Dramatic mechanistic change in acid-catalyzed arylation of azafulleroids depending on their ambident N/C basicity: Formation of cyclopentene centered pentakisadduct

Article abstract of DOI:10.1002/asia.201402728

Azafulleroid, amino-bridged [5,6]-open fullerene, has the ambident N/C basicity of the incorporated enamine moiety. Acid-catalyzed arylation of N-substituted azafulleroids proceeded via two types of initial N/C protonation to perform monoarylation or 1,4-

Full text of DOI:10.1002/asia.201402728

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DOI: 10.1002/asia.201402728
Dramatic Mechanistic Change in Acid-Catalyzed Arylation of Azafulleroids
Depending on their Ambident N/C Basicity: Formation of Cyclopentene
Centered Pentakisadduct
Naohiko Ikuma,* Yuta Doi, Koichi Fujioka, Tsubasa Mikie, Ken Kokubo, and
Takumi Oshima[a]
Abstract: Azafulleroid, amino-bridged [5,6]-open fullerene,
has the ambident N/C basicity of the incorporated enamine
moiety. Acid-catalyzed arylation of N-substituted azafulle-
roids proceeded via two types of initial N/C protonation to
perform monoarylation or 1,4-bisarylation for the N-alkyl
substituents and shuttlecock-type pentakisarylation for the
N-phenyl substituent. The dramatic product change was ex-
plained by considering the possible mechanism as well as
the DFT computational results.
Azafulleroid[1] is an attractive [5,6] open fullerene deriva-
tive because its amino-bridged highly twisted double bonds
À
N C=C (anti-Bredt olefins) seem to exhibit the enamine-
like ambident reactivity depending on the steric and the
electronic nature. For instance, acid-catalyzed hydrolysis of
Figure 1. Proton affinities of azafulleroids, pyridine, N,N-dimethylena-
mine, and C60 (B3LYP6-31G** including zero point energy, in vacuum,
kcalmolÀ1). Bold value is the largest energy.
tricyclic enamine, 9-methyl-9-azabicycloACTHNUTRGNEUGN[3.3L]non-l-ene, pro-
ceeds through the dual N/C-acidification to give N-protonat-
ed intermediate and double bond protonated product, re-
spectively.[2] However, the possible dual reactivity of azaful-
leroid has not been reported so far, although regioselective
additions to the bridgehead double bonds have been found
for azafulleroids,[3] and their analogues methano-bridged
fulleroid[4] and azahomoazafullerene C59N(NH)R.[5] Here,
we report that the acid-induced arylation of N-substituted
azafulleroids results in monoarylation or 1,4-bisarylation for
N-alkyl substituents, while shuttlecock type pentakisaryla-
tion for N-phenyl substituent. We also explain this dramatic
product change in terms of the substituent effects on the ini-
molÀ1)[6,7] as compared with C60, pyridine, and N,N-dimethy-
lenamine (Figure 1). It was noted that N-methylazafulleroid
showed the most effective proton affinity at the N atom,
while N-phenylazafulleroid at the adjacent C(a) atom of
twisted C=C double bond. Their basicities were slightly
lower than that of the weak base pyridine, but considerably
higher than that of pristine C60, indicating some possible re-
activity with acids, in contrast to the lower acid-reactivity of
C60. The comparatively reduced N basicity of N-phenylaza-
fulleroid is explained by the p-delocalization through the
phenyl ring. Therefore, we can assume that N-alkylazafulle-
roids preferably cause the N-protonation, whereas N-aryla-
zafulleroids the C(a)-protonation.
Considering these computational results, we prepared
three alkyl azafulleroids 1a–c via thermal denitrogenation
of triazolinofullerene[8] and phenylazafulleroid 1d according
to the previously reported methods.[1a,d] Acid-catalyzed reac-
tion of butyrate-substituted 1a in the presence of various ar-
omatic compounds including thiophene and pyrene gave the
corresponding 4-monoarylated products 2a–e. This reaction
À
tial protonation at the N/C basic site of the N C=C linkage.
First, we preliminary estimated the relevant N/C basicity
of the representative N-methyl- and N-phenylazafulleroids
based on the DFT-computational proton affinity (kcal
[a] Dr. N. Ikuma, Y. Doi, K. Fujioka, T. Mikie, Dr. K. Kokubo,
Prof. Dr. T. Oshima
Division of Applied Chemistry
Graduate School of Engineering
Osaka University
2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)
Fax : (+81)6-6879-4593
E-mail: ikuma@chem.eng.osaka-u.ac.jp
À
involves acid-induced C N bond cleavage followed by the
nucleophilic arylation and the closure of [5,6] open ring
(Table 1). The stronger protic acid CF3SO3H (TfOH) was
practical for this arylation, similarly to the acidic arylation
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201402728.
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Naohiko Ikuma et al.
Table 1. Acid-catalyzed arylation of azafulleroid 1a with various aromat-
ic compounds (Ar-H) by several protic and Lewis acids.
Scheme 2. 1,4-Cross arylation of 2a by stepwise treatment.
Various Ar-H (10 equiv)
with TfOH (5 equiv)
t [h]
Yield of 2 [%][a]
has been achieved via relatively stable 1,4-arylfullerenols.[13]
Therefore, practical stability of monoarylated 2a–e can be
ascribed to the less facile leaving group of protonated butyl-
amine than tosyl amine.
On the other hand, benzyl-substituted 1b,c underwent the
preferential acid-induced intramolecular Friedel–Crafts ary-
lation of benzyl groups to afford tetrahydroisoquinolinoful-
lerenes 5b,c in excellent yields (Scheme 3). Particularly, tri-
3.5
3
86 (2a)
80 (2b)
49 (2c)
98 (2d)
1.3
2.5
2
94 (2e)
Toluene (10 equiv)
with various acids
t [h]
Yield of 2a [%][a]
TfOH (1 equiv)
TfOH (5 equiv)
MsOH (10 equiv)
MsOH (50 equiv)
BF3·Et2O (5 equiv)
AlCl3 (10 equiv)
5
no reaction
86
no reaction
99
27
74
3.5
20
3
20
29
Scheme 3. Intramolecular Friedel–Crafts reaction of benzyl-substituted
[a] Yield of isolated product.
azafulleroids 1b,c. MsOH=CH3SO3H.
of aziridinofullerene;[9] while the weaker CH3SO3H (MsOH)
required far more excess amount of acid. The Lewis acid
BF3 provided relatively low yield of 2a due to the forma-
methoxybenzyl-substituted 1c was activated even with
weaker acid MsOH. Such acid-catalyzed intramolecular ary-
lation of iminofullerenes[14] can be useful pathway for ob-
taining heterocyclic fullerenes.
[10]
tion of unidentified multiadducts. AlCl3 under the anhy-
drous condition also gave a fair amount of 2a rather than
hydroarylated adducts, which were major products in the
similar reaction of fullerene,[11] probably because of the ab-
sence of hydrolyzed HAlCl4.
Interestingly, the reaction at 1008C provided 1,4-bisary-
ladduct 3a probably via the second arylation of monoaryl-
fullerenyl cation arising from the acid-induced deamination
of 2a (Scheme 1). This elevated temperature reaction is
useful for the cross arylation as represented in Scheme 2.
Although the similar acid-catalyzed homobisarylation was
also reported for the [6,6] closed tosyl aziridinofullerene[9,10]
and fullerene epoxide,[12] these fullerenes cannot be applied
for the stepwise cross arylation because of the lability of pri-
mary monoarylated products. So far, such cross arylation
In marked contrast to the alkyl- and benzylazafulleroids
1a–c, phenylazafulleroids 1d in o-xylene solvent under the
excess TfOH demonstrated the elimination of phenylamino
substituents and the formation of shuttlecock-type pentaki-
sarylfullerene 6[15] without forming dihydroindole product[9]
1
by the intramolecular arylation (Scheme 4). The H NMR of
Scheme 1. 1,4-Diarylation of 1a at elevated temperature. TfOH=
CF3SO3H. o-DCB=o-dichlorobenzene.
Scheme 4. Acid-catalyzed pentakisarylation of phenylazafulleroids 1d.
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Naohiko Ikuma et al.
Figure 2. a,b) Crystal structure of 6 with thermal ellipsoids set at 50%
probability; side view (a), top view (b). c,d) DFT-calculated (B3LYP/6-
31G*) structures[6] of cyclopentenyl (C60H3Ph5, CS symmetry, (c)) and cy-
clopentadienyl (C60HPh5, CS symmetry, (d)) pentakisphenylfullerenes.
Solvent molecule (for (a,b)) and backside atoms (for (b–d)) are omitted
Figure 3. UV-Vis-NIR spectra (at rt) of a) 1a and b) 1d in TfOH (solid
line) and in o-DCB (dotted line).
À
for clarity. The values of the central pentagon (b–d) indicate their C C
bond lengths (ꢁ) and values of outer pentagon (c,d) indicate distances
(ꢁ) between C4ACHTUNGTRENNUNG(para) carbon atoms of the five phenyl substituents.
are similar in shape to those of chloromethylfullerenyl
cation.[19] On the other hand, aryl azafulleroid 1d provided
a characteristic sharp peak at 960 nm in TfOH (Figure 3b).
Although determination of the detailed cationic structures
requires NMR measurements and/or some computational
simulations for the exciting species, the spectra of 1d indi-
cated the unprecedented cationic intermediate derived from
the initial protonation at the C(a) atom of twisted bridge-
head double bond. Such C-protonated cation of aryl azaful-
leroid should be a key intermediacy for 6. In fact, arylation
of alkyl azafulleroid 1a with o-xylene under the same reac-
tion condition of 1d gave a mixture of multiarylated prod-
ucts not containing 6 (Figure S1). In this condition, 1,4-bi-
sadduct similar to 3 can be formed, but further arylation
occurs not regioselectively, because of no specific basic site
in the 1,4-bisadduct.
6 showed multiplet 3H peaks at 4.6–4.7 ppm, and 13C NMR
indicated Cs symmetry of fullerene sphere with ca. 30 sp2
peaks (along with 6 peaks of o-xylene) and five sp3 peaks.
The XRD structural analysis[16] apparently exhibited the
pentakisarylation around the central cyclopentenyl ring (Fig-
ure 2b) characterized by one short sp2 type C C bond
À
(1.34 ꢁ) and the other longer sp3 type C C bonds (1.49–
À
1.59), in consistent with the calculated lengths by B3LYP/6-
31G(d) (Ar=Ph, Figure 2c)[7] and the analogous trihydroxy
(OOtBu)2.[17] Thus, the
cyclopentene ring of C60(OH)4ACHTUNRTGENNUG(OiPr)2ACHTUNGTRENNGUN
present cyclopentenyl pentakisarylated adduct 6 somewhat
structurally differs from the previously reported cyclopenta-
dienyl pentakisarylated adducts (Figure 2d) derived from
the nucleophilic addition of Grignard reagents under copper
catalysts.[18] By comparison of the DFT structures (Figure 2c
and 2d), compound 6 is characterized by the appreciable
opening of three aryl petals (7.15 vs 6.74 ꢁ) due to the adja-
cent protonated sp3 carbons. This flower opening will bring
about the different packing features and the electric proper-
ties as compared to the more symmetric cyclopentadienyl
adducts.
We ascribed the dramatic product change to the change
of the initial protonation sites based on the above DFT cal-
culation (Figure 1). To know the structural and electric dif-
ference between the protonated intermediates of alkyl/aryl
azafulleroids, we have carried out the UV-Vis-NIR spectro-
scopic measurements of 1a,d in neat TfOH vs in o-DCB. In
TfOH, alkylazafulleroid 1a showed three broad bands in
the range of 500–650, 800–900, and 1050–1100 nm (Fig-
ure 3a). These absorption bands, though slightly red shifted,
Finally, we describe a plausible mechanism for the acid-
catalyzed arylation of azafulleroids as shown in Scheme 5.
For alkylazafulleroid 1a (R=(CH2)3COOMe, path a), the
ammonium ion A by the protonation of nitrogen suffers the
À
cleavage of one bridged enamine C N bond and the [5,6]
ring closure to generate fullerenyl cation B.[13,19] The nucleo-
philic attack of aromatic compounds preferably occurs at
the less hindered para-position[9,10,12,13] to afford 1,4-mono-
arylated aminofullerenes 2a-e. However, benzylazafulleroids
1b,c (R=CH2Ar) become tetrahydroisoquinolinofullerenes
5b,c via an intramolecular nucleophilic cyclization of the
corresponding fullerenyl cation B at the adjacent ortho-
carbon. On the other hand, due to the reduced N-basicity by
p-conjugation, arylazafulleroid 1d (R=Ar, path b) would
exhibit the acid-catalyzed arylation at the twisted bridge-
head C(a)=C(b) double bonds by way of the favorable pro-
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Naohiko Ikuma et al.
sential for the final arylation at the adjacent carbocation
center C(5). As a result, pentakisarylation was performed in
a clockwise/counterclockwise direction around the central
À
pentagon ring depending on which bridge (C N bond) of F
is first cleaved by the SN2’ reaction.
In conclusion, we have found that the acid-catalyzed ary-
lation of variously N-substituted [5,6] open azafulleroids
much depended on the nature of the substituents R (=alkyl,
benzyl, and phenyl group), because the initial protonation
of the incorporated bridged enamine framework varies with
the substituents. Alkylazafulleroid brought about the mono-
arylation via the [5,6] ring closure and the protonated ami-
nobridge opening. However, benzylazafulleroid gave rise to
tetrahydroisoquinolinofullerene via the preferential intra-
molecular cyclization. On the other hand, phenylazafulleroid
exhibited the protonation at the most strained Ca carbon
and underwent the multi SN2’ type reactions to perform the
metal-free pentakisarylation around the central cyclopen-
tene ring.
Acknowledgements
We thank Dr. Nobuko Kanehisa for X-ray crystallography. This work
was supported by Grant-in-Aid for Young Scientist (B) (No. 24750039)
from Japan Society for the Promotion of Science (JSPS), and partly by
Health Labour Sciences Research Grants from the Ministry of Health,
Labour and Welfare of Japan (MHLW).
Keywords: arylation · homogeneous catalysis · fullerenes ·
nucleophilic substitution · protonation
Scheme 5. A plausible mechanism for a) monoarylation of alkylazafulle-
roid 1a and b) pentakisarylation of phenylazafulleroid 1d. Although an
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Naohiko Ikuma et al.
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À
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À
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¯
space group P1 (#2), a=14.8043(3), b=14.8372(3), c=18.2953(3),
a=99.7765(10), b=95.1935(10), g=109.9613(10), V=3674.22(12)3;
l=1.54187; 2qmax =136.58, Z=2; 1calc =1.213 mgmÀ3; m=5.259 cmÀ1
;
Received: June 25, 2014
T=93 K; Rigaku RAXIS RAPID imaging plate area detector with
Published online: September 9, 2014
Chem. Asian J. 2014, 9, 3084 – 3088
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