Fluorescence redox switches based on the opening and closing of an oxazabicyclic ring

Article abstract of DOI:10.1055/s-0029-1218387

A reversible donor-acceptor fluorescence redox switch connected by a rigid but redox-adjustable spacer that can be chemically turned ON and OFF through the ring opening and ring closing of a heterobicyclic moiety is demonstrated. A coumarin-based oxazabic

Full text of DOI:10.1055/s-0029-1218387

LETTER
111
Fluorescence Redox Switches Based on the Opening and Closing of an
Oxazabicyclic Ring
F
luoresce
i
u
ox
S
witchesn-Ting Lai, Yu-Ju Yang, Jian-Hung Lin, Ding-Yah Yang*
Department of Chemistry, Tunghai University, No. 181, Section 3, Taichung Port Road, Taichung City 40704, Taiwan, Republic of China
Fax +886(4)23590426; E-mail: yang@thu.edu.tw
Received 24 September 2009
by a macrocyclic receptor.4 The fluorescence emission of
Abstract: A reversible donor–acceptor fluorescence redox switch
the complex can be controlled by the different oxidation
state of the centered metal ion. The latter comprises a flu-
orophore (the donor) and an active redox switch (the ac-
connected by a rigid but redox-adjustable spacer that can be chem-
ically turned ON and OFF through the ring opening and ring closing
of a heterobicyclic moiety is demonstrated. A coumarin-based ox-
azabicyclic derivative was efficiently synthesized as an example for ceptor), which are covalently connected by a conjugated
or unconjugated spacer.5 The fluorescence emission of the
illustration. While the rigid ring-closed oxazabicycle emits moder-
ate fluorescence in toluene, the sodium borohydride induced ring
donors can be reversibly quenched depending upon the
opening of the heterobicyclic moiety results in a distinct decrease in
oxidation state of the acceptors. Many variables may in-
fluorescence. The resulting nonfluorescence ring-opened form can
fluence the electronic communication between the fluoro-
be reverted to the original fluorescence ring-closed form via DDQ
phore and the active redox quencher. For instance, the
fluorescence quenching efficiency of a donor–acceptor
system is highly sensitive to the structure, length, and ri-
gidity of the spacer.6 Therefore, we envisioned a fluores-
cence redox switch with a rigid but redox-adjustable
spacer may have a major influence on the quenching effi-
ciency of the resulting donor–acceptor system. The aim of
the present study is to design a fluorescence redox switch
system using a structural rigid but redox-sensitive spacer
to manipulate the donor–acceptor quenching efficiency
and to explore how the redox-controlled ring-opening and
ring-closing of a heterobicyclic skeleton may affect its
switching photochemical property.
or H2O2 oxidation.
Key words: oxazabicycle, fluorescence redox switch, redox-
adjustable spacer
The field of molecular switches has attracted great interest
in the past few decades because of their relevance in the
development of molecular electronics and photonics.1
Particular attention is focused on molecular switches
whose emission properties are regulated by redox poten-
tial since they may have a wide range of applications in
this area, such as biochemical and biophysical investiga-
tions.2 Two different types of molecular fluorescent
switching systems have been reported in the literature.
One contains a metal ion and the other is metal-free and
all organic. The former normally consists of a metal-
centered redox couple3 or a luminescent ion core encircled
For the current study, the coumarin derivatives were cho-
sen as the fluorophore, since they have been intensively
studied for their wide applications as laser dyes, iono-
phores, and fluorescence markers.7 The aromatic amines
O
H
MeO
MeO
CF3
MgSO4, CH2Cl2
N
NH2
r.t., 5 h, 92%
1
CF3
O
Yb(OTf)3 (cat.)
H2O, THF
r.t., 12 h, 62%
OH
H
CF3
OH
Me2N
O
O
MeO
3
NH
O
H
p-TsOH (cat.)
DCE, reflux, 3 h
86%
N
H
CF3
2
Me2N
O
O
4
OMe
Scheme 1
SYNLETT 2010, No. 1, pp 0111–0114
x
x.
x
x.
2
0
0
9
Advanced online publication: 27.11.2009
DOI: 10.1055/s-0029-1218387; Art ID: W15709ST
© Georg Thieme Verlag Stuttgart · New York

112
J.-T. Lai et al.
LETTER
were selected as the intramolecular quencher, because the
fluorescence quenching of organic compounds by aromat-
ic amines has been well documented.8 In this particular
design, the fluorophore and the quencher are connected by
a rigid heterobicyclic ring. The gem-dimethyl groups are
also introduced onto the methylene carbon of the hetero-
cyclic moiety to prevent the possible undesired aromatiza-
tion reaction after reduction. Scheme 1 describes the
preparation of the designed oxazabicyclic compound 4. It
began with the MgSO4-mediated condensation of p-anisi-
dine and p-trifluoromethyl-benzaldehyde to afford the
imine 1, followed by a Yb(OTf)3-catalyzed coupling with
isobutyraldehyde to give the cyclic amino alcohol 2.9 Sub-
sequent coupling of 2 with 4-hydroxy-7-dimethylamino-
coumarin (3) in the presence of a catalytic amount of p-
toluenesulfonic acid in 1,2-dichloroethane under reflux
conditions yielded the cyclized target compound 4.10 The
bond formation during the construction of the bicyclic
skeleton of 4 was highly efficient, with a total mass loss
of only 38 g/mol, that is, the release of two molecules of
water and one molecule of hydrogen. Since the aforemen-
tioned three synthetic steps could all be acid-catalyzed,
compound 4 was alternatively prepared via a multicompo-
nent reaction (MCR),11 as shown in Scheme 2. The ox-
azabicycle 4 was obtained in a one-pot tandem reaction
with 67% yield by first mixing p-anisidine with p-trifluo-
romethylbenzaldehyde, isobutyraldehyde, and Yb(OTf)3
(0.4 equiv) in 1,2-dichloroethane at room temperature for
12 hours, following by addition of 3 and subsequently re-
fluxing for 3 hours.12 It is noteworthy that the yield of 4
(67%) by the MCR method is much higher than the over-
all yield (49%) of the stepwise reactions shown in
Scheme 1. In the 1H NMR spectra of the synthesized 4, a
characteristic bridgehead hydrogen absorption peak for
the oxazabicyclic ring was observed at d = 3.67 ppm. The
heterobicyclic structure was further elucidated by X-ray
crystallography. Figure 1 shows the ORTEP diagrams of
the oxazabicycle 4, which clearly revealed a rigid oxaza-
bicyclo[3.3.1] skeleton.13
Figure 1 X-ray crystal structure of the oxazabicycle 4
fluorescence emission of the amino alcohol 5 was found
to be entirely quenched by the aromatic amine (anisidine)
upon reduction. The reduction process was reversible, and
the fluorescent emission of 5 could be instantly switched
on via 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
or H2O2 oxidation. The reversible reduction–oxidation
sequence between compounds 4 and 5 was repeated more
than 10 times without the observation of any detectable
byproducts. Scheme 3 shows the redox switch between
the ring-closed form 4 and ring-opened form 5.
Table 1 lists the fluorescence parameters and quantum
yields (FF) of the ring-closed oxazabicycle 4 and amino
alcohol 5 in different solvents. When the coumarin fluoro-
phore and the anisidine quencher were fixed by a rigid bi-
cyclic ring as in the ring-closed oxazabicycle 4, the
emission of the coumarin fluorophore is partially
quenched by the amine group. Also, the emission is sol-
vent dependent, that is, the fluorescence of 4 increases as
the solvent polarity decreases, presumably due to the pres-
ence of amine hydrogen atom at the anisidine moiety. Af-
ter sodium borohydride mediated heterobicyclic ring
opening, the bond between C-3 and C-9 in 5 (see com-
While the oxazabicycle 4 emitted moderate fluorescence
with the quantum yield of 0.29 in toluene, instant fluores-
cence quenching occurred upon reaction of the heterobi-
cycle with a reducing agent. Addition of sodium
borohydride to the oxazabicycle 4 in methanol caused ring
opening and subsequent imine reduction. The intrinsic
MeO
OH
CF3
NH2
+
O
Me2N
O
O
Yb(OTf)3 (0.4 equiv)
3
NH
H
O
H
DCE, r.t.
12 h
reflux, 3 h
CF3
+
O
Me2N
O
O
OMe
4 67%
H
Scheme 2
Synlett 2010, No. 1, 111–114 © Thieme Stuttgart · New York

LETTER
Fluorescence Redox Switches
113
pound 5 in Scheme 3 for atom labeling) can now freely ro- sibility of using a structural rigid but redox-sensitive spac-
tate. The intrinsic fluorescence of the coumarin in the er to control the donor–acceptor quenching efficiency. We
ring-opened amino alcohol 5 was found to be substantially believe that this new molecular switching mechanism
quenched by the adjacent amine group in most of the sol- may lead to future development of the fluorescence redox
vents. Apparently, a more flexible conformation upon switches with novel molecular structures.
ring opening of 4 might contribute a certain role in
quenching the fluorescence of 5. This observation sug-
gested that the donor–acceptor quenching efficiency of
the fluorescence redox switch can be manipulated by a
rigid but redox-adjustable heterobicyclic spacer. For easy
comparison, Figure 2 shows the bar graph of the fluores-
cence quantum yields of 4 and 5 in different solvents.
Note that the emission of both compounds is solvent-de-
pendent, however, in contrast to compound 4, the fluores-
cence of 5 increases as the solvent polarity increases,
probably due to the presence of the 4-hydroxyl hydrogen
atom at the coumarin moiety after reduction, which may
form a hydrogen bonding between 5 and a solvent mole-
cule in an excited singlet state.
CF3
CF3
NaBH4
H2O2
Figure 2 Fluorescence quantum yields of 4 and 5 in different sol-
vents
NH
NH
O
H
OH
H
4
2
9
3
In summary, a novel oxazabicycle-based reversible fluo-
rescence redox switch, in which the fluorophore and the
quencher were connected by a rigid but redox-adjustable
heterobicyclic spacer, was designed and synthesized via a
stepwise reaction and by MCR. Our studies indicated that
the emission of the fluorophore could be controlled by so-
dium borohydride induced ring opening and DDQ or
H2O2-mediated ring closing of the heterobicyclic moiety.
Thus, we have demonstrated that the all-organic donor–
acceptor quenching efficiency can be manipulated by a re-
dox-adjustable oxazabicyclic spacer. Investigations for
the development of more sophisticated systems based on
the same mechanism for colorimetric/fluorescent redox
switches are in progress in our laboratory.
7
Me2N
Me2N
O
O
O
O
1
OMe
OMe
5
4
fluorescent in nonpolar solvents
weakly fluorescent
Scheme 3
Table 1 Fluorescence Parameters for Compounds 4 and 5
Compd Solvent
l
ex (nm)
l
em (nm) Stoke’s shift FF
(cm–1)
4405
3779
2996
3396
3852
3874
3964
3441
4
4
4
4
5
5
5
5
MeOH
MeCN
CH2Cl2
toluene
MeOH
MeCN
CH2Cl2
toluene
353
352
354
335
333
332
346
329
418
406
396
378
381
383
401
371
0.042
0.133
0.239
0.290
0.052
0.026
0.017
0.007
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors would like to thank the National Science Council of the
Republic of China, Taiwan, for financially supporting this research
under Contract No. NSC 97-2113-M-029-004.
References and Notes
Since the oxazabicycle 4 and amino alcohol 5 can be
swiftly interconverted by redox reaction, and the fluores-
cence intensity of the oxidized 4 in toluene is more than
40-fold stronger than that of the reduced 5, this reversible
redox process between 4 and 5 can be considered to be a
molecular switch. Our studies have demonstrated the fea-
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Synlett 2010, No. 1, 111–114 © Thieme Stuttgart · New York

114
J.-T. Lai et al.
LETTER
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was extracted twice with CH2Cl2. The combined organic
extracts were dried over MgSO4, filtered, and concentrated.
The resulting crude product was purified by column
chromatography (1:9, EtOAc–hexanes) to give a white solid
in a 67% yield; mp 287–288 °C. 1H NMR (300 MHz,
CDCl3): d = 7.90 (d, J = 8.1 Hz, 2 H, ArH), 7.73 (d, J = 8.1
Hz, 2 H, ArH), 7.59 (d, J = 9.0 Hz, 1 H, ArH), 7.09 (d,
J = 3.0 Hz, 1 H, ArH), 6.63 (dd, J = 8.4, 3.0 Hz, 1 H, ArH),
6.58 (dd, J = 8.7, 2.4 Hz, 1 H, ArH), 6.54 (d, J = 8.4 Hz, 1 H,
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(s, 1 H, CH), 3.78 (s, 3 H, OCH3), 3.03 [s, 6 H, N(CH3)2],
0.99 (s, 3 H, CH3), 0.94 (s, 3 H, CH3). 13C NMR (75 MHz,
CDCl3): d = 163.0, 159.9, 154.3, 153.1, 152.9, 142.7, 132.7,
131.0 (q, JCF = 32.0 Hz), 129.4, 129.2, 126.1, 124.8 (q,
JCF = 3.5 Hz), 123.9 (q, JCF = 270.0 Hz), 113.8, 113.5, 113.4,
108.6, 104.2, 101.2, 97.9, 95.4, 55.7, 41.8, 40.1, 33.2, 22.9,
22.1. IR (KBr): n = 3280, 2935, 1685, 1616, 1326, 1125 cm–
1. HRMS (EI): m/z calcd for C30H27F3N2O4: 536.1923;
found: 536.1922 [M+].
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(12) Procedure for the Preparation of 4
To a solution of p-anisidine (1.0 mmol), 4-(trifluoromethyl)-
benzaldehyde (1.0 mmol), isobutyraldehyde (1.0 mmol), and
a catalytic amount of Yb(OTf)3 (0.4 mmol) in DCE (10 mL)
was stirred at r.t. for 12 h. 4-Hydroxy-7-dimethylamino-
coumarin (1.0 mmol) was added to the mixture, and the
resulting solution was refluxed for 3 h. After being cooled to
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