Excited-state intramolecular proton transfer in 2-(2′- arylsulfonamidophenyl)benzimidazole derivatives: The effect of donor and acceptor substituents

Article abstract of DOI:10.1021/jo070433l

(Chemical Equation Presented) A series of water-soluble 2-(2′-arylsulfonamidophenyl)benzimidazole derivatives containing electron-donating and accepting groups attached to various positions of the fluorophore π-system has been synthesized and characterize

Full text of DOI:10.1021/jo070433l

Excited-State Intramolecular Proton Transfer in
2-(2′-Arylsulfonamidophenyl)benzimidazole Derivatives: The Effect
of Donor and Acceptor Substituents
Maged M. Henary, Yonggang Wu, John Cody, S. Sumalekshmy, Jing Li,
Subrata Mandal, and Christoph J. Fahrni*
School of Chemistry and Biochemistry and Petit Institute for Bioengineering and Bioscience, Georgia
Institute of Technology, 901 Atlantic DriVe, Atlanta, Georgia 30332
fahrni@chemistry.gatech.edu
ReceiVed March 1, 2007
A series of water-soluble 2-(2′-arylsulfonamidophenyl)benzimidazole derivatives containing electron-
donating and accepting groups attached to various positions of the fluorophore π-system has been
synthesized and characterized in aqueous solution at 0.1 M ionic strength. The measured pKa’s for
deprotonation of the sulfonamide group of monosubstituted derivatives range between 6.75 and 9.33 and
follow closely Hammett’s free energy relationship. In neutral aqueous buffer, all compounds undergo
efficient excited-state intramolecular proton transfer (ESIPT) to yield a strongly Stokes-shifted fluorescence
emission from the phototautomer. Upon deprotonation of the sulfonamide nitrogen at high pH, ESIPT is
interrupted to yield a new, blue-shifted emission band. The peak absorption and emission energies were
strongly influenced by the nature of the substituents and their attachment positions on the fluorophore
π-system. The fluorescence quantum yield of the ESIPT tautomers revealed a significant correlation
with the observed Stokes shifts. The study provides valuable information regarding substituent effects
on the photophysical properties of this class of ESIPT fluorophores in an aqueous environment and may
offer guidelines for designing emission ratiometric pH or metal-cation sensors for biological applications.
Introduction
gated as potential laser dyes,1,2 photostabilizers,3,4 scintillators,5,6
hydrogen-bonding7,8 and membrane polarity probes,9,10 and as
Excited-state intramolecular proton transfer (ESIPT) repre-
sents a fundamental photophysical process that occurs in a wide
range of fluorophores containing an intramolecular hydrogen
bond. Upon photoexcitation, the proton moves from the
hydrogen-bonding donor site to a nearby acceptor, resulting in
ultrafast formation of an excited-state tautomer. Because a
significant amount of excited-state energy is dissipated in this
process, the phototautomer fluoresces at lower energy with an
unusually large Stokes shift. Due to their unusual photophysical
properties, ESIPT fluorophores have been extensively investi-
(1) Sakai, K.; Tsuzuki, T.; Itoh, Y.; Ichikawa, M.; Taniguchi, Y. Appl.
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* To whom correspondence should be addressed. Phone: 404-385-1164.
Fax: 404-894-2295.
10.1021/jo070433l CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/25/2007
4784
J. Org. Chem. 2007, 72, 4784-4797

ESIPT in 2-(2′-Arylsulfonamidophenyl)benzimidazoles
sensors for anions11,12 or metal cations.13-19 Among the diverse
fluorophore architectures known to undergo ESIPT, aryl-
substituted benzazoles (I) have been particularly extensively
studied (Chart 1);20-26 however, most of the work has focused
on characterization of the unsubstituted fluorophore platform.
To explore the effect of electron-donating and withdrawing
groups on the photophysical properties of this class of fluoro-
phores, we synthesized a series of benzimidazole derivatives
with the general structure II containing cyano, methoxy,
dimethylamino, or thiazolyl substituents attached to various
positions of the fluorophore π-system. While the photophysics
of 2-hydroxyphenyl-substituted benzimidazoles I (X1 ) O, X2
) NH) is often complicated due to the presence of ground-
state rotamers that cannot undergo ESIPT, their sulfonamide
counterparts II (X1 ) NHSO2R, X2 ) NH) exhibit clean ESIPT
emission with high quantum yield in a wide range of sol-
vents.14,27 For the present study, we therefore chose aryl-
sulfonamides as hydrogen-bonding donors rather than phenols.
Given our interest in the development of fluorescent sensors
for biological applications, we characterized all compounds in
aqueous solution at 0.1 M ionic background. To increase the
solubility under these conditions, we functionalized the fluo-
rophore with a carboxylic acid group that is expected to be fully
dissociated at pH 6 or higher. Of particular interest was the
question of to what extent the substituents might shift the UV-
vis absorption and ESIPT fluorescence bands toward lower
energy, a desirable property for minimizing background fluo-
rescence in context of biological imaging applications. Further-
more, we were interested in the photophysical properties of the
fully deprotonated fluorophore, which, due to the absence of
the sulfonamide proton, cannot undergo ESIPT and should emit
CHART 1
with normal Stokes shift at higher energy. This property of
ESIPT fluorophores is a particularly attractive feature for the
design of emission ratiometric pH or metal-cation sen-
sors.14,15,17,18
Results and Discussion
1. Synthesis. Scheme 1 outlines the two synthetic routes that
were utilized for the synthesis of benzimidazole derivatives 5a-
5l. Key step in both routes is formation of the benzimidazole
ring from the corresponding substituted aryl precursors. While
the condensation of carboxylic acids with phenylenediamines
provides facile access to 2-aryl-substituted benzimidazoles,28
the reaction proceeds typically only under harsh conditions
which are not compatible with functional groups such as
carboxylic acid esters or nitriles. Alternatively, phenylenedi-
amine can be condensed with aldehydes to give the correspond-
ing imine intermediate, which is, upon ring-closing to the
aminal, readily oxidized under mild conditions to yield the
desired benzimidazoles.14 We found that the latter strategy was
well suited for the synthesis of the substituted benzimidazole
derivatives 5a-5l. Due to rapid annular tautomerization, deriva-
tives 5c and 5h-5k with a substituent R3 attached to the
benzimidazole ring are obtained as mixtures of the correspond-
ing 5- and 6-substituted tautomers (vide infra).
As outlined in Scheme 1, the aryl-sulfonamide moiety was
installed either prior or after formation of the benzimidazole
ring. In the latter case (route A), the amino functionality was
first masked as a nitro group. After oxidative coupling with the
corresponding phenylenediamine derivative, the nitro group in
intermediates 2a-2e was reduced to the amine by palladium-
catalyzed hydrogenation at ambient pressure. These conditions
were sufficiently mild such that the cyano group remained
unaffected in the conversion of 2b to 3b. The synthesis was
concluded by coupling of 3 with the sulfonyl chloride deriva-
tive14 10 followed by selective hydrolysis of the carboxylate
ester to give the water-soluble fluorophores 5a-5e.
(8) Shynkar, V. V.; Klymchenko, A. S.; Piemont, E.; Demchenko, A.
P.; Mely, Y. J. Phys. Chem. A 2004, 108, 8151-8159.
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Mely, Y.; Demchenko, A. P. Chem. Biol. 2002, 9, 1199-1208.
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124, 12372-12379.
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2006, 16, 9-15.
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5220.
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3025.
(15) Ohshima, A.; Momotake, A.; Arai, T. Tetrahedron Lett. 2004, 45,
9377-9381.
(16) Qin, W.; Obare, S. O.; Murphy, C. J.; Angel, S. M. Analyst 2001,
126, 1499-1501.
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V. G.; Demchenko, A. P. J. Phys. Chem. A 1998, 102, 5907-5914.
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Chem. 2001, 66, 7328-7333.
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Chim. Acta 2006, 567, 189-195.
(20) Abou-Zied, O. K.; Jimenez, R.; Thompson, E. H. Z.; Millar, D. P.;
Romesberg, F. E. J. Phys. Chem. A 2002, 106, 3665-3672.
(21) Barbara, P. F.; Brus, L. E.; Rentzepis, P. M. J. Am. Chem. Soc.
1980, 102, 5631-5635.
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Photochem. Photobiol., A 1994, 78, 127-138.
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5296-5301.
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2002, 106, 7655-7663.
Installation of the sulfonamide moiety prior to formation of
the benzimidazole ring (route B) led through intermediates 9,
which served as versatile precursors for the synthesis of a range
of substituted benzimidazoles 4f-4l. The syntheses were again
completed with hydrolysis of the carboxylate esters to give
fluorophores 5f-5l. Methoxy- and dimethylamino-substituted
intermediates 9f and 9g were obtained from the corresponding
nitro derivatives 1f and 1g, respectively, which, after reduction
to the amine, were coupled with sulfonyl chloride 10. The
synthesis of both derivatives succeeded with moderate to low
yields (45% and 28%, respectively), which is presumably due
to the instability of intermediate 6 toward formation of oli-
(28) Phillips, M. A. J. Chem. Soc. 1928, 2393-2399.
J. Org. Chem, Vol. 72, No. 13, 2007 4785

Henary et al.
SCHEME 1
goimines. In the case of intermediates 9i and 9l, we thought to
bypass this problem by starting with the corresponding ami-
nobenzyl alcohols 7i and 7l, which were reacted with sulfonyl
chloride 10 and then oxidized to give aldehydes 9i and 9l,
respectively. However, the yield did not improve substantially
and was even lower in the case of 9l, thus rendering this pathway
less attractive compared to the first approach.
Although in the present study the strategy for synthesizing a
particular derivative was primarily governed by the accessibility
of the starting materials, the two routes A and B outlined in
Scheme 1 offer distinct synthetic flexibilities. Because the
sulfonamide moiety is installed toward the end of route A, this
approach is well suited for optimizing fluorophore properties
that depend on the nature of the sulfonamide substituent, for
example the pKa of the sulfonamide nitrogen. In contrast, route
B offers the opportunity to readily change the substituents on
the benzimidazole ring, for example to tune the photophysical
properties of the fluorophore or to build a multidentate ligand
environment for optimizing the selectivity and affinity toward
coordination of metal cations.14
2. Ground-State Protonation Equilibria. To study the
substituent effects without being misled by pH-dependent
absorption changes, it was necessary to determine the UV-vis
and fluorescence emission spectra under conditions at which
the sulfonamide group is either fully protonated or deprotonated.
While spectra of the latter species (L2-) are readily obtained at
high pH, quantitative protonation of the sulfonamide nitrogen
might require a proton concentration at which significant
amounts of the double-protonated species (LH2) are also present.
To alleviate this problem, we determined the UV-vis spectra
of the monoprotonated fluorophores LH- from pH titrations by
means of spectral deconvolution, which at the same time yielded
the corresponding pKa values for each protonation equilibrium.
As exemplified by the titration of fluorophore 5f, a set of UV-
vis absorption spectra were acquired over the pH range of 4-10
at 0.1 M ionic strength (Figure 1a). The traces revealed two
sets of isosbestic points suggesting two distinct protonation
equilibria. Least-squares fit analysis over the entire spectral
range provided deconvoluted absorption spectra along with the
pKa’s for each of the two protonation equilibria. On basis of
the large shifts in the absorption spectrum, the first pKa of 8.34
can be unambiguously assigned to protonation of the sulfona-
mide nitrogen. In contrast, the second pKa of 4.54 involved only
small absorption changes, which are consistent with protonation
of the electronically decoupled carboxylate group rather than
the benzimidazole nitrogen. A species distribution diagram
calculated from these data indicates (Figure 1b) that the
monoprotonated fluorophore LH- is present as a single species
only within a rather narrow pH range centered around -log-
[H3O+] ) 6.5.
Following this approach, the pKa values were measured for
the protonation equilibria of each fluorophore (Table 1). To
determine the -log[H3O+] value at which the monoprotonated
species LH- is most abundant, a species distribution diagram
was calculated for each compound. The corresponding proton
concentrations obtained from these analyses are compiled in
Table 1. In addition, the last column in Table 1 indicates the
calculated fractional concentration of fully deprotonated ligand
that is present at that proton concentration. All fluorescence
emission spectra and quantum yields of the monoprotonated
species LH- were acquired at this -log[H3O+] value without
further deconvolution. All spectral data, including absorption
and emission maxima, Stokes shifts, and fluorescence quantum
yields, are listed in Table 2. For comparison, the data previously
4786 J. Org. Chem., Vol. 72, No. 13, 2007

ESIPT in 2-(2′-Arylsulfonamidophenyl)benzimidazoles
TABLE 1. Protonation Constants of Benzimidazole Derivatives 5a-5l in Aqueous Solutiona
substituents
[L2-]/[L]tot
[%]e
b
c
R1
R2
R3
pKa1
pKa2
-log[H3O+]d
5af
5b
5c
5d
5e
5f
5g
5h
5i
H
CN
CN
2-thiazolyl
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
H
H
H
8.04 ( 0.03
6.75 ( 0.02
6.88 ( 0.03
7.30 ( 0.01
7.60 ( 0.01
8.34 ( 0.01
9.33 ( 0.05
7.96 ( 0.02
7.63 ( 0.02
7.95 ( 0.02
7.98 ( 0.01
4.46 ( 0.08
n.d.g
7.0
5.2
5.2
6.0
6.2
6.5
6.7
6.7
6.5
6.5
6.3
4
3
3
3
3
<1
<1
5
6
3
n.d.g
n.d.g
4.79 ( 0.03
4.53 ( 0.06
8.01 ( 0.02h
5.51 ( 0.1
5.21 ( 0.1
4.91 ( 0.1
4.65 ( 0.02
OCH3
N(CH3)2
OCH3
H
H
CN
CN
OCH3
H
5k
5l
H
-OCH2O-
1
b
c
a 0.1 M KCl, 25 °C. Ka1 ) [L2-][H+]/[LH-]. Ka2 ) [LH-][H+]/[LH2]. d Proton concentration used for photophysical characterization of LH-. e Residual
concentration of fully deprotonated L2- f Data from ref 14. g Spectral deconvolution insufficient for accurate determination. h Protonation of the carboxylate
.
group occurs at pKa3 ) 4.81 ( 0.05.
TABLE 2. Photophysical Data of Benzimidazole Derivatives 5a-5l in Aqueous Solutiona
monoprotonated species (LH-) deprotonated species (L2-
)
abs λmax
em λmax
Stokes shift
[cm-1
abs λmax
em λmax
Stokes shift
isosbestic point
[nm]
emission shift
[nm]e
c
d
[nm]b
[nm]c
]
ΦF
[nm]b
[nm]d
[cm-1
]
ΦF
5af
5b
5c
5d
5e
5f
5g
5h
5i
300
319
341
331
305
298
273
306
307
316
314
460
483 (404)
481
484 (403)
432
497
568 (448)
534
489
452
459
11 590
10 640
8540
9550
9640
13 440
14 760h
13 950
12 120
9520
0.23
0.37
0.46
0.41
0.17g
0.14
<0.01
0.03
0.25
0.13
0.04
329
355
362
361
329
334
348
340
333
333
340
418
447
452
475
396
444
505
480
452
416
423
6470
5800
5500
6650
5140
7420
8930
8580
7910
5990
5770
0.26
0.70
0.34
0.42
0.06
0.27
0.08
0.02
0.29
0.29
0.04
315
341
350
352
314
322
296
326
320
320
326
42
36
29
9
36
53
63
54
37
36
36
5k
5l
10 060
a 0.1 M KCl, 25 °C. b From deconvolution analysis. c At the proton concentration as indicated in Table 1; excitation at isosbestic point. d pH 10.8, 0.1 M
KCl. e Difference of peak emission wavelength of species LH- and L2-
h Based on excitation spectrum acquired at 650 nm.
.
f Data from ref 14. g Excitation at 370 nm increases the quantum yield to 0.35.
SCHEME 2
Substitution with a dimethylamino group, a stronger π-donor
compared to methoxy, further increased the sulfonamide pKa
to 9.33 (compound 5g). As expected, the electron-withdrawing
cyano substituent significantly increased the acidity of the
sulfonamide group. The effect is more pronounced if CN is
attached to the central aryl ring (compound 5b) than the
benzimidazole moiety (compound 5i). Consistent with the
smaller electron-withdrawing ability of the 2-thiazolyl substitu-
ent, the sulfonamide in 5d is less acidic than that in 5b but still
more acidic than that in the unsubstituted parent compound 5a.
The double-substituted compounds 5c and 5h exhibit pKa’s that
reflect the influence of both groups; however, substitution on
the central aryl ring appears to carry more weight compared to
substitution on the benzimidazole ring.
3. Ground-State Tautomerism. In solution, 1H-benzimida-
zole derivatives are typically subject to rapid annular tautomer-
ization.14,31 Whereas the N1(H)/N3(H) prototropic equilibrium
of unsubstituted benzimidazole is energetically degenerate,
derivatives with a substituent R3 attached to the benzimidazole
ring yield a nondegenerate tautomer pair (Scheme 2). The
concentration ratio of the two species at equilibrium corresponds
to the tautomeric equilibrium constant KT which can be used to
estimate the stability difference ∆GT ) -RTlnKT of the
tautomer pair.
reported14 for the unsubstituted parent fluorophore 5a are also
included in Tables 1 and 2.
The measured acidity constants for deprotonation of the
sulfonamide nitrogen range between 6.7 and 9.3 and depend
strongly on the nature and attachment position of the substituents
(Table 1). The measured pKa’s follow closely Hammett’s free
energy relationship (Figure 2),29 thus directly reflecting the
degree of resonance stabilization and inductive effects imposed
by the corresponding substituents. For example, substitution with
a methoxy group in the para-position to the sulfonamide group
increased the pKa by 0.3 units (compound 5f), while substitution
in the meta-position resulted in a decrease by 0.4 units
(compound 5e). In the former case, resonance stabilization
dominates over the inductive effect imposed by the electrone-
gative oxygen, while in the latter case the opposite holds true.
(31) Minkin, V. I.; Garnovskii, A. D.; Elguero, J.; Katritzky, A. R.;
Denisko, O. V. In AdVances in Heterocyclic Chemistry; Katritzky, A. R.,
Ed.; Academic Press: New York, 2000; Vol. 76, pp 157-323.
(29) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96-103.
(30) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165-195.
J. Org. Chem, Vol. 72, No. 13, 2007 4787

Henary et al.
FIGURE 3. Variable temperature 1H NMR spectra 5(6)-cyano-
substituted benzimidazole derivative 4i in acetone-d6 (20 mM).
FIGURE 1. (a) Spectrophotometric pH titration of fluorophore 5f in
aqueous solution (0.1 M KCl, 25 °C). (b) Calculated species distribution
diagram for fluorophore 5f.
At this temperature, the exchange kinetics was sufficiently slow
such that the tautomer pair yielded two well-separated benz-
imidazole NH resonances. As indicated by the dashed lines in
Figure 4 (left), the NH proton at 13.40 ppm is in NOE contact
with the benzimidazole proton C7(H) appearing as a singlet at
8.17 ppm, while the more intense, upfield-shifted NH proton
at 13.32 ppm shows a correlation with the doublet resonance at
7.83 ppm. On the basis of these NOE contacts it is possible to
unambiguously identify the 5-cyano-substituted tautomer as the
major species, which, in concurrence with the experimental data,
is expected to show an NOE correlation between N1(H)/C7(H)
but not between N1(H)/C4(H). A quantum chemical study of
5(6)-cyano-benzimidazole at the AM1 level of theory predicted
also the 5-substituted tautomer to be slightly more stable (KT
) 1.62) compared to its 6-substituted counterpart.32 Accordingly,
intramolecular hydrogen bonding with the neighboring sulfona-
mide proton does not appear to significantly alter the position
of the tautomeric equilibrium of 4i.
The corresponding low-temperature 2D NOESY NMR ex-
periment of methoxy-substituted derivative 4k revealed that the
6- rather than 5-substituted tautomer is the major species (Figure
4, right). The measured tautomerization equilibrium constant
lies with KT ) 0.66 ( 0.01 also near unity, corresponding to a
similarly small free energy difference of ∆GT ) 0.66 ( 0.01
kJ mol-1 for the methoxy-substituted tautomer pair. In agree-
ment with the computational study,32 differences in tautomer
stabilities seem to be primarily governed by substituent-
dependent resonance effects, whereas polarizability and induc-
tive contributions appear less important. In summary, given the
rapid tautomerization kinetics combined with near unity equi-
librium constants for the investigated 5(6)-substituted benzimi-
dazole derivatives, the photophysical data must be interpreted
as averaged properties of the two tautomers.
FIGURE 2. Linear dependence of the sulfonamide acidity (pKa1) on
Hammett’s σ parameters (ref 30) for monosubstituted fluorophores 5a,
5b, 5d-5g, and 5l (r ) correlation coefficient).
To investigate the effect of the 5(6)-cyano and 5(6)-methoxy
substituents on the energetics of the tautomerization equilibrium,
we performed a series of variable temperature 1H NMR
experiments with derivatives 4i and 4k. While the exchange
kinetics in protic solvents lies at the fast exchange limit with
regard to the NMR time scale,14 the tautomerization proved to
be sufficiently slow in acetone-d6 at cryo temperatures. As
illustrated in Figure 3, the 1H NMR spectrum of cyano-
substituted 4i exhibited exchange-broadened benzimidazole
proton resonances that gradually sharpened up with decreasing
temperature. At -60 °C two sets of well-resolved signals were
observed for the two tautomers, indicating slow exchange with
regard to the NMR time scale. From the integrated intensity
ratio of the C4(H) and C7(H) resonances at 8.43 and 8.11 ppm,
a tautomeric equilibrium constant of KT ) 1.43 ( 0.008 was
measured, corresponding to a free energy difference of ∆GT )
0.63 ( 0.01 kJ mol-1
.
To elucidate whether the equilibrium position is in favor of
the 5- or 6-cyano-substituted tautomer of 4i, we performed a
2D NOESY experiment at -80 °C in acetone-d6 (Figure 4, left).
(32) Raczynska, E. D. J. Chem. Res., Synop. 1998, 704-705.
4788 J. Org. Chem., Vol. 72, No. 13, 2007

ESIPT in 2-(2′-Arylsulfonamidophenyl)benzimidazoles
1
FIGURE 4. Two-dimensional 500 MHz H-1H NOESY spectra of (a) 4i (left) and (b) 4k (right) in acetone-d6 at -80 °C. The dashed lines
indicate the correlation signals for the benzimidazole proton N1(H) of each tautomer. For both derivatives, N1(H) shows NOE contact with the
C7(H) singlet of the 6-substituted tautomer, while the 5-substituted tautomer shows an NOE contact with C(7)H appearing as a doublet (atom
numbering shown in Scheme 2). Structural assignments were confirmed with 2D COSY experiments acquired at the same temperature (see the
Supporting Information, Figures S1 and S2).
4. Substituent Effects on Absorption and Fluorescence
Spectra. 4.1. Effect of Donor Substitution. To explore the
effect of a single electron-donating substituent in relation to its
attachment position on the fluorophore π-system, we first
compared the UV-vis absorption and fluorescence emission
spectra of the monosubstituted methoxy derivatives 5e, 5f, and
5k with those of the unsubstituted parent compound 5a (Figure
5). The deconvoluted spectra corresponding to the monoproto-
nated species LH- exhibit for all four compounds a single high-
energy absorption maximum (Figure 5, solid traces); however,
the 4′-substituted derivative 5e revealed an additional low-energy
band centered around 360 nm (Figure 5b, left). On the basis of
literature reports on structurally related compounds,13,33 the band
is most likely caused by an interannular prototropic tautomer
T (Chart 2) that is present in the ground-state equilibrium (vide
infra). When substituted with a methoxy group in the 4′-position
of the central benzene ring (compound 5e), the absorption
maximum of the monoprotonated species LH- is red-shifted
by 5 nm or 550 cm-1 (Figure 5b), while substitution in the 5′-
position leads to a small blue-shift of 2 nm or 220 cm-1
(compound 5f, Figure 5c) compared to the parent compound
5a. In contrast, substitution of the benzimidazole ring with a
methoxy group (compound 5k) yields a significantly larger red-
shift of 16 nm or 1690 cm-1 (Figure 5d).
transfer species T* in the excited state, the peak emission of
all four compounds exhibit exceptionally large Stokes shifts
ranging from 9520 to 13 440 cm-1. Notably, none of the
derivatives exhibits dual emission, indicating that formation of
the ESIPT tautomer is very efficient and neither compromised
through solvent-solute hydrogen-bonding interactions,34 solvent-
polarization-induced barriers,35 or ground-state stabilization
of a rotamer that cannot undergo ESIPT.13 Interestingly, the
fluorescence maximum of monoprotonated 5k is very similar
compared to 5a, while the 4′- and 5′-substituted derivatives
5e and 5f are significantly red- and blue-shifted by 28 nm
(1410 cm-1) and 37 nm (1620 cm-1), respectively. The quantum
yield of all three monomethoxy-substituted derivatives is
markedly lower compared to that of their parent compound 5a
(Table 2).
To further investigate the nature of the low-energy absorption
band observed for fluorophore 5e, we studied the emission
properties of this compound in more detail. Excitation into this
low-energy band at 350 nm yielded an emission spectrum that
was upon normalization indistinguishable from the spectrum
obtained with excitation at <300 nm. Furthermore, the excitation
spectrum revealed across the entire emission energy range a
similar low-energy band as found in the UV-vis absorption
spectrum (data not shown). These observations strongly support
that fluorescence emission occurs exclusively from the proton-
transfer tautomer T*, which is to some extent already present
At a proton concentration where the monoprotonated species
LH- is predominantly present (see Table 1), all four compounds
exhibit a single, low-energy fluorescence emission band (Figure
5, right; solid traces). Consistent with formation of the proton-
(34) Penedo, J. C.; Mosquera, M.; Rodriguez-Prieto, F. J. Phys. Chem.
A 2000, 104, 7429-7441.
(35) Cheng, Y. M.; Pu, S. C.; Hsu, C. J.; Lai, C. H.; Chou, P. T.
ChemPhysChem 2006, 7, 1372-1381.
(33) Mosquera, M.; Penedo, J. C.; Rios Rodriguez, M. C.; Rodriguez-
Prieto, F. J. Phys. Chem. 1996, 100, 5398-5407.
J. Org. Chem, Vol. 72, No. 13, 2007 4789

Henary et al.
FIGURE 6. Effect of acceptor substituents: deconvoluted UV-vis
absorption spectra (left) and fluorescence emission spectra (right) of
compounds (a) 5b, (b) 5i, (c) 5d, and (d) 5c in aqueous solution (0.1
M KCl, 25 °C). UV-vis traces for the species with protonated (s)
and deprotonated (- - -) sulfonamide group were obtained through
deconvolution analysis of a series of spectra with -log[H3O+] ranging
between 6 and 10. Emission spectra were acquired with excitation at
the isosbestic point and were recorded near neutral pH as specified
in Table 1 (s) and at pH 11 (- - -) without further deconvolution.
The four vertical grid lines are intended as a guide to the eye indi-
cating the position of the peak absorption and emission of parent
compound 5a.
FIGURE 5. Effect of donor substituents: deconvoluted UV-vis
absorption spectra (left) and fluorescence emission spectra (right) of
compounds (a) 5a, (b) 5e, (c) 5f, and (d) 5k in aqueous solution (0.1
M KCl, 25 °C). UV-vis traces for the species with protonated (s)
and deprotonated (- - -) sulfonamide group were obtained through
deconvolution analysis of a series of spectra with -log[H3O+] ranging
between 6 and 10. Emission spectra were acquired with excitation at
the isosbestic point and were recorded near neutral pH as specified
in Table 1 (s) and at pH 11 (- - -) without further deconvolution.
The four vertical grid lines are added as a guide to the eye indi-
cating the position of the peak absorption and emission of parent
compound 5a.
in the ground-state equilibrium along with the normal cis-
tautomer Nc (Chart 2).
attached to the benzimidazole ring revealed again a similar
spectrum compared to that of parent compound 5a, while the
peak emission of 5e and 5f were strongly blue- and red-shifted
by 22 nm (1330 cm-1) and 26 nm (1400 cm-1), respectively.
Given the current data set, we can only speculate about the
underlying reason for the observed divergent trends in the peak
emission energies of derivative 5e versus 5f. As apparent from
Table 2, the emission energies parallel the changes in Stokes
shifts, thus indicating significant differences in the relaxation
energetics of the initially formed Franck-Condon state. Since
the attachment position of the methoxy group is the only
structural difference between 5e and 5f, specific solvent-solute
interactions are presumably less important. However, the
attachment position could influence the degree of excited-state
polarization, thus potentially leading to formation of an emissive
ESIPT species with varying degree of charge-transfer character.
Isotropic dipole-dipole interactions with solvent molecules
would additionally pronounce such differences of the excited-
state polarization. Alternatively, the methoxy substituent may
differentially stabilize the frontier orbital energies of the proton-
Upon deprotonation of the sulfonamide nitrogen (-log[H3O+]
> 10), the UV-vis absorption spectra were changed dramati-
cally (Figure 5, left, dashed traces). In comparison to the
monoprotonated species LH-, the absorption traces of all four
compounds display a red-shifted band centered around 330 nm,
whose energy is essentially invariable of the methoxy-substituent
position. Furthermore, the spectrum of fully deprotonated 5e
reveals that the position of the lowest energy absorption band
is significantly different from the low-energy band observed
for its monoprotonated form, thus further corroborating forma-
tion of the interannular tautomer T at neutral pH.
Consistent with disruption of the ESIPT process upon
sulfonamide deprotonation at high pH, all four fluorophores
exhibit strongly blue-shifted emission bands with normal Stokes
shifts (Figure 5, right, dashed traces). The influence of the
methoxy substituents on the emission energy follows in essence
the same trends as observed for the spectra of the monoproto-
nated species LH-: derivative 5k containing a methoxy group
4790 J. Org. Chem., Vol. 72, No. 13, 2007

ESIPT in 2-(2′-Arylsulfonamidophenyl)benzimidazoles
CHART 2
transfer species, thus leading to the divergent emission shifts.
Finally, differences in the strengths of the intramolecular
hydrogen bond might influence the ESIPT energetics and thus
result in the observed differences of the Stokes shifts.
compared to those of 5a. Interestingly, the emission spectrum
of the monoprotonated fluorophore reveals an additional band
at higher energy, which was not observed for any of the donor-
substituted derivatives (Figure 6a, right, solid trace). The overall
band shape fits well to a double-Gaussian function with maxima
centered at 483 (20 720 ( 10 cm-1) and 404 nm (24 770 ( 30
cm-1). The corresponding single-Gaussian components are
shown as dotted traces in Figure 6a. On the basis of the pH at
which the emission spectrum of LH- was acquired, the estimated
residual concentration of L2- is less than 3% (Table 1), an
amount that is too small to account for the intensity of the higher
energy emission band. Furthermore, the emission spectrum of
fully deprotonated L2- shows a distinctly different maximum
at 447 nm (Figure 6a, right, dashed trace). Conclusively, the
observed higher energy fluorescence band cannot be attributed
to emission from fully deprotonated L2-, neither as a species
formed by means of excited-state deprotonation, nor as a
significant component of the ground-state equilibrium prior to
excitation. Dual fluorescence is not uncommon for ESIPT
fluorophores and is often due to the presence of a rotamer that
cannot undergo ESIPT.13,33 Recent quantum chemical calcula-
tions suggested, however, that the cis/trans-rotamer equilibrium
for 2′-sulfonamidophenyl-substituted benzimidazoles is strongly
in favor of the ESIPT capable cis-rotamer.27 Ground-state
equilibration of 5b between the normal cis-rotamer Nc and the
corresponding non-ESIPT trans-rotamer Nt is therefore rather
unlikely (Chart 2). Consistent with this assumption, the normal-
ized excitation spectra acquired at 375 and 485 nm were
identical within experimental error (data not shown), suggesting
that the two emissive species originate from the same ground-
state structure. The observed dual emission is therefore most
likely due to an excited-state process that involves competition
between radiative deactivation of the normal tautomer Nc* and
formation of the phototautomer T* through ESIPT. It appears
that the electron-withdrawing cyano substituent in 5b adversely
affects the rate of ESIPT, possibly through an unfavorable
change of the excited-state acidity of the sulfonamide proton36
or through a substantially different polarization between vibra-
tionally equilibrated T* and Ec*. The latter scenario would yield
a solvent-polarization-induced barrier of the ESIPT process, and
thus an excited-state equilibrium between the phototautomer T*
and the normal tautomer Nc*, resulting in competitive radiative
deactivation of both species.35
4.1.1. Effect of Donor Strength. To explore the influence
of π-donor strength, we studied the spectral properties of the
dimethylamino-substituted fluorophore 5g in comparison with
the methoxy-substituted compound 5f. Consistent with the
increased π-donor strength of the dimethylamino group com-
pared to methoxy, the peak fluorescence wavelength of mono-
protonated 5g is strongly red-shifted by 71 nm compared to 5f,
yielding an exceptionally large Stokes shift of 14 760 cm-1
(Table 2). Upon deprotonation of the sulfonamide nitrogen,
the fluorescence maximum of 5g is blue-shifted by 63 nm or
2200 cm-1 but remains still at significantly lower energy
compared to that of fully deprotonated 5f. As previously
observed for the methoxy-substituted compounds 5e, 5f, and
5k, at high pH the ESIPT process is effectively disrupted,
yielding emission exclusively from the fully deprotonated
species L2-. In comparison to 5f, the quantum yield of 5g
is dramatically lowered at neutral pH and recovered only
slightly to 8% at basic pH. Interestingly, repetitive measurements
of the fluorescence emission spectrum in neutral buffered
aqueous solution revealed gradual appearance of a new band,
indicating significant photochemical instability under these
conditions.
Although electron donation into the central aryl ring is
expected to increase by derivatizing with a 4′,5′-methylenedioxy
moiety (fluorophore 5l), the spectral shifts were less dramatic
(Table 2). The divergent emission energy trends observed for
the two monomethoxy-substituted derivatives 5e and 5f appeared
to be averaged out in this case. The fluorescence emission
maxima and Stokes shifts fall for both the monoprotonated and
fully deprotonated species of 5l in between the values measured
for 5e and 5f. Interestingly, the fluorescence quantum yield of
5l is also much lower compared to that of the monosubstituted
derivatives 5e and 5f, indicating additional nonradiative deac-
tivation channels.
4.2. Effect of Acceptor Substitution. To assess the effect
of electron-withdrawing substituents on the fluorophore proper-
ties, we explored next the photophysical properties of the cyano-
substituted derivatives 5b and 5i. As shown in Figure 6a,
compared to the parent compound 5a the 4′-cyano-substituted
derivative 5b exhibits dramatically red-shifted absorption bands
for both the monoprotonated LH- (19 nm or 1990 cm-1 shift)
and fully deprotonated species L2- (26 nm or 2230 cm-1 shift).
The peak emission energies are also red-shifted, but to a lesser
degree, by 23 nm or 1040 cm-1 for LH-, and 29 nm or 1550
cm-1 for L2-, resulting in slightly smaller Stokes shifts
In contrast, derivative 5i substituted with a cyano group at
the benzimidazole ring lacks the higher energy emission band
and exhibits solely fluorescence from the ESIPT tautomer
(36) Doroshenko, A. O.; Posokhov, E. A.; Verezubova, A. A.; Ptyagina,
L. M. J. Phys. Org. Chem. 2000, 13, 253-265.
J. Org. Chem, Vol. 72, No. 13, 2007 4791

Henary et al.
the Stokes shift for the ESIPT emission is the smallest among
all studied compounds, deprotonation of the sulfonamide still
resulted in a significantly blue-shifted emission band (29 nm
or 1330 cm-1). It is noteworthy that the quantum yield of
monoprotonated 5c is with 46% 2-fold greater than for 5a and
the highest of all studied compounds.
While the double-substitution pattern in 5c resulted in
improved photophysical properties compared to the correspond-
ing monosubstituted counterparts, fluorophore 5h revealed low
quantum yields regardless of the protonation state. Nevertheless,
the compound exhibits qualitatively the same behavior with a
large Stokes-shifted emission for the monoprotonated species
and normal emission at high pH.
FIGURE 7. Linear correlation between Stokes shift and quantum yield
for the monoprotonated fluorophores 5a-5l (r ) correlation coefficient;
5e, 5k, and 5l were excluded from the correlation).
4.4. Quantum Yields. The fluorescence quantum yield of
the ESIPT tautomer appears to correlate significantly with the
observed Stokes shift. As illustrated in Figure 7, with exception
of the methoxy-substituted derivatives 5e, 5k, and 5l, the
quantum yields linearly decrease with increasing Stokes shifts
(correlation coefficient r ) 0.984). The data suggest that the
degree of excited-state reorganization and geometrical relaxation
in the course of the proton-transfer process is an important factor
that determines the fluorescence efficiency in competition with
nonradiative deactivation processes. It is noteworthy that no
appreciable correlation was found regarding the trends in
emission energies of the ESIPT species, indicating that the
quantum yield trends are not just a reflection of the energy gap
rule.
(Figure 6b). The peak emission energy is also red-shifted relative
to that of unsubstituted 5a and very similar compared to that of
5b. At high pH, the fully deprotonated species L2- emits at
almost identical energy compared to 5b, though with signifi-
cantly lower quantum yield. The UV-vis maxima at basic and
neutral pH are both red-shifted compared to those of the parent
compound 5a, but to a lesser degree than those of 5b, thus
resulting in larger Stokes shifts.
While acting also as an electron-withdrawing substituent, the
thiazolyl ring in 5d naturally extends the π-system of the parent
fluorophore. This is best reflected by the fact that the absorption
maxima of 5d are even more red-shifted compared to those of
5i (Figure 6c), although the sulfonamide pKa is lowered to a
lesser degree by thiazolyl compared to cyano substitution
(Table 1). As already observed for fluorophore 5b, the emission
spectrum of monoprotonated 5d reveals two bands, which fit
well to a double-Gaussian function with maxima centered at
484 nm (20 650 ( 10 cm-1) and 403 nm (24 810 cm-1 ( 30
cm-1). Analogous to 5b, the normalized excitation spectra
acquired at 403 and 484 nm exhibit no differences within
experimental error (data not shown), suggesting that the dual
emission is again due to competing excited-state processes
rather than ground-state equilibration between cis- and trans-
rotamers.
Deprotonation of the sulfonamide nitrogen yields again a
single emission band; however, the observed blue-shift is with
9 nm (390 cm-1) substantially smaller compared to that of 5b.
As evident from Table 2, this reduction is mainly a consequence
of the decreased Stokes shift of the lower energy band in 5d
compared to 5b, rather than anomalous emission behavior of
the fully deprotonated species.
4.3. Effect of Donor-Acceptor Double Substitutions.
Double substitution with a donor and acceptor group has the
potential to increase the charge-transfer character in the ground
and excited state, which in turn might lead to further red-shifted
absorption and emission spectra. To explore the effect of such
modifications, we studied the spectral properties of derivative
5c and 5h, both containing a methoxy and cyano group in
opposing positions of the fluorophore framework. As shown in
Figure 6d, compared to unsubstituted 5a fluorophore 5c exhibits
indeed strongly red-shifted absorption bands for both the
monoprotonated species LH- (41 nm or 4010 cm-1 shift) and
fully deprotonated L2- (33 nm or 2770 cm-1 shift). The emission
band of the former species peaks at 481 nm, corresponding to
a 21 nm (950 cm-1) red-shift compared to 5a. Interestingly,
ESIPT is very efficient in 5c and results in a single emission
band without the high-energy component found for 5b. Although
Concluding Remarks
The primary motivation for this study was to explore whether
donor and acceptor substituents are capable of shifting the peak
absorption and emission wavelength of 2-(2′-arylsulfonamido-
phenyl)benzimidazole fluorophores toward lower energy, an
important aspect in light of biological imaging applications.
Standard fluorescence microscopes are typically equipped with
optics that are not transmissible below 350 nm, thus hampering
unsubstituted 5a as a fluorophore platform for biological sensing
applications. In this context, several of the studied substituted
derivatives were found to meet this requirement. Notably,
derivatives 5c and 5d exhibit strongly red-shifted absorption
bands. Upon deprotonation at basic pH, both compounds
revealed isosbestic points that also match the desired wavelength
criteria (Table 2), making it possible to excite the mono- and
fully deprotonated form with equal efficiency. In addition,
derivative 5c stands out due to its high quantum yield and a
significant blue-shift of the fluorescence emission upon depro-
tonation.
All derivatives yielded emission from the ESIPT tautomer
T*; however, fluorophore 5b and 5d revealed an additional
higher energy band that is most likely due to emission from
the normal tautomer Nc*. While alteration of the fluorophore
π-system can be used to effectively tune the ESIPT emission
energy, this strategy unavoidably carries also the risk of reducing
the rate of ESIPT and thus of introducing additional, competing
radiative deactivation channels. Further complications might
arise from hydrogen-bonding interactions with solvent molecules
and/or the presence of rotamers that cannot undergo ESIPT.
The prediction of such excited-state processes remains a
challenging task based on simple structural arguments; however,
the results of this study may provide guidelines for tuning the
4792 J. Org. Chem., Vol. 72, No. 13, 2007

ESIPT in 2-(2′-Arylsulfonamidophenyl)benzimidazoles
(70 eV) m/z 194.1 ([M+], 100), 164.1 (18), 136.3 (100), 119.1 (32),
105.1 (18); EI-HRMS calcd for [M+] C9H10N2O3 194.0691, found
194.0674.
properties of this class of fluorophores to design emission
ratiometric pH or metal-cation sensors for biological applica-
tions.
General Procedure A: Synthesis of Benzimidazole Deriva-
tives through Oxidative Coupling with Benzoquinone. An
equimolar solution of the corresponding aldehyde and phenylene-
diamine (0.5 mmol) in EtOH (2 mL) was heated under reflux until
all starting material was converted to the imine intermediate (ca.
1.5 h). After addition of 1,4-benzoquinone (119 mg, 1.10 mmol)
the reaction mixture was heated at reflux until the imine intermediate
was completely converted to the benzimidazole product (typically
30-60 min). The reaction mixture was then cooled to room
temperature, diluted with saturated aqueous NaHCO3, and the
product was extracted twice with ethyl acetate. The combined
organic extracts were dried with anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by FC on silica to give the analytically pure benzimidazole.
4-(1H-Benzimidazol-2-yl)-3-nitrobenzonitrile (2b). Starting
from 200 mg of aldehyde 1b (0.12 mmol) and 1,2-phenylenedi-
amine (129 mg, 1.19 mmol), benzimidazole derivative 2b was
obtained in 43% yield (FC, EtOAc/hexanes, gradient 1:2 to 1:1).
Experimental Section
Synthesis. Benzimidazole derivatives 4a and 5a, (4-chlorosul-
fonyl-phenoxy)acetic acid ethyl ester 10, and 2-(4-(N-(2-formylphe-
nyl)sulfamoyl)phenoxy)acetic acid ethyl ester 9i were synthesized
as previously described.14 Compounds 4-cyano-2-nitrobenzalde-
hyde37 (1b), 5-methoxy-2-nitrobenzaldehyde38 (1f), 4-methoxy-2-
nitrobenzaldehyde39 (1e), and 4-bromo-2-nitrobenzaldehyde40 were
synthesized according to published procedures. NMR: δ in ppm
versus SiMe4 (0 ppm, 1H, 400 MHz; 0 ppm, 13C, 100 MHz). Note:
due to the presence of prototropic exchange equilibria, benzimi-
dazole hydrogens are in many cases broadened (indicated as “br”)
or not resolved. Similarly, 13C resonances for C3a(7a), C4(7), and
C5(6) of the benzimidazole ring were either broadened or absent.
For variable temperature NMR experiments, the actual sample
temperature was determined by means of a calibration curve using
neat methanol as chemical-shift thermometer.41 Two-dimensional
1
1
NOESY H-1H NMR spectra were acquired in acetone-d6 at 193
Mp 209-211 °C; H NMR (CD3OD, 400 MHz) δ 7.33 (m, 2H),
7.64 (br, 2H), 8.06 (d, J ) 8.2 Hz, 1H), 8.20 (dd, J ) 8.2, 1.6 Hz,
1H), 8.53 (d, J ) 1.6 Hz, 1H); 13C NMR (acetone-d6, 100 MHz) δ
115.7, 117.2, 124.5 (br), 129.5, 130.1, 133.7, 137.1, 147.5, 150.0;
IR (KBr) 3198, 3097, 3072, 2236, 1560, 1535, 1425, 1354, 787,
747 cm-1; MS (70 eV) m/z 264.1 ([M+], 100), 247.1 (65), 234.1
(26); EI-HRMS calcd for [M+] C14H8N4O2 264.06473, found
264.06592.
4-(5(6)-Methoxy-1H-benzimidazol-2-yl)-3-nitrobenzonitrile (2c).
Starting from 200 mg of aldehyde 1b (0.12 mmol) and 4-meth-
oxybenzene-1,2-diamine (165 mg, 1.19 mmol), benzimidazole
derivative 2c was obtained in 30% yield (FC, EtOAc/hexanes,
gradient 1:2 to 1:1). Mp 75-77 °C; 1H NMR (CD3OD, 400 MHz)
δ 3.86 (s, 3H), 6.95 (dd, J ) 8.9, 2.4 Hz, 1H), 7.09 (br, 1H), 7.52
(d, J ) 8.7 Hz, 1H), 8.02 (d, J ) 8.0 Hz, 1H), 8.16 (dd, J ) 8.0,
1.6 Hz, 1H), 8.49 (d, J ) 1.6 Hz, 1H); 13C NMR (acetone-d6, 100
MHz) δ 55.9, 114.0, 114.2, 117.1, 128.5, 128.7, 131.9, 136.0, 145.3,
149.6, 157.9; IR (KBr) 3074, 2946, 2234, 1617, 1540, 1269,
1198, 1157, 1025, 1001, 831 cm-1; MS (70 eV) m/z 294.1 ([M+],
100); EI-HRMS calcd for [M+] C15H10N4O3 294.07529, found
294.07582.
2-(2-Nitro-4-thiazol-2-yl-phenyl)-1H-benzimidazole (2d). Start-
ing from 28 mg of aldehyde 1d (0.12 mmol) and 1,2-phenylene-
diamine (15 mg, 0.14 mmol), benzimidazole derivative 2d was
obtained in 31% yield (FC, EtOAc/hexanes, 1:1). Mp 120-122
°C; 1H NMR (CD3OD/CDCl3 1:1, 400 MHz) δ 7.29-7.35 (m, 2H),
7.61-7.68 (br, 2H), 7.69 (d, J ) 3.2 Hz, 1H), 7.96 (d, J ) 8.1 Hz,
1H), 8.00 (d, J ) 3.2 Hz, 1H), 8.33 (dd, J ) 8.1, 1.8 Hz, 1H), 8.65
(d, J ) 1.8 Hz, 1H); 13C NMR (CD3OD/CDCl3, 100 MHz) δ 122.1,
123.0, 123.9 (br), 126.9, 130.8, 133.5, 136.5, 144.9, 148.2, 150.0,
165.6; IR (KBr) 3120, 3091, 1534, 1518, 1474, 1448, 1433, 1369,
1354, 1276, 771, 746 cm-1; MS (70 eV) m/z 322 ([M+], 50), 292
(100), 129 (57), 57(52), 40.9 (37); EI-HRMS calcd for [M+]
C16H10N4O2S 322.0525, found 322.0496.
K with a 500 MHz spectrometer (300 ms mixing time). Structural
assignments of the observed signals were made on the basis of 2D
COSY experiments acquired at the same temperature (see the
Supporting Information, Figures S1 and S2). MS: selected peaks;
m/z. Melting points are uncorrected. Flash chromatography (FC):
silica gel (240-400 mesh).
2-Nitro-4-(thiazol-2-yl)benzaldehyde (1d). A solution of 4-bromo-
2-nitrobenzaldehyde40 (310 mg, 1.3 mmol), 2-(tributylstannyl)-
thiazole (500 mg, 410 µL, 1.3 mmol), and Pd(PPh3)4 (50 mg, 0.043
mmol) in DMF (10 mL) was degassed and then heated at 80 °C
overnight. After cooling to room temperature, the reaction mixture
was diluted with CH2Cl2, washed with deionized water, and
concentrated under reduced pressure. The residual crude product
was purified on silica gel (FC, EtOAc/hexanes, 1:3) providing 340
mg (1.45 mmol, quantitative yield) of thiazole 1d as a yellow solid.
Mp 101-103 °C; 1H NMR (CDCl3, 400 MHz) δ 7.55 (d, J ) 3.1
Hz, 1H), 8.01 (d, J ) 3.2 Hz, 1H), 8.06 (d, J ) 8.0 Hz, 1H), 8.34
(dd, J ) 8.0 Hz, 1.7 Hz, 1H), 8.71 (d, J ) 1.7 Hz, 1H), 10.45 (s,
1H); 13C NMR (CDCl3, 100 MHz) δ 121.6, 122.0, 130.4, 130.87,
130.91, 138.6, 144.8, 150.1, 163.8, 187.3; IR (KBr) 3121, 3106,
2926, 1691, 1526, 1506, 1348, 1141, 824, 770, 736 cm-1; MS (70
eV) m/z 234 ([M+], 11), 204 (100), 176 (25), 159 (27); EI-HRMS
calcd for C10H6N2O3S 234.0099, found 234.0078.
5-(Dimethylamino)-2-nitrobenzaldehyde (1g). A mixture of
5-fluoro-2-nitrobenzaldehyde (100 mg, 0.59 mmol), dimethylamine
hydrochloride (77 mg), and anhydrous K2CO3 (245 mg) in DMSO
(2 mL) was heated at 105 °C for 2 h. After cooling to room
temperature, the reaction mixture was diluted with water, and the
precipitated product was extracted twice with diethylether (40 mL).
The combined organic extracts were dried with anhydrous MgSO4,
filtered, and concentrated under reduced pressure, providing 92 mg
(0.47 mmol, 80% yield) of compound 1g as a yellow solid. Mp
1
124-126 °C; H NMR (CDCl3, 400 MHz) δ 3.16 (s, 6H), 6.72
2-(4-Methoxy-2-nitro-phenyl)-1H-benzimidazole (2e). Starting
from 410 mg of aldehyde 1e (2.26 mmol) and 1,2-phenylenediamine
(257 mg, 2.37 mmol), benzimidazole derivative 2e was obtained
in 82% yield (FC, EtOAc/hexanes, gradient 1:4 to 1:2). Mp 178-
(dd, J ) 9.3, 3.0 Hz, 1H), 6.91 (d, J ) 3.0 Hz, 1H), 8.11 (d, J )
9.3 Hz, 1H), 10.51 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 40.3,
110.0, 112.7, 127.4, 135.0, 136.2, 153.3, 190.0; IR (KBr) 2902,
1701, 1600, 1573, 1295, 1261, 1231, 1198, 886, 811 cm-1; MS
1
180 °C; H NMR (CD3OD, 400 MHz) δ 3.96 (s, 3H), 7.25-7.29
(m, 2H), 7.38 (dd, J ) 8.6, 2.6 Hz, 1H), 7.58 (br, 2H), 7.65 (d, J
) 2.6 Hz, 1H), 7.74 (d, J ) 8.6 Hz, 1H); 13C NMR (DMSO-d6,
100 MHz) δ 56.3, 109.6, 115.9, 117.8, 122.1 (br), 131.6, 147.1,
149.7, 160.1; IR (KBr) 2844, 1628, 1531, 1500, 1449, 1430, 1304,
1272, 1238, 1027, 755 cm-1; MS (70 eV) m/z 269 ([M+], 90), 239.1
(100), 196 (32), 110.1 (77); EI-HRMS calcd for [M+] C14H11N3O3
269.0800, found 269.0816.
(37) Dann, O.; Ruff, J.; Wolff, H. P.; Griessmeier, H. Liebigs Ann. Chem.
1984, 409-425.
(38) Manetsch, R.; Zheng, L.; Reymond, M. T.; Woggon, W.-D.;
Reymond, J.-L. Chem. Eur. J. 2004, 10, 2487-2506.
(39) Katritzky, A. R.; Xu, Y.-J.; Vakulenko, A. V.; Wilcox, A. L.; Bley,
K. R. J. Org. Chem. 2003, 68, 9100-9104.
(40) Jung, M. E.; Dansereau, S. M. K. Heterocycles 1994, 39, 767-
778.
(41) Amman, C.; Meier, P.; Merbach, A. E. J. Magn. Reson. 1982, 46,
319-321.
3-Amino-4-(1H-benzimidazol-2-yl)benzonitrile (3b). A solution
of nitro-substituted benzimidazole intermediate 2b (102 mg, 0.39
J. Org. Chem, Vol. 72, No. 13, 2007 4793

Henary et al.
mmol) in 5 mL of methanol was hydrogenated at room temperature
under ambient pressure in the presence of Pd on activated carbon
as catalyst (25 mg, 5 wt % Pd). After completion of the reaction
(TLC), the catalyst was filtered off through a pad of Celite, and
the filtrate was concentrated under reduced pressure providing 85
mg (0.36 mmol, 94% yield) of amine 3b as a yellow solid. Mp
88-90 °C; 1H NMR (CD3OD, 400 MHz) δ 6.92 (dd, J ) 8.2, 1.6
Hz, 1H), 7.12 (d, J ) 1.6 Hz, 1H), 7.22-7.25 (m, 2H), 7.58 (br,
2H), 7.79 (d, J ) 8.2 Hz, 1H); 13C NMR (CD3OD, 100 MHz) δ
114.0, 116.0, 119.1, 119.7, 120.1, 129.0, 149.2, 151.9; IR (KBr)
3305 (br), 3060, 2228, 1617, 1586, 1577, 1454, 1437, 1334, 1267,
766, 741 cm-1; MS (70 eV) m/z 234.1 ([M+], 100); EI-HRMS calcd
for [M+] C14H10N4 234.0906, found 234.0907.
3-Amino-4-(1H-benzimidazol-2-yl)benzonitrile (3c). Synthe-
sized from 2c as described for 3b, 53% yield. Mp 193-195 °C;
1H NMR (CD3OD, 400 MHz) δ 3.83 (s, 3H), 6.87 (dd, J ) 8.8,
2.7 Hz, 1H), 6.93 (dd, J ) 8.2, 1.6 Hz, 1H), 7.07 (d, J ) 2.2 Hz,
1H), 7.12 (d, J ) 1.6 Hz, 1H), 7.49 (d, J ) 8.8 Hz, 1H), 7.79 (d,
J ) 8.2 Hz, 1H); 13C NMR (CD3OD, 100 MHz) δ 56.2, 97.6, 113.3,
113.5, 116.2, 117.3, 119.0, 119.9, 128.7, 135.4, 139.3, 148.9, 151.6,
157.9; IR (KBr) 3296, 2224, 1631, 1610, 1590, 1453, 1434, 1338,
1263, 1199, 1158, 832 cm-1; MS (70 eV) m/z 264 ([M+], 100),
249.1 (52), 167 (28), 147.9 (78), 129 (90); EI-HRMS calcd for
[M+] C15H12N4O 264.1011, found 264.1014.
2-(4-(N-(5-Cyano-2-(5(6)-methoxy-1H-benzimidazol-2-yl)phe-
nyl)sulfamoyl)phenoxy)acetic Acid Ethyl Ester (4c). Synthesized
from amine 3c as described for 4b, 43% yield. Mp 83-85 °C; 1H
NMR (CD3OD) δ 1.20 (t, J ) 7.1 Hz, 3H), 3.87 (s, 3H), 4.17 (q,
J ) 7.1 Hz, 2H), 4.65 (s, 2H), 6.81 (d, J ) 9.0 Hz, 2H), 6.97 (dd,
J ) 8.9, 2.4 Hz, 1H), 7.11 (d, J ) 2.3 Hz, 1H), 7.49 (dd, J ) 8.2,
1.6 Hz, 1H), 7.57 (d, J ) 8.9 Hz, 1H), 7.64 (d, J ) 9.0 Hz, 2H),
7.92 (d, J ) 8.2 Hz, 1H), 7.98 (d, J ) 1.5 Hz, 1H); 13C NMR
(DMSO-d6/CDCl3, 100 MHz) δ 13.6, 55.1, 60.7, 64.5, 111.9, 113.1
(br), 114.2, 117.4, 119.6, 121.2, 125.5, 127.0, 128.3, 130.9, 137.0,
147.4, 156.4, 160.4, 166.9; IR (KBr) 3400, 2980, 2231, 1759, 1595,
1496, 1400, 1273, 1200, 1158, 1095, 828, 554 cm-1; MS (70 eV)
506.1 ([M+], 47), 263.1 (100); EI-HRMS m/z calcd for [M+]
C25H22N4O6S 506.1260, found 506.1281.
(4-(2-(1H-Benzimidazol-2-yl)-5-thiazol-2-yl-phenylsulfamoyl)-
phenoxy)-acetic Acid Ethyl Ester (4d). Synthesized from amine
3d as described for 4b, yield 68% (FC, EtOAc/hexanes, 1:1). Mp
1
202-204 °C; H NMR (CD3OD/CDCl3 1:1, 400 MHz) δ 1.23 (t,
J ) 7.1 Hz, 3H), 4.20 (q, J ) 7.1 Hz, 2H), 4.59 (s, 2H), 6.76 (d,
J ) 9.0 Hz, 2H), 7.30-7.36 (m, 2H), 7.57 (d, J ) 3.3 Hz, 1H),
7.64-7.71 (m, 2H), 7.74 (d, J ) 9.0 Hz, 2H), 7.77 (dd, J ) 8.3,
1.8 Hz, 1H), 7.91 (d, J ) 3.3 Hz, 1H), 7.93 (d, J ) 8.3 Hz, 1H),
8.29 (d, J ) 1.7 Hz, 1H); 13C NMR (CD3OD/CDCl3 1:1, 100 MHz)
δ 14.2, 62.2, 65.5, 115.1, 119.0, 119.3, 120.8, 121.9, 123.8, 128.1,
129.9, 132.2, 135.3, 138.6, 144.2, 150.3, 161.7, 168.0, 169.1; IR
(KBr) 2923, 2852, 2265, 1775, 1758, 1594, 1577, 1497, 1406, 1330,
1151, 654, 573, 555 cm-1; MS (70 eV) m/z 534 ([M+], 48), 470
(13), 383 (24), 291 (100); EI-HRMS calcd for [M+] C26H22N4O5S2
534.1032, found 534.1023.
2-(1H-Benzimidazol-2-yl)-5-thiazol-2-yl-phenylamine (3d).
Synthesized from 2d as described for 3b, 88% yield. Mp dec
1
>230 °C; H NMR (CD3OD, 400 MHz) δ 7.12-7.16 (m, 2H),
7.21 (dd, J ) 8.2, 1.8 Hz, 1H), 7.37 (d, J ) 1.8 Hz, 1H), 7.47-
7.52 (m, 2H), 7.53 (d, J ) 3.3 Hz, 1H), 7.73 (d, J ) 8.2 Hz, 1H),
7.79 (d, J ) 3.3 Hz, 1H); 13C NMR (CD3OD, 100 MHz) δ 114.2,
114.7, 115.1 (br), 115.3, 120.1, 123.0, 128.9, 135.1, 139.9 (br),
143.6, 148.3, 152.3, 169.4; IR (KBr) 3321, 2500, 1617, 1452, 1286,
1262, 1138, 1060, 868, 806, 730, 658 cm-1; FAB-MS (thioglycerol)
m/z 293 ([M+], 100), 237 (13); FAB-HRMS calcd for [M+]
C16H13N4S 293.0861, found 293.0876.
(4-(2-(1H-Benzimidazol-2-yl)-5-methoxy-phenylsulfamoyl)-
phenoxy)-acetic Acid Ethyl Ester (4e). Synthesized from amine
3e as described for 4b, 36% yield (FC, hexanes/EtOAc, gradient
2:1 to 1:1). Mp 75-77 °C; 1H NMR (CDCl3, 400 MHz) δ 1.28 (t,
J ) 7.1 Hz, 3H), 3.71 (s, 3H), 4.25 (q, J ) 7.1 Hz, 2H), 4.57 (s,
2H), 6.53 (d, J ) 8.9 Hz, 2H), 6.57 (d, J ) 2.5 Hz, 1H), 7.20 (d,
J ) 2.5 Hz, 1H), 7.22-7.26 (m, 2H), 7.42 (d, J ) 8.7 Hz, 1H),
7.50 (br, 2H), 7.52 (d, J ) 8.9 Hz, 2H), 7.75 (br, 1H), 9.88 (br,
1H); 13C NMR (CDCl3, 100 MHz) δ 14.2, 29.8, 55.5, 61.9, 64.8,
106.8, 110.5, 110.7 (br), 111.0, 114.0, 118.9 (br), 122.9 (br), 127.4,
128.9, 131.3, 132.8 (br), 138.7, 142.2 (br), 149.8, 160.4, 161.0,
168.2; IR (KBr) 3367, 2925, 1754, 1596, 1582, 1497, 1409, 1274,
1200, 1143, 1094, 1082, 585 cm-1; MS (70 eV) m/z 481 ([M+],
46), 330 (21), 238 (100); EI-HRMS calcd for [M+] C24H23N3O6S
481.1308, found 481.1297.
2-(4-Methoxy-2-amino-phenyl)-1H-benzimidazole (3e). Syn-
thesized from 2e as described for 3b, 99% yield (FC, hexanes/
1
EtOAc, gradient 3:1 to 2:1). Mp 140-143 °C; H NMR (DMSO-
d6, 400 MHz) δ 3.74 (s, 3H), 6.27 (dd, J ) 8.7, 2.4 Hz, 1H), 6.37
(d, J ) 2.4 Hz, 1H), 7.11-7.18 (m, 2H), 7.32 (br, 2H), 7.45 (d, J
) 7.3 Hz, 1H), 7.59 (d, J ) 7.3 Hz, 1H), 7.76 (d, J ) 8.7 Hz, 1H),
12.47 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 54.8, 99.2, 102.7,
103.7, 110.3, 117.6, 121.0, 121.7, 128.4, 133.2, 142.8, 149.6, 149.7,
152.4, 160.9; IR (KBr) 3201, 1627, 1614, 1502, 1447, 1431, 1251,
1214, 1026, 735 cm-1; MS (70 eV) m/z 239 ([M+], 100), 210 (7),
196 (32); EI-HRMS calcd for [M+] C14H13N3O 239.1058, found
239.1056.
Imidazole derivatives 4f-l were synthesized according to
procedure A.
4-(2(1H-Benzimidazol-2-yl)-4-methoxy-phenylsulfamoyl)-phe-
noxy-acetic Acid Ethyl Ester (4f). Starting from 50 mg of aldehyde
9f (0.13 mmol) and 1,2-phenylenediamine (15 mg, 0.13 mmol),
benzimidazole 4f was obtained in 74% yield (FC, EtOAc/hexanes,
2-(4-(N-(2-(1H-Benzimidazol-2-yl)-5-cyanophenyl)sulfamoyl)-
phenoxy)acetic Acid Ethyl Ester (4b). To a solution of amine 3b
(35 mg, 0.149 mmol) in anhydrous pyridine (2 mL) was added
(4-chlorosulfonyl-phenoxy)-acetic acid ethyl ester14 10 (50 mg,
0.179 mmol). After stirring at room temperature for 18 h, the
reaction mixture was poured into aqueous 1 M HCl (20 mL), and
the product was extracted twice with ethyl acetate. The combined
organic extracts were dried with anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified on silica gel (EtOAc/hexanes, gradient 1:3 to 1:1) providing
25 mg (0.053 mmol, 35%) of sulfonamide 4b as a tan solid. Mp
1
gradient 1:4 to 1:2). Mp 76-78 °C; H NMR (CDCl3, 400 MHz)
δ 1.38 (t, J ) 7.1 Hz, 3H), 3.83 (s, 3H), 4.36 (q, J ) 7.1 Hz, 2H),
4.65 (s, 2H), 6.13 (d, J ) 8.9, 2H), 6.89 (d, J ) 2.9 Hz, 1H), 6.95
(d, J ) 8.9 Hz, 2H), 6.97 (dd, J ) 8.9, 2.9 Hz, 1H), 7.29-7.34
(m, 2H), 7.43 (br, 1H), 7.71 (d, J ) 8.9, 1H), 7.78 (br, 1H), 9.76
(s, 1H), 10.68 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.2, 55.6,
62.0, 64.4, 111.2 (br), 112.0, 113.3, 115.6, 119.1 (br), 122.4, 122.6
(br), 123.5 (br), 126.8, 128.5, 129.4, 130.0, 133.2 (br), 133.6, 149.1,
157.0, 160.0, 168.7; IR (KBr) 3338, 2936, 1757, 1735, 1595, 1502,
1325, 1279, 1214, 1158, 1094, 831, 566 cm-1; MS (70 eV) m/z
481 ([M+], 38), 238 (100); EI-HRMS calcd for [M+] C24H23N3O6S
481.1307, found 481.1320.
1
208-210 °C; H NMR (CDCl3, 400 MHz) δ 1.34 (t, J ) 7.1 Hz,
3H), 4.31 (q, J ) 7.1 Hz, 2H), 4.65 (s, 2H), 6.45 (d, J ) 9.0 Hz,
2H), 7.34-7.40 (m, 4H), 7.43 (dd, J ) 8.1 Hz, 1.6 Hz, 1H), 7.50
(br, 1H), 7.58 (d, J ) 8.0 Hz, 1H), 7.83 (br, 1H), 8.05 (d, J ) 1.5
Hz, 1H), 9.93 (s, 1H), 12.18 (s, 1H); 13C NMR (CDCl3/acetone-d6,
100 MHz) δ 13.7, 61.2, 64.7, 112.9, 114.2, 117.4, 119.9, 122.3,
123.3 (br), 125.9, 126.9, 128.7, 131.2, 137.6, 147.9, 160.6, 167.4;
IR (KBr) 3313, 3068, 2983, 2232, 1757, 1595, 1497, 1403, 1277,
1226, 1155, 1095, 555 cm-1; MS (70 eV) m/z 476.1 ([M+], 39),
412.1 (35), 325.1 (37), 233.1(100); EI-HRMS calcd for [M+]
C24H20N4O5S 476.1154, found 476.1156.
2-(4-(N-(2-(1H-Benzimidazol-2-yl)-4-(dimethylamino)phenyl)-
sulfamoyl)phenoxy)acetic Acid Ethyl Ester (4g). Starting from
131 mg of aldehyde 9g (0.32 mmol) and 1,2-phenylenediamine (26
mg, 0.20 mmol), benzimidazole 4g was obtained in 50% yield (FC,
EtOAc/hexanes, gradient 1:3 to 1:1). Mp 82-84 °C; 1H NMR (CD3-
OD, 400 MHz) δ 1.17 (t, J ) 7.1 Hz, 3H), 2.89 (s, 6H), 4.13 (q,
J ) 7.1 Hz, 2H), 4.43 (s, 2H), 6.40 (d, J ) 8.8 Hz, 2H), 6.73 (dd,
4794 J. Org. Chem., Vol. 72, No. 13, 2007

ESIPT in 2-(2′-Arylsulfonamidophenyl)benzimidazoles
J ) 9.3, 2.7 Hz, 1H), 6.97 (d, J ) 3.3 Hz, 1H), 7.20-7.26 (m,
4H), 7.48 (d, J ) 9.3 Hz, 1H), 7.55 (br, 2H); 13C NMR (CDCl3,
100 MHz) δ 14.2, 40.4, 61.8, 64.3, 109.7, 113.2, 114.1, 122.5, 122.6
(br), 125.1, 126.8, 128.5, 130.0, 148.1, 150.1, 159.8, 168.6; IR
(KBr) 3318, 2981, 2904, 2806, 1752, 1735, 1595, 1510, 1497, 1279,
1215, 1158, 1094 cm-1; MS (70 eV) m/z 494.2 ([M+], 18), 251.2
(100); EI-HRMS calcd for [M+] C25H26N4O5S 494.1624, found
494.1615.
2-(4-(N-(2-(5(6)-Cyano-1H-benzimidazol-2-yl)-4-methoxyphe-
nyl)sulfamoyl)phenoxy)acetic Acid Ethyl Ester (4h). Starting
from 72 mg of aldehyde 9f (0.183mmol) and 3,4-diaminobenzoni-
trile (26 mg, 0.20 mmol), benzimidazole 4h was obtained in 53%
yield (FC, EtOAc/hexanes, gradient 1:3 to 1:1). Mp 72-74 °C;
1H NMR (CD3OD, 400 MHz) δ 1.23 (t, J ) 7.1 Hz, 3H), 3.85
(s, 3H), 4.19 (q, J ) 7.1 Hz, 2H), 4.57 (s, 2H), 6.57 (d, J ) 9.0
Hz, 2H), 7.07 (dd, J ) 9.0, 2.9 Hz, 1H), 7.29-7.34 (m, 3H),
7.60 (dd, J ) 8.3, 1.5 Hz, 1H), 7.65 (d, J ) 9.0 Hz, 1H), 7.72 (br,
1H), 8.06 (br, 1H); 13C NMR (acetone-d6, 400 MHz) mixture
of two tautomers (ratio 2:3) δ 14.4, 56.0, 61.6, 65.5, 106.5,
107.0, 112.6, 113.4, 114.9, 116.8, 118.2, 118.5, 119.3, 119.9, 120.6,
124.3, 124.8, 126.7, 127.5, 129.5, 129.6, 131.5, 131.6, 132.1, 132.2,
133.8, 137.0, 142.6, 145.8, 153.4, 154.1, 157.2, 161.7, 168.3; IR
(KBr) 3283, 2936, 2223, 1752, 1735, 1594, 1503, 1318, 1293, 1214,
1159, 1094, 832 cm-1; MS (70 eV) m/z 506.1 ([M+], 47), 263.1
(100); EI-HRMS calcd for [M+] C25H22N4O6S 506.1260, found
506.1251.
119.4, 123.4, 124.3, 129.9, 132.0, 132.8, 134.7, 143.1, 145.4, 150.5,
151.6, 162.1, 168.7; IR (KBr) 3372, 2922, 1731, 1597, 1499, 1482,
1429, 1328, 1279, 1250, 1161, 1098, 1037, 916, 769 cm-1; MS
(70 eV) m/z 495 ([M+], 32), 252 (100); EI-HRMS calcd for [M+]
C24H21N3O7S 495.1100, found 495.1089.
General Procedure B: Hydrolysis of Esters 4 to Acids 5. A
solution of the corresponding ester (0.085 mmol) and LiOH‚H2O
(87 mg) in 1.5 mL of MeOH/water/THF (1:1:2) was heated at reflux
for 3 h. After removing the organic solvents under reduced pressure,
the residue was acidified with aqueous HCl (1 M) until the acid
precipitated. The product was filtered off, washed with water, and
dried in vacuum to give the free acid.
2-(4-(N-(2-(1H-Benzimidazol-2-yl)-5-cyanophenyl)sulfamoyl)-
phenoxy)acetic Acid (5b). From 4b, 92% yield. Mp >210 °C (dec);
1H NMR (CD3OD, 400 MHz) δ 4.60 (s, 2H), 6.80 (d, J ) 8.9 Hz,
2H), 7.33-7.38 (m, 2H), 7.51 (dd, J ) 8.2 Hz, 1.3 Hz, 1H), 7.62
(d, J ) 8.9 Hz, 2H), 7.65-7.69 (m, 2H), 7.97 (d, J ) 8.2 Hz, 1H),
8.00 (d, J ) 1.4 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 65.7,
111.7, 114.5, 115.1, 118.7, 121.0, 121.5, 122.6, 128.1, 128.5, 131.3,
133.6, 137.5, 143.0, 150.2, 160.4, 170.2; IR (KBr) 3071, 2922,
2851, 2233, 1735, 1594, 1581, 1570, 1497, 1401, 1333, 1274, 1155,
1094, 566, 552 cm-1; ESI-MS m/z 449.0918 ([M + H]+); ESI-
HRMS calcd for [M + H]+ C22H17N4O5S 449.0914, found
449.0913.
2-(4-(N-(5(6)-Cyano-2-(5-methoxy-1H-benzoimidazol-2-yl)-
phenyl)sulfamoyl)phenoxy)acetic Acid (5c). From 4c, 85% yield.
1
2-(4-(N-(2-(5(6)-Cyano-1H-benzimidazol-2-yl)phenyl)sulfamoyl)-
phenoxy)acetic Acid Ethyl Ester (4i). Starting from 150 mg of
aldehyde 9i (0.41 mmol) and 3,4-diaminobenzonitrile (60 mg, 0.41
mmol), benzimidazole 4i was obtained in 50% yield (FC, EtOAc/
Mp 112-115 °C; H NMR (CD3OD, 400 MHz) δ 3.89 (s, 3H),
4.61 (s, 2H), 6.82 (d, J ) 9.0 Hz, 2H), 6.98 (dd, J ) 8.9 Hz, 2.4
Hz, 1H), 7.12 (d, J ) 2.4 Hz, 1H), 7.51 (dd, J ) 8.2 Hz, 1.6 Hz,
1H), 7.58 (d, J ) 9.1, 1H), 7.62 (d, J ) 9.0 Hz, 2H), 7.92 (d, J )
8.2 Hz, 1H), 8.00 (d, J ) 1.3 Hz, 1H); 13C NMR (DMSO-d6, 100
MHz) δ 55.6, 64.9, 96.7, 111.8, 113.6, 114.9, 118.1, 120.1, 121.2,
126.0, 128.0, 128.6, 130.8, 137.9, 148.1, 156.6, 161.1, 169.3; IR
(KBr) 2924, 2851, 2231, 1735, 1636, 1594, 1570, 1496, 1405, 1272,
1157, 1094, 833, 554 cm-1; MS (70 eV) m/z 478 ([M+], 8), 263.1
(100); EI-HRMS calcd for [M+] C23H18N4O6S 478.0947, found
478.0946.
1
hexanes, gradient 1:2 to 1:1). Mp 169-171 °C; H NMR (CD3-
OD, 400 MHz) δ 1.21 (t, J ) 7.1 Hz, 3H), 4.17 (q, J ) 7.1 Hz,
2H), 4.61 (s, 2H), 6.72 (d, J ) 9.0 Hz, 2H), 7.22 (ddd, J ) 8.5,
7.5, 1.1 Hz, 1H), 7.44 (ddd, J ) 8.5, 7.5, 1.5 Hz, 1H), 7.54 (d, J
) 9.0 Hz, 2H), 7.58 (dd, J ) 8.4, 1.5 Hz, 1H), 7.73 (br, 1H), 7.75
(dd, J ) 8.3, 1.0 Hz, 1H), 7.82 (d, J ) 7.9, 1.4 Hz, 1H), 8.02 (br,
1H); 13C NMR (CD3OD, 100 MHz) δ 14.1, 61.1, 64.9, 105.1 (br),
113.2 (br), 115.7, 119.5, 119.9, 124.0, 127.0 (br), 128.2, 129.2,
131.2, 132.0, 136.7 (br), 137.5, 141.4 (br), 144.5 (br), 153.4 (br),
161.2, 168.2; IR (KBr) 3332, 2985, 2220, 1758, 1740, 1594, 1496,
1315, 1154, 1095, 921, 572 cm-1; MS (70 eV) m/z 476.2 ([M+],
36), 412.1 (32), 325.1 (34), 233.1 (100); EI-HRMS calcd for [M+]
C24H20N4O5S 476.1154, found 476.1135.
(4-(2-(1H-Benzimidazol-2-yl)-5-thiazol-2-yl-phenylsulfamoyl)-
phenoxy)-acetic Acid (5d). From 4d, 71% yield. Mp >300 °C;
1H NMR (CD3OD, 400 MHz) δ 4.43 (s, 2H), 6.73 (d, J ) 9.0 Hz,
2H), 7.30-7.36 (m, 2H), 7.58 (d, J ) 9.0 Hz, 2H), 7.64-7.71 (m,
3H), 7.78 (dd, J ) 8.1, 1.8 Hz, 1H), 7.89-7.95 (m, 2H), 8.33 (d,
J ) 1.7 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 66.0, 114.9,
115.9, 117.5, 121.5, 123.1, 128.6, 130.9, 134.4, 139.0, 144.3, 150.2,
161.7, 166.0, 169.6; IR (KBr) 3401 (br), 1612, 1595, 1577, 1496,
1426, 1324, 1247, 1162, 1095, 1065, 576 cm-1; FAB-MS (thioglyc-
erol) m/z 507 ([M+], 24), 349.1 (26), 327 (28), 311 (62), 279 (58),
237 (100); FAB-HRMS calcd for [M+] C24H19N4O5S2 507.0797,
found 507.0835.
(4-[2-(1H-Benzimidazol-2-yl)-5-methoxy-phenylsulfamoyl]-
phenoxy)-acetic Acid (5e). From 4e, 88% yield. Mp 128-131 °C;
1H NMR (CD3OD, 400 MHz) δ 3.72 (s, 3H), 4.52 (s, 2H), 6.67
(dd, J ) 8.8, 2.5 Hz, 1H), 6.73 (d, J ) 8.9 Hz, 2H), 7.09 (d, J )
2.5 Hz, 1H), 7.22-7.26 (m, 2H), 7.54-7.58 (m, 4H), 7.67 (d, J )
8.8 Hz, 1H); 13C NMR (CD3OD, 100 MHz) δ 56.0, 65.9, 107.8,
111.3, 111.8, 115.35, 115.42, 124.1, 129.8, 130.0, 132.2, 137.9,
139.8, 151.5, 162.5, 162.6, 171.9; IR (KBr) 2934, 1735, 1629, 1611,
1594, 1581, 1497, 1302, 1261, 1230, 1155, 1092 cm-1; MS (70
eV) m/z 454 ([M + H+] 100); ESI-TOF-HRMS calcd for [M +
H+] C22H20N3O6S 454.1067, found 454.1097.
2-(4-(N-(2-(5(6)-Methoxy-1H-benzimidazol-2-yl)phenyl)sulfa-
moyl)phenoxy)acetic Acid Ethyl Ester (4k). Starting from 200
mg of aldehyde 9i (0.55 mmol) and 1,2-diamino-4-methoxybenzene
(80 mg, 0.58 mmol), benzimidazole 4k was obtained in 60% yield
(FC, EtOAc/hexanes, gradient 1:3 to 1:1). Mp 72-74 °C; 1H NMR
(CD3OD, 400 MHz) δ 1.19 (t, J ) 7.1 Hz, 3H), 3.85 (s, 3H), 4.16
(q, J ) 7.1 Hz, 2H), 4.58 (s, 2H), 6.69 (d, J ) 9.0 Hz, 2H), 6.91
(dd, J ) 8.8, 2.4 Hz, 1H), 7.09 (d, J ) 2.2 Hz, 1H), 7.16 (ddd, J
) 8.5, 7.8, 1.2 Hz, 1H), 7.33 (ddd, J ) 8.3, 7.4, 1.5 Hz, 1H), 7.49-
7.54 (m, 3H), 7.69-7.75 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ
14.0, 55.6, 61.8, 64.7, 113.0 (br), 114.1, 116.1, 118.2, 121.5, 124.1,
126.2, 128.9, 130.2, 131.2, 136.8, 149.4 (br), 156.8 (br), 160.6,
168.4; IR (KBr) 3325, 2938, 1752, 1497, 1333, 1283, 1200, 1160,
1148, 1094, 570 cm-1; MS (70 eV) m/z 481.2 ([M+], 38), 238
(100); EI-HRMS calcd for [M+] C24H23N3O6S 481.13076, found
481.13063.
2-(4-(N-(6-(1H-Benzimidazol-2-yl)benzo[1,3]dioxol-5-yl)sulfa-
moyl)phenoxy)acetic Acid Ethyl Ester (4l). Starting from 51 mg
of aldehyde 9l (0.12 mmol) and 1,2-phenylenediamine (14 mg, 0.12
mmol), benzimidazole 4l was obtained in 44% yield (FC, EtOAc/
hexanes, gradient 1:3 to 1:1). Mp 168-170 °C; 1H NMR (acetone-
d6, 400 MHz) δ 1.17 (t, J ) 7.1, 3H), 4.15 (q, J ) 7.1 Hz, 2H),
4.70 (s, 2H), 6.09 (s, 2H), 6.80 (d, J ) 8.6 Hz, 2H), 7.28-7.31
(m, 2H), 7.32 (s, 1H), 7.40 (s, 1H), 7.50 (br, 1H), 7.60 (d, J ) 8.6
Hz, 2H), 7.76 (br, 1H), 11.78 (br, 1H); 13C NMR (acetone-d6, 100
MHz) δ 14.4, 61.7, 65.7, 102.8, 103.2, 106.6, 111.2, 112.0, 115.4,
2-(4-(N-(2-(1H-Benzimidazol-2-yl)-4-methoxyphenyl)sulfamoyl)-
phenoxy)acetic Acid (5f). From 4f, 96% yield. Mp 187-190 °C;
1H NMR (DMSO-d6, 400 MHz) δ 3.81 (s, 3H), 4.64 (s, 2H), 6.82
(d, J ) 8.9 Hz, 2H), 7.06 (dd, J ) 9.0, 2.8 Hz, 1H), 7.29-7.34
(m, 2H), 7.54 (d, J ) 8.9 Hz, 2H), 7.59 (d, J ) 8.9 Hz, 1H), 7.59
(d, J ) 2.9 Hz, 1H), 7.68 (br, 2H); 13C NMR (DMSO-d6, 100 MHz)
δ 55.6, 64.5, 109.4, 111.9, 114.5, 114.6, 116.8, 117.6, 121.4, 123.3
(br), 128.5, 130.0, 130.6, 149.9, 155.2, 160.6, 169.1; IR (KBr) 3067,
2928, 2853, 2736, 1735, 1594, 1582, 1500, 1330, 1233, 1159, 1095,
J. Org. Chem, Vol. 72, No. 13, 2007 4795

Henary et al.
835 cm-1; MS (70 eV) m/z 453 ([M+], 18), 238 (100); EI-HRMS
calcd for [M+] C22H19N3O6S453.0994, found 453.1009.
The combined organic extracts were dried with MgSO4 and
concentrated under reduced pressure. The residue was purified on
silica gel (FC, gradient hexanes/EtOAc, 2:1 to 1:1) providing
243 mg of aldehyde 9f as a tan solid (0.62 mmol, 45%). Mp 133-
2-(4-(N-(2-(1H-Benzimidazol-2-yl)-4-(dimethylamino)phenyl)-
sulfamoyl)phenoxy)acetic Acid (5g). From 4g, 67% yield. Mp
1
1
>230 °C; H NMR (CD3OD, 400 MHz) δ 2.93 (s, 6H), 4.28 (s,
135 °C; H NMR (CDCl3, 400 MHz) δ 1.28 (t, J ) 7.1 Hz, 3H),
2H), 6.58 (d, J ) 9.3 Hz, 2H), 6.81 (d, J ) 7.7 Hz, 1H), 7.23-
7.32 (m, 5H), 7.43 (d, J ) 8.8 Hz, 1H), 7.59-7.63 (m, 2H); 13C
NMR (DMSO-d6, 100 MHz) δ 41.4, 67.6, 112.0, 113.8, 116.7,
118.2, 120.5, 121.0, 127.6, 128.6, 143.1, 153.8, 159.7, 171.0; IR
(KBr) 3436, 1686, 1648, 1444, 1384, 1212, 1140, 846, 804, 726
cm-1; MS (70 eV) m/z 466.1 ([M+], 9), 252.2 (100), 238.1 (100),
184 (44), 125 (46); EI-HRMS calcd for [M+] C23H22N4O5S
466.1311, found 466.1326.
2-(4-(N-(2-(5(6)-Cyano-1H-benzimidazol-2-yl)-4-methoxyphe-
nyl)sulfamoyl)phenoxy)acetic Acid (5h). From 4h, 49% yield. Mp
236-239 °C; 1H NMR (DMSO-d6, 400 MHz) δ 3.85 (s, 3H), 4.54
(s, 2H), 6.57 (d, J ) 9.0 Hz, 2H), 7.08 (dd, J ) 9.0, 2.9 Hz, 1H),
7.30 (d, J ) 9.0 Hz, 2H), 7.32 (d, J ) 2.9 Hz, 1H), 7.61 (dd, J )
8.4, 1.5 Hz, 1H), 7.65 (d, J ) 9.0 Hz, 1H), 7.73 (br, 1H), 8.05 (br,
1H); 13C NMR (DMSO-d6, 100 MHz) δ 55.6, 64.6, 104.8, 112.4,
114.4, 117.6, 119.5, 122.5, 126.3, 128.5, 130.0, 130.2, 152.8, 155.5,
160.7, 169.1; IR (KBr) 3293 (br), 3078, 2927, 2224, 1735, 1592,
1502, 1339, 1240, 1158, 1095, 835, 570 cm-1; ESI-MS m/z 479.10
([M + H+]); ESI-HRMS calcd for [M + H+] C23H19N4O6S
479.1020, found 479.1053.
2-(4-(N-(2-(5(6)-Cyano-1H-benzimidazol-2-yl)phenyl)sulfamoyl)-
phenoxy)acetic Acid (5i). From 4i, 68% yield. Mp 279-281 °C;
1H NMR (DMSO-d6, 400 MHz) δ 4.69 (s, 2H), 6.92 (d, J ) 8.9
Hz, 2H), 7.26 (td, J ) 7.4, 1.0 Hz, 1H), 7.50 (td, J ) 7.4, 1.4 Hz,
1H), 7.63-7.62 (m, 4H), 7.81 (br, 1H), 8.05 (d, J ) 7.8 Hz, 1H),
8.24 (br, 1H), 12.71 (br, 1H); 13C NMR (DMSO-d6, 100 MHz) δ
64.6, 104.8, 114.8, 115.3, 119.0, 119.5, 123.5, 126.3, 126.4, 127.9,
128.8, 130.5, 131.6, 137.1, 153.0, 161.0, 169.2; IR (KBr) 3300,
2923, 2220, 1741, 1594, 1581, 1492, 1339, 1251, 1160, 1095, 576
cm-1; MS (70 eV) m/z 448 ([M+], 10), 234.1 (100); EI-HRMS
calcd for [M+] C22H16N4O5S 448.0841, found 448.0867.
2-(4-(N-(2-(5(6)-Methoxy-1H-benzimidazol-2-yl)phenyl)sulfa-
moyl)phenoxy)acetic Acid (5k). From 4k, 90% yield. Mp 133-
135 °C; 1H NMR (CD3OD, 400 MHz) δ 3.83 (s, 3H), 4.53 (s, 2H),
6.68 (d, J ) 9.0 Hz, 2H), 6.91 (dd, J ) 8.8, 2.4 Hz, 1H), 7.08 (d,
J ) 2.3, 1H), 7.17 (td, J ) 7.6, 1.2 Hz, 1H), 7.33 (td, J ) 7.5, 1.5
Hz, 1H), 7.46-7.51 (m, 3H), 7.61 (dd, J ) 9.2, 1.0 Hz, 1H), 7.71
(dd, J ) 7.9, 1.4 Hz, 1H); 13C NMR (CD3OD, 100 MHz) δ 56.2,
65.9, 97.5, 114.2, 115.3, 116.9, 119.9, 123.1, 125.6, 128.1, 130.0,
131.3, 132.2, 133.6, 137.8, 138.3, 150.6, 158.3, 162.4, 171.8; IR
(KBr) 3068, 2943, 1636, 1595, 1492, 1403, 1332, 1302, 1274, 1233,
1155, 824, 573 cm-1; MS (70 eV) m/z 453.2 ([M+], 26), 238 (100);
EI-HRMS calcd for [M+] C22H19N3O6S 453.0995, found 453.1032.
2-(4-(N-(6-(1H-Benzimidazol-2-yl)benzo[1,3]dioxol-5-yl)sulfa-
moyl)phenoxy)acetic Acid (5l). From 4l, 81% yield. Mp
>128 °C (dec); 1H NMR (CD3OD, 400 MHz) δ 4.34 (s, 2H), 6.00
(s, 2H), 6.57 (d, J ) 9.0 Hz, 2H), 7.18 (s, 1H), 7.22 (s, 1H), 7.23-
7.28 (m, 2H), 7.35 (d, J ) 9.0 Hz, 2H), 7.55-7.58 (m, 2H); 13C
NMR (DMSO-d6, 100 MHz) δ 67.0, 101.6, 102.6, 106.6, 110.6,
114.9, 115.0, 123.2, 128.8, 130.0, 133.5, 144.3, 149.5, 151.0, 162.3,
171.1; IR (KBr) 3068, 2923, 1595, 1503, 1484, 1256, 1226, 1157,
1037 cm-1; MS (70 eV) 467 ([M+], 18), 252.1 (100); EI-HRMS
m/z calcd for [M+] C22H17N3O7S 467.0787, found 467.0791.
4-(2-Formyl-4-methoxy-phenylsulfamoyl)-phenoxy]-acetic Acid
Ethyl Ester (9f). A solution of 5-methoxy-2-nitrobenzaldehyde38
1f (250 mg, 1.38 mmol) in methanol (15 mL) was hydrogenated at
atmospheric pressure in the presence of Pd on activated carbon
(10 wt %, 50 mg) as catalyst. After completion of the reaction (3
h) the reaction mixture was filtered through a pad of Celite and
concentrated under reduced pressure. The crude amine 6f was
immediately dissolved in anhydrous pyridine (4 mL), and ethyl (4-
chlorosulfonyl-phenoxy)-acetate14 10 (770 mg, 2.76 mmol) was
added. The mixture was stirred at room temperature for 3 h, diluted
with water (10 mL), and extracted twice with ethyl acetate (20 mL).
3.81 (s, 3H), 4.25 (q, J ) 7.1 Hz, 2H), 4.62 (s, 2H), 6.87 (d, J )
8.9 Hz, 2H), 7.05 (d, J ) 3.0 Hz, 1H), 7.09 (dd, J ) 9.0, 3.3 Hz,
1H), 7.67 (d, J ) 9.0 Hz, 1H), 7.73 (d, J ) 8.9, 2H), 9.73 (s, 1H),
10.19 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.2, 55.7, 61.7,
65.2, 114.6, 119.2, 121.0, 121.9, 123.4, 129.2, 131.7, 132.6, 155.5,
160.9, 167.6, 194.3; IR (KBr) 2924, 1735, 1654, 1593, 1580, 1497,
1271, 1163, 1149, 1095 cm-1; MS (70 eV) m/z 393 ([M+], 5), 241
(11), 129 (100); EI-HRMS calcd for [M+] C18H19NO7S 393.0882,
found 393.0869.
2-(4-(N-(4-(Dimethylamino)-2-formylphenyl)sulfamoyl)phe-
noxy)acetic Acid Ethyl Ester (9g). A solution of 2-nitro-5-
dimethylamino-benzaldehyde 1g (255 mg, 1.3 mmol) in methanol
(50 mL) was hydrogenated at room temperature and ambient
pressure in the presence of Pd on activated carbon as catalyst (60
mg, 5 wt % Pd). After completion of the reaction (TLC), the catalyst
was filtered off through a pad of Celite, and the solvent was
evaporated under reduced pressure. The crude amine (227 mg) was
immediately dissolved in pyridine (3 mL), and (4-chlorosulfonyl-
phenoxy)-acetic acid ethyl ester14 10 (462 mg, 1.66 mmol) was
added. After stirring for 2 h at room temperature, the reaction
mixture was poured into 1 M aqueous HCl (10 mL), and the product
was extracted twice with ethyl acetate. The combined organic
extracts were dried with MgSO4, filtered, and concentrated under
reduced pressure. The crude product was recrystallized from diethyl
ether to give 146 mg (0.36 mmol) of aldehyde 9g as a tan solid
1
(28% total yield). Mp 85-87 °C; H NMR (CDCl3, 400 MHz) δ
1.27 (t, J ) 7.1 Hz, 3H), 2.94 (s, 6H), 4.25 (q, J ) 7.1 Hz, 2H),
4.61 (s, 2H), 6.80 (d, J ) 3.3 Hz, 1H), 6.84 (d, J ) 9.3 Hz, 2H),
6.88 (dd, J ) 8.8, 3.3 Hz, 1H), 7.57 (d, J ) 8.8 Hz, 1H), 7.67 (d,
J ) 8.8 Hz, 2H), 9.70 (s, 1H), 9.85 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 14.1, 40.5, 61.6, 65.1, 114.4, 118.1, 119.0, 121.7, 124.1,
128.1, 129.1, 131.8, 147.1, 160.7, 167.6, 195.1; IR (KBr) 3206,
2987, 2812, 1762, 1663, 1591, 1507, 1364, 1204, 1152, 1094, 921,
563 cm-1; MS (70 eV) m/z 406.2 ([M+], 68), 163.1 (100), 135.1
(100); EI-HRMS calcd for [M+] C19H22N2O6S 406.1199, found
406.1197.
2-(4-(N-(6-Formylbenzo[1,3]dioxol-5-yl)sulfamoyl)phenoxy)-
acetic Acid Ethyl Ester (9l). A solution of 6-nitropiperonal (1.0
g, 5.12 mmol) in ethanol (30 mL) was hydrogenated at room
temperature and ambient pressure in the presence of Pd on activated
carbon (200 mg, 5% Pd) as catalyst. After completion of the reaction
(2 h), the catalyst was filtered through a pad of Celite, and the
filtrate was concentrated under reduced pressure providing 885 mg
of crude 7l as a yellow solid. A solution of crude amine 7l (885
mg) and (4-chlorosulfonyl-phenoxy)acetic acid ethyl ester14 10 (1.79
g, 6.4 mmol) in 22 mL of pyridine was stirred at room temperature
for 48 h. The mixture was poured into 1 N HCl and extracted twice
with ethyl acetate. The combined organic extracts were dried with
anhydrous MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by silica FC (EtOAc/hexanes,
gradient 1:2 to 1:1) to give 584 mg of intermediate 8l as a yellowish
solid. A mixture of intermediate 8l (576 mg, 1.41 mmol) and MnO2
(1.6 g, 18.4 mmol) in 5 mL of CH2Cl2 was stirred overnight at
room temperature. The reaction mixture was filtered through a pad
of Celite and concentrated under reduced pressure to give aldehyde
9l as a pale yellow solid (378 mg, 0.928 mmol, 18% yield over
three steps). Mp 166-168 °C; 1H NMR (CDCl3, 400 MHz) δ 1.28
(t, J ) 7.1 Hz, 3H), 4.26 (q, J ) 7.1 Hz, 2H), 4.64 (s, 2H), 6.04
(s, 2H), 6.90 (d, J ) 9.0 Hz, 2H), 6.91 (s, 1H), 7.27 (s, 1H), 7.79
(d, J ) 9.0 Hz, 2H), 9.57 (s, 1H), 11.07 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 14.3, 61.8, 65.2, 99.6, 102.5, 112.8, 114.8, 115.9,
129.3, 131.8, 137.9, 143.5, 153.7, 161.1, 167.7, 192.2; IR (KBr)
2913, 1735, 1641, 1594, 1487, 1361, 1283, 1245, 1225, 1151, 1093,
4796 J. Org. Chem., Vol. 72, No. 13, 2007

ESIPT in 2-(2′-Arylsulfonamidophenyl)benzimidazoles
1038, 574 cm-1; MS (70 eV) 407 ([M+], 37), 164 (100); EI-HRMS
m/z calcd for [M+] C18H17NO8S 407.0675, found 407.0662.
Steady-State Absorption and Fluorescence Spectroscopy. All
sample solutions were filtered through 0.45 µm Teflon membrane
filters to remove interfering dust particles or fibers. UV-vis
absorption spectra were recorded at 25 °C using a UV-vis
spectrometer with a constant-temperature accessory. Steady-state
emission and excitation spectra were recorded with a fluorimeter
and FELIX software. For all measurements the path length was 1
cm with a cell volume of 3.0 mL. The fluorescence spectra have
been corrected for the spectral response of the detection system
(emission correction file provided by the instrument manufacturer)
and for the spectral irradiance of the excitation channel (via
calibrated photodiode). Quantum yields were determined using
quinine sulfate dihydrate in 0.5 M H2SO4 as fluorescence standard
(ΦF ) 0.54 ( 0.05).42
Determination of pKa Values. A combination microelectrode
electrode was calibrated for -log[H3O+] by titration of a standard-
ized HCl solution (0.1 N volumetric standard) with KOH (0.1 N
volumetric standard) at 25 °C and 0.1 M ionic strength (KCl). The
end point, electrode potential, and slope were determined by Gran’s
method43 as implemented in the software GLEE.44 The calibration
procedure was repeated three times prior to each pKa value
determination. The electrode potentials were measured with a pH/
ion analyzer, and the potentials were reproducible with (0.1 mV
accuracy. A series of UV-vis spectra of each fluorophore were
acquired for which -log[H3O+] was varied between 3 and 10. The
emf of each solution was directly measured in the quartz cell and
converted to -log[H3O+] using E° and slope as obtained from the
electrode calibration procedure. The raw spectral and emf data were
then processed via nonlinear least-squares fit analysis using the
SPECFIT software package,45 providing deconvoluted spectra for
each species present as well as the corresponding acidity constants
for all involved protonation equilibria.
Acknowledgment. We thank Dr. Leslie Gelbaum for
acquisition of the 2D NMR data and David Bostwick for mass
spectral characterization of all compounds. This work was
supported by the National Institutes of Health (DK68096) and
the Georgia Institute of Technology.
Supporting Information Available: 1H and 13C NMR spectra
for compounds 1b, 1d, 1e-1g, 2b-2e, 3b-3e, 4b-4l, 5b-5l, 9f,
9g, 9l. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070433L
(42) Demas, J. N.; Crosby, G. A. J. Phys. Chem. 1971, 75, 991-1024.
(43) Gran, G. Analyst 1951, 77, 661.
(44) Gans, P.; O’Sullivan, B. Talanta 2000, 51, 33-37.
(45) Binstead, R. A.; Zuberbu¨hler, A. D. SPECFIT, v. 3.0.27; Spectrum
Software Associates: Marlborough, MA, 2001.
J. Org. Chem, Vol. 72, No. 13, 2007 4797