A hybrid macrocycle containing benzene and pyridine subunits is a better anion receptor than both its homoaromatic congeners

Article abstract of DOI:10.1016/j.tetlet.2005.03.007

The hybrid tetraamide receptor 3 containing both 2,5-diamidopyridine and 1,3-diamidobenzene anion binding units has been synthesized. NOESY spectroscopy revealed that the new receptor is well preorganized for anion complexation, presumably owing to the macrocyclic topology and the rigidity of the 2,5-diamidopyridine unit. Association constants of 3 with several anions are higher than those determined earlier for its homoaromatic congeners 1 and 2. X-ray crystallographic analysis of the chloride complex of hybrid macrocycle 3 enabled direct comparison of structural aspects of anion recognition by the 2,5-diamidopyridine and 1,3-diamidobenzene moieties.

Full text of DOI:10.1016/j.tetlet.2005.03.007

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3085–3088
A hybrid macrocycle containing benzene and pyridine subunits is
a better anion receptor than both its homoaromatic congeners
a
Michał J. Chmielewski and Janusz Jurczak
a,b,
*
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
b
Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
Received 28 December 2004; revised 19 February 2005; accepted 1 March 2005
Available online 16 March 2005
Abstract—The hybrid tetraamide receptor 3 containing both 2,5-diamidopyridine and 1,3-diamidobenzene anion binding units has
been synthesized. NOESY spectroscopy revealed that the new receptor is well preorganized for anion complexation, presumably
owing to the macrocyclic topology and the rigidity of the 2,5-diamidopyridine unit. Association constants of 3 with several anions
are higher than those determined earlier for its homoaromatic congeners 1 and 2. X-ray crystallographic analysis of the chloride
complex of hybrid macrocycle 3 enabled direct comparison of structural aspects of anion recognition by the 2,5-diamidopyridine
and 1,3-diamidobenzene moieties.
ꢀ
2005 Published by Elsevier Ltd.
Amides are frequently used in nature as hydrogen bond
donors for anion binding. One prominent example is the
antibiotic vancomycin, which is active against Gram-po-
sitive bacteria. Three adjacent amide NHs of this natural
receptor bind to the terminal COO group of its peptide
substrate providing the major part of the binding en-
hydrogen bond acceptors. Macrocyclic topology is very
effective in gathering many binding sites in close proxim-
ity and directing them in a convergent manner. There-
fore we have undertaken systematic studies of
ꢀ
6
macrocyclic amide receptors for anions. At the begin-
ning we examined a series of macrocyclic tetraamides
built from two 2,5-pyridinedicarbamoyl moieties linked
1
ꢀ
ergy. Despite the fact that single CONHꢁ ꢁ ꢁA hydro-
6
c
gen bonds are weak and manifest only in non-polar
organic solvents, proteins are able to use such multiple
interactions to achieve strong and selective binding of
anions even in a highly competitive aqueous medium.
Accordingly, researchers try to design receptors having
by flexible, aliphatic chains of various lengths. It
turned out that the maximum affinity towards model
anions was observed for the 20-membered tetraamide 1.
2
3
a Ôhigh densityÕ of hydrogen bond donating groups prop-
erly arranged around the anion. This is not an easy
4
task, however, as documented by numerous examples
in the literature, when increasing the amount of hydro-
gen bond donors led to disappointing results. For exam-
ple, incorporation of a fourth amide group to the anion
binding domain of vancomycin did not improve its affin-
O
O
O
O
O
O
O
O
O
O
O
O
N
N
NH
NH
HN
HN
NH
NH
HN
HN
NH
NH
HN
HN
5
ity for an anionic substrate. The reason was due to the
N
incorrect conformation taken by the fourth amide group
which precluded its participation in anion binding. An-
other common problem in the design of anion receptors
is the formation of undesired intramolecular hydrogen
bonds—most hydrogen bond donating groups are also
1
2
3
In trying to construct even better anion receptors, we
6
d
synthesized tetraamide 2, keeping in mind that simple
isophthalic acid amides bind anions stronger than
Keywords: Anion recognition; Anion binding; Macrocyclic receptor.
*
Corresponding author. Tel.: +48 22 632 05 78; fax: +48 22 632 66
1; e-mail: jurczak@icho.edu.pl
7
8
their pyridine analogues. However, we found that the
0
040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.03.007

3086
M. J. Chmielewski, J. Jurczak / Tetrahedron Letters 46 (2005) 3085–3088
The reaction of isophthalic acid chloride with a commer-
cially available monoprotected 1,3-diaminopropane
gave a 74% yield of 4. Deprotection of 4 with trifluoro-
acetic acid afforded the amine salt 5 which, without any
further purification, was dissolved in a methanolic solu-
tion of sodium methoxide and the diester 6. The aminol-
ysis of the diester 6 at room temperature gave a 16%
yield of macrocyclic receptor 3.
H
N
O
O
O
O
O
NH
NH
HN
HN
anion
N
O
H
H
O
complexation
A
N
N
O
H
The NOESY spectrum of 3 (dissolved in DMSO-d ) re-
6
vealed close contacts between the isophthalic amide NH
protons and the internal benzene CH protons and pyr-
idine amide NH protons (see Fig. 1 and Supplementary
data). Simultaneously, there were no signs of contact be-
tween external benzene CH protons and the isophthalic
amide NH protons. These observations are in agreement
with the desired conformation of the receptor, in which
all four amide NHÕs are directed inwards.
2
Scheme 1.
isophthalic acid-based macrocyclic tetraamide 2 binds
anions more weakly than its pyridine analogue 1. This
is because 2 adopts an unfavourable conformation with
two carbonyl oxygens directed towards the centre of the
macrocyclic cavity. The conformation is stabilized by
two intramolecular hydrogen bonds that have to be
broken during anion complexation (Scheme 1).
O
O
N
H
N
H
N
Receptor 1, on the other hand, prefers an open conform-
ation with the convergent arrangement of N–H vectors,
stabilized by four intramolecular hydrogen bonds to
pyridine nitrogen atoms. These bonds, in contrast to
those existing in 2, do not have to be broken upon anion
binding. Efforts to combine the benefits of both binding
units, namely good preorganization provided by pyr-
idine amides with stronger anion binding by isophthalic
amides, led us to design the hybrid macrocycle 3. We
hoped that the pyridine-2,6-dicarbamoyl moiety, locked
in the syn–syn conformation by two intramolecular
bonds, would enforce, through the macroring, the same
conformation on the isophthalic unit. The synthesis of
receptor 3 was accomplished according to Scheme 2.
H
N
H
N
O
O
3
Figure 1. Selected NOEÕs visible in the NOESY spectrum of receptor
3
.
Anion binding properties of 3 were studied in DMSO-d
6
1
8
solutions by H NMR titrations (Table 1). In accord
with our expectations, the binding constants of the hy-
brid receptor 3 were higher than the corresponding val-
ues obtained for either 1 or 2 under the same conditions.
ꢀ
The only exception is HSO , which shows the highest
affinity for 1, possibly due to additional stabilization
4
ꢀ
of its complexes by a O SO–Hꢁ ꢁ ꢁN hydrogen bond.
3
py
Qualitatively, all the receptors display the same selectiv-
ity: H PO > PhCOO > Cl > Br > HSO which is
ꢀ ꢀ ꢀ ꢀ
ꢀ
2
4
4
not surprising, given their similar structures. Neverthe-
less, they do show some individual character; for exam-
ple 1 displays exceptionally strong affinity towards
chloride versus the much more basic benzoate, whereas
2 and 3 prefer benzoate. Apparently, the change of
aromatic ring in the receptor scaffold from pyridine to
H N
O
O
2
CH2Cl2
Et3N
NH
HN
O
O
+
HN
O
Cl
Cl
NH
HN
O
O
O
O
O
ꢀ1
Table 1. Stability constants (M ) for the formation of 1:1 complexes
a
6
of 1, 2 and 3 with various anions in DMSO-d at 298 K
4
(74%)
Anion
1
2
3
ꢀ
ꢀ
b
c
c
c
Cl
Br
1930
378
20
2148
175
O
O
O
1
. CF3COOH
150
ꢀ
b
NH
NH
HN
HN
2. CH3ONa, CH3OH
PhCOO
ꢀ
2283
7410
75
601
c,d
—
3612
>8000
51
b
b
H2PO
4
ꢀ
HSO
<5
3.
4
O
O
a
N
N
Errors are estimated to be <10%. Tetrabutylammonium salts were
used as anion sources.
Values from Ref. 6c.
O
O
O
b
c
3
(16 %)
6
Values from Ref. 6d.
The data does not fit satisfactorily to a simple 1:1 binding model.
d
Scheme 2. The synthesis of receptor 3.

M. J. Chmielewski, J. Jurczak / Tetrahedron Letters 46 (2005) 3085–3088
Table 2. Stability constants (M ) for the formation of 1:1 complexes
3087
ꢀ1
a
of 1, 2 and 3 with various anions in DMSO-d
6
+ 5% H
2
O at 298 K
Anion
1
2
3
ꢀ
Cl
PhCOO
373
292
575
98
169
555
666
ꢀ
ꢀ
H2PO4
1320
2680
a
Errors are estimated to be <10%. Tetrabutylammonium salts were
used as anion sources.
benzene affects not only the binding strength, but also
the selectivity. Similar effects were also observed for sim-
7
ple acyclic diamides by Crabtree and co-workers
(isophthalamides vs diamidopyridines) and by Gale
9
and co-workers (diamidopyrroles vs diamidofurans).
The high stability constants measured for hydrogen-
phosphate, benzoate and chloride complexes of 1, 2
and 3 in DMSO solution prompted us to investigate
an even more challenging medium—a DMSO–water
mixture (95:5 v/v). The results are collected in Table 2.
Despite the presence of several hundred equivalents of
H O, all three tetraamides formed remarkably stable
Figure 2. Top view of the crystal structure of 3 · TBACl ·
2
0.5C H Cl .
2
4
2
complexes with the anions. Nevertheless, the hybrid
receptor 3 was clearly superior to 1 and 2, even more
so than in pure DMSO. Particularly impressive was
the stability constant of the hydrogenphosphate—3
probably a simple geometric effect. The isophthalamide
moiety has wider outspread amide arms than 2,6-pyri-
dinediamide (the distance between amide nitrogens is
ꢀ1
complex: K = 2680 M . Although these limited data
do not allow for firm generalizations, it seems pyridine
receptor 1 is the most sensitive to the presence of water.
This was probably why, in the presence of water, recep-
tor 2 turned out to be better than 1 with respect to
˚
0.37 A longer) and therefore the anion has to approach
the benzene ring more closely in order to form compara-
ꢀ
bly short NHꢁ ꢁ ꢁCl hydrogen bonds. As a result, the
distance between the chloride anion and the benzene
1
0
˚
C4 carbon atom (3.56 A) is shorter than that to the pyr-
hydrogenphosphate binding. Conversely, the anion
binding properties of isophthalamide-containing recep-
tors 2 and 3 seemed to be less affected by addition of
water. Another interesting effect of water addition is
the reversal of the chloride/benzoate selectivity of 1 in
favour of the less basic chloride anion.
˚
idine nitrogen atom N14 (3.70 A). The chloride anion
probably cannot further shorten its contacts with the
isophthalic amide protons because of steric crowding
with the internal aromatic CH proton, even though
the benzene ring reduces this hindrance by bending aside
by about 25ꢁ with respect to the appended amide
groups. (Such tilting is also typical for the structures
of free isophthalamides and arises from steric repulsion
between amide protons and aromatic hydrogen atoms
On the basis of the results summarized in Tables 1 and 2,
we conclude, that the isophthalamide moiety is indeed a
better anion binding unit than 2,6-dicarbamoylpyridine,
displaying slightly different selectivity. The X-ray crystal
structure analysis of a chloride complex of the hybrid
receptor 3 provides a unique opportunity for the direct
comparison of the structural aspects of anion binding
by both building blocks. Diffraction-grade single crys-
tals of 3 · TBACl · 0.5C H Cl were obtained by slow
1
1
in the ortho position.) The close contact between
the chloride anion and internal aromatic CH
ꢀ
1
˚
proton (CHꢁ ꢁ ꢁCl 2.73 A) manifests in the solution H
NMR spectra as a very high anion induced chemical
corresponding
Ddmax(Cl ) = 0.80 ppm. Similar shifts have been ob-
served in the case of other anion complexes:
shift
change
of
the
signal,
ꢀ
2
4
2
diffusion of diethyl ether into the solution of 3 and tet-
rabutylammonium chloride (TBACl) in 1,2-dichloroeth-
ane. As expected, the chloride anion is held within the
ꢀ
ꢀ
Ddmax(Br ) = 0.66 ppm, Ddmax(PhCOO ) = 1.06 ppm,
ꢀ
DdmaxðH PO Þ ¼ 0:77 ppm). Such large downfield shifts
2
4
are usually interpreted as indicative of CH
ꢀ
ꢀ
macrocyclic cavity by four NHꢁ ꢁ ꢁCl hydrogen bonds
ꢁ ꢁ ꢁA
arom
ꢀ
12
and one CH
the anion resides slightly closer to the pyridine amides
ꢁ ꢁ ꢁCl interaction (Fig. 2). Interestingly,
bonding interactions.
arom
ꢀ
˚
(
hthalic amides (mean
3
mean Namideꢁ ꢁ ꢁCl distance is 3.27 A) than to the isop-
In conclusion, intramolecular hydrogen bonds present
in the structures of receptors may be divided into two
main categories: those that have to be broken upon sub-
strate binding, and therefore are in direct competition
with the binding, as in receptor 2, and those that survive
ꢀ
N
.34 A) suggesting a higher hydrogen bond donating
ꢁ ꢁ ꢁCl
distance is
amide
˚
ability of the former. This is somewhat surprising at
first, because the pyridine appended amide NHÕs are al-
ready engaged in hydrogen bonds with another accep-
tor, that is, pyridine nitrogen atom N14. However,
closer inspection of the structure reveals that this is
complexation, like the CON–Hꢁ ꢁ ꢁN interactions in
py
receptors 1 and 3. Whereas hydrogen bonds falling into
the first category are detrimental to strong binding, as in

3088
M. J. Chmielewski, J. Jurczak / Tetrahedron Letters 46 (2005) 3085–3088
the case of 2, interactions of the second type can be use-
ful. As an example, we have shown that the 2,5-diamido-
pyridine moiety could force, via the macroring, another
anion binding unit to adopt a convergent conformation
of its hydrogen bond donors. Thus, we have prepared
hybrid receptor 3 which overcomes the two problems
appearing in the purely isophthalic receptor 2—the
wrong conformation of the isophthalic moieties and
the existence of competing intramolecular hydrogen
bonds. Gratifyingly, 3 shows high affinity to the anions
tested even in a very strongly competitive DMSO–water
mixture.
3. Supramolecular Chemistry of Anions; Bianchi, A., Bow-
man-James, K., Garc ´ı a-Espa n˜ a, E., Eds.; Wiley-VCH:
New York, 1997; Chapter 3.
4
. For selected reviews on anion receptors see: (a) Bondy, C.
R.; Loeb, S. J. Coord. Chem. Rev. 2003, 240, 77–99;
(
2
b) Choi, K.; Hamilton, A. D. Coord. Chem. Rev. 2003,
40, 101–110; (c) Beer, P. D.; Gale, P. A. Angew. Chem.,
Int. Ed. 2001, 40, 486–516; (d) Schmidtchen, F. P.;
Berger, M. Chem. Rev. 1997, 97, 1609–1646; (e) Supramo-
lecular Chemistry of Anions; Bianchi, A., Bowman-James,
K., Garc ´ı a-Espa n˜ a, E., Eds.; Wiley-VCH: New York,
1997.
5
. G o¨ rlitzer, J.; Gale, T. F.; Williams, D. H. J. Chem. Soc.,
Perkin Trans. 1 1999, 22, 3253–3257.
Crystallographic data (excluding structure factors) for
the structure in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 250961. Copies of
the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
6. (a) Szumna, A.; Gryko, D. T.; Jurczak, J. Heterocycles
002, 56, 361–368; (b) Szumna, A.; Jurczak, J. Eur. J. Org.
2
Chem. 2001, 21, 4031–4040; (c) Chmielewski, M. J.;
Jurczak, J. Tetrahedron Lett. 2004, 45, 6007–6010; (d)
Chmielewski, M. J.; Szumna, A.; Jurczak, J. Tetrahedron
Lett. 2004, 45, 8699–8703.
7
. Kavallieratos, K.; Bertao, C. M.; Crabtree, R. H. J. Org.
Chem. 1999, 64, 1675–1683.
[fax: +44 0 1223 336033 or e-mail: deposit@ccdc.
cam.ac.uk].
8
9
. Fielding, L. Tetrahedron 2000, 56, 6151–6170.
. Camiolo, S.; Gale, P. A.; Hursthouse, M. B.; Light, M. E.;
Warriner, C. N. Tetrahedron Lett. 2003, 44, 1367–
1369.
Supplementary data
1
0. As revealed by NOE spectra, isophthalamide receptor 2 in
a DMSO–H O (95:5 v/v) mixture still exists as an
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tetlet.
2005.03.007. Synthetic procedures and characterization
data for compounds 3 and 4 and details concerning
determination of the binding constants are available.
2
intramolecularly hydrogen bonded conformation as
depicted in Scheme 1. Nevertheless, in the presence of
water, breaking of hydrogen bonds, as necessary for anion
binding, may be easier.
ˇ
1
1. (a) Based on CSD searches; (b) Cajan, M.; Stibor, I.;
Ko cˇ a, J. J. Phys. Chem. A 1999, 103, 3778–3782.
2. (a) Kwon, J. Y.; Jang, Y. J.; Kim, S. K.; Lee, K.-H.;
Kim, J. S.; Yoon, J. J. Org. Chem. 2004, 69, 5155–5157;
1
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2
4