Thermal [2 + 2] cycloaddition of morpholinoenamines with C60 via a single electron transfer

Article abstract of DOI:10.1021/ol201590a

The thermal reaction of C₆₀ with five- and six-membered morpholinocycloalkenes in refluxing toluene exclusively gave the [2 + 2] cycloadducts in high yields. However, a seven-membered homologue sluggishly reacted with C₆₀ because of the increasing steric hindrance. This cycloaddition reaction is likely to proceed via a single electron transfer (SET), a radical-coupling, and subsequent ion cyclization rather than the prior proton transfer between the radical ions.

Full text of DOI:10.1021/ol201590a

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4244–4247
Thermal [2 þ 2] Cycloaddition of
Morpholinoenamines with C60 via a Single
Electron Transfer
Tsubasa Mikie, Haruyasu Asahara, Kazuaki Nagao, Naohiko Ikuma, Ken Kokubo, and
Takumi Oshima*
Division of Applied Chemistry, Graduate School of Engineering, Osaka University 2-1,
Yamadaoka, Suita, Osaka 565-0871, Japan
oshima@chem.eng.osaka-u.ac.jp
Received June 14, 2011
ABSTRACT
The thermal reaction of C60 with five- and six-membered morpholinocycloalkenes in refluxing toluene exclusively gave the [2 þ 2] cycloadducts in
high yields. However, a seven-membered homologue sluggishly reacted with C60 because of the increasing steric hindrance. This cycloaddition
reaction is likely to proceed via a single electron transfer (SET), a radical-coupling, and subsequent ion cyclization rather than the prior proton
transfer between the radical ions.
Cycloaddition reactions of fullerenes at the [6,6] con-
junct double bond are valuable methods for chemical
modification and have attracted continuous attention in
view of the synthesis of fullerene derivatives and new
materials.1 Especially, a vast amount of study has been
made of the thermally allowed [2 þ 4] and [2 þ 3] concerted
reactions such as DielsꢀAlder2 and 1,3-dipolar cyclo-
additions.3 In these reactions, fullerenes behave as electron-
poor 2π components due to the highly conjugated low
lying LUMO. In contrast to the photochemical [2 þ 2]
cycloadditions,4 however, the thermal [2 þ 2] cycloaddi-
tion of fullerenes is very scarcely known in fullerene
chemistry as found in some extreme cases such as the
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r
10.1021/ol201590a
Published on Web 07/21/2011
2011 American Chemical Society

reactions with tetraalkoxyethylenes,5 1,2-dicarbometho-
xycyclobutadiene,6 and allenamides.7 In this paper, we
report that morpholinocycloalkenes (enamines) react with
C
60 to give exclusively [2 þ 2] monoadducts in high yields
in refluxing toluene. We also proposed a possible mecha-
nism of this cyclobutanation of C60 in view of a single
electron transfer (SET).
The reaction of a 50 equiv excess of five- to seven-
membered morpholinocycloalkenes 1aꢀc (7 mmol) with
C60 (100 mg, 0.14 mmol) was carried out in the dark under
an Ar atmosphere in dry toluene (50 mL) at the refluxing
temperature to afford exclusively the 1:1 adducts 2 in
excellent (for 1aꢀb) but very low (for 1c) yields (Table 1).
The products 2a,b were isolated by silica gel column
chromatography, eluted with toluene, and purified by
recrystallization by a vapor diffusion method using CS2
and hexane. Unfortunately, the product 2c could not be
isolated probably because of very low yield (Figure S1,
Supporting Information) and/or a possible lability on
column chromatographic treatment.
1
Figure 1. 1H and 13C NMR chemical shifts (δ) and 1Hꢀ H
COSY (red) and selected HMBC (blue) correlations.
Table 1. Reaction of Enamines 1aꢀc with C60
Scheme 1. A Suggested Pathway of Thermal [2 þ 2] Addition of
Morpholinoenamines 1 to C60
temp
time
(h)
yield of
2 (%)a
run
enamine
(°C)
1
2
3
1a
1b
1c
115
115
115
3
46
72
97 (77)
92 (64)
6 (ꢀ)b
a Determined by HPLC area ratio. Values in parentheses are isolated
yields by column chromatography on silica gel. b Not isolated.
The reactivity of morpholinocycloalkenes 1aꢀc de-
creases with increasing cycloalkene ring size as seen in
Table 1. This trend in reactivity reduction is probably because
of the increasing steric hindrance of enaminocycloalkenes in
going from almost planar cyclopentene to the chair-formed
cycloheptene.8 Such a steric problem will significantly disturb
the approach of 1 to the fullerene surface regardless of the
mechanistic features and also enhance the lability of possible
product 2c. Another noticeable point of this thermal [2 þ 2]
addition is the high yield of monoadducts even in the presence
of a large excess of enamine addend (50 equiv) as shown in
time-course HPLC measurements (Figure 2a). An attempt to
follow the disappearance of C60 provided the pseudo-first-
order plots of ꢀln([C60]/[C60]0) vs time (Figure 2b),9 and thus
the second-order rate constants were obtained for both of the
enamines at 115 °C in toluene, i.e., 3.45 ꢁ 10ꢀ4 for 1a and
The structures of 2a and 2b were fully characterized by
1
1
1
LCMS, H NMR, 13C NMR, HSQC, HMBC, Hꢀ H
COSY, and UVꢀvis spectroscopic techniques. The HSQC
1
and 1Hꢀ H COSY spectra of 2a revealed the presence of a
methine proton (3.67 ppm, C3ꢀH proton) linked with
three methylene segments (C4ꢀH2, C5ꢀH2, and C6ꢀH2)
and the adjacent C7-substituted morpholino group (Figure 1).
The absence of the methine peak at around 6 ppm unequi-
vocally denied the presence of the proton directly bound to
the fullerene cage as depicted in the hypothetical com-
pound A (Scheme 1). Moreover, cyclobutane fusion was
proven by the HMBC spectrum in which C3ꢀH showed no
crosspeak with C1 and C5 but a clear two-bond crosspeak
with C2 and C7.
(7) Nair, V.; Sethumadhavan, D.; Nair, S. M.; Shanmugam, P.;
Treesa, P. M.; Eigendorf., G. K. Synthesis 2002, 12, 1655–1657.
(8) Ermolaeva, L. I.; Mastryukov, V. S.; Allinger, N. L.; Almenningen,
A. J. Mol. Struct. 1989, 196, 151–156.
(9) Oshima, T.; Kitamura, H.; Higashi, T.; Kokubo, K.; Seike, N.
J. Org. Chem. 2006, 71, 2995–3000.
Org. Lett., Vol. 13, No. 16, 2011
4245

Table 2. Cyclic Voltammograms and Reduction Potentials of
2a, 2b, and C60 in PhCNa
E
1/2V vs Fc/Fcþ
compd
E1red (LUMO level/eV)b
E2red
E3red
2a
ꢀ1.06 (ꢀ3.74)
ꢀ1.07 (ꢀ3.73)
ꢀ0.92 (ꢀ3.88)
ꢀ1.45
ꢀ1.46
ꢀ1.35
2b
C60
ꢀ1.83
a Electrolyte 0.1 M TBAP; scan rate 100 mV sꢀ1; potentials measured
vs Ag/Agþ reference electrode and standardized to Fc/Fcþ couple [EFc/
= þ0.15 V vs Ag/Agþ (PhCN)]. b Values from the vacuum level were
4.8).13
Fcþ
1/2
estimated using the following equation; LUMO level = ꢀ(E1red
þ
Figure 2. (a) Time-dependent HPLC charts for the reaction of 1a
with C60. Column: Buckeyprep; eluent: toluene (1 mL/min). (b)
Pseudo-first-order plot of ꢀln[C60]/[C60]0 vs time for the reac-
tion of C60 with 1a and 1b.
þ0.18 V vs Ag/Agþ),11 the ∼0.96 V of potential difference
(Eox(1a,b)ꢀ Ered(C60)) is likely to cause such an electron
transfer.12
The LUMO levels of compounds 2a and 2b are found to
be considerably raised by ca. 0.1 eV as compared with that
of C60, thus suppressing the secondary SET necessary for
the [2 þ 2] cycloaddition (vide infra).
3.50 ꢁ 10ꢀ5 Mꢀ1 sꢀ1 for 1b, respectively. It was found that 1a
is 10 times more reactive than the more sterically hindered 1b.
Considering that multiaddition usually takes place in the
chemical modification of fullerenes, the present reaction is
very profitable for the selective formation of monofunc-
tionalized fullerenes.10 To explore the reason for the high
selectivity, we carried out cyclic voltammetry analysis since
the electronic nature of fullerenes and their derivatives play
a decisive role in the fullerene chemistry. The obtained first
to third one-electron reduction potentials (E1red, E2red, and
E3red) of 2a, 2b, and pristine C60 are collected along with
the estimated LUMO level of these compounds in Table 2.
In light of the oxidation potentials (Eox) of 1a,b (þ0.19 V,
The thermal reaction of amines with C60 is well recog-
nized to start with a single electron transfer (SET).14 Thus,
primary and secondary aliphatic amines give rise to hydro-
aminofullerenes via the first radical ion pair formation,
radical recombination, and final proton transfer. How-
ever, usual tertiary amines do not add to C60 because of the
fast back electron transfer as well as the absence of a labile
proton. The present reactionisalsomarkedlyin contrastto
the thermal reaction of morpholine itself because the cyclic
secondary amines are reported to bring about the tetra-
amination of C60 via oxygen-mediated ground state SET in
DMSO.15
(10) Nambo, M.; Segawa, Y.; Itami, K. J. Am. Chem. Soc. 2011, 133,
2402–2405.
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433–434.
Since morpholinoenamines 1a,b are classified as tertiary
amines having a cycloalkenyl substituent, the double bond
(12) For example, electron þ hydrogen transfer reaction from 1-ben-
zyl-1,4-dihydronicotinamide to chloro-p-benzoquinone with 0.91 V of
(Eoxꢀ Ered) showed high reactivity (k = 7.6 Mꢀ1 sꢀ1, at 298 K), while the
reaction of p-benzoquinone with more gap (1.07 V) showed far reduced
reactivity (k = 1.3 ꢁ 10ꢀ2). See: Fukuzumi, S.; Nishizawa, N.; Tanaka,
T. J. Chem. Soc., Perkin Trans. 2 1985, 371–378.
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6, 521–527.
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Skiebe, A.; Hirsch, A.; Klos, H.; Gotschy, B. Chem. Phys. Lett. 1994,
220, 138–140.
ꢀ
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E. J. Org. Chem. 2005, 70, 4826–4832.
(16) Woodward, R. B; Hoffmann, R. Angew. Chem., Int. Ed. Engl.
1969, 8, 781–853.
4246
Org. Lett., Vol. 13, No. 16, 2011

is expected to behave as a 2π component. Although the
concerted [2 þ 2] cycloaddition is a symmetry forbidden
process,16 the stepwise one via a biradical/zwitterion inter-
mediate is thermally allowed. Mechanistically, we there-
fore suggest that the first SET generates a radical ion pair
which performs the radical collapse to give the zwitterion
intermediate which then cyclizes to the [2 þ 2] adduct
(Scheme 1). As far as we know, this is the first example of
the [2 þ 2] cycloaddition of enamine to C60.
Scheme 2. A Plausible Mechanism for Hydrolysis of 2a
If the proton transfer precedes the radical-coupling
process, the possible product would be A. Over ten
years ago, Wu et al. proposed the formation of type A
adduct in a similar SET reaction of C60 with enamines
such as pyrrolidino- and piperidinocyclopentene.17
They have only isolated the compound 3a on acid-
catalyzed hydrolysis of the reaction products. This
observation prompted us to investigate the acid-cata-
lyzed hydrolysis of the [2 þ 2] adduct 2a and compare
the reactivity with that of the type A product. Interest-
ingly, we have obtained the same product 3a and
considered a plausible mechanism as shown in Scheme
2. The hydrolysis reaction seems to proceed through a
sequential process involving acid-catalyzed demorpho-
lination to bicyclo[3.2.0]hept-1-ene fused C60, the het-
erolytic bond cleavage assisted by water, the formation
of hydrofullerene-substituted cyclopentenol via proton
transfer, and tautomerization to ketone 3a.
In summary, we first obtained the thermal [2 þ 2]
cycloadducts in good yields in the reaction of enamines
1a,b with C60. This reaction seems to proceed via a
mechanism involving initial ground state single elec-
tron transfer (SET), radical collapse of the generated
radical ion pair, and final cyclization of the zwitterion
intermediate. The cycloadduct 2a underwent acid-
catalyzed hydrolysis to afford the 3-cycloalkanone
substituted hydrofullerene 3a in fair yields. The pre-
sent facile [2 þ 2] additions will add to the methods
of preparation of new functionalized fullerene deri-
vatives.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research (C)(No. 20550040) and
partly supported by a Grant-in-Aid for Exploratory Research
(No. 23651111) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Supporting Information Available. General procedure
for the reaction of 1aꢀc with C60 and for the acid-
catalyzed hydrolysis of the [2 þ 2] adducts 2a,b; the HPLC
1
chart for the reaction of 1c with C60; H, 13C NMR
spectra; the HꢀH COSY and HMBC correlations and
FAB/MALDI-MS of 2a,b and hydrolysis products 3a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Gao, X.; Ma, S.-L.; Guo, L.-W.; Zhang, D.-W.; Wu, S.-H.; Wu,
H.-M.; Li, Y.-J. Chem. Lett. 1999, 671–672.
Org. Lett., Vol. 13, No. 16, 2011
4247