Diaza-18-Crown-6 Ligands Containing Two Aminophenol Side Arms: New Heterobinuclear Metal Ion Receptors

Article abstract of DOI:10.1021/jo9816212

Three diaza-18-crown-6 ligands substituted with two aminophenol side arms were synthesized as possible heterobinuclear metal ion receptors. Bis(p-aminophenol)-substituted diaza-18-crown-6 ligand (13) was prepared by treating the diazacrown with α-bromo-4-nitro-o-cresol in the presence of N,N-diisopropylethylamine followed by reduction of the nitro groups. Bis(o-aminophenol)-substituted diaza-18-crown-6 ligands (11 and 12) were prepared in two steps by the aminomethylation of either an o-nitrophenol or o-(trifluoroacetamido)phenol followed by reduction of the nitro groups or hydrolysis of the trifluoroacetamide groups. All new bisphenol-armed diazacrown ligands were purified by ultrasonication in MeOH followed by filtration and drying. Interaction of the ligands with Na⁺, K⁺, Ag⁺, and Cu²⁺ was evaluated by a calorimetric titration technique at 25°C in MeOH. The complexes of Ag⁺ and Cu²⁺ are much more stable than those of Na⁺ and K⁺. Heterobinuclear complexes were observed for 11-Cu²⁺ - Na⁺ and 12-Cu²⁺-Na⁺ but not for 13-Cu²⁺-Na⁺ or for 12-Cu²⁺-Ag⁺.

Full text of DOI:10.1021/jo9816212

J . Org. Chem. 1999, 64, 3825-3829
3825
Dia za -18-Cr ow n -6 Liga n d s Con ta in in g Tw o Am in op h en ol Sid e
Ar m s: New Heter obin u clea r Meta l Ion Recep tor s
Ning Su, J erald S. Bradshaw,*,† Xian Xin Zhang, Paul B. Savage,
Krzysztof E. Krakowiak,‡ and Reed M. Izatt
Department of Chemistry & Biochemistry, Brigham Young University, Provo, Utah 84602
Received August 10, 1998 (Revised Manuscript Received J anuary 21, 1999)
Three diaza-18-crown-6 ligands substituted with two aminophenol side arms were synthesized as
possible heterobinuclear metal ion receptors. Bis(p-aminophenol)-substituted diaza-18-crown-6
ligand (13) was prepared by treating the diazacrown with R-bromo-4-nitro-o-cresol in the presence
of N,N-diisopropylethylamine followed by reduction of the nitro groups. Bis(o-aminophenol)-
substituted diaza-18-crown-6 ligands (11 and 12) were prepared in two steps by the aminometh-
ylation of either an o-nitrophenol or o-(trifluoroacetamido)phenol followed by reduction of the nitro
groups or hydrolysis of the trifluoroacetamide groups. All new bisphenol-armed diazacrown ligands
were purified by ultrasonication in MeOH followed by filtration and drying. Interaction of the ligands
with Na+, K+, Ag+, and Cu2+ was evaluated by a calorimetric titration technique at 25 °C in MeOH.
The complexes of Ag+ and Cu2+ are much more stable than those of Na+ and K+. Heterobinuclear
complexes were observed for 11-Cu2+- Na+ and 12-Cu2+-Na+ but not for 13-Cu2+-Na+ or for 12-
Cu2+-Ag+.
In tr od u ction
molecule. This type of ditopic receptors has received
considerable attention in recent years because having two
metal ions close together affects the redox properties of
the complexed transition metal ions and they may be
used for bimetalic catalysis and activation of small
molecules such as O2, CO, etc.5 The negatively charged
pseudocryptand, formed from the biscatechol-containing
diazacrown ether and boron, can form neutral complexes
Functionalization of crown ethers with additional
ligating units is an effective way to increase metal ion
complexing ability and selectivity.1 Double-armed crown
ethers have different, often better, metal ion complexing
abilities than their mononuclear analogues.2 Also, proton-
ionizable phenol-containing azacrown ethers are effective
complexing agents for transfer of metal cations from an
aqueous to an organic phase.1a,3 In some cases, these
phenol-containing azacrown ethers display high selectiv-
ity and can be used for spectrophotometric determination
of alkali and alkaline-earth metal cations.1b,d,4 For the
biscatechol-containing diazacrown ether,5 an important
application is its possible use as a heteronuclear metal
ion receptor for simultaneous binding of soft transition
and hard-alkali or alkaline-earth metal ions in one
+
with NH4 and K+.5c,d
A series of phenol-containing azacrown ethers with
substituents such as Br, Cl, F, OH, CN, CH3, OCH3, Ph,
C(CH3)3, NO2, and CHO, which are ortho or para to the
phenolic hydroxy group, have been prepared.5-8 However,
to our knowledge, no ortho- or para-aminophenol-
substituted azacrown ethers have been reported. Double-
armed aminophenol-substituted diaza-18-crown-6 ligands
are expected to be interesting ionophores because the
strongly electron donating amine group will make the
phenol hydroxy group more electron rich and should
influence its complexing ability. The amino group also
has good complexing ability and may offer a competition
or cooperation between amino and hydroxy groups in
binding metal cations.
In this paper, we report the syntheses of seven new
phenol-containing proton-ionizable diaza-18-crown-6
ligands (6-9 and 11-13, Scheme 1), including three new
aminophenol-substituted diaza-18-crown-6 ligands (11-
13). Compounds 11 and 12 are bis(o-aminophenol)-
substituted diaza-18-crown-6 ligands, and compound 13
is a bis(p-aminophenol)-substituted diaza-18-crown-6
† Fax: 801-378-5474. E-mail: jerald_bradshaw@byu.edu.
‡ Current address for K.E.K., IBC Advanced Technologies, Inc., P.O.
Box 98, American Fork, UT 84003.
(1) (a) Nishida, H.; Katayama, Y.; Katsuki, H.; Nakamura, H.;
Takagi, M.; Ueno, K. Chem. Lett. 1982, 1853. (b) Katayama, Y.;
Fukuda, R.; Iwasaki, T.; Nita, K.; Takagi, M. Anal. Chim. Acta 1988,
204, 113. (c) Alihodzˇic, S.; Zˇinic, M.; Klaic, B.; Kiralj, R.; Kojic-Prodic,
B.; Herceg, M.; Cimerman, Z. Tetrahedron Lett. 1993, 34, 8345. (d)
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R.; De Cian, A.; Fischer, J . J . Chem. Soc., Chem. Commun. 1995, 1505.
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X.-X.; Kou, X.-L.; Dalley, N. K.; Yang Z.-X.; Savage, P. B.; Izatt, R. M.
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10.1021/jo9816212 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/30/1999

3826 J . Org. Chem., Vol. 64, No. 11, 1999
Sch em e 1. Syn th eses of Bisp h en ol-Ar m ed Dia za -18-Cr ow n -6 Liga n d sa
Su et al.
a
(i) (CH2O)n and C6H6; (ii) N(i-Pr)2Et and MeCN; (iii) 2.0 M NH3 in MeOH; (iv) PtO2/50-60 psi H2.
ligand. We expected that the complexing ability of these
three ligands would be affected by the position of the
amino group relative to the hydroxy groupsortho or para.
For compounds 11 and 12, one or both of the two groups
may take part in complexation with one metal ion. We
also expected that compounds 11 and 12 would bind one
transition metal ion among their amino and hydroxy
groups and the resulting pseudocryptands5,9 would bind
another alkali metal ion. Compared to their biscatechol
analogues,5 the side arms of compounds 11 and 12
contain two soft donors (amino groups) and two hard
donors (hydroxy groups). This arrangement was expected
to make compounds 11 and 12 selective for soft metal
ions. In contrast, compound 13 was not expected to form
heterobinuclear complexes because only one of the two
donating groups could take part in the complexation.
Results from preliminary investigations demonstrate that
ligands 11 and 12 do form binuclear complexes with Cu2+
and Na+ while 13 does not.
molecules. Preformation of the methoxymethylamines
also allows the reaction to be performed in nonpolar
solvents (CCl4, C6H6, toluene, or xylene), which is im-
portant for some self-assembly cyclization processes.12
A
variety of phenol-, â-naphthol-, and amide-, sulfonamide-,
imide- or azole-substituted monoaza-, diaza-, and pyri-
dinoaza-crown ethers and cryptands have been prepared
by this method.8,11-17 One-pot Mannich reactions6 of 4,-
13-diaza-18-crown-6 with paraformaldehyde and a series
of para-substituted phenols in refluxing benzene have
been shown to give double-armed proton-ionizable crown
ethers in good yields.5 Solvent selection proved crucial
for the successful synthesis of the Mannich base via this
method.6 Katritzky and co-workers have used bis(ben-
zotriazolylmethyl)-substituted diaza-18-crown-6 as a ver-
satile intermediate in the preparation of bislariat crown
ethers.18 Recently, the Einhorn reaction (amidomethyla-
tion) to construct anisole-containing building blocks for
macrocyclization19 was reported. The anisole-containing
macrocycles were demethylated to form phenol-contain-
ing macrocycles.19
Resu lts a n d Discu ssion
Treatment of the azacrown ether with benzyl halides
or carboxylic acid derivatives in the presence of base is
another method to prepare phenol-containing macro-
cycles. This method is not always convenient because of
the difficulties in preparing the starting materials, the
need to reduce the carbonyl group if carboxylic acid
derivatives are used, and the need of the phenolic
hydroxy group to be protected.20,21
The major methods for functionalizing azacrown mac-
rocycles with proton-ionizable phenol groups include the
following: (1) the Mannich reaction; (2) treatment of an
azacrown ether with a benzyl or benzoyl halide; and (3)
reductive amination with aromatic aldehydes.
The classical Mannich condensation reaction uses
amines, formaldehyde, and an appropriate receptor for
aminomethylation.10 Many variations of this reaction
have been developed. Methoxymethylamines, prepared
quantitatively by treating the azacrown ethers with
paraformaldehyde in MeOH, have been used successfully
in functionalizing azacrown ethers.8,11 This variation
prevents the interaction of free formaldehyde with sub-
stances undergoing aminomethylation and possible side
reactions between amine groups of the azacrown and
functional groups such as carbonyls on the receptor
Reductive amination is another convenient method to
synthesize phenol-containing azacrown ethers. Treat-
ment of the azacrown ethers with the appropriate alde-
(12) Bordunov, A. V.; Lukyanenko, N. G.; Pastushok, V. N.; Kra-
kowiak, K. E.; Bradshaw, J . S.; Dalley N. K.; Kou, X.-L. J . Org. Chem.
1995, 60, 4912.
(13) Bordunov, A. V.; Hellier, P. C.; Bradshaw, J . S.; Dalley, N. K.;
Kou, X.-L.; Zhang, X.-X.; Izatt, R. M. J . Org. Chem. 1995, 60, 6097.
(14) Lukyanenko, N. G.; Pastushok, V. N.; Bordunov, A. V.; Vetrogon,
V. I.; Vetrogen, N. I.; Bradshaw, J . S. J . Chem. Soc., Perkin Trans. 1
1994, 1489.
(9) (a) Lehn, J .-M. Frontiers of Chemistry; Laidler, K. J ., Ed.;
Pergamon Press: Oxford, 1982. (b) Izatt, R. M.; Pawlak, K.; Bradshaw,
J . S.; Bruening, R. L. Chem. Rev. 1991, 91, 1721. (c) Fenton, D. E.;
Casellato, U.; Vigato, P. A.; Vidali, M. Inorg. Chim. Acta 1982, 62, 57.
(d) Zanello, P.; Tamburini, S.; Vigato, P. A.; Mazzocchin, G. A. Coord.
Chem. Rev. 1987, 77, 165. (e) Smith, D. C.; Gray, H. B. Chem. Rev.
1990, 90, 169.
(10) (a) Tramontini, M. Synthesis 1973, 703. (b) Tramontini, M.;
Angliolini, L. Tetrahedron 1990, 46, 1791.
(11) (a) Bogatsky, A. V.; Lukyanenko, N. G.; Pastushok, V. N.;
Kostyanovsky, R. G. Synthesis 1983, 992. (b) Bogatsky, A. V.; Luky-
anenko, N. G.; Pastushok, V. N.; Kostyanovsky, R. G. Dokl. Akad. Nauk
SSSR 1982, 265, 619; Chem Abstr. 1982, 97, 216146c.
(15) Lukyanenko, N. G.; Pastushok, V. N.; Bordunov, A. V. Synthesis
1991, 241.
(16) Pastushok, V. N.; Bradshaw, J . S.; Bordunov, A. V.; Izatt, R.
M. J . Org. Chem. 1996, 61, 6888.
(17) (a) Kimura, E.; Kimura, Y.; Yatsunami, T.; Shionoya. M.; Koike,
T. J . Am. Chem. Soc. 1987, 109, 6212. (b) Czech, A.; Czech, B. P.;
Bartsch, R. A.; Chang, C. A.; Ochaya, V. O. J . Org. Chem. 1988, 53, 5.
(18) Katritzky, A. R.; Belyakov, S. A.; Sorochinsky, A. E.; Steel, P.
J .; Schall, O. F.; Gokel, G. W. J . Org. Chem. 1996, 61, 7585.
(19) (a) Pastushok, V. N.; Hu, K. J .; Bradshaw, J . S.; Dalley, N. K.;
Bordunov, A. V.; Lukyanenko, N. G. J . Org. Chem. 1997, 62, 212. (b)
Hu, K. J .; Bradshaw, J . S.; Pastushok, V. N.; Krakowiak, K. E.; Dalley,
N. K.; Zhang, X.-X.; Izatt, R. M. J . Org. Chem. 1998, 63, 4786.

Diaza-18-Crown-6 Ligands with Aminophenol Side Arms
J . Org. Chem., Vol. 64, No. 11, 1999 3827
Ta ble 1. log K, ∆H (k J /m ol), a n d T∆S (k J /m ol) Va lu es for
In ter a ction s of Ma cr ocyclic Liga n d s w ith Meta l Ion s in
Meth a n ol Solu tion a t 25.0 °C
hydes in dichloroethane in the presence of sodium
triacetoxyborohydride yields the proton-ionizable bis-
lariat azacrown ethers in one step.22,23
ligand
cation
log K
∆H
T∆S
We anticipated that the simplest route to synthesize
compounds 11-13 would be via the Mannich reacction.
However, this reaction with diaza-18-crown-6 and the
aminophenols should lead to a mixture of regioisomers
because both the OH and NH2 groups would activate
different substitution sites. In addition, byproducts with
N-CH2-N linkages24,25 would also form. To avoid these
problems, the amino group was either temporarily pro-
tected as a trifluoroacetamide group or obtained by
hydrogenation of a nitro group after connection of the
nitrophenol to the azacrown ether.
Our approaches to prepare compounds 6-13 are
outlined in Scheme 1. For compound 10, which was first
synthesized by Nishida and co-workers and has been
used to selectively determine the calcium ion concentra-
tion in blood serum,4,21 method ii (Scheme 1) was used.
In the presence of N,N-diisopropylethylamine, R-bromo-
4-nitro-o-cresol (5) was refluxed with diaza-18-crown-6
in MeCN to give 10 in a 74% yield.4,13 The yield is
significantly higher than the 15% yield reported by
Lagow’s group using the one-pot Mannich reaction.6
Thus, for electron deficient phenol compounds, this
method may be the better choice if the appropriate benzyl
halides are available. Method ii also works well for the
reaction of diaza-18-crown-6 with 5,7-dichloro-2-iodo-
methyl-8-quinolinol.23 We found that adding a small
amount of MeOH to the crude product and agitating it
with ultrasound, followed by filtration and vacuum-
drying, gave 10 in high purity. All of the crown ethers
synthesized in this paper were purified by this method
without the need for column chromatography or recrys-
tallization.
Compounds 6-9 were synthesized by the one-pot
Mannich reaction (Scheme 1).6 Trifluoroacetamides 1 and
3, needed to synthesize 6 and 8, were prepared by
treating the corresponding aminophenol with 2.2 equiv
of trifluoroacetic anhydride and 3 equiv of pyridine in
CH2Cl2. The trifluoroacetate was selectively hydrolyzed
by stirring the resulting trifluoroacetate-trifluoroacet-
amide compounds in dry MeOH containing anhydrous
K2CO3 at room temperature for 5 h.26 For the one-pot
Mannich reaction, 2-(trifluoroacetamido)-p-cresol (1) gave
the highest yield (90%) presumably because it is more
electron rich than its 4-chloro analogue 3 and compounds
2 and 4.
6
8
Na+
K+
a
a
-70.0 ( 0.5
-39.7
Cu2+
K+
5.30 ( 0.04
2.72 ( 0.05
-12.1 ( 0.8
-65 ( 3
3.42
>-33.6
9.22
2.87
>-37.6
7.12
Cu2+
Na+
K+
>5.5
11
12
3.00 ( 0.05
2.36 ( 0.08
-7.9 ( 0.8
-10.6 ( 0.7
-69 ( 3
Cu2+
Na+
K+
>5.5
3.42 ( 0.04
-12.4 ( 0.7
a
Ag+
Cu2+
Na+
K+
>5.5
>5.5
2.73 ( 0.06
2.81 ( 0.02
>5.5
1.41 ( 0.05
1.86 ( 0.06
a
-47.9 ( 0.5
-68 ( 3
>-16.5
>-36.7
-9.01
-18.8
>-33.6
25.8
13
-24.6 ( 0.7
-34.8 ( 0.4
-65 ( 3
Cu2+
Na+
Na+
Na+
Cu2+-11b
Cu2+-12
Cu2+-13
17.8 ( 0.6
8.9 ( 0.4
19.5
a
No measurable heat other than heat of dilution indicating that
∆H or/and log K is small. MeOH solutions of Cu2+ ligand (1:1)
b
were titrated by an Na+-MeOH solution.
Compounds 11 and 12 were prepared by removing the
TFA groups of 6 and 8 with 2.0 M NH3 in MeOH27 or by
hydrogenation of the nitro groups of 7 and 9 with 50-60
psi H2 in the presence of PtO2 as catalyst.28 Both methods
gave 11 and 12 in high yields. Compound 13 was only
obtained by hydrogenation of 10.
Interactions of the ligands 6, 8, and 11-13 with Na+,
K+, Ag+, and Cu2+ have been evaluated by a calorimetric
titration technique30 at 25.0 °C in absolute MeOH solu-
tion. The values of equilibrium constants (log K) and
enthalpy (∆H) and entropy changes (T∆S) for these
interactions are listed in Table 1. In most cases, the
ligands form stable complexes with the metal ions
studied. The complexes of Cu2+ and Ag+ are much more
stable than those of Na+ and K+. Among the ligands
studied, 6 shows weaker interaction with Na+, K+, and
Cu2+ than the other ligands. The two o-nitrophenol-
substituted compounds 7 and 9 have very low solubility
in MeOH, and compound 9 (1 × 10-3 M in MeOH) forms
a precipitate with K+. Hence the thermodynamic quanti-
ties involving 7 and 9 were not evaluated.
Ligands 11-13 have been evaluated as heterobinuclear
metal ion receptors. When MeOH solutions of 11-Cu2+
and 12-Cu2+ (1:1) were titrated by Na+, appreciable
interactions were observed as shown by log K values (1.41
and 1.86, respectively, see Table 1). These results indicate
(20) (a) Tsukube, H.; Uenishi, J .; Higaki, H.; Kikkawa, K.; Tanaka,
T.; Wakabayashi, S.; Oae, S. J . Org. Chem. 1993, 58, 4389. (b)
Gustowski, D. A.; Gatto, V. J .; Mallen, J .; Echegoyen, L.; Gokel, G. W.
J . Org. Chem. 1987, 52, 5172. (c) Tsukube, H.; Takagi, K.; Higash-
iyama, T.; Iwachido, T.; Hayama, N. J . Chem. Soc., Perkin Trans. 1
1986, 1033. (d) Tsukube, H.; Yamashita, K.; Iwachido, T.; Zenki, M.
Tetrahedron Lett. 1988, 29, 569.
(21) Nishida, H.; Tazaki, M.; Takagi, M.; Ueno, K. Microchim. Acta
1981, 281.
(22) (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff,
C. A.; Shah, R. D. J . Org. Chem. 1996, 61, 3849. (b) Borch, R. F.;
Hassid, A. I. J . Org. Chem. 1972, 37, 1673. (c) McEvoy, F. J .; Allen, G.
R. J . Med. Chem. 1974, 17, 281.
the formation of heterobinuclear complexes of 11-Cu2+
-
Na+ and 12-Cu2+-Na+. As expected, these log K values
are smaller than those for direct 11-Na+ and 12-Na+
interactions (3.00 and 3.42, respectively). Interactions of
Na+ with 11-Cu2+ and 12-Cu2+ are endothermic (positive
∆H values) while the direct interactions of Na+ with
ligands 11 and 12 are exothermic. It is possible that a
weak interaction between Cu2+ and the diaza-18-crown-6
(23) Yang, Zh.; Bradshaw, J . S.; Zhang, X. X.; Savage, P. B.;
Krakowiak, K. E.; Dalley, N. K.; Su, N.; Bronson, R. T.; Izatt, R. M. J .
Org. Chem. 1999, 64, in press.
(24) (a) Alcock, N. W.; Tasker, P. A. J . Chem. Soc., Chem. Commun.
1972, 1239. (b) Herlt, A. J .; Sargeson, A. M.; Springborg, J .; Taylor,
D.; Geue, R.; Snow, M. R. J . Chem. Soc., Chem. Commun. 1976, 285.
(25) (a) Naik, K. B.; Sahoo, B. Ind. J . Chem. 1982, 21A, 282. (b)
Rout, A. K.; Sahoo, B. Ind. J . Chem. 1984, 23A, 541. (c) Suh, M. P.;
Kang, S.-G. Inorg. Chem. 1988, 27, 2544.
(27) Imazawa, M.; Eckstein, F. J . Org. Chem. 1979, 44, 2039.
(28) Shinkai, S.; Ogawa, T.; Kusano, Y.; Manabe, O.; Kikukawa, K.;
Goto, T.; Matsuda T. J . Am. Chem. Soc. 1982, 104, 1960
(29) (a) Oscarson, J . L.; Izatt, R. M. In Physical Methods of
Chemistry. Vol. VI: Determination of Thermodynamic Properties;
Rossiter, B. W., Baetzold, R. C., Eds.; J ohn Wiley & Sons: New York,
1992; Chapter 7. (b) Izatt, R. M.; Zhang, X.-X.; An, H. Y.; Zhu, C. Y.;
Bradshaw, J . S. Inorg. Chem. 1994, 33, 1007.
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Acta 1972, 3, 219 and 233.
(26) Pyne, S. G. Tetrahedron Lett. 1987, 28, 4737.

3828 J . Org. Chem., Vol. 64, No. 11, 1999
Su et al.
pot Mannich reaction of diaza-18-crown-6 with para-
formaldehyde and the appropriate phenol (to form 6-9)
or reacting the diazacrown with benzyl halide 5 in the
presence of N,N-diisopropylethylamine (to form 10).
Ligands 11 and 12 containing two o-aminophenol sub-
stituents form binuclear complexes with Cu2+ and Na+
as determined by log K values.
Exp er im en ta l Section
1
The H NMR spectra (300 MHz) and 13C NMR spectra (75
MHz) were recorded in DMSO-d6 or CDCl3. FAB ionization
was used to record the high-resolution mass spectra. Solvents
and starting materials were purchased from commercial
sources where available.
F igu r e 1.
7,16-Bis(2-h yd r oxy-5-n it r ob en zyl)-1,4,10,13-t et r a oxa -
7,16-d ia za cycloocta d eca n e (10) (Scheme 1). R-Bromo-4-
nitro-o-cresol (5) (3.90 g, 16.8 mmol) and N,N-diisopropyleth-
ylamine (5.40 mL, 30.5 mmol) were added to a solution of 4,13-
diaza-18-crown-6 (2.00 g, 7.18 mmol) in 200 mL of MeCN. The
resulting mixture was refluxed for 12 h and cooled to room
temperature. After standing overnight, the bright yellow
deposit was filtered and dried. It was further purified by
ultrasonication in a small amount of MeOH followed by
filtration and drying to give 3.20 g (74%) of 10 as a bright
yellow solid. The mp and NMR spectral data were identical to
those reported.6
2-(Tr iflu or oa ceta m id o)-p-cr esol (1) (Scheme 1). To a
solution of 2-hydroxy-5-methylaniline (10.0 g, 81.2 mmol) in
180 mL of CH2Cl2 were added trifluoroacetic anhydride (26.0
mL, 184 mmol) and anhydrous pyridine (20.0 mL, 244 mmol).
The mixture was stirred at room temperature for 24 h, and
the solvent was removed under vacuum. Anhydrous K2CO3
(16.8 g, 122 mmol) and 200 mL of dry MeOH were added, and
the mixture was stirred at room temperature for another 5 h.
The solvent was evaporated, and the resulting solid was
washed with H2O and CHCl3 to give 16.9 g (95%) of 1 as a
light green solid: mp 193-194 °C; 1H NMR (DMSO-d6) δ 2.20
(s, 3 H), 6.83 (d, J ) 8.4 Hz, 1 H), 6.93 (dd, J ) 1.8, 8.1 Hz, 1
H), 7.16 (d, J ) 1.8 Hz, 1 H), 9.65 (s, 1 H), 10.41 (s, 1 H); 13C
NMR (DMSO-d6) δ 20.06, 116.04, 116.84 (q, J CF ) 288.5 Hz),
122.03, 126.61, 127.81, 128.44, 148.95, 155.05 (q, J CF ) 36.3
Hz); HRMS calcd for C9H8F3NO2 (M + H)+ 220.0586, found
220.0582. A satisfactory elemental analysis was obtained for
macrocycle 6, a derivative of 1.
4-Ch lor o-2-tr iflu or oa ceta m id op h en ol (3) (Scheme 1).
Compound 3 was synthesized as above from 5-chloro-2-
hydroxyaniline (10.0 g, 69.6 mmol), trifluoroacetic anhydride
(22.0 mL, 153 mmol), anhydrous pyridine (17.0 mL, 209 mmol),
and K2CO3 (14.4 g, 104 mmol) to give 16.3 g (98%) of 3 as a
light yellow solid: mp 184-185 °C; 1H NMR (DMSO-d6) δ 6.97
(d, J ) 8.4 Hz, 1 H), 7.20 (dd, J ) 2.4, 9.0 Hz, 1 H), 7.455 (d,
J ) 2.4 Hz, 1 H), 10.38 (bs, 1 H), 10.65 (s, 1 H); 13C NMR
(DMSO-d6) δ 111.81 (q, J CF ) 288.6 Hz), 113.35, 117.82, 119.43,
121.71, 123.55, 146.20, 151.00 (q, J CF ) 36.7 Hz); HRMS calcd
for C8H5ClF3NO2 (M + H)+ 240.0040, found 240.0041. A
satisfactory elemental analysis was obtained for macrocycle
8, a derivative of 3.
Gen er a l P r oced u r e for th e On e-P ot Syn th eses of
Com p ou n d s 6-9 Usin g th e Ma n n ich Rea ction (Scheme
1).6 An anhydrous C6H6 solution (180 mL) of 4,13-diaza-18-
crown-6 (1.0 g, 3.81 mmol), paraformaldehyde (280 mg, 9.30
mmol), and the appropriate phenol (9.10 mmol) was refluxed
at 80 °C for 20 h. The solvent was evaporated under reduced
pressure, and a small amount of MeOH was added. The
mixture was ultrasonicated for 20-30 min. The resulting solid
was collected by filtration and dried.
macroring is present in the complexes of 11-Cu2+ and 12-
Cu2+. As Na+ is titrated into the Cu2+ ligand solutions,
this weak interaction is broken by the Na+ ion and Na+
is then complexed in the diaza-18-crown-6 macroring (see
Figure 1). The elimination of Cu2+-macroring interactions
by Na+ would be an energy-consuming process resulting
in positive ∆H values for formation of the heterobinuclear
complexes as was observed. The formation of heterobi-
nuclear complexes of 11-Cu2+-Na+ and 12-Cu2+-Na+
originates from an increase in the entropy changes which
arise from the liberation of organized solvent molecules
in the solvation sphere of Na+ and those associated with
the Cu2+ ligands. These favorable entropy changes over-
come the energetically unfavorable enthalpy change
arising from coordination of Na+ within the ligand cavity.
The soft Cu2+ is probably strongly coordinated by both
amino nitrogen and hydroxy oxygen atoms of two o-
aminophenol side arms of 11 and 12. Unfortunately, solid
crystals of these binuclear complexes could not be isolated
for X-ray analyses.
Although ligand 13 forms a very stable complex with
Cu2+ and a stable complex with Na+, calorimetric titra-
tion shows no interaction between Na+ and the 13-Cu2+
complex. This is not surprising since the two p-ami-
nophenol side arms of 13 could not provide a stable
coordination array for Cu2+. In this case, Cu2+ may be
strongly coordinated by the ring nitrogen atoms and the
two side arm amine nitrogen atoms and not with the
hydroxy groups (see 13-Cu2+ in Figure 1). This would
place Cu2+ in the macrocycle cavity. Therefore, the hard
Na+ would not be able to break the Cu2+-N bonds and
no heterobinuclear complex would form.
We have also examined the interaction between Ag+
and the 12-Cu2+ complex. Calorimetric titration of AgNO3
into a Cu(NO3)2-12 (1:1) solution (halogenide anions may
not be used due to possible interactions with Ag+) showed
a small endothermic effect but the log K value was too
small to be accurately calculated. These results indicate
that Ag+ probably does not form a heterobinuclear
complex with the 12-Cu2+ complex or the stability of 12-
Cu2+-Ag+ is too low to be determined by this method.
Con clu sion
Three bis(aminophenol)-substituted diaza-18-crown-6
ligands (compounds 11-13) were synthesized by reducing
the nitro groups of the corresponding bis(nitrophenol)-
containing ligands or hydrolyzing the trifluoroacetamide
groups of bis(trifluoroacetamidophenol)-containing di-
azacrown ethers. The nitro- or trifluoroacetamido-
containing diazacrown ethers were prepared via the one-
7,16-Bis(2-h yd r oxy-5-m e t h yl-3-t r iflu or oa ce t a m id o-
ben zyl)-1,4,10,13-tetr a oxa -7,16-d ia za cycloocta d eca n e (6)
(Scheme 1). Compound 6 was prepared by the above procedure
1
from 1 to give a white solid; mp 155-157 °C; yield 90%; H
NMR (DMSO-d6) δ 2.20 (s, 6 H), 2.74 (t, J ) 4.8 Hz, 8 H), 3.51
(s, 8 H), 3.59 (t, J ) 4.8 Hz, 8 H), 3.80 (s, 4 H), 6.83 (d, J ) 1.5
Hz, 2 H), 7.12 (d, J ) 1.5 Hz, 2 H); 13C NMR (DMSO-d6) δ

Diaza-18-Crown-6 Ligands with Aminophenol Side Arms
J . Org. Chem., Vol. 64, No. 11, 1999 3829
20.04, 52.98, 57.21, 67.95, 69.89, 116.03 (q, J CF ) 289.1 Hz),
121.80, 123.24, 124.91, 126.93, 127.81, 148.99, 154.70 (q, J CF
) 36.3 Hz); HRMS calcd for C32H42F6N4O8 (M+) 724.2907,
found 724.2899. Anal. Calcd for C32H42F6N4O8: C, 53.04; H,
5.84. Found: C, 53.23; H, 6.05.
C28H44N4O6 (M + Na)+ 555.3159, found 555.3149. Anal. Calcd
for C28H44N4O6: C, 63.13; H, 8.33. Found: C, 62.97; H, 8.21.
7,16-Bis(3-a m in o-5-ch lor o-2-h yd r oxyben zyl)-1,4,10,13-
tetr aoxa-7,16-diazacyclo-octadecan e (12) (Scheme 1). Com-
pound 12 was prepared by the above procedure from 9 to give
a dark yellow solid: mp 126-127 °C; yield 98%; 1H NMR
(CDCl3) δ 2.84 (t, J ) 5.4 Hz, 8 H), 3.61 (s, 8 H), 3.66 (t, J )
5.4 Hz, 8 H), 3.71 (s, 4 H), 3.84 (bs, 4 H); 6.38 (d, J ) 2.4 Hz,
2 H), 6.61 (d, J ) 2.4 Hz, 2 H); 13C NMR (CDCl3) δ 54.01, 58.36,
69.21, 70.94, 114.20, 117.77, 122.94, 123.78, 136.60, 144.03;
7,16-Bis(2-h yd r oxy-5-m et h yl-3-n it r ob en zyl)-1,4,10,13-
tetr a oxa -7,16-d ia za cycloocta d eca n e (7) (Scheme 1). Com-
pound 7 was prepared by the above procedure from 2 to give
a yellow solid: mp 146-148 °C; yield 36%; 1H NMR (CDCl3) δ
2.29 (s, 6 H), 2.88 (t, J ) 5.4 Hz, 8 H), 3.60 (s, 8 H), 3.69 (t, J
) 5.4 Hz, 8 H), 3.90 (s, 4 H), 7.14 (s, 2 H), 7.66 (s, 2 H); 13C
NMR (CDCl3) δ 20.43, 53.91, 57.73, 69.00, 70.99, 124.55,
126.39, 127.91, 135.41, 136.82, 151.85; HRMS calcd for
HRMS calcd for
573.2229. Anal. Calcd for C26H38N4O6: C, 54.45; H, 6.68.
Found: C, 54.60; H, 6.75.
C
26H38N4O6 (M + H)+ 573.2247, found
C
28H40N4O10 (M + Na)+ 615.2624, found 615.2636. Anal. Calcd
7,16-Bis(5-a m in o-2-h yd r oxyben zyl)-1,4,10,13-tetr a oxa -
7,16-d ia za cycloocta d eca n e (13) (Scheme 1). Compound 13
was prepared by the above procedure from 10 to give a light
for C28H40N4O10: C, 56.75; H, 6.80. Found: C, 56.74; H, 6.90.
7,16-Bis(5-ch lor o-2-h yd r oxy-3-t r iflu or oa ce t a m id o-
ben zyl)-1,4,10,13-tetr a oxa -7,16-d ia za cycloocta d eca n e (8)
(Scheme 1). Compound 8 was prepared by the above procedure
from 3 to give a light yellow solid: mp 136-137 °C; yield 64%;
1H NMR (DMSO-d6) δ 2.77 (t, J ) 4.5 Hz, 8 H), 3.51 (s, 8 H),
3.59 (t, J ) 4.5 Hz, 8 H), 3.88 (s, 4 H), 7.14 (d, J ) 2.4 Hz, 2
H), 7.40 (d, J ) 2.4 Hz, 2 H); 13C NMR (DMSO-d6) δ 52.92,
56.54, 67.74, 69.86, 115.87 (q, J CF ) 288.6 Hz), 121.12, 123.29,
124.08, 125.33, 126.78, 150.65, 154.85 (q, J CF ) 36.3 Hz);
1
yellow solid: mp 142-143 °C; yield 98%; H NMR (CDCl3) δ
2.84 (t, J ) 5.4 Hz, 8 H), 3.31 (bs, 4 H), 3.60 (s, 8 H), 3.65 (t,
J ) 5.4 Hz, 8 H), 3.71 (s, 4 H), 6.38 (d, J ) 2.7 Hz, 2 H), 6.54
(dd, J ) 2.7, 8.4 Hz, 2 H), 6.65 (d, J ) 8.1 Hz, 2 H); 13C NMR
(CDCl3) δ 53.90, 58.88, 69.35, 70.91, 116.07, 116.41, 116.93,
123. 29, 138. 45, 150.81; HRMS calcd for C26H40N4O6 (M +
Na)+ 527.2846, found 527.2836. Anal. Calcd for C26H40N4O6:
C, 61.88; H, 7.99. Found: C, 61.94; H, 7.75.
HRMS calcd for
C
30H36Cl2F6N4O8 (M+) 764.1814, found
Gen er a l Meth od for Syn th esizin g Com p ou n d s 11 a n d
12 fr om 6 a n d 8 by Hyd r olyzin g th e TF A Gr ou p s (Scheme
1). The corresponding trifluoroacetamidophenol-containing
crown ether (3 mmol) was added to 20 mL of 2.0 M NH3 in
MeOH and stirred for 20 h. The solvent was removed under
vacuum, and the residue was treated as before to give 11 (95%)
and 12 (97%) which had the same spectra as reported above.
764.1823. Anal. Calcd for C30H36Cl2F6N4O8: C, 47.07; H, 4.74.
Found: C, 47.07; H, 5.01.
7,16-Bis(5-ch lor o-2-h yd r oxy-3-n it r ob en zyl)-1,4,10,13-
tetr a oxa -7,16-d ia za cycloocta d eca n e (9) (Scheme 1). Com-
pound 9 was prepared by the above procedure from 4 to give
a light yellow solid: mp 152-153 °C; yield 41%; 1H NMR
(CDCl3) δ 2.88 (t, J ) 5.4 Hz, 8 H), 3.59 (s, 8 H), 3.70 (t, J )
5.4 Hz, 8 H), 3.95 (s, 4 H), 7.30 (d, J ) 2.7 Hz, 2 H), 7.84 (d,
J ) 2.4 Hz, 2 H); 13C NMR (CDCl3) δ 54.01, 57.72, 68.66, 71.03,
122.58, 124.31, 128.30, 133.87, 137.22, 153.34; HRMS calcd
for C26H34Cl2N4O10 (M + H)+ 633.1731, found 633.1749. Anal.
Calcd for C26H34Cl2N4O10: C, 49.30; H, 5.41. Found: C, 49.52;
H, 5.24.
Gen er a l Meth od for Syn th esizin g Com p ou n d s 11, 12,
a n d 13 fr om 7, 9, a n d 10 by Red u ction w ith H 2 (Scheme
1). To a solution of the corresponding nitrophenol-containing
crown ether (2 mmol) in 50 mL of MeOH was added PtO2 (40
mg). The reaction mixture was shaken under 50-60 psi of H2
until the absorption of H2 ceased (about 5 h). The mixture was
filtered to remove the catalyst, and the solvent was evaporated.
Ultrasonification of the resulting solid in a small amount of
MeOH for 20-30 min followed by filtration and drying gave
the corresponding aminophenol-containing crown ether in
almost quantitative yield.
7,16-Bis(3-a m in o-2-h yd r oxy-5-m eth ylben zyl)-1,4,10,13-
tetr a oxa -7,16-d ia za cycloocta d eca n e (11) (Scheme 1). Com-
pound 11 was prepared by the above procedure from 7 to give
a yellow solid: mp 131-132 °C; yield 98%; 1H NMR (CDCl3) δ
2.17 (s, 6 H), 2.84 (t, J ) 5.4 Hz, 8 H), 3.61 (s), 3.66 (t, J ) 5.4
Hz), 3.71 (s), the peak for four amine hydrogen atoms merged
into the peaks at 3.61, 3.66, and 3.71 as proved by the total
intergration of those peaks (24 H), 6.22 (s, 2 H), 6.47 (s, 2 H);
13C NMR (CDCl3) δ 20.90, 53.95, 58.80, 69.42, 70.93, 115.58,
119.09, 121.75, 128. 45, 135.01, 143.21; HRMS calcd for
Deter m in a tion of Th er m od yn a m ic Qu a n tities. Values
of log K, ∆H, and T∆S were determined as described29 in
absolute MeOH solutions at 25.0 ( 0.1 °C by titration
calorimetry using a Tronac Model 450 calorimeter equipped
with a 20-mL reaction vessel. For single metal ion-ligand
interactions, a metal ion solution was titrated into the mac-
rocyclic ligand solution and the titrations were carried out to
a 2-2.5-fold excess of the metal ions. In general, concentra-
tions of the ligands were 2.0 × 10-3 to 3.0 × 10-3 M and those
of the metal ions were 0.1 M (Na+ and Ag+) and 7.1 × 10-2
M
(K+). In the case of Cu2+, concentrations of the ligands were
1.2 × 10-3 M and that of Cu2+ was 4.0 × 10-2 M. For the
interactions of Na+ and Ag+ with the Cu2+ ligand complexes,
the Na+ or Ag+ solution was titrated into the Cu2+ ligand
solutions and the titrations were carried out to a 2-fold excess
of the Na+ or Ag+. Concentrations of Na+ and Ag+ were 0.1
M, and those of the Cu2+ ligand (1:1) complex were 3.0 × 10-3
M. For the titrations involving Ag+, Cu(NO3)2, instead of CuCl2,
was used. The method used to process the calorimetric data
and to calculate the log K and ∆H values has been described.30
Reagant grade inorganic chemicals were obtained from com-
mercial sources and used without further purification.
Ack n ow led gm en t. This work was supported by the
Office of Naval Research.
J O9816212