Regioselective electrophilic addition vs epoxidation of mCPBA towards anti-Bredt olefin of fulleroid

Article abstract of DOI:10.1016/j.tetlet.2012.05.007

The mCPBA oxidation of methano-bridged [5,6] open fulleroid 1 anomalously resulted in the selective electrophilic addition at the bridgehead anti-Bredt double bond rather than the usual epoxidation. The mechanistic preference for the unprecedented stepwis

Full text of DOI:10.1016/j.tetlet.2012.05.007

Tetrahedron Letters 53 (2012) 3581–3584
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Tetrahedron Letters
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Regioselective electrophilic addition vs epoxidation of mCPBA towards
anti-Bredt olefin of fulleroid
⇑
⇑
Naohiko Ikuma , Satoko Sumioka, Haruyasu Asahara, Takumi Oshima
Division of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The mCPBA oxidation of methano-bridged [5,6] open fulleroid 1 anomalously resulted in the selective
electrophilic addition at the bridgehead anti-Bredt double bond rather than the usual epoxidation. The
mechanistic preference for the unprecedented stepwise addition of mCPBA vs the concerted epoxidation
Received 14 March 2012
Revised 26 April 2012
Accepted 2 May 2012
Available online 11 May 2012
was explained in terms of the notable
calculation.
p
-orbital misalignment (>30°) based on the B3LYP/6-31G(d) level
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Fullerene
Oxidation
Anti-Bredt olefin
Electrophilic addition to olefin
Although, fullerenes are well known as electrophiles due to the
low-lying LUMO orbitals,1 they can also behave as nucleophiles in
some chemical modifications such as epoxidation2 with m-chloro-
perbenzoic acid (mCPBA). The fullerene epoxides are useful reactive
intermediates in the synthesis of regioselective bis-adducts3 and
fullerene dimer.4 However, the control of reaction conditions to
selectively give monoepoxide has been a challenging task because
of the presence of a number of reactive [6,6] bonds in spherical ful-
lerenes. In fact, the reaction of C60 with mCPBA gives a mixture of
monoepoxide and various multiepoxides, from which it is difficult
to separate each of them. We are interested in the reactivity of
[5,6] open fulleroid5,6 1 with highly-twisted bridgehead double
bonds7 as a useful synthetic entity to develop a new regioselective
synthetic methodology in fullerene chemistry. Fulleroids are
oxidation of fulleroids with the aim of bringing about the regiose-
lective epoxidation. In this paper, we would like to report the
unprecedented electrophilic addition of mCPBA to the anti-Bredt
olefin of the fulleroid 1 as shown in Scheme 1 and discuss the
mechanistic feature on the basis of the B3LYP/6-31G(d) calculation.
known as homofullerenes still retaining 60p-electron system and
to exhibit the regioselective Zn(Cu) catalyzed hydrogenation8 and
photooxygenation with singlet oxygen9 at the bridgehead olefin.
In our recent study on the comparative reactivity of the [5,6]
open fulleroids vs C60, we have found the noticeably enhanced
reactivity of the fulleroids at the bridgehead double bonds in
Diels–Alder reaction with some flexible 1,3-dienes.10 It was also
expected that the higher
p
-orbital misalignment angle s11
(ꢀ30°),8,10 as compared to the usual anti-Bredt olefins (10ꢀ20°,
vide infra), would result in a dramatic change in the reactivity
mode. These situations prompted us to investigate the mCPBA
⇑
Corresponding authors. Tel./fax: +81 6 6879 4593.
E-mail addresses: ikuma@chem.eng.osaka-u.ac.jp (N. Ikuma), oshima@chem.
eng.osaka-u.ac.jp (T. Oshima).
Scheme 1. Electrophilic addition of mCPBA to fulleroid.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.007

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N. Ikuma et al. / Tetrahedron Letters 53 (2012) 3581–3584
Methano-bridged fulleroid 1 was prepared by the literature
the characteristic IR absorption at 1727 cmÀ1 assignable to the
benzoate ester group. Unfortunately, this fraction was still the
regioisomeric mixture (major/minor = 3) of 1:1 adducts 2a/2b by
1H NMR spectrum (Fig. 2). Although, an attempt to separate and as-
sign these region-isomers was failed, we tentatively assign 2a to
the major isomer according to the calculation (vide infra).
However, the 1,2-addition at the bridgehead double bond was
undoubtedly evidenced by the following facts. (1) The significant
down-field shift (1.6–2.3 ppm) of the methano-bridged H(b) was
found for the major (d = 5.2 ppm, Fig. S2) and for the minor (4.5),
respectively, as compared to that of parent 1 (2.9).12d These shifts
were clearly explained by the reduction of the shielding effects of
underlying hexagonal triene ring by 1,2-addition of mCPBA. (2) The
2D HMBC correlation is observed (Fig. S3) between each of the
bridged H(a)/H(b) and the OH or m-chlorobenzoate (mCB)-substi-
tuted remote sp3-carbon (Cb, red circle). (3) The existence of NOE
interaction between the hydroxy proton H(g) and the magnetically
isolated o-proton H(f) would support the formation of 1,2-adducts
(Fig. S4). However, there is no NOE enhancement between the
bridged CH2 and any proton of the mCB group, indicating the less
congested outward orientation of mCB moiety.
methods.10,12 The oxidation of 1 with mCPBA (10 equiv.) at 30 °C
gave several oxidized products, as seen in the HPLC chart of the
reaction mixture (Fig. 1a). The APCI-LCMS measurement showed
the sharp peak of the residual 1 along with the following broad
peak consisting of a mixture of 1:1 adduct (1 + mCPBA: m/
z = 906) and its fragment (m/z = 751, 1+OH+) (Fig. 1b). The preced-
ing shoulder fraction overlapped with 1 seems to be monoepoxide
(m/z = 922) of the 1:1 adduct and its fragment (m/z = 767) (Fig. 1c).
The portion of 1:1 adduct was successfully fractionated by silica
gel column chromatography (15.4 mg; 15% isolated yield).13,14 The
purity was verified by HPLC (Fig. S1). The isolated product showed
This electrophilic esterification of fulleroid by mCPBA is unprec-
edented and markedly contrast to the usual epoxidation of C60 as
well as the common olefins.15 It is likely that the highly twisted
double bond of 1 plays a crucial role in the present 1,2-addition
of mCPBA. Then, we calculated its transition state (TS) and intrinsic
reaction coordinate (IRC) with B3LYP/6-31G(d) level (Fig. 3) in or-
der to gain a mechanistic insight into the mCPBA oxidation of 1.16
The results showed the asymmetric transition state TS-1 (Fig. 3a)
in which the relevant OH group is located more closer to the
bridgehead C than to the adjacent Cb carbon and then leads to
a
the ionic intermediate 1aOH+(Fig. 3b).17 On the other hand, the
Figure 1. (a) HPLC chart for mCPBA oxidation of 1 (after 6 h) and APCI-MS (positive)
of (b) 2a + 2b and (c) byproduct.
Figure 2. 1H NMR chemical shifts (d of 2a/2b (red: major, blue: minor) in (a) 7.5–
8.5 ppm and (b) 4.4–5.7 ppm range.

N. Ikuma et al. / Tetrahedron Letters 53 (2012) 3581–3584
3583
Scheme 2. Comparative reaction pathways; (a) concerted epoxidation versus (b)
stepwise electrophilic addition.
interaction with mCPBA as in route (a). The generated intermediate
1aOH+ undergoes the addition of m-chlorobenzoate (mCBÀ), rather
than the ring-closure to epoxide. Indeed, the intervention of such
intermediate was proved by formation of the crossover p-methyl
benzoate adduct (m/z = 886) when p-toluic acid coexists (route
(c) in Scheme 2 and Fig. S7).
Figure 3. Relative energy versus the reaction coordinate (translated to the distance
between C or Cb) and OCPBA for TS-1 or TS-2, respectively, obtained from TS and IRC
a
calculations. (a) Geometry of the TS-1 of 1 + mCPBA reaction (imaginary
One question is raised why mCPBA oxidation of several anti-
freq. = À504 cmÀ1, dipole moment (
l
) = 3.6 D). (b) Geometry of the 1aOH+ and m-
Bredt olefins23 exclusively gave the epoxides. The
p-orbital mis-
chlorobenzoate (mCBÀ) obtained from the IRC calculation (not optimized struc-
ture).17 (c) Geometry of the TS-2 of 1 + mCPBA reaction (Imaginary freq. =
alignment angle
s (15.7° for bicyclo[3.3.l]non-l-ene, calculated by
À496 cmÀ1 = 5.4 D). (d) Geometry of the 1bOH+ and m-chlorobenzoate (mCBÀ)
, l
B3LYP/6-31G(d)) is considerably smaller than those of the fulle-
roids (>30°).8,10 The calculation for the bicyclic compound provided
rather symmetrical TS (Fig. S8) in accord with the actual epoxida-
tion, implying that even anti-Bredt olefins allow the symmetric TS
obtained from the IRC calculation (not optimized structure).17 These geometries
and energies were calculated by B3LYP/6-31G(d) level without solvation parameter.
The yellow balls denote the cycloheptatriene ring.
via route (a), when
s is not so large.
In conclusion, we have found that the methano-bridged [5,6]
open fulleroid 1 underwent the stepwise bimolecular electrophilic
addition (AdE2) of mCPBA at the twisted bridgehead double bond
asymmetric approach of mCPBA to the Cb carbon would generate
the energetically higher transition state TS-2 and provide the less
stable intermediate 1bOH+ (Fig. 3c,d),17 in conformity with the
minor 2b. Although the energy difference (3.8 kcal/mol) between
TS-1 and TS-2 is larger than the value deduced from the experi-
mental product ratio (3:1), this may be ascribed to the several rea-
sons.18 The appreciable difference in HOMO orbital coefficients of
the anti-Bredt double bond moiety is also likely responsible for
such an asymmetric electrophilic attack (Fig. S6). These two
pathways can be terminologically categorized as bimolecular elec-
trophilic addition (AdE2).
to afford the regioisomeric mixture of
robenzoates. This unusual addition was rationalized by the larger
torsional angle of double bond (
a-hydroxyfullerenyl m-chlo-
s
ꢀ30°), which would inhibit the
symmetric TS (so-called butterfly TS) generally argued for the con-
certed epoxidation of olefins.
Acknowledgment
This work was supported by Grant-in-Aid for Young Scientist
(B) (No. 24750039) from Japan Society for the Promotion of Science
(JSPS), Japan.
To verify whether the present calculations are reasonable, we
have compared our results with those of the previously reported
mCPBA oxidation of olefins.19–21 Though, the reported studies have
mainly concerned the simple and less twisted alkenes, two reac-
tion pathways have been proposed; one is the generally accepted
concerted process via a butterfly-like symmetrical transition state
(route (a) in Scheme 2)19 and another is the stepwise process via
asymmetric transition state and the ionic intermediate,20 similar
to the present calculation (route (b) in Scheme 2). While the higher
level calculations19a and the detailed investigation of isotope effec-
t15a,21 supported the concerted mechanism, our results indicated
that twisted olefin prefers the route (b),22 probably because the
Supplementary data
Supplementary data (NMR of 2a + 2b, DFT calculation for 2a and
2b, crossover experiment with p-toluic acid, transition state
calculation of bicyclo[3.3.l]non-l-ene, and full citation of Gaussian
09) associated with this article can be found, in the online version,
at http://dx.doi.org/10.1016/j.tetlet.2012.05.007. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
highly twisted p-orbital could not perform the symmetrical orbital

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N. Ikuma et al. / Tetrahedron Letters 53 (2012) 3581–3584
24%, and isolated yield is 15%) and recovered 1 (29.4 mg) and byproduct
References and notes
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(d, J = 11.4 Hz, 1H), 5.59 (d, J = 11.4 Hz, 1H), 7.56 (t, J = 8.4, 7.8 Hz, 1H,
overlapped with minor), 7.67 (d, J = 7.8 Hz, 1H, overlapped with minor), 8.18
(d, J = 8.4 Hz, 1H), 8.24 (s, 1H); Minor isomer: d 4.56 (s, 1H), 4.62 (d, J = 11.4 Hz,
1H), 5.13 (d, J = 11.4 Hz, 1H), 7.56 (t, J = 8.4, 7.8 Hz, 1H, overlapped with major),
7.67 (d, J = 7.8 Hz, 1H, overlapped with major), 8.31 (d, J = 8.4 Hz, 1H), 8.40 (s,
1H). 13C NMR(150 MHz, CS2:CDCl3 = 3:1) d 32.7(s, CH2), 85.7(s, C), 94.6(s, C),
127.8(s, CH), 130.0(s, CH), 130.3(s, CH), 134.0(s, CH), 163.3(s, C@O), except for
the signals assigned to the fulleroid sp2 carbons (125–155 ppm, See Fig. S2). IR
(KBr) 3438, 2929, 1727, 1282, 1251, 1086 cmÀ1. HRMS (FAB-MS): Calcd for
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with mCPBA produce
a-hydroxyl esters, although the mechanism was not
discussed or featured to involve an epoxidation/acidic ring-opening sequence.
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(Fig. S5). One reason for the inconsistency between the differential TS energy
and the isomer ratio may be the absence of entropy term (
calculation in addition to the lack of solvation parameter. One can also
conceive that the solvent toluene = 0.375 D, from CRC Handbook of
Chemistry and Physics 91st ed.) will more stabilize the polar TS-2 ( = 5.4 D)
than TS-1 ( = 3.6 D), thus reducing the differential isomer ratio of 2a/2b.
D
Sà) on the present
(
l
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compared to the previous theoretical calculations (such as QCISD in Ref.
19a), these higher calculations cannot be straight forwardly applied to fulleroid
with too many atoms and electrons. Multi-layered method such as ONIOM will
enable such higher level calculation to fulleroid, as the following recent ONIOM
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13. Reaction procedure and spectral data of the regioisomeric mixture of 2a and
2b. mCPBA (386 mg, 2.23 mmol) and 1 (82.1 mg, 0.112 mmol) were dissolved
in toluene. The solution was stirred overnight at 30 °C, and the progress of
reaction was traced by HPLC (buckyprep). The reaction mixture was
concentrated and submitted to silica gel column chromatography (toluene/
hexane) to give 15.4 mg of 2a + 2b mixture (0.017 mmol, conversion yield is