Hierarchical selectivity in fullerenes: Site-, regio-, diastereo-, and enantiocontrol of the 1,3-dipolar cycloaddition to C70

Article abstract of DOI:10.1002/anie.201101246

Make your choice of stereochemistry: The first enantioselective cycloaddition of N-metalated azomethine ylides to the C₇₀ molecule affords both pyrrolidino[70]fullerene enantiomers, with ee values over 90 %, depending on the chiral metal comple

Full text of DOI:10.1002/anie.201101246

Communications
DOI: 10.1002/anie.201101246
Fullerenes
Hierarchical Selectivity in Fullerenes: Site-, Regio-, Diastereo-, and
Enantiocontrol of the 1,3-Dipolar Cycloaddition to C70**
Enrique E. Maroto, Abel de Cꢀzar, Salvatore Filippone, ꢁngel Martꢂn-Domenech,
Margarita Suarez, Fernando P. Cossꢂo,* and Nazario Martꢂn*
Dedicated to Professor Luis Echegoyen on the occasion of his 60th birthday
Since the discovery of fullerenes[1] and their further prepara-
tion on a multigram scale,[2] these molecular carbon allotropes
have been thoroughly investigated from the chemical view-
point in the search for new modified fullerenes that are able
to exhibit unconventional properties for practical applica-
tions.[3] Furthermore, this knowledge has allowed a faster and
better understanding of the chemical reactivity of the related
carbon nanostructures, in particular of the promising carbon
nanotubes, endohedral fullerenes, and the most recent
graphenes.[4] However, the number of studies on the reactivity
of higher fullerenes is comparatively scarce and the use of
asymmetric catalysis in these systems has been neglected so
far.[5]
covalent chemistry, in which chirality is an important and
fascinating aspect.[6] The preparation of chiral fullerenes has
been based on chiral starting materials or, alternatively, on
the most common racemic syntheses followed by complex,
expensive, and highly time-consuming chromatographic iso-
lation and purification processes.[7] However, even when the
isolation of the different isomers is feasible, the high costs and
low abundance of higher fullerenes make necessary the
availability of an efficient synthetic methodology to limit a
broad distribution of products.
Recently, we reported a straightforward procedure cata-
lyzed by silver or copper acetate to efficiently obtain
pyrrolidino[60]fullerenes with stereochemical control by
enantioselective cycloaddition of azomethine ylides to the
Higher fullerenes include a great diversity of molecules
with different structures and chemical behavior that, because
of the minor degree of symmetry, give rise to a complex
C
60 molecule.[8] However, the extension of the scope of such a
methodology to higher fullerenes, namely C70, is not a trivial
process because C70 has to face many distinct levels of
selectivity.
[*] E. E. Maroto, Dr. S. Filippone, Dr. ꢀ. Martꢁn-Domenech,
Prof. Dr. N. Martꢁn
Unlike C60, C70 lacks a spherical symmetry and has four
different types of double bonds on the cage. The most
common additions to [70]fullerene proceed in a 1,2 manner
with a regioselectivity driven by the release of the strain of the
double bond. Accordingly, additions occur preferentially at
the most strained fullerene double bonds, namely those
located at the polar zone (a site followed by b and g sites).
The flatter equatorial region is less reactive and the
addition only rarely takes place at the double bond of the
d site.[9] Particularly, cycloadditions of azomethine ylides
typically give rise to the a, followed by the b, and a small
Departamento de Quꢁmica Orgꢂnica I
Facultad de Ciencias Quꢁmicas
Ciudad Universitaria s/n, 28040 Madrid (Spain)
Fax: (+34)91-394-4103
E-mail: nazmar@quim.ucm.es
Homepage: http://www.ucm.es/info/fullerene
Prof. Dr. N. Martꢁn
IMDEA-Nanociencia
Campus Cantoblanco, 28049 Madrid (Spain)
Prof. Dr. M. Suarez
Laboratorio de Sꢁntesis Orgꢂnica, Facultad de Quꢁmica
Universidad de La Habana, 10400 La Habana (Cuba)
ꢀ
ꢀ
amount of the g regioisomers (C(8) C(25), C(7) C(22),
ꢀ
Dr. A. de Cꢃzar, Prof. Dr. F. P. Cossꢁo
Departamento de Quꢁmica Orgꢂnica
Facultad de Ciencias Quꢁmicas
Departamento de Quꢁmica Orgꢂnica I
Universidad del Paꢁs Vasco (UPV/EHU)
and
Donostia International Physics Center (DIPC)
P. O. Box 1072, 20018 San Sebastiꢂn-Donostia (Spain)
Fax: (+34)943-01-52-70
C(1) C(2) according to the systematic numbering;
Figure 1).[10]
We propose to refer to these isomers (a, b, etc.) and to this
form of selectivity as “site isomers” and site selectivity,
respectively,[11] to distinguish them from the regioisomers that
result from the addition of nonsymmetric 1,3-dipoles to a
double bond of the fullerene sphere. Indeed, depending on
the orientation of the asymmetric azomethine ylide addition
to the fullerene double bond, two regioisomers are, in turn,
possible for each of the formed cycloadducts (see Figure 1).
Furthermore, each of these regioisomeric pyrrolidines could
be formed in a cis or trans configuration (diastereomers) and,
in turn, in both of the enantiomeric forms.
E-mail: fp.cossio@ehu.es
[**] Financial support by the Ministerio de Ciencia e Innovaciꢃn
(MICINN) of Spain (projects CTQ2010-16959, CTQ2008-00795/
BQU; Consolider-Ingenio CSD2007-00010, CSD2007-00006;
research grant, E.E.M.; R y C grant; S.F), the Basque Goverment (IT-
324-07) and the CAM (MADRISOLAR-2 project S2009/PPQ-1533) is
aknowledged. The authors also thank the SGI/IZO-SGIker UPV/
EHU for generous allocation of computational resources.
Herein we describe an efficient catalytic site-, regio-,
diastereo-, and enantioselective cycloaddition of N-metalated
azomethine ylides to C70 at low temperatures and while
maintaining the atom economy principle. This methodology
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101246.
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Angew. Chem. Int. Ed. 2011, 50, 6060 –6064

Table 1: The cycloaddition reaction of iminoesters (1a–f) to [70]fullerene
selectively affords compounds 2 and 3 (a-site isomer), which are formed
as a mixture of two regioisomers constituted in turn by cis and trans
stereoisomers.
Entry Iminoester t [h]
Selectivity
(T [8C])
(Yield [%])[c]
Site- (a:b) Regio-
Diastereo-
(2:3)[d]
(cis:trans)[e]
1
2
3
4
5
6
7
8
9
10
1a (ꢀ30)[a] 12 (47)
1b (ꢀ45)[a] 15 (40)
1c (ꢀ40)[a] 15 (41)
1d (ꢀ40)[a] 15 (41)
1e (ꢀ39)[a] 15 (41)
97:3
99:1
94:6
94:6
94:6
97:3
95:5
95:5
95:5
94:6
82:18
90:10
85:15
88:12
83:17
80:20
85:15
91:9
97:3
97:3
99:1
99:1
96:4
15:85
11:89
9:91
11:89
15:85
Figure 1. Different levels of selectivity for a cycloaddition reaction with
the C70 molecule (site-, regio-, diastereo-, and enantioselectivity). Each
highlighted molecule gives rise to the following level of selectivity.
1a (25)[b]
1b (25)[b]
1c (25)[b]
1d (25)[b]
1e (25)[b]
0.3 (77)
0.3 (77)
0.3 (75)
0.3 (72)
0.3 (72)
97:3
82:18
allows the synthesis of chiral pyrrolidino[70]fullerenes with a
controlled stereochemistry that depends on the metal com-
plexes used. The azomethine ylide cycloaddition to [60]ful-
lerenes is one of the most employed and versatile methods for
the functionalization of C60.[12] However, it has been mainly
limited to symmetric 1,3-dipoles for [70]fullerene. Indeed, for
the most simple example reported, the thermal cycloaddition
of N-methylazomethine ylide to C70 gave a mixture of the
[a] Experimental conditions: dppe (5), AgAcO; [b] Experimental con-
ditions: binap (4), [Cu(TfO)2]/Et3N; [c] Determined by HPLC, with
respect to the sum of monoadduct isomers; [d] Determined by 1H NMR
spectroscopy and HPLC (see the Supporting Information and Ref. [14]);
[e] Compound 2.
would produce very low yields, even after chromatographic
separation using chiral stationary phases.
ꢀ
ꢀ
ꢀ
three site isomers C(8) C(25), C(7) C(22), and C(1) C(2)
(a:b:g) in a 46:41:13 ratio.[13] As a first step in our present
study, we investigated the cycloaddition of iminoesters (1a–f)
as stabilized 1,3-dipoles to [70]fullerene (Table 1).
To address this issue, we have carried out the cyclo-
addition to C70 by using copper or silver catalysts (exper-
imental conditions [a] and [b] in Table 1). In the presence of
20% of silver acetate and [1,2-bis(diphenylphosphino)-
ethane] (dppe, 5), imino esthers 1a–f undergo cycloaddition
in toluene at low temperatures to form the cis pyrroli-
dino[70]fullerenes 2a–e in relatively good yields (up to 40%).
The good values of site selectivity shown in the previous
thermal addition are improved and, therefore, the amount of
the minor b-site isomers formed at higher temperatures
decreased to 1–6% (Table 1, entries 1–5). More important,
however, was the effect on the regioselectivity; the regioisom-
ers with the ester moiety on the polar region and the aromatic
ring on the equatorial region were formed preferentially with
a ratio ranging from 8:2 to 9:1, as in the case of dipole 1b
(Table 1, entry 2).
By thermal treatment in refluxing toluene, the addition to
C70 occurs with a good a-site selectivity. b-Site isomers are
formed only in low yield (from 4% to 10%, see the
Supporting Information) and no trace of the g isomer was
detected. However, such a-site isomers are formed as a 1:1
regioisomeric mixture of 2-methoxycarbonyl-5-aryl pyrroli-
dino[3,4:25’,8’][70]fullerene (2) and 2-methoxycarbonyl-5-
aryl pyrrolidino[3,4:,8’:25’][70]fullerene (3).[14] Each regioiso-
mer is formed in turn in a diastereomeric ratio (cis/trans) of
around 60:40 (Table S1 in the Supporting Information,
entries 1–5). The symmetric 1,3-dipole 1 f cannot form
regioisomers and therefore only one product is obtained as
previously reported (Table S1, entry 6).[15] Despite this
increase of site selectivity, the thermal treatment is not a
suitable method to obtain efficiently chiral pyrrolidinoful-
lerenes because a broad product distribution of stereoisomers
Copper triflate along with racemic Binap (4) and triethyl-
amine as a base were found to be a complementary catalyst
system for the preparation of pyrrolidinofullerenes with a 2,5
trans configuration (Table 1, entries 6–10). At room temper-
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Communications
ature, this complex prompts the cycloaddition on the a site of
induction between them for both the major (2a) and the
minor (3a) regioisomers (see Table 2 and the Supporting
Information).
the C70 within 15 minutes and with yields over 70%. The
regioselectivity observed is similar to that obtained with the
silver complex, and the 2-methoxycarbonyl-5-aryl pyrroli-
dino[3,4:25’,8’] [70]fullerene regioisomer that bears the ester
group on the polar zone is formed in a 80–97% ratio. The
copper complex at room temperature is able to invert the
diastereoselectivity to form trans pyrrolidinofullerene with a
ratio that ranges from 85:15 to 91:9. The obtained results
clearly showed the ability of the metal catalyst to control the
cycloaddition process of azomethine ylides, thus avoiding the
undesired broad product distribution.
Therefore, we looked for a broadening of the scope of
such a methodology towards the synthesis of optically active
pyrrolidino[70]fullerenes through chiral induction. To this
end, we used the chiral metal complex 7, based on the pair
silver acetate and (ꢀ)1,2-bis[(2R,5R)-2,5-diphenylphosphola-
no]ethane, and the Fesulphos-copper(II) acetate 6 (Table 2).
In particular, it is worth mentioning that the metal
complex formed by copper acetate and Fesulphos 6 gives
rise to an even better chiral induction than the related
[60]pyrrolidines with ee ranging from 92% to 99% as in the
case of pyrrolidines 2b and 3b (Table 2). These selectivity
levels allow, for the first time, to gain control over the
enantiomeric outcome of the cycloaddition process on
[70]fullerene, and they allow to obtain a single stereoisomer
(with the indicated ee) in relatively good yield (20–30%) after
purification by column chromatography.[16] As expected, the
two metal complexes 6 and 7 give rise to enantiomers with the
same UV/Vis spectra but with opposite Cotton effects in
circular dichroism (CD) spectroscopy (see Figures S31–S37).
Since in these reactions the fullerene acts as an electro-
philic dipolarophile, we performed DFT calculations[17–20]
(B3LYP/LANL2DZ level of theory) on C70 (Figure 2A) to
Table 2: Asymmetric AgI and CuII-catalyzed 1,3-dipolar cycloadditions of
azomethyne ylides derived from imines 1a–e to [70]fullerene using
different chiral ligands.
Imine Ligand
Yield
[%][a]
regioselectivity
2:3
de 2 ee 2 (ee 3)
(T [8C])
Figure 2. a) Electrostatic potential projected on the electron density of
C70 (B3LYP/LANL2DZ level of theory). Given numbers are the electro-
philic Fukui indexes at the a–g sites in arbitrary units. The higher the
number, the higher the local electrophilicity. b) Fully optimized silver
azomethine ylide (B3LYP/LANL2DZ:PM6 level of theory) derived from
imine 1b and diphosphine 7. B3LYP and PM6 layers are represented in
ball and stick and tube modes, respectively). The blockage of the
(re,re) face is readily appreciated. Numbers correspond to the nucleo-
philic Fukui indices in arbitrary units.
1a
1a
7(ꢀ30)
20
23
24
31
23
30
22
24
20
24
81:19
82:18
90:10
90:10
85:15
85:15
87:13
88:12
83:17
83:17
94 89 (90)
6 (ꢀ35)
94 ꢀ93 (ꢀ93)
1b[b] 7 (ꢀ43)
1b[b] 6 (ꢀ45)
94 80 (80)
94 ꢀ99 (ꢀ99)
98 88 (88)
1c
1c
1d
1d
1e
1e
7 (ꢀ40)
6 (ꢀ45)
7 (ꢀ40)
6 (ꢀ48)
7 (ꢀ30)
6 (ꢀ35)
99 ꢀ95 (ꢀ94)
98 87 (87)
99 ꢀ92 (ꢀ92)
93 86 (86)
94 ꢀ92 (ꢀ93)
[a] With respect to the product isolated after column chromatography on
silica gel and HPLC purification and with the ee indicated. [b] The
presence of the thienyl changes the priority on the C 5 chiral carbon
atoms.
assess the local electrophilicity of the different sites by means
of the electrophilic Fukui functions fkþ of different atoms.[21]
Our results are compatible with the site selectivity observed.
Thus, the a site is the most electrophilic one (highest fkþ
values), followed by the b and g sites.
These complexes showed a very similar behavior in
obtaining almost the same level of site- and regioselectivity
that was obtained when no chiral complexes were used.
Indeed, both 6 and 7 direct the cycloaddition of iminoester 1a
towards the a site with a 98% selectivity, whereas the
regioisomeric ratio between 2 and 3 ranged from 4:1 to 9:1
(Table 2). The stereoselectivity values determined with these
chiral complexes were similar to those obtained for the
related C60.[8]
These reactive sites exhibit different values for the
individual atoms, thus predicting asynchronous reaction
paths and regioselectivity issues. Geometry optimization
(B3LYP/LANL2DZ:PM6 level of theory) of the azomethine
ylide derived from imine 1b, silver acetate, and diphosphine 7
(Figure 2B) shows an efficient blockage of the (si,re) face
induced by a phenyl group.
In addition, the fꢀ Fukui nucleophilic functions localized
on the carbon atoms of the dipole show an enolate-like
nucleophilicity of the azomethine moiety, since the fꢀ value
for the a carbon atom of the dipole is larger than that
Finally, metal complexes formed by silver-phosphine 7
and copper-Fesulphos 6 presented a high and opposite chiral
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corresponding to the other carbon terminus of the dipole
(Figure 2B).
Figure 3 shows the geometries and energies of the possible
transition structures associated with the different processes
gathered in Figure 1. The outcome is consistent with the
result is indicative of the appropriate coupling between the
centres that possess the largest nucleophilic and electrophilic
Fukui indexes (see above). This factor is also responsible for
the large asynchrony of the computed transition structures
that actually correspond to stepwise mechanisms (see the
Supporting Information).
The diastereoselectivity observed is also compatible with
the higher stability of the cis dipoles, which favors formation
of the corresponding cis cycloadducts (Figure 3). However,
the stepwise nature of the cycloaddition results in zwitterionic
intermediates that cyclize to give the corresponding pyrroli-
dines with quite low activation barriers. Therefore, our
calculations indicate that the origins of the observed selec-
tivity are determined by the first step of the cycloaddition at
the site-, regio-, and enantio- levels, although a small loss of
diastereocontrol cannot be ruled out during the second step of
the reaction. It is interesting to note that our calculations also
indicate that the metal-catalyst complex shows a lower
affinity for the cycloadduct than for the starting azomethine
ylide, thus allowing the completion of the catalytic cycle (see
Figure S38).
In summary, we describe the first enantioselective cyclo-
addition of N-metalated azomethine ylides with the C70
molecule that affords the respective enantiomers, with ee
values higher than 90%, depending on the chiral metal
complex used. Furthermore, the highly regioselective process
observed for the formation of the regioisomers that results
from the cycloaddition of the 1,3-dipole to the a-site double
bond of the C70 (up to 9:1) has been accounted for by the
nucleophilic and electrophilic Fukui indexes determined by
theoretical calculations (B3LYP/LANL2DZ). This work
paves the way to the selective control (site-, regio-, dia-
stereo-, enantiocontrol) in the functionalization of higher
fullerenes, as well as endohedral fullerenes, which still
represents a challenge in fullerene research.
Figure 3. Fully optimized first transition structures (B3LYP/LANL2DZ//
B3LYP/LANL2DZ:HF/PM6+DZPVE) associated with the formation of
(R,S) and (S,R) cis-2b by reaction between imine 1b and [70]fullerene
catalyzed by diphosphine 7. High and low computational levels in the
ONIOM partition are represented in ball and stick and tube modes,
respectively. Bond lengths are given in ꢄ.
Received: February 18, 2011
Published online: May 9, 2011
Keywords: asymmetric catalysis · computational chemistry ·
.
1,3-dipolar cycloaddition · fullerenes · stereoselectivity
predictions made on the basis of the previous DFT analysis.
Thus, saddle points associated with nucleophilic attacks on
the a site of C70 reported in Figure 3 show that (R,S) cis-TS1b
is approximately 1.5 kcalmolꢀ1 lower in energy than its (S,R)
analogue. The calculated deformation energy for the dipole
catalyst moiety in (R,S) cis-TS1b is 4.5 kcalmolꢀ1, whereas
the corresponding value for (S,R) cis-TS1b is 5.7 kcalmolꢀ1.
This result indicates that the (si,re) attack requires a larger
deviation of the catalyst conformation from its optimum
conformation shown in Figure 2A, thus favoring the (re,si)
attack, which is consistent with the experimentally observed
enantioselectivity.
As far as the regioselectivity of the reaction is concerned,
transition structure (R,S) cis-TS1’b is calculated to be
approximately 2 kcalmolꢀ1 higher in energy than that ((R,S)
cis-TS1b) associated with the formation of the saddle point
and leading to the predominant regioisomer that bears the
metyhoxycarbonyl substituent above the polar region. This
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[11] The different isomers formed in the addition reactions to
[70]fullerene have been called regioisomers (a, b, g, and d).
This nomenclature is very useful for most of the examples
reported in the literature. However, we feel that the use of the
term “regioisomers” to describe the addition to different double
bonds on the fullerene sphere and, simultaneously, to refer to the
different orientations in which the asymmetric 1,3-dipole can be
added to one double bond, could generate a certain degree of
confusion or ambiguity. For the use of “site-isomers” nomen-
clature, see: I. Fleming in Molecular Orbitals and Organic
Chemical Reactions, Wiley, Chichester, 2010.
[12] a) M. Maggini, G. Scorrano, M. Prato, J. Am. Chem. Soc. 1993,
115, 9798 – 9799; b) M. Prato, M. Maggini, Acc. Chem. Res. 1998,
31, 519 – 526.
[13] a) S. R. Wilson, Q. Lu, J. Org. Chem. 1995, 60, 6496 – 6498; b) F.
Langa, P. de La Cruz, A. de La Hoz, E. Espꢂldora, F. P. Cossꢂo, B.
Lecea, J. Org. Chem. 2000, 65, 2499 – 2507.
[14] The structural assignment has been done based on the 1H NMR
spectroscopy deshielding effect of the polar zone on the
substituent located above this zone (see the Supporting Infor-
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