Synthesis and orthogonal functionalization of [60]fullerene e,e,e-trisadducts with two spherically defined addend zones

Article abstract of DOI:10.1002/chem.200900329

e,e,e-Trisadducts 13 and 15 have been prepared by a highly regioselective threefold cyclopropanation of tripodal malonates 10 and 12 with C₆₀. The yield and regioselectivity depend on the length and structure of the tethers that connect the malonate units to the focal benzene core of 13-15. As a consequence of the template-directed synthesis, all ce.e-trisadducts were formed as in/out isomers exclusively and contain two spherically well-defined addend zones with equatorial and polar orientation, respectively. By variation of the outer malonate termini of the tethers, selective functionalization of the equatorial addend zone could be achieved, thus leading to fine-tuning of intermolecular interactions, such as solubility or aggregation phenomena. After removal of the focal benzene moiety in 14 and 15, selective functionalization of the polar addend zone could be achieved. Strong intramolecular hydrogen-bonding networks of the polar substituents in the polar addend zone could be observed by ¹H NMR spectroscopic analysis. By orthogonal functionalization of both addend zones, fullerene derivatives 44-48 could be synthesized as one single in/out isomer, thus greatly enhancing the potential of e,e,e-trisadducts as building blocks in supramolecular architectures.

Full text of DOI:10.1002/chem.200900329

DOI: 10.1002/chem.200900329
Synthesis and Orthogonal Functionalization of [60]Fullerene e,e,e-
Trisadducts with Two Spherically Defined Addend Zones
Florian Beuerle and Andreas Hirsch*[a]
Abstract: e,e,e-Trisadducts 13 and 15
polar orientation, respectively. By var-
iation of the outer malonate termini of
the tethers, selective functionalization
of the equatorial addend zone could be
achieved, thus leading to fine-tuning of
intermolecular interactions, such as sol-
ubility or aggregation phenomena.
After removal of the focal benzene
moiety in 14 and 15, selective function-
have been prepared by a highly regio-
selective threefold cyclopropanation of
tripodal malonates 10 and 12 with C60.
The yield and regioselectivity depend
on the length and structure of the teth-
ers that connect the malonate units to
the focal benzene core of 13–15. As a
consequence of the template-directed
synthesis, all e,e,e-trisadducts were
formed as in/out isomers exclusively
and contain two spherically well-de-
fined addend zones with equatorial and
alization of the polar addend zone
could be achieved. Strong intramolecu-
lar hydrogen-bonding networks of the
polar substituents in the polar addend
zone could be observed by 1H NMR
spectroscopic analysis. By orthogonal
functionalization of both addend zones,
fullerene derivatives 44–48 could be
synthesized as one single in/out isomer,
thus greatly enhancing the potential of
e,e,e-trisadducts as building blocks in
supramolecular architectures.
Keywords: cyclopropanation · ful-
lerenes · regioselectivity · trisad-
ducts
Introduction and Background
an all equatorial e,e,e-addition pattern, which represents a
fundamental structural motif in fullerene chemistry.[12] The
most prominent e,e,e-trisadduct is the trismalonic acid 1,
which we synthesized in
Shortly after their discovery[1] and accessibility in macro-
scopic amounts,[2] fullerenes were identified as versatile mo-
lecular building blocks due to unprecedented chemical and
physical properties.[3–11] On one hand, intrinsic properties
such as hydrophobicity, pronounced stacking interactions
with other conjugated p systems, and their unrivalled elec-
tronic properties make C60 and its derivatives promising can-
didates for functional components in supramolecular aggre-
gates. On the other hand, fullerenes can serve as versatile
templates that can arrange several addends in a spherically
well-defined manner. Well-established exohedral functional-
ization protocols provided access to a large variety of de-
fined fullerene derivatives with tunable chemical and mate-
rials properties.[12] An example is the threefold cyclopropa-
nation of C60 that leads to C3 symmetrical trisadducts with
1994.[13] This compound exhibits
pronounced solubility in water
and shows very promising activ-
ities as an antioxidant or neuro-
protective agent both in cul-
tured central nervous system
(CNS) cells and in whole
animal models.[14–19] The toxicity
of this trisadduct due to facile
metabolic
decarboxylation,[20]
however, requires the design of new structural analogues as
potential drug candidates. In another context, fullerene com-
pounds with an e,e,e-addition pattern allow ready access to
amphiphilic [3:3]hexakisadducts.[21,22] Based on e,e,e-trisad-
ducts with lipophilic addends, such as cyclo[n]alkylmalonate
macrocycles, new prototypes of functional amphiphiles were
readily obtained by the subsequent threefold addition of
malonates with hydrophilic side chains. These amphiphiles
aggregate to structurally persistent micelles in water and
consist of exactly six molecules arranged in a highly sym-
metrical fashion as determined by cryo-transmission elec-
tron microscopy (cryo-TEM).[23]
[a] Dr. F. Beuerle, Prof. Dr. A. Hirsch
Department of Chemistry and Pharmacy
Interdisciplinary Center of Molecular Materials (ICMM)
Friedrich-Alexander-Universitꢀt Erlangen-Nꢁrnberg
Henkestrasse 42, 91054 Erlangen (Germany)
Fax : (+49)9131-85-26864
E-mail: andreas.hirsch@chemie.uni-erlangen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900329.
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FULL PAPER
The bisfunctionalization of C60 is elegantly controllable by
tether-directed remote approaches,[12,24–26] whereas the
highly regioselective synthesis of C60 trisadducts, which are
suitable for subsequent functionalization still remains a
more challenging task. For threefold additions, the number
of theoretically possible regioisomers raises from 8 to 46,
thus making it almost impossible to obtain pure isomers
after a threefold cyclopropanation without any preorganiza-
tion of the malonates or by applying stepwise procedures.
The first success in this direction was accomplished by the
stepwise addition of segregated malonates and the separa-
tion of several trisadducts with a defined addition pattern,
such as e,e,e or trans-3,trans-3,trans-3.[27] By switching from
achiral malonates to chiral bisoxazolines addends, we could
isolate inherently chiral e,e,e-trisadducts in an enantiomeri-
cally pure form.[28] In a one-step synthesis of e,e,e-trisadducts
starting from pristine C60 through a tethered approach, the
final C3 symmetry of the product should be reflected in the
malonate precursor to avoid unfavorable strain energy
within the resulting trisadduct. Following this strategy, the
first one-pot synthesis of an e,e,e-trisadduct was achieved by
Diederich and co-workers in 1999 after treating a C3-sym-
metrical tripodal malonate based on a cyclotriveratrylene
core with C60.[29] We developed an efficient concept in 2002
that utilized flexible cyclo[3]alkylmalonates for the selective
formation of trisadducts. When cyclo[3]octylmalonate was
employed as an addend, the e,e,e-adduct was obtained as a
single regioisomer in good yield.[30] We also introduced opti-
cally active diols into the alkyl chains, thus achieving diaste-
reoselectivity for the threefold cyclopropanation, and isolat-
ed the two diasteroisomers with the corresponding enantio-
morphic e,e,e-addition patterns.[31] Despite this success, one
major point still has not been satisfactorily solved so far,
namely, the development of trisadducts that can be readily
and selectively further functionalized both at the fullerene
core and the attached addends. We recently reported a first
conceptual step to accomplish this goal.[32] By using tripodal
malonate tethers, we could synthesize a new class of e,e,e-tri-
sadduct in good yield with two distinct addend zones, which
potentially can be used for further side-chain modification.
We recently demonstrated the potential of some water-solu-
ble representatives as pharmaceutical agents by investigating
their antioxidant[33] and superoxide-quenching[34] activities in
vitro and neuroprotective activity[20] in vivo. Herein, we
report for the first time on the development of an entire
family of e,e,e-trisadducts that can be readily and specifically
functionalized in two spherically well-defined addend zones.
As a consequence, a multitude of functional fullerene deriv-
atives with a defined three-dimensional structure and widely
tunable properties has been made available. Due to the
presence of the redox- and photoactive fullerene core com-
bined with the features brought in by the very versatile com-
bination of functionalities within the separately addressable
polar and equatorial addend zones, this compound class has
great potential for both biomedical and materials applica-
tions.
Results and Discussion
Regioselective formation of e,e,e-trisadducts based on tripo-
dal malonate tethers: To achieve straightforward access to a
great variety of structurally tunable e,e,e-trisadducts contain-
ing diverse functionalities, a synthetic concept that fulfills
the following aspects has to be implemented: 1) the use of
readily accessible precursors that preorganize the malonate
units in an appropriate manner, 2) highly regioselective cy-
clopropanation reactions that lead to e,e,e-trisadducts in
good yields, 3) the facile removal of the structural template
by appropriate deprotection strategies, 4) the possibility of
further functionalization of deprotected derivatives, and
5) complete control of in/out isomerism[35] in case of asym-
metrically substituted malonates. Based on these considera-
tions, we chose a 1,3,5-trisubstituted benzene core as the
most prominent structural template. The corresponding
threefold symmetry should be compatible with the C3 sym-
metry of the e,e,e-trisadducts, and favorable p–p interactions
between the aromatic ring and the fullerene surface were
supposed to facilitate sufficient preorganization of the reac-
tion partners. On each side arm, malonate units are connect-
ed through a short ethylene spacer. The second terminus of
the malonate groups can be used for further functionaliza-
tion (Figure 1). After a highly regioselective trisaddition, the
structural template can be removed by using appropriate de-
protection techniques. Due to the template-assisted synthe-
sis, the two different side arms of each malonate unit are
thereby spherically well arranged as one single in/out isomer
(Figure 1). The three free side chains of the tripodal malo-
nate tether are topologically well oriented and define an
equatorial addend zone in which selective functionalization
is possible. After removal of the aromatic template, the re-
maining malonate termini define a second functionalizable
and spatially well-arranged region, that is, the polar addend
zone. Therefore, this sequence allows us to independently
address two sterically well-added regions of e,e,e-trisadducts.
Based on these conceptual considerations, we synthesized
three trisalcohols 2, 8, and
9 as template precursors
(Scheme 1). Compound 2 was obtained in one step from
phloroglucinol and ethylene carbonate catalyzed by tetrabu-
tylammonium bromide in DMF.[36] The ethylene spacer units
are thereby directly connected to the benzene core by
phenyl ether linkages. As a precursor for 8 and 9, 1,3,5-tris-
bromomethylbenzene 5 was used.[37,38] Quantitative esterifi-
cation of trimesic acid with methanol under acidic condi-
tions led to trisester 3, which was then reduced with lithium
aluminum hydride in THF to trisalcohol 4. Final bromina-
tion was achieved by the use of phosphorus tribromide in di-
ethyl ether, thus yielding 5 in good yield. The incorporation
of the ethylene units was accomplished by using a slightly
modified procedure.[39] Monoprotection of ethylene glycol
with dihydropyran under acidic catalysis gave 6 in 59%
yield. Deprotonation of 6 with NaH in dry THF and subse-
quent nucleophilic substitution of the bromine atoms of 5
led to the THP-protected trisalcohol 7. The deprotected
triol 8 was obtained after quantitative acetal cleavage with
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A. Hirsch and F. Beuerle
products, for example, mono-
and bisadducts were formed
and were removed by flash
chromatography.
Therefore,
e,e,e-trisadduct 13 could be iso-
lated in pure form in 29%
yield. For the tether system 11
with elongated spacer side
chains, the same threefold cy-
clopropanation afforded two
main fractions, which both ex-
hibited the molecular-ion peak
for trisadducts (m/z 1315) in the
FAB-mass-spectrometric spec-
tra, after separation by column
chromatography on silica gel.
The HPLC elugram of the first,
less-polar fraction consisted of
one dominant peak and the
UV/Vis spectra of which
matched those of previously re-
Figure 1. General concept for the synthesis of e,e,e-trisadducts with two spherically defined addend zones.
ported
trisadducts.[30,40]
13C NMR spectroscopic analy-
trans-3,trans-3,trans-3-
1H
and
HCl in CH2Cl2/MeOH.[39] Tripodal alcohol 9 was synthesized
by a threefold nucleophilic substitution with glycolic acid.
Altogether three types of trismalonate have been made
available that differ either in the chain length or connection
to the focal point with respect to the used tether. According
to the above-mentioned concept, suitable deprotection strat-
egies would therefore create different kinds of functionality,
for example, hydroxy or carboxyl groups, within the polar
addend zone. To investigate the regioselectivity of a three-
fold Bingel reaction with respect to the individual tether
system, malonates 10, 11, and 12, each containing a methyl
ester as the second terminus, were synthesized (Scheme 1).
All the three tripodal malonates were readily accessible by
a threefold condensation of malonic acid monomethylester
chloride with the appropriate tripodal building block 2, 8, or
9 in the presence of pyridine. Purification by column chro-
matography on silica gel afforded 10, 11, and 12 in good
yield. Subsequently, the final triscyclopropanation of C60 was
carried out (Scheme 1). To avoid the formation of polymeric
material, the reactions were carried out under high-dilution
conditions. The best yields of the macrocyclization products
13–15 were obtained for fullerene concentrations of around
0.5 mmolLꢀ1. In the case of 10, treatment with iodine and
DBU in toluene and subsequent separation by column chro-
matography afforded only one main fraction that showed
the expected protonated molecular ion peak (m/z 1274) for
13 in the MALDI-TOF mass spectrum. As demonstrated by
the HPLC elugrams, this fraction consisted of one single re-
gioisomer and its addition pattern could be assigned as e,e,e
by comparison with the UV/Vis spectra and 1H and
13C NMR spectroscopic data with those of previously report-
ed e,e,e-trisadducts.[27,29,30,40] The reaction proceeded with
complete regioselectivity. Only traces of lower addition
sis, however, revealed that this fraction was a mixture of tri-
sadducts. Separation by chromatographic methods could not
be achieved. The second, more-polar fraction consisted of a
single trisadduct and was formed in 55% relative yield. By
comparing the UV/Vis spectra of this second fraction with
those of known e,e,e-trisadducts, the e,e,e-addition pattern of
14 could be clearly assigned. As a matter of fact, this regio-
isomer could be isolated from the reaction mixture by one
simple column-chromatographic step and was obtained in
23% yield. For tether 12 with its malonate side chains at-
tached by benzylic esters instead of benzylic ethers, surpris-
ingly no favored reactions could be detected under the stan-
dard cyclopropanantion conditions successfully applied for
10 and 11. By using iodine as a halogenation reagent and
DBU as a base, only small amounts of multiple adducts
could be observed and most of the C60 remained unreacted.
TLC analysis, however, indicated the complete conversion
of the starting malonate 12 and a brownish precipitate was
formed. This lack of sufficient conversion is probably due to
the enhanced reactivity of benzylic esters towards nucleo-
philic substitution. The presence of iodine or iodide ions
generated in situ during the reaction probably led to sub-
stantial ester cleavage and therefore degradation of the mal-
onate. Indeed, by using CBr4 as a bromination reagent in
situ and the even more non-nucleophilic phophazene base
P1-tBu instead of DBU led to slow conversion of C60 into
e,e,e-isomer 15 as the only trisadduct. Several separation
steps with column chromatography were required in the pu-
rification, after which 15 was obtained in 8% yield.
1
The H NMR spectra of 13, 14, and 15 are represented in
Figure 2. Due to the inherent chirality of the e,e,e-addition
pattern, the protons of the side chains (2) and (3) become
diastereotopic, thus giving rise to pronounced splitting pat-
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Regioselective Synthesis of [60]Fullerene Trisadducts
FULL PAPER
11.7 Hz) and one strong vicinal coupling between protons
(2’) and (3) (3J2’,3 =10.0 Hz). In contrast, the other vicinal
3
coupling constants are comparatively small (3J2,3 =1.7, J2,3’
=
2.0, 3J2’,3’ =1.8 Hz) and only visible as small shoulders and
splittings at higher resolution. These observations strongly
indicate that the spherical structure of 13 is very rigid with
ꢀ
almost no rotational degree of freedom around the C C
bonds in the ethylene chains, even in solution. If the geome-
try of these ethylene groups is fixed in the staggered confor-
mation shown in Figure 2, the individual vicinal coupling
constants can be estimated by using the relation developed
by Karplus.[41,42] For this staggered conformation, the Kar-
3
plus curve predicts one large vincinal coupling constant J2’,3
of around 10–12 Hz (f2’,3 =1808) and small coupling con-
3
3
3
stants in the range 2–3 Hz for J2,3, J2,3ꢃ, and J2’,3ꢃ each with
f=608. Indeed, this finding is in perfect agreement with the
experimental observations, thus giving very strong evidence
for the postulated rigid structure of 13. In contrast, the more
flexible structure of the capping benzene moiety due to the
1
longer side chains in 14 is reflected in its H NMR spectrum
as well. Whereas the two protons of the CH2 group (2) near-
est to the fullerene core exhibit two multiplets with a diaste-
reotopic splitting of Dd=0.53 ppm, the chemical environ-
ment of the two other methylene protons (3) is very similar
since they give rise to only one multiplet. For the benzylic
protons (4), there are also two doublets with a small diaste-
reotopic shift of Dd=0.07 ppm. By changing the linkage
from benzylic ethers to benzylic esters as exemplified in 15,
the flexibility of the attached benzene core is again dimin-
ished. This outcome can be evidenced by an increased split-
ting of Dd=0.38 ppm for the two diastereotopic benzylic
protons (4), thus showing doublets at d=5.04 and 5.46 ppm,
respectively. The remaining methylene groups (2) also split
up in two doublets with a shift of Dd=0.33 ppm. Therefore,
these spectroscopic data nicely mirror the effects of small
structural changes within the tether systems on the flexibili-
ty and selectivity of the resulting fullerene adduct.
Scheme 1. Synthesis of the e,e,e-trisadducts 13–15 based on tripodal malo-
nate tethers: a) Bu4+Brꢀ, DMF, 1508C, 14 h (24%); b) H2SO4, MeOH,
reflux, 12 h (98%); c) LiAlH4, THF, RT, 12 h (78%); d) PBr3, Et2O, RT,
12 h (80%); e) DHP, PPTS, RT, 14 h (58%); f) 6, NaH, THF, reflux, 12 h
(60%); g) HCl, CH2Cl2/MeOH (1:1), RT, 14 h (90%); h) glycolic acid,
DBU, MeCN, RT, 12 h (83%); i) methyl malonyl chloride, pyridine, THF,
08C!RT, 24 h (10: 80%, 11: 75%, 12: 81%); j) C60, I2, DBU, toluene,
RT, 12 h (13: 29%, 14: 23%); k) C60, CBr4, P1-tBu, toluene, RT, 48 h
(8%). DHP=dihydropyran, PPTS=pyridinium para-toluenesulfonate,
Selective functionalization of the equatorial addend zone:
One possibility for targeting e,e,e-trisadducts bearing various
functional groups on the periphery is to modify the equato-
rial addend zone. This modification can in principle be ach-
ieved by a simple variation of the monofunctionalized ma-
lonic acid derivative in threefold esterifications that lead to
tripodal malonate tethers such as 10, 11, or 12. As the most
suitable template for such an approach, we chose 2 because
the highest yield for the threefold cyclopropanation was ob-
tained for 10. Condensation reactions of the Meldrum acid
(i.e., 2,2-dimethyl-1,3-dioxane-4,6-dione) with suitable alco-
hols resulted in the formation of the monofunctionalized
malonic acids 16 and 17 (Scheme 2). Whereas 16 was ob-
tained by simple melting equivalent amounts of the Mel-
drum acid and dodecanol in quantitative yield, the synthesis
of 17 had to be carried out in toluene as the solvent and an
aqueous workup was required probably due to the enhanced
sensitivity of the bromide compounds at higher tempera-
tures. To introduce carboxylic acids as functional groups in
DBU=1,8-diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene.
terns. In the spectral region of the ABCD spin system of the
ethylene side chains of 13, four signals are exhibited due to
the diastereotopicity of both CH2 groups. Each CH2 group
splits into one doublet and one triplet with a diastereotopic
shift of J=0.16 and 0.34 Hz, respectively, as demonstrated
by 2D NMR spectroscopic analysis (1H–1H COSY,
HETCOR). A closer analysis of the coupling constants re-
vealed that there are two geminal couplings of each proton
2
with its diastereotopic counterpart (2J2,2’ =11.9, J3,3’
=
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A. Hirsch and F. Beuerle
Newkome
amino dendrimer 23
first-generation
[44]
in the
presence of EDC and DMAP
in CH2Cl2 afforded the dendrit-
ic malonate 24 containing nine
tert-butyl-protected acid groups.
With trismalonates 19–21 and
24 in hand, a series of tethers
could be synthesized all bearing
various kinds of functional
group, for example, alkyl
chains, dendritic moieties, pro-
tected carboxylic acids, or bro-
mides, at their peripheral side
arms. Because the reactive mal-
onate groups of these tethers
are connected in the same
manner to the focal benzene
template as in 10, the same re-
gioselectivity for a threefold cy-
clopropanation reaction as for
13 was expected. To synthesize
the corresponding e,e,e-trisad-
ducts, cyclopropanations of C60
with the D3h-symmetrical teth-
ers 19–21 and 24 were carried
out under the same experimen-
tal conditions as those used for
the synthesis of 13. All tethers
showed similar regioselectivity,
thus leading to the formation of
the respective e,e,e-trisadduct as
the only regioisomer that was
eluted in one single fraction
during purification by column
chromatography of the reaction
mixture with mixtures of tolu-
ene/EtOAc as the eluent. Tri-
sadducts 25, 26, 28, and 30
could be isolated in 35–40%
yield and were characterized
by FAB mass spectrometric,
1H and 13C NMR spectroscop-
ic, and UV/Vis spectroscopic
analysis. The structure of the
side chains attached to the
malonate units did not signifi-
Figure 2. 1H NMR spectra (400 MHz, RT, CDCl3) of e,e,e-trisadducts a) 13, b) 14, and c) 15. Insets represent
the spectra of the free malonates, respectively.
the equatorial addend zone, the tert-butyl-protected butano-
ic acid derivative 18 was synthesized according to reported
procedure.[32,43] With the malonic acid derivatives 16–18 in
hand, the synthesis of tripodal malonate tethers 19–21 was
straightforward (Scheme 2). Threefold esterification with tri-
salcohol 2 and the appropriate malonic acid derivative
under modified Steglich conditions in THF gave trismalo-
nates 19–21 in good yield. To obtain satisfactory yields for
the cyclopropanation reactions of malonates bearing steri-
cally demanding groups, the introduction of spacer groups
between the malonate and the bulky group turned out to be
necessary. Therefore, 21 with three C4 spacer units at the
malonate termini was chosen as a precursor for the e,e,e-tri-
sadducts containing bulky groups in the equatorial addend
zone. Acidic deprotection of the tert-butyl esters by means
of formic acid provided the triscarboxylic acid 22 in almost
quantitative yield as a versatile building block for further
functionalization. For example, the treatment of 22 with the
cantly influence the regioselectivity and yield for the three-
fold cyclopropanation, thus making 2 an ideal building block
for the synthesis of functionalized e,e,e-trisadducts. Further
functionalization of the equatorial addend zone could be
achieved by means of appropriate chemical conversions. To
introduce positive charges within the equatorial addend
zone, trisbromide 26 was heated in pyridine at 608C
(Scheme 2). After stirring overnight, the fully quarternized
product was precipitated. Coevaporation of the precipitate
with toluene and several reprecipitations from a solution of
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Regioselective Synthesis of [60]Fullerene Trisadducts
FULL PAPER
turned out to be interesting candidates for biomedical appli-
cations.[20,33,34] Concerning their water solubility, the trisca-
tionic fullerene derivative 27 is very soluble over the whole
pH range and even in nonbuffered water, whereas trisacid
29 is very soluble in water at pH 8 or higher due to com-
plete deprotonation. Furthermore, polar dendritic derivative
31 bearing nine carboxylic acid groups on its periphery is
well soluble in aqueous solutions at pH 7 due to the in-
creased number of polar groups. In contrast, amphiphilic
monoadducts containing one dendritic branch with three
carboxylic acids are virtually insoluble, even under basic
conditions.[33] This outcome correlates well with the general-
ized observation that at least three ionic charges with an ap-
propriate arrangement at the fullerene surface or some com-
bination of net charging and other polar moieties is required
for sufficient water solubility.[33,45–49]
Selective functionalization of the polar addend zone: For
the selective functionalization of the polar addend zone, the
focal benzene moiety has to be removed first. In principle,
this removal could be achieved through suitable disconnec-
tion reactions that cleave the ether or ester bonds in 13–15.
Unfortunately, it was not possible to cleave all the phenylic
ether bonds of 13 in a preparative manner, even when
trying with a large variety of ether-cleaving reagents. Treat-
[50]
ment of 13 with BBr3 in CH2Cl2 resulted in complete de-
composition of the fullerene compound, as indicated by a
strong color change. The use of LiI/SiCl4/BF3·OEt2,[51]
BCl3,[52] BCl3/NBu4+ Brꢀ[53], or HBr/H3CCOOH as ether-
cleaving reagents showed no conversion of the reactant
even after several days and at higher temperatures. In con-
trast, after heating a solution of 13 and NaI in HBr/
H3CCOOH (1:1) and CHCl3 to reflux, cleavage of one ether
bond could be detected by mass-spectrometric analysis, but
this deprotection was reversible. However, longer reaction
times caused gradual deprotection of the methyl esters after
2–3 days. This lack of deprotection is probably due to a de-
creased reactivity of the ether compounds because of the
1,3,5-trisalkoxy-substitution pattern and the very rigid
capped structure. This very strong preorganization can be
assumed to favor reclosing the tethered system after cleav-
age of one out of three ether linkages. In contrast, the more
reactive benzylic ether and ester groups in 14 and 15 were
shown to be much more labile. The drawback of lower yield
in the regioselective threefold cyclopropanation is thereby
overcompensated by the favorable disconnection properties
of these functionalities. Whereas hydrogenation of benzylic
ethers seemed to be unsuitable for fullerene derivatives due
to partial hydrogenation of the fullerene surface,[54] other
common ether-cleaving reagents smoothly cleaved these
protecting groups in the presence of fullerenes. The benzylic
ester groups of 15 were cleaved by stirring a solution in
CH2Cl2 in the presence of HBr/H3CCOOH (Scheme 3).
Aqueous workup and reprecipitation from CHCl3 with pen-
tane yielded the triscarboxylic acid 32 in reasonable yield.
Depending on the reaction conditions, the benzylic ethers of
14 were cleaved to yield alcohol or bromide derivatives
Scheme 2. Selective functionalization of the equatorial addend zone:
a) DCC, DMAP, THF, 08C!RT, 48 h (19: 81%, 20: 55%, 21: 85%;
b) HCOOH, RT, 18 h (99%); c) 23, EDC, HOBt, DMAP, CH2Cl2, 08C!
RT, 48 h (64%); d)C60, I2, DBU, toluene, RT, 12 h (25: 45%, 26: 32%,
28: 35%, 30: 33%); e) pyridine, 608C, 14 h (91%); f) HCOOH, CH2Cl2,
RT, 24 h (95%). DCC=N,N-dicyclohexylcarbodiimide, DMAP=4-dime-
thylaminopyridine, EDC=N’-(3-dimethylaminopropyl)-N-ethylcarbodi-
imide; HOBt=1-hydroxybenzotriazole.
methanol induced by the addition of diethyl ether yielded
cationic e,e,e-trisadduct 27 in 90% yield. Deprotection of
the tert-butyl-protected tris- and nonakisacids 28 and 30 was
achieved by stirring in formic acid at room temperature for
several days (Scheme 2). Structural characterization of all
these compounds was achieved by NMR and UV/Vis spec-
troscopic and mass-spectrometric analysis.
In summary, a variety of functional groups was introduced
into the equatorial addend zone by a simple variation of the
second malonate terminus. Derivatives containing alkyl
chains 25 or dendritic moieties 30 are versatile building
blocks and precursors for supramolecular ensembles and
functional groups such as bromide 26 or protected carboxyl-
ic acid 28, thus facilitating further functionalization. Further-
more, polar or charged derivatives such as 27, 29, or 31
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A. Hirsch and F. Beuerle
spectra of 32 and 34 were re-
corded in polar and apolar sol-
vents, respectively. Spectra re-
corded in protic media such as
methanol or dipolar aprotic sol-
vents such as THF show the ex-
pected two triplets for the eth-
ylene units (2) and (3) in 34
and one singlet for the methyl-
ene groups (2) of 32 (Figure 3).
However, in the case of pure
CDCl3 as the solvent, compara-
ble splitting patterns to those
for the capped precursors 14
and 15 (Figure 2) were ob-
served. The protons of the CH2
groups directly attached to the
malonates (2) in 34 split into
two multiplets at d=4.29 and
4.54 ppm with a diastereotopic
shift of Dd=0.25 ppm. The cor-
responding signal for 32 splits
into an unstructured multiplet
in the range d=4.5–5.0 ppm.
These NMR spectroscopic data
Scheme 3. Selective functionalization of the polar addend zone: a) HBr/CH3COOH, CH2Cl2, RT, 14 h (86%);
b) CTAB, HBr/H2O, CHCl3, reflux, 7 days (77%); c) BCl3, CH2Cl2, 08C, 12 h (75%); d) nonanoyl chloride,
pyridine, CH2Cl2, 08C!RT, 48 h (94%). CTAB=cetyltrimethylammonium bromide.
(Scheme 3). Heating a two-phase system of CHCl3 and 48%
HBr in water with 14 and the phase-transfer catalyst
CTAB[55] to reflux for seven days gave tribromide 33 in rea-
sonable yield. Furthermore, treating a solution of 14 in
CH2Cl2 with boron trichloride and subsequent aqueous
workup led to the formation of triol 34 in good yield
(Scheme 3). Depending on the starting materials and the ap-
plied reaction conditions, functionalities such as bromide,
hydroxy, and carboxyl groups were introduced into the polar
addend zone that could be further chemically modified in
subsequent transformations. As an example, the acid chlo-
ride coupling of 34 with nonanoyl chloride in the presence
of pyridine in CH2Cl2 resulted in the formation of the e,e,e-
trisadduct 35 in good yield (Scheme 3).
Because of their proximal alignment within the polar
region of the fullerene surface, these functional groups ex-
hibit close contact with each other, thus influencing the
chemical behavior significantly. For example, the solubility
of trisacids 29 and 32 in aqueous and organic media strongly
depends on the spherical arrangement of their polar groups.
Trisadduct 29 exhibits three carboxylic groups well distribut-
ed in the equatorial addend zone. It is very soluble in buf-
fered water at pH 8 or in the presence of NaHCO3 but is vir-
tually insoluble in apolar organic solvents such as CH2Cl2 or
CHCl3. In contrast, 32 with three acid groups located in the
polar addend zone is reasonably soluble in organic media in
the fully protonated form. In aqueous phases, solubility
could only be achieved under basic conditions (pH>10). A
reasonable explanation for these differences is the establish-
ment of favorable intramolecular hydrogen-bonding interac-
tions due to the close contact of the functional groups in the
polar addend zone. On closer investigation, the 1H NMR
provide strong evidence for an inherent structural rigidity of
the attached side arms in the polar region for 32 and 34 in
apolar solvents such as CHCl3. This finding can most likely
be rationalized by an intramolecular hydrogen-bonding
system that fixes the three polar functionalities together in a
ring-like structure with threefold symmetry. The very weak,
broad, and almost undetectable bands for the OH stretching
vibrations in the IR spectra of 32 and 34 are further hints
for strong intramolecular hydrogen bonding. In contrast,
fullerene derivatives with carboxylic acids in the equatorial
addend zone showed broad OH stretching bands at n˜ =
3500 cmꢀ1 (see Figure S1 in the Supporting Information for
the spectra). For both e,e,e-trisadducts, the thermodynamical
feasibility of such intramolecular hydrogen-bonding net-
works could be evidenced by molecular modeling on the
PM3-level.[56] The calculated minimum structures and sche-
matic representations of the respective bonding motifs are
depicted in Figure 3. Both the hydroxy and carboxyl groups
are thereby connected by three hydrogen bonds in cyclic
structures containing six and twelve atoms, respectively. In
comparison to its covalently bridged precursor 14, the split-
ting for the diastereotopic ester protons in 34 is significantly
smaller (Dd=0.53 and 0.25 ppm, respectively), thus indicat-
ing the expected higher degree of flexibility for the supra-
molecular system. Thereby, effective intramolecular com-
plexation of the polar groups avoids unfavorable interac-
tions with the solvent in apolar media, thus explaining the
great discrepancies in solubilities of 29 and 32 in organic
media. In polar or protic solvents, the intramolecular hydro-
gen bonds are broken and the flexibility of the side arms is
drastically enhanced, which is evidenced by the disappear-
ance of the diastereotopic splitting in the NMR spectra.
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Regioselective Synthesis of [60]Fullerene Trisadducts
FULL PAPER
the periphery (Scheme 4). In
the case of bromoethyl-func-
tionalized side chains, the use
of EDC as a coupling agent sig-
nificantly improved the yield
and reaction time as well as the
ease of purification because re-
moval of the formed N,N-dicy-
clohexylurea (DCU) appeared
to be very difficult with DCC
as the activating reagent. Based
on the individual linkage of the
side chains to the central ben-
zene ring, malonates 36–39
were subjected to a threefold
cyclopropanation with C60 by
using either iodine and DBU or
CBr4 and the phosphazene base
P1-tBu for halogenation in situ,
as it was described for the
tether systems 11 and 12, re-
spectively (Scheme 4). The tris-
adducts 40–43 could be ob-
tained with comparable regiose-
lectivity and yield as the parent
adducts 14 and 15. Benzylic
ether-linked compounds 40 and
41 could be isolated in 25–30%
yield as the major regioisomers
beside other trisadducts. On the
other hand, 42 and 43 contain-
ing benzylic esters as connect-
ing units were isolated in up to
10% yield as the only charac-
terizable fullerene adducts.
Again, the regioselectivity and
isolation of the favored e,e,e-tris-
adducts appeared to be inde-
pendent of the chemical nature
of the attached side chains that
Figure 3. a) 1H NMR spectra (300 MHz, RT) of e,e,e-trisadducts 34 (left) and 32 (right) in polar and apolar sol- utilized 8 and 9 as highly versa-
vents (top: [D4]MeOD/CDCl3 and [D8]THF; bottom: CDCl3). b) Energy-minimized structures for intramolec-
ular hydrogen bonding in the polar addend zone for 64 (top) and 62 (bottom) and schematic representations
of the respective binding motif.
tile building blocks for the
preparation of e,e,e-trisadducts
in the same manner as 2. For
the successful deprotection and
Orthogonal functionalization of both addend zones: To
target the orthogonal functionalization of both addend
zones, a suitable combination of both functionalization of
the equatorial addend zone and facile template deprotection
followed by further chemical transformation of the polar
addend zone is required. For this purpose, tether building
blocks 8 and 9 were chosen as focal templates capable of
being readily deprotected after addition to C60. Standard
esterification reactions of the monofunctionalized malonic
acids 17 and 18 with DCC and DMAP afforded the tripodal
malonate tethers 36–39, which exhibit benzylic ether or
ester linkages and bromides or tert-butyl-protected acids on
removal of the structural template, the appropriate synthetic
protocols developed for 14 and 15 were applied to the equa-
torially functionalized derivatives as well. The reaction of 40
with boron trichloride in CH2Cl2 afforded the mixed bro-
moalcohol 44 in good yield. Subsequent bromination with
the aid of HBr and the phase-transfer catalyst CTAB in a
biphasic H2O/CHCl3 mixture resulted in the formation of
hexabromide 45 in an almost quantitative yield. The treat-
ment of 42 with HBr/H3CCOOH in CH2Cl2 and subsequent
aqueous workup afforded trisbromoacid 46 in good yield
(Scheme 4). Therefore, the deprotection of 40 and 42 could
be achieved without any problems because the bromide
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7441

A. Hirsch and F. Beuerle
boxylic acids could not be ach-
ieved in any case. Due to the
very high sensitivity of tert-
butyl-protected carboxylic acids
towards acidic reagents, depro-
tection of the tert-butyl esters
always occurred instantaneously
under reaction conditions asso-
ciated with the precipitation of
the free acids in reaction media
such as CH2Cl2 or CHCl3. The
subsequent or removal in situ
of the capped moiety was there-
fore greatly hampered in the
case of 40 and could not be
achieved in
a
preparative
manner. For 43, complete cleav-
age of both benzylic and tert-
butyl esters could be achieved
by stirring in
a mixture of
CH2Cl2 and HBr/H3CCOOH at
room temperature to afford
hexaacid 47 in almost quantita-
tive yield (Scheme 4). Because
the cleavage of the benzylic
esters is supposed to proceed
through an SN2 pathway, these
groups were anticipated to be
stable under acidic conditions
in the absence of strong nucleo-
philes. As a matter of fact, the
treatment of 43 in CH2Cl2 with
formic acid resulted in the ex-
clusive deprotection of the tert-
butyl esters and the formation
of trisacid 48. Thus, depending
on the reaction conditions, car-
Scheme 4. Orthogonal functionalization of both addend zones: a) 17, EDC, DMAP, THF, 08C!RT, 48 h (36:
89%, 38: 28%; b) 18, DCC, DMAP, THF, 08C!RT, 48 h (37: 95%, 39: 48%); c) C60, I2, DBU, toluene, RT,
12 h (40: 32%, 41: 25%); d) C60, CBr4, P1-tBu, toluene, RT, 48 h (42: 7%, 43: 8%; e) BCl3, CH2Cl2, 08C, 12 h boxylic acids could be selective-
(76%); f) Br/CH3COOH, CH2Cl2, RT, 14 h (75%); g) CTAB, HBr/H2O, CHCl3, reflux, 7 days (77%); h) HBr/
CH3COOH, CH2Cl2, RT, 14 h (79%); i) HCOOH, CH2Cl2, RT, 24 h (97%).
ly generated in both addend
zones, thus leading to versatile
building blocks 47 and 48,
which are capable of being fur-
groups in the equatorial addend zone appeared to be inert
under the applied reaction conditions. Thus, the orthogonal-
ly functionalized e,e,e-trisadducts 44, 45, and 46 all bearing
bromide groups in the equatorial addend zone and alcohol,
bromide, or carboxylic acid groups in the polar addend zone
could be synthesized and fully characterized by using stan-
dard analytical methods, such as mass spectometric, NMR
spectroscopic, and UV/Vis spectroscopic analysis. In case of
trisadducts 41 and 43, the presence of tert-butyl-protected
acid groups in the equatorial addend zone turned out to be
very crucial in terms of a facile removal of the focal benzene
moiety. Because all the synthetic protocols for the sufficient
deprotection of 14 and 15 required activation of the ether or
ester bonds by Bronsted or Lewis acid reagents, such as
BCl3 or HBr, cleavage without affecting the protected car-
ther functionalized in subsequent synthetic steps.
By appropriate orthogonal functionalization, both the
inter- and intramolecular effects of selective equatorial and
polar functionalization, respectively, should be combined in
a concise manner (Figure 4). For fullerene derivatives of this
type, these two effects might interact in a very elegant
manner to lead to versatile supramolecular building blocks
that can efficiently bind appropriate guest molecules and si-
multaneously control their chemical environment and aggre-
gation processes.
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Regioselective Synthesis of [60]Fullerene Trisadducts
FULL PAPER
Experimental Section
Chemicals: All the chemicals were purchased from chemical suppliers
and used without further purification. All the analytical-reagent-grade
solvents were purified by distillation. Dry solvents were prepared by
using customary procedures.[58] Thin layer chromatography (TLC) was
carried out on Riedel-de Haen silica gel F254 and Merck silica gel 60
F254. Detection was performed by using a UV lamp and iodine chamber.
Flash column chromatography (FC) was carried out on Merck silica gel
60 (230–400 mesh, 0.04–0.063 nm). A Shimadzu liquid chromatograph
LC-10 with a Bus module CBM-10A, autoinjector SIL-10A, two pumps
LC-10AT, and diode array detector was used for analytical HPLC. The
HPLC-grade solvents were purchased from SDS or Acros Organics. The
HPLC analytical column was a Nucleosil 5Lm, 200ꢄ4 mm from Macher-
ey–Nagel, Dꢁren. The UV/Vis spectra were recorded on a Shimadzu UV-
3102 PC UV/Vis/NIR scanning spectrophotometer, and the absorption
maxima lmax are given in nm. The mass spectra were recorded on a Mi-
cromass Zabspec in the FAB (LSIMS) mode on a matrix of 3-nitrobenzyl
alcohol and on a Shimadzu AXIMA Confidence MALDI-TOF mass
spectrometer using a nitrogen UV laser at 50 Hz at a 337-nm wavelength
on a matrix of 2,5-dihydroxybenzoic acid (DHB), sinapinic acid (SIN), or
2-[(2E)-3-(4-tert-butylphenyl)-2-methylprop-2-enylidene]malononitrile
(DCTB). The NMR spectra were recorded on JEOL JNM EX 400,
JEOL JNM GX 400, and Bruker Avance 300 spectrometers. The chemi-
cal shifts are given in ppm relative to trimethylsilane (TMS). The reso-
nance multiplicities are indicated as s=singlet, d=doublet, t=triplet, q=
quartet, quin=quintet, and m=multiplet; nonresolved, or broad (br). El-
emental analysis (CHN) was succeeded by combustion and gas-chroma-
tographic analysis on an EA 1110 CHNS analyzer (CE Instruments).
References to previously reported precursors are given in the main text.
The synthetic procedures and characterization details of 11, 14, 18, 21,
28, 29, 37, and 41[32] and 17, 20, 26, and 27[33] have been reported recently.
The synthetic procedures and full characterization details for 12, 25, 30,
36, 38–40, and 42–48 are given in the Supporting Information.
Figure 4. Combination of inter- and intramolecular interactions by or-
thogonal functionalization of both addend zones.
Conclusions and Outlook
In conclusion, it was possible to show that the introduced
concept of tripodal malonate tethers is a very powerful tool
for synthesizing e,e,e-trisadducts with good regioselectivity
and control over in/out isomerism. Both the equatorial and
polar addend zones of these novel fullerene derivatives
were shown to be selectively functionalizable in an orthogo-
nal fashion, thus giving access to unique classes of molecules
not accessible by any other known synthetic procedures.
Furthermore, it could be shown that the selective functional-
ization of both addend zones influences the chemical and
physical properties of the respective e,e,e-trisadducts in a
different fashion. Whereas variations in the equatorial
region effectively impact the intermolecular interactions,
modifications in the polar region are dominated by intramo-
lecular forces. Owing to the rigid structure and close preor-
ganization of substituents in the polar addend zone, these
derivatives are ideal candidates for supramolecular hosts ca-
pable of complexing metal ions or hydrogen-bonding sys-
tems. In the case of different functionalities in these two dis-
tinct addend zones, the corresponding fullerene derivatives
are the first example of a novel class of e,e,e-trisadducts that
exhibit asymmetrically substituted malonate addends in a
spherically well-defined manner. Further functionalization
by means of suitable chemical transformations of these mo-
lecular building blocks will give access to a great diversity of
molecular structures with a defined arrangement of different
functionalities. Up to now, no other synthetic methods have
been reported that can synthesize fullerene derivatives of
such a type. Thereby, well-directed modifications for both
addend regions may lead to novel tailor-made building
blocks that can control both close interactions with appro-
priate guest systems within the polar region and intermolec-
ular interplay by fine-tuning the equatorial belt. The combi-
nation of the functionalities brought by the addition chemis-
try introduced herein with the redox properties of the re-
maining p system of the fullerene core makes such deriva-
tives promising candidates for a variety of applications, such
as redox-active components for new molecule-based materi-
als.
2-(Tetrahydro-2H-pyran-2-yloxy)ethanol
(6):
2,3-Dihydro-2H-pyran
(DHP; 10.8 mL, 119 mmol, 1.0 equiv) in CH2Cl2 (50 mL) was added
dropwise to a solution of ethylene glycol (10.0 mL, 179 mmol, 1.5 equiv)
and PPTS (0.45 g, 0.15 equiv) in CH2Cl2 (250 mL) over 1 h. After the re-
action mixture was stirred overnight and the solvent was removed under
reduced pressure, the crude product was purified by flash column chro-
matography (SiO2, hexanes/THF 3:1 and 1:1). Removal of the solvents
and drying under high vacuum gave
6 as a colorless oil (10.2 g,
69.4 mmol, 58%). 1H NMR (400 MHz, RT, CDCl3): d=1.48 (m, 4H;
CH2), 1.73 (m, 2H; CH2), 3.11 (s, 1H; OH), 3.48 (m, 1H), 3.65 (m, 4H;
OCH2), 3.86 (m, 1H; OCH2), 4.52 (m, 1H; OHCO) ppm; 13C NMR
(100.5 MHz, RT, CDCl3): d=19.7 (1C; CH2), 25.0 (1C; CH2), 30.5 (1C;
CH2), 61.9 (1C; CH2OH), 62.9 (1C; OCH2), 70.4 (1C; OCH2), 99.9 (1C;
OHCO) ppm; MS (FAB, NBA): m/z: 147 [M+H]+; elemental analysis
(%) calcd for C7H14O3: C 57.51, H 9.65; found C 57.21, H 9.93.
1,3,5-Tris-(2-hydroxy-1-oxo)ethoxymethyl benzene (9): DBU (2.05 mL,
13.8 mmol, 3.3 equiv) was added to a solution of 5 (1.50 g, 4.20 mmol,
1 equiv) and glycolic acid (1.05 g, 13.8 mmol, 3.3 equiv) in acetonitrile
(20 mL). The reaction mixture was stirred at ambient temperature over-
night. After the removal of the solvent under reduced pressure, the resi-
due was purified by flash column chromatography (SiO2, acetonitrile).
Removal of the solvent and drying under high vacuum gave 9 as a color-
1
less solid (1.20 g, 3.51 mmol, 83%). H NMR (400 MHz, RT, CDCl3): d=
2.39 (s, br, 3H; OH), 4.20 (s, 6H; CH2OH), 5.21 (s, 6H; Ar-CH2), 7.32 (s,
3H; Ar-H) ppm; 13C NMR (100.5 MHz, RT, CDCl3): d=60.7 (3C;
CH2OH), 66.4 (3C; Ar-CH2), 128.5 (3C; ArC-H), 136.3 (3C; ArC-CH2),
173.1 (3C; CO) ppm; MS (FAB, NBA): m/z: 342 [M]+; elemental analy-
sis (%) calcd for C15H18O9: C52.63, H 5.30; found C 51.52, H 5.40. m.p.
115–1178C.
1,3,5-Tris-(2-methylmalonyl)ethoxybenzene (10): Methyl malonyl chlo-
ride (2.10 mL, 19.6 mmol, 5.1 equiv) in THF (15 mL) was added dropwise
at 08C to a solution of 2 (1.00 g, 3.87 mmol, 1 equiv) and dry pyridine
(2.10 mL, 25.8 mmol, 6.7 equiv) in dry THF (35 mL). The reaction mix-
ture was slowly warmed and stirred at room temperature overnight. Af-
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7443

A. Hirsch and F. Beuerle
terwards, the precipitated pyridinum salts were removed by filtration.
The filtrate was evaporated and the crude product was purified by flash
column chromatography (SiO2, CH2Cl2/MeOH 97:3) to give 10 as a pale
yellow oil (1.73 g, 3.10 mmol, 80%). 1H NMR (400 MHz, RT, CDCl3):
yield 19 as
a
colorless solid (7.99 g, 7.82 mmol, 81%). 1H NMR
(400 MHz, RT, CDCl3): d=0.87 (t, 3J=6.9 Hz, 9H; CH3), 1.25 (m, 54H;
CH2), 1.60 (m, 6H; COOCH2CH2CH2), 3.43 (s, 6H; OCCH2CO), 4.12
3
(m, 12H; COOCH2CH2CH2, Ar-OCH2CH2), 4.47 (t, J=4.7 Hz, 6H; Ar-
OCH2), 6.09 (s, 3H; Ar-H) ppm; 13C NMR (100.5 MHz, RT, CDCl3): d=
14.0 (3C; CH3), 22.6, 25.7, 28.4, 29.1, 29.3, 29.4, 29.5, 29.6, 31.8 (30C;
CH2), 41.3 (3C; OCCH2CO), 63.5 (3C; ArOCH2CH2), 65.7 (3C; Ar-
OCH2), 65.8 (3C; COOCH2CH2CH2), 94.6 (3C; ArC-H), 160.4 (3C;
ArC-CH2), 166.5, 166.7 (6C; OCCH2CO) ppm; MS (FAB, NBA): m/z:
1021 [M]+; elemental analysis (%) calcd for C57H96O15: C67.03, H 9.47;
found C 67.63, H 9.72.
3
d=3.43 (s, 6H; OCCH2CO), 3.72 (s, 9H; OCH3), 4.12 (t, J=4.7 Hz, 6H;
Ar-OCH2), 4.47 (t, 3J=4.7 Hz, 6H; Ar-OCH2CH2), 6.09 (s, 3H; Ar-
H) ppm; 13C NMR (100.5 MHz, RT, CDCl3): d=41.1 (3C; OCCH2CO),
52.5 (3C; OCH3), 63.6 (3C; Ar-OCH2CH2), 65.7 (3C; Ar-OCH2), 94.6
(3C; ArC-H), 160.2 (3C; ArC-O), 166.4, 166.8 (6C; OCCH2CO) ppm;
MS (MALDI-TOF, without matrix): m/z: 581 [M+Na]+; elemental analy-
sis (%) calcd for C24H30O15·0.5CH2Cl2: C48.97, H 5.20; found C 49.40, H
5.57.
1,3,5-Tris-[2’-(3’’-amido[G1]-tert-butyl)propylmalonyl]ethoxybenzene 24:
Malonate 21 (990 mg, 1.05 mmol) was dissolved in formic acid (10 mL)
and stirred at ambient temperature overnight. After removal of the sol-
vent under reduced pressure, the crude product was mixed with toluene
and distilled several times to remove the remaining traces of formic acid.
Drying under high vacuum gave trisacid 22 as a yellow viscous oil
(810 mg, 1.04 mmol, 99%). Complete deprotection was checked by
1H NMR spectroscopic analysis and the product was used without further
purification in the next synthetic step.
e,e,e-Trisadduct 13: C60 (500 mg, 0.693 mmol, 1 equiv) was dissolved in
degassed, dry toluene (1200 mL). After complete dissolution of the fuller-
ene was obtained, iodine (580 mg, 2.28 mmol, 3.3 equiv) and malonate 10
(360 mg, 0.645 mmol, 0.95 equiv) were added. Afterwards, a solution of
DBU (670 mL, 4.49 mmol, 6.5 equiv) in toluene (500 mL) was added
dropwise over 4 h. After stirring overnight at ambient temperature, the
reaction mixture was subjected directly to flash column chromatography
with toluene as the eluent. After elution of traces of starting material C60
with toluene, the eluent was changed to toluene/EtOAc (8:2) to isolate
the product. Final reprecipitation from CHCl3 with pentane gave 13 as a
red solid (238 mg, 0.187 mmol, 29%). 1H NMR (400 MHz, RT, CDCl3):
d=3.96 (s, 9H; OCH3), 4.08 (d, 2J=11.6 Hz, 3H; Ar-OCH2), 4.24 (dd,
2J=11.6, 3J=10.0 Hz, 3H; Ar-OCH2), 4.47 (dd, 2J=12.0, 3J=10.0 Hz,
3H; Ar-OCH2CH2), 4.81 (d, 2J=12.0 Hz, 3H; Ar-OCH2CH2), 5.83 (s,
3H; Ar-H) ppm; 13C NMR (100.5 MHz, RT, CDCl3): d=52.7 (3C;
OCCCO), 53.9 (3C; OCH3), 65.8 (3C; Ar-OCH2CH2), 66.1 (3C; Ar-
OCH2), 69.4, 70.7 (6C; C60 sp3), 94.2 (3C; ArC-H), 141.0, 141.0, 141.7,
142.0, 142.7, 143.3, 143.7, 144.2, 145.2, 145.8, 146.0, 146.3, 146.5, 146.6,
146.8, 146.9, 146.9, 147.0 (54C; C60 sp2), 160.3 (3C; ArC-O), 163.1, 163.4
(6C; OCCCO) ppm; MS (MALDI-TOF, SIN): m/z: 1274 [M+H]+, 1297
[M+Na+H]+; UV/Vis (CH2Cl2): lmax =252.5, 281.5, 305 (sh), 380.5 (sh),
480.5, 565 (sh) nm.
H2N-[G1] 23 (1.82 g, 4.39 mmol, 4 equiv), butan-1-ol (0.52 g, 3.84 mmol,
3.5 equiv), and DMAP (70 mg, 0.55 mmol, 0.5 equiv) were added to a so-
lution of trisacid 22 (850 mg, 1.10 mmol, 1 equiv) in dry CH2Cl2 (50 mL).
The solution was cooled to 08C and EDC (740 mg, 3.84 mmol, 3.5 equiv)
was added. The reaction mixture was slowly warmed up and stirred at
room temperature for two days. After completion of the reaction was de-
tected by TLC analysis, the organic phase was washed with water (3ꢄ
25 mL) and dried over MgSO4. After evaporation of the solvent under
reduced pressure, the crude product was purified by flash column chro-
matography (SiO2, CH2Cl2/EtOAc 1:1) to yield 24 as a colorless cera-
ceous solid (1.38 g, 700 mmol, 64%). 1H NMR (400 MHz, RT, CDCl3):
d=1.43 (s, 81H;
CH2CH2CONH), 2.20 (m, 24H; CH2COOCAHCUTNGTRENNNUG
C
N
ACHTUNGTRENNUNG(CH3)3,
6H; OCCH2CO), 4.14 (m, 6H; Ar-OCH2), 4.18 (t, 3J=6.2 Hz, 6H;
CH2CH2CH2CONH), 4.49 (m, 6H; Ar-OCH2CH2), 6.00 (s, 3H; NH),
6.10 (s, 3H; Ar-H) ppm; 13C NMR (100.5 MHz, RT, CDCl3): d=24.6
e,e,e-Trisadduct 15: C60 (500 mg, 0.693 mmol, 1 equiv) was dissolved in
thoroughly degassed toluene (1100 mL) under nitrogen. After complete
dissolution was obtained, CBr4 (760 mg, 2.29 mmol, 3.3 equiv) and malo-
nate 12 (416 mg, 0.647 mmol, 0.95 equiv) were added. Afterwards, a solu-
tion of P1-tBu (615 mL, 2.42 mmol, 3.5 equiv) in toluene (250 mL) was
added dropwise over 4 h. The reaction mixture was stirred at room tem-
perature and monitored by TLC analysis. After completion of conver-
sion, the mixture was subjected directly to column chromatography with
toluene as the eluent. After elution of traces of starting material C60, the
eluent was changed to toluene/EtOAc (7:3) to isolate the crude product.
For final purification, the residue was subjected to multiple column-chro-
matographic steps (SiO2, CH2Cl2/EtOAc 8:2). Reprecipitation from
CHCl3 with pentane yielded 15 as a red solid (70.2 mg, 0.051 mmol, 8%).
1H NMR (400 MHz, RT, CDCl3): d=3.97 (s, 9H; OCH3), 4.73 (d, 2J=
(3C; CH2CH2CONH), 28.0 (27C; C
(CH3)3), 29.8 (9C; CH2COOC(CH3)3), 33.2 (3C; CH2CONH), 41.4 (3C;
OCCH2CO), 57.4 (3C; CONHC), 63.6 (3C; ArOCH2CH2), 64.7 (3C;
CH2CH2CH2CONH), 66.0 (3C; Ar-OCH2), 80.7 (9C; C(CH3)3), 86.7
(3C; ArC-H), 160.3 (3C; ArC-O), 166.3, 167.0 (6C; OCCH2CO), 171.3
ACHTUNGNERT(UNNG CH3)3), 29.7 (9C; CH2CH2COOC-
G
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(3C; CONH), 173.0 (9C; COOCACHTNUGTRNEUNG(CH3)3) ppm; MS (FAB, NBA): m/z:
1462 [Mꢀ9C4H8]+, 1967 [M]+, 1990 [M+Na]+; elemental analysis (%)
calcd for C99H159N3O36: C60.44, H 8.15, N 2.14; found C 60.52, H 8.27, N
2.18.
e,e,e-Trisadduct 31: Trisadduct 30 (75 mg, 28.0 mmol) was dissolved in
CH2Cl2 (10 mL) and formic acid (5 mL) was added. The reaction mixture
was stirred at room temperature and the progress of the reaction was
monitored by TLC analysis. The solvent was removed under vacuum and
traces of formic acid were removed by repeated coevaporation with tolu-
ene and THF. Reprecipitation from THF with pentane gave 31 as a red
solid (54 mg, 24.8 mmol, 95%). 1H NMR (400 MHz, RT, [D8]THF): d=
1.99 (m, 24H; CH2CH2COOH; CH2CH2CONH), 2.23 (m, 24H;
2
15.7 Hz, 3H; OCCH2O), 5.04 (d, J=12.8 Hz, 3H; Ar-CH2), 5.06 (d, 3H;
2J=15.7 Hz, OCCH2O), 5.46 (d, 2J=12.8 Hz, 3H; Ar-CH2), 6.94 (s, 3H;
Ar-H) ppm; 13C NMR (100.5 MHz, RT, CDCl3): d=51.8 (3C; OCCCO),
54.0 (3C; OCH3), 63.0 (3C; OCCH2O), 66.1 (3C; Ar-CH2), 69.2, 70.3
(6C; C60 sp3), 126.0 (3C; ArC-H), 135.8 (3C; ArC-CH2), 140.6, 141.0,
141.4, 142.0, 142.8, 143.47, 144.4, 144.9, 145.4, 145.7, 145.9, 146.3, 146.5,
146.5, 146.7, 146.8, 147.0, 147.3 (54C; C60 sp2), 163.5, 163.6 (6C;
OCCCO), 166.8 (3C; OCCH2O) ppm; MS (FAB, NBA): m/z: 1358
[M+H]+; UV/Vis (CH2Cl2): lmax =252, 280, 305 (sh), 381 (sh), 480, 565
(sh) nm.
CH2COOH;
CH2CONH),
3.9–4.7
(m,
15H;
Ar-OCH2CH2,
CH2CH2CH2CONH), 4.82 (m, 3H; Ar-OCH2CH2), 6.59 (m, 6H; Ar-H;
NH), 10.86 (s, br, 9H; COOH) ppm; 13C NMR (100.5 MHz, RT,
[D8]THF): d=23.6 (3C; CH2CH2CONH), 30.4 (9C; CH2CH2COOH),
30.7 (9C; CH2COOH), 32.9 (3C; CH2CONH), 54.6 (3C; OCCCO), 57.9
(3C; CONHC), 64.1 (3C; Ar-OCH2CH2), 98.9 (3C; ArC-H), 141.6,
143.0, 144.3, 144.9, 146.1, 146.6, 147.1, 147.1, 147.5, 147.5, 147.8, 148.0
(54C; C60 sp2), 159.0 (3C; ArC-O), 161.9, 162.2 (6C; OCCCO), 171.8
(3C; CONH), 175.0 (9C; COOH) ppm; MS (MALDI-TOF, SIN): m/z:
2178 [M+H]+; UV/Vis (DMSO): lmax =281, 305 (sh), 380 (sh), 481, 565
(sh) nm.
1,3,5-Tris-(2-dodecylmalonyl)ethoxybenzene
(19):
DCC
(6.99 g,
33.8 mmol, 3.5 equiv) was added to a solution of trisalcohol 2 (2.50 g,
9.68 mmol, 1 equiv) and DMAP (421 mg, 3.45 mmol, 0.35 equiv) in dry
THF at 08C in an inert gas atmosphere. The reaction mixture was
warmed up slowly, stirred at room temperature for several days, and
monitored by TLC analysis. After completion of the reaction, the solu-
tion was filtered and the solvent was evaporated under vacuum. The resi-
due was dissolved in a small amount of ethyl acetate and filtered again
for several times to remove the remaining DCU. The crude product was
purified by flash column chromatography (SiO2, toluene/EtOAc 9:1) to
e,e,e-Trisadduct 32: Trisadduct 15 (65 mg, 47.9 mmol) was dissolved in
CH2Cl2 (10 mL) and 33% HBr in H3CCOOH (5 mL) was added. The re-
action mixture was stirred at ambient temperature and the progress of
the reaction was monitored by TLC analysis. After complete conversion,
7444
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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7434 – 7446

Regioselective Synthesis of [60]Fullerene Trisadducts
FULL PAPER
CH2Cl2 (15 mL) was added and the organic phase was washed with water
(3ꢄ10 mL). After drying over MgSO4 and removal of the solvent, the
residue was dissolved in a small amount of THF and the insoluble by-
product 1,3,5-trisbromobenzene was removed by filtration. Reprecipita-
tion from THF with pentane gave 32 as a red solid (51.2 mg, 41.2 mmol,
86%). 1H NMR (400 MHz, RT, [D8]THF): d=3.03 (s, br, 3H; COOH+
H2O), 3.91 (s, 9H; OCH3), 4.76 (m, 6H; CH2) ppm; 13C NMR
(100.5 MHz, RT, [D8]THF): d=46.4 (3C; OCCCO), 54.2 (3C; OCH3),
63.2 (3C; CH2), 71.6, 72.4 (6C; C60 sp3), 142.0, 142.9, 143.0, 143.3, 144.7,
144.8, 145.3, 146.5, 146.7, 146.9, 147.4, 147.7, 147.8, 148.0, 149.2 (54C; C60
sp2), 163.4, 164.0 (6C; OCCCO), 168.6 (COOH) ppm; MS (MALDI-
TOF, DHB): m/z: 1245 [M+3H]+, 1268 [M+3H+Na]+, 1291
[M+3H+2Na]+; UV/Vis (CH2Cl2): lmax =250, 285, 308 (sh), 380 (sh),
480, 570 (sh) nm.
(100.5 MHz, RT, CDCl3): d=14.0 (CH2CH3), 22.6, 24.7, 29.1, 29.2, 31.7,
33.9 (21C; CH2), 52.3 (3C; OCCCO), 53.7 (3C; OCH3), 61.2 (3C;
COOCH2CH2O), 64.5 (3C; COOCH2CH2O), 69.8, 70.6 (6C; C60 sp3),
141.0, 141.6, 141.9, 142.6, 142.7, 143.5, 144.4, 144.9, 145.1, 145.4, 145.7,
146.4, 146.5, 146.6, 146.7, 146.8, 146.9, 147.1 (54C; C60 sp2), 163.1, 163.6
(OCCCO), 173.6 (3C; OOCCH2CH2O) ppm; MS (MALDI-TOF, SIN):
m/z: 1622 [M]+, 1645 [M+Na]+; UV/Vis (CH2Cl2): lmax =250, 285, 305
(sh), 380 (sh), 480, 565 (sh) nm.
Acknowledgements
This work was supported by the Fonds der Chemischen Industrie (Chem-
iefondsstipendium for F.B.) and the Deutsche Forschungsgemeinschaft
(SFB 583: Redox-aktive Metallkomplexe: Reaktivitꢀtssteuerung durch
molekulare Architekturen) and the Cluster of Excellence Engineering of
Advanced Materials.
e,e,e-Trisadduct 33: Trisadduct 14 (100 mg, 76.0 mmol) was dissolved in
CHCl3 (20 mL) and mixed with a 48% HBr in water (20 mL). After
adding hexadecyltrimethylammonium bromide (85.0 mg), the biphasic
system was heated to reflux for several days. The progress of the reaction
was monitored by TLC analysis. After quantitative conversion, CHCl3
(30 mL) and water (30 mL) were added. After separation of the phases,
the organic layer was extracted with a saturated aqueous NaHCO3 solu-
tion (2ꢄ30 mL) and water (30 mL). After drying over MgSO4 and re-
moval of the solvent, the residue was purified by flash column chroma-
tography (SiO2, toluene/ethyl acetate 9:1). Reprecipitation from CHCl3
with pentane gave 33 as a red solid (81.2 mg, 58.5 mmol, 77%). 1H NMR
(400 MHz, RT, CDCl3): d=3.54 (t, 3J=5.9 Hz, 6H; CH2Br), 3.94 (s, 9H;
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e,e,e-Trisadduct 34: Trisadduct 14 (208 mg, 158 mmol, 1 equiv) was dis-
solved in dry CH2Cl2 (100 mL) under nitrogen and cooled to 08C. After-
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from CHCl3 with pentane gave 34 as a red solid (142 mg, 118 mmol,
75%). 1H NMR (400 MHz, RT, CDCl3): d=2.64 (s, br, 3H; OH), 3.83
(m, 6H; CH2OH), 3.95 (s, 9H; OCH3), 4.29 (m, 3H; CH2CH2OH), 4.54
(m, 3H; CH2CH2OH) ppm; 13C NMR (100.5 MHz, RT, CDCl3): d=52.6
(3C; OCCCO), 53.9 (3C; OCH3), 60.5 (3C; CH2OH), 68.1 (3C;
CH2CH2OH), 69.9, 70.6 (6C; C60 sp3), 141.0, 141.9, 142.2, 142.3, 142.9,
143.3, 144.2, 144.3, 144.3, 145.7, 146.0, 146.3, 146.4, 146.4, 146.6, 146.7,
146.7, 146.8 (54C; C60 sp2), 163.3, 163.8 (6C; OCCCO) ppm; MS (FAB,
NBA): m/z: 720 [C60]+, 1201 [M]+; UV/Vis (CH2Cl2): lmax =251, 282, 305
(sh), 380 (sh), 480, 565 (sh) nm.
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1
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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7434 – 7446