the oxygen
pentagonal ring is highly favored and occurs spontaneously
in a one synthetic step. These results are underpinned by
theoretical calculations (DFT) which show that the 1,3-
dipolar cycloaddition reaction involving the formation of
the pyrrolidino ring is an exothermic process with a low
activation barrier. The 5-exo-trig cyclization reaction invol-
ving the nucleophilic attack of the hydroxyl group to the
fullerene surface is also moderately exothermic but it has a
substantially higher energy barrier in accordance with the
fact that high temperatures have to be reached to obtain the
final product.
Preparation of Fulleropyrrolidine Derivative 7. A solution of
Et3N (101 mg, 1 mmol) and methyl serinate hydrochloride
(155 mg, 1 mmol) was stirred at room temperature for 30 min.
This mixture was added to a solution of formaldehyde (30 mg,
1 mmol) and C60 (180 mg, 0.25 mmol) in toluene (150 mL) and
was refluxed for 1 h and 30 min. After the solution had cooled to
room temperature, the solvent was removed in vacuo, and the
crude product was purified by flash chromatography over silica
gel, using toluene as eluent, to obtain product 7 in 20% yield. 1H
NMR (CDCl3, 298 K, 700 MHz) δ 3.90 (s, 3H, CH3), 4.89 (d,
1H, J=10.6 Hz, CH2-O), 4.94 (d, 1H, J=9.2 Hz, CH2-N), 5.06
(d, 1H, J=9.2 Hz, CH2-N), 5.11 (d, 1H, J=6.0 Hz, N-CH2-
O), 5.21 (d, 1H, J=10.6 Hz, CH2-O), 5.32 (d, 1H, J=6.0 Hz,
N-CH2-O); 13C NMR (CDCl3, 298 K, 175 MHz) δ 53.1, 65.6,
70.3, 70.9, 74.6, 86.1, 87.2, 135.0, 135.5, 137.1, 137.12, 139.4,
139.7, 140.5, 141.6, 141.7, 141.8, 141.88, 141.9, 142.1, 142.2,
142.23, 142.3, 142.7, 142.77, 142.79, 142.8, 143.2, 143.22, 144.3,
144.4, 144.5, 144.7, 144.9, 145.3, 145.4, 145.5, 145.56, 145.6,
145.7, 145.8, 145.9, 146.07, 146.1, 146.2, 146.3, 146.4, 146.5,
This new and facile reaction opens the way to the pre-
paration of a variety of new heterocycle-fused fullerenes
from readily available alcohols. Work is currently in pro-
gress to explore the scope of the reaction with other alcohols
and heteroatoms such as sulfur (-SH) and nitrogen (-NH)
as nucleophilic reagents.
147.3, 147.4, 150.6, 150.7, 154.3, 154.7, 171.0; FTIR (KBr, cm-1
)
526, 700, 1110, 1262, 1741; HRMS (ESI) calcd for C66H9NO3Na
886.0480, found 886.04746.
Experimental Section
Preparation of Compound 11. A mixture of hydroxyacetalde-
hyde 9 (15.61 mg, 0.13 mmol), C60 (180 mg, 0.25 mmol), and
sarcosine (89 mg, 1 mmol) in chlorobenzene (150 mL) was
refluxed for 2 days. After the solution had cooled to room
temperature, the solvent was removed in vacuo and the crude
product was purified by flash chromatography over silica gel,
using initially CS2 as eluent (to separate the unreacted fullerene),
then with toluene, and, finally, with toluene/ethyl acetate (9:1)
to obtain product 11 in 25% yield together with N-methylfuller-
opyrrolidine 12 in 40% yield.13
Full geometry optimizations have been carried out with the
two-layered ONIOM approach,19,20 using the Gaussian 03
program.21 The density functional theory (DFT) SVWN meth-
od22,23 together with the standard STO-3G basis set24 was used
for the low-level calculations, and the hybrid density functional
(19) Svensson, M.; Humbel, S.; Froese, R. D. J.; Matsubara, T.; Sieber,
S.; Morokuma, K. J. Phys. Chem. 1996, 100, 19357–19363.
ꢁ
(20) Dapprich, S.; Komaromi, I.; Byu, K. S.; Morokuma, K.; Frisch, M.
Spectral Data for Compound 11. 1H NMR (CDCl3, 298 K, 500
MHz) δ 2.89 (s, 3H, CH3), 3.81 (d, 1H, J=3.0 Hz, CH-N), 3.99
(d, 1H, J=9.2 Hz, CH2-N), 4.49 (dd, 1H, J=10.8, 3.0 Hz,
CH2-O), 4.69 (d, 1H, J=9.2 Hz, CH2-N), 4.82 (d, 1H, J=10.8
Hz, CH2-O), 6.34 (s, 1H, H-C60); 13C NMR (CDCl3, 298 K,
125 MHz) δ 39.8, 58.5, 65.5, 67.0, 70.5, 74.8, 81.7, 94.6, 128.1,
135.0, 135.8, 136.0, 138.0, 138.9, 140.7, 141.0, 141.4, 142.1,
J. J. Mol. Struct. (Theochem) 1999, 461-462, 1–21.
(21) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, G.; Dapprich, S.; Daniels, A.
D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komar-
omi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision C.01;
Gaussian, Inc., Pittsburgh, PA, 2003.
(29) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213–222.
ꢀ
´
n, N.; Sola, M. J. Org.
(30) Cases, M.; Duran, M.; Mestres, J.; Martı
Chem. 2001, 66, 433–442.
(31) Di Valentin, C.; Freccero, M.; Gandolfi, R.; Rastelli, A. J. Org.
Chem. 2000, 65, 6112–6120.
(32) Dinadayalane, T. C.; Vijaya, R.; Smitha, A.; Sastry, G. N. J. Phys.
Chem. A 2002, 106, 1627–1633.
(22) Slater, J. C. Quantum Theory of Molecules and Solids; McGraw-Hill:
New York, 1974; Vol. 4.
(33) Freccero, M.; Gandolfi, R.; Sarzi-Amade, M.; Rastelli, A. J. Chem.
Soc., Perkin Trans. 2 1998, 2413–2419.
(23) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200–1211.
(24) Hehre, W. J.; Stewart, R. F.; Pople, J. A. J. Chem. Phys. 1969, 51,
2657–2664.
(34) Goldstein, E.; Beno, B.; Houk, K. N. J. Am. Chem. Soc. 1996, 118,
6036–6043.
(35) Isobe, H.; Yamanaka, S.; Yamaguchi, K. Int. J. Quantum Chem.
2003, 95, 532–545.
(25) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
(26) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
(27) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J.
Phys. Chem. 1994, 98, 11623–11627.
(36) Wiest, O.; Houk, K. N. Top. Curr. Chem. 1996, 183, 1–24.
(37) Wiest, O.; Houk, K. N.; Black, K. A.; Thomas, B. J. Am. Chem. Soc.
1995, 117, 8594–8599.
(28) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56,
2257–2261.
(38) Atkins, P.; De Paula, J. Physical Chemistry; Oxford University Press:
Oxford, UK, 2006.
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Izquierdo et al.
JOCArticle
Societat de la Informacio (DURSI) of the Generalitat de
ꢁ
Catalunya project No. 2005SGR-00238. S.F. thanks the MEC
142.16, 142.2, 142.24, 142.3, 142.4, 142.5, 142.7, 142.9, 143.3,
143.4, 143.5, 143.7, 143.8, 143.9, 143.97, 144.0, 144.01, 144.1,
144.2, 144.3, 144.5, 144.6, 144.7, 144.9, 145.1, 145.4, 145.6,
146.1, 146.14, 146.2, 146.7, 146.8, 146.9, 147.8, 147.88, 147.9,
ꢁ
for Ramon y Cajal contract and S.O. thanks the MEC for
Doctoral Fellowship AP2005-2992.
148.0, 148.6, 148.9, 149.0, 150.6, 151.5, 152.4; FTIR (KBr, cm-1
)
527, 861, 1146, 1459; HRMS (MALDI TOF) calcd for C64H9NO
807.0684, found 807.0688.
Supporting Information Available: 1H NMR and 13C NMR
spectra of fulleropyrrolidines 7 and 11, MS spectrum of com-
pound 11, cyclic voltammogram of compound 11, and xyz
optimized Cartesians coordinates for all minima and transition
states located. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the MICINN
of Spain (project CTQ2008-00795/BQU and Consolider-
Ingenio 2010C-07-25200), the CAM (project P-PPQ-000225-
0505), and the Catalan Departament d’Universitats, Recerca i
J. Org. Chem. Vol. 74, No. 16, 2009 6259