The first one-pot synthesis of a chiral pentakis-adduct of C60 utilising an opened-structure malonate tether

Article abstract of DOI:10.1039/c3cc46755d

A pentakis-adduct of C₆₀ with an incomplete octahedral addition pattern was synthesised via a one-pot procedure using a tether equipped with five malonate moieties. The five-fold Bingel cyclopropanation of C₆₀ was completely regiosel

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The first one-pot synthesis of a chiral pentakis-adduct of C60 utilising a
opened-structure malonate tether†
Charalambos P. Ioannou and Nikos Chronakis*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
octahedral sites of
a C60 triazoline mono-adduct. Bingel
A pentakis-adduct of C60 with an incomplete octahedral
addition pattern was synthesised in a one-pot procedure using
a tether equipped with five malonate moieties. The five-fold
Bingel cyclopropanation of C60 was completely regioselective
10 and afforded a chiral, C2-symmetric pentakis-adduct which
was easily separated by column chromatography on SiO2.
50 cyclopropanation with an excess of diethyl 2-bromomalonate
afforded the corresponding hexakis-adduct and subsequent
thermal removal of the triazoline group furnished a pentakis-
adduct which was separated by preparative HPLC. In 1997,
Diederich7 reported the synthesis of pentakis-adducts of C60
55 starting from a tethered e,e,trans-1 tris-adduct and by performing
selective
e
additions. The synthesised pentakis-adducts
The arrangement of functional organic moieties in
a
functionalised both with Bingel and Diels-Alder reactions were
isolated by column chromatography. In a different approach,
Duarte-Ruiz et al.,8 cyclopropanated an e,e,e tris-adduct of C60
60 bearing three anthracene addends with diethyl 2-bromomalonate.
An unstable pentakis-adduct, due to the lability of the attached
anthracene groups, was subsequently isolated by column
chromatography and characterised. Finally, the most efficient
synthesis of pentakis-adducts of C60 with an incomplete
65 octahedral addition pattern was reported in 2012, by Hirsch.2
Bingel nucleophilic cyclopropanations of a series of malonates at
the e bonds of isoxazoline monoadduct 1 (Scheme 1) led to the
successful synthesis of hexakis-adducts 2. Subsequent
deprotection of the isoxazoline moiety under irradiation with light
70 furnished the C2v-symmetric pentakis-adducts 3 which were
isolated by column chromatography. The overall yield of the
sequence starting from C60 (over three steps: cycloaddition/five-
fold Bingel cyclopropanation/retro-cycloaddition) was in the
range of 8-13%.
stereochemically well-defined orientation in space requires a
highly symmetric and reactive organic scaffold with a three-
15 dimensional structure. Absolute control of the reactions employed
for the covalent connection of the desired addends is another
important issue targeting novel materials with specific properties
and function. [60]Fullerene is the only organic molecule that
fulfils these requirements and the development of strategies for
20 the regioselective synthesis of multi-adducts has flourished the
literature with unprecedented structures with potential
applications in biological and materials science.1
Pentakis-adducts of C60 with an incomplete octahedral addition
pattern2 (Scheme 1, 3) represent molecular building blocks with
25 unique importance in storing and transferring structural and
functional information. The five addends bound on the equatorial
(e) double bonds located at the octahedral sites of the fullerene
sphere can be endowed with a specific structural or functional
property which can be transferred to another organic molecule via
30 the ligation on the unreacted double bond at the remaining
octahedral site. This activated [6,6] double bond can be
selectively functionalised with a wide range of molecules, in a
completely regioselective manner as has been well-established in
the literature both theoretically and experimentally.3,4
N
N
X
X
X
X
a ona e
r
a e c an
r
e
d id
y
X
M
l
t
/ CB
M
l
i
h
4
N
N
X
X
v
h
n
e
/ 24 h
o uene
DBU / t l
r
o ue
t
l
/
/ t
O
O
X
X
-
-
35
The first synthesis of a cyclopropanated pentakis-adduct of C60
was reported in 1994, by Hirsch.3 Starting from an e,e,e tris-
adduct and employing stepwise Bingel5 additions followed by
preparative HPLC separations, a pentakis-adduct equipped with
malonate ester moieties was successfully isolated and fully
29 53
44 79
%
%
X
X
1
2
3
75
Scheme 1 Protection-deprotection strategy for the synthesis of pentakis-
adducts of C60 reported by Hirsch.2
Our recent report9 on the synthesis of a stable eedge,eface,trans-1
tris-adduct of C60 via a three-fold Bingel reaction with a tether
40 characterised. An improved synthesis was published in 1996 by
the same group6 where 9,10-dimethylanthracene (DMA) was
used as a template in order to activate the e bonds at the
80 bearing three malonate groups incorporated in
a
well
preorganized molecular system, stimulated us to attempt the
synthesis of a pentakis-adduct of C60 with an incomplete
octahedral addition pattern in a one-pot procedure, via a five-fold
Bingel cyclopropanation with an appropriate tether. The
85 realisation of this quite challenging task was based on our
previous report10 where a tripodal tether with a phenoxy focal
Department of Chemistry, University of Cyprus, University str. 1,
45 Building No 13, 2109 Aglantzia, Nicosia, Cyprus. Fax: =357 22895088;
Tel: =357 22892781; E-mail: nchronak@ucy.ac.cy
† Electronic Supplementary Information (ESI) available: Experimental
section and spectroscopic data. See DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
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DOI: 10.1039/C3CC46P75a5gDe 2 of 3
point was designed and successfully afforded an e,e,e tris-adduct 35 excess of carbon tetrabromide.12 TLC and HPLC monitoring of
of C60. As the e,e,e addition pattern is part of the addition pattern
of the targeted pentakis-adduct, we designed tether 6 (Scheme 2),
featuring similar structural characteristics with the tripodal tether
employed for the synthesis of the e,e,e tris-adduct but bearing
five reactive malonate groups.
the reaction progress revealed the formation of a single fullerene
adduct which was isolated by flash column chromatography on
SiO2 using a mixture of toluene/EtOAc (8:2) as an eluent.
Pentakis-adduct 7 was isolated as an orange solid, in 10% yield
40 after column chromatography and precipitation from
DCM/pentane. It has to be highlighted here that the obtained
yield is considered very satisfactory taking into account that the
overall yield (over three steps) of the synthetic procedure
introduced by Hirsch2 ranged between 8-13%. The structural
5
OH
OH
OH
O
O
e
r
ma on
l
c
or e
hl id
M
d
th
y
l
l
y
y
/
O
+
r-
n
e
r n
e
d
i i
py
ace o
DMF / Et4N B
t
+
150 oC / 14 h / 39
t
48 h / 43
%
0 oC 2 h
%
O
O
O
en r
t
h
HO
OH
O
O
O
O
1
45 assignment of 7 was accomplished by H-, 13C NMR, UV-Vis
O
O
O
4
5
O
O
O
H
OH
O
O
O
spectroscopy and by MALDI-TOF mass spectrometry.
O
O
O
In the MALDI-TOF mass spectrum (positive mode, DCTB
matrix) of the purified product 7, the [M+Na]+ ion at 1718 m/z
(see ESI†) was clearly observed confirming that the five-fold
50 Bingel cyclopropanation of C60 was successful and led to the
formation of a pentakis-adduct. The incomplete octahedral
addition pattern was unambiguously assigned with the aid of UV-
Vis spectroscopy. In the UV-Vis spectrum of pentakis-adduct 7
(see ESI†), the pattern of absorptions in the region between 250-
55 600 nm was identical with that of previously synthesized
pentakis-adducts.2
O
O
O
O
O
O
O
O
O
O
O
O
a on
c
or
e
r
y
M
l
l di hl id / d DCM
y
r
ne r
/
t / 24 h / 67
idi
%
py
O
O
6
O
O
O
O
O
O
O
O
Scheme 2 Synthesis of tether 6.
In the first step of our synthetic approach (Scheme 2), triol 4
NMR spectroscopy was crucial for the assignment of the
proposed structure and molecular symmetry of pentakis-adduct 7
and the spectra were easily recorded due to the pronounced
60 solubility of the compound in common organic solvents such as
CHCl3. In the 1H NMR spectrum of 7, all hydrogens were clearly
observed but a complete assignment was difficult due to the
diastereotopicity of the methylenic hydrogens induced by the
covalent binding of the tether on the fullerene sphere.
65 Nevertheless, the 13C NMR spectrum was fully informative and
provided an accurate assignment of the pure compound’s
structure. Specifically, in the 13C NMR spectrum of 7 (Fig. 1), 24
signals for the sp2 carbons of the fullerene skeleton were
observed in the region between 149-138 ppm clearly indicating a
70 C2-symmetric structure. This was further confirmed by the
presence of five signals between 164-162 ppm corresponding to
the ten carbonyl carbons, three signals for the six ArC-O aromatic
carbons at 160.35, 160.25 and 160.21 ppm, three distinct peaks at
94.28, 94.17, 94.10 ppm attributed to the six ArC-H aromatic
75 carbon atoms and five peaks at around 69 ppm characteristic for
the ten fullerene sp3 carbons. Furthermore, all the other resonance
signals in the 13C NMR spectra were in full accordance with the
C2 symmetry of adduct 7 (for detailed 13C NMR spectroscopic
data see ESI†).
10 was synthesised according to a literature procedure11 followed by
a two-fold esterification with methyl malonyl chloride. The
reaction led to the formation of the mono-, bis- and tris-esterified
products and thus, we optimised the reaction parameters (solvent,
stoichiometry, concentration) in an effort to obtain the highest
15 possible yield for the desired bis-ester 5. Under the optimised
conditions, the best yield for 5 was 43% while, the two by-
products (mono- and tris-ester) were also isolated by column
chromatography and fully characterised (see ESI†). In the last
step, 5 was allowed to react with malonyl dichloride, in DCM
20 solvent and in the presence of pyridine as a base to afford tether 6
which was isolated in 67% yield after purification with column
chromatography on SiO2.
In the next step, the one-pot, five-fold Bingel cyclopropanation
of C60 with tether 6 was investigated (Scheme 3). The remote
25 functionalisation was carried out in a mixture of toluene/DCM
(4:1) as a solvent due to the insolubility of 6 in pure toluene. High
dilution conditions were employed in order to avoid the
attachment of more than one C60 molecules on the same tether
and the reaction was performed in the presence of 1,8-
30 diazabicyclo[5.4.0]undec-7-ene (DBU) as a base and a large
O
O
O
80
O
O
C=O
ArC-H
ArC-O
O
O
Toluene / DCM
DBU / CBr4
O
O
O
O
(4:1)
O
94.4
94.0
ppm
164 163 162
ppm
160.4 160.0
ppm
sp2 C of C60
24 signals
O
O
O
O
O
+
C60
6
O
rt 4 d
/
/ 10%
O
O
O
O
165
160
155
150
145
140
135
130
ppm
125
120
115
110
105
100
95
90
O
O
O
Fig. 1 13C NMR spectrum (125 MHz, CDCl3) of pentakis-adduct 7 in the
O
7
region 90-170 ppm.
Scheme 3 Synthesis of pentakis-adduct 7. Bonds in red denote the reacted
double bonds of C60 while the blue represents the unreacted [6,6] double
bond at the remaining octahedral site.
Pentakis-adduct 7 possesses a C2 axis of symmetry intersecting
85 the unreacted double bond and its trans-1 cyclopropanated one
located in the opposite hemisphere (Scheme 3). As
a
2
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consequence, the molecule has axial chirality which results from
the helicity adopted by the tether upon cyclopropanation of the
five double bonds of C60. The spherical structure of C60 and the
achiral incomplete octahedral addition pattern built up by the five
double bonds which are cyclopropanated, lock the tether
molecule in a helically chiral arrangement and thus, pentakis-
adduct 7 exists as a pair of enantiomers. Following the CIP
rules13 and with the aid of 3D-models, we have set an axis
passing from the phenoxy groups of the tether and we observed
6
4
.…..... 7 (first eluted enantiomer at 26.86 min)
_____ 7 (second eluted enantiomer at 30.54 min)
5
2
0
-2
-4
-6
10 the helicity of the organic chain connecting them, regarding its
handedness (Fig. 2). This operation results in two enantiomeric
forms namely, right-handed (P) and left-handed (M).
250
300
350
400
450
500
O
O
Wavelength (nm)
O
O
O
O
O
O
35
O
O
O
O
Fig. 4 CD spectra of the P and M enantiomers of pentakis-adduct 7.
O
O
O
O
O
O
O
In conclusion, we have designed and synthesised a opened-
structure tether equipped with five malonate moieties in an effort
to target, for the first time, the one-pot synthesis of a pentakis-
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
40 adduct of C60 with an incomplete octahedral addition pattern. The
remote functionalisation of C60 with tether 6 was successful and
afforded pentakis-adduct 7 in a completely regioselective manner.
Isolation and purification was easily carried out by column
chromatography on SiO2 and 7 was obtained in 10% yield, as an
45 orange solid. Its solubility was very good in common organic
solvents and allowed a complete spectroscopic characterisation.
Adduct 7 has axial chirality due to the helicity of the anchored
tether and is the first chiral pentakis-adduct of C60. Thus, it exists
as a pair of enantiomers namely, (P)-7 and (M)-7 which were
50 resolved by analytical HPLC on a chiral column. Isolation of the
pure enantiomers allowed the measurement of their circular
dichroism spectra which showed a perfect mirror-image pattern.
This work was financially supported by the Cyprus Research
Promotion Foundation (Grant NEKYP/0308/02).
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
M
P
( )
(
)
Fig. 2 Representation of the P and M enantiomers of pentakis-adduct 7.
15
The chirality of pentakis-adduct 7 prompted us to attempt the
resolution of the P- and M-enantiomers with the aid of analytical
HPLC. For this purpose, we used a chiral Whelk-O 1 analytical
column and a mixture of heptane/acetone (60:40) as an eluent.
Under these conditions, a baseline separation was achieved for
20 the racemic mixture (P)-7/(M)-7, as shown is Fig. 3. Small
55 Notes and references
mAU
340nm,4nm (1.00)
1
(a) A. W. Jensen, S. R. Wilson and D. I. Schuster, Bioorg. Med.
Chem., 1996, 4, 767; (b) F. Giacalone and N. Martín, Chem. Rev.,
2006, 106, 5136; (c) A. J. Ferguson, J. L. Blackburn and N.
Kopidakis, Mater. Lett., 2013, 90, 115.
Column: (R,R)-Whelk-O 1
Eluent: Heptane/Acetone = 60:40
Flow rate: 1 ml/min
O
O
O
O
100
75
50
25
0
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
UV Detection: 340 nm
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
60 2 F. Hörmann, W. Donaubauer, F. Hampel and A. Hirsch, Chem.‒Eur.
J., 2012, 18, 3329.
O
O
O
O
O
O
(P)-7
(M)-7
3
A. Hirsch, I. Lamparth and T. Grösser, J. Am. Chem. Soc., 1994, 116,
9385.
Integration: 50.21
49.79
30.0
4
F. Hörmann, M. Brettreich, W. Donaubauer, F. Hampel and A.
0.0
5.0
10.0
15.0
20.0
25.0
35.0
40.0
45.0
min
65
Hirsch, Chem.‒Eur. J., 2013, 19, 2814.
5
6
7
C. Bingel, Chem. Ber., 1993, 126, 1957.
Fig. 3 HPLC analytical resolution of the (P)-7 and (M)-7 enantiomers.
I. Lamparth, A. Herzog and A. Hirsch, Tetrahedron, 1996, 52, 5065.
L. Isaacs, F. Diederich and R. F. Haldimann, Helv. Chim. Acta, 1997,
80, 317.
quantities (~0.5 mg) of each enantiomer were isolated in pure
form by analytical HPLC in order to measure their circular
25 dichroism (CD) spectra. As the concentration of the solutions
could not be determined accurately due to the limited isolated
quantities of (P)-7 and (M)-7, the specific optical rotation values
were not measured. The enantiomeric relationship of (P)-7/(M)-7
resulting from the axial chirality of pentakis-adduct 7 was clearly
30 reflected in their CD spectra (Fig. 4). The measured spectra
showed mirror-image behaviour but the absolute configuration (P
or M) of the first (26.86 min) and second eluted (30.54 min)
enantiomer cannot be assigned at the moment without the aid of
theoretical calculations.
70 8 A. Duarte-Ruiz, L. Echegoyen, A. Aya and F. Gómez-Baquero, J.
Mex. Chem. Soc., 2009, 53, 169.
9
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80 13 R. S. Cahn, C. Ingold and V. Prelog, Angew. Chem. Int. Ed., 1966, 5,
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This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3