Photo-regulated cyclization reactions of tetraazamacrocycles with
azobenzene derivatives†
Wen-hao Wei, Takenori Tomohiro,* Masato Kodaka and Hiroaki Okuno
Biomolecules Department, National Institute of Bioscience and Human-Technology,
1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan. E-mail: tomohiro@nibh.go.jp
Received (in Cambridge, UK) 31st August 1999, Accepted 22nd October 1999
The cyclization reaction between 1 and 2 was carried out in
high dilution and was photochemically regulated to give
1:1 (29–33 membered rings, 52–55%) and 2:2 (58–66
membered rings, 20–49%) adducts as photo-controllable
compounds.
Assemblies of various controllable molecular mechanical
systems have been studied in the past,1–5 and azobenzene deriv-
atives have often been used as a photo-switch.5,6 However, prep-
aration of cyclic compounds bearing an azobenzene moiety was
difficult and the yields were usually low. Ring closure reactions
have been performed by the reduction of nitrophenyl groups to
azobenzene.6 To develop compounds capable of undergoing a
reversible photochemical reaction, we synthesized two series of
1,4,7,10-tetraazacyclododecane derivatives (3, 4) having an
azobenzene moiety via the photochemically controlled reac-
tions for 1:1 and 2:2 cyclization products.
The cyclization reaction between cis-formed azobenzene (1)
and cyclen (2) derivatives was employed because the product 3
was expected to be sterically distorted in the trans-form, which
is usually a stable form in ordinary azobenzene derivatives. The
reaction was dependent on both the wavelength of light and the
length of methylene chains of the linker, and it selectively pro-
ceeded to give two kinds of macrocycles; 3 as 1:1 adducts under
UV irradiation (330 nm < λ < 380 nm, 52–55%) and large sized
2:2 adducts 4 in the dark (20–49%). The reactions are summar-
ized in Scheme 1.
Scheme 1
The typical procedures are as follows. The compound 1b was
derived from 4-nitrophenol and γ-bromopropylamine hydro-
bromide, Br(CH2)3NH2ؒHBr. The activated diacid derivative 2
was obtained by a condensation reaction7 of 1,7-dicarb-
oxymethyl-4,10-di(benzyloxycarbonyl)-1,4,7,10-tetraazacyclo-
dodecane8 with TTH in the presence of WSC or DCC.‡
According to the high dilution method, a solution of 2 (0.190 g,
0.25 mmol) in THF (75 ml) and a solution of 1b (0.123 g, 0.25
mmol) and Et3N (0.05 g, 0.5 mmol) in 50% THF–H2O (75 ml)
were simultaneously added to a 90% THF–H2O solution (350
ml) at a rate of 2 cm3 minϪ1 with vigorous stirring at room
temperature. After the addition, the solution was continuously
stirred for 1 hour. The solvents were removed under reduced
pressure. The residue was dissolved in CH2Cl2 followed by
washing with 1 M K2CO3, dil. HCl (15 ml) and H2O. The prod-
ucts were isolated by TLC. When the reaction was carried out
under UV light irradiation provided by a 500 W super high-
pressure Hg lamp through a color glass filter (UV-D36B, 330
nm < λ < 380 nm), a 1:1 cyclic product 3b was predominantly
isolated in 52% yield. In the dark 3b was not detected on
an alumina TLC plate, and a 2:2 cyclic product 4b and a
1:1 “acyclic” intermediate [Rf = 0.18 MeCN–MeOH–Et3N
(8:1:0.1), m/z (FAB) 868.0 (M ϩ H)ϩ] were isolated in 49 and
8% yields. When the reaction was carried out under common
laboratory illumination, 3b produced only a 13% yield. Analo-
gous observations were made in the reaction of 1a and 2. Com-
pound 3a yielded 51% under UV irradiation but produced
nothing in the dark. In contrast to 1a and 1b, 1c reacted with 2
in the dark to produce 3c and 4c at 27 and 20% yields, but under
UV irradiation, 1c reacted with 2 and yielded 3c at 55%. UV
spectra of the unclosing intermediate (n = 3) showed that the
trans-form [λmax(MeOH) 359 nm (ε 24560 dm3 molϪ1 cmϪ1)]
accounted for more than 90% in the dark, and that 1a–c form
only trans-isomers in the dark at room temperature.9 Under UV
irradiation through a UV-D36B filter, these compounds were
completely converted to the cis-form within 2 minutes. Namely,
the 1:1 ring-closure reaction depended on the distance between
the two amino groups of 1 and did not proceed in the dark in
the case of 3a, 3b (n = 2, 3) even though the high dilution condi-
tion is preferential to intramolecular cyclization. This was also
suggested by the CPK model examinations. The 2:2 adducts (4)
were not obtained under UV irradiation through a UV-D36B
filter. The cis-isomer of the unclosing intermediate may be
advantageous to the intramolecular cyclization.
All compounds of 3 and 4 were characterized on the basis of
1H, 13C NMR, FAB-MS or MALDI TOF-MS, elemental
analysis and UV–Vis absorption spectra. Typical data of 1b, 3b
1
and 4b are shown in Table 1. H NMR spectra showed the
different ring current effects of benzene rings. An especially
large low-field shift was observed in the OCH2 of trans-3b com-
pared to its cis isomer. For methylene protons of the cyclen
moiety, the signals of trans-3b appeared at a higher field in
comparison to those of 2 (3.42 and 2.91 ppm). In addition, 3,5-
protons of azobenzene appeared only as a broad signal. These
† Experimental data and structure of the reaction intermediate are
available as supplementary data. For direct electronic access see http://
www.rsc.org/suppdata/p1/1999/3397, otherwise available from BLDSC
(SUPPL. NO. 57670, pp. 3) or the RSC Library. See Instructions for
J. Chem. Soc., Perkin Trans. 1, 1999, 3397–3398
This journal is © The Royal Society of Chemistry 1999
3397
Wci, Wen-Hao
