Synthesis of water-soluble cyclen-functionalised fullerene C60 derivatives

Article abstract of DOI:10.3184/174751914X13945582435462

The fullerene family has interesting photophysical, electrochemical and mechanical properties with applications in organic solar cells, nanotechnology, superconductivity, chemosensors and biomedicine. Water-soluble cyclen-functionalised fullerene derivati

Full text of DOI:10.3184/174751914X13945582435462

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 APRIL, 251–253
RESEARCH PAPER 251
Synthesis of water-soluble cyclen-functionalised fullerene C60 derivatives
Jiaheng Hea, Lipeng Yanb, Guoping Liua, Zongping Maa, Shunzhong Luoa, Songhua Hec*, Qiang
Guob, Jingbo Lanb and Di Wub
aInstitute of Nuclear Physics and Chemistry, China Academy of Engineering Physics, Mianyang 621900, P.R. China
bKey Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road,
Chengdu 610064, P.R. China
cInstitute of Media and Communication, Shenzhen Polytechnic, Shenzhen 518055, P.R. China
The fullerene family has interesting photophysical, electrochemical and mechanical properties with applications in organic
solar cells, nanotechnology, superconductivity, chemosensors and biomedicine. Water-soluble cyclen-functionalised fullerene
derivatives cyclen-C60-1 and bis(cyclen)-C60-2 have been synthesised. The whole synthetic routes are simple and the total yields
are relatively high.
Keywords: fullerene, C60, cyclen, water-soluble synthesis
Since their discovery in 1985, fullerenes have attracted
considerable attentions in different fields of science.1–6
The fullerene family, especially C60, possesses interesting
photophysical, electrochemical, and mechanical properties
for utilisation in organic solar cells, nanotechnology,
superconductivity, chemosensors and body armour
construction.7–17 Due to their size, hydrophobicity, three-
dimensionality and electronic configurations, fullerenes have
also been studied in the field of biomedicine including as
anti-HIV agents, radical scavengers, antioxidants, antibiotics,
antiviral drugs, DNA photocleavage, and carriers in gene
and drug delivery.18–20 However, unfunctionalised fullerenes
are completely insoluble in water, which limits their use in
biomedical studies.21,22 Cyclen (1,4,7,10-tetraazacyclododecane)
is known to have a very high binding constant with transition-
metal ions such as Cu2+, Zn2+, Cd2+ and Pb2+.5 What is more,
in neutral buffer solution, cyclen is partially protonated
by an uptake of two protons, and so possesses good water-
solubility.23,24 We now present the design and synthesis of
water-soluble cyclen-functionalised fullerene C60 derivatives.
Result and discussion
Scheme 1 shows the synthetic strategy used to obtain cyclen-
functionalised fullerene C60 derivatives. The cyclen-C60-1
anchored with one cyclen pendant was successfully synthesised
by a four-step reaction with tri-tert-butyl-10-(2-aminoethyl)-
1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylate (1) and C60
as starting materials, in 11% overall yield. This product was
soluble in MeOH, EtOH, DMSO, and most importantly, it was
slightly soluble in water. The bis(cyclen)-C60-2 was also obtained
via the similar method, and exhibited a very good water-
solubility (>10 mg mL–1). Unfortunately, bis(cyclen)-C60-2 was
a mixture of various isomers, which could not been purified
through silica gel chromatography.
The Boc-protected cyclen 3 was prepared according to the
literature.25 The electrophilic substitution was then performed
between amino group of 3 and benzyl 2-bromoacetate to give
the intermediate cyclen 4 in a yield of 43%. In the next step,
benzyl group was removed through hydrogenation catalysed
by Pd/C in a good yield of 84%. This resulting carboxyl
cyclen 5 was then reacted with C60 to form fulleropyrrolidine
O
O
H
H
N
OBn
OH
N
NH2
O
Boc
Boc
Boc
Boc
Boc
Boc
Br
N
N
N
N
N
N
N
N
N
N
N
Pd/C, H2, MeOH
OBn
TEA, CH2Cl2
0 oC to rt, 48 h
N
Boc
Boc
Boc
3
4
5
(84%)
(43%)
Boc
N
N
H
Boc
HN
N
N
N
N
N
CF3COOH
H
N
N
CH2Cl2, rt
Boc
3 TFA
C60, (CH2O)n
toluene, reflux
1
- (86%)
cyclen-C60
6
(37%)
N
Boc
H
NH
N
N
H
Boc
N
Boc
N
H
N
HN
N
N
N
N
Boc
N
N
H
CF3COOH
CH2Cl2, rt
N
N
N
N
N
Boc
N
6 TFA
Boc
2
- (98%)
bis(cyclen)-C60
7
(43%)
Scheme 1 Synthesis routes of cyclen-functionalised fullerene C60 derivatives.
* Correspondent. E-mail: hdh1818@szpt.edu.cn
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252 JOURNAL OF CHEMICAL RESEARCH 2014
Fig. 1 The ESI-TOF mass spectrum of bis(cyclen)-C60-2.
liquid. 1H NMR (400 MHz, CDCl3): δ 7.37–7.30 (m, 5H), 5.14 (s, 2H),
3.52–3.25 (m, 14H), 2.74–2.63 (m, 8H), 1.45 (s, 9H), 1.42 (s, 18H) ppm;
13C NMR (100 MHz, CDCl3): δ 172.3, 156.2, 155.8, 155.5, 135.6, 128.7,
128.54, 128.51, 79.7, 79.6, 79.4, 66.7, 55.8, 54.5, 53.1, 51.2, 50.2, 48.6,
48.2, 48.0, 47.7, 45.1, 28.8, 28.6 ppm; IR: νmax/cm−1 =2973, 1680, 1457,
1412, 1363, 1247, 1153; HRMS (ESI+): calcd for C34H58N5O8 [M+H]+
664.4285; found 664.4286.
2-(2-(4,7,10-tris(Tert-butoxycarbonyl)-1,4,7,10-tetraazacyclo-
dodecan-1-yl)ethylamino)acetic acid (5): 3% Pd/C (1.05 g) catalyst was
added to a solution of 4 (3.6 g, 5.4 mmol) in 50 mL of methanol, and the
mixture was reacted under 1.5 MPa of hydrogen at room temperature
for 3 hours. Then the mixture was filtered through a Celite pad and
washed with methanol. The solution was concentrated under reduced
pressure affording the carboxyl derivative (5) (2.6 g, 84%) as a white
solid, m.p. 91–93°C. 5 was used in the next step without any further
purification. 1H NMR (400 MHz, CDCl3): δ 3.49–3.32 (m, 14H), 3.07–
3.01 (m, 4H), 2.68 (s, 4H), 1.44 (s, 9H), 1.42 (s, 18H) ppm; 13C NMR
(100 MHz, CDCl3): δ 170.1, 155.9, 155.3, 79.7, 79.4, 54.6, 53.9, 50.1, 49.7,
47.7, 42.9, 41.9, 28.6, 28.5 ppm; IR: νmax/cm−1 =2976, 1656, 1462, 1414,
1402, 1315, 1249, 1155; HRMS (ESI+): calcd for C27H52N5O8 [M+H]+
574.3816; found 574.3814.
6 and 7 according to the classic procedure developed by Prato
and co-workers.26,27 Boc-protection was finally removed
under a strong acid condition to give cyclen-functionalised
fullerene C60 derivatives cyclen-C60-1 and bis(cyclen)-C60-2.
1
The cyclen-C60-1 and its intermediates were confirmed by H
1
NMR, 13C NMR and HRMS. The H NMR and 13C NMR of
bis(cyclen)-C60-2 did not give meaningful results,28,29 but its
TOF-MS spectrum showed the expected molecular ions peaks
in high intensity (Fig. 1, m/z 1203.4613).
In conclusion, we have synthesised water-soluble cyclen-
functionalised fullerene derivatives cyclen-C60-1 and
bis(cyclen)-C60-2. The whole synthetic routes are simple and the
total yields are relatively high. This result may be advantageous
for the application of fullerenes in biomedical field.
Experimental
1
NMR spectra were obtained on a Bruker AMX-400. The H NMR
(400 MHz) chemical shifts were measured relative to CDCl3 or
DMSO-d6 as the internal reference (CDCl3: δ 7.26 ppm; DMSO-d6: δ
2.50 ppm). The 13C NMR (100 MHz) chemical shifts were given using
CDCl3 or DMSO-d6 as the internal standard (CDCl3: δ 77.16 ppm;
DMSO-d6: δ 39.52 ppm). The molecular weights were tested on
Autoflex MALDI-TOF-MS (Bruker, USA) in the linear mode with
(R)-cyano-4-hydroxycinnamic acid as a matrix. High-resolution mass
spectra (HRMS) were obtained with a Waters-Q-TOF-Premier (ESI).
Progress of their reactions was monitored by TLC. Unless otherwise
noted, all reagents and solvents were obtained from commercial
suppliers and used without further purification.
Boc-Cyclen-C60 (6): A mixture of 5 (58 mg, 0.1 mmol), C60 (72 mg,
0.1 mmol), paraformaldehyde (4.5 mg, 0.05 mmol, 1.5 equiv.) and
toluene (15 mL) was stirred at 110 °C and then refluxed for 6 hours.
The mixture was concentrated under reduced pressure to remove
toluene. The crude product was purified by column chromatography
on silica gel (toluene/ethyl acetate=5/1, v/v) to give the desired product
1
6 (47 mg, 37%) as a black solid. m.p.>260 °C; H NMR (400 MHz,
CDCl3): δ 4.46 (s, 4H), 3.71 (s, 2H), 3.62 (s, 2H), 3.45 (s, 8H), 3.30–3.27
(m, 2H), 3.18–3.15 (m, 2H), 2.96–2.90 (m, 4H), 1.49–1.47 (m, 27H)
ppm; 13C NMR (100 MHz, CDCl3): δ 154.9, 147.4, 146.3, 146.2, 146.1,
145.8, 145.5, 145.4, 144.6, 143.2, 142.7, 142.3, 142.2, 142.0, 140.3,
136.3, 79.8, 79.7, 79.5, 70.8, 68.5, 55.6, 54.8, 51.2, 50.2, 48.3, 28.8,
28.73, 28.67 ppm; IR: νmax/cm−1 =2924, 1683, 1455, 1411, 1363, 1246,
1154; HRMS (ESI+): calcd for C87H52N5O6 [M+H]+ 1262.3918; found
1262.3911.
Boc-bis(cyclen)-C60 (7): A mixture of 5 (570 mg, 1.0 mmol), C60
(720 mg, 1.0 mmol), paraformaldehyde (45 mg, 0.5 mmol, 1.5 equiv.)
and toluene (200 mL) was stirred at 110 °C and then refluxed for
6 hours. The mixture was concentrated under reduced pressure
Tri-tert-butyl 10-(2-aminoethyl)-1,4,7,10-tetraazacyclododecane-
1,4,7-tricarboxylate (3): Prepared according to the literature.25
Tri-tert-butyl-10-(2-(2-(benzyloxy)-2-oxoethylamino)ethyl)-1,4,7,10-
tetraazacyclododecane-1,4,7-tricarboxylate (4): Benzyl 2-bromoacetate
(2.5 mL, 16 mmol) in CH2Cl2 (10 mL) was added to a solution of Boc-
protected cyclen (3) (6.9 g, 13.4 mmol) and triethylamine (2.8 mL,
20 mmol) in CH2Cl2 (180 mL) at 0 °C over a period of 30 minutes, and the
solution was stirred at room temperature for 48 hours.
The mixture was then concentrated under reduced pressure, and the
product was purified by column chromatography on silica gel (ethyl
acetate) to provide the desired product (4) (3.8 g, 43%) as a clear sticky
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JOURNAL OF CHEMICAL RESEARCH 2014 253
4
M. Arndt, O. Nairz, J. Vos-Andreae, C. Keller, G. van der Zouw and A.
Zeilinger, Nature, 1999, 401, 680.
R.F. Curl, Angew. Chem. Int. Ed. Engl., 1997, 36, 1566.
H.W. Kroto, J.R. Heath, S.C. O’Brien, R.F. Curl and R.E. Smalley, Nature,
1985, 318, 162.
E. Nakamura, Angew. Chem. Int. Ed., 2013, 52, 236.
M. Wielopolski, A. Molina-Ontoria, C. Schubert, J.T. Margraf, E. Krokos,
J. Kirschner, A. Gouloumis, T. Clark, D.M. Guldi and N. Martín, J. Am.
Chem. Soc., 2013, 135, 10372.
to remove toluene. The crude product was purified by column
chromatography on silica gel (toluene/ethyl acetate=1/1, v/v) to give
the desired product 7 (389 mg, 43%) as a black solid. HRMS (ESI+):
calcd for C114H102N10O12Na [M+Na]+ 1826.7610; found 1826.7611.
Cyclen-C60-1: Trifluoroacetic acid (1.0 mL, 13.4 mmol) was added
slowly to a solution of 6 (90 mg, 71.3 µmol) in 50 mL of CH2Cl2, at room
temperature. The solution was stirred at room temperature overnight.
The mixture was concentrated under reduced pressure to remove
the solvent and then washed with CH2Cl2 to remove the impurities.
Deprotected product cyclen-C60-1 (80 mg, 86%) was obtained as a
brownish solid. m.p.>260 °C; 1H NMR (400 MHz, DMSO-d6): δ
4.75–4.62 (m, 4H), 3.53 (s, 2H), 3.28 (s, 4H), 3.16–3.06 (m, 10H), 2.91
(s, 4H) ppm; 13C NMR (100 MHz, DMSO-d6): δ 155.5, 146.6, 145.9,
145.6, 145.4, 145.2, 144.71, 144.68, 144.0, 142.6, 142.1, 141.8, 141.5,
5
6
7
8
9
T. Liu and A. Troisi, Adv. Mater., 2013, 25, 1038.
10 R. Charvet, Y. Yamamoto, T. Sasaki, J. Kim, K. Kato, M. Takata, A. Saeki,
S. Seki and T. Aida, J. Am. Chem. Soc., 2012, 134, 2524.
11 B. Ballesteros, G. de la Torre, A. Shearer, A. Hausmann, M.Á. Herranz,
D.M. Guldi and T. Torres, Chem.–Eur. J., 2010, 16, 114.
12 J.-C. Wu, D.-X. Wang, Z.-T. Huang and M.-X. Wang, J. Org. Chem., 2010,
75, 8604.
141.3, 139.5, 135.4, 72.1, 67.1, 48.2, 44.3, 42.2, 42.0 ppm; IR: νmax
/
13 J. Iehl, R.P. de Freitas, B. Delavaux-Nicot and J.-F. Nierengarten, Chem.
Commun., 2008, 2450.
14 H. Isobe, K. Cho, N. Solin, D.B. Werz, P.H. Seeberger and E. Nakamura,
Org. Lett., 2007, 9, 4611.
15 A. Biebersdorf, R. Dietmüller, A.S. Susha, A.L. Rogach, S.K. Poznyak,
D.V. Talapin, H. Weller, T.A. Klar and J. Feldmann, Nano Lett., 2006, 6,
1559.
16 D.M. Guldi and M. Prato, Acc. Chem. Res., 2000, 33, 695.
17 H.W. Kroto, A.W. Allaf and S.P. Balm, Chem. Rev., 1991, 91, 1213.
18 T. Baati, F. Bourasset, N. Gharbi, L. Njim, M. Abderrabba, A. Kerkeni, H.
Szwarc and F. Moussa, Biomaterials, 2012, 33, 4936.
19 R. Bakry, R.M. Vallant, M. Najam-ul-Haq, M. Rainer, Z. Szabo, C.W.
Huck and G.K. Bonn, Int. J. Nanomed., 2007, 2, 639.
20 S. Bosi, T. Da Ros, G. Spalluto, J. Balzarini and M. Prato, Bioorg. Med.
Chem. Lett., 2003, 13, 4437.
21 Y. Marcus, A.L. Smith, M.V. Korobov, A.L. Mirakyan, N.V. Avramenko
and E.B. Stukalin, J. Phys. Chem. B, 2001, 105, 2499.
cm−1 =3400–2500, 1667, 1424, 1123; UV-Vis: λmax/nm=253, 325;
HRMS (ESI+): calcd for C72H28N5 [M+H]+ 962.2345; found 962.2342.
Bis(cyclen)-C60-2: Trifluoroacetic acid (1.0 mL, 13.4 mmol) was
added slowly to a solution of 7 (90 mg, 49.9 µmol) in 50 mL of CH2Cl2,
at room temperature. The solution was stirred at room temperature
overnight. The mixture was concentrated under reduced pressure
to remove the solvent and then washed with CH2Cl2 to remove the
impurities. Deprotected product bis(cyclen)-C60-2 (92 mg, 98%)
was obtained as a brownish solid. IR: νmax/cm−1 =3434, 1677, 1198,
1128; HRMS (ESI+): calcd for C84H55N10 [M+H]+ 1203.4611; found
1203.4613.
This work was supported by grants from the Basic Research
Program of National Defense of China (B1520110007).
22 R.S. Ruoff, D.S. Tse, R. Malhotra and D.C. Lorents, J. Phys. Chem., 1993,
97, 3379.
23 S. Shinoda, Chem. Soc. Rev., 2013, 42, 1825.
24 R.D. Hancock and A.E. Martell, Chem. Rev., 1989, 89, 1875.
25 R. Reichenbach-Klinke, M. Kruppa and B. König, J. Am. Chem. Soc.,
2002, 124, 12999.
Received 9 January 2014; accepted 21 February 2014
Paper 1402390 doi: 10.3184/174751914X13945582435462
Published online:2 April 2014
26 M. Maggini, G. Scorrano and M. Prato, J. Am. Chem. Soc.,1993, 115, 9798.
27 M. Prato, M. Maggini, C. Giacometti, G. Scorrano, G. Sandonà and G.
Farnia, Tetrahedron, 1996, 52, 5221.
28 G. Angelini, C. Cusan, P. De Maria, A. Fontana, M. Maggini, M. Pierini,
M. Prato, S. Schergna and C. Villani, Eur. J. Org. Chem., 2005, 1884.
29 K. Kordatos, T. Da Ros, S. Bosi, E. Vázquez, M. Bergamin, C. Cusan, F.
Pellarini, V. Tomberli, B. Baiti, D. Pantarotto, V. Georgakilas, G. Spalluto
and M. Prato, J. Org. Chem., 2001, 66, 4915.
References
1
J. Zhang, F.L. Bowles, D.W. Bearden, W.K. Ray, T. Fuhrer, Y. Ye, C.
Dixon, K. Harich, R.F. Helm, M.M. Olmstead, A.L. Balch and H.C. Dorn,
Nature Chem., 2013, 5, 880.
2
3
J. Cami, J. Bernard-Salas, E. Peeters and S.E. Malek, Science, 2010, 329,
1180.
A. Mishra and P. Bäuerle, Angew. Chem. Int. Ed., 2012, 51, 2020.
JCR1402390_FINAL.indd 253
27/03/2014 14:16:08

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