Application of 2-(3,5,6-trifluoro-2-hydroxy-4-methoxyphenyl)benzoxazole and -benzothiazole to fluorescent probes sensing pH and metal cations

Article abstract of DOI:10.1021/jo010462a

2-(3,5,6-Trifluoro-2-hydroxy-4-methoxyphenyl)benzoxazole (3) and benzothiazole analogue (4) are prepared by the two-step procedures from the corresponding 2-(pentafluorophenyl)benzazoles. Benzoxazole 3 is applicable to a fluorescent probe sensing magnesium cation, and 4 is suitable for sensing zinc cation. Both fluorophores 3 and 4 are sensitive to the pH change at pH 7-8, resulting in large fluorescence enhancement under basic conditions. Their high sensitivity to pH and selectivity in metal cations are ascribed to the high acidity of the fluorophenol moiety.

Full text of DOI:10.1021/jo010462a

7328
J . Org. Chem. 2001, 66, 7328-7333
Ap p lica tion of
2-(3,5,6-Tr iflu or o-2-h yd r oxy-4-m eth oxyp h en yl)ben zoxa zole a n d
-ben zoth ia zole to F lu or escen t P r obes Sen sin g p H a n d Meta l
Ca tion s
Kiyoshi Tanaka,* Tsutomu Kumagai, Hiroko Aoki, Makoto Deguchi, and Satoru Iwata
Faculty of Engineering, Seikei University, Musashino-shi, Tokyo 180-8633, J apan
tanaka@ge.seikei.ac.jp
Received May 7, 2001
2-(3,5,6-Trifluoro-2-hydroxy-4-methoxyphenyl)benzoxazole (3) and benzothiazole analogue (4) are
prepared by the two-step procedures from the corresponding 2-(pentafluorophenyl)benzazoles.
Benzoxazole 3 is applicable to a fluorescent probe sensing magnesium cation, and 4 is suitable for
sensing zinc cation. Both fluorophores 3 and 4 are sensitive to the pH change at pH 7-8, resulting
in large fluorescence enhancement under basic conditions. Their high sensitivity to pH and
selectivity in metal cations are ascribed to the high acidity of the fluorophenol moiety.
In tr od u ction
tion of complexation of 1 or its benzothiazole analogue
with a metal cation is limited to a few papers.8,9 In this
paper, we will describe pH-sensing fluorescence behavior
of 2-(3,5,6-trifluoro-2-hydroxy-4-methoxyphenyl)benzox-
azole (3) and -thiazole (4) and demonstrate that 3 is
applicable to the fluorescent probe sensing magnesium
cation and 4 is suitable for sensing zinc cation.
2-(2-Hydroxyphenyl)benzoxazole (1) has been widely
studied from the viewpoint of photophysics because of its
dual emission via the excited-state intramolecular proton
transfer (ESIPT).1 In nonpolar solvent, 1 emits long-
wavelength fluorescence (∼500 nm) exclusively via the
ESIPT process of the exicited state of the intramolecu-
larly hydrogen-bonded enol, and the intensity of short
wavelength fluorescence (∼ 360 nm), which arises from
the excited state of the intermolecularly hydrogen-bonded
rotamer, gradually increases in accordance with an
increase of the polarity of the solvent.2,3 In continuing
research on the function of polyfluorobenzene deriva-
tives,4,5 we have reported that 2-(3,4,5,6-tetrafluoro-2-
hydroxyphenyl)benzoxazole (2) emits similar long-wave-
length fluorescence in nonpolar solvent and exclusively
emits the intermediate wavelength fluorescence around
440 nm in polar solvents such as acetonitrile, which is
assumed to originate from the excited state of the
phenolate anion of 2.6 Polyfluorophenol derivative is
expected to be sensitive to a pH change of surrounds and
also to complexation with a metal cation because of its
rather high acidic property,7 so that it is of interest to
apply the intermediate wavelength fluorescence of the
fluorinated benzoxazole derivative to an output signal for
pH or metal cation sensor. On the other hand, a descrip-
Resu lts a n d Discu ssion
The benzoxazole 3 and thiazole 4 were synthesized in
moderate yields by methoxylation of 2-(pentafluorophen-
yl)benzoxazole and -benzothiazole with sodium methoxide
in methanol, followed by hydroxylation with sodium
hydroxide. Substituted positions in 3 and 4 were deter-
mined by the 19F NMR analysis. Ortho/para selectivity
is an important problem in nucleophilic aromatic sub-
stitution of polyfluorobenzenes, and the selective para
substitution in the first methoxylation was attained by
the coexistence of methanol, which seems to interfere
with the coordination of sodium cation to the azole-
nitrogen atom to result in retardation of the ortho attack
by the accompanied methoxide.4,10 Para substitution of
methoxide is important because it leads to the selective
ortho substitution of the hydroxyl group in the second
reaction (Scheme 1).
(1) Mordzinski, A.; Grabowska, A. Chem. Phys. Lett. 1982, 90, 122.
Grellmann, K. H.; Mordzinski, A.; Heinrich, A. Chem. Phys. 1989, 136,
201. A.-Engeland, Th.; Bultmann, T.; Ernsting, N. P.; Rodriguez, M.
A.; Thiel, W. Chem. Phys. 1992, 163, 43. Lavtchieva, L.; Enchev, V.;
Smedarchina, Z. J . Phys. Chem. 1993, 97, 306. Purkayastha, P.;
Chattopadhyay, N. Phys. Chem. Chem. Phys. 2000, 2, 203. Ikegami,
M.; Arai, T. Chem. Lett. 2000, 996.
(2) Woolfe, G. J .; Melzig, M.; Schneider, S.; Dorr, F. Chem. Phys.
1983, 77, 213.
(3) Das, K.; Sarkar, N.; Ghosh, A. K.; Majumdar, D.; Nath, D. N.;
Bhattacharyya, K. J . Phys. Chem. 1994, 98, 9126.
(4) Tanaka, K.; Deguchi, M.; Iwata, S. J . Chem. Res., Synop. 1999,
528; J . Chem. Res., Miniprint 1999, 2279.
Absorption and fluorescence spectra of the toluene
solution of 3 are essentially the same as those of the
(5) Tanaka, K.; Yamamoto, Y.; Machida, I.; Iwata, S. J . Chem. Soc.,
Perkin Trans. 2 1999, 285.
(6) Tanaka, K.; Deguchi, M.; Yamaguchi, S.; Yamada, K.; Iwata, S.
J . Heterocycl. Chem. 2001, 38, 131.
(8) Gladilovich, D. B.; Stolyarov, K. P. Russ. J . Inorg. Chem. 1984,
29, 1748.
(9) Shimizu, K.; Furuhashi, A. Bull. Chem. Soc. J pn. 1984, 57, 3593.
(10) Kobrina, L. S.; Furin, G. G.; Yakobson, G. G. Zh. Obshch. Khim.
1967, 38, 514.
(7) Schlosser, M. Angew. Chem., Int. Ed. 1998, 110, 1496.
10.1021/jo010462a CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/06/2001

Fluorescent Probes Sensing pH and Metal Cations
J . Org. Chem., Vol. 66, No. 22, 2001 7329
F igu r e 1. Absorption and fluorescence spectra of 3 and 4 in various solvents. λex ) 298.5 nm for 3 and 306.5 nm for 4: [4] ) 1.0
× 10-5 M, [3] ) 9.6 × 10-5 M and 2.4 × 10-5 M for absorption and fluorescence spectra, respectively.
Sch em e 1
Spectral changes caused by the concentration and the
polarity of the solvent point out that under the polar
environment 3 or 4 equilibrates with its phenolate anion,
which emits the intermediate wavelength fluorescence
and absorbs at longer wavelength.6,12,13 A larger fluores-
cence quantum yield of 3 than 4 supports the formation
of 3 (anion) in preference to that of 4 (anion) in methanol.
To understand the ease of formation of 3 (anion), ab initio
calculations were performed for the ground states of the
anions of 3 and 4.14 Optimized structures, net charges of
the selected atoms based on Mulliken population analy-
sis, and dipole moments are collected in Figure 4.
Calculations suggest that a coplanar conformation of 4
(anion) is preferable to a twisted one, and this coplanarity
is ascribed to an ionic interaction between the anionic
phenolate oxygen atom and the cationic sulfur atom.15
With 3 (anion), a twisted conformation is optimized, and
it will come from an electronic repulsion between the
phenolate and oxazole oxygen atoms. The large dipole
moment of 3 (anion), compared to 4 (anion), is another
notable property, and this polarity will be one of the
reasons why the formation of 3 (anion) is easy in polar
methanol solution.
benzoxazole 2, and slightly red-shifted absorption and
fluorescence are notable.6 Fluorescence spectra of the
ethyl acetate solution show a slight shoulder due to the
intermediate wavelength fluorescence around 447 nm,
along with the appreciable 513 nm emission, and those
of the acetonitrile solution indicate the 447 nm emission
as the main fluorescence. Absorption and fluorescence
spectra of the benzothiazole 4 are similar to those of 3,
and fluorescence spectra of the acetonitrile solution show
the intermediate wavelength fluorescence around 465 nm
(Figure 1). Fluorescence intensities of 3 and 4 in aceto-
nitrile are very small, but additions of methanol to the
solutions bring about the considerable enhancement of
the intermediate wavelength fluorescences and their
intensities increase in proportion to methanol, as shown
in Figure 2. A gradual increase in the absorbance at
longer wavelength around 350 nm is also remarkable. It
is another noteworthy behavior of 3 that fluorescence
quantum yield is highly sensitive to the concentration;
for example, the fluorescence quantum yield of the
methanol solution of 1 × 10-5 M is Φf ) 0.03 and that of
the 2 × 10-7 M solution is substantially enhanced to
almost 12 times of that of the 1 × 10-5 M solution.
Relative absorbance of the longer wavelength band is
considerably large in dilute solution.6,11 The fluorescence
quantum yield of 4 is not so largely affected by the
concentration, but a similar trend is still observed, with
two times fluorescence quantum yield being estimated
for the 2 × 10-7 M solution, compared to that of the 1 ×
10-5 M solution (Figure 3).
The effect of pH on the fluorescence spectra along with
absorption spectra was investigated under the conditions
of [3 or 4] ) 1 × 10-5 M in methanol/water (9:1) and the
(12) Stryukov, M. B.; Lyubarkaya, A. E.; Knyazhanskii, M. I. Zh.
Prikl. Specktrosk. 1977, 27, 1055.
(13) Potter, C. A. S.; Brown, R. G.; Vollmer, F.; Rettig, W. J . Chem.
Soc., Faraday Trans. 1994, 90, 59. Potter, C. A. S.; Brown, R. G. Chem.
Phys. Lett. 1988, 7. Elsaesser, T.; Schmetzer, B. Chem. Phys. Lett. 1987,
293.
(14) GAUSSIAN 98 (Revision A.1): Frisch, M. J .; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J . R.;
Zakrzewski, V. G.; Montgomery, J . A.;. Stratmann, R. E.; Burant, J .
C.; Dapprich, S.; Millam, J . M.; Daniels, A. D.; Kudin, K. N.; Strain,
M. C.; Farkas, O.; Tomasi, J .; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J .;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J . B.; Cioslowski, J .; Ortiz,
J . V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P.
M. W.; J ohnson, B. G.; Chen, W.; Wong, M. W.;. Andres, J . L.; Head-
Gordon, M.; Replogle, E. S.; Pople, J . A. Gaussian, Inc., Pittsburgh,
PA, 1998.
(15) Minyaev, R. M.; Minkin, V. I. Can. J . Chem. 1998, 76, 776.
Gruter, G. J . M.; van Klink, G. P. M.; Akkerman, O. S.; Bickelhaupt,
F. Chem. Rev. 1995, 95, 2405.
(11) Cohen, M. D.; Flavian, S. J . Chem. Soc. B 1967, 317. Cohen,
M. D.; Flavian, S. J . Chem. Soc. B 1967, 321.

7330 J . Org. Chem., Vol. 66, No. 22, 2001
Tanaka et al.
F igu r e 2. Absorption and fluorescence spectra of 3 and 4 in a mixture of acetonitrile and methanol: [3] ) [4] ) 1.0 × 10-5 M,
λex ) 298.5 nm for 3, 306.5 nm for 4.
alkali and alikaline earth metal cations, 3 recognizes
magnesium cation to bring about large fluorescence
enhancement and slightly recognizes calcium cation to
cause appreciable fluorescence enhancement. For other
alkali and alkaline earth metal cations, a meaningful
fluorescence change is not detected. From the obser-
vation that, in an aqueous methanol solution (methanol/
water ) 9:1), magnesium cation causes the similar
fluorescence enhancement but calcium cation has no
meaningful effect on the fluorescence intensity, 3 can be
regarded as a probe sensing magnesium cation selec-
tively. It should be added that fluorescence enhancement
of 3 with magnesium cation is in sharp contrast to no
appreciable change in fluorescence of the nonfluorinated
benzoxazole 1. On the other hand, fluorescence intensity
of 4 is not affected by alkali metal cations but 4 is
reversely quenched with all kind of alkaline earth metal
cations, which is comparable to quenching by ammonium
cation.
F igu r e 3. Concentration dependence of fluorescence quantum
Dramatic fluorescence enhancement of 3 with magne-
sium cation may be interpreted by the formation of a
complex 5 (X ) O, Mn+ ) Mg2+), where the benzoxazole
and phenolate rings lie on the same plane by the bridging
magnesium cation, and this coplanarity and the anionic
property of the phenolate ring bring about large fluores-
cence enhancement.16 The formation of the coplanar
anion type of 3 is supported by the red-shifted absorption
(λab ) 359 nm),6,8,12,13 excitation of which also results in
the same fluorescence enhancement (Figure 8). The curve
fitting of the fluorescence intensity according to the
Benesi-Hildebrand plot supported the formation of a 1:1
complex of 3 and magnesium cation, its binding constant
being estimated to be K ) 5.4 × 103 M-1 in methanol
(Figure 9). The curve fitting of the absorbance change
gave similar results. On the other hand, 4 is reversely
quenched with magnesium cation, and this quenching
will be explained by the assumption that the equilibrium
between 4 and 4 (anion) shifts to the 4 side under the
presence of magnesium cation, which is supported by the
yields of 3 and 4 in methanol. λex ) 300 nm.
constant ionic strength (0.1 M) (Figure 5). Results show
that the fluorescence intensity of 3 or 4 is almost zero
under acidic conditions and increases under basic condi-
tions. The fluorescence quantum yields were estimated
to be Φf ) 0.233 for 3 and Φf ) 0.228 for 4 at pH 10.3. It
is also notable that the absorbance at longer wavelength
(345 nm for 3 or 371 nm for 4) increases under basic
conditions. Typical titration curves are depicted in Figure
6. The sharp titration curves show that 3 and 4 are fairly
sensitive to the change at pH 7-8. For the demonstration
of the pH sensing of 3 and 4, changes in the fluorescence
intensity are checked in the presence of 2-, 3-, or
4-aminopyridines in methanol. In both cases of 3 and 4,
only 4-aminopyridine brings about large fluorescence
enhancement and that is attributed to relatively high
basicity (pKa ) 9.1) of 4-aminopyridine, compared to 2-
and 3-aminopyridines (pKa ) 6.9 and pKa ) 6.0, respec-
tively).
The effect of metal cation on the emissions of 3 and 4
in methanol was next investigated, and the change in
the fluorescence intensity in the presence of a 50 molar
ratio of metal cation is summarized in Figure 7. Among
(16) Chou, Pi-T.; Cooper, W. C.; Clements, J . H.; Studer, S. L.;
Chang, C. P. Chem. Phys. Lett. 1993, 300.

Fluorescent Probes Sensing pH and Metal Cations
J . Org. Chem., Vol. 66, No. 22, 2001 7331
F igu r e 4. RHF/6-31G** (B3LYP/6-31G**)-optimized structures of 3 (anion) and 4 (anion), net charges of the selected atoms
based on Mulliken population analysis, and dipole moments (µ). θ: dihedral angle between benzazole and phenyl rings.
F igu r e 5. Absorption and fluorescence spectra of 3 and 4 under acidic and basic conditions: [3] ) [4] ) 1.0 × 10-5 M, [NaCl] )
0.1 M, 20 °C; solvent MeOH/H2O ) 9/1. λex) 298.5 nm for 3 and 306.5 nm for 4.
benzothiazole ring, and this stability shifts the equilib-
rium to the complex side (eq 1).
Among transition metal cations such as silver, zinc,
cadmium, nickel, copper, and mercury cations together
with lead and aluminum cations, 3 recognizes zinc and
aluminum cations and 4 does only zinc cation in metha-
F igu r e 6. Dependence of pH on fluorescence intensity of 3
and 4: [3] ) [4] ) 1.0 × 10-5 M, [NaCl] ) 0.1 M, 20 °C; solvent
MeOH/H2O ) 9/1. λex ) 298.5 nm for 3, 306.5 nm for 4. F0
stands for fluorescence intensity without hydrochloric acid and
sodium hydroxide.
nol to cause fluorescence enhancement, accompanied by
the increase in absorbance at longer wavelength. The
curve fitting of the fluorescence intesity again supported
the formations of 1:1 complexes of 3 or 4 with the
corresponding metal cations, and their estimated associa-
tion constants are summarized in Figure 9. With regard
to cadmium cation, both 3 and 4 cause the fluorescence
enhancement at low concentration of cadmium cation, but
the fluorescence intensity gradually decreases at rela-
tively high concentration of cadmium cation. This be-
havior is rationalized by the assumption that the ability
of complexation of 3 and 4 with cadmium cation is not
so large that once formed complexes are degraded into 3
decrease of absorbance at longer wavelength around 370
nm (Figure 8). This equlibrium shift to the 4 side will be
led by the slightly acidic conditions, which is caused by
magnesium cation and methanol, and is also the case
with other alkaline earth metal cations and with am-
monium cation. It is noteworthy that the benzoxazole
ring complexes with magnesium cation more strongly to
form the stable 5 (X ) O, Mn+ ) Mg2+), compared to the

7332 J . Org. Chem., Vol. 66, No. 22, 2001
Tanaka et al.
F igu r e 7. Effects of metal cations on fluorescence intensity of 3 and 4: [3] ) [4] ) 1.0 × 10-5 M in methanol, [metal cation] )
5.0 × 10-4 M, λex ) 298.5 nm for 3 and 306.5 nm for 4. F0 stands for fluorescence intensity without metal cation, F for fluorescence
intensity with metal cation. Thiocyanate salts are used for alkali and alkaline earth metal cations and ammonium cation. For
other metal cations, perchlorate salts are used.
F igu r e 8. Absorption and fluorescence spectra of 3 and 4 in the presence of magnesium cation: [3] ) [4] ) 1.0 × 10-5 M in
methanol, λex ) 298.5 nm for 3 and 306.5 nm for 4.
and 4 under acidic conditions, generated by cadmium
cation and methanol, giving rise to fluorescence quench-
ing (Figure 10, eq 1). Another interesting behavior is
observed in the case of mercury cation. Thus, fluorescence
intensity of 3 or 4 decreases but absorbance at longer
wavelength reversely increases, as the concentration of
mercury cation increases. The change in absorbance in
the case of 4 is too small to evaluate the association
constant, whereas in the case of 3 the 1:1 complexation
and its association constant (K ) 5.9 × 105 M-1) could
be evaluated by the curve fitting of the absorbance
change. Observations that excitations in longer wave-
length bands resulted in no fluorescence in both cases of
3 and 4 indicate rather low quantum yields of 5 (X ) O
and S, Mn+ ) Hg2+). It should be added that fluorescence
F igu r e 9. Fluorescence enhancement of 3 and 4 in methanol
behavior of 3 and 4 with nickel, copper and lead cations
upon addition of metal cation: [3] ) [4] ) 1.0 × 10-5 M, λ ex
)
is similar to those with mercury cation.
298.5 nm for 3, 306.5 nm for 4. F0 stands for fluorescence
intensity without metal cation, F for fluorescence intensity
with metal cation. Estimated association constants (K/M-1) are
shown in parentheses.
In conclusion, 3 and 4 were found to be very sensitive
to the pH change at pH 7-8, giving rise to large
fluorescence enhancement under basic conditions. They
can be regarded as the very sensitive pH sensors, and
the relatively large Stokes shift, compared to the con-
ventional fluorophores such as fluorescein, is character-
istic of them. For metal cation sensing, it was found that
3 was applicable to the fluorescent probe sensing mag-

Fluorescent Probes Sensing pH and Metal Cations
J . Org. Chem., Vol. 66, No. 22, 2001 7333
(0.10 g, 2.50 mmol) were stirred at 50 °C for 48 h in 10 mL of
dioxane. The mixture was acidified with 1 M hydrochloric acid
and extracted with ethyl acetate. The extracts were washed
with water and brine, dried over magnesium sulfate, and
evaporated to leave a solid. Chromatography on silica gel
(hexane/ethyl acetate, 3:1) of the solid produced 0.18 g (91%)
of 3, which was recrystallized from hexane-ethyl acetate to
give white crystals: mp 132-134 °C; IR 3100-2600 (OH), 2950
1
(CH), 1660 (C6F3), 1250, 1230 cm-1 (COC); H NMR δ 12.27
(s, 1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.45 (m, 2H), 4.19 (dd, J )
3.4, 1.8 Hz, 3H); 19F NMR δ 23.4 (dd, J ) 21.4, 10.9 Hz, 1F),
7.3 (d, J ) 10.9 Hz, 1F), -0.5 (d, J ) 21.4 Hz, 1F). Anal. Calcd
for C14H8NF3O3: C, 56.94; H, 2.73; N, 4.75. Found: C, 57.03;
H, 2.69.; N, 4.73.
2-(3,5,6-Tr iflu or o-2-h ydr oxy-4-m eth oxyph en yl)ben zoth i-
a zole (4). A mixture of pentafluorobenzaldehyde (6.00 g, 30.6
mmol), 2-aminothiophenol (3.83 g, 30.6 mmol), and acetic acid
(1 mL) in 50 mL of ethanol was stirred at 60 °C for 42 h. After
the solvent was removed, the residue was extracted with ethyl
acetate. The extracts were washed with aqueous sodium
bicarbonate, water, and brine and dried over sodium sulfate.
The extracts were evaporated to leave a residue that was
chromatographed on silica gel (hexane/ethyl acetate, 5:1) to
give 4.98 g (54%) of 2-(pentafluorophenyl)benzothiazole. Fur-
ther purification was performed by recrystallization from
hexane-ethyl acetate to give pale yellow crystals: mp 118-
F igu r e 10. Fluorescence change of 3 and 4 in methanol upon
addition of cadmium cation: [3] ) [4] ) 1.0 × 10-5 M, λex
)
298.5 nm for 3 and 306.5 nm for 4. F0 stands for fluorescence
intensity without Cd2+, F for fluorescence intensity with Cd2+
.
nesium cation strongly among alkali and alkaline earth
metal cations and 4 was suitable for sensing zinc cation.
The ease of exchange of phenolic proton with a metal
cation in almost neutral methanol solution arises from
the strongly electron-withdrawing fluorine atoms, and
the strategy that phenol moiety is exchanged for fluori-
nated phenol moiety will be applicable to other probes
recognizing metal cations.
1
120 °C; IR 2900 (CH) and 1650 cm-1 (C6F5); H NMR δ 8.21
(d, J ) 8.1 Hz, 1H), 8.00 (d, J ) 8.7 Hz, 1H), 7.59 (dt, J ) 7.0,
1.3 Hz, 1H), 7.51 (dt, J ) 7.1, 1.2 Hz, 1H); 19F NMR δ 24.0 (m,
2F), 12.2 (tt, J ) 21.1, 3.4 Hz, 1F), 1.7 (m, 2F). Anal. Calcd for
C
13H4NF5S: C, 51.83; H, 1.34; N, 4.65. Found: C, 51.96; H,
1.33; N, 4.37.
Exp er im en ta l Section
A mixture of 2-(pentafluorophenyl)benzothiazole (1.00 g,
3.32 mmol) and sodium methoxide (0.30 g, 5.56 mmol) in 50
mL of methanol was stirred at room temperature for 2 h. After
the solvent was removed, the residue was extracted with ethyl
acetate. The extracts were washed with water and brine, dried
over sodium sulfate, and evaporated to leave a residue that
was recrystallized from hexane-ethyl acetate to give 0.74 g
(71%) of 2-(2,3,5,6-tetrafluoro-4-methoxyphenyl)benzothiaz-
ole: white needles; mp 97-98 °C; IR 2950 (CH), 1640 (C6F4),
Gen er a l Meth od s. The IR spectra were measured in KBr
pellets. The 400 MHz 1H and 376 MHz 19F NMR spectra were
measured for solutions of CDCl3, unless otherwise noted. The
chemical shifts are given in δ/ppm downfield from tetrameth-
ylsilane as an internal standard for 1H NMR and from
hexafluorobenzene as an external standard for 19F NMR,
respectively; J values are given in Hz. The absorption and
fluorescence spectra were recorded at room temperature.
Methanol, toluene, cyclohexane, ethyl acetate, and acetonitrile
for spectroscopy were the highest quality from KOKUSAN
Chemical Co. and were used without further purification.
Fluorescence quantum yields were relatively estimated on the
basis of ΦF ) 0.786 for 2-phenylbenzoxazole in cyclohexane.17
2-(Pentafluorophenyl)benzoxazole was prepared according to
the previously reported method.6
1
1200, 1160 cm-1 (COC); H NMR δ 8.19 (d, J ) 8.3 Hz, 1H),
7.98 (d, J ) 8.0 Hz, 1H), 7.57 (m, 1H), 7.49 (m, 1H), 4.20 (tt,
J ) 1.7, 0.7 Hz, 3H); 19F NMR δ 24.7 (AA′BB′, 2F), 7.6 (AA′BB′,
2F). Anal. Calcd for C14H7NF4OS: C, 53.67; H, 2.25; N, 4.47.
Found: C, 53.58; H, 2.15; N, 4.60.
A mixture of 2-(2,3,5,6-tetrafluoro-4-methoxyphenyl)ben-
zothiazole (1.00 g, 3.19 mmol), crushed sodium hydroxide (1.28
g, 32.0 mmol), and 18-crown-6-ether (0.43 g, 1.63 mmol) in 75
mL of dioxane was stirred at 60 °C for 70 h. After acidification
with 1 M of hydrochloric acid, the mixture was extracted with
ethyl acetate. The extracts were washed with water and brine
and dried over sodium sulfate. The extracts were evaporated
to leave a residue that was chromatographed on silica gel with
eluents of hexane/ethyl acetate/triethylamine (2:2:1) and then
with eluents of hexane/ethyl acetate (1:1) to give 0.66 g (66%)
of 4. Further purification was performed by recrystallization
from hexane-ethyl acetate to give pale yellow crystals: mp
157-158 °C; IR 3100-2600 (OH), 2950 (CH), 1650 (C6F3),
1210, 1170 cm-1 (COC); 1H NMR δ 13.70 (s, 1H), 8.05 (d, J )
7.9 Hz, 1H), 7.97 (d, J ) 7.9 Hz, 1H), 7.58 (t, J ) 7.9 Hz, 1H),
4.18 (t, J ) 1.5 Hz, 3H); 19F NMR δ 24.0 (dd, J ) 22.0, 9.0 Hz,
1F), 6.9 (d, J ) 9.0 Hz, 1F), -1.6 (d, J ) 22.0 Hz, 1F). Anal.
Calcd for C14H8NF3O2S: C, 54.02; H, 2.59; N, 4.50. Found: C,
54.06; H, 2.69; N, 4.35.
2-(3,5,6-Tr iflu or o-2-h yd r oxy-4-m eth oxyp h en yl)ben zox-
a zole (3). A mixture of 2-(pentafluorophenyl)benzoxazole (2.00
g, 7.02 mmol) and sodium methoxide (0.76 g, 14.1 mmol) in
60 mL of methanol was stirred at room temperature for 2 h.
After removal of the solvent, the mixture was extracted with
ethyl ether, and the extracts were washed with water and
brine, dried over magnesium sulfate, and evaporated to leave
a residue. Chromatography on silica gel (hexane) of the residue
produced 1.58 g (76%) of 2-(2,3,5,6-tetrafluoro-4-methoxyphen-
yl)benzoxazole, which was recrystallized from hexane: white
crystals; mp 87-88 °C; IR 2960 (CH), 1650 (C6F4), 1230 cm-1
1
(COC); H NMR δ 7.88 (m, 1H), 7.65 (m, 1H), 7.43 (m, 2H),
4.22 (t, J ) 1.8 Hz, 3H); 19F NMR δ 23.5 (AA′BB′, 2F), 5.1
(AA′BB′, 2F). Anal. Calcd for C14H7NF4O2: C, 56.56; H, 2.38;
N, 4.71. Found: C, 56.67; H, 2.19.; N, 4.71.
Thus obtained 2-(2,3,5,6-tetrafluoro-4-methoxyphenyl)ben-
zoxazole (0.20 g, 0.67 mmol) and crushed sodium hydroxide
(17) Roussilhe, J .; Paillous, N. J . Chim. Phys. 1983, 80, 595.
J O010462A