MONOFUNCTIONAL TETRAAZACROWNS FOR BIOCONJUGATION AND CATALYSIS
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precipitate of [Et3NH]þBr2 was removed via filtration through DichlorofN-[(4-vinylphenyl)methyl]-1,4,7,10-
a pad of Celite. The solvent was removed under rotary evapor- tetraazacyclotetradecanegcobalt(III) chloride,
ation to give crude 2 as a sticky yellow solid (1.23 g, 49%). IR [Co(cycmst)Cl2]Cl (6)
(KBr pellet): n(OH) br, 3394 cm21. 1H NMR (CD3OD): d 7.8–
A 100-mL flask was charged with 4 (1.976 g, 6.85 mmol),
cobalt chloride hexahydrate (1.630 g, 6.850 mmol), and
methanol (30 mL) and the solution was gently warmed for
30 min. Then, hydrochloric acid (ca. 1 mL) was added
dropwise and the solution was stirred in air for 4 h. The
solution was concentrated to 15 mL via rotary evaporation
and the resulting blue solid collected, washed with methanol
(20 mL) and ether (20 mL), and dried in vacuo to give 6
(1.067 g, 2.350 mmol, 34% yield). Electron absorption
spectra, lmax, nm (1, dm3 mol21 cm21): MeOH, 576 (310),
396 (347). ESI-MS (m/z): 345 ([Co(cycmst)]3þ 2 2H), 381
([Co(cycmst)Cl]2þ 2 H), 417 ([Co(cycmst)Cl2]þ 2 H).
7.4 (m, 4H, C6H4), 4.6 (s, 2H, C6H4CH2O), 3.8 (s, 2H,
C6H4CH2N), 3.6–2.4 (m, 19H of 8CH2, 3NH).
N-(4-iodobenzyl)-1,4,7,10-tetraazacyclotetradecane (3)
A 100-mL three-neck flask was charged with cyclen (0.58 g,
3.4 mmol), acetonitrile (45 mL), and triethylamine (2.00 mL).
Then, a solution of 4-iodobenzyl bromide (1.00 g, 3.36 mmol)
in acetonitrile (20 mL) was added dropwise with stirring over
a period of 45 min. The solution was refluxed for 4 h, and
reduced under rotary evaporation to give a yellow oil.
CH2Cl2 (20 mL) was added and the resulting precipitate of
[Et3NH]þBr2 was removed via filtration through a pad of
Celite and the solvent removed by rotary evaporation. This
process was repeated (ꢀ4) to give 3 (0.569 g, 43%).
1H NMR (CDCl3): d 7.77 (d, 2H, C6H4), 7.51 (d, 2H, C6H4),
3.51 (s, 2H, C6H4CH2), 3.6–2.4 (m, 19H of 8CH2, 3NH).
RESULTS AND DISCUSSION
Synthesis of N-Monoalkylated Cyclen Ligands
To expand the availability of N-monoalkylated cyclen
ligands with pendant reactive groups, we chose hydroxy-
methyl-, nitro-, iodo-, and vinyl- groups attached in the para
position of the benzene ring. The hydroxymethyl group was
chosen for potential entry into phosphoramidite chemistry
(DNA synthesis), the nitro group may be further reduced to a
synthetically useful primary amine, aryl iodides are useful
for palladium-catalyzed arylations (C–C, C–O, C–N, and
C–P bond-forming reactions, and the vinyl groups is useful
for epoxide formation and can be readily converted to
aminated, hydrated, or reduced, to give amines, alcohols, or
alkanes, respectively. Benzylic halide, either bromide or
chloride, was chosen as the electrophile to achieve sufficient
reactivity. Following the synthetic protocol described in a
previous publication (Knight, 2004), alkylation of the tetraaza-
macrocycle, cyclen, using either chloro- or bromomethyl-
disubstituted aryl compounds proceeded in a straightforward
manner as shown in Scheme 2. Very slow addition of an aceto-
nitrile solution of the alkylation agent to the macrocycle in
acetonitrile, in the presence of triethylamine, is necessary to
prevent extensive polyalkylation of the ring, and triethylamine
hydrochloride salt is formed during the reaction, which is
removed by filtration. After work-up, the crude monoalkylated
cyclen ligands 1–4 were obtained as either viscous oils or
glassy solids, and analyzed by ESI-MS and then purified by
N-(4-vinylbenzyl)-1,4,7,10-tetraazacyclotetradecane (4)
A 100-mL three-neck flask was charged with cyclen (0.50 g,
2.9 mmol), acetonitrile (35 mL), and triethylamine (2.0 mL).
Then, a solution of 4-vinylbenzyl bromide (0.44 g, 2.9 mmol)
in acetonitrile (15 mL) was added dropwise with stirring over
a period of 45 min. The solution was stirred at room tempera-
ture for 48 h, and reduced under rotary evaporation to give a
yellow oil. CH2Cl2 (50 mL) was added and the resulting pre-
cipitate of [Et3NH]þBr2 was removed via filtration through a
pad of Celite and the solvent removed by rotary evaporation.
The residue was dissolved in CHCl3/MeOH (75:25) and the
solution chromatographed on a 110-mm silica gel column
[90 g, CHCl3/MeOH (75:25) then adjusted to 100:0 MeOH]
1
to give 4 as a yellow glassy solid (0.32 g, 38%). H NMR
(CD3CN): d 7.47–7.20 (m, 4H, C6H4), 6.70 (m, 1H,
CH55CH2), 5.80 (t, 2H, CH55CH2), 3.74 (s, 2H, C6H4CH2),
3.56–2.67 (m, 19H of 8CH2, 3NH) ESI-MS (m/z): 289
(cycmst þ Hþ).
DichlorofN-(4-iodobenzyl)-1,4,7,10-
tetraazacyclotetradecanegcobalt(III) chloride,
[Co(cycmbi)Cl2]Cl (5)
A 100-mL flask was charged with 3 (0.570 g, 1.48 mmol), chromatography on silica gel, or used without further purifi-
cobalt chloride hexahydrate (0.35 g, 1.5 mmol), and methanol cation for the preparation of cobalt complexes (see Experimen-
(35 mL) and the solution was gently warmed for 30 min. tal section). ESI-MS analysis prior to purification showed
Then, hydrochloric acid (1 mL) was added dropwise and the either no, or surprisingly small, amounts of di- and trialkylated
solution was stirred in air for 3 h. The resulting blue solid cyclen compounds. Thus, tetrazamacrocycle ligands with
was collected via filtration and dried in vacuo to give 5 pendant hydroxymethyl-, iodo-, nitro-, and vinyl-functional
(0.454 g, 55%). Electron absorption spectra, lmax, nm (1, groups were obtained with overall yields of 1–4 of 38–60%.
dm3 mol21 cm21): MeOH, 569 (137), 398 (122). ESI-MS All of the ligands are hygroscopic in the free base form and
(m/z): 467 ([Co(cycmbi)(OH2)]2þ þ 2H).
were stored under dry N2 or in a dessicator before use.