Bis-8-hydroxyquinoline-armed diazatrithia-15-crown-5 and diazatrithia-16-crown-5 ligands: Possible fluorophoric metal ion sensors

Article abstract of DOI:10.1021/jo0017584

The synthesis and preliminary photophysical properties of a series of diazatrithia-15-crown-5 and diazatrithia-16-crown-5 ligands containing two 8-hydroxyquinoline sidearms are reported. The ligands were prepared by a two-step process. First, diazatrithiacrown ethers 11 and 12 were prepared by treating bis(α-chloroamide) 5 with various dimercaptans followed by reduction using a boron-THF complex. Hydroxymethyl-substituted macrocycle 12 was rearranged to hydroxy-substituted diazatrithia-16-crown-5 in refluxing aqueous HCl. Macrocyclic diamines 11-13 were converted to either 5-chloro-8-hydroxyquinolin-7-ylmethyl-substituted diazatrithiacrown ethers 14-16 by a Mannich aminomethylation reaction or to 8-hydroxyquinolin-2-ylmethyl-substituted diazatrithiacrown ethers 17-19 by reductive amination using 8-hydroxyquinoline-2-carboxaldehyde. Preliminary photophysical studies show that ligands 16 and 19 exhibit increased fluorescence in the presence of Zn²⁺, indicating that these ligands could be chemical sensors for Zn²⁺.

Full text of DOI:10.1021/jo0017584

4752
J . Org. Chem. 2001, 66, 4752-4758
Bis-8-h yd r oxyqu in olin e-Ar m ed Dia za tr ith ia -15-cr ow n -5 a n d
Dia za tr ith ia -16-cr ow n -5 Liga n d s: P ossible F lu or op h or ic Meta l Ion
Sen sor s
R. Todd Bronson, J erald S. Bradshaw,* Paul B. Savage, Saowarux Fuangswasdi,
Sang Chul Lee, Krzysztof E. Krakowiak,† and Reed M. Izatt
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602
jerald_bradshaw@byu.edu
Received December 19, 2000
The synthesis and preliminary photophysical properties of a series of diazatrithia-15-crown-5 and
diazatrithia-16-crown-5 ligands containing two 8-hydroxyquinoline sidearms are reported. The
ligands were prepared by a two-step process. First, diazatrithiacrown ethers 11 and 12 were
prepared by treating bis(R-chloroamide) 5 with various dimercaptans followed by reduction using
a boron-THF complex. Hydroxymethyl-substituted macrocycle 12 was rearranged to hydroxy-
substituted diazatrithia-16-crown-5 in refluxing aqueous HCl. Macrocyclic diamines 11-13 were
converted to either 5-chloro-8-hydroxyquinolin-7-ylmethyl-substituted diazatrithiacrown ethers 14-
16 by a Mannich aminomethylation reaction or to 8-hydroxyquinolin-2-ylmethyl-substituted
diazatrithiacrown ethers 17-19 by reductive amination using 8-hydroxyquinoline-2-carboxaldehyde.
Preliminary photophysical studies show that ligands 16 and 19 exhibit increased fluorescence in
the presence of Zn2+, indicating that these ligands could be chemical sensors for Zn2+
.
In tr od u ction
crown-6 ligands 1-4 (Figure 1) prepared in our labora-
tory have important ligating and luminescent properties
when treated with certain metal ions.4,5 Ligand 1 with
the two 5-chloro-8-hydroxyquinoline (CHQ) substituents
attached through CHQ positions 7 has a high affinity for
Mg2+ (log K ) 6.82 in MeOH) and lower affinity for the
other alkaline earth and alkali metal ions (log K ) 2.89-
5.31 in MeOH).5d Ligand 4, on the other hand, exhibits
very strong affinities in MeOH for Ba2+ and K+ (log K )
There is much interest in the development of com-
pounds that selectively respond to specific metal ions for
use as ion sensors.1 Emphasis has been placed on the
development of compounds that selectively respond to the
presence of specific metal ions through changes in redox
potentials,2 UV absorption,3 or fluorescence spectra.1,4
We have studied several series of macrocyclic ligands
with appended chromophores and fluorophores for use
as selective metal-ion chemosensors.5 8-Hydroxyquinoline
is an analytical ligating reagent wherein its fluorescence
is changed upon complexation with certain metal ions.6
8-Hydroxy- and 8-methoxyquinoline appended diaza-18-
12.2 and 6.7, respectively) and no affinity for Mg2+ 5d
.
Ligands 1 and 2 have proven to be effective chemosen-
sors for Mg2+ and Hg2+, respectively.4 Uncomplexed 1 and
2 exhibit very weak luminescence bands at 540 nm in
MeOH/H2O (1:1 v/v), which are consistent with the
luminesence behavior of 8-hydroxyquinoline in protic
solvents. Addition of Mg2+ to 1 and Hg2+ to 2 in neutral
1:1 MeOH/H2O solutions results in strong enhancements
of the luminesence bands at 520 nm (1)4a and 476 nm
(2).4b These increases in luminsence occurred even in the
presence of other metal ions. Ligand 3 has an 8-meth-
oxyquinoline attached through its position 2 rather than
position 7 as in 1 and 2. As a chemosensor, 3 selectively
binds and selectively responds to Cd2+.7 A large increase
in the fluorescence of 3 occurs in the presence of Cd2+
and Zn2+; however, the log K value for the association of
Cd2+ with 3 is 2 orders of magnitude greater than that
* To whom correspondence should be addressed. Fax: 801-378-5474.
† Current address: IBC Advanced Technologies, Inc., 856 East Utah
Valley Drive, American Fork, UT 84003.
(1) (a) Fluorescent Chemosensors for Ion and Molecular Recognition;
Czarnik, A. W., Ed.; American Chemical Society: Washington, DC,
1992. (b) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.;
Huxley, A. J . M.; McCoy, C. P.; Rademacher, J . T.; Rice, T. E. Chem.
Rev. 1997, 97, 1515. (c) Bargossi, C.; Fiorini, M. C.; Montalti, M.; Prodi,
L.; Zaccheroni, N. Coord. Chem. Rev. 2000, 208, 17. (d) Xue, G.-P.;
Savage, P. B.; Bradshaw, J . S.; Zhang, X. X.; Izatt, R. M. Functionalized
Macrocyclic Ligands as Sensory Molecules for Metal Ions. In Advances
in Supramolecular Chemistry; Gokel, G. W., Ed.; J AI Press: New York,
2000; Vol. 7, pp 99-137. (e) Prodi, L.; Bolletta, F.; Montalti, M.;
Zaccheroni, N. Coord. Chem. Rev. 2000, 208, 59.
(2) For example, see: (a) Marsella, M. J .; Newland, R. J .; Carroll,
P. J .; Swager, T. M. J . Am. Chem. Soc. 1995, 117, 9842. (b) Reinhoudt,
D. N. Recl. Trav. Chim. Pays-Bas 1996, 115, 109.
of Zn2+ (6.1 vs 3.98 in MeOH). Addition of K+, Ca2+, Sr2+
,
(3) For example, see: (a) Bartsch, R. A.; Chapoteau, E.; Czech, B.
P.; Krzykawski, J .; Kumar, A.; Robison, T. W. J . Org. Chem. 1994, 59,
616. (b) Zazula, W.; Chapoteau, E.; Czech, B. P.; Kumar, A. J . Org.
Chem. 1992, 57, 6720. (c) Fery-Forgues, S.; Bourson, S.; Dallery, L.;
Valeur B. New J . Chem. 1990, 14, 617.
(4) (a) Prodi, L.; Bolletta, F.; Montalti, M.; Zaccheroni, N.; Savage,
P. B.; Bradshaw, J . S.; Izatt, R. M. Tetrahedron Lett. 1998, 39, 5451.
(b) Prodi, L.; Bargossi, C.; Montalti, M.; Zaccheroni, N.; Su, N.;
Bradshaw, J . S.; Izatt, R. M.; Savage, P. B. J . Am. Chem. Soc. 2000,
122, 6769. (c) Rurack, K.; Kollmannsberger, M.; Resch-Genger, U.;
Daub, J . J . Am. Chem. Soc. 2000, 122, 968. (d) Torrado, A.; Walkup,
G. K.; Imperiali, B. J . Am. Chem. Soc. 1998, 120, 609.
(5) (a) Su, N.; Bradshaw, J . S.; Zhang, X. X.; Song, H.-C.; Savage,
P. B.; Xue, G.-P.; Krakowiak, K. E.; Izatt, R. M. J . Org. Chem. 1999,
64, 8855. (b) Yang, Z.; Bradshaw, J . S.; Zhang, X. X.; Savage, P. B.;
Krakowiak, K. E.; Dalley, N. K.; Su, N.; Bronson, T.; Izatt, R. M. J .
Org. Chem. 1999, 64, 3162. (c) Zhang, X. X.; Bordunov, A. V.;
Bradshaw, J . S.; Dalley, N. K.; Kou, K.-L.; Izatt, R. M. J . Am. Chem.
Soc. 1995, 117, 11507. (d) Bordunov, A. V.; Bradshaw, J . S.; Zhang, X.
X.; Dalley, N. K.; Kou, K.; Izatt, R. M. Inorg. Chem. 1996, 35, 7229.
(6) Ueno, K.; Imamura, T.; Cheng, K. L. Handbook of Organic
Analytical Regents; 2nd Ed.; CRC Press: Boca Raton, FL, 1992.
(7) Prodi, L.; Montalti, M.; Zaccheroni, N.; Savage, P. B.; Bradshaw,
J . S.; Izatt, R. M. Tetrahedron Lett. 2000, 42, 2941.
10.1021/jo0017584 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/03/2001

Possible Fluorophoric Metal Ion Sensors
J . Org. Chem., Vol. 66, No. 14, 2001 4753
The rearrangement product of 12 proved to be a new
hydroxy-substituted diazatrithia-16-crown-5 (13) (Scheme
2). Ligand 13 is also of value in our research program.
In an acid environment with heating, the protonated
primary hydroxyl group from 12 becomes a leaving group
when attacked by the neighboring ring sulfur atom. This
leads to a charged epithio intermediate that is in turn
attacked by water at the carbon atom most able to
support a positive charge, forming 13. A minor product
from this reaction resulted from the intramolecular
attack by a neighboring ring nitrogen atom forming 13a
in a very low yield. A trace amount of another compound
which has very similar properties to those of 13a was
also observed. This material could be a result of the
attack of the other ring nitrogen atom on the epithio
intermediate.
Syn t h esis of 8-H yd r oxyq u in olin e-Su b st it u t ed
Liga n d s. Ligands 14-16 with the CHQ units attached
at the CHQ 7-position were formed using Mannich
reaction conditions as shown in Scheme 3.5d,9 The best
results were achieved by first forming the N,N′-bis-
(methoxymethyl)diazacrown ethers by stirring the diaza
crowns in methanol and a slight excess of paraform-
aldahyde.9 After removal of methanol and addition of
benzene to the mixtures, CHQ was added and the
mixtures were refluxed. Benzene proved to be a good
reaction solvent since there were few side products.
Products 14-16 were purified using radial chromatog-
raphy.
F igu r e 1. Compounds mentioned in the Introduction.
Ba2+, Cu2+, and Ni2+ ions increases the luminescence of
3 by varying amounts, but they form weaker complexes
with 3. These findings show that 3 is a promising
candidate as a chemosensor in a sensory device for Cd2+ 7
.
This paper reports the synthesis and preliminary
photophysical properties of a series of diazatrithia-15-
crown-5 and diazatrithia-16-crown-5 ligands containing
two 8-hydroxyquinoline sidearms. The introduction of
sulfur atoms in the crown ether ring was expected to
enhance selectivity toward various transition and post-
transition metal ions, leaving more or less unaffected the
luminescence properties of the 8-hydroxyquinoline units,
which have proven to be suitable for metal ion sensing.
Compounds 17-19 (Scheme 4) were obtained in good
yields using a reductive amination procedure.5a,b Ligands
17-19 with the 8-hydroxyquinoline sidearms attached
at their 2-positions were more readily isolated than
compounds 14-16 with CHQ units attached at their
7-positions.
Resu lts a n d Discu ssion
Syn th esis of Dia za tr ith ia Cr ow n Eth er s. Second-
ary ring nitrogen atoms in crown ethers offer a conve-
nient site for attachment of alkyl substituents. The
crablike synthesis of diazacrown ethers using the bis(R-
chloroacetamide)s provides a relatively high yield method
to form macrocycles containing two secondary amine
functions.5b,8 In this regard, bis(R-chloroamide) 5 was
treated with various dimercaptans in MeCN using a
carbonate base to form macrocylic diazatrithiadiamides
6-8 in good yields (Scheme 1). As expected, the larger
2:2 cycloaddition products, macrocyclic tetraamides 9 and
10, were also isolated in two cases in small yields. The
NMR spectra of 9 and 10 were similar to those of 6 and
8, respectively. High dilution techniques helped minimize
the production of these undesired byproducts. Macrocyclic
diazatrithia ligands 11 and 12 were prepared by reducing
macrocyclic diamides 6 and 8, respectively, using a
borane-THF complex. Initially, work up of the borane
reduction products was done in refluxing 6 M HCl, but
this process caused the formation of unexpected rear-
rangement and ring-opened products as discussed below.
Exposure to 6 M HCl at room temperature for a period
of 10 min, along with extraction, was adequate for freeing
the desired product from boron giving diazatrithia-18-
crown-6 (11) and hydroxymethyl-substituted diazatrithia-
15-crown-5 (12) in good yields.
UV-Vis Stu d ies. Due to the low solubilities of the
ligands in methanol, stability constants of 15, 18, and
19 could be determined by UV-vis spectrophotometry.
Addition of metal ions to solutions of these ligands caused
a decrease in intensity of the UV-vis absorption as well
as formation of a new peak leading to at least one
isosbestic point. Spectral variations in the UV-vis of 19
exhibited evidence of the formation of a second complex.
In the case of Zn2+ and 19 (Figure 2), the first series of
spectral lines passed through two isosbestic points at
226.5 and 253 nm until CM/CL ≈ 1, then a new isosbestic
point at 261 nm was observed at higher values of CM/CL.
These spectral changes were interpreted as the result of
formation of both mono- and binuclear complexes. The
stoichiometry of complexation was found from interpreta-
tion of the spectrophotometric data and is given in Table
1. Whenever there was ambiguity in choosing the best
stoichiometry, the simplest one was chosen if there is no
other clear evidence to support another one.
All three ligands formed strong mononuclear complexes
(log â g 5) with the metal ions studied. The complexes
of 18, for example, were of sufficient thermodynamic
stability that equilibrium constants for their formation
could not be determined accurately by UV-vis spectro-
(9) (a) Bogatsky, A. V.; Lukyanenko, N. G.; Pastushok, V. N.;
Kostyanovsky, R. G. Synthesis 1983, 992. (b) Lukyanenko, N. G.;
Pastushok, V. N.; Bordunov, A. V.; Vetrogon, V. I.; Vetrogon, N. I.;
Bradshaw, J . S. J . Chem. Soc., Perkin Trans. 1 1994, 1489. (c)
Bordunov, A. V.; Bradsahw, J . S.; Pastushok, V. N.; Izatt, R. M. Synlett
1996, 933.
(8) (a) Bradshaw, J . S.; Krakowiak, K. E.; Izatt, R. M. J . Heterocycl.
Chem. 1998, 26, 1431. (b) Krakowiak, K. E.; Bradshaw, J . S.; Izatt, R.
M. J . Org. Chem. 1990, 55, 3364. (c) Krakowiak, K. E.; Bradshaw, J .
S.; Izatt, R. M. J . Heterocycl. Chem. 1990, 27, 1585. (d) Krakowiak, K.
E.; Bradshaw, J . S.; Izatt, R. M. Synlett 1993, 611.

4754 J . Org. Chem., Vol. 66, No. 14, 2001
Bronson et al.
Sch em e 1
Sch em e 2
Sch em e 3
photometry. Only a lower limit of log â values could be
given (log â g 7).
Among the three ligands studied, 18 possesses the
highest affinity toward transition metal ions. The higher
constants for the formation of complexes of 18 over those
of 15 with a given cation can be explained by participa-
tion of quinoline nitrogen atoms in complexation. This
demonstrates how the attachment site of the quinoline
to the crown can effect complexation. When attached at
the 7-position, the quinoline nitrogen atoms may not bind
metal ions as effectively. Crown size effects can be seen
by comparison of 18 and 19. Although complexes formed
by 19 with Ni2+ and Cu2+ are less stable than those
formed by 18, 19 can accommodate two cations. No
comparison between 18 and 19 can be made for the other
cations as only the lower limit of log â can be assigned.
P r elim in a r y F lu or escen ce Stu d ies. Among the
transition metal ions studied, complexes of ligands 15,
16, 18, and 19 with Cd2+, Zn2+, and Pb2+ gave emission
wavelengths as shown in Table 2. Compounds 15 and 16
containing CHQ groups attached at the quinoline 7-posi-
tions, formed strongly fluorescent complexes of the type
ML2 with Cd2+. However, the Cd2+ complexes of 18 and
19 with the 8-HQ sidearms attached through quinoline
7-positions, exhibited weaker fluorescence intensities at

Possible Fluorophoric Metal Ion Sensors
J . Org. Chem., Vol. 66, No. 14, 2001 4755
Sch em e 4
F igu r e 2. Spectral changes in the UV-vis absorption of 19
(CL ) 1 × 10-5 M) upon addition of Zn(NO3)2 in MeOH: (a) 0
< CM/CL < 1; (b) 1.2 < CM/CL < 10.1.
Exp er im en ta l Section
1
The H and 13C NMR spectra were recorded at 200 and 50
MHz in either DMSO-d6 or CDCl3. MS spectra were deter-
mined using chemical ionization (CI) and fast atom bombard-
ment (FAB) methods. All starting materials were purchased
from commercial sources or synthesized by known methods.
UV-vis spectral measurements were carried out using a
previously described procedure.10 The ligand stock solutions
were prepared by dissolution of a weighed amount of ligand
in methanol (HPLC grade, Fisher Scientific). Titrations of the
ligand (CL ≈ (1-2) × 10-5 M) by metal ion solutions were
performed directly in the spectrophotometric cell of 1 cm path
length. The resulting spectra were recorded from 190 to 1100
nm at room temperature with an HP 8453 spectrophotometer
after each addition of metal salt. The final metal-to-ligand
ratios were varied between 5 and 25. The ionic strength was
kept constant at 0.01 M by addition of sodium acetate
(certified, Fisher Scientific). The process results in apparent
equilibrium constants as a result of the high NaOAc concen-
tration. The metal salts were the following: Co(NO3)2 (certified
A.C.S., spectrum), Ni(NO3)2‚6H2O (Baker’s Analyzed), Cu-
(NO3)2, and Zn(NO3)2 (certified A.C.S., Fisher Scientific), Pb-
(NO3)2 and Cd(NO3)2‚4H2O (AR, Mallinckrodt), and Hg(NO3)2‚
H2O. The concentrations of stock solutions of metal salts were
determined by complexometric titration with EDTA in the
presence of the appropriate indicator.11 The spectral variations
recorded have been interpreted by the program Sirko.12
Since the UV spectra of the complexes exhibited low
intensity absorption at longer wavelengths, the fluorescence
longer wavelengths and formed complexes of the type
ML. Presumably, the fluorescence properties of the Cd2+
complexes were influenced by sidearm orientation.
Complexes with Zn2+ gave different results. Com-
pounds 16 and 19 containing 16-membered rings gave
strong emission bands, but 15 and 18 with 15-membered
rings showed relatively weak fluorescence intensites with
Zn2+. Figures 3 and 4 illustrate the fluorescence spectra
of the complexes formed by the interactions of Zn2+ with
16 and 19, respectively. Interestingly, Figures 3 and 4
show that ML and M2L complexes have emission maxima
at different wavelengths (540 and 500 nm, respectively).
Figures 5 and 6 illustrate the titration curves of 16 and
19 with Zn2+ showing a sharp endpoint for 16 at a 2:1
metal/ligand ratio. Figure 6 shows that 19 forms more
than one type of complex with Zn2+. It appears that 19
does not bind the second Zn2+ as strongly as does 16. The
fluorescence spectra of the 18-M2+ complexes were simi-
lar to those of 8-HQ with the same metal ions. These
results suggest a lack of crown participation in complex-
ation by 18. Complexes of Pb2+ with all ligands gave weak
fluorescent responses while forming ML complexes.
8-Hydroxyquinoline and 5-chloro-8-hydroxyquinoline ex-
hibited low fluorescence intensities with Cd2+, Zn2+, and
Pb2+ relative to the ligands studied.
(10) Arnaud-Neu, F.; Asfari, Z.; Souley, B,; Vicens, J . New J . Chem.
1996, 20, 453.
(11) J effery, G. H.; Bassett, J .; Mendham, J .; Denney, R. C. Vogels’s
Textbook of Quantitive Chemistry Analysis, 5th ed.; J ohn Wiley &
Sons: New York, 1989.
(12) Vetrogon, V.; Lukyanenko, N. G.; Schwing-Weill, M. J .; Arnaud-
Neu, F. Talanta 1994, 41, 2105.

4756 J . Org. Chem., Vol. 66, No. 14, 2001
Ta ble 1. Sta bility Con sta n ts for th e F or m a tion of Meta l Ion Com p lexes (log âxy
Bronson et al.
a
)
in MeOHb
CHQd
15
18
19
19
8-HQc
8-HQc
CHQd
log â
Co2+
Ni2+
Cu2+
Zn2+
Cd2+
Hg2+
Pb2+
ML
g7
ML
g7
g7
g7
g7
g7
g7e
g7
ML
M2L
ML
4.5 ( 0.2
ML2
ML
5.6 ( 0.3
ML2
g7
5.93 ( 0.06
6.72 ( 0.05
g7
11.6 ( 0.3
11.8 ( 0.2
13.3 ( 0.4
10.4 ( 0.1
9.2 ( 0.2
11.7 ( 0.1
11.7 ( 0.1
g14
10.8 ( 0.05
9.5 ( 0.2
9.29 ( 0.06
6.82 ( 0.03
6.7 ( 0.2
6.8 ( 0.1
5.18 ( 0.06
4.92 ( 0.02
5.44 ( 0.01
12.7 ( 0.2
11.4 ( 0.2
g11
5.7 ( 0.1
6.1 ( 0.2
4.24 ( 0.06
4.30 ( 0.01
5.58 ( 0.01
g7
6.17 ( 0.07
g7
g7
g7
g14
8.60 ( 0.01
4.50 ( 0.03
5.3 ( 0.3
a
xn+
b
Corresponding to the general equilibrium: xMn + yL h MxLy
(room temperature, I ) 0.01 M NaOAc). Mean values of n g 2
independent determinations, with the standard deviation σn-1 on the mean. c 8-HQ ) 8-hydroxyquinoline. CHQ ) 5-chloro-8-
d
hydroxyquinoline. e Value of one determination only.
Ta ble 2. F lu or escen ce P r op er ties of 8-Hyd r oxyqu in olin e, 5-Ch lor o-8-h yd r oxyqu in olin e, 15, 16, 18, a n d 19 in Meth a n ol
Con ta in in g 0.01 M Na OAc
Cd2+
8-HQa CHQa 15
Zn2+
19 8-HQa CHQa 15
Pb2+
19 8-HQa CHQa 15
ligand
16
513 511 544 540
335 265 15 36
18
16
18
16
517 521 520 530
11
18
19
wavelengthb (nm)
maximum intensityc
complexation
540
17
548
29
541
15
545
22
515 511 541 500
74 188 20 240
2:1 2:1 1:1 2:1
531
3
552
6
9
3
8
1:1
1:1
1:2 1:2 1:1 1:1
1:1
1:1
d
d
1:1 1:1 1:1 1:1
a
b
d
8-HQ and CHQ are defined in Table 1. Wavelength of maximum intensity. c Intensity of 10 µM of each ligand. Could not be
determined from the fluorescence data.
F igu r e 3. Fluorescence spectra of the 16-Zn2+ complex: [16]
) 10 µM, Zn2+ ) 0.25-5 equiv.
F igu r e 5. Fluorescence intensity (550 nm) of 16 (1-10 µM)
titrated with Zn2+ (10-100 µM) in MeOH containing 0.01 M
NaOAc.
F igu r e 4. Fluorescence spectra of the 19-Zn2+ complex:; [19]
) 10 µM, Zn2+ ) 0.25-5 equiv.
spectra were measured using λex ) 390 nm at wavelengths
between 400 and 600 nm with a Perkin-Elmer LS50B Fluo-
rimeter. Fluorescence intensities were measured in methanol
containing 0.01 M NaOAc. The titrations were performed with
titrant (metal ions; 10-100 µM) and titrate (ligand; 1-10 µM).
The metal ion sources were identical to those used to perform
the UV-vis studies.
Gen er a l P r oced u r e A: Cycliza tion of 5 w ith Dim er -
ca p ta n s (Sch em e 1). A mixture of 55b and a slight excess of
the appropriate dimercaptan along with 4 equiv of K2CO3 were
stirred at reflux in MeCN (60-150 mL/mmol of 5) for 48 h
under nitrogen gas. The mixture was then filtered hot, and
the solvent was removed by evaporation. The crude cyclic
diamides were purified by flash chromatography on silica gel
using a CH2Cl2/MeOH/NH4OH solvent system. The insolubility
of the desired products often required the absorption of the
F igu r e 6. Fluorescence intensity (550 nm) of 19 (1-10 µM)
titrated with Zn2+ (10-100 µM) in MeOH containing 0.01 M
NaOAc.
crude product onto a small amount of silica gel, for loading
purposes, to obtain good separations.
7,13-Dia za -1-oxa -4,10,16-tr ith ia cycloocta d eca n e-6,14-
d ion e (6). Compound 6 (1.81 g, 58%) was obtained as a white
solid following general procedure A from 2.50 g (9.20 mmol)
of 5, 1.29 g (9.30 mmol) of 2,2′-oxydiethanethiol, and 5.10 g of
K2CO3 in 1500 mL of MeCN after refluxing for 48 h: Rf 0.25
(silica gel, 100:4:0.4 of CH2Cl2/MeOH/NH4OH); mp ) 146-47
°C; 1H NMR δ 8.07 (br t, J ) 5.1 Hz, 2 H), 3.58 (t, J ) 6.6 Hz,
4 H), 3.30 (dt, J 1 ) 5.9 Hz, J 2 ) 5.9 Hz, 4 H), 3.19 (s, 4 H),
2.80-2.65 (m, 8 H); 13C NMR δ 169.1, 69.8, 39.2, 35.1, 31.7,
31.1; HRMS (FAB) calcd for C12H22N2O3S3Na (M + Na+)

Possible Fluorophoric Metal Ion Sensors
J . Org. Chem., Vol. 66, No. 14, 2001 4757
361.0690, found 361.0687. Anal. Calcd for C12H22N2O3S3: C,
42.58; H, 6.55. Found: C, 42.72; H, 6.37.
for C12H27N2OS3 (M + H+) 311.1285, found 311.1299. Anal.
Calcd for C12H26N2OS3: C, 46.41; H, 8.44. Found: C, 46.58,
H, 8.23.
10,16-Diaza-1,4,7,13-tetr ath iacyclooctan e-9,17-dion e (7).
Compound 7 (2.50 g, 64%) was obtained as a white solid
following general procedure A from 3.00 g (10.99 mmol) of 5,
1.12 g (11.00 mmol) of 2-mercaptoethyl sulfide, and 4.90 g of
K2CO3 in 600 mL of MeCN after refluxing for 48 h: Rf 0.3
(silica gel, 100:5:0.5 of CH2Cl2/MeOH/NH4OH); mp ) 138-40
2-Hyd r oxym eth yl-7,14-d ia za -1,4,10-tr ith ia cyclop en ta -
d en ca n e (12). Compound 12 (3.70 g, 85%) was isolated as a
white solid following general procedure B from 4.80 g (14.8
mmol) of 8, 150 mL (150 mmol) of BH3-THF, and 60 mL of
dry THF: mp ) 75-78 °C; Rf 0.3 (silica gel, 100:13:2 of CH2-
1
1
Cl2/MeOH/NH4OH); H NMR δ 3.70 (d, J ) 5.1 Hz, 2 H),3.2,
°C; H NMR δ 8.21 (br t, J ) 5.5 Hz, 2 H), 3.30 (dt, J 1 ) 6.2
3.1-2.2 (m, 21 H); 13C NMR δ 64.2, 49.3, 48.1, 48.1, 47.8, 47.6,
35.5, 33.9, 33.5, 33.5, 32.2; HRMS (FAB) calcd for C11H25N2-
OS3 (M + H+) 297.1130, found 297.1116. Anal. Calcd for
C11H24N2OS3: C, 44.56; H, 8.16. Found: C, 44.65, H, 8.08.
3-Hydr oxy-8,14-diaza-1,5,11-tr ith iacycloh exadecan e (13)
(Sch em e 2). Rearranged product 13 was obtained by refluxing
101 mg (3.41 mmol) of 12 in 250 mL of 6 M HCl for 4 h. After
being cooled to room temperature, the resulting solution was
neutralized with 50% w/w NaOH and then evaporated to
approximately 100 mL. NaOH 50% w/w was again added until
a pH of 13-14 was reached, and then crude 13 was extracted
with CH2Cl2 (3 × 100 mL). The combined, unwashed organic
layer was dried (Na2SO4). Purification was done by flash
chromatography on silica gel (100:20:3 of CH2Cl2/MeOH/NEt3)
to yield 69 mg (69%) of 13 as a clear solid: mp ) 78-80 °C; Rf
0.3 (silica gel, 100:10:1 of CH2Cl2/MeOH/NH4OH); 1H NMR δ
3.91 (tt, J 1 ) 3.6 Hz, J 2 ) 8.0 Hz, 1 H), 3.0-4.0 (br s, 3 H),
2.76-2.94 (m, 18 H), 2.64 (dd, J 1 ) 8.0 Hz, J 2 ) 14.2 Hz, 2 H),
3.2, 3.1, 2.2 (m, 21 H); 13C NMR δ 71.5, 48.8, 47.8, 39.6, 33.8,
32.4; HRMS (FAB) calcd for C11H25N2OS3 (M + H+) 297.1130,
found 297.1120. Anal. Calcd for C11H24N2OS3: C, 44.56; H,
8.16. Found: C, 44.38, H, 7.95.
1,7-Diaza-4,10,14-tr ith iabicyclo[10.4.0]h exadecan e (13a).
Compound 13a (25 mg, 4%) was isolated as a side product of
the reaction to form 13 as a clear oil: Rf 0.5 (silica gel, 100:
10:1 of CH2Cl2/MeOH/NH4OH); 1H NMR δ 2.2-3.5 (m, 22 H);
13C NMR 57.4, 51.2, 49.8, 49.0, 46.6, 33.0, 32.6, 32.3, 30.2, 27.5,
22.3; HRMS (EI+) calcd for C11H22N2S3 (M+) 278.0945, found
278.0947.
Gen er a l P r oced u r e C: Atta ch m en t of 5-Ch lor o-8-
h yd r oxyqu in olin e a t th e 7-P osition Usin g th e Ma n n ich
Rea ction (Sch em e 3). The macrocyclic diamine and an excess
of paraformaldehyde (2.1 equiv) were first mixed in MeOH (60
mL/1 mmol of macrocycle) and stirred overnight. MeOH was
then removed, and benzene was added (60 mL/mmol of
macrocycle). 5-Chloro-8-hydroxyquinoline (2.1 equiv) was then
added, and the solution was refluxed for 24 h. The resulting
solution was then filtered hot, and the solvent was removed
by evaporation. The crude products were purified by radial
arm chromatography using a CH2Cl2/MeOH/NH4OH solvent
system.
Hz, J 2 ) 5.1 Hz, 4 H), 3.19 (s, 4 H), 2.75 (s, 8 H), 2.66 (t, J )
6.2 Hz, 4 H); 13C NMR δ 169.4, 39.2, 34.5, 32.3, 31.7, 30.9;
HRMS (FAB) calcd for C12H22N2S4Na (M + Na+) 377.0462,
found 377.0449. Anal. Calcd for C12H22N2O2S4: C, 40.05; H,
6.25. Found: C, 40.48; H, 6.12.
3-Hyd r oxym eth yl-7,13-d ia za -1,4,10-tr ith ia cyclop en ta -
d eca n e-6,14-d ion e (8). Compound 8 (1.50 g, 50%) was also
isolated as a white solid following general procedure A from
2.50 g (9.20 mmol) of 5, 1.19 g (9.30 mmol) of 2,3-dimercap-
topropanol, and 5.10 g of K2CO3 in 1500 mL of MeCN after
refluxing for 48 h: Rf 0.3 (silica gel, 100:10:1 of CH2Cl2/MeOH/
1
NH4OH); mp ) 132-34 °C; H NMR δ 8.15 (t, J ) 5.3 Hz, 2
H), 4.84 (t, J ) 4.0 Hz, 1 H), 3.7-2.6 (m, 17 H); 13C NMR δ
170.0, 169.7, 61.6, 47.9, 38.6, 38.4, 35.1, 34.2, 34.1, 31.6, 31.5;
HRMS (FAB) calcd for C11H20N2O3S3Na (M + Na+) 347.0525,
found 347.0529. Anal. Calcd for C11H20N2O3S3: C, 40.72; H,
6.21. Found: C, 40.53; H, 6.07.
7,13,25,31-Tetr a a za -1,19-d ioxa -4,10,16,22,28,34-h exa th i-
a cycloh exa tr icon ta n e-6,14,24,32-tetr a on e (9). Following
general procedure A, compound 9 (156 mg, 4%) was carefully
isolated as a side product using 3.20 g (11.76 mmol) of 5, 1.63
g (11.76 mmol) of 2,2′-oxydiethanethiol, and 5.20 g of K2CO3
in 640 mL of MeCN after refluxing for 48 h: Rf 0.2 (silica gel,
100:4:0.4 of CH2Cl2/MeOH/NH4OH); mp ) 153-54 °C; 1H
NMR δ 8.14 (br t, J ) 5.1 Hz, 4 H), 3.57 (t, J ) 6.6 Hz, 8 H),
3.26 (dt, J 1 ) 6.2 Hz, J 2 ) 6.2 Hz, 8 H), 3.16 (s, 8 H), 2.73 (t,
J ) 6.6 Hz, 8 H), 2.60 (t, J ) 6.6 Hz, 8 H); 13C NMR δ 169.1,
69.5, 38.7, 34.8, 31.1, 30.5; HRMS (FAB) calcd for C24H44N4O6S6-
Na (M + Na+) 699.1483, found 699.1470. Anal. Calcd for
C24H44N4O6S6: C, 42.58; H, 6.55. Found: C, 42.67; H, 6.63.
3,17(18)-Bis(h yd r oxym et h yl)-7,13,21,27-t et r a a za -1,4,-
10,16,18,24-h ext h ia cyclon on a icosa n e-6,14,20,28-t et r a -
on e (10). Following general procedure A, compound 10 (120
mg, 4%) was also isolated as a side product from 1.25 g (4.60
mmol) of 5, 0.58 g (4.65 mmol) of 2,3-dimercaptopropanol, and
2.10 g of K2CO3 in 800 mL of MeCN after refluxing for 48 h:
Rf 0.2 (silica gel, 100:10:1 of CH2Cl2/MeOH/NH4OH); 1H NMR
δ 8.16 (t, J ) 3.0 Hz, 4 H), 4.91 (t, J ) 3.6 Hz, 2 H), 3.7-3.5
(m, 4 H), 3.4-2.5 (m, 30 H);HRMS (FAB)calcd for C22H40N4O6S6-
Na (M + Na+) 671.1170, found 671.1154.
7,14-Bis(5-ch lor o-8-h yd r oxyqu in olin -7-ylm eth yl)-7,14-
d ia za -4,10,16-t r it h ia -1-oxa cyclooct a d eca n e (14). Com-
pound 14 (840 mg, 75%) was formed as a fluffy white solid
following general procedure C from 500 mg (1.61 mmol) of 11,
120 mg (3.93 mmol) of paraformaldehyde, and 690 mg (3.85
mmol) of 5-chloro-8-hydroxyquinoline in 20 mL of benzene and
refluxed for 24 h: mp ) 147-50 °C; Rf 0.5 (silica gel, 100:5:
0.5 of CH2Cl2/MeOH/NH4OH); 1H NMR δ 10.2-9.2 (brs, 2 H),
8.87 (dd, J 1 ) 4.2 Hz, J 2 ) 1.3 Hz, 2 H), 8.46 (dd, J 1 ) 8.4 Hz,
J 2 ) 1.5 Hz, 2 H), 7.50-7.47 (m, 4 H) 3.90 (s, 4 H), 3.70 (t, J
) 6.0 Hz, 4 H), 3.00-2.70 (m, 20 H); 13C NMR δ 151.1, 149.1,
139.4, 133.0, 128.0, 126.0, 122.2, 120.3, 119.6, 71.8, 54.9, 53.9,
53.7, 32.0, 30.2, 29.9; HRMS (FAB) calcd for C32H3835Cl2N4O3S3-
Na (M + Na+) 715.1381, found 715.1396. Anal. Calcd for
C32H3835Cl2N4O3S3: C, 55.40; H, 5.52. Found: C, 55.38, H, 5.50.
8,13-Bis(5-ch lor o-8-h yd r oxyqu in olin -7-ylm eth yl)-3-h y-
d r o x y m e t h y l-8,13-d ia za -1,3,10-t r it h ia c y c lo p e n t a d e -
ca n e (15). Compound 15 (210 mg, 45%) was isolated as a fluffy
white solid following general procedure C from 200 mg (0.67
mmol) of 12, 49 mg (1.62 mmol) of paraformaldehyde, and 291
mg (1.62 mmol) of 5-chloro-8-hydroxyquinoline in 25 mL of
benzene and refluxed for 24 h: mp ) 75-80 °C; Rf 0.6 (silica
Gen er al P r ocedu r e B: Bor an e-THF Redu ction (Sch em e
1). The macrocylic diamides were dissolved in dry THF (5 mL/
mmol of macrocycle). After the mixture was cooled in an ice
bath, the borane-THF complex (1 M) was added (10 mmol/
mmol of macrocycle) and the resulting mixture was refluxed
for approximately 72 h. After being quenched with water (1
mL/20 mmol of the borane-THF complex), the solvent was
removed by evaporation and 6 M HCl (10 mL/mmol of
macrocycle) was used to dissolve the crude solid. The mixture
was stirred at room temperature until gas ceased to be evolved
(approximately 10 min). After the solution was cooled in an
ice bath, NaOH (50% w/w) was added until a pH of 14-15
was reached, the resulting solution was then extracted with
CH2Cl2 and dried (Na2SO4), and solvent was removed by
evaporation. The crude product was purified by flash chroma-
tography on silica gel using a CH2Cl2/MeOH/NH4OH solvent
system.
7,13-Dia za -4,10,16-tr ith ia -1-oxa cycloocta d eca n e (11).
Compound 11 (2.08 g, 79%) was prepared as clear oil following
general procedure B from 2.86 g (8.46 mmol) of 6 and 85 mL
(85 mmol) of BH3-THF along with 50 mL of dry THF: Rf 0.25
(silica gel, 100:7:0.5 of CH2Cl2/MeOH/NH4OH); 1H NMR δ 3.70
(t, J ) 5.9 Hz, 4H), 3.3-3.0 (m, 20 H), 2.85 (br s, 2 H); 13C
NMR δ 71.5, 48.5, 48.2, 33.2, 33.1, 32.2; HRMS (FAB) calcd
1
gel, 100:4:0.5 of CH2Cl2/MeOH/NH4OH); H NMR δ 8.90 (dd,
J 1 ) 4.0 Hz, J 2 )1.1 Hz, 2 H), 8.48 (d, J ) 8.8 Hz, 2 H), 8.4-
7.4 (brs, 2 H), 7.55-7.49 (m, 4 H), 3.92 (s, 4 H),), 3.85 (dd, J 1

4758 J . Org. Chem., Vol. 66, No. 14, 2001
Bronson et al.
) 11.7 Hz, J 2 ) 4.8 Hz, 1 H), 3.67 (dd, J 1 ) 11.4 Hz, J 2 ) 6.2
Hz, 1H), 3.1-2.6 (m, 20 H); 13C NMR δ 151.0, 150.9, 149.2,
149.2, 139.4, 139.4, 133.2, 133.2, 128.3, 128.1, 126.1, 126.1,
122.4, 122.4, 120.5, 120.5, 119.6, 119.6, 64.0, 55.1, 54.7, 54.5,
54.1, 53.9, 53.9, 49.7, 35.1, 30.5, 29.9, 29.9, 29.4; HRMS (FAB)
calcd for C31H3635Cl2N4O3S3Na (M + Na+) 701.1224, found
701.1212. Anal. Calcd for C31H3635Cl2N4O3S3: C, 54.78; H, 5.34.
Found: C, 54.54, H, 5.41.
30.9, 30.7; HRMS (FAB) calcd for C32H40N4O3S3Na (M + Na+)
647.2160, found 647.2156. Anal. Calcd for C32H40N4O3S3: C,
61.51; H, 6.45. Found: C, 61.42, H, 6.42.
3-Hyd r oxym eth yl-7,13-bis(8-h yd r oxyqu in olin -2-ylm e-
th yl)-7,13-diaza-1,4,10-tr ith iacyclopen tadecan e (18). Com-
pound 18 (393 mg, 69%) was prepared following general
procedure D as a greenish/white solid from 275 mg (0.93 mmol)
of 12, 337 mg (1.95 mmol) of 8-hydroxyquinolin-2-carboxalde-
hyde, and sodium triactetoxyborohydride (530 mg, 2.50 mmol)
in 12 mL of DCE and stirred for 5 h: mp ) 60-65 °C; Rf 0.7
(silica gel, 100:7:1 of CH2Cl2/MeOH/NH4OH); 1H NMR δ 8.8-
7.8 (brs, 2 H), 8.11 (d, J ) 8.4 Hz, 2 H), 7.62 (dd, J 1 ) 8.8 Hz,
J 2 ) 8.4 Hz, 2 H), 7.42 (dd, J 1 ) 7.7 Hz, J 2 ) 7.7 Hz, 2 H),
7.30 (d, J ) 8.1 Hz, 2 H), 7.16 (d, J ) 7.7 Hz, 2 H), 3.96 (s, 4
8,14-Bis(5-ch lor o-8-h yd r oxyqu in olin -7-ylm eth yl)-3-h y-
dr oxy-8,14-diaza-1,5,11-tr ith iacycloh exadecan e (16). Com-
pound 16 (70 mg, 31%) was made following general procedure
C from 98 mg (0.33 mmol) of 13, 20 mg (0.68 mmol) of
paraformaldehyde, and 124 mg (0.69 mmol) of 5-chloro-8-
hydroxyquinoline in 20 mL of benzene and refluxed for 24 h:
mp ) 70-75 °C; Rf 0.5 (silica gel, 100:7:0.5 of CH2Cl2/MeOH/
NH4OH); 1H NMR δ 8.86 (d, J ) 4.0 Hz, 2 H), 8.48 (d, J ) 8.8
Hz, 2 H), 8.4-7.4 (brs, 2 H), 7.55-7.48 (m, 4 H), 3.93-3.80
(m, 5 H), 3.0-2.6 (m, 21 H); 13C NMR δ 150.9, 149.2, 139.4,
133.2, 128.4, 126.1, 122.4, 120.4, 119.5, 71.1, 54.3, 54.3, 54.0,
H), 3.90 (dd, J 1 ) 11.7 Hz, J 2 ) 4.4 Hz, 2 H) 3.69 (dd, J 1
)
11.4 Hz, J 2 ) 6.6 Hz, 2 H), 3.2-2.6 (m, 21 H); 13C NMR δ 158.1,
157.6, 152.4, 152.2, 137.7, 137.5, 136.8, 136.7, 127.8, 127.8,
127.6, 127.5, 122.0, 122.0, 117.9, 117.8, 110.5, 110.3, 64.4, 61.5,
61.5, 55.5, 55.0, 54.6, 54.4, 49.8, 35.3, 31.0, 30.3, 30.2, 29.9;
HRMS (FAB) calcd for C31H40N4O3S3Na (M + Na+) 633.2004,
found 633.1988. Anal. Calcd for C31H40N4O3S3: C, 60.95; H,
6.27. Found: C, 60.93, H, 6.43.
38.3, 30.4, 29.6; HRMS (FAB) calcd for C31H3735Cl2N4O3S3Na
(M + H+) 679.1405, found 679.1407. Anal. Calcd for C31H36
Cl2N4O3S3: C, 54.78; H, 5.34. Found: C, 54.68, H, 5.13.
-
35
Gen er a l P r oced u r e D: Atta ch m en t of 8-Hyd r oxyqu in -
olin e a t th e 2-P osition by Red u ctive Am in a tion Usin g
8-Hyd r oxyqu in olin e-2-ca r boxa ld eh yd e (Sch em e 4). A
mixture of 8-hydroxyquinoline-2-carboxaldehyde and the mac-
rocyclic diamine in DCE (15 mL/mmol of macrocycle) was
stirred with 1.3-1.6 equiv of NaBH(OAc)3 under a nitrogen
atmosphere at room temperature for 4-6 h. The reaction was
then quenched with saturated NaHCO4 and extracted with
CH2Cl2 several times. The combined CH2Cl2 extracts were then
dried (Na2SO4) and filtered, and the solvent was removed by
evaporation to give the crude product. The crude product was
purified by radial arm chromatography with a CH2Cl2/MeOH/
NH4OH solvent system.
3-Hyd r oxy-8,14-bis(8-h yd r oxyqu in olin -2-ylm eth yl)-8,-
14-d ia za -1,5,11-t r it h ia cycloh exa d eca n e (19). Compound
19 (130 mg, 64%) was obtained following general procedure D
as a greenish/white solid from 97 mg (0.33 mmol) of 13, 119
mg (0.69 mmol) of 8-hydroxyquinolin-2-carboxaldehyde, and
sodium triactetoxyborohydride (189 mg, 0.89 mmol) in 4.5 mL
of DCE and stirred for 4 h: mp ) 60-63 °C; Rf 0.8 (silica gel,
1
100:7:0.5 of CH2Cl2/MeOH/NH4OH); H NMR δ 9.1-8.3 (brs,
2 H), 8.09 (d, J ) 8.8 Hz, 2 H), 7.54 (d, J ) 8.4 Hz, 2 H), 7.46
(dd J 1 ) 8.1 Hz, J 2 ) 7.7 Hz, 2 H), 7.28 (d, J ) 8.1 Hz, 2 H),
7.16 (d J ) 7.3 Hz, 2 H), 4.01 (d J ) 14.7 Hz, 2 H) 4.00 (m, 1
H), 3.89 (d, J ) 14.7, 2 H) 3.0-2.6 (m, 21 H); 13C NMR δ 157.4,
152.6, 137.8, 136.7, 127.8, 127.6, 121.8, 117.8, 110.6, 72.5, 61.1,
55.5, 55.0, 38.6, 31.3, 29.9; HRMS (FAB) calcd for C31H38N4O3S3-
Na (M + Na+) 633.1925, found 633.1932. Anal. Calcd for
7,13-Bis(8-h yd r oxyqu in olin -2-ylm eth yl)-7,13-d ia za -4,-
10,16-t r it h ia -1-oxa cyclooct a d eca n e (17). Compound 17
(240 mg, 32%) was isolated following general procedure D as
an off-white solid from 367 mg (1.18 mmol) of 11, 306 mg (1.77
mmol) of 8-hydroxyquinolin-2-carboxaldehyde (>2 equiv was
used to maximize yield), and sodium triactetoxyborohydride
(526 mg, 2.48 mmol) in 15 mL of DCE and stirring for 4 h:
mp ) 55-60 °C; Rf 0.8 (silica gel, 100:7:0.5 of CH2Cl2/MeOH/
C
31H38N4O3S3: C, 60.95; H, 6.27. Found: C, 60.81, H, 6.17.
Ack n ow led gm en t. A grant from the Office of Naval
Research is gratefully acknowledged. We also express
our gratitude to Dr. Francoise Arnaud-Neu, Laboratoire
de Chemie-Physique, ECPM-ULP, France, for the pro-
gram Sirko and to Dr. Luca Prodi, Dipartimento di
Chimica “G. Ciamician,” Universita di Bologna, Italy,
for helpful suggestions.
1
NH4OH); H NMR δ 8.5-8.0 (brs 2 H), 8.10 (d, J ) 8.4 Hz, 2
H), 7.69 (d, J ) 8.4 Hz, 2 H), 7.42 (dd, J 1 ) 8.4 Hz, J 2 ) 7.7
Hz, 2 H), 7.30 (dd, J 1 ) 8.1 Hz, J 2 )1.1 Hz, 2 H), 7.15 (dd, J 1
) 7.7 Hz, J 2 )1.1 Hz, 2 H), 3.95 (s, 4 H), 3.70 (t, J ) 6.2 Hz,
4 H) 2.89-2.68 (m, 20 H); 13C NMR δ 158.4, 152.1, 137.5, 136.7,
127.7, 127.4, 122.1, 117.9, 110.2, 71.8, 61.1, 54.6, 54.4, 32.1,
J O0017584