Preparation of quinolinium salts differing in the length of the alkyl side chain

Article abstract of DOI:10.3390/molecules17066395

Quaternary quinolinium salts differing in alkyl chain length are members of a widespread group of cationic surfactants. These compounds have numerous applications in various branches of industry and research. In this work, the preparation of quinoline-derived cationic surface active agents differing in the length of the side alkyl chains (from C8 to C20) is described. An HPLC method was successfully developed for distinction of all members of the series of prepared long-chain quinolinium derivatives. In conclusion, some possibilities of intended tests or usage have been summarized. In vitro testing using a microdilution broth method showed good activity of a substance with a C12 chain length against Gram-positive cocci and Candida species.

Full text of DOI:10.3390/molecules17066395

Molecules 2012, 17, 6395-6414; doi:10.3390/molecules17066395
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Review
Chemistry of Fullerene Epoxides: Synthesis, Structure, and
Nucleophilic Substitution-Addition Reactivity
1
,2,
2
3
4
Yusuke Tajima *, Kazumasa Takeshi , Yasuo Shigemitsu and Youhei Numata
1
Organic Optoelectronics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Graduate School of Science and Engineering, Saitama University, 255 Shimoohkubo,
Saitama 338-8570, Japan
2
3
4
FLOX Corporation, 2-3-13 Minami, Wako, Saitama 351-0104, Japan
Photovoltaic Materials Unit, National Institute for Materials Science, 1-2-1 Sengen, Tsukuba,
Ibaraki 305-0047, Japan
*
Author to whom correspondence should be addressed; E-Mail: tajima@riken.jp;
Tel.: +81-48-467-5499; Fax: +81-48-467-5689.
Received: 28 March 2012; in revised form: 14 May 2012 / Accepted: 16 May 2012 /
Published: 25 May 2012
n
Abstract: Fullerene epoxides, C60O , having epoxide groups directly attached to the
fullerene cage, constitute an interesting class of fullerene derivatives. In particular, the
chemical transformations of fullerene epoxides are expected to play an important role in
the development of functionalized fullerenes. This is because such transformations can
readily afford a variety of mono- or polyfunctionalized fullerene derivatives while
conserving the epoxy ring arrangement on the fullerene surface, as seen in representative
regioisomeric fullerene polyepoxides. The first part of this review addresses the synthesis
and structural characterization of fullerene epoxides. The formation of fullerene epoxides
through different oxidation reactions is then explored. Adequate characterization of the
isolated fullerene epoxides was achieved by concerted use of NMR and LC-MS techniques.
The second part of this review addresses the substitution of fullerene epoxides in the
presence of a Lewis acid catalyst. Most major substitution products have been isolated as
pure compounds and their structures established through spectroscopic methods. The
correlation between the structure of the substitution product and the oxygenation pattern of
the starting materials allows elucidation of the mechanistic features of this transformation.
This approach promises to lead to rigorous regioselective production of various fullerene
derivatives for a wide range of applications.

Molecules 2012, 17
Keywords: fullerene; epoxidation; regioselectivity; nucleophilic substitution; Lewis acid
6396
1
. Introduction
Since the first detection of fullerene epoxides via mass spectrometry in a fullerene mixture
generated by the arc discharge of graphite in 1991, many studies on fullerene oxides have been
performed for the purpose of developing new materials. The epoxidation of fullerene can proceed
readily in the presence of oxidants such as ozone [1], organic peroxide [2], dimethyldioxirane [3],
methyltrioxorhenium-hydrogen peroxide [4], and cytochrome P450 [5]. Under several circumstances,
in different oxidations fullerene C60 has been shown to give higher oxides (C60
only a few regioisomers. For instance, although there are indeed eight possible regioisomers of C60
and 43 isomers of C60 given the multiple reaction sites available on the C60 cage [6], the actual
products of most oxidations are only two isomers of C60 and three isomers of C60 . However, few
isomers have been isolated and identified thus far, and experimental data on the regioselective
n
O , n ≥ 2) that possess
O
2
O
3
O
2
O
3
60 n
C O
epoxidation of C60 are also scarce.
Meanwhile, the structures of C60
n
O isomers were first studied theoretically on the basis of the
thermodynamic stability of ground state molecules and on the dynamic behavior of the molecules via
the transition states. Those results regarding the structures of C60O and the predominant isomers of
60 2
C O can explain these experimental observations. Manoharan showed computationally that multiple
epoxidations of C60 preferentially proceeds at the adjacent rather than distant double bonds of the
existing epoxide group, and predicted that multiple epoxidations should occur on one benzenoid ring
of C60 to form the C60
using the semiempirical quantum mechanical INDO method, and predicted that the three types of
isomers with C3v, C and C symmetries, respectively, should be very stable, and reported their
calculated electronic spectra [7]. Curry et al. predicted that the three lowest-energy isomers (C3v, C
and C
3 3
O isomer with C3v symmetry. Feng et al. studied three isomers of C60O by
C
60
O
3
s
2
s
2
) of C60
O
3
should exist in equilibrium at room temperature by using a modified and extended
Hűckel method [8].
Previously, we found three types of C60
O
3
isomers in a reaction solution of C60 with m-CPBA by
means of a chromatographic technique involving the use of two different columns [9]. Electronic
spectroscopy and mass-spectroscopy examinations of these isomers were mostly consistent with
the calculated results by Feng et al. However, the precise structures of these isomers could not be
1
3
confirmed by C-NMR and X-ray studies, which are unavailable due to the low solubility and
1
3
poor crystallinity. We carried out measurements of FT-IR and C-NMR spectra precisely after the
isolation and further purification of two types of C O isomers and three types of C O isomers.
6
0
2
60
3
Simultaneously, we demonstrated experimentally the regioselectivity of the epoxidation of C60 by
means of the identification of products from each oxidation of the isolated isomers.
Fullerene epoxides exhibit interesting properties applicable to new materials development.
However, the chemical transformations of fullerene epoxides have been studied sparingly, despite
the general recognition that they could serve as convenient starting materials for the synthesis
of functionalized fullerene derivatives [10]. We first succeeded in converting fullerene epoxide

Molecules 2012, 17
6397
stoichiometrically into a 1,3-dioxolane derivative [11]. Reaction of C60O with benzaldehyde in the
presence of a Lewis acid led to the formation of a 1,3-dioxolane derivative of C60 in high yield. This
implies the possibility of other nucleophilic substitutions of the epoxy rings on a fullerene cage. The
chemical transformation of fullerene epoxide is expected to play an important role in the development
of functionalized fullerenes, because such transformations can readily afford a variety of mono- or
polyfunctionalized fullerene derivatives, such as regioisomeric fullerene polyepoxides, while
conserving the epoxy ring arrangement on the fullerene surface. The recent development of large-scale
production techniques for fullerene epoxide [12] thus prompted us to develop a new methodology to
synthesize polyfunctionalized fullerene derivatives by means of efficient chemical transformation of
regioisomerically pure fullerene polyepoxides. Then, we also achieved the efficient formation of
fullerene derivatives from C O with aromatic nucleophilic compounds by Lewis acid-assisted
6
0
nucleophilic substitution of the epoxy ring. The direct substitution of epoxide oxygen atoms on the
fullerene epoxide—a versatile and advantageous synthetic methodology we report here—provides
highly regioselective access to a variety of fullerene adducts.
2
. Epoxidation of Fullerene C and Their Regioisomeric Structure
60
The epoxidation of C60 generally affords the higher fullerene epoxides (C60
only a few types of regioisomers. For instance, the epoxidation of C60 with m-chloroperoxybenzoic
acid (m-CPBA) forms a few C60 regioisomers (see Figure 1 for positional notation of C60O) that can
n
O , n ≥ 2), which have
O
2
be separated into two fractions by high-performance liquid chromatography (HPLC) (peaks A or B in
Figure 2), although from the standpoint of the multiple reacting sites available on a C60 cage there are
eight possible regioisomers of C60
isomer with both oxygen atoms positioned over 6:6 ring junctions on a common six-membered ring of
the carbon cage, namely the cis-1 adduct [5]. Meanwhile, a minor fraction of C60 has been
considered to contain more than one isomer [13]. These isomers could not be separated by any HPLC
2 2
O [6]. A major C60O fraction is known to be composed of only one
O
2
1
3
column and their precise structures have hardly been ascertained by C-NMR or X-ray studies
because of the low yield and the non-crystalline nature of the products.
Figure 1. Positional notation of the fullerene epoxide, C60O.
O
cis-1
cis-2
cis-3
equatorial
trans-4
trans-3
trans-2
trans-1

Molecules 2012, 17
Figure 2. HPLC reversible-phase chromatograms (Develosil C30 RPFULLERENE, 34:66
6398
acetonitrile/toluene, 335 nm detection) for reaction mixtures resulting from the
m-CPBA of C60 (in toluene, 80 C, 30 min).
60
C O
C O
60 2
C
60
A
60 3
C O
C
60
O
4
B
0
2
4
6
8
10
12
14
Elution time / min
The splitting pattern of each fraction in HPLC varies with both the position of the epoxy group on
the C cage and its structural symmetry. A detailed comparison of these patterns is informative in
6
0
relation to the structure of existing C60
preferentially formed C60 , we also performed calculation of the static reaction index of oxygen
addition sites on the C60 cage, and compared the experimental observations with the calculated results [14].
In the past, the structure of C60 isomers was studied on the basis of the thermodynamic stability
of ground state molecules and the dynamic behavior of the molecules via the transition states. The
results of these studies can explain the experimental observations regarding the structures of C60
and the predominant isomer of C60 . Manoharan demonstrated computationally that the multiple
2
O isomers. In order to explain the isomeric structure of the
O
2
O
n
O
O
2
epoxidations of C60 preferentially proceeds at the adjacent rather than distant double bonds of the
existing epoxide group [15]. By using a modified extended Hűckel method, Curry et al. also correctly
predicted for C O that the cis-1 adduct has exceptionally low energy compared to the next stable
6
0
2
isomers [8]. Feng et al. studied the possible structure of C60
2
O isomers by using the semiempirical
quantum mechanical INDO method, and showed that three types of C O with the regioisomeric
6
0
2
structures of cis-1, cis-2, and trans-4 adduct, respectively, should be very stable [7]. A more detailed
theoretical elucidation of the regioselective epoxidation on fullerene, however, is required to provide
information concerning the possible structures of other experimentally obtained C O isomers.
6
0
2
The reactivity for regioselective epoxidation on fullerene is assumed to be predicted by calculating
the static reaction index for addition sites. On the basis of theoretical studies on the epoxidation of
alkenes with peroxide [16,17], we hypothesized that the reaction index should fall between fullerene
and m-CPBA. The electrophilicity of peroxide was attributed to its relatively weak O-O bond, which
can provide an empty * orbital that can mix with the nucleophilic -bond of fullerene. The
electrophilic oxygen tends to attack the bonds with a high electron density. In the same manner, the

Molecules 2012, 17
6399
epoxidation of fullerene by the electrophilic oxygen of m-CPBA is likely to occur on electron rich
double bonds. Thus the electron density of a bond is expected to give a good index of a probable
reaction site. A similar calculation has been reported for the first oxygen addition sites on fullerenes [18].
Since the epoxidation of fullerene is a step-wise reaction, the yield for C60
n
O (n ≥ 2) can be
calculated by considering the yield of the parent isomer C60 n−1. The electron density of a bond has
O
been determined by semiempirical molecular orbital calculations (PM3). The yield of the j-th isomer of
C O , Y , can then be determined by the summation of the product of the yield of i-C O , Y(n−1,i),
6
0
n
(n,j)
60 n−1
and the branching probability from i-C60
n
On-1 to j-C60O , p(i,j) as follows:
m
Y(n, j)

Y(n1,i) p(i, j)

(1)
i1
where m denotes the number of the parent isomer. If the branching probability increases linearly with
the difference in electron density, p(i,j) is defined by utilizing the difference between the electron
density of the bond of the addition site and the minimum electron density of the bond that undergoes
epoxidation as follows:
N (  c)
j
j
p(i, j)

l
(
2)
N (  c)

k
k
k1
j j
where  and N denotes the electron density of the bond of the addition site j, and the number of the
symmetrically equivalent bond of j, respectively. The constant c is the minimum electron density that
undergoes epoxidation. The variables l denotes the number of equivalent bonds of the possible
addition sites.
Table 1 shows the calculated yield for the C60
isomers based on the calculated yield. The cis-1 adduct overwhelmingly dominated the other isomers.
The next dominant isomer of C60 was predicted to be the equatorial adduct. The structure of the
2
O isomers, and the candidates for the dominant
O
2
predominant isomer, the cis-1 adduct (1b in Figure 3), agreed with the structure actually confirmed by
X-ray analysis [2], whereas the next dominant isomer is differed from a previous suggestion [1] that
2
the C60O isomers in fraction B are probably the cis-2 or trans-4 adducts. From both our experiment
and calculations, at a minimum, we expect that the main product in fraction B is not the trans-1 but
rather the equatorial adduct of C O (1c in Figure 3).
6
0
2
Table 1. Calculated percentage yield and point group of constitutional isomers of
diepoxidized fullerene C60
2
O .
Structure
cis-1
equatorial
trans-4
trans-2
trans-1
Symmetry
Yield / %
C
s
C
s
C
s
88
12
<0
<0
<0
C
2
D2h

Molecules 2012, 17
6400
Figure 3. Fullerene mono-epoxide and regioisomeric di-epoxides isolated by means of
preparative HPLC from a mixture of C60(O)
n
.
3
. Lewis Acid-Assisted Reaction of Fullerene Epoxides with Nucleophiles
Epoxides are well-known to undergo heterolytic C–O bond cleavage in the presence of an acid
catalyst to generate active carbocationic species for further reactions with nucleophiles. These active
species react with various types of nucleophile such as carbonyl compounds, alcohols, and amines to
afford 1,3-dioxolanes, 1,2-hydroxyethers, and 1,2-aminoalcohols, respectively. We have studied the
reaction of fullerene epoxide 1a with various nucleophiles in the presence of a Lewis acid. Reaction
with a carbonyl compound led to the formation of a 1,3-dioxolane derivative in high yield;
interestingly, reaction with a phenol or aniline derivative afforded an O- or N-heterocycle-fused
fullerene derivative. These reactions are considered to proceed via a nucleophilic reaction on the
carbocationic active species generated on the carbon atom of fullerene epoxide 1a (Scheme 1). The
formation of the heterocycle-fused fullerene derivative can be accounted for by the ring closure
reaction induced by intramolecular dehydration of the initially formed 1,2-substituted product. In
contrast, a Lewis acid-assisted nucleophilic reaction of C O with an aromatic nucleophile such as
6
0
toluene gave a 1,4-bisadduct. Application of these reactions to a regioisomeric fullerene polyepoxide
would provide a convenient synthetic route to a variety of polyfunctionalized fullerene derivatives with
a regioisomerically pure structure. These chemical transformations of fullerene epoxides are expected
to play an important role in the development of functionalized fullerene cages. In this section, we
review our recent progress in the work on the acid-assisted reaction of fullerene epoxides with various
types of nucleophile.
Scheme 1. Generation of active carbocationic species from 1a in the presence of an acid catalyst.
Cat
Cat

O
O
O
+
C+
C
Acid Catalyst
or
1
a
Carbocationic Active Species
3
.1. Acetalization of Fullerene Epoxides
Several methods have been reported for the preparation of fullerene-fused 1,3-dioxolane
derivatives, such as the reactions of C60 fullerene with dioxiranes [3], acyl hypohalogenites [19], and

Molecules 2012, 17
6401
diacyl peroxides [20], or the reaction of C60 fullerene with a sodium alkoxide in the presence of air [21].
However, all of these reactions afforded fullerene-fused 1,3-dioxolane derivatives in only low to
moderate yields, (i.e., <50%). As described in the previous section, we recently developed a
preparative HPLC isolation method for some regioisomeric fullerene epoxides (Figure 3) [7]. Isolation
of these epoxides prompted us to employ them as a starting material for efficient synthesis of
fullerene-fused 1,3-dioxolane derivatives. We have found that the acetalization reactions of fullerene
epoxide 1a with various carbonyl compounds occur in the presence of a Lewis acid catalyst, an ion-
exchange resin such as Amberlite, and a clay mineral such as montmorillonite to afford the
corresponding 1,3-dioxolane derivatives in very high yields (Table 2) [9,22].
Table 2. Acetalization of fullerene epoxide 1a with carbonyl compound in the presence of
an acid catalyst.
a
Entry
2
Catalyst (equiv./amount)
Reaction Time
Yield of 3 / %
1
60 min
92
4
a (0.29)
2
4b (0.28)
90 min
91
3
4
4
a (0.29)
60 min
4.5 h
95
88
4
b (0.28)
5
6
BF ·Et O (one drop)
60 min
3 h
89
96
3
2
®
Amberlyst 15 (268 mg/0.02 mmol)
Montmorillonite
7
4 h reflux
60
(
250 mg/0.02 mmol)
8
9
4a (0.27)
30 min
45
R =CH , R =C H
5
4a (0.27)
30 min
44
60
75
1
3
2
2
®
1
0
1
Cyclohexanone
Amberlyst 15 (250 mg/0.02 mmol)
65 C, 5 h in benzene
3 h in benzene
1
γ-Butyrolactone
3 2
BF ·Et O (one drop)
a
Isolated yield.
The reaction of a toluene solution of fullerene epoxide 1a with excess amounts (200 equiv.) of a
benzaldehyde derivative at 75 °C in the presence of a Lewis acid catalyst led to the formation of
,3-dioxolane 3 in very high yield. Table 2 also shows that a similar acetalization of 1a with other
1

Molecules 2012, 17
6402
ketone compounds such as acetophenone, methyl ethyl ketone or cyclohexanone took place to give
the corresponding 1,3-dioxolanes in moderate yields. Furthermore, a similar reaction of 1a with
γ-butyrolactone in benzene afforded an ortho-ester type 1,3-dioxolane derivative in high yield,
although in toluene, it resulted in the formation of a 1,4-addition product of toluene to 1a. This fact
suggests that the nucleophilicity of a carbonyl group of an ester compound is not as strong as that of an
aldehyde or a ketone, such that toluene instead acts preferentially as a nucleophile to the carbocationic
species to yield a 1,4-addition product (1,4-bis(p-tolyl)-1,4-dihydro[60]fullerene). The Lewis acid
catalyzed 1,4-addition reaction of aromatic nucleophiles to 1a will be discussed in Section 3.2.
Recently Gan and Zhang et al. reported that a Lewis acid such as BF ·Et O catalyzes the acetalization
3
2
reaction of the fullerene epoxide bearing t-butylperoxo groups to yield the corresponding
1
,3-dioxolane derivatives in moderate yields [23].
An epoxy ring is known to undergo a Lewis acid catalyzed acetalization to afford 1,3-dioxolane
[
24–26]. Generally the acetalization is assumed to follow a concerted S 2-like mechanism involving
N
backside attack of a carbonyl oxygen on an epoxide carbon followed by rotation of the C–C bond of
the epoxide and then the second C–O bond formation to produce a 1,3-dioxolane [26]. However, such
a backside attack on a fullerene epoxide is not expected to occur owing to occupation of the entire side
opposite the epoxy ring by the fullerene cage. According to this view, an acetalization of a fullerene
epoxide is not expected to occur unless an alternative mechanism is involved in a front side attack of a
carbonyl compound on the epoxy ring of the fullerene epoxide. The acetalization reaction of fullerene
epoxide 1a with benzaldehyde at 75 °C for 1 d did not proceed at all in the absence of a Lewis acid and
resulted in the complete recovery of 1a. This result suggests that the Lewis acid catalyzes the
N
acetalization reaction to proceed by a stepwise S 1-like mechanism (Scheme 2). A Lewis acid induces
a catalytic C–O bond cleavage of the epoxy ring to generate a carbocation on the carbon atom of the
fullerene moiety. This is followed by nucleophilic attack of a carbonyl compound on the carbocation.
N
An energetically unfavorable S 1-like attack of a carbonyl compound on the carbocation from the
fullerene surface would be forced to occur with the requirement of relatively high activation energy for
the C–O bond cleavage of the epoxy ring.
N
Scheme 2. Stepwise S 1-like acetalization of fullerene epoxide 1a with benzaldehyde derivative.
R
Stepwise S 1-like attack of
N
NC
aldehyde on a carbocation
R
+
Bz
N
SbF6
C
H
H
O
O
O
O
O
+
C C
CO bond
cleavage
1a
−1
The activation energy for the reaction of 1a with benzaldehyde was determined to be 112.7 kJ·mol
from the Arrhenius plots of ln k vs. 1/T, where k is the pseudo-first order rate constant and T is the
reaction temperature. Based on the activation energy determined, the rate constant at room temperature

Molecules 2012, 17
6403
−
7
−1
3
(
(
293 K) can be calculated to be 9.5 × 10 s , which is more than 10 times smaller than that at 75 °C
−3
−1
k = 1.43  10 s ). Therefore, that the Lewis acid catalyzed acetalization of 1a with benzaldehyde
did not occur at room temperature is unsurprising, although a similar acetalization of oxiranes such as
but-2-ene epoxide or styrene oxide readily proceeds at room temperature and even at 0 °C to yield
1
,3-dioxolanes according to an energetically favorable S 2-like mechanism [24–26].
N
The application of the above acetalization reaction to the regioisomerically pure fullerene
di-epoxide 1b (cis-isomer) or 1c (equatorial isomer) would lead to chemical transformation of the two
epoxy rings while conserving their arrangement on the fullerene cage. Under reaction conditions
similar to those for mono-epoxide 1a, the fullerene di-epoxides 1b and 1c were also subjected to
acetalization with benzaldehyde derivatives to give bis-1,3-dioxolanes 5a and 5b, respectively in high
yields (Table 3) [9,21]. The visible absorption spectra of 5a and 5b show the bands characteristic to
those of the di-epoxides 1b and 1c, respectively, that is, 5a showed a sharp band at 423 nm, which is
the characteristic band for the cis-isomer 1b [11,15]. This fact suggests that during the acetalization
reaction, no migration of the carbocation on the fullerene moiety occurs and that the acetalization
reaction of the fullerene di-epoxide proceeds while the rearrangement of the two epoxy rings on the
fullerene cage is conserved.
Table 3. Acetalization of fullerene epoxide 1b or 1c with benzaldehyde derivatives 2 in the
presence of pyridinium salt 4a or 4b shown in Table 2.
Epoxide
2
Catalyst (equiv.)
Yield of 5 / %
1b
R
3
= H
4b (0.28)
5a (R
3
= H), 92
1
b
R
3
3
= n-BuO
5a (R
3
= n-BuO), 91
4
a (0.29)
1
1
1
c
c
c
R = H
3
4b (0.28 equiv.)
4a (0.27 equiv.)
4a (0.27 equiv.)
3
5b (R = H), 76
R
= n-BuO
5b (R
3
= n-BuO), 73
= n-C ), 82
R
3
= n-C
3
H
7
5b (R
3
3 7
H
1
3
The H-NMR spectrum of 5a (R = n-BuO) showed the two unequivalent acetal methine protons of
equal intensity. In addition, it showed two sets of four phenyl protons and nine n-butoxy protons, also
1
of equal intensity. Thus, the H-NMR spectrum of 5a clearly demonstrates that the two phenyl groups
1
3
are unsymmetrically disposed with respect to the fullerene moiety. The C-NMR spectrum of 5a

Molecules 2012, 17
6404
2
showed 51 signals for the fullerene sp carbons, indicating a lack of symmetry of the fullerene cage.
Based on the above NMR analysis, bis-1,3-dioxolane 5a is confirmed to have the structure of the
stereoisomer depicted in Table 3. However, the configuration of the two phenyl groups in 5b remains
undetermined because no definitive information suggesting their configuration could be obtained from
1
the H-NMR spectra of 5b. We assume that 5b is likely to be a mixture of two stereoisomers.
The fullerene di-epoxide 1b (cis-isomer) or 1c (equatorial isomer) also reacts with a ketone
®
compound such as cyclohexanone in the presence of a Lewis acid catalyst or Amberlyst 15 to yield
the corresponding bis-1,3-dioxolane derivative in moderate yields (50–70%) [27]. These acetalization
reactions are presumed to proceed with conservation of their arrangement on the fullerene cage.
The present work has clearly shown that the epoxy moiety of fullerene epoxides can be readily
converted to 1,3-dioxolane derivatives in high yield by treatment with a carbonyl compound in the
presence of a Lewis acid, ion-exchange resin or clay mineral. The acetalization reaction proceeds by a
stepwise S 1-like mechanism which involves the nucleophilic attack of a carbonyl moiety at the
N
carbocationic active species generated on the carbon atom of fullerene epoxides. Furthermore, the
efficient bis-acetalization of a regioisomerically pure fullerene di-epoxide occurs under conservation
of the arrangement of the two epoxy moieties to yield bis-1,3-dioxolane derivatives in high yield.
These results could lead to development of a new methodology for facile synthesis of a variety of
regioisomeric polyfunctionalized fullerene derivatives by means of efficient chemical transformation
of a specific regioisomeric fullerene polyepoxide. In order to elucidate the reactivity of the
carbocationic active species generated from fullerene epoxides, the next part of this section is oriented
toward studies on the reaction of fullerene epoxides with nucleophiles other than carbonyl compounds.
3
.2. Nucleophilic Substitution of Fullerene Epoxide with Aromatic Compounds
The reaction of a toluene solution of fullerene epoxide 1a in the presence of 5 equiv. of boron
trifluoride etherate (BF
3
OEt
2
) at r.t. for 60 min led to the formation of 1,4-bis(p-tolyl)-1,4-dihydro
[
60]fullerene (7a) in 80.8% yield together with a very small amount of pristine fullerene C based on
6
0
HPLC analysis [28]. Compound 7a was purified by flash column chromatography on a silica gel with
n-hexane as an eluent. A detailed spectral characterization of 7a revealed that two p-tolyl moieties
were introduced to the C60 core in a 1,4-addition pattern. The FT-IR spectrum was in good agreement
with that in an earlier report [29,30]. The characteristic vibrations for the 1,4-adduct were found at
−
1
1
,430, 1,187, 573, and 527 cm , and the C-H vibrations for toluene showed strong vibrations at 2,963
−1
and 810 cm . The atmospheric pressure photochemical ionization (APPI) mass spectrum showed a
molecular ion peak at m/z 902 (i.e., 166 units more than 1a), corresponding to a 1:2 adduct of C60 and
1
toluene-H. In the H-NMR spectrum, in addition to two doublets at 7.94 (2H), 7.93 (2H), 7.28 (2H),
and 7.27 (2H) ppm for eight phenyl protons, one singlet methyl proton was observed at 2.46 (6H) ppm.
1
3
The C-NMR showed the characteristic absorption of aromatic carbons in the p-tolyl group at 138.25
2C), 136.91 (2C), 129.52 (4C), and 126.94 (4C) ppm, and two quaternary carbons of the C60 moiety
(
were observed at 60.86(2C) ppm. The UV-VIS spectrum showed a characteristic absorption band
around 450 nm. The 1,4-bisadduct structure for 7a was evidently confirmed by comparing these
1
13
spectra with FT-IR, H-NMR and C-NMR spectra for similar compounds [29,30].

Molecules 2012, 17
6405
Reactions of 1 with other aromatic compounds were carried out under the same conditions as
described above, the results of which are listed in Table 4. In anisole, o-xylene and m-xylene the
reaction produced the corresponding 1,4-bisadducts (7b, 7c and 7d) in 45–95% yields, whereas neither
the 1,2-(6e) nor 1,4-bisadduct (7e) was produced in p-xylene.
Table 4. Substitution of 1 with aromatic compounds.
a
b
c
Aromatic Compound
toluene
Isolated Yield of 6 / %
Isolated Yield of 7 / %
a
b
c
0
80.8
95.8
76.5
anisole
0
o-xylene
0
Trace
0
d
d
e
m-xylene
45.3
p-xylene
0
Trace
0
f
1,3,5-trimethylbenzene
chlorobenzene
benzene
35.3
0
g
h
a
0
0
b,c
All reactions were performed according to the procedure described in the text; All reactions
d
were continued until complete disappearance of the starting material 1; Overall yield of the
structural isomeric mixture of 1,4-adducts.
Although the purification of 1,4-bisadducts 7a, 7b, and 7c was easily carried out with the HPLC
apparatus, 3d was not well separated owing to the formation of structural isomers. In the case of
1
,3,5-trimethylbenzene, the corresponding 1-(substituted phenyl)-2-hydroxyl-1,2-dihydro[60]fullerene
1
(
1
6f) was dominantly formed instead of the 1,4-bisadduct, as identified by UV-VIS, APPI mass, H- and
3
3
C-NMR spectra. Usually the sp carbons of the C60 cage were observed to shift downfield ca. 10 ppm
3
for 1,2-adducts relative to the 1,4-adducts. The two peaks at 86.9 and 72.0 ppm for the two sp carbons
of the fullerene core in 6f indicate a typical structure of 1,2-adduct. This suggests that the formation of
1
,4-bisadduct from 1a proceeds stepwise via 1,2-adduct 6 as an intermediate. In fact, the formation of
6
d can be observed as a transient intermediate in the course of the reaction in m-xylene. With respect
to the UV-VIS spectrum beyond wavelengths of 300 nm, 6d is identical to 6f. The substitution reaction
scarcely proceeded in benzene and chlorobenzene, even above 75 C, and pristine C60 was observed
instead of 1,4-adducts. The formation of pristine C60 without epoxy group was observed. Thus, it
appears that the progress of the reaction depends considerably on the nucleophilicity of the aromatic
compound. In the absence of BF
3
2
OEt , no reaction was observed in any solvent. From this general
behavior, we may conclude that the first substitution of 1a to obtain 6 occurs via a carbocationic
intermediate generated with the assistance of the Lewis acid, followed by a nucleophilic attack of an
aromatic compound on the cation. In the transformation of 6 into 7, a reasonable assumption is that the

Molecules 2012, 17
6406
N N
substitution of the hydroxyl group proceeded by an S 1- or S 2-type mechanism with allylic
rearrangement (Scheme 3).
Scheme 3. Proposed mechanism for the substitution of C60O with aromatic compounds.
Part of the fullerene surface is shown.
Generally, the Lewis acid-assisted substitution of the epoxy group is assumed to follow a concerted
N
2-like mechanism involving a backside attack of a nucleophilic reagent on an epoxide carbon atom [26].
S
However, such an attack is rather unrealistic, because the fullerene cage occupies the entire side
opposite the epoxy ring. The first substitution of the epoxy ring on a fullerene, therefore, would occur
with an energetically unfavorable S
generated by the CO bond cleavage of the epoxy ring. On the other hand, the second substitution for
might occur by an S 2'-type mechanism, in which the nucleophilic attack on the residual hydroxyl
N
1-like attack of a nucleophilic reagent on the carbocation
6
N
group occurs first, followed by the elimination of -OH on the side with an allylic rearrangement [31].
The fact that no reaction proceeded in the absence of the Lewis acid catalyst suggests that the second
N N
substitution occurs by an S 1- or S 2-type mechanism with allylic rearrangement, where 7 is formed
via a carbocationic intermediate with an allylic resonance [32–36], generated with the assistance of
BF OEt . In no case was the formation of 1,2-bis(substituted phenyl)adduct observed, presumably
3
2
because of the steric hindrance between the two substituents.
.3. Formation of Indolino[2',3':1,2][60]fullerene Derivatives from C60O and Aniline Derivatives
As shown in section 3.1, the reactions of C60 with nucleophiles in the presence of acidic
3
O
x
compounds have uncovered a means to achieve the regioselective functionalization of various
fullerene derivatives. In extending this procedure, we found that a reaction of C60O with aniline
derivatives in the presence of acidic compounds afforded the indoline-fused fullerene derivatives:
indolino[2',3':1,2]-1,2-dihydro[60]fullerene (Figure 4), in moderate to excellent isolated yields (ca.
60–80%) [37]. To the best of our knowledge, only a few cases have thus far been reported on the
preparation of indolino[60]fullerene analogues [38–42]. This method enabled access to a wide variety
of indolino[60]fullerene derivatives because numerous anilines are commercially available.

Molecules 2012, 17
Figure 4. Molecular structure of indolino[2',3':1,2]-1,2-dihydro[60]fullerene derivatives 8.
6407
First, we examined the catalytic activities of different types of acidic compound for this reaction by
using 4-dodecylaniline as a model compound. The examined acidic compounds were BiCl
3
, BF
3
·OEt
2
,
®
Montmorillonite K10, Sepiolite, TsOH, and Amberlyst 15 . The Brønsted acids TsOH and Amberlyst
®
1
5 did not exhibit catalytic activities for the reactions, and all of the C O was converted to pristine
60
C . Although the Lewis acid compound; BiCl gave products with moderate production yields
6
0
3
(
−50%), BF
3
OEt
2
did not give products and only the pristine C60 was obtained. The clay compounds,
Montmorillonite K10 and Sepiolite exhibited excellent catalytic activities toward the cyclization
reactions (Table 5).
Table 5. Catalytic activities of acidic compounds on formation of 5-dodecylindolino[60]fullerene.
a
Catalyst
Montmorillonite K10
Sepiolite
Type
Time
6 h
6 h
2 h
2 h
Yield of 8a / %
56.7
clay mineral
clay mineral
Lewis acid
Lewis acid
Brønsted acid over 5 days
Brønsted acid over 5 days
63.8
50.3
BiCl
BF ·OEt
3
3
2
0 (C60 was given)
0 (C60 was given)
trace (C60 was given)
p-TsOH
Amberlyst 15
®
a
Isolated yields, estimated from HPLC areas. Reaction condition: C60O 100 mg, 0.136 mmol;
-dodecylaniline 355 mg, 1.357 mmol; Catalyst ×2,000 wt%, chlorobenzene 100 mL, 100 °C.
4
The lack of catalytic activity of the Brønsted acid may be attributed to a neutralization process
between the Brønsted acid and anilines. For BiCl , the Lewis acidity may be slightly strong; thus, the
3
epoxy oxygen may have been removed from the C60 core more quickly than with the nucleophilic
addition of anilines. In contrast, BF
3
2
OEt forms a Lewis acid-base complex with aniline. The capped
aniline may have lost its nucleophilicity, and thus completely prevented the reaction from proceeding.
3
Cray minerals presumably have moderate Lewis acidity relative to BF , and may thus be appropriate
for the reaction.
Subsequently, in order to examine the versatility of this reaction, we carried out the reactions with a
wide variety of anilines. The examined anilines and results are summarized in Table 6. Each aniline
examined gave the corresponding indolino[60]fullerene derivative in good yield except for the reaction
with N-Me-p-toluidine (Entry 8f). For 8f, the steric hindrance of the methyl group on the nitrogen atom
might inhibit nucleophilic addition to the carbon atom of the fullerene core.

Molecules 2012, 17
6408
Table 6. Isolated yields of indolino[60]fullerene derivatives.
a
Entry
Aromatic Amine
4-Dodecylaniline
4-n-Butylaniline
p-Toluidine
4-Fluoroaniline
Aniline
5-
N-
H
H
H
H
Yield / %
77.7
8
8
a
b
n-C12
H
H
25
n-C
4
9
64.1
84.0
75.7
78.9
8
c
Me
F
H
8
d
8
e
H
8
f
N-Me-p-toluidine
Me
Me
29.3
a
Isolated yield, estimated from HPLC areas. Reaction conditions: C60O 100 mg, 0.136 mmol;
aromatic amines 1.357 mmol; Sepiolite 2.0 g; chlorobenzene 100 mL, 100 °C.
Next, we attempted to reveal the reaction mechanism of the formation of indolino[60]fullerene from
60O and anilines. By tracing the reaction with an HPLC-MS system, we revealed that the cyclization
C
reaction proceeded via 1,2-anilinoalcohol fullerene derivative. The time course of the HPLC chart and
the change in the relative peak area for each compound are shown in Figure 5.
Figure 5. Time course of the HPLC chart for the reaction of C O with 4-dodecylaniline.
6
0
At the start time, peaks corresponding to C60O at 9.3 min and slightly impure C60 at 11.8 min
appeared. At first, a new peak (9a) appeared at 5.4 min in the LC chart, and then, a peak corresponding
to 8a at 6.8 min increased as the peak area of 9a decreased. Finally, the peaks of the starting C60O and
9
a were completely consumed and the peak 8a and a small peak corresponding to pristine C as a
60
decomposed compound at 11.8 min were observed. Therefore, we surmised that 9a was an
intermediate of the indolino[60]fullerene derivative. To confirm our assumption, isolated 9a with the
catalyst under similar reaction conditions, whereupon the reaction gave 8a.
In order to assign each peak, we isolated and characterized compound 9a by means of IR, APPI-MS,
and NMR spectra. In the IR spectrum, an absorption corresponding to O–H stretching was observed at
–
1
3
,793 cm . The MS spectrum of 9a showed a peak at m/z = 998. The MS of the peak corresponds to
1
the summation of C60O (mw = 736) and dodecylaniline (mw = 262). As a result of H-NMR, we
observed in the range of 0.87–2.60 ppm, two doublet peaks of aryl protons corresponding to four
aniline protons at 7.19 and 7.61 ppm, and one singlet peak of NH at 5.93 ppm. Taking these results
into consideration, we assigned 9a to a 1-anilino-2-hydroxy[60]fullerene derivative (Scheme 4).

Molecules 2012, 17
6409
Scheme 4. Plausible reaction mechanism of indolino[60]fullerene derivative formation
from C60O and anilines.
Based on the experimental results, we proposed a plausible mechanism for the formation of
indolino[60]fullerene (8) via 1,2-anilinohydroxy fullerene (9) (Scheme 4). At first, the epoxy ring is
opened by adding a Lewis acid to the oxygen of the epoxide. Then, nucleophilic addition of anilines to
the carbon atom underlying the epoxy oxygen forms a 1,2-anilinohydroxy fullerene derivatives.
Consequently, the Lewis acid again adds to the oxygen atom of the hydroxyl group, and a C–C bond
forms between the carbon of C60 and the ortho-position of the anilino group to give the indoline-fused
fullerene derivative.
3
.4. Formation of Benzo[b]furano[2',3':1,2][60]fullerene Derivatives from C O and Phenols
60
A similar nucleophilic addition to the fullerene core and the consequent cascade cyclization reaction
with phenols via a 1-hydroxy-2-phenolic fullerene derivative as an intermediate was also observed.
This reaction gave benzo[b]furano[2',3':1,2][60]fullerene derivatives in good yields as well (Figure 6) [43].
Figure 6. Molecular structure of benzo[b]furano[2',3':1,2][60]fullerene derivatives.

Molecules 2012, 17
6410
Unlike in the case of anilines, BF
3
·OEt
2
exhibited superior catalytic activity for the reaction of C60
O
with phenols. The reaction of C60O with phenol derivatives in the presence of BF
3
·OEt
2
was complete
within 30 min for nearly all examined phenols. The different catalytic activities of the Lewis acids may
be attributed to the Lewis acidity of a catalyst, the Lewis basicity of a nucleophile, or both. For the
reaction with anilines, a complexation between BF and the amine occurs preferentially over the
3
3 3
addition of BF to the epoxy oxygen. Therefore, either BF or the aniline is completely consumed, and
the reaction cannot proceed at all. On the other hand, for benzo[b]furano[60]fullerenes, the Lewis
basicity of nearly all phenols is weaker than that of anilines. BF thus effectively catalyzes the reaction
3
of epoxy ring opening, nucleophilic addition, and cyclization.
The production yields of the benzo[b]furano[60]fullerene derivatives were subjected to the electron-
donating and withdrawing properties of the substituent of the phenols. The isolated yields are
summarized in Table 7.
Table 7. Isolated yields of benzo[b]furano[60]fullerene derivatives.
a
Entry
0b
0c
0d
0e
0g
0h
Phenols
4-n-octylphenol
4-n-butylphenol
4-methylphenol
4-methoxyphenol
4-fluorophenol
phenol
Yield / %
91.5
88.8
91.5
72.9
30.8
41.1
82.2
0
1
1
1
1
1
1
1
0i
0l
3,5-di-methoxyphenol
4-nitrophenol
1
a
Isolated yields, estimated from HPLC areas. Reaction conditions: C60O 100 mg, 0.136 mmol;
phenols 1.357 mmol; BF ·OEt 37 μL 0.136 mmol; chlorobenzene 100 mL, 70 °C.
3
2
Unlike the case of anilines, the yields of benzo[b]furano[60]fullerene derivatives were strongly
influenced by the type of substituent of the phenols. Figure 7 shows a plot of the isolated yields for
benzo[b]furano[60]fullerene derivatives as a function of the Hammett constant for the 2-position of the
precursor 4-substituted phenols [44]. Negative Hammett constants correspond to electron-withdrawing
(
EW) property, and positive ones correspond to the electron-donating (ED) property. The stronger ED
property of the substituent increases the nucleophilicity of the oxygen atom of phenols and the carbon
atoms of ortho-position of the phenols. In contrast, EW groups reduce the nucleophilicity of the
phenolic oxygen and the carbon atoms of ortho-position. Therefore, ED functional groups improve
the production yields of nucleophilic addition and cascade cyclization reactions. Conversely,
4
-nitorophenol could not produce the benzo[b]furano[60]fullerene owing to the strong electron-
withdrawing property of the nitro group. The low yield with pristine phenol (entry 10h) is presumably
due to the competitive formation of the 1,4-bisadduct (Section 3.2), because the para-position of the
phenol is not substituted.

Molecules 2012, 17
6411
Figure 7. A plot of Hammett constant vs. production yields forbenzo[b]furano[60]fullerene derivatives.
1
00
(MeO)2
Me
80
60
40
20
0
MeO
*
H
F
Cl
NO2
-0.2
0.0
0.2
0.4
0.6
0.8
Hammett constant m
4
. Conclusions
In summary, this review presents an overview of our works on the nature and chemical
transformation of fullerene epoxides. The structures of the formed fullerene epoxides, C60 , were
O
n
1
3
characterized on the basis of their LC-MS and C-NMR spectral analyses. The number of carbon
peaks and structural symmetry correlations enable the different oxygen addition sites on the fullerene
framework to be distinguished. The obtained results show highly regioselective exohedral oxygenation
of fullerene with oxidizing agents such as m-CPBA and ozone.
A variety of fullerene derivatives are easily prepared from fullerene epoxides, in which the epoxy
groups on the fullerene framework are efficiently activated to undergo chemical transformations in the
presence of a Lewis acid. We have found several Lewis acid-assisted reactions of fullerene epoxide
with various types of nucleophiles. In all of the examined nucleophilic substitution reactions on
fullerene epoxides, carbon-oxygen bond cleavage of the epoxy ring occurs with a front side attack of a
nucleophile. Moreover, the substitution reaction of the fullerene di-epoxide proceeds while the
rearrangement of the two epoxy rings on the fullerene cage is conserved. Fullerene epoxides are
0
.39"materials in many industrial fields.
Acknowledgments
The author is deeply grateful to Kazuo Takeuchi (Senior Research Priority Planning Member of
RIKEN’s Research Priority Committee) for his kind and continuous help, as well as to Takumi Hara,
Takeshi Honma, Shizuka Seo, Yumiko Yamada, Jun-ichi Kawashima and Mikio Hoshino of RIKEN
Nano-integration Materials Research Unit for their experimental contributions and helpful discussions.
This work was financially supported by NEDO (Grant for Practical Application of University R&D
Results under the Matching Fund Method).

Molecules 2012, 17
6412
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