Synthesis and characterization of binuclear Zn(II)-cyclen complexes bridged by α,ω-bis(4-methylphenoxy) alkanes

Article abstract of DOI:10.1007/s11164-012-0528-7

A series of novel α,ω-bis(4-methylphenoxy) alkane functionalized cyclen ligands were synthesized by the nucleophilic substitution reaction of 1,4,7-tris(tert-butyloxycarbonyl)-1,4,7,10-tetraazacyclododecane and α,ω-bis(4-bromomethylphenoxy) alkanes. The corresponding dimeric Zn(II)-cyclen complexes were obtained by reaction of these ligands with Zn(ClO₄)₂·6H₂O. Ligands and complexes were characterized by FT-IR, ¹H NMR, and elemental analysis. Springer Science+Business Media B.V. 2012.

Full text of DOI:10.1007/s11164-012-0528-7

Res Chem Intermed (2012) 38:2085–2096
DOI 10.1007/s11164-012-0528-7
Synthesis and characterization of binuclear Zn(II)–
cyclen complexes bridged by a,x-bis(4-methylphenoxy)
alkanes
•
Fuxian Wan Changcheng Li Lin Jiang Ying Li
•
•
Received: 29 October 2011 / Accepted: 3 March 2012 / Published online: 18 March 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A series of novel a,x-bis(4-methylphenoxy) alkane functionalized
cyclen ligands were synthesized by the nucleophilic substitution reaction of 1,4,7-
tris(tert-butyloxycarbonyl)-1,4,7,10-tetraazacyclododecane and a,x-bis(4-bromom-
ethylphenoxy) alkanes. The corresponding dimeric Zn(II)–cyclen complexes were
obtained by reaction of these ligands with Zn(ClO4)2ꢀ6H2O. Ligands and complexes
1
were characterized by FT-IR, H NMR, and elemental analysis.
Keywords Dinuclearmacrocyclic polyamine ꢀ Cyclen ꢀ Zn(II) complex ꢀ
Synthesis a,x-bis(4-methylphenoxy) alkane
Introduction
Macrocyclic polyamine compounds have been a rewarding topic of research since
the 1960s [1–3]. Most recently synthesized macrocyclic polyamine compounds are
based on cyclen (1,4,7,10-tetraazacyclododecane, first synthesized in 1961 [4]) and
its derivatives, because of their strong coordination of a wide range of cations
including transition metals and lanthanides [5]. The complexes obtained are suitable
for a variety of applications in modern chemistry, biochemistry, and medicine;
cyclen-based complexes have, for example, been widely used as magnetic resonance
imaging contrast agents [6], as DNA cleavers [7], for DNA recognition [8], as
luminescent probes [9], as enzyme mimics [10], and for radioimmunotherapy [11].
In recent years, there has been much interest in the synthesis of multi-nuclear
complexes, because of their potential cooperative effects between metal centers
[12, 13]. Yu et al. [14, 15] synthesized a variety of bridged binuclear complexes,
F. Wan (&) ꢀ C. Li ꢀ L. Jiang ꢀ Y. Li
College of Chemistry and Material Science, Shandong Agricultural University, Taian 271018,
People’s Republic of China
e-mail: wfx@sdau.edu.cn
123

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F. Wan et al.
and found their catalytic activity in the cutting of DNA (Puc18) to be different
from that of the mono-metal-cyclen complex. The aromatic groups of dinuclear
complexes can strengthen structural stability, improve the efficiency of catalysis
of phosphate ester hydrolysis, and enhance DNA-cutting capacity [16, 17].
The connections in the dicyclens are flexible groups, for example hydrocarbon
chains, which is conducive to super-molecular recognition and can thus enhance the
interaction between molecules [18].
Therefore, in the work discussed in this paper we used a,x-bis(4-methylphenoxy)
alkanes as bridges to link the cyclens. Further, to determine the effect of the distance
between the cyclens on super-molecular recognition, spacers of different lengths (3,
4, 5, or 6 methylene groups) were inserted in the dicyclen. As a result, four ligands
(9a–9d) and subsequent Zn(II) complexes (10a–10d) were prepared. The synthetic
route to the target molecules is shown in Schemes 1 and 2.
Experimental
General
Melting points were determined by use of digital apparatus and are uncorrected.
TLC analysis was performed on glass sheets coated with Merck silica gel 60 F254
.
Compounds were visualized by use of I2 vapor or by UV–visible illumination.
1H NMR spectra were recorded on Bruker AV-400 spectrometers. Chemical shifts
(d) are reported in parts per million from the internal standard tetramethylsilane
(TMS). Coupling constants (J) are measured in Hertz. Multiplicity is reported as
follows: s (singlet), d (doublet), t (triplet), m (multiplet), and combinations of these
signals. Column chromatography was performed on silica gel 60 (200–300 mesh).
IR spectra were recorded with a Nicolet 380 FT-IR. Elemental analysis was
NTs TsN
(i)
(iii)
(iv)
(ii)
TsO
NHTs
N
OTs
TsHN
N
Ts
Ts
NTs TsN
2
1
3
O
O
(H3C)3CO
(H3C)3CO
OC(CH3)3
N
N
NH HN
(v)
N
HN
NH HN
O
4 Cyclen
5 Tri-Boc-Cyclen
Scheme 1 Synthetic route to cyclen and tri-Boc-cyclen. Reagents and conditions: (i) K2CO3, DMF,
100 °C; (ii) H2SO4, 100 °C, MIA; (iii) 36 % HCl; (iv) 50 % NaOH; (v) (Boc)2O, NEt3, CHCl3
123

Synthesis and characterization of binuclear Zn(II)–cyclen
2087
(i)
O
CH2 O
n
OH
6a-6d(n=3-6)
Br
Br
(iii)
(ii)
O
CH2 O
n
7a-7d(n=3-6)
(iv)
R1
R1
O
CH2
O
n
8a-8d(n=3-6)
(v)
8HCl
R2
R2
O
CH2 O
n
(vi)
9a-9d(n=3-6)
-
4ClO4
R3
R3
O
CH2 O
n
10a-10d(n=3-6)
Boc
Boc
HN
NH
Zn2+
NH HN
N
N
N
N
R2=
R3=
R1=
N
NH
N
HN
Boc
Scheme 2 Synthetic route to binuclear Zn(II)–cyclen complex bridged by a,x-bis(4-methylphenoxy)
alkane. Reagents and conditions: (i) NaOH, EtOH, TEBA, Br(CH2)nBr; (ii) NBS, BPO/CCl4, reflux;
(iii) 5K2CO3, CH3CN reflux; (iv) HBr, EtOH, ultrasound; (v) NaOH; (vi) Zn(ClO4)2ꢀ6H2O, EtOH
performed with a Vario EL III (Elementary). An MARS5 microwave digestion
system and an RT1001-RT1002 ultrasonic cleaning machine were also used.
N,N0,N00-Tritosyldiethylenetriamine (1) and N-tosyl-bis[2-(tosyloxy)ethyl]amine
(2) were synthesized in accordance with the reference method [19]. All solvents
used for reactions were anhydrous and all reactions were carried out under an inert
atmosphere.
Synthesis of 1,4,7,10-tetra(p-toluenesulfonyl)-1,4,7,10-tetraazacyclododecane (3)
[19]
A solution of N,N0,N00-tritosyldiethylenetriamine (1) (34.0 g, 60 mmol) in
anhydrous DMF (100 mL) was slowly added to a mixture of N-tosyl-bis[2-
(tosyloxy)ethyl]amine (2) (34.4 g, 60 mmol) and anhydrous K2CO3 powder (24.9 g,
180 mmol) in anhydrous DMF (150 mL) at 100 °C over a period of 2 h; stirring
123

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F. Wan et al.
was then continued at 100 °C for 3 h. The reaction mixture was cooled to room
temperature, filtered, and the filtrate was collected and evaporated to dryness under
reduced pressure. The residue was washed with water and recrystallized from
methanol to give 3 as a white solid. Yield: 33.6 g; 71 %; mp 291–294 °C; 1H NMR
(400 MHz, CDCl3, d/ppm): 2.43 (s, 12H, –CH3), 3.40 (s, 16H, NCH2CH2N), 7.30
(d, 8H, –C6H4CH3), 7.65 (d, 8H, –C6H4CH3). Anal. calcd for C36H44N4O8S4
(wB/%): C 54.82; H 5.56; N 7.23. Found C 54.96; H 5.47; N 7.14.
Synthesis of 1,4,7,10-tetraazacyclododecane (4) [20]
1,4,7,10-Tetra(p-toluenesulfonyl)-1,4,7,10-tetraazacyclododecane (3) (18.0 g,
24 mmol) and 36 mL 98 % sulfuric acid were mixed in a flask equipped with an
electromagnetic stirrer and reflux condenser and reacted intermittently for 180 s in a
microwave oven (at 400 W). After cooling to room temperature, the reaction
mixture was added dropwise to anhydrous ethanol (300 mL), cooled in an ice–water
bath, with intense stirring. The mixture was filtered through a sand core funnel and
washed with anhydrous ether. The solid was dissolved in H2O (30 mL) and
decolorized with activated charcoal. Concentrated hydrochloric acid (30 mL, 36 %)
was added to the filtrate, the precipitate was collected and dissolved in H2O
(10 mL), and 50 % aqueous NaOH solution was added slowly, furnishing a white
solid precipitate. This was isolated by filtration and washed with diethyl ether, to
give approximately 4.0 g crude cyclen. The crude product was extracted with
CHCl3 (100 mL), and the extract was dried with Na2SO4 and evaporated to dryness
under reduced pressure to give 4 as a white solid. Yield: 3.59 g; 87 %; mp
1
110–112 °C; H NMR (400 MHz, CDCl3, d/ppm): 2.13 (s, 4H, NH), 2.71 (s, 16H,
NCH2CH2N). Anal. Calcd for C8H20N4 (wB/%): C 55.78; H 11.70; N 32.52. Found:
C 55.57; H 11.60; N 32.73.
Tri-Boc-cyclen(1,4,7-tris(tert-butyloxycarbonyl)-1,4,7,10-tetraazacyclododecane)
(5) [21]
A solution of di-tert-butyl dicarbonate (3.6 g, 16.85 mmol) in anhydrous CHCl3
(100 mL) was slowly added to a mixture of cyclen (1.0 g, 5.81 mmol) and
triethylamine (2.5 mL, 17.27 mmol) in anhydrous CHCl3 (120 mL) over a period of
4 h at room temperature under N2 atmosphere. The reaction mixture was stirred at
room temperature for 24 h under N2 atmosphere, then the organic solvent was
removed under reduced pressure. The residue was purified by silica gel column
chromatography (petroleum ether–ethyl acetate, 1:3 v/v) to afford tri-boc-cyclen as
a colorless amorphous solid. Yield: 2.16 g, 78.5 %; mp 58–61 °C; 1H NMR
(400 MHz, CDCl3, d/ppm): 1.45–1.49 [3s, 27H, OC(CH3)3], 2.80–2.90 (m, 4H,
NCH2CH2N), 3.17–3.40 (m, 8H, NCH2CH2N), 3.54–3.72 (m, 4H, NCH2CH2N);
FT-IR (KBr, pellet): 3,522 (mN–H), 2,976, 2,818 (mC–H), 1,691 (mC=O), 1,464, 1,418,
1,366, 1,272, 1,250, 1,171, 1,100 cm-1. Anal. Calcd for C23H44N4O6 (wB/%): C
58.45; H 9.38; N 11.85. Found: C 58.27; H 9.50; N 11.73.
123

Synthesis and characterization of binuclear Zn(II)–cyclen
2089
General procedure for synthesis of compounds 6
To NaOH (8.8 g, 0.22 mol) in ethanol (100 mL) was added 4-methylphenol (21.
6 g, 0.2 mol), with cooling in an ice–water bath. After stirring for 0.5 h, a slightly
red solution of sodium 4-methylphenol was formed. The resulting mixture was
added to the a,x-dibromoalkanes (0.1 mol), with stirring at reflux, monitoring the
reaction by TLC (mobile phase cyclohexane–ethyl acetate, 6:1 v/v), and then heated
under reflux with stirring for another 6–24 h, the solution was cooled to room
temperature and added to 5 % NaOH solution (500 mL). The solid was collected by
filtration, washed with distilled water (2 9 30 mL) and ethanol (2 9 20 mL), and
dried under vacuum to give colorless crystals (6a–6d).
6a (n = 3) Yield: 12.9 g (50 %); mp 99–100 °C;1H NMR (400 MHz, CDCl3,
d/ppm): 2.23–2.25 (m, 2H, CH2), 2.28 (s, 6H, 2CH3) 4.12 (t, J = 6.4 Hz, 4H,
2CH2), 6.78 (d, J = 8.4 Hz, 4H, 2C6H4), 7.07 (d, J = 8.4 Hz, 4H, 2C6H4). Anal.
Calcd for C17H20O2 (wB/%): C 79.65; H 7.86. Found: C 79.93; H7.98.
6b (n = 4) Yield: 14.8 g (65.2 %); mp 110–111 °C;1H NMR (400 MHz, CDCl3,
d/ppm): 1.94–1.95 (m, 2H, CH2), 2.28 (s, 6H, 2CH3) 3.99 (t, J = 5.2 Hz, 4H,
2CH2), 6.78 (d, J = 8.4 Hz, 4H, 2C6H4), 7.06 (d, J = 8.4 Hz, 4H, 2C6H4). Anal.
Calcd for C18H22O2 (wB/%): C 79.96; H 8.20. Found: C 80.15; H 8.36.
6c (n = 5) Yield: 23.6 g (83.1 %); mp 68.5–71 °C; 1H NMR (400 MHz, CDCl3,
d/ppm): 1.64–1.65 (m, 2H, CH2), 1.82–1.88 (m, 4H, CH2), 2.28 (s, 6H, 2CH3) 3.95
(t, J = 6.4 Hz, 4H, 2CH2), 6.80 (d, J = 8.4 Hz, 4H, 2C6H4), 7.06 (d, J = 8.4 Hz,
4H, 2C6H4). Anal. Calcd for C19H24O2 (wB/%): C 80.24; H 8.51. Found: C 80.39;
H 8.68.
6d (n = 6) Yield: 26.2 g (88 %); mp 88–90 °C;1H NMR (400 MHz, CDCl3,
d/ppm): 1.52–1.54 (m, 4H, CH2), 1.78–1.81 (m, 4H, CH2), 2.28 (s, 6H, 2CH3) 3.93
(t, J = 6.4 Hz, 4H, 2CH2), 6.78 (d, J = 8.4 Hz, 4H, 2C6H4), 7.05 (d, J = 8.4 Hz,
4H, 2C6H4). Anal. Calcd for C20H26O2 (wB/%): C 80.50; H 8.78. Found: C 80.83;
H 8.92.
General procedure for synthesis of a,x-bis(4-bromomethylphenoxy) alkanes (7a–
7d) [22]
To 6a (6.05 g, 25 mmol) in CCl4 (100 mL) was added NBS (9.10 g, 51 mmol) and
benzoyl peroxide (0.5 g, 2 mmol), and the mixture was heated under reflux with
stirring for 5 h. After removing the solvent under reduced pressure, the residue was
poured into 400 mL distilled water, and the solid was collected by filtration, washed
with distilled water (3 9 100 ml), and recrystallized from THF to give colorless
crystals (7a).
To 6b (6.76 g, 25 mmol) in CCl4 (80 mL) was added NBS (9.10 g, 51 mmol)
and benzoyl peroxide (0.5 g, 2 mmol) with stirring, and the mixture was heated
under reflux with stirring until a large amount of white solid appeared. The insoluble
material was removed by filtration, and the filtrate was cooled to room temperature
to produce a precipitate. This was isolated by filtration and recrystallized from
CHCl3 to give colorless needle-like crystals 7b.
123

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F. Wan et al.
To 6c (7.10 g, 25 mmol) in CCl4 (80 mL) was added NBS (9.10 g, 51 mmol)
and benzoyl peroxide (0.5 g, 2 mmol) with stirring, and the mixture was heated
under reflux with stirring until a large amount of white solid appeared. The insoluble
material was removed by filtration, and the filtrate was cooled to room temperature
to produce a precipitate. This was isolated by filtration and recrystallized from
CHCl3 to give colorless needle-like crystals 7c.
To 6d (7.46 g, 25 mmol) in CCl4 (80 mL) was added NBS (9.10 g, 51 mmol)
and benzoyl peroxide (0.5 g, 2 mmol) while stirring, and the mixture was heated
under reflux with stirring until a large amount of white solid appeared. The insoluble
material was removed by filtration, and the filtrate was cooled to room temperature
to produce a precipitate. This was isolated by filtration and recrystallized from
CHCl3 to give colorless needle-like crystals 7d.
1
7a (n = 3) Yield: 6.73 g (65 %); mp 144–146 °C; H NMR (400 MHz, CDCl3,
d/ppm): 2.24–2.28 (m, J = 6.0 Hz, 2H, CH2), 4.15 (t, J = 6.0 Hz, 4H, 2CH2), 4.50
(s, 4H, 2CH2) 6.86 (d, J = 8.8 Hz, 4H, 2C6H4), 7.30 (d, J = 8.8 Hz, 4H, 2C6H4).
Anal. Calcd for C17H18Br2O2 (wB/%): C 49.30; H 4.38. Found: C 49.66; H 4.45.
7b (n = 4) Yield: 7.73 g (72.3 %); mp 138–140 °C; 1H NMR (400 MHz,
CDCl3, d/ppm): 1.96–1.98 (m, 4H, 2CH2), 4.02 (t, J = 5.2 Hz, 4H, 2CH2), 4.51
(s, 4H, 2CH2), 6.85 (d, J = 8.8 Hz, 4H, 2C6H4), 7.31 (d, J = 8.8 Hz, 4H, 2C6H4).
Anal. Calcd for C18H20Br2O2 (wB/%): C 50.49; H 4.71. Found: C 50.77; H 4.82.
7c (n = 5) Yield: 6.62 g (60 %); mp 112–114.5 °C; 1H NMR (400 MHz,
CDCl3, d/ppm): 1.61–1.67 (m, 4H, 2CH2), 1.82–1.89 (m, 4H, 2CH2), 3.98 (t,
J = 6.4 Hz, 4H, 2CH2), 4.50 (s, 4H, 2CH2), 6.84 (d, J = 8.4 Hz, 4H, 2C6H4), 7.30
(d, J = 8.4 Hz, 4H, 2C6H4). Anal. Calcd for C19H22Br2O2 (wB/%): C 51.61; H 5.01.
Found: C 51.82; H 5.16.
7d (n = 6) Yield: 7.06 g (62 %); mp 116.5–118 °C; 1H NMR (400 MHz,
CDCl3, d/ppm): 1.51–1.55 (m, 4H, 2CH2), 1.79–1.83 (m, 4H, 2CH2), 3.96 (t,
J = 6.4 Hz, 4H, 2CH2), 4.50 (s, 4H, 2CH2), 6.84 (d, J = 8.4 Hz, 4H, 2C6H4), 7.29
(d, J = 8.4 Hz, 4H, 2C6H4). Anal. Calcd for C20H24Br2O2 (wB/%): C 52.65; H 5.30.
Found: C 52.94; H 5.52.
General procedure for synthesis of compounds 8
A
solution of 1,4,7-tris(tert-butyloxycarbonyl)-1,4,7,10-tetraazacyclododecane
(0.946 g, 0.21 mmol), a,x-bis(4-bromomethylphenoxy) alkane (0.1 mmol), and
anhydrous K2CO3 (0.345 g, 2.5 mmol) in dry CH3CN (50 mL) was stirred at 80 °C
under argon. After stirring for 24 h, the insoluble inorganic salts were removed by
filtration and the filtrate was concentrated under reduced pressure. The crude
product was purified by column chromatography (petroleum–ethyl acetate, 1:1.2
v/v) to give 8 as a colorless amorphous solid.
1
8a (n = 3) Yield: 0.65 g (56 %); mp 87–88.6 °C; H NMR (400 MHz, CDCl3,
d/ppm): 1.279 (brs, 54H, CH3), 2.235–2.265 (t, J = 6.0 Hz, 2H, CH2), 2.637–3.581
(m, 32H, CH2 of cyclen), 3.673 (brs, 4H, C6H5CH2), 4.113–4.145 (t, J = 5.6 Hz,
4H, OCH2), 6.833–6.854 (d, J = 8.8 Hz, 4H, C6H4), 7.136–7.156 (d, J = 8.4 Hz,
4H, C6H4); FT-IR (KBr, pellet): 3,030 (mC–H of Ar), 2,974, 2,929, 2,871 (mC–H),
1,688 (mC=O), 1,610, 1,511, 1,460 (mC=C of Ar), 1,415, 1,365, 1,248, 1,173, 1,106,
123

Synthesis and characterization of binuclear Zn(II)–cyclen
2091
1,047, 1,022, 979, 859, 772 cm-1. Anal. Calcd for C61H100N8O14 (wB/%): C 62.65;
H 8.62; N 9.58. Found: C 63.02; H 8.65; N 9.35.
8b (n = 4) Yield: 0.55 g (51 %); mp 65.3–67.8 °C; 1H NMR (400 MHz, CDCl3,
d/ppm): 1.432 (brs, 54H, CH3), 1.974 (s, 4H, CH2), 2.638–3.586 (m, 32H, CH2 of
cyclen), 3.680 (brs, 4H, C6H5CH2), 4.007 (t, J = 5.6 Hz, 4H, OCH2), 6.823–6.844
(d, J = 8.4 Hz, 4H, C6H4), 7.137–7.158 (d, J = 8.4 Hz, 4H, C6H4); FT-IR (KBr,
pellet): 3,030 (mC–H of Ar) 2,975, 2,930, 2,871 (mC–H), 1,688 (mC=O), 1,610, 1,511,
1,460 (mC=C of Ar), 1,415, 1,365, 1,249, 1,173, 1,106, 1,060, 979, 858, 772 cm-1
.
Anal. Calcd for C62H102N8O14 (wB/%): C 62.92; H 8.69; N 9.47. Found: C 63.24;
H 8.63; N 9.26.
8c (n = 5) Yield: 0.69 g (57.6 %); mp 77.8–78.9 °C; 1H NMR (400 MHz,
CDCl3, d/ppm): 1.474 (brs, 54H, CH3), 1.637 (m, 2H, CH2), 1.837–1.873 (brs, 4H,
CH2), 2.635–3.580 (m, 32H, CH2 of cyclen), 3.665 (s, 4H, C6H5CH2), 3.947–3.978
(t, J = 6.0 Hz, 4H, OCH2), 6.814–6.835 (d, J = 8.4 Hz, 4H, C6H4), 7.130–7.151
(d, J = 8.4 Hz, 4H, C6H4); FT-IR (KBr, pellet): 3,030 (mC–H of Ar), 2,975, 2,931,
2,871 (mC–H), 1,689 (mC=O), 1,610, 1,511, 1,460 (mC=C of Ar), 1,414, 1,365, 1,248,
1,172, 1,106, 1,030, 979, 858, 772 cm-1. Anal. Calcd for C63H104N8O14 (wB/%):
C 63.19; H 8.75; N 9.36. Found: C 62.89; H 8.78; N 9.45.
8d (n = 6) Yield: 0.63 g (52 %); mp 80.2–81.4 °C; 1H NMR (400 MHz, CDCl3,
d/ppm): 1.432 (brs, 54H, CH3), 1.540 (brs, 4H, CH2),1.813 (brs, 4H, CH2),
2.637–3.578 (m, 4H, CH2 of cyclen), 3.673 (s, 4H, C6H5CH2), 3.960–3.928
(t, J = 6.4 Hz, 4H, OCH2), 6.816 (d, J = 8.4 Hz, 4H, C6H4), 7.134 (d, J = 7.2 Hz,
4H, C6H4); FT-IR (KBr, pellet); 3,030 (mC–H of Ar), 2,975, 2,931, 2,869 (mC–H),
1,689 (mC=O), 1,610, 1,511, 1,460 (mC=C of Ar), 1,414, 1,365, 1,248, 1,172, 1,106,
1,030, 979, 858, 772 cm-1. Anal. Calcd for C64H106N8O14 (wB/%): C 63.45; H 8.82;
N 9.25. Found: C 63.56; H 8.87; N 9.06.
General procedure for synthesis of compounds 9
HBr (40 %; 4.5 ml, 0.66 mmol) was added dropwise to a solution of 8 (0.30 mmol)
in ethanol (5 mL) at 0 °C under N2 atmosphere. After ultrasonic vibration for 1 h at
50 °C, a large amount of white precipitate appeared. The solid was isolated by
filtration and washed three times with cold ethanol to give a white solid (Fig. 1a, b).
1
9a (n = 3) Yield: 0.20 g (72.5 %); mp 277–279 °C; H NMR (400 MHz, D2O,
d/ppm): 1.990–2.020 (t, J = 6.0 Hz, 2H, CH2), 2.657–2.949 (m, 32H, CH2 of
cyclen), 3.574 (s, 4H, C6H5CH2), 3.994–4.024 (t, J = 6.4 Hz, 4H, OCH2), 6.784–
6.806 (d, J = 8.4 Hz, 4H, C6H4), 7.061–7.083 (d, J = 8.4 Hz, 4H, 2C6H4); FT-IR
(KBr, pellet): 3,432 (mN–H), 3,030 (mC–H of Ar), 2,927, 2,851 (mC–H), 2,800–2,491
þ
(s, br, mNH ), 1,610, 1,514, 1,449 (mC=C of Ar), 1,308, 1,251, 1,182, 1,057, 996,
2
757 cm-1. Anal. Calcd for C31H60Br8N8O2 (wB/%): C 30.62; H 4.97; N 9.21.
Found: C 30.43; H 4.95; N 9.32.
1
9b (n = 4) Yield: 0.22 g (55 %); mp 194–197 °C; H NMR (400 MHz, D2O,
d/ppm): 2.101–2.131 (t, J = 6.0 Hz, 4H, CH2), 2.686–3.134 (m, 32H, CH2 of
cyclen), 3.792 (s, 4H, C6H5CH2), 4.056–4.088 (t, J = 6.4 Hz, 4H, OCH2), 6.939–
6.961 (d, J = 8.8 Hz, 4H, C6H4), 7.248–7.270 (d, J = 8.8 Hz, 4H, 2C6H4); FT-IR
123

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F. Wan et al.
(a)
(b)
Fig. 1 a FT-IR of 9a. b 1H NMR spectra of 9a
(KBr, pellet): 3,438 (mN–H), 2,990 (mC–H of Ar), 2,925, 2,852 (mC–H), 2,830–2,341 (s,
þ
br, mNH ), 1,610, 1,513, 1,488 (mC=C of Ar), 1,428, 1,215, 1,180, 1,118, 1,045,
2
758 cm-1. Anal. Calcd for C32H62Br8N8O2 (wB/%): C 31.24; H 5.08; N 9.11.
Found: C 31.35; H 5.04; N 9.24.
1
9c (n = 5) Yield: 0.19 g (49 %); mp 191–193 °C; H NMR (400 MHz, D2O,
d/ppm): 1.349–1.366 (dd, J = 8.4 Hz, 2H, CH2), 1.545–1.597 (m, 4H, CH2), 2.690–
3.077 (m, 32H, CH2 of cyclen), 3.615 (s, 4H, C6H5CH2), 3.827–3.859 (t,
J = 6.4 Hz, 4H, OCH2), 6.768–6.789 (d, J = 8.8 Hz, 4H, C6H4), 7.075–7.097 (d,
J = 8.8 Hz, 4H, 2C6H4); FT-IR (KBr, pellet): 3,439 (mN–H), 2,990 (mC–H of Ar),
þ
2,929, 2,850 (mC–H), 2,830–2,400 (s, br, m ), 1,610, 1,513, 1,488 (mC=C of Ar),
NH2
123

Synthesis and characterization of binuclear Zn(II)–cyclen
2093
1,457, 1,427, 1,251, 1,180, 1,044, 1,025, 829, 758 cm-1. Anal. Calcd for
C33H64Br8N8O2 (wB/%): C 31.86; H 5.18; N 9.01. Found: C 32.01; H 5.05; N 9.12.
1
9d (n = 6) Yield: 0.22 g (58.6 %); mp 274–277 °C; H NMR (400 MHz, D2O,
d/ppm): 1.540 (brs, 4H, CH2), 1.813 (brs, 4H, CH2), 2.737–3.178 (m, 32H, CH2 of
cyclen) 3.800 (s, 4H, C6H5CH2), 3.990–4.022 (t, J = 6.4 Hz, 4H, OCH2), 6.940–
6.962 (d, J = 8.8 Hz, 4H, C6H4), 7.248–7.270 (d, J = 8.8 Hz, 4H, C6H4); FT-IR
(KBr, pellet): 3,433 (mN–H), 2,987 (mC–H of Ar), 2,929, 2,867 (mC–H), 2,830–2,365 (s,
þ
br, mNH ), 1,611, 1,513, 1,488 (mC=C of Ar), 1,459, 1,418, 1,366, 1,252, 1,179, 1,120,
2
1,025, 758 cm-1. Anal. Calcd for C34H66Br8N8O2 (wB/%): C 32.46; H 5.29; N 8.91.
Found: C 32.35; H 5.32; N 9.01.
General procedure for synthesis of complexes 10a–10d
The HBr salts of ligands 9 (0.5 mmol) were dissolved in water (5 mL) and the
aqueous solutions were adjusted to alkaline (pH C12) with 50 % aqueous NaOH.
The solutions were extracted with CH2Cl2 (4 9 10 mL). The organic layers were
dried over anhydrous Na2SO4 and the solutions were concentrated under reduced
pressure to give yellow oils. To ethanol solutions (5 mL) of the free amine was
added excess Zn(ClO4)2 solution in 10 mL ethanol and the mixture was stirred
overnight at room temperature and then heated under reflux for 2 h. The solution
was concentrated under reduced pressure, and the solid was purified by centrifu-
gation and washed with ethanol (3 9 10 mL) (Fig. 2a, b).
10a (n = 3) Yield: 0.31 g (55 %); mp 277–279 °C; 1H NMR (400 MHz,
CD3COCD3, d/ppm): 2.138–2.166 (t, J = 6.0 Hz, 2H, CH2), 2.572–2.951 (m, 32H,
CH2 of cyclen), 3.891 (s, 4H, C6H5CH2), 4.083–4.113 (t, J = 6.0 Hz, 4H, OCH2),
6.877–6.898 (d, J = 8.4 Hz, 4H, C6H4), 7.215–7.236 (d, J = 8.4 Hz, 4H, 2C6H4);
FT-IR (KBr, pellet): 3,433 (mO–H), 3,299 (mN–H), 3,030 (mC–H of Ar), 2,936, 2,884
(mC–H), 1,610, 1,513, 1,472 (mC=C of Ar), 1,442, 1,295, 1,252, 1,089 (m3 of ClO4-),
970, 625 (m4 of ClO4-), 432 (mZn–N) cm-1. Anal. Calcd for Zn2C33H55N8O18Cl4
(wB/%): C 35.25; H 4.93; N 9.97. Found: C 34.87; H 4.98; N 10.06.
10b (n = 4) Yield: 0.28 g (50 %); mp 274–276 °C; 1H NMR (400 MHz,
CD3COCD3, d/ppm): 1.839 (t, J = 6.0 Hz, 4H, CH2), 2.739–3.181 (m, 32H, CH2 of
cyclen), 3.766 (s, 4H, C6H5CH2), 3.982 (t, J = 6.4 Hz, 4H, OCH2), 6.857–6.878 (d,
J = 8.8 Hz, 4H, C6H4), 7.205–7.226 (d, J = 8.8 Hz, 4H, 2C6H4); FT-IR (KBr,
pellet): 3,441 (mO–H), 3,296 (mN–H), 3,030 (mC–H of Ar), 2,934, 2,881 (mC–H), 1,611,
1,513, 1,473 (mC=C of Ar), 1,250, 1,091 (m3 of ClO4-), 972, 850, 624 (m4 of ClO4-),
441 (mZn–N) cm-1. Anal. Calcd for Zn2C34H57N8O18Cl4 (wB/%): C 35.87; H 5.05; N
9.84. Found: C 35.58; H 5.11; N 9.78.
10c (n = 5) Yield: 0.30 g (53 %); mp 265–270 °C; 1H NMR (400 MHz,
CD3COCD3 d/ppm): 1.512 (t, J = 8.4 Hz, 2H, CH2), 1.713 (m, 4H, CH2),
2.568–3.147 (m, 32H, CH2 of cyclen), 3.862 (s, 4H, C6H5CH2), 3.924 (t,
J = 6.4 Hz, 4H, OCH2), 6.814–6.867 (d, J = 8.8 Hz, 4H, C6H4), 7.192–7.214 (d,
J = 8.8 Hz, 4H, 2C6H4); FT-IR (KBr, pellet): 3,440 (mO–H), 3,297 (mN–H), 3,030
(mC–H of Ar), 2,939, 2,881 (mC–H), 1,611, 1,513, 1,474 (mC=C of Ar), 1,250, 1,092 (m3
of ClO4-), 968, 850, 623 (m4 of ClO4-), 433 (mZn–N) cm-1. Anal. Calcd for
123

2094
F. Wan et al.
(a)
(b)
Fig. 2 a FT-IR of 10a. b 1H NMR spectra of 10a
Zn2C35H59N8O18Cl4 (wB/%): C 36.47; H 5.16; N 9.72. Found: C 36.55; H 5.21;
N 9.55.
10d (n = 6) Yield: 0.31 g (54 %); mp 195–197 °C; 1H NMR (400 MHz,
CD3COCD3 d/ppm): 1.424 (brs, 4H, CH2), 1.690 (brs, 4H, CH2), 2.571–3.317 (m,
32H, CH2 of cyclen) 3.843 (s, 4H, C6H5CH2), 3.900–3.931 (t, J = 6.4 Hz, 4H,
OCH2), 6.843–6.864 (d, J = 8.8 Hz, 4H, C6H4), 7.201–7.222 (d, J = 8.8 Hz, 4H,
C6H4); FT-IR (KBr, pellet): 3,432 (mO–H), 3,296 (mN–H), 3,030 (mC–H of Ar), 2,936,
2,878 (mC–H), 1,611, 1,513, 1,467 (mC=C of Ar), 1,250, 1,093 (m3 of ClO4-), 975, 850,
623 (m4 of ClO4-), 466 (mZn–N) cm-1. Anal. Calcd for Zn2C36H61N8O18Cl4 (wB/%):
C 37.07; H 5.27; N 9.61. Found: C 37.12; H 5.24; N 9.77.
123

Synthesis and characterization of binuclear Zn(II)–cyclen
2095
Results and discussion
Improved synthetic method for 1,4,7,10-tetra(p-toluenesulfonyl)-1,4,7,
10-tetraazacyclododecane (3) and 1,4,7,10-tetraazacyclododecane (4)
Cyclen (1,4,7,10-tetraazacyclododecane) is a commercial but expensive product.
Methods for synthesis of cyclen have recently been reviewed by Wang et al. [23].
The Richman–Atkins method is still the most popular and generally accepted
method for synthesis of cyclen. By using this method, the material cost is greatly
reduced and the materials are also widely available. However, because the cyclic
condensation is conducted at high dilution a large quantity of reagents and tedious
operations are required. In the work discussed in this paper, the Richman–Atkins
method was improved by using ‘‘one-pot’’ condensation–cyclization between
N,N0,N00-tritosyldiethylenetriamine (1) and 2-(tosyloxy)ethyl]amine (2) in DMF at
100 °C in the presence of anhydrous potassium carbonate to give 1,4,7,10-
tetrakis(p-toluenesulfonyl)-1,4,7,10-tetraazacyclododecane, with a yield of 71 %.
Efficient and rapid detosylation of 1,4,7,10-tetra(p-toluenesulfonyl)-1,4,7,10-tetra-
azacyclododecane (3) was achieved by hydrolysis in concentrated sulfuric acid (98 %),
with irradiation in a microwave oven (power 400 W), under reflux and with
electromagnetic stirring. The results indicated that hydrolysis and detosylation of
poly(p-tosyl) compounds were complete within 120–180 s. In comparison with
conventional hydrolysis in concentrated sulfuric acid, which was complete after
48–72 h at 100 °C, microwave irradiation-accelerated (MIA) hydrolysis is rather rapid.
The 1,4,7,10-tetraazacyclododecane (4) was extracted with hot toluene and
recrystallized form toluene to give a colorless powder. Curiously, with a yield of
115 %, mp 98–100 °C (lit [24], mp 110 °C), after testing, we found the product
contained a substantial amount of water of crystallization. When extracted with
chloroform directly, the water and organic layers are difficult to separate, and the
yield is 50–59 %. The crude cyclen was isolated by filtration first, then the solid
residue was extracted with chloroform. This additional step improves the yield to
87 %, mp 110–112 °C.
Tri-Boc-cyclen(1,4,7-tris(tert-butyloxycarbonyl)1,4,7,10-
tetraazacyclododecane) (5)
Tri-boc-cyclen, a commercial but very expensive product, is an important
intermediate in the synthesis of mono-N-substituted of cyclen derivatives. The
dose and speed of addition of the di-tert-butyl dicarbonate solution is important
for good chemical yield and purity. It was found that appropriate conditions for
preparation of 5 were: room temperature; N2 atmosphere; and a mole ratio of di-tert-
butyl dicarbonate to 1,4,7,10-tetraazacyclododecane of 2.9:1.
Synthesis of a,x-bis(4-bromomethylphenoxy) alkanes
Four a,x-bis(4-methylphenoxy) alkanes were synthesized by nucleophilic substi-
tution reaction of the salts of 4-methylphenol and a,x-dibromoalkanes with ethanol
123

2096
F. Wan et al.
as solvent instead of CH3CN [25], and then reaction with N-bromosuccinimide
to produce the a,x-bis(4-bromomethylphenoxy) alkanes. This method has several
advantages, including simple work-up procedure, shorter reaction time, milder
conditions, and environment-friendly procedure.
Synthesis of dicyclen ligands and binuclear Zn(II)–cyclen complexes bridged
by a,x-bis(4-methylphenoxy) alkane
Compounds 8 were synthesized easily by nucleophilic substitution reaction of
1,4,7-tris-tert-butyloxycarbonyl-1,4,7,10-tetraazacyclododecane (5) and a,x-bis(4-
bromomethylphenoxy) alkanes (7). It was found that appropriate conditions for
preparation of 8a–8d were: CH3CN as solvent; 80 °C under argon atmosphere;
anhydrous K2CO3 as base; and a mole ratio of 1,4,7-tris-tert-butyloxycarbonyl-
1,4,7,10-tetraazacyclododecane to a,x-bis(4-bromomethylphenoxy) alkane of 2.1:1.
It was found that ultrasonic vibration at a frequency of 90 kHz accelerated
hydrolysis of 8a–8d. The rapid reaction was complete within 1 h, compared with
48–72 h for traditional methods.
Acknowledgments The authors thank Dr Xiao-hui Xiao (College of Chemistry and Life Science,
Zhejiang Normal University, Jinhua Zhengjiang P.R. China) for help with the experiments.
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