Ortho-substituted catechol derivatives: The effect of intramolecular hydrogen-bonding pathways on chloride anion recognition

Article abstract of DOI:10.1021/jo0623989

(Chemical Equation Presented) This paper reports a series of chloride anion receptors containing two catechol head groups connected through their ortho-positions via a spacer chain. The linking group chosen to attach the spacer chain to the catechol units has a major impact on the anion-binding potential of the receptor. Linking groups that are capable of forming stable six-membered intramolecular hydrogen-bonded rings with the catechol O-H groups significantly inhibit the ability of the catechol units to hydrogen bond to chloride anions. However, where the linking groups are only capable of forming five- or seven-membered intramolecular hydrogen-bonded rings, then anion binding via hydrogen bonding through the catechol O-H groups becomes a possibility. This process is solvent dependent; the presence of competitive solvent (e.g., DMSO-d₆) disrupts the intramolecular hydrogen-bonding pattern and enhances anion binding relative to simple unfunctionalized catechol. The most effective receptor is that in which the hydrogen-bonding linker (-CH ₂CONH-) is most distant from the catechol units and can only form a seven-membered intramolecular hydrogen-bonded ring. In this case, the receptor, which contains two catechol units, is a more effective chloride anion binder than simple unfunctionalized catechol, demonstrating that the two head groups, in combination with the N-H groups in the linker, act cooperatively and enhance the degree of anion binding. In summary, this paper provides insight into the hydrogen-bonding patterns in orthofunctionalized catechols and the impact these have on the potential of the catechol O-H groups to hydrogen bond to a chloride anion.

Full text of DOI:10.1021/jo0623989

Ortho-Substituted Catechol Derivatives: The Effect of
Intramolecular Hydrogen-Bonding Pathways on Chloride Anion
Recognition
Keith J. Winstanley and David K. Smith*
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, United Kingdom
dks3@york.ac.uk
ReceiVed NoVember 21, 2006
This paper reports a series of chloride anion receptors containing two catechol head groups connected
through their ortho-positions via a spacer chain. The linking group chosen to attach the spacer chain to
the catechol units has a major impact on the anion-binding potential of the receptor. Linking groups that
are capable of forming stable six-membered intramolecular hydrogen-bonded rings with the catechol
O-H groups significantly inhibit the ability of the catechol units to hydrogen bond to chloride anions.
However, where the linking groups are only capable of forming five- or seven-membered intramolecular
hydrogen-bonded rings, then anion binding via hydrogen bonding through the catechol O-H groups
becomes a possibility. This process is solvent dependent; the presence of competitive solvent (e.g., DMSO-
d6) disrupts the intramolecular hydrogen-bonding pattern and enhances anion binding relative to simple
unfunctionalized catechol. The most effective receptor is that in which the hydrogen-bonding linker
(-CH2CONH-) is most distant from the catechol units and can only form a seven-membered
intramolecular hydrogen-bonded ring. In this case, the receptor, which contains two catechol units, is a
more effective chloride anion binder than simple unfunctionalized catechol, demonstrating that the two
head groups, in combination with the N-H groups in the linker, act cooperatively and enhance the degree
of anion binding. In summary, this paper provides insight into the hydrogen-bonding patterns in ortho-
functionalized catechols and the impact these have on the potential of the catechol O-H groups to hydrogen
bond to a chloride anion.
Introduction
interest in linked bis-catechol-type ligands as metal binders.3
Depending on the nature of the linking group connecting the
catechol units together, such systems can either use both catechol
Catechol derivatives have been the subject of intense interest
over recent years, in no small measure due to their ability to
act as chelating ligands, in analogy with naturally occurring
siderophores, such as enterobactin, which use catechols as
ligating groups for metals.1 This bio-inspiration has led many
research groups to synthesize synthetic analogues of siderophore
structures and explore their potential as ligands for metal
cations.2 Over the past 10 years, there has been significant
(2) d’Hardemare, A. D.; Torelli, S.; Serratrice, G.; Pierre, J. L. Biometals
2006, 19, 349-366.
(3) (a) Enemark, E. J.; Stack, T. D. P. Angew. Chem., Int. Ed. Engl.
1995, 34, 996-998. (b) Kersting, B.; Meyer, M.; Powers, R. E.; Raymond,
K. N. J. Am. Chem. Soc. 1996, 118, 7221-7222. (c) Caulder, D. L.;
Raymond, K. N. Angew. Chem., Int. Ed. Engl. 1997, 36, 1440-1442. (d)
Albrecht, M.; Kotila, S. Angew. Chem., Int. Ed. Engl. 1995, 34, 2134-
2137. (e) Albrecht, M.; Kotila, S. Angew. Chem., Int. Ed. Engl. 1996, 35,
1208-1210. (f) Albrecht, M.; Schneider, M. Eur. J. Inorg. Chem. 2002,
1301-1306. (g) Yeh, R. M.; Ziegler, M.; Johnson, D. W.; Terpin, A. J.;
Raymond, K. N. Inorg. Chem. 2001, 40, 2216-2217.
(1) (a) Braun, V. Front. Biosci. 2003, 8, S1409-S1421. (b) Winkelmann,
G. Biochem. Soc. Trans. 2002, 30, 691-696. (c) Boukhalfa, H.; Crumbliss,
A. L. Biometals 2002, 15, 325-339.
10.1021/jo0623989 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/16/2007
J. Org. Chem. 2007, 72, 2803-2815
2803

Winstanley and Smith
groups to bind a single metal or each catechol can bind a
separate metal, with multiple ligand strands assembling in a
helical manner around the metals.
between the O-H groups and the halide anion.12 However, it
was only in the early 1990s that solution studies began to be
performed. The groups of Aoyama and Koga reported that
phenols could help bind anions, which were predominantly
Recently, Duhme-Klair and co-workers have demonstrated
that synthetic catechol derivatives also have potential in anion
binding, in particular recognizing molybdate anions using a
binding mode in which the deprotonated catecholate binds
directly to the molybdenum center;4 a similar binding mode has
also been employed for the recognition of boric acids.5 In
contrast, we have been exploiting the ability of protonated
catechol to bind anions, in particular the chloride anion,6 as a
consequence of hydrogen bonds between the O-H groups and
the chloride anion. This binding mode of catechol is also
biologically relevant, as O-H‚‚‚anion interactions are observed
in the crystal structure of the ClC chloride transport channel,
with the amino acid side chains of serine and tyrosine being
involved.7
bound as part of an ion pair with a pyridinium cation.13
A
number of other groups subsequently also reported the ability
of OH‚‚‚anion interactions to supplement an existing anion-
binding process. Davis and co-workers made use of steroid
cryptands, in which steroidal O-H groups supplemented the
anion binding afforded by amide N-H groups (in nonpolar
solvents, e.g., CDCl3).14 Meanwhile, Kondo and co-workers used
alcohols to augment the binding strength of simple sulfonamide-
based anion receptors.15 It has also been shown that phenolic
groups on calixarenes can interact with anions16 and that simple
phenolic compounds can be employed as anion sensors.17 In a
recent study, Scott and Libra demonstrated that metal salens
functionalized with phenolic groups showed effective anion
binding via hydrogen-bond interactions.18 Furthermore, Maitra
and co-workers have recently demonstrated that macrocylic
steroids can bind anions in apolar media using O-H groups,
supplemented by C-H‚‚‚anion interactions.19
In 2003, we first reported that catechol was a surprisingly
effective chloride binder,6a and, in 2006, we went on to
investigate this process in more detail and demonstrate that it
could optically sense fluoride anions.6b We therefore became
interested in combining multiple catechol units to try and
enhance the anion-binding event. We reasoned that this approach
would be analogous to the development of siderophore ligands
for metal cations, only in the case of siderophores, the active
ligand contains deprotonated catecholates, whereas in our case,
anion binding would be achieved using the protonated catechol
form of the ligand to ultimately yield “siderophores” for anions.
In this paper, we report the synthesis of a range of catechol
derivatives and uncover the factors that control their anion-
binding potential. We report that these receptors, which bind
anions via hydrogen bonding, are remarkably sensitive to the
internal hydrogen-bonding possibilities of the receptor frame-
work.
Anion binding is of intense current interest,8 in particular the
ability of receptor species to act as transport agents for anions
across synthetic membranes.9 The importance of defective
chloride transport channels in the pathology of cystic fibrosis
means this research has biomedical relevance.10 Given the
biomimetic importance of O-H‚‚‚anion interactions, we find
it particularly surprising that there have been only limited
systematic investigations of this kind of anion-binding interac-
tion, whereas amides and ureas have been extensively studied
in this way.11 Indeed, only a few studies over the past 20 years
have reported the use of O-H groups as a key component in
achieving anion binding. Crystal structures from the 1980s
showed that phenols and catechols crystallized in the presence
of tetrabutylammonium halides had hydrogen-bond interactions
(4) (a) Duhme-Klair, A.-K.; Vollmer, G.; Mars, C.; Fro¨hlich, R Angew.
Chem., Int. Ed. 2000, 39, 1626-1628. (b) Jedner, S. B.; James R.; Perutz,
R. N.; Duhme-Klair, A.-K. J. Chem. Soc., Dalton Trans. 2001, 2327-2329.
(c) Peacock, A. F. A.; Batey, H. D.; Ra¨ndler, C.; Whitwood, A. C.; Perutz,
R. N.; Duhme-Klair, A.-K. Angew. Chem., Int. Ed. 2005, 44, 1712-1714.
(5) (a) Pizer, R.; Babcock, L. Inorg. Chem. 1977, 16, 1677-1681. (b)
Graf, E.; Hosseini, M. W.; Ruppert, R.; De Cian, A.; Fischer, J. J. Chem.
Soc., Chem. Commun. 1995, 1505-1506. (c) Gallant, A. J.; Hui, J. K.-H.;
Zahariev, F. E.; Wang, Y. A.; MacLachlan, M. J. J. Org. Chem. 2005, 70,
7936-7946.
(6) (a) Smith, D. K. Org. Biomol. Chem. 2003, 1, 3874-3877. (b)
Winstanley, K. J.; Sayer, A. M.; Smith, D. K. Org. Biomol. Chem. 2006,
4, 1760-1767.
(7) Dutzler, R.; Campbell, E. B.; Cadene, M.; Chait, B. T.; MacKinnon,
R. Nature 2002, 415, 287-294.
Results and Discussion
Strategy. We aimed to synthesize a library of potential
catechol-based anion receptors with different linking groups in
(8) Gale, P. A. Coord. Chem. ReV. 2003, 240, 1 and articles therein.
(9) (a) Smith, B. D.; Lambert, T. N. Chem. Commun. 2003, 2261-2268.
(b) Koulov, A. V.; Lambert, T. N.; Shukla, R.; Jain, M.; Boon, J. M.; Smith,
B. D.; Li, H.; Sheppard, D. N.; Joos, J.-B.; Clare, J. P.; Davis, A. P. Angew.
Chem., Int. Ed. 2003, 42, 4931-4933. (c) McNally, B. A.; Koulov, A. V.;
Smith, B. D.; Joos, J. B.; Davis, A. P. Chem. Commun. 2005, 1087-1089.
(d) Djedovic, N.; Ferdani, R.; Harder, E.; Pajewska, J.; Pajewski, R.; Weber,
M. E.; Schlesinger, P. H.; Gokel, G. W. New J. Chem. 2005, 29, 291-305.
(10) (a) Rosenstein, B. J.; Zeitlin, P. L. Lancet 1998, 351, 277-282. (b)
Broughman, J. R.; Shank, L. P.; Takeguchi, W.; Schultz, B. D.; Iwamoto,
T.; Mitchell, K. E.; Tomich, J. M. Biochemistry 2002, 41, 7350-7358 and
references therein.
(11) For reviews, see: (a) Bondy, C. R.; Loeb, S. J. Coord. Chem. ReV.
2003, 240, 77-99. (b) Go´mez, D. E.; Fabbrizzi, L.; Licchelli, M.; Monzani,
E. Org. Biomol. Chem. 2005, 3, 1495-1500. For more recent papers, see:
(c) Brooks, S. J.; Gale, P. A.; Light, M. E. Chem. Commun. 2006, 4344-
4346. (d) Kim, Y. J.; Kwak, H.; Lee, S. J.; Lee, J. S.; Kwon, H. J.; Nam,
S. H.; Lee, K.; Kim, C. Tetrahedron 2006, 62, 9635-9640. (e) Stanley, C.
E.; Clarke, N.; Anderson, K. M.; Elder, J. A.; Lenthall, J. T.; Steed, J. W.
Chem. Commun. 2006, 3199-3201. (f) Blanco, J. L. J.; Bootello, P.; Benito,
J. M.; Mellet, C. O.; Fernandez, J. M. G. J. Org. Chem. 2006, 71, 5136-
5143. (g) Schazmann, B.; Alhashimy, N.; Diamond, D. J. Am. Chem. Soc.
2006, 128, 8607-8614. (h) Gunnlaugsson, T.; Kruger, P. E.; Jensen, P.;
Tierney, J.; Ali, H. D. P.; Hussey, G. M. J. Org. Chem. 2005, 70, 10875-
10878.
(12) (a) Khan, M. A.; McCulloch, A. W.; McInnes, A. G. Can. J. Chem.
1985, 63, 2119-2122. (b) Khan, M. A. J. Mol. Struct. 1986, 145, 203-
218. (c) Weglikowska, U. D.; Hawkins, E. H.; Thiery, D.; von Schnering,
H. G. Z. Kristallogr. 1991, 197, 115-120. (d) Goddard, R.; Herzog, H.
M.; Reetz, M. T. Tetrahedron 2002, 58, 7847-7850.
(13) (a) Motomura, T.; Aoyama, Y. J. Org. Chem. 1991, 56, 7224-
7228. (b) Manabe, K.; Okamura, K.; Date, T.; Koga, K. J. Am. Chem. Soc.
1992, 114, 6940-6941.
(14) Davis, A. P.; Gilmer, J. F.; Perry, J. J. Angew. Chem., Int. Ed. Engl.
1996, 35, 1312-1315.
(15) (a) Kondo, S.-i.; Suzuki, T.; Yano, Y. Tetrahedron Lett. 2002, 43,
7059-7061. (b) Kondo, S.; Suzuki, T.; Toyama, T.; Yano, Y. Bull. Chem.
Soc. Jpn. 2005, 78, 1348-1350.
(16) (a) Arduini, A.; Giorgi, G.; Pochini, A.; Secchi, A.; Ugozzoli, F. J.
Org. Chem. 2001, 66, 8302-8308. (b) Ito, K.; Miki, H.; Ohba, Y. Yakugaku
Zasshi 2002, 122, 413-417.
(17) (a) Miyaji, H.; Sessler, J. L. Angew. Chem., Int. Ed. 2001, 40, 154-
157. (b) Lee, D. H.; Lee, K. H.; Hong, J. I. Org. Lett. 2001, 3, 5-8. (c)
Lee, D. H.; Lee, H. Y.; Lee, K. H.; Hong, J. I. Chem. Commun. 2001,
1188-1189. (d) Lee, K. H.; Lee, H. Y.; Lee, D. H.; Hong, J. I. Tetrahedron
Lett. 2001, 42, 5447-5449. (e) Lee, C.; Lee, D. H.; Hong, J. I. Tetrahedron
Lett. 2001, 42, 8665-8668.
(18) Libra, E. R.; Scott, M. J. Chem. Commun. 2006, 1485-1487.
(19) Ghosh, S.; Choudhury, A. R.; Guru Row, T. N.; Maitra, U. Org.
Lett. 2005, 7, 1441-1444.
2804 J. Org. Chem., Vol. 72, No. 8, 2007

Anion Binding with Catechol DeriVatiVes
SCHEME 1. Synthesis of Amide (CONH)-Linked Receptors
4-6a
FIGURE 1. Chelate binding mode between catechol and chloride
anions leads to effective anion binding.
TABLE 1. Summary of Binding Constants (K, mol-1 dm3, (10%)
Determined by Fitting NMR Titration Data to a 1:1 Model for
Receptors with Chloride Anions in Different Solvent Systemsa
K (mol-1 dm3)
K (mol-1 dm3)
CD3CN:DMSO-d6 (9:1)
receptor
type of linkage
CD3CN
catechol none
1575
-
100
25
25
25
<5
-
<5
-
110
115
235
4
5
6
11
12
14
18
21
22
24
amide (-CONH-)
amide (-CONH-)
amide (-CONH-)
ester (-COO-)
-
-
-
imine (-CdN-)
5b
amide (-CH2NHCO-)
amine (-CH2NH-)
amide (-NHCO-)
amide (-NHCO-)
amide (-CH2CONH-)
-
<5
270
185
-
a The symbol “-” represents “not measured”, usually due to lack of
solubility. Bold amounts represent the optimum binding in a given solvent.
b Binding measured in CDCl3 due to insolubility in CD3CN.
a (a) SOCl2; (b) H2N-R-NH2 Et3N, CH2Cl2, 25% (1), 43% (2), 64%
(3); (c) BBr3, CH2Cl2, 14% (4), 21% (5), 27% (6).
the ortho-position and investigate their ability to bind chloride
anions in apolar media. We hoped that these studies would allow
us to determine the effect of the linking group on the ability of
the catechol head groups to bind a simple anionic target, and
we also hoped to improve on the ability of simple unfunction-
alized catechol to bind anions. For purposes of comparison, the
ability of simple catechol to bind chloride anions was initially
determined by NMR titration. NMR titrations were the method
of choice in this paper as they enable the effects of hydrogen
bonding in anion binding to be clearly visualized; furthermore,
other techniques, such as UV-vis titrations, only led to small
changes in intensity. We have previously reported the binding
affinity of catechol for chloride anions in CD3CN solution,
where the Ka value was relatively high, 1575 mol-1 dm3
(Figure 1).6a For this new study, we also determined the binding
strength in CD3CN:DMSO-d6 (9:1). Fitting the data to a 1:1
binding model gave a binding constant, Ka, of 100 mol-1 dm3
(Table 1). This expected drop in binding strength is a conse-
quence of the higher polarity of DMSO-d6, and its greater ability
to form competitive intermolecular hydrogen bonds with the
O-H protons. We anticipated that on comparison with simple
catechol, our new linked bis-catechol receptors, although
flexible, should exhibit an enhanced degree of anion-binding
potential due to the presence of multiple hydrogen-bonding
catechol units capable of cooperating in anion recognition.
Catechols Linked via Amide (-CONH-) Groups. Our
initial target receptors each contained two ortho-substituted
catechol units connected with flexible spacer groups via amide
(-CONH-) linking groups. The synthesis of three compounds
with spacer chains of different lengths was achieved via methyl
ether protected intermediates. 2,3-Dimethoxybenzoic acid was
converted to the acid chloride with neat thionyl chloride and
then reacted with the appropriate diaminoalkane in the presence
of triethylamine to give protected compounds 1-3 in acceptable
yields. Methyl ethers 1-3 were subsequently deprotected using
BBr3 in dry CH2Cl2 to provide receptors 4-6 (Scheme 1).
Purification was achieved using washing/recrystallization pro-
tocols and yielded the target materials in low, but acceptable
yields. It should be noted that compounds 4 and 5 have
previously been synthesized and investigated as metal sequestra-
tion agents by Raymond and co-workers,20 while 4-6 have been
investigated to the same end by Bhargava et al.21
A crystal of compound 6 was grown from methanol
(Figure 2). It is worth noting that the two catechol head groups
are involved in intramolecular hydrogen-bonding networks with
the amide group of the linker unit (CdO‚‚‚H-O‚‚‚H-O). The
CdO group of the amide forms a hydrogen bond with the ortho
O-H group of the catechol, while the meta O-H group forms
a hydrogen-bond interaction with the oxygen atom in the ortho
location (Figure 3). This type of hydrogen-bonding pattern is
well-known for amide-functionalized catechol units,22 with the
intramolecular CdO‚‚‚H-O hydrogen bond constituting a stable
six-membered ring. There is also solution-phase evidence for
the existence of this intramolecular hydrogen-bonding pattern.
1
Two discrete O-H resonances were observed in the H NMR
spectrum of compound 6, and in DMSO-d6 solution, at ca. 12.9
and 9.2 ppm. The strongly downfield shifted O-H proton at
12.9 ppm indicates a strongly deshielded environment, consistent
with the presence of a very stable intramolecular hydrogen bond
in solution.
In unfunctionalized catechol, one of the O-H groups forms
an O-H‚‚‚O intramolecular hydrogen bond with the other
oxygen. This leaves the other hydrogen atom available, and
crystallography has previously shown that the presence of a
chloride anion is sufficient to break the intramolecular O-H‚
‚‚O hydrogen bond, and the two O-H groups then hydrogen
bond to the chloride anion in a chelate manner.12
We investigated the ability of compounds 4-6 to bind
tetrabutylammonium chloride. The studies were performed in
(20) Weitl, F. L.; Raymond, K. N. J. Am. Chem. Soc. 1980, 102, 2289-
2293.
(21) Bhargava, K. K.; Grady, R. W.; Cerami, A. J. Pharm. Sci. 1980,
69, 986-989.
(22) (a) Hay, B. P.; Dixon, D. A.; Vargas, R.; Garza, J.; Raymond, K.
N. Inorg. Chem. 2001, 40, 3922-3935. (b) Dertz, E. A.; Xu, J.; Raymond,
K. N. Inorg. Chem. 2006, 45, 5465-5478.
J. Org. Chem, Vol. 72, No. 8, 2007 2805

Winstanley and Smith
FIGURE 2. Crystal structure of compound 6 grown from methanol solution, illustrating the intramolecular CdO‚‚‚H-O‚‚‚H-O hydrogen-bond
pathway.
SCHEME 2. Synthesis of Ester-Linked Compound 11a
FIGURE 3. Intramolecular hydrogen-bond pathway proposed for
compounds 4-6, which inactivates the ability of the catechol O-H
groups to hydrogen bond with anionic guests.
CD3CN:DMSO-d6 (9:1) due to lack of solubility in 100% CD3-
CN. Disappointingly, when the data were fitted to a 1:1 binding
model, these receptors exhibited weaker chloride binding than
simple unfunctionalized catechol (Table 1). Furthermore, there
was no noticeable effect of the spacer chain on the binding
affinity for chloride; it might have been expected that changing
the length of this unit would modify the strength or stoichiom-
etry of halide anion binding.23
We therefore postulate that in receptors 4-6 the presence of
the amide unit in the linking group prevents initial binding of
either catechol O-H group to the anion and hence switches
off binding. We argue that the small amount of residual binding
observed for compounds 4-6 (Ka ca. 25 mol-1 dm3) can be
attributed to interaction of the amide N-H groups with the
anion, rather than the catechol O-H groups. In support of this
hypothesis, it is worth noting that the NH resonance was the
most perturbed peak during the NMR titration. Notably, the
induced shift of the N-H peak (on addition of 5 equiv of
tetrabutylammonium chloride) was significantly greater for the
compounds with shorter spacer chains (4, ∆δ ) 0.332 ppm; 5,
∆δ ) 0.276 ppm; 6, ∆δ ) 0.208 ppm). This indicates that the
two amide (N-H) protons may act cooperatively in binding
the chloride anion.
Catechols Linked via Ester (-COO-) Groups. To explore
the hypothesis proposed above, we decided to synthesize an
ester-linked receptor (11) analogous to amide-linked compound
6. We reasoned that the CdO group should still form the
intramolecular hydrogen bond, which inactivates the catechol
O-H groups, but in this case there would be no N-H group to
provide residual anion binding.
For the synthesis of an ester-linked receptor (Scheme 2), we
could not employ a methyl ether protection-deprotection
scheme analogous to that used to synthesize amide-linked 4-6,
as we were concerned about potential ester hydrolysis during
the final BBr3-mediated deprotection step. As a consequence,
we made use of a benzyl ether protecting group strategy. 2,3-
Dihydroxybenzoic acid was protected as a methyl ester (7) using
thionyl chloride in methanol.24 The hydroxy groups were then
a (a) SOCl2, MeOH, 50%; (b) BnBr, NaI, K2CO3, DMF, 81%; (c) NaOH,
MeOH, 1,4-dioxane, 50%; (d) HO(CH2)8OH, DCC, DMAP, CH2Cl2, 47%;
(e) H2, 10% Pd-C, EtOH, 71%.
benzylated with benzylbromide in dry DMF, using K2CO3 as
base and NaI to enhance reactivity of the bromide, providing
compound 8 in excellent yield.24 Hydrolysis of the methyl ester
to give carboxylic acid 9 was achieved using standard basic
conditions and proceeded in acceptable yield.24 Ester coupling
to yield compound 10 was achieved using dicyclohexylcarbo-
diimide (DCC) and a catalytic amount of dimethylaminopyridine
(DMAP). Finally, the benzyl ether protecting groups were
removed by hydrogenation with 10% Pd/C to provide ester-
linked target compound 11.
(23) See, for example: Beer, P. D.; Hesek, D.; Kingston, J. E.; Smith,
D. K.; Stokes, S. E. Organometallics 1995, 14, 3288-3295.
(24) Sharma, S. K.; Miller, M. J.; Payne, S. M. J. Med. Chem. 1989, 32,
357-367.
On investigating the chloride binding ability of this compound
via the NMR titration method, there were no significant shifts
in the NMR spectrum, and the binding constant was therefore
2806 J. Org. Chem., Vol. 72, No. 8, 2007

Anion Binding with Catechol DeriVatiVes
SCHEME 3. Synthesis of Imine (CdN)-Linked Compound
SCHEME 4. Synthesis of Amide (-CH2NHCO-)-Linked
12a
Receptor 14a
a (a) H2N(CH2)8NH2, MeOH, 90%.
FIGURE 4. Proposed intramolecular hydrogen-bond pathway in imine-
linked receptor 12.
considered to be negligible (Table 1). This was in agreement
with our hypothesis that the intramolecular CdO‚‚‚H-O‚‚‚H-O
hydrogen-bond pathway completely inactivates the anion-
binding potential of both catechol O-H groups and supports
the argument that the only reason compounds 4-6 show some
weak affinity for chloride is due to the residual affinity of the
N-H protons for the anion.
a (a) ClOC(CH2)6COCl, Et3N, CH2Cl2, 58%; (b) BBr3, CH2Cl2, 32%.
Catechols Linked via Imine Groups. Imine-linked com-
pound 12 was synthesized in excellent yield by the simple
condensation of 2,3-dihydroxybenzaldehyde and 1,8-diaminooc-
tane (Scheme 3). Related catechol imines have previously been
reported by Albrecht and co-workers with regard to their metal
binding ability.25 This compound would be expected to form a
CdN‚‚‚H-O intramolecular hydrogen-bonded six-membered
ring (Figure 4). Indeed, it has be shown that certain ortho-
substituted catechol imines have such strong intramolecular
hydrogen bonds that proton exchange and tautomerization can
occur.25,26
FIGURE 5. Proposed intramolecular hydrogen bonds in (a) amide-
linked 14 and (b) amine-linked 18.
As may have been predicted based on the hypothesis above,
the chloride affinity of this receptor was very low. Solubility
limited the chloride binding studies to chloroform, but even in
this noncompetitive solvent, the observed shifts were very small
(<0.01 ppm), and a binding constant could not be determined
(Table 1). Once again, this illustrates the role the ortho-
substituent plays in deactivating the hydrogen-bonding potential
of the catechol O-H groups, making them unavailable for
chloride binding.
Catechols Linked via Amide and Amine (-CH2NHCO-
and -CH2NH-) Groups. We then decided to synthesize
compounds in which the hydrogen-bond (CdX) acceptor present
in compounds 4-6, 11, and 12 was replaced with a potential
hydrogen-bond donor group (N-H). We therefore targeted
substituted catechols in which a CH2NH group was located in
the ortho position. Albrecht and co-workers have recently
employed this type of -CH2NHCO- linkage in the synthesis
of various catechol-derived metal-binding ligands.27 First, 2,3-
dimethoxyphenylaniline was reacted with bis-acid chloride to
yield compound 13, which on BBr3-mediated deprotection gave
rise to target amide-linked compound 14 (Scheme 4).
Compound 14 has an N-H group in an appropriate position
to form an N-H‚‚‚O-H hydrogen bond. This has not previously
been reported by Albrecht for the neutral catechols with this
type of ortho-linkage, although it is known that the N-H group
interacts with the deprotonated catechol in this manner.27 This
pattern of intramolecular hydrogen bonding should leave a single
O-H group of the catechol uninvolved in the hydrogen-bonding
network and hence available for binding to chloride (Figure 5a).
Our NMR evidence supported this proposal, with one of the
O-H protons being more sensitive to changes in solvent than
the other. We reasoned initial chloride binding might then
encourage the intramolecular hydrogen-bond network to break
and yield high affinity chelate-mode anion binding. However,
when the binding of compound 14 with chloride was investi-
gated in CD3CN:DMSO-d6 (9:1), the shifts in NMR peaks were
negligible, and a binding constant could not be determined. It
seems likely that, once again, the six-membered intramolecular
hydrogen-bonded ring is too stable and cannot be disrupted by
the presence of chloride anions.
(25) Albrecht, M.; Janser, I.; Fro¨hlich, R. Chem. Commun. 2005, 157-
165 and references therein.
(26) Pizzala, H.; Carles, M.; Stone, W. E. E.; Thevand, A. J. Chem.
Soc., Perkin Trans. 2 2000, 935-939 and references therein.
(27) (a) Albrecht, M.; Napp, M.; Schneider, M.; Weis, P.; Fro¨hlich, R.
Chem.-Eur. J. 2001, 7, 3966-3975. (b) Albrecht, M.; Zauner, J.; Eisele,
T.; Weis, P. Synthesis 2003, 1105-1111.
To synthesize amine-linked compound 18 (Scheme 5),
attempts were initially were made to reduce imine 12; however,
decomposition was observed during the reduction step. We next
attempted a synthetic strategy that made use of methyl-ether
J. Org. Chem, Vol. 72, No. 8, 2007 2807

Winstanley and Smith
SCHEME 5. Synthesis of Amine (-CH2NH-)-Linked
Receptor 18a
FIGURE 6. Proposed hydrogen-bonding pattern in receptors 21 and
22 incorporating a five-membered intramolecular hydrogen-bonded ring.
1
tion that in the H NMR spectra of methyl-ether protected
compound 17 the Ar-CH2-NH protons appear at 3.78 ppm,
while in compound 18, with free O-H groups, this resonance
has shifted downfield to 3.95 ppm. Crystallographic evidence
for the interaction of catechol O-H groups with basic nitrogens
has also previously been reported.29 This proposal is also
supported by the observed instability of compound 18, as
deprotonated catechols are known to be oxidized more readily
than their protonated analogues.30 Such an intramolecular
hydrogen-bonded system (Figure 5b) has no free O-H protons
available for hydrogen bonding to chloride anions.
Catechols Linked via Amide (-NHCO-) Groups. We then
targeted the synthesis of amide-linked catechols in which the
amide functional group was directly attached to the catechol
ring, but inverted (i.e., NHCO rather than CONH). In this
system, only five-membered intramolecular hydrogen-bonded
rings would be expected, rather than six-membered rings, and
we were interested in the impact of this on the anion-binding
process (Figure 6). References reporting the synthesis of
catechols with this type of ortho-linkage are surprisingly
limited.31 Amide (-NHCO-)-linked compounds 19 and 20
were formed by simply reacting the appropriate bis-acid chloride
with 2,3-dimethoxyaniline in the presence of Et3N, using
CH2Cl2 as solvent. Boron tribromide-mediated deprotection of
19 and 20 gave rise to linked-catechol target compounds 21
and 22 (Scheme 6).
a (a) BnBr, K2CO3, NaI, DMF, 74%; (b) H2N(CH2)8NH2, MeOH, 90%;
(c) NaBH4, MeOH, 35%; (d) H2, 10% Pd/C, EtOH, 80%.
protecting groups. However, the final BBr3-mediated deprotec-
tion yielded the target amine (18) in protonated form; this could
not be deprotonated without also deprotonating the catechol
O-H groups. We therefore synthesized the amine-linked
compound using an alternative approach in which the catechol
OH groups were protected as benzyl ethers. 2,3-Dihydroxy-
benzaldehyde was benzylated using benzyl bromide in dry DMF
with K2CO3 and NaI to give compound 15 in excellent yield.28
This compound was then converted to imine 16 in 90% yield
by reaction with 1,8-diaminooctane in methanol. Reduction of
this imine with NaBH4 over a period of 2 h gave compound 17
in moderate yield. Finally, debenzylation using H2 and 10%
Pd/C in ethanol yielded target amine 18. However, it should be
noted that this compound had a relatively limited shelf life
(ca. 1 week).
On titration with tetrabutylammonium chloride, compound
18 also exhibited very small NMR shifts, and once again a
reliable binding constant could not be determined. For this
compound, the amine N-H group can act either as a hydrogen-
bond donor (through the H atom) or as a hydrogen-bond
acceptor (through the N atom). The lack of anion binding is
consistent with a model in which the nitrogen accepts a
hydrogen bond from the ortho catechol O-H group. Indeed,
intramolecular proton transfer can then occur, to yield a
protonated amine and a deprotonated catechol unit (Figure 5b).
Experimental support for this proposal comes from the observa-
It was noted that in the 1H NMR spectrum of compound 21,
the N-H (amide) peaks appeared downfield of their expected
position (ca. 9.5 ppm for compound 21 in DMSO-d6 as
compared to 8.8 ppm for compound 6 in the same solvent).
This is consistent with the amide N-H group of compound 21
being involved in an intramolecular N-H‚‚‚O-H hydrogen
bond, forming a five-membered ring (Figure 6), although it
should be noted the N-H group is also now directly attached
to the aromatic ring. In this hydrogen-bond pattern, the O-H
group in the ortho position would form a hydrogen bond with
the O-H group in the meta position. However, the proton of
the meta O-H group would not be involved in the hydrogen-
bond pathway.
1
This proposal was further supported by measuring the H
NMR spectra of compound 22 in different solvents (Figure 7).
On changing the solvent from CD3CN to CD3CN:DMSO-d6
(9:1), one of the O-H protons (proton 2) shifted ca. 1.7 ppm
downfield (appearing from underneath an aromatic signal), while
the other O-H proton (proton 1) only moved about 0.2 ppm,
and in this case was shifted upfield. Proton 2 shifts 1.7 ppm
(29) Bazzicalupi, C.; Bencini, A.; Bianchi, A.; Fusi, V.; Giorgi, C.;
Messori, L.; Migliorini, M.; Paoletti, P.; Valtancoli, B. J. Chem. Soc., Dalton
Trans. 1998, 359-367.
(30) Cornard, J.-P.; Rasmiwetti Merlin, J.-C. Chem. Phys. 2005, 309,
239-249.
(28) Ve´riot, G.; Dutasta, J.-P.; Matouzenko, G.; Collet, A. Tetrahedron
1995, 51, 389-400.
(31) For an example, see: Whiteley, C. G. Bioorg. Med. Chem. 2002,
10, 1221-1227.
2808 J. Org. Chem., Vol. 72, No. 8, 2007

Anion Binding with Catechol DeriVatiVes
SCHEME 6. Synthesis of Amide (-NHCO-)-Linked
Compounds 21 and 22 were then titrated with tetrabutylam-
monium chloride in CD3CN:DMSO-d6 (9:1), and significant
shifts were observed in the H NMR spectra (Figure 8). The
Receptors 21 and 22a
1
N-H proton exhibited a large downfield shift, followed by a
small upfield shift (Figure 8A), while the aromatic protons
showed a gradual, large downfield shift (Figure 8B). The O-H
protons were broadened during the titration and could not be
followed directly; however, the large shift in the aromatic proton
suggests the O-H groups are directly involved in binding the
chloride anion.
The differences in titration curve shape for different protons
indicate that the binding process cannot be a simple 1:1 binding
event. However, Job plot methods indicated that the aromatic
protons could be fitted to a 1:1 binding model (Figure 9), and
we therefore calculated apparent 1:1 binding constants using
the titration profiles for these aromatic protons (Table 1). This
does not explain the shape of the binding curve for the N-H
proton shown in Figure 8A (for further discussion, see below).
The data for compound 21 could be handled in exactly the same
way as those for compound 22.
We performed binding experiments in both CD3CN and CD3-
CN:DMSO-d6 (9:1). Interestingly, both receptors are slightly
more effective than unfunctionalized catechol in CD3CN:
DMSO-d6 (9:1), but much less effective in CD3CN. When the
solvent becomes more competitive (i.e., addition of DMSO),
this will disrupt the intramolecular hydrogen-bonded pattern.
Therefore, we propose that, in CD3CN:DMSO-d6 (9:1), both
catechol O-H groups can bind to anions, and the strength and
mode of binding is analogous to that of catechol itself. In
acetonitrile, however, the intramolecular hydrogen-bond patterns
of 21 and 22 remain intact, and therefore each catechol group
can only employ the one “free” O-H group (proton 2) to
a (a) ClOC(CH2)nCOCl, Et3N, CH2Cl2, 71% (19), 33% (20); (b) BBr3,
CH2Cl2, 40% (21), 35% (22).
downfield because on the addition of 10% DMSO, an inter-
molecular hydrogen bond can be formed to this solvent-exposed
proton. Proton 1 shifts less dramatically because this proton is
already in an intramolecular hydrogen-bonded environment. We
propose that the small upfield shift is observed because this
intramolecular hydrogen-bond pattern is disrupted by the
presence of DMSO.
FIGURE 7. NMR spectra of compound 22 measured in (A) CD3CN:DMSO-d6 (9:1), and (B) CD3CN. Note the large solvent-dependent response
of proton 2.
J. Org. Chem, Vol. 72, No. 8, 2007 2809

Winstanley and Smith
FIGURE 8. NMR titration profiles for the addition of tetrabutylammonium chloride to compound 22 in CD3CN:DMSO-d6 (9:1): (A) N-H
proton, and (B) Ar-H proton.
FIGURE 9. Job plot analysis for the Ar-H proton of compound 22 on the addition of tetrabutylammonium chloride in CD3CN:DMSO-d6 (9:1),
indicating 1:1 stoichiometry is a reasonable assumption when fitting this proton.
SCHEME 7. Synthesis of Amide (-CH2CONH-)-Linked
Receptor 24a
FIGURE 10. Proposed chloride binding modes for compounds 21 and
22 in different solvents.
a (a) H2N(CH2)6NH2, DCC, HOBt, Et3N, CH2Cl2, 15%; (b) BBr3, CH2Cl2,
20%.
FIGURE 11. Proposed intramolecular seven-membered hydrogen-
bonded ring in compound 24.
have higher binding constants than this, suggesting that the two
hydrogen bond with the chloride anion; therefore, the binding
catechol head groups may act cooperatively. Furthermore,
is weaker (Figure 10).
compound 21, with the shorter spacer chain, shows higher
affinity chloride anion binding than compound 22, presumably
because the “free” OH groups on each of the two head groups
We previously reported that in CD3CN, simple phenols had
binding constants typically ranging from 50 to 100 mol-1 dm3.6a
It is worth noting that in CD3CN, both compounds 21 and 22
2810 J. Org. Chem., Vol. 72, No. 8, 2007

Anion Binding with Catechol DeriVatiVes
FIGURE 12. Summary of potential intramolecular hydrogen-bonding patterns and consequent chloride recognition pathways.
are closer together and are more able to bind cooperatively to
the anionic guest.
for analogous -CONH-linked receptors 4-6. We propose this
is because the five-membered intramolecular ring in receptors
21 and 22 is more labile and can therefore be disrupted by
DMSO and chloride anions, unlike the six-membered intramo-
lecular ring in receptors 4-6.
The unusual titration curve shape observed for the N-H
protons in compounds 21 and 22 (Figure 7A) could also be
explained by this proposal. Initially, the N-H proton is involved
in the intramolecular hydrogen-bond network. We propose that
the addition of chloride anions has several different effects: (i)
the anion binds to the O-H groups, which will also perturb
the N-H resonance, (ii) the intramolecular hydrogen-bond
pattern is disrupted, and (iii) residual chloride anions may also
be able to interact with the “free” N-H proton (as in compounds
4-6). This combination of factors will lead to more complex
lineshapes, such as that observed in Figure 7A.
Catechols Linked via Amide (-CH2CONH-) Groups. We
also targeted the synthesis of another receptor in which a CH2
group was incorporated between the catechol ring and an amide
(CONH) functionality. This unusual type of linking group
prevents the formation of either five- or six-membered intramo-
lecular hydrogen-bonded rings. 2,3-Dimethoxyphenylacetic acid
was reacted with 1,6-diaminohexane under DCC/HOBt coupling
conditions to give rise to compound 23. The methyl ether
protecting groups were then removed using BBr3 in dry CH2-
It is worth noting that binding can be switched on for
-NHCO-linked receptors 21 and 22, but could not be activated
J. Org. Chem, Vol. 72, No. 8, 2007 2811

Winstanley and Smith
Cl2 to provide target compound 24 (Scheme 7). These reactions
only proceeded in poor yields, but provided sufficient compound
for study.
In particular, the formation of stable six-membered intramo-
lecular hydrogen-bonded rings significantly inhibits anion
binding; such rings are not even disturbed by the addition of
competitive solvents such as DMSO-d6. Only the receptors that
are incapable of forming six-membered intramolecular rings
show effective chloride anion binding. Compounds 21 and 22
form five-membered hydrogen-bonding rings; in CD3CN, these
compounds do not bind chloride anions as efficiently as catechol
itself, but on the addition of 10% DMSO-d6, binding is enhanced
as compared to that of unfunctionalized catechol, as the five-
membered ring intramolecular hydrogen-bond interactions are
weakened. Compound 24, which can only form a seven-
membered hydrogen-bonded ring, shows the strongest binding
of all, and significantly outperforms catechol in its ability to
bind chloride anions in CD3CN:DMSO-d6 (9:1). These results
are summarized in Figure 12.
In future work, we aim to develop anion receptors in which
the catechol units are connected by linkers with minimal
hydrogen-bonding functionality. Furthermore, we intend to
explore the linkage of catechol units through their meta
positions, so that any hydrogen-bonding groups in the linker
cannot directly interact with the catechol O-H groups that are
required for anion binding. Results of these studies will be
reported in due course.
Compound 24 has the hydrogen-bonding groups in the linker
located further away from the catechol O-H groups. It might
be expected that, in this case, a seven-membered intramolecular
hydrogen-bonded ring would form between the CdO and the
ortho O-H group (Figure 11). However, such a ring would not
be particularly stable, and it should therefore be relatively
straightforward for the catechol O-H groups to achieve chelate-
type binding to the target chloride anion. In CD3CN:DMSO-d6
(9:1), the O-H protons resonate at 9.84 and 7.78 ppm, while
in DMSO-d6, these protons appeared at 9.30 and 8.99 ppm. This
indicates that when increasing amounts of DMSO are present,
the ortho O-H proton, which was involved in an intramolecular
hydrogen bond, shifts upfield (by 0.54 ppm) as the hydrogen
bond is broken. The meta OH proton, however, is sensitive to
intermolecular hydrogen bonding with the DMSO solvent and
shifts downfield by 1.21 ppm. It is worth noting that in neat
DMSO-d6, the ortho O-H proton of 24 appeared at 9.30 ppm,
while in compound 6, this proton resonated at 12.90 ppm. This
indicates that the seven-membered hydrogen-bonded ring in 24
is considerably less effective than the six-membered analogue
in compound 6.
Receptor 24 showed the highest affinity for chloride anions
of any of the receptors reported in this paper (Table 1), with a
binding constant of 235 mol-1 dm3 in CD3CN:DMSO-d6 (9:1).
The O-H protons shifted significantly on the addition of
chloride anions (5 equiv). The meta O-H proton shifted 0.340
ppm downfield, while the ortho proton sharpened and shifted
slightly upfield (indicative of the intramolecular hydrogen bond
being broken as the receptor binds to chloride anions). The N-H
proton was also shifted downfield by 0.141 ppm, indicative
that this proton may contribute to the anion-binding event
(Figure 11).
This clearly demonstrates that moving the hydrogen-bonding
functionalities in the linker away from the catechol ring has a
positive impact on the anion-binding process by preventing the
formation of the stable intramolecular hydrogen-bond networks,
which deactivate the catechol O-H groups. Furthermore,
receptor 24 is a somewhat more effective anion binder than
unfunctionalized catechol, and this demonstrates that the
multiple catechol units, in part assisted by the N-H groups,
are acting cooperatively in binding to the chloride anion. It is
worth noting that the improved ability of compound 24 as
compared to catechol in CD3CN:DMSO-d6 (9:1) can be ascribed
to an enhanced hydrogen-bonding ability of the modified
catechol unit, the combination of two such units into a single
receptor, or a combination of these effects. In any case,
compound 24 can be considered as a first step toward anion-
binding receptors based on catechol subunits.
Experimental Section
Synthesis and Characterization. Compounds 1-6 are known
in the literature.20,21 Synthetic methods and characterization data
are provided in the Supporting Information as our methods were
modified and literature data are not always complete. Compounds
7-924 and 1528 are also known in the literature, and the synthesis
and data are not reproduced here.
General Method 1. A mixture of methyl ether protected
bis-catechol (0.0014 mol) and dry dichloromethane (70 mL)
was maintained under an inert atmosphere with stirring, and
BBr3 (5 mL) was added by syringe. The reaction mixture was
connected to a 1 M NaOH trap to remove evolved HBr. The reaction
mixture was then stirred for 3 d. The reaction mixture was quenched
by the slow addition of iced water to the reaction flask until ad-
dition no longer caused the evolution of HBr. The product
was evaporated to dryness and dissolved in methanol; the meth-
anol was then evaporated under vacuum (to remove boron
impurities).
1,8-Bis-(2,3-benzyloxybenzyloxy)octane (10). Compound 9
(0.71 g, 0.0021 mol) was dissolved in dichloromethane; DMAP
(0.05 g), DCC (0.88 g, 0.0043 mol), and 1,8-octanediol (0.16 g,
0.0011 mol) were added to it with stirring at room temperature.
The reaction mixture was left to stir overnight and then washed
with deionized water, 1 M NaOH, deionized water, 1 M HCl, and
finally deionized water. The product was dried with MgSO4 and
evaporated to dryness. The product was then extracted into toluene,
filtered, and the solvent was evaporated. The product was washed
with cyclohexane to give a white solid. A yield of 47% of
compound 10 was obtained and used without further purification
(there was some contamination of compound 10 with DCC, not
listed in the NMR here). mp 74-76 °C. 1H NMR (CDCl3): δ 7.49-
7.27 (22H, m, Ar-H), 7.16-7.03 (4H, m, Ar-H), 5.13 (4H, s,
Ar-CH2-O), 5.11 (4H, s, Ar-CH2-O), 4.24 (4H, t, J ) 6.7 Hz
O-CH2-CH2), 1.65 (4H, quin, J ) 7.0 Hz, C-CH2-C), 1.38-
1.19 (8H, m, C-CH2-C). 13C NMR (CDCl3): δ 166.8 (CdO),
153.1 (ArC-O), 148.5 (ArC-O), 137.9 (ArC-CH2), 137.0 (ArC-
CH2), 129.0 (ArC), 128.8 (ArC), 128.6 (ArC), 128.5 (ArC), 128.2
(ArC), 127.9 (ArC), 127.7 (ArC), 124.3 (ArC), 123.1 (ArC), 118.1
(ArC-CO2R), 75.9 (Ar-CH2-O), 71.7 (Ar-CH2-O), 65.7 (O-
CH2-CH2), 29.5 (C-CH2-C), 29.0 (C-CH2-C), 26.3 (C-CH2-
Conclusions and Outlook
This paper demonstrates that, by combining catechol-type
fragments, it is possible to create catechol-derived anion
receptors that outperform simple unfunctionalized catechol.
However, this paper also clearly demonstrates that this process
is not straightforward and that the choice of linking group in
the ortho position is crucial. Having hydrogen-bonding groups
in this position has a direct impact on the catechol O-H groups
via the formation of intramolecular hydrogen-bonding patterns
and can significantly inhibit the ability of the catechol O-H
groups to achieve “chelate-type” anion binding.
2812 J. Org. Chem., Vol. 72, No. 8, 2007

Anion Binding with Catechol DeriVatiVes
C). ESIMS m/z: 801 ([M + Na]+, 100%). νmax (solid): 3067m
(C-H), 3032m (C-H), 2930s (C-H), 2856s (C-H), 2118s, 1726s
(CdO), 1599m, 1580m, 1499m, 1470m, 1381m, 1314m, 1248m,
1221m, 1159s.
118.7 (ArC), 114.3 (ArC), 37.8 (CH2), 35.1 (CH2), 28.4 (CH2),
25.2 (CH2). ESIMS m/z: 415 ([M - H]-, 100%). νmax (solid):
3325m (N-H), 3102w, 2928m (C-H), 2854w (C-H), 2731w,
2635w, 1558s (CdO), 1501m, 1481m, 1435m, 1412m, 1365m,
1339m, 1258s, 1219s, 1084m, 1049w, 1014m, 968w, 880w,
841m. HRCIMS calculated for C22H29N2O6, 417.2026; found,
417.2023.
1,8-Bis-(2,3-hydroxybenzyloxy)octane (11). Compound 10
(0.60 g, 0.00077 mol) and 10% Pd-C (25% w/w) were suspended
in ethanol, and the mixture was placed under hydrogen with stirring
for 48 h. The mixture was filtered, and the ethanol was evaporated
under vacuum to give a brown solid. Compound 11 was obtained
in a yield of 71%. mp 113 °C. 1H NMR (DMSO-d6): δ 10.54 (2H,
s, O-H), 9.47 (2H, s, O-H), 7.25 (2H, d, J ) 7.9 Hz, Ar-H),
7.05 (2H, d, J ) 7.9 Hz, Ar-H), 6.78 (2H, t, J ) 7.9 Hz, Ar-H),
4.33 (4H, t, J ) 6.4 Hz, CH2-O), 1.82-1.69 (4H, m, CH2-CH2-
O), 1.51-1.29 (8H, m, CH2). 13C NMR (DMSO-d6): 170.5 (Cd
O), 150.5 (ArC-OH), 147.0 (ArC-OH), 121.7 (ArC), 120.4 (ArC),
119.9 (ArC), 114.0 (ArC-CO2R), 66.1 (O-CH2), 29.4 (C-CH2-
C), 28.9 (C-CH2-C), 26.3 (C-CH2-C). ESIMS m/z: 417 ([M
- H]-, 85%), 439 ([M - 2H + Na]-, 100%). νmax (solid): 3472s
(O-H), 2936m (C-H), 2859m (C-H), 1670s (CdO), 1605w,
1466s, 1400m, 1366w, 1308s, 1269s, 1153s, 1072s, 984m. HRCI:
calculated for C22H30NO8, 436.1971; found, 436.1957.
N,N′-Bis(2,3-bis(hydroxy)benzylidene)diaminooctane (12). 2,3-
Dihydroxybenzaldehyde (2.00 g, 0.015 mol) was dissolved in
methanol, and to it was added 1,8-diaminooctane (1.05 g, 0.0073
mol) with stirring. The yellow precipitate was collected as
compound 12 in a yield of ∼90%. mp 141 °C. 1H NMR (CDCl3):
δ 8.09 (2H, s, NdCH), 6.91 (2H, d, J ) 7.3 Hz, Ar-H), 6.69 (2H,
d, J ) 7.9 Hz, Ar-H), 6.56 (2H, t, J ) 7.9 Hz, Ar-H), 3.57 (4H,
t, J ) 6.7 Hz, N-CH2), 1.69 (4H, bquin, C-CH2-C), 1.49-1.25
(8H, m, C-CH2-C). 13C NMR (CDCl3): δ 164.7 (NdCH), 159.4
(ArC-OH), 147.5 (ArC-OH), 122.2 (ArC-H), 116.1 (ArC-H),
116.0 (ArC-H), 115.3 (ArC-C), 55.3 (N-CH2), 30.7 (C-CH2-
C), 29.2 (C-CH2-C), 26.9 (C-CH2-C). ESIMS m/z: 383 ([M
- H]-). νmax (solid): 3132m (O-H), 2924m (C-H), 2855m (C-
H), 1643s (CdN), 1539m, 1512s, 1458s, 1389s, 1354s, 1227s,
1184s, 1157s, 1018s. HRCI: calculated for C22H29N2O4, 385.2127;
found, 385.2117.
N,N′-Bis-(2,3-bis-benzyloxybenzylidene)-octane-1,8-diamine
(16). Compound 15 (8.40 g, 0.026 mol) was dissolved in methanol,
and to it was added 1,8-diaminooctane (1.87 g, 0.013 mol) with
stirring. The white precipitate was collected as compound 16 in a
yield of ∼90%. mp 95 °C. 1H NMR (CDCl3): δ 8.50 (2H, s, CHN),
7.56-7.52 (2H, m, Ar-H), 7.49-7.44 (4H, m, Ar-H), 7.42-7.28
(16H, m, Ar-H), 7.09-7.03 (4H, m, Ar-H), 5.16 (4H, s, O-CH2),
5.07 (4H, s, O-CH2), 3.50 (4H, t, J ) 7.0 Hz, N-CH2), 1.70-
1.57 (4H, m, CH2), 1.38-1.28 (8H, m, CH2). 13C NMR (CDCl3):
δ 157.0 (NdCH), 152.1 (ArC-O), 148.4 (ArC-O), 137.2 (ArC-
CH2), 136.9 (ArC-CH2), 130.9 (ArC), 128.8 (ArC), 128.7 (ArC),
128.5 (ArC), 128.3 (ArC), 128.2 (ArC), 127.6 (ArC), 124.4 (ArC),
119.4 (ArC), 116.1 (ArC), 76.1 (O-CH2), 71.1 (O-CH2), 62.2 (Nd
CH2), 31.0 (CH2), 29.6 (CH2), 27.5 (CH2). ESIMS m/z: 745 ([M
+ H]+, 100%). νmax (solid): 3067w (C-H), 3032w (C-H), 2927m
(C-H), 2854m (C-H), 2812m (C-H), 1643s (CdN), 1578m,
1497w, 1454s, 1385m, 1362s, 1335m, 1308s, 1265s, 1231s, 1192s,
1069s, 1053s, 1022s, 972s. HRESIMS calculated for C50H53N2O4,
745.4000; found, 745.3979.
N,N′-Bis-(2,3-bis-benzyloxybenzyl)-octane-1,8-diamine (17).
Compound 16 (3.50 g, 4.70 mmol) was suspended in methanol,
and NaBH4 (0.91 g, 23.5 mmol) was added with stirring. The
reaction was left to stir for a period of 2 h, and the solvent was
removed in vacuo. The product was dissolved in dichloromethane
and washed with NaOHaq (0.5 M). The product was dried with
MgSO4, filtered, and evaporated to dryness. The product was
purified using column chromatography (SiO2) with eluent of
dichloromethane and employing gradient elution until an eluent of
95:5 dichloromethane:methanol was reached. A small amount of
triethylamine was added to the eluent. The product was a white
Octanedioic Acid Bis-(2,3-dimethoxybenzylamide) (13). Sub-
eroyl chloride (0.27 mL, 1.50 mmol) was dissolved in a minimum
amount of dry dichloromethane, and to it was added a solution of
2,3-dimethoxybenzylamine (0.50 g, 3 mmol) and triethylamine (0.4
mL, 3 mmol) in dry dichloromethane dropwise with stirring under
an inert atmosphere. The reaction was then left to stir overnight.
The product was purified by washing with deionized water, 1 M
NaOH, deionized water, 1 M HCl, and finally with deionized water.
The product was dried with MgSO4, filtered, and evaporated to
dryness, to give compound 13 as a white solid in 58% yield. mp
1
solid and was obtained in a yield of 35%. mp 61 °C. H NMR
(CDCl3): δ 7.48-7.46 (2H, m, Ar-H), 7.41-7.30 (16H, m, Ar-
H), 7.00 (2H, t, J ) 7.6 Hz, Ar-H), 6.95-6.90 (4H, m, Ar-H),
5.14 (4H, s, O-CH2), 5.07 (4H, s, O-CH2), 3.73 (4H, s, Ar-
CH2-NH), 2.51 (4H, t, J ) 7.3 Hz, NH-CH2-CH2), 1.49-1.38
(4H, m, CH2), 1.33-1.18 (8H, m, CH2). 13C NMR (CDCl3): δ
151.9 (ArC-O), 146.7 (ArC-O), 137.8 (ArC-CH2), 137.1 (ArC-
CH2), 134.7 (ArC), 128.7 (ArC), 128.5 (ArC), 128.1 (ArC), 128.1
(ArC), 127.6 (ArC), 124.0 (ArC), 122.4 (ArC), 113.3 (ArC), 75.1
(O-CH2), 71.0 (O-CH2), 49.5 (CH2-NH), 49.3 (CH2-NH), 30.2
(CH2), 29.6 (CH2), 27.4 (CH2). ESIMS m/z: 749 ([M + H]+,
100%), 771 ([M + Na]+, 97%). νmax (solid): 3070w (C-H), 3030w
(C-H), 2924m (C-H), 2851m (C-H), 2816m (C-H), 2747w (C-
H), 1582m, 1497m, 1474s, 1451s, 1369m, 1335m, 1273s, 1204s,
1111w, 1084s, 1061s, 1026m, 984m. HRESIMS calculated for
C50H57N2O4, 749.4313; found, 749.4284.
1
136 °C. H NMR (CDCl3): δ 7.01 (2H, t, J ) 7.9 Hz, Ar-H),
6.86 (4H, m, Ar-H), 5.96 (2H, bt, NH), 4.43 (4H, d, J ) 5.8 Hz,
CH2-NH), 3.86 (6H, s, O-CH3), 3.85 (6H, s, O-CH3), 2.13 (4H,
t, J ) 7.3 Hz, CO-CH2), 1.60 (4H, b quin, CH2), 1.39-1.21 (4H,
m, CH2). 13C NMR (CDCl3): δ 172.8 (CdO), 152.8 (ArC-OMe),
147.3 (ArC-OMe), 132.2 (ArC), 124.4 (ArC), 121.6 (ArC), 112.0
(ArC), 60.9 (O-CH3), 55.9 (O-CH3), 39.1 (CH2), 36.7 (CH2), 28.9
(CH2), 25.6 (CH2). ESIMS m/z: 495 ([M + Na]+, 100%).
N,N′-Bis-(2,3-bis-hydroxy)-octane-1,8-diamine (18). Com-
pound 17 (0.80 g, 1.07 mmol) and 10% Pd-C (25% w/w) were
suspended in ethanol, and the mixture was stirred under hydrogen
for 48 h. The mixture was filtered over celite, and the solvent was
removed under vacuum to give a light brown solid in a yield of
νmax (solid): 3291m (N-H), 2928m (C-H), 2847m (C-H), 1740m
(CdO), 1632s, 1535s, 1481s, 1365m, 1277s, 1210s, 1076s, 1003s.
HRCIMS calculated for C26H37N2O6, 473.2652; found,
473.2648.
1
80%. This compound only had a short shelf life, ca. 1 week. H
Octanedioic Acid Bis-(2,3-dihydroxybenzylamide) (14). Using
general method 1 with compound 13 and purifying the product by
suspending in deionized water and placing in an ultrasonic bath
for ∼6 h yielded compound 14 as a light brown solid in 32% yield.
NMR (CD3CN): δ 6.69 (2H, dd, J ) 7.9, 1.5 Hz, Ar-H), 6.61
(2H, t, J ) 7.6 Hz, Ar-H), 6.52 (2H, d, J ) 7.6 Hz, Ar-H), 3.95
(4H, s, CH2-NH), 2.60 (4H, t, J ) 7.3 Hz, NH-CH2-CH2), 1.59-
1.47 (4H, m, CH2), 1.40-1.25 (8H, m, CH2). 13C NMR (DMSO-
d6): δ 145.8 (ArC-OH), 145.1 (ArC-OH), 123.5 (ArC), 118.8
(ArC), 118.1 (ArC), 114.3 (ArC), 50.9 (CH2-NH), 47.9 (CH2-
NH), 28.9 (CH2), 28.7 (CH2), 26.6 (CH2). ESIMS (-ion) m/z: 387
([M - H]-, 100%). ESIMS (+ion) m/z: 389 ([M + H]+, 77%),
411 ([M + Na]+, 100%).
1
mp 184 °C. H NMR (DMSO-d6): δ 9.07 (2H, s, OH), 8.93 (2H,
s, OH), 8.39 (2H, t, J ) 5.8 Hz, NH), 6.69 (2H, dd, J ) 7.3, 2.4
Hz, Ar-H), 6.59 (4H, m, Ar-H), 4.19 (4H, d, J ) 5.8 Hz, CH2-
NH), 2.15 (4H, t, J ) 7.3 Hz, CH2-CO), 1.62-1.48 (4H, m, CH2),
1.37-1.18 (4H, m, CH2). 13C NMR (DMSO-d6): 173.1 (CdO),
145.3 (ArC-OH), 142.9 (ArC-OH), 126.1 (ArC), 119.2 (ArC),
J. Org. Chem, Vol. 72, No. 8, 2007 2813

Winstanley and Smith
Octanedioic Acid Bis-[(2,3-dimethoxyphenyl)-amide] (19).
Suberoyl chloride (0.47 mL, 2.6 mmol) was dissolved in a minimum
amount of dry dichloromethane under an inert atmosphere, and to
it was added a solution of 2,3-dimethoxyaniline (0.80 g, 5.2 mmol)
and triethylamine (0.7 mL, 5.2 mmol) in dry dichloromethane
dropwise with stirring. The reaction was left to stir overnight. The
product was purified by washing with deionized water, 1 M NaOH,
deionized water, 1 M HCl, and finally with deionized water. The
product was dried with MgSO4, filtered, and evaporated to dryness
to give compound 19 as a light brown solid in a yield of 71%. mp
ultrasonic bath for ∼6 h yielded compound 22 as a light brown
solid in 35% yield. mp 165 °C. 1H NMR (DMSO-d6): δ 9.51 (2H,
s, NH), 9.06 (4H, s, OH), 7.02 (2H, dd, J ) 7.3, 2.1 Hz, Ar-H),
6.67-6.55 (4H, m, Ar H), 2.41 (4H, t, J ) 7.3 Hz, CH2-CO),
1.71-1.55 (4H, m, CH2), 1.42-1.25 (8H, m, CH2). 13C NMR
(DMSO-d6): δ 172.4 (CdO), 146.5 (ArC-OH), 136.5 (ArC-OH),
127.1 (ArC), 118.8 (ArC), 113.2 (ArC), 111.6 (ArC), 35.8 (CH2-
CO), 28.7 (CH2), 28.6 (CH2), 25.3 (CH2). ESIMS m/z: 415 ([M -
H]-, 100%). νmax (solid): 3518m (O-H), 3337m (N-H), 2920m
(C-H), 2850m (C-H), 1636s (CdO), 1605m, 1535s, 1497s,
1470m, 1416w, 1366s, 1180s, 1157s, 1072m, 999w, 957m, 876w,
841m, 779s. HRCIMS calculated for C22H29N2O6, 417.2026; found,
417.2025.
1
111 °C. H NMR (CDCl3): δ 7.99 (2H, d, J ) 8.2 Hz, Ar-H),
7.81 (2H, s, NH), 7.03 (2H, t, J ) 8.5 Hz Ar-H), 6.66 (2H, d, J
) 8.2 Hz, Ar-H), 3.87 (6H, s, O-CH3), 3.87 (6H, s, O-CH3),
2.41 (4H, t, J ) 7.3 Hz, CH2-CO), 1.75 (4H, bt, CH2), 1.44 (4H,
bt, CH2). 13C NMR (CDCl3): δ 171.4 (CdO), 152.0 (ArC-OMe),
137.3 (ArC-OMe) 132.3 (ArC-C), 124.3 (ArC-H), 112.7 (ArC-
H), 107.5 (ArC-H), 60.8 (O-CH3), 55.9 (O-CH3), 38.0 (CH2-
CO), 29.0 (CH2), 25.3 (CH2). ESIMS m/z: 467 ([M + Na]+, 100%).
2-(2,3-Dimethoxyphenyl)-N-{6-[2,3-dimethoxyphenyl)-acety-
lamino]-hexyl}-acetamide (23). 2,3-Dimethoxyphenyl acetic acid
(1.00 g, 5.10 mmol) was dissolved in ∼30 mL of CH2Cl2. To the
solution were added DCC (2.10 g, 10.2 mmol) and HOBt (1.39 g,
10.2 mmol) as a mixture of solids. The solution was stirred under
a nitrogen atmosphere and cooled to 0 °C. After 10 min, 1,6-
diaminohexane (0.30 g, 2.55 mmol) and triethylamine (0.7 mL,
5.10 mmol) in CH2Cl2 were added to the reaction. The reaction
was allowed to return to room temperature and stirred for 24 h.
The precipitate was removed by filtration and discarded. The filtrate
was then washed with deionized water, 1 M NaOH, deionized water,
1 M HCl, and finally with deionized water. The product was dried
with MgSO4 and evaporated to dryness. The excess DCU was
removed by multiple recrystallizations from CH2Cl2 to yield
compound 23 as a white solid in a 15% yield. mp 135 °C. 1H NMR
(CDCl3): δ 7.03 (2H, t, J ) 7.6 Hz, Ar-H), 6.89-6.71 (4H, m,
Ar-H), 5.86 (2H, b t, N-H), 3.87 (6H, s, O-CH3), 3.85 (6H, s,
O-CH3), 3.54 (4H, s, Ar-CH2CO), 3.12 (4H, q, J ) 6.7 Hz, CH2-
NH), 1.42-1.30 (4H, m, CH2), 1.22-1.10 (4H, m, CH2). 13C NMR
(CDCl3): 171.1 (CdO), 152.9 (ArC-O), 146.9 (ArC-O), 129.5
(ArC), 124.6 (ArC), 122.8 (ArC), 111.7 (ArC), 60.7 (O-CH3), 55.8
(O-CH3), 39.4 (CH2), 38.7 (CH2), 29.4 (CH2), 26.3 (CH2). ESIMS
m/z: 495 ([M + Na]+, 100%). νmax (solid): 3283s (N-H), 2936m
(C-H), 2925w (C-H), 1639s (CdO), 1539s, 1477s, 1354m, 1261s,
1238s, 1169m, 1072s, 1003s. HRESIMS calculated for C26H37N2O6,
473.2646; found, 473.2645.
νmax (solid): 3287m (N-H), 2935m (C-H), 2900w (C-H), 1639s
(CdO), 1560w, 1535s, 1477s, 1354m, 1258s, 1169m, 1072s, 1003s,
940w, 741s. HRCIMS calculated for C24H33N2O6, 445.2339; found,
445.2344.
Decanedioic Acid Bis-[(2,3-dimethoxyphenyl)-amide] (20). A
mixture of sebacic acid (0.66 g, 3.27 mmol) and thionyl chloride
(10 mL) was allowed to react overnight under an inert atmosphere
at 35 °C. The excess SOCl2 was removed by distillation in vacuo
at room temperature. The residue was dissolved in dry CH2Cl2 under
an inert atmosphere, the solvent was removed as before, and this
procedure was repeated again. The newly formed acid chloride was
dissolved in a minimum amount of CH2Cl2 under an inert
atmosphere, and 2,3-dimethoxyaniline (1.00 g, 6.54 mmol) and
triethylamine (0.9 mL, 6.54 mmol) in dry CH2Cl2 were added
dropwise to the solution at room temperature with stirring for a
period of 2 h. The reaction was then left to stir overnight. The
product was purified by washing with deionized water, 1 M NaOH,
deionized water, 1 M HCl, and finally with deionized water. The
product was dried with MgSO4, filtered, and evaporated to dryness
to give compound 20 as a red solid in a yield of 33%. mp 132 °C.
1H NMR (CDCl3): δ 7.99 (2H, d, J ) 8.2 Hz, Ar-H), 7.81 (2H,
s, N-H), 7.02 (2H, t, J ) 8.2 Hz, Ar-H), 6.65 (2H, d, J ) 8.5
Hz, Ar-H), 3.87 (6H, s, O-CH3), 3.86 (6H, s, O-CH3), 2.39 (4H,
t, J ) 7.6 Hz, CH2-CO), 1.72 (4H, quin, J ) 7.3 Hz, CO-CH2-
CH2), 1.47-1.28 (8H, m, CH2). 13C NMR (CDCl3): δ 171.5 (Cd
O), 152.0 (ArC-OMe), 137.3 (ArC-OMe) 132.3 (ArC), 124.4
(ArC), 112.7 (ArC), 107.4 (ArC), 60.8 (O-CH3), 55.9 (O-CH3),
38.2 (CH2-CO), 29.3 (C-CH2-C), 29.3 (C-CH2-C), 25.7 (C-
CH2-C). ESIMS m/z: 495 ([M + Na]+, 100%). νmax (solid):
3341m (N-H), 2928m (C-H), 2854m (C-H), 1690s (CdO),
1604s, 1510m, 1462s, 1420s, 1296s, 1261s, 1227s, 1165s, 1080s,
980s. HRCIMS calculated for C26H37N2O6, 473.2652; found,
473.2646.
Octanedioic Acid Bis-[(2,3-dihydroxyphenyl)-amide] (21).
Using general method 1 with compound 19 and purifying the
product by suspending in deionized water and placing in an
ultrasonic bath for ∼6 h yielded compound 21 as a light brown
solid in 40% yield. mp 156-158 °C. 1H NMR (DMSO-d6): δ 9.51
(2H, s, NH), 9.08 (2H, s, OH), 9.05 (2H, s, OH), 7.02 (2H, dd, J
) 7.0, 2.1 Hz, Ar-H), 6.69-6.59 (4H, m, Ar-H), 2.43 (4H, t, J
) 7.3 Hz, COCH2), 1.69-1.56 (4H, m, CH2), 1.43-1.20 (4H, m,
CH2). 13C NMR (DMSO-d6): δ 172.3 (CdO), 146.5 (ArC-OH),
136.5 (ArC-OH), 127.2 (ArC), 118.8 (ArC), 113.2 (ArC), 111.7
(ArC), 35.8 (CH2-CO), 28.4 (CH2), 25.2 (CH2). ESIMS m/z: 387
([M - H]-, 100%). νmax (solid): 3518m (O-H), 3333w, 3283m
(N-H), 2931m (C-H), 2858m (C-H), 1636s (CdO), 1535s,
1477s, 1358s, 1238s, 1172s, 964m. HRCIMS calculated for
C20H25N2O6, 389.1713; found, 389.1702.
2-(2,3-Dihydroxyphenyl)-N-{6-[2-(2,3-dihydroxyphenyl)-acety-
lamino]-hexyl}-acetamide (24). Using general method 1 with
compound 23 and purifying the product by washing the solid with
dichloromethane and water provided compound 24 as a light brown
1
solid in a 20% yield. mp 110 °C. H NMR (DMSO-d6): δ 9.30
(2H, s, O-H), 8.99 (2H, s, O-H), 8.13 (2H, b t, N-H), 6.69 (2H,
dd, J ) 7.9, 1.8 Hz, Ar-H), 6.59 (2H, t, J ) 7.3 Hz, Ar-H), 6.53
(2H, dd, J ) 7.6, 1.5 Hz, Ar-H), 3.43 (4H, s, Ar-CH2CO), 3.06
(4H, q, J ) 6.7 Hz, CH2-NH), 1.50-1.34 (4H, m, CH2), 1.32-
1.22 (4H, m, CH2). 13C NMR (CD3COD): δ 175.0 (CdO), 146.8
(ArC-O), 144.9 (ArC-O), 123.8 (ArC), 122.4 (ArC), 120.8 (ArC),
115.4 (ArC), 40.4 (CH2), 39.4 (CH2), 30.1 (CH2), 27.3 (CH2).
ESIMS (+ion) m/z: 439 ([M + Na]+, 100%). ESIMS (-ion) m/z:
415 ([M - H]-, 100%), 495 ([M + 79Br]-, 25%), 497 ([M + 81Br]-,
25%). νmax (solid): 3421m (O-H), 3306m (N-H), 3109w (C-
H), 2935m (C-H), 2855w (C-H), 1635s (CdO), 1593s, 1570s,
1477s, 1435s, 1362s, 1342s, 1281s, 1254s, 1180s, 1076m, 1018w,
988w. HRESIMS calculated for C22H27N2O6, 415.1875; found,
415.1866.
NMR Titrations. NMR titrations were performed in undried
CDCl3, CD3CN, or CD3CN:DMSO-d6 (9:1) using a host concentra-
tion of 2 mM. A solution containing the anionic guest (as its
tetrabutylammonium salt) at a concentration of 50 mM, and host
at a concentration of 2 mM, was made up in the same solvent. The
guest solution was added in aliquots (via Gilson pipet) to the host
solution, and NMR spectra were recorded. Data were fitted to a
Decanedioic Acid Bis-[(2,3-dihydroxyphenyl)-amide] (22).
Using general method 1 with compound 20 and purifying the
product by suspending in deionized water and placing in an
2814 J. Org. Chem., Vol. 72, No. 8, 2007

Anion Binding with Catechol DeriVatiVes
1:1 model by nonlinear least-squares fitting methods; the com-
mercial program HypNMR was used.32
Acknowledgment. We thank EPSRC and The University
of York for funding this research.
Job Plot Method. The Job plot was performed in CD3CN:
DMSO-d6 (9:1). Host and guest solutions with concentrations of 2
mM were used. Aliquots were added to each sample to give a total
volume of 1 mL and a constant total concentration of host and
guest (2 mM). For data analysis, we used the relationship
[complex]R∆δ × [host].
Supporting Information Available: General experimental
methods, synthesis and data for compounds 1-6, CIF file for
compound 6, and 1H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(32) Frassineti, C.; Ghelli, S.; Gans, P.; Sabatini, A.; Moruzzi, M. S.;
Vacca, A. Anal. Biochem. 1995, 231, 374-382.
JO0623989
J. Org. Chem, Vol. 72, No. 8, 2007 2815