Highly effective acyclic carbohydrate receptors consisting of aminopyridine, imidazole, and indole recognition units

Article abstract of DOI:10.1002/chem.200701269

Neutral imidazole/aminopyridine- and indole/aminopyridine-based receptors, 1 and 2, have been established as highly effective and selective carbohydrate receptors. These receptors effectively recognise neutral carbohydrates through multiple interactions, including neutral hydrogen bonds and CH...π interactions between the sugar CH groups and the aromatic rings of the receptors. The design of these receptors was inspired by the binding motifs observed in the crystal structures of protein-carbohydrate complexes. The formation of very strong complexes with β-glucopyranoside 5, β-maltoside 8, and α-maltoside 9 in organic media has been characterised by ¹H NMR spectroscopy and confirmed by a second, independent technique, namely fluorescence spectroscopy. The syntheses, molecular-modelling studies, binding properties of the receptors 1 and 2 toward selected mono- and disaccharides as well as comparative binding studies with receptors 3 and 4 are described.

Full text of DOI:10.1002/chem.200701269

FULL PAPER
DOI: 10.1002/chem.200701269
Highly Effective Acyclic Carbohydrate Receptors Consisting of
Aminopyridine, Imidazole, and Indole Recognition Units
[a]
Monika Mazik* andMatthias Kuschel
Abstract: Neutral imidazole/aminopyri-
dine- and indole/aminopyridine-based
receptors, 1 and 2, have been estab-
lished as highly effective and selective
carbohydrate receptors. These recep-
tors effectively recognise neutral carbo-
hydrates through multiple interactions,
including neutral hydrogen bonds and
CH···p interactions between the sugar
CH groups and the aromatic rings of
the receptors. The design of these re-
ceptors was inspired by the binding
motifs observed in the crystal struc-
tures of protein–carbohydrate com-
plexes. The formation of very strong
complexes with b-glucopyranoside 5, b-
maltoside 8, and a-maltoside 9 in or-
ganic media has been characterised by
1H NMR spectroscopy and confirmed
by a second, independent technique,
namely fluorescence spectroscopy. The
syntheses, molecular-modelling studies,
binding properties of the receptors 1
and 2 toward selected mono- and disac-
charides as well as comparative binding
studies with receptors 3 and 4 are de-
scribed.
Keywords: carbohydrates · hydro-
gen bonds · molecular recognition ·
receptors
chemistry
·
supramolecular
Introduction
indole group, see Figure 1a, b and c). Main-chain amides
also contribute to hydrogen bonding, but to a lesser ex-
tent[1h] (in contrast with antibodies, which seem to make
greater use of main-chain amides[1j]). Packing of an aromatic
ring of the protein, such as the indole of tryptophan or the
phenyl ring of phenylalanine (see Figure 1d), against the
sugar is observed in most carbohydrate-binding proteins.
The interactions observed in the crystal structures of pro-
tein–carbohydrate complexes inspire the development of
different artificial receptor structures for the recognition of
carbohydrates.[2–5] Our previous studies showed that acyclic
receptors containing two to four recognition units intercon-
nected by a phenyl, biphenyl or diphenylmethane spacer
perform effective recognition of carbohydrates through mul-
tiple interactions.[3b–d,g–j,s,t,4k,s,t] Depending on the nature and
number of recognition subunits and connecting bridges used
as the building blocks, a variety of structures with different
binding properties could be obtained (for examples of rec-
ognition and spacer units used for the construction of the
acyclic receptors, see Scheme 1; for examples of binding
motifs found in the receptor–sugar complexes, see Figure 2).
The acyclic scaffold of the receptors provides simplicity in
the synthetic plan for many modifications of the receptor
structure, supplying a base for systematic studies toward rec-
ognition motifs for carbohydrates.
Natural carbohydrate recognition is mediated by various
classes of protein, such as lectins (the most intensively stud-
ied class), bacterial periplasmic proteins and antibodies. A
number of interactions contribute to the stabilisation of pro-
tein–carbohydrate complexes, including neutral and ionic
hydrogen bonds, metal coordination and packing of aromat-
ic side chains against the sugar rings.[1] In the case of lectins
and bacterial periplasmic proteins, most of the hydrogen
bonds involve amino acid side-chain groups of the pro-
tein,[1a,f,g,h] such as amide (Asn, Gln), carboxylate (Asp, Glu),
quanidinium (Arg), ammonium (Lys), hydroxy (Ser, Thr,
Tyr), imidazole (His), and indole (Trp) groups (for examples
of hydrogen-bonding interactions involving the imidazole or
[a] Prof. Dr. M. Mazik, Dipl.-Chem. M. Kuschel
Institut für Organische Chemie
der Technischen Universität Braunschweig
Hagenring 30, 38106 Braunschweig (Germany)
Fax : (+49)5313-9181-85
E-mail: m.mazik@tu-bs.de
Supporting information for this article is available on the WWW
1
under http://www.chemeurj.org/ or from the author and contains H
und 13C NMR spectra of compounds 1–4, IR data of compounds 1–4,
1
examples of H NMR titrations of receptor 3 and 4 with b-glucopyra-
1
noside 5, an example of H NMR titration of b-glucopyranoside 5
Herein, we describe the synthesis and binding properties
of new carbohydrate receptors containing a 4(5)-substituted
imidazole or a 3-substituted indole ring (receptors 1 and 2,
with receptor 3 (inverse titration), further examples of titration
curves, representative mole-ratio plots and X-ray data for compound
11.
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see Scheme 2). The design of
these receptors was inspired by
the binding motifs shown in
Figure 1; the imidazole or
indole group is able to partici-
pate in both hydrogen bonding
(Figure 1a, b and c) and stack-
ing interactions with the sugar
ring
(Figure 1d).
Figure 1a
shows the participation of both
the imidazole ring and the
amide group of galactose-bind-
ing protein in hydrogen bond-
ing with d-glucose. To mimic
such a combination of noncova-
lent interactions, the 2-amino-
pyridine unit was incorporated
into the receptor structure as a
heterocyclic analogue of the as-
paragine/glutamine
primary
amide side chain (see also refer-
ence [6]). Our previous binding
studies showed that aminopyri-
dines provide an excellent
structural motif for binding car-
bohydrates. This is associated
with the ability to form cooper-
ative and bidentate hydrogen
bonds with the sugar OH
groups.[3g,s,t,4k,s,t] As in previous-
ly described artificial systems
(Figure 2),[3j] the participation
of the phenyl ring of the recep-
tor in the interactions with
Figure 1. Examples of hydrogen bonds in the complex of a) galactose-binding protein with d-glucose,[1a] b) mal-
tose-binding protein with maltose[1b] and c) Amaranthus caudatus with benzyl a-glycoside of Galb3GalNAc.[1i]
d) Intermolecular hydrogen bonds and stacking interactions in the complex between d-glucose and galactose-
binding protein (adapted from reference [1a]; the glucose is sandwiched between the indole of Trp183 and the
phenyl ring of Phe16).
À
sugar C H units was expected
to provide additional stabilisa-
tion of the receptor–sugar
complexes (the character of
carbohydrate–aromatic interac-
tions is still a subject of con-
troversy; see reference [7]). In
addition, we describe compara-
tive binding studies with com-
pounds 3 and 4, which incorpo-
rate a 2-substituted pyrrole or
1-substituted imidazole group,
respectively (see Scheme 2).
Quiochio has shown that the
hydrogen
bonds
between
sugar-binding proteins and es-
sential recognition determi-
nants on sugars are shielded
from the bulk solvent, meaning
that they exist in an environ-
ment with a lower dielectric
constant[1a] (see also refer-
ence [8]). Thus, investigations
Scheme 1. Examples of spacer and recognition units X that were used by our group for the construction of acy-
clic carbohydrate receptors.[3b–d,g–j,s,t,4k,s,t]
.
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Artificial Acyclic Carbohydrate Receptors
FULL PAPER
of the receptor–sugar complexes was determined by mole
ratio plots and by the curve-fitting analysis of the titration
data). The fluorescence binding titration data were analysed
by using the Hyperquad program.[11b]
Results andDiscussion
Synthesis of the receptors: The synthesis of compounds 1–4
started from 1,3,5-tris(bromomethyl)-2,4,6-triethyl benzene
(10),[12] which was converted into compound 11 through a
reaction with two equivalents of 2-amino-4,6-dimethylpyri-
dine. The separation of the product 11 and the byproducts
11a and 11b (see Scheme 3) was carried out by column
chromatography. The crystal structure of 11 is shown in
Figure 3; it should be noted that the three arms of 11 point
to the same face of the central phenyl ring, whereas the
three ethyl groups point in the opposite direction. The reac-
tion of 11 with aqueous ammonia gave the amino derivative
12, which was the base for the synthesis of compounds 1–3.
The reaction of 12 with one equivalent of the corresponding
carbaldehyde, such as 4(5)-imidazole-carbaldehyde (for a
discussion on annular NH tautomerism of imidazoles, see
reference [13]), 3-indole-carbaldehyde or 2-pyrrole-carbalde-
hyde, provided the corresponding imine (for example, com-
pound 13, as shown in Scheme 3), which was further re-
duced with sodium borohydride. Compound 4 was synthes-
ised by reaction of 11 with one equivalent of imidazole (see
the Experimental Section).
Figure 2. Examples of binding motifs observed in the crystal structure of
the 2:1receptor–sugar complex formed between pyrimidine-based recep-
tor[3j] and octyl b-d-glucopyranoside.
Scheme 2. Structures of receptors 1–4.
with synthetic receptors in organic media make an impor-
tant contribution to our understanding of the complex car-
bohydrate binding processes in nature (recognition of neu-
tral sugars in aqueous solution through noncovalent interac-
tions remains an important challenge in artificial receptor
chemistry; for some examples, see references [3h,l,9]).
To evaluate the recognition capabilities of receptors 1–4
in organic media and compare their binding properties with
the properties of the previously published receptors, the
octyl b-d-glucopyranoside (5), octyl a-d-glucopyranoside
(6), octyl b-d-galactopyranoside (7), dodecyl b-d-maltoside
(8) and dodecyl a-d-maltoside (9) were selected as sub-
strates.
Binding properties of receptors 1 and 2 toward b-glucopyra-
1
noside 5: The H NMR titration experiments[14] with b-glu-
copyranoside 5 were carried out by adding increasing
amounts of the sugar to a CDCl3 solution of the receptor 1
or 2. In addition, inverse titrations were performed in which
the concentration of sugar 5 was held constant and that of
the receptor was varied.
The complexation between the receptors 1 or 2 and b-glu-
copyranoside 5 was evidenced by several changes in the
NMR spectra (see Figures 4, 5, and 6). After the addition of
one equivalent of sugar 5 to a solution of the receptor 1 or
2, almost no more change was observed in the chemical shift
of the receptor signals.
The interactions of the receptors and carbohydrates were
During the titration of 1 with 5, the signal due to the
amine NHA of 1 (for labelling, see Scheme 2) moved down-
field by about 1.5 ppm with broadening (see Figure 4d); the
NHD signal showed very strong broadening and was unob-
servable after the addition of only 0.1equivalents of 5. Fur-
thermore, the 1H NMR spectra showed changes in the chem-
ical shifts of the CH3 (protons F, G), CH2 (protons B, C, E),
pyridine CH (protons H, I) and imidazole CH resonances of
1 (see Figure 4a, b, c and e). The signal for the protons B
moved upfield by 0.17 ppm with broadening, whereas those
for the protons C and E shifted down- and upfield by
1
C
investigated by H NMR and fluorescence spectroscopy. The
0.05 ppm (splitting of the CH2 signal of 1 was observed
after the addition of about 0.3 equivalents of 5; see Fig-
ure 4b). The two imidazole CH protons shifted downfield by
1H NMR binding titration data were analysed by using the
Hostest 5.6[10] and the HypNMR programs[11a] (stoichiometry
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2407

M. Mazik and M. Kuschel
Scheme 3. Reaction conditions: a) 2-amino-4,6-dimethylpyridine (2 equiv), CH3CN/THF, K2CO3, 48 h (30%); byproducts 11a and 11b: 1,3-bis(bromo-
methyl)-5-[(4,6-dimethylpyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene and 1,3,5-tris[(4,6-dimethyl-pyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene;
b) NH3/H2O (25% solution), 12 h (72%); c) 4(5)-imidazole-carbaldehyde (1 equiv), CH3OH, 24 h; d) NaBH4 (1.2 equiv, 32%).
tion). The binding constants for 1·5 were found to be
191730mÀ1 (K11) and 8560mÀ1 (K21; b21 =1.64”109 mÀ2
;
Table 1).[14c]
The addition of b-glucopyranoside 5 to a solution of the
receptor 2 also caused significant downfield shift of the
amine NHA signal of 2 as well as changes in the chemical
B,C,E
shifts of the indole NH, CH3F,G, CH2
(see Figure 6),
indole CH and pyridine CHH,I resonances. The signal for the
protons A moved by about 1.9 ppm with broadening, where-
as those for the protons F, G, H and I shifted in the range
0.03–0.08 ppm. The CH2 (see Figure 6b) and CH2 signals
moved upfield by 0.20 and 0.03 ppm, respectively, whereas
B
E
C
the CH2 signal shifted downfield by 0.08 ppm (see Fig-
ure 6b). The signals for the protons C and E were overlap-
ping during the titration, the indole NH signal shifted down-
field with very strong broadening and the NHD signal of 2
was unobservable after the addition of only 0.1equivalent
of 5; these signals could not be used for the determination
of the binding constants. Both the curve fitting of the titra-
tion data (the complexation-induced chemical shifts of the
B
F,G
NHA, CH2 and CH3 signals were analysed) and the mole-
ratio plots suggested again the existence of 1:1and 2:1re-
ceptor–sugar complexes in the chloroform solution, with the
stronger association constant for 1:1 binding and a weaker
association constant for the 2:1receptor–sugar complex.
The association constants for 2·5 were determined to be
Figure 3. Crystal structure of 11, side (upper image) and top (lower
image) views (the hydrogen-bonded diethyl ether molecule is shown).
156100mÀ1 (K11) and 10360mÀ1 (K21; b21 =1.62”109 mÀ2
;
B
F
0.03 and 0.08 ppm (see Figure 4f). The NHA, CH2 , CH3
Table 1).
and imidazole CH signals were monitored for the determi-
nation of the binding constants; the typical titration curves
are shown in Figure 5a and b. The best fit of the titration
data was obtained with the mixed :11and 2:1receptor–
sugar binding model; this model was further supported by
mole-ratio plots (see Figure S5 in the Supporting Informa-
The high values of the binding constants for 1·5 and 2·5
determined on the base of the H NMR spectroscopic titra-
tions were confirmed by a second, independent technique,
namely fluorescence spectroscopy[15] (for a discussion on
limitations of the NMR method, see reference [16]). The anal-
ysis of the fluorescence titration data (fluorescence intensity
1
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Artificial Acyclic Carbohydrate Receptors
FULL PAPER
Figure 4. Partial 1H NMR spectra (500 MHz; CDCl3) of receptor 1 after the addition of (from bottom to top) 0.00, 0.10, 0.21, 0.32, 0.43, 0.54, 0.65, 0.76,
G
0.87, 1.09, 1.31, 1.53, 1.75, 1.97, 2.19, 2.41, 2.63, 2.85, 3.07 and 3.28 equivalents of 5 ([1]=0.98mm). Shown are chemical shifts of the a) CH3F and CH3
b) CH2C, c) CH2B, d) NHA, e) pyridine CHI and f) imidazole CH resonances of 1 (for labelling, see Scheme 2).
,
ble with those determined on
the base of the NMR spectro-
scopic titrations.
In addition, the interactions
between b-glucopyranoside 5
and the receptors 1 and 2 were
investigated on the base of in-
verse titrations in which the
concentration of sugar 5 was
held constant and that of re-
ceptor 1 or 2 varied. During
the titration of 5 with 1 or 2,
the signals due to the OH pro-
F
Figure 5. a and b) Plot of the chemical shifts of the NHA (downfield shift) and CH3 (upfield shift) of 1 as a
tons of
5 shifted downfield
function of added b-glucopyranoside 5. The [receptor]:[sugar] ratio is marked. c) Chemical shift changes ob-
AHCTREUNG
with strong broadening and
were unobservable after the
addition of only 0.1equivalent
of the receptor (see Figure 7b),
served for the 2-CH group of 5 during the titration of 5 with 1 (inverse titration). The [sugar]:[receptor] ratio
is marked.
A
decreased with increasing monosaccharide concentration)
confirmed also the mixed 1:1and 2:1receptor–glucopyrano-
side binding model; the binding constants determined on
the base of fluorescence titrations in CHCl3 were compara-
indicating the important contribution of the OH groups of 5
to the complex formation. The complexation between 5 and
the receptor 1 or 2 was further evidenced by significant
chemical-shift changes of the CH units of 5 (for examples,
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M. Mazik and M. Kuschel
Figure 7. Partial 1H NMR spectra (500 MHz; CDCl3) of b-glucopyrano-
side 5 after the addition of (from bottom to top) 0.00, 0.15, 0.32, 0.49,
0.65, 0.81, 0.98, 1.14, 1.30, 1.47, 1.63, 1.87, 2.12, 2.36, 2.61, 3.26, 3.67, 4.08
and 4.89 equivalents of 1 ([5]=0.70mm). Shown are the chemical shifts of
the a) CH-1and b) CH-2,-3,-4, and CH-5 resonances of 5.
Figure 6. Partial 1H NMR spectra (500 MHz; CDCl3) of receptor 2 after
the addition of (from bottom to top) 0.00, 0.11, 0.22, 0.32, 0.43, 0.54, 0.65,
0.76, 0.87, 1.09, 1.30, 1.52, 1.74, 1.96, 2.18, 2.39, 2.61, 2.83, 3.05 and
3.27 equivalents of 5 ([2]=0.99mm). Shown are the chemical shifts of the
F,G
B,C
a) CH3 and b) CH2 resonances of 2 (for labelling, see Scheme 2).
see Figure 7a and b). During the titrations of 5 with 1, the
signals due to the 1-, 2-, 3-, 4- and 5-CH protons of 5 shifted
upfield by 0.21, 1.53, 0.29, 0.55 and 0.18 ppm, respectively
(after the addition of about 4 equivalents of receptor 1). The
titrations of 5 with 2 caused upfield shifts of the 1-, 2-, 4-
and 5-CH signals of 5 by 0.25, 1.72, 0.61 and 0.15 ppm, re-
spectively. These complexation-induced chemical-shift
changes are significantly larger than those usually reported
for the CH protons of b-glucopyranoside in the literature.
Among the CH signals, the signals due to the 2-CH and 4-
CH protons of 5 show the largest shift, suggesting a particu-
larly important contribution of these CH units to the com-
plex stabilisation (through formation of CH···p interactions
with the phenyl ring of the receptor). The participation of
the CH units of 5 in CH···p interactions with the central
phenyl ring of the receptor was also indicated by molecular
modelling (see below, Table 2, Figure 8). In both cases, 5·1
and 5·2, the best fit of the titration data was obtained with
the mixed 1:1 and 1:2 sugar–receptor binding model (for ex-
ample, see Figure 5c); thus, the inverse titrations supported
the existence of 1:1and 2:1receptor–sugar complexes in
chloroform solution, with a stronger association constant for
1:1binding and a weaker association constant for the 2:1re-
ceptor–sugar complex. The association constants obtained
on the base of these titrations are identical within the limits
of uncertainty to those determined from titrations in which
the role of the receptor and substrate was reversed.
Molecular-modelling studies suggested that all OH groups
and the ring oxygen atom of the bound sugar 5 in the com-
plex 1·5 are involved in the formation of hydrogen bonds
À
(see Table 2). Interactions of sugar C H bonds with the cen-
tral phenyl ring of 1 (2-CH···p and 4-CH···p interactions; see
Figure 8a) provide additional stabilisation of the complex.
Furthermore, the molecular-modelling calculations indicated
that in the 2:1receptor–sugar complex, the two receptor
molecules almost completely enclose the sugar, leading to
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Artificial Acyclic Carbohydrate Receptors
FULL PAPER
Table 1. Association constants[a,b] for receptors 1–4 and carbohydrates 5–9.
involvement of all sugar hy-
droxy groups in interactions
with the two receptor mole-
cules (see Table 2, Figure 8b).
The OH groups are involved in
the formation of cooperative
hydrogen bonds resulting from
the simultaneous participation
of a sugar OH as the donor
and acceptor of hydrogen
bonds. The phenyl units of
both receptors stack on the
sugar ring; both sides of the
pyranose ring are involved in
[c]
[d]
[e]
Host–guest
complex
K11
[mÀ1
K21 or K12
[mÀ1
b21 =K11K21 or
b12 =K11K12
Ddobs
[ppm]
G
]
A
]
ACHTREUNG
A
1·5
1·6
191730
3160
8560[c]
1540[d]
1.64”109
4.86”106
NH: 1.50; CH2: À0.17; CH3: À0.08
1-CH: À0.21; 2-CH: À1.53; 4-CH: À0.55
NH: 1.11; CH2: À0.14; CH3: À0.06
1-CH: À0.22; 2-CH: À0.67 ; 4-CH: À0.55
NH: 1.20; CH2: À0.13; CH3: À0.05
NH: 1.34; CH2: À0.13; CH3: À0.06
NH: 1.39; CH2: À0.17; CH3: À0.06
1·7
1·8
1·9
3320
205760
147200
300[d]
9.96”105
1.78”109
9.49”108
8670[c]
6450[c]
2·5
156100
10360[c]
1.62”109
NH: 1.85; CH2: À0.20; CH3: À0.08
1-CH: À0.25; 2-CH: À1.72; 4-CH: À0.61
NH: 1.17; CH2: À0.14; CH3: À0.05
NH: 1.21; CH3: À0.05
2·6
2·7
2·8
2·9
2820
7470
182690
123650
350[d]
9.87”105
8.25”106
2.71”10 9
1.28”109
1100[d]
14840[c]
10390[c,f]
NH: 1.32; CH2: À0.17; CH3: À0.06
CH···p
interactions
(see
Table 2 and Figure 8b).
7470[c]
1.34”109
NH: 1.60, CH2: À0.18; CH3: À0.08
1-CH: À0.21; 2-CH: À1.60; 4-CH: À0.56
NH: 1.17; CH2: À0.15, CH3: À0.06
NH: 1.22; CH2: À0.13, CH3: À0.06
The comparison of the bind-
ing properties of the receptors
1 and 2 with those of the previ-
ously described three-armed
pyridine-based analogues[3s,4k]
shows that the incorporation of
a suitable substituted imidazole
or indole unit into the acyclic
receptor structure significantly
affects the binding affinity and
selectivity of the new receptors
(for comparison of the binding
constants, see Table 1). As in
natural complexes, the high
binding affinity and selectivity
of the receptors 1 and 2 is ach-
ieved through the participation
of different types of binding
units in the recognition process.
3·5
179370
3·6
3·7
2300
4100
–
–
–
–
4·5
3560
48630
1300[d]
1320[d]
4.87”106
6.42”107
NH: 0.98; CH2: À0.08; CH3: À0.03
NH: 1.31; CH2: À0.16; CH3: À0.07
11b·5[g]
[a] Average Ka values from multiple titrations in CDCl3 (the high values of the binding constants for 1·5, 2·5,
1
1·8 and 2·8 determined on the basis of the H NMR spectroscopic titrations were confirmed by fluorescence ti-
trations). [b]Errors in Ka are less than 10%. [c]K21 corresponds to 2:1receptor–sugar association constant.
[d]K12 corresponds to 1:2 receptor–sugar association constant. [e]Largest change in chemical shift observed
B
F
during the titration for NHA, CH2 and CH3 signals of the receptor (the concentration of receptor was kept
constant and that of sugar varied) as well as for the 1-CH, 2-CH or 4-CH groups of the sugar in the case of in-
verse titrations (the concentration of sugar was kept constant and that of the receptor was varied). [f]Deter-
mined only on the basis of fluorescence titrations. [g]Results from reference [3s], compound 11b: 1,3,5-
tris[(4,6-dimethylpyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene.
Table 2. Examples of noncovalent interactions indicated by molecular-modelling calculations[a] for the com-
plexes formed between receptor 1 and sugars 5 and 8.
[c]
Receptor–substrate
system
1:1 Receptor–sugar complex[b]
2:1Receptor–sugar complex
Binding properties of receptors
1 and2 towardmonosacchar-
ides 6 and 7: Binding studies
with a-glucopyranoside 6 and
b-galactopyranoside 7 showed
that the interactions of recep-
tors 1 and 2 with these mono-
saccharides are less favourable
than those with b-glucopyrano-
side 5. Similar to the binding
studies with sugar 5, the com-
plexation between receptors 1
and 2 and pyranosides 6 and 7
was evidenced by several
changes in the NMR spectra.
With the monosaccharides 6
and 7, chemical shift changes
1·5
pyridine-N···HO-2
NHA···OH-2
(I) imidazole-NH···OH-2
(II) imidazole-NH···OH-2; (II) HND···HO-2
(I) pyridine-N···HO-3; (II) NHA···OH-3
(II) pyridine-N···HO-4; (I) NHA···OH-4
(II) pyridine-N···HO-6
NHD···OH-3
imidazole-NH···OH-3
imidazole-HN···HO-4
HND···HO-4
(II) NHA···O-ring; (II) NHD···O-1
(I) phenyl···HC-1; (I) phenyl···HC-3
(I) phenyl···HC-5; (II) phenyl···HC-2
(II) phenyl···HC-4
pyridine-N···HO-6
NHA···O-ring
phenyl···HC-2; phenyl···HC-4
1·8
pyridine-N···HO-2 (g1)
NHA···OH-2 (g1)
(I) imidazole-NH···OH-2 (g1)
(I) HND···HO-2 (g1)
NHD···OH-3 (g1)
(I) NHD···OH-3 (g1)
imidazole-NH···OH-3 (g1)
pyridine-N···HO-6 (g1)
NHA···O-ring (g1)
imidazole-HN···HO-2 (g2)
phenyl···HC-2 (g1)
(I) NHA···O-1(g1)
(II) NHA···OH-2 (g2)
(I) pyridine-N···HO-2 (g2)
(II) NHA···OH-3 (g2)
(II) pyridine-N···HO-4 (g2)
phenyl···HC-4 (g1)
imidazole···HC-3 (g2)
(II) NHD···O-ring (g2)
(I) phenyl···HC-1 (g1); (I) phenyl···HC-3 (g1)
(I) phenyl···HC-5 (g1); (II) imidazole···HC-2 (g1)
(II) imidazole···HC-4 (g1); (II) phenyl···HC-2 (g2)
continue to higher [sugar]/[re-
A
ceptor] ratios, indicating lower
affinity of 1 and 2 toward 6 and
7, whereas after the addition of
[a] MacroModel V.8.5, OPLS-AA force field, MCMM, 50000 steps. [b] g1and g2: the glucose units of 8. [c] I
and II: the two receptors molecules in the 2:1receptor–sugar complex.
Chem. Eur. J. 2008, 14, 2405 – 2419
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2411

M. Mazik and M. Kuschel
CHH,I as well as imidazole CH
groups (in the range of 0.02–
0.14 ppm). In contrast with the
titrations with b-glucopyrano-
C
side 5, no splitting of the CH2
signal of 1 was observed after
the addition of the a-anomer
6. The curve fitting of the titra-
tion data indicated the forma-
tion of complexes with 1:1 and
1:2 receptor–sugar stoichiome-
try (different binding model
than that determined for the
receptor 1 and 2 and b-gluco-
pyranoside 5 (see Figure S1a in
the Supporting Information);
the binding constants for 1·6
were found to be 3160mÀ1
(K11) and 1540mÀ1 (K12; b12 =
4.86”106 mÀ2) and those for 2·6
were 2820mÀ1 (K11) and 350mÀ1
(K12; b12 =9.87”105 mÀ2
;
see
Table 1).
The interactions between a-
glucopyranoside 6 and the re-
ceptor 1 were also investigated
on the base of inverse titra-
tions (see Figure 9). The sig-
nals due to the OH protons of
6 shifted downfield with strong
broadening and were unob-
servable after the addition of
only 0.1equivalents of the re-
ceptor 1 (similar to the titra-
tions of 5 with 1), indicating
again the important contribu-
tion of the OH groups of 6 to
the complex formation. The
signals of the 1-, 2-, 3-, 4-, and
5-CH protons shifted upfield
by 0.22, 0.67, 0.25, 0.55 and
0.15 ppm, respectively (after
the addition of about 6 equiva-
lents of receptor 1). Similar to
the titration of 5 with 1, the
signals due to the 2- and 4-CH
group of the a-glucopyranoside
Figure 8. Energy-minimised structure of a) the 1:1 complex formed between receptor 1 and b-glucopyranoside
5 (different representations) and b) the 2:1complex between receptor 1 and b-glucopyranoside 5 (different
representations). MacroModel V.8.5, OPLS-AA force field, MCMM, 50000 steps. Colour code: receptor C,
blue; receptor N, green; sugar molecule, yellow.
6
showed the largest shifts
(however, the chemical-shift
one equivalent of b-glucopyranoside 5, almost no further
change was observed in the chemical shift of the receptor
signals. During the titration of 1 and 2 with a-glucopyrano-
side 6, the signal due to the amine NHA of the receptor
moved downfield by about 1.1 and 1.2 ppm, respectively
(after the addition of about four equivalents of 6). Further-
more, the 1H NMR titrations of 1 or 2 with 6 produced
chemical shift changes of the CH2B,C,E, CH3F,G, pyridine
changes of the 2-CH signal of 6 are less substantial than
those of the 2-CH signal of 5). The analysis of the titration
data indicated the formation of complexes with 1:1 and 2:1
sugar–receptor binding stoichiometry; thus, the inverse titra-
tions fully confirmed the binding model determined through
the titrations of the receptor 1 with the a-anomer 6 (see
above). The association constants obtained on the basis of
these titrations are again identical within the limits of uncer-
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Chem. Eur. J. 2008, 14, 2405 – 2419

Artificial Acyclic Carbohydrate Receptors
FULL PAPER
could be solubilised in this solvent in the presence of the re-
ceptor 1 or 2, indicating favourable interactions between the
binding partners. Thus, the receptor in CDCl3 was titrated
with a solution of maltoside dissolved in the same receptor
solution. During the titrations of 1 and 2 with 8, the signal
due to the amine NHA moved downfield by about 1.3 ppm
with broadening; the NHD signal was unobservable after the
F,G
addition of only 0.1equivalents of 8. The CH3
signals
shifted up- and downfield in the range of 0.03–0.06 ppm, as
shown in Figure 10a. The saturation occurred after the addi-
B
tion of approximately 0.75 equivalents of 8. The CH2 signal
of 1 and 2 moved upfield by 0.13 and 0.17 ppm, respectively,
whereas the pyridine CH resonances shifted in the range of
0.01–0.06 ppm. The imidazole CH resonances of 1 shifted
downfield by 0.05 and 0.07 ppm with broadening. The indole
NH signal showed broadening and downfield shifting by
0.31ppm. Both the curve fitting of the titration data (typical
titration curves are shown in Figure 10b and c) and the
mole-ratio plots (see Figure S5 in the Supporting Informa-
tion) suggested again the existence of 1:1 and 2:1 receptor–
sugar complexes in the chloroform solution, with a stronger
association constant for 1:1 binding and a weaker associa-
Figure 9. Partial 1H NMR spectra (500 MHz; CDCl3) of a-glucopyrano-
side 6 after the addition of (from bottom to top) 0.00, 0.20, 0.41, 0.62,
0.83, 1.04, 1.25, 1.46, 1.67, 1.88, 2.09, 2.40, 2.72, 3.03, 3.35, 3.66, 4.18, 4.71,
5.23 and 6.28 equivalents of 1 ([6]=0.58mm).
tainty to those determined from titrations in which the role
of the receptor and substrate was reversed.
The 1H NMR spectra obtained through titrations of recep-
tor 1 and 2 with b-galactopyranoside 7 showed downfield
shifting of the NHA resonances of 1 and 2 by about 1.2 ppm
(see Figure S1b in the Supporting Information). The signals
F,G
for the CH3 and pyridine CHH,I protons of 1 and 2 moved
up- and downfield in the range of 0.02–0.06 ppm, whereas
B
those for the CH2 protons shifted upfield by about
0.14 ppm. The analysis of the titration data with galactopyr-
anoside 7 indicated the formation of complexes with 1:1 and
1:2 receptor–sugar stoichiometry. The binding constants for
1·7 were found to be 3320mÀ1 (K11) and 300mÀ1 (K12; b12 =
9.96”105 mÀ2), whereas those for 2·7 were 7470mÀ1 (K11) and
1100mÀ1 (K12; b12 =8.25”106 mÀ2). Thus, the complexes
formed between the receptors 1 and 2 and sugars 6 and 7
are much less stable than those formed with the b-glucopyr-
anoside 5.
Figure 10. a) Partial 1H NMR spectra (400 MHz, CDCl3) of 1 after the
addition of (from bottom to top) 0.00–2.73 equivalents of b-maltoside 8
F,G
([1]=0.98mm). Shown are the chemical shifts of the CH3 resonances of
1 (for labelling, see Scheme 2). b and c) Plot of the observed (+) and cal-
culated (c) chemical shifts of the CH3F and NHA resonances of 1 as a
Binding properties of receptors 1 and 2 towards disacchar-
ides 8 and 9: b-Maltoside 8 is poorly soluble in CDCl3, but
function of added b-maltoside 8; the [receptor]:[sugar] ratio is marked.
A
Chem. Eur. J. 2008, 14, 2405 – 2419
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2413

M. Mazik and M. Kuschel
tion constant for the 2:1recep-
tor–sugar complex. The associ-
ation constants for 1·8 were de-
termined to be 205760mÀ1
(K11) and 8670mÀ1 (K21; b21 =
1.78”109 mÀ2), those for 2·8
were found to be 182690mÀ1
(K11) and 14840mÀ1 (K21; b21 =
2.71”10 9 mÀ2).[17]
According to molecular-
modelling calculations, the 1:1
complex formed between the
receptor 1 and b-maltoside 8
can potentially be stabilised by
several hydrogen bonds be-
tween the OH groups of the
sugar and the amine NHA and
NHD, the pyridine-N and imi-
dazole-NH of the receptor (see
Table 2 and Figure 11a). Fur-
thermore, interactions of sugar
CH groups with the phenyl
group of the receptor molecule
should provide additional stabi-
lisation of the receptor–sugar
complex (for example, the in-
teractions between the 2- and
4-CH groups of the g1unit of 8
and the phenyl ring of 1; see
Table 2). The 2:1receptor–mal-
toside complex (see Fig-
ure 11b) can be stabilised by at
least ten hydrogen bonds as
well as several CH···p interac-
tions (see Table 2). As shown
in Figure 11b, the central
phenyl rings of the two recep-
tors stack on the two glucose
rings of 8; the 2-, 3- and 5-CH
groups of the g1unit interact
with the phenyl ring of one re-
ceptor molecule, whereas the
2-CH group of the g2 unit in-
teracts with the central phenyl
ring of the other receptor. In
addition, interactions of the 2-
and 4-CH groups of the g1unit
with the imidazole group of
Figure 11. Energy-minimised structure of a) the 1:1 complex formed between receptor 1 and b-maltoside 8
(different representations) and b) the 2:1receptor–sugar complex between receptor 1 and b-maltoside 8 (dif-
ferent representations). MacroModel V.8.5, OPLS-AA force field, MCMM, 50000 steps. Colour code: receptor
C, blue; receptor N, green; sugar molecule, yellow.
one receptor molecule should provide additional stabilisa-
tion of the 2:1receptor–sugar complexes.
147200mÀ1 (K11) and 6450mÀ1 (K21; b21 =9.49”108 mÀ2). Thus,
1H NMR titrations indicated that the receptor 1 exhibits
about a twofold higher affinity for b-maltoside 8 than for
the a-anomer 9.
a-Maltoside 9 is almost insoluble in CDCl3 but could be
solubilised in this solvent in the presence of the receptor 1.
The 1H NMR titrations of 1 with a-maltoside 9 produced
similar spectral changes as those with b-maltoside 8. The fit
The formation of strong complexes between the receptors
1 or 2 and disaccharides 8 and 9 was also confirmed by fluo-
rescence spectroscopy. The fluorescence titration experi-
ments were carried out by adding increasing amounts of the
sugar 8 or 9 (both disaccharides are soluble in CHCl3 in the
F
of NMR shift changes of the NHA and CH3 resonances
agreed again with the 1:1and 2:1receptor–sugar binding
model; the binding constants for 1·9 were found to be
2414
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Chem. Eur. J. 2008, 14, 2405 – 2419

Artificial Acyclic Carbohydrate Receptors
FULL PAPER
Comparative binding studies with receptors 3 and 4: Molec-
ular-modelling calculations indicated that the 3-N of the imi-
dazole ring of 1 does not participate in the formation of hy-
drogen bonds with b-glucopyranoside 5, as shown in Fig-
ure 8a. To evaluate the role of this nitrogen atom in the
binding process, the pyrrole derivative 3 was synthesised
and its binding properties toward 5 were studied. The bind-
ing studies showed that no significant difference in the bind-
ing efficiency was found between the receptors 3 and 1, indi-
cating a less important contribution of the imidazole 3-N of
1 to complex stabilisation. Thus, the results of the molecu-
lar-modelling calculations were confirmed by the experimen-
tal data.
The 1H NMR titration experiments with b-glucopyrano-
side 5 were carried out by adding increasing amounts of the
sugar to a CDCl3 solution of the receptor 3 (Figure 13). Sim-
ilar to the binding studies between 1 or 2 and 5, the com-
plexation between 3 and 5 was evidenced by several changes
in the NMR spectra, as shown in Figure S2 in the Support-
ing Information. The signal due to the amine NHA of 3 (for
labelling, see Scheme 2) moved downfield by about 1.6 ppm
with broadening (see Figure S2a in the Supporting Informa-
B
E
tion), the CH2 and CH2 resonances moved upfield by 0.18
C
and 0.06 ppm, respectively, and the CH2 signal shifted
downfield by 0.05 ppm (Figure S2b and c in the Supporting
C
Information). The splitting of the CH2 signal of 3 was ob-
served after the addition of about 0.2 equivalents of 5, as
shown in Figure S2c in the Supporting Information. Further-
1
more, the H NMR spectra showed changes in the chemical
Figure 12. Fluorescence titration of receptor 2 with b-maltoside 8 (a) and
a-maltoside 9 (b) in CHCl3; [2]=0.17 and 0.22mm, respectively; equiva-
lents of 8=0.00–3.40; equivalents of 9=0.00–3.37. Excitation wavelength
330 nm. The fluorescence intensity decreases with increasing concentra-
tion of 8 and 9 (see arrows).
shifts of the CH3 group (protons F, G; see Figure S2d in the
Supporting Information) and pyridine CH (protons H, I)
resonances in the range of 0.03–0.08 ppm. The signal due to
the pyrrole NH shifted downfield by 0.73 ppm with broaden-
ing. The curve fitting of the titration data suggested the exis-
tence of 1:1and 2:1receptor–sugar complexes in the chloro-
form solution; typical titration curves are shown in Fig-
ure 13a and Figure S2e in the Supporting Information. The
binding constants for 3·5 were found to be 179370mÀ1 (K11)
and 7470mÀ1 (K21; b21 =1.34”109 mÀ2); thus, the receptor 3
concentration range required for fluorescence titrations) to
a CHCl3 solution of the receptor 1 or 2 (for example, see
Figure 12). The best fit of the titration data was obtained
with 1:1and 2:1receptor–sugar binding model; the forma-
tion of the 2:1complexes was
further supported by the mole-
ratio plots. The binding con-
stants for 1·8 were found to be
198580mÀ1 (K11) and 8900mÀ1
(K21; b21 =1.76”109 mÀ2), those
for
2·8
amounted
to
169900mÀ1 (K11) and 13810mÀ1
(K21; b21 =2.34”109 mÀ2). The
K11 and K21 binding constants
for 2·9 were found to be
123650mÀ1
(b21 =1.28”109 mÀ2),
and
10390mÀ1
respec-
tively. Thus, the binding con-
stants are comparable with
those determined on the basis
of the NMR spectroscopic ti-
trations.
Figure 13. a) Plot of the chemical shifts of the NHA resonances of 3 as a function of added 5. Plot of the chem-
ical shifts of the NHA (b) and imidazole CH resonances (c) of 4 as a function of added 5 in CDCl3. The
[receptor]:[sugar] ratio is marked.
A
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2415

M. Mazik and M. Kuschel
exhibits a similar level of affinity towards b-glucopyranoside
as the receptors 1 and 2 (see Table 1).
clic analogues of the asparagine/glutamine primary amide
side chains (in analogy to the binding motifs shown in Fig-
ure 1a). The recognition units are interconnected by a
phenyl spacer, which was incorporated into the receptor
structure to provide additional apolar contacts to a saccha-
ride; similar to sugar-binding proteins, which commonly
place aromatic surfaces against patches of sugar CH groups
(see Figure 1d). The amine NHD from the -CH2NHCH2-
linker provides an additional hydrogen-bonding site for the
binding of carbohydrates (see also reference [3i]), as is also
indicated by molecular modelling (Table 2). The compounds
1 and 2 have been established as highly effective receptors
for b-glucopyranoside 5, b-maltoside 8 and a-maltoside 9,
showing 1:1 and 2:1 receptor–substrate complexation behav-
iour toward the carbohydrates. These receptors are able to
bind the selected carbohydrates with an overall binding con-
stant b21 of 109 mÀ2 in chloroform solutions (with K11 and K21
of 105 and 103–104 mÀ1, respectively; see Table 1). Both hy-
drogen bonding and interactions of the carbohydrate CH
units with the phenyl rings of the receptors contribute to the
stabilisation of the 1:1 and 2:1 receptor–carbohydrate com-
plexes. Furthermore, the receptors 1 and 2 display remark-
able b- versus a-anomer selectivity in the recognition of glu-
copyranosides as well as epimer selectivity in the recogni-
tion of b-glucopyranoside and -galactopyranoside (see
Table 1).
The interactions between receptor 3 and b-glucopyrano-
side 5 were also investigated on the basis of inverse titra-
tions in which the concentration of sugar 5 was held con-
stant. Similar to the inverse titrations with receptors 1 and
2, during the titration of 5 with 3, the signals due to the OH
protons of sugar 5 shifted downfield with strong broadening
and were almost unobservable after the addition of only
0.1equivalents of the receptor (see Figure S3b in the Sup-
porting Information), indicating again the important contri-
bution of the OH groups of 5 to complex formation. The
complexation between 5 and the receptor 3 was further evi-
denced by significant chemical shift changes of the CH units
of 5 (for examples see Figure S3a and b in the Supporting
Information). The signals due to the 1-, 2-, 3-, 4- and 5-CH
protons shifted upfield by 0.21, 1.60, 0.26, 0.56 and
0.17 ppm, respectively (after the addition of about 4 equiva-
lents of receptor 3), indicating the participation of the CH
units of 5 in the formation of CH···p interactions with the
aromatic ring of the receptor 3.
In contrast with the strong binding of 3 with b-glucopyra-
noside 5, the binding of a-glucopyranoside 6 and b-galacto-
1
pyranoside 7 is relatively weak. The H NMR titrations of 3
with 6 and 7 produced similar spectral changes as those with
b-glucopyranoside 5; however, saturation occurred after the
addition of more than four equivalents of 6 or 7. The
The formation of receptor–sugar complexes has been
1H NMR spectra showed changes in the chemical shifts of
characterised by H NMR spectroscopy and confirmed by a
1
B,C,E
the NHA (downfield shift by about 1.2 ppm), CH2
(up-
second, independent technique, namely fluorescence spec-
troscopy. The 1H NMR titration experiments were carried
out by adding increasing amounts of the corresponding
mono- or disaccharide to a CDCl3 solution of the receptor 1
or 2. In addition, inverse titrations were performed in which
the concentration of the monosaccharide was held constant
and that of the receptor was varied. The association con-
stants obtained on the basis of these titrations are identical,
within the limits of uncertainty, to those determined from ti-
trations in which the role of the receptor and substrate was
reversed. The very high values of the binding constants for
1·5, 2·5, 1·8, 2·8 and 2·9 determined on the basis of the
1H NMR spectroscopic titrations[16] were fully confirmed by
the fluorescence titrations in CHCl3.
A significant feature observed during the titrations of b-
glucopyranoside 5 with 1 or 2 (inverse titrations) was the
upfield shifts of the CH signals of 5, particularly the strong
complexation-induced shift of the 2-CH proton (1.5 and
1.7 ppm for the titration with 1 and 2, respectively). These
complexation-induced chemical-shift changes are significant-
ly larger than those usually reported for the CH protons of
b-glucopyranoside in the literature. The results of the NMR
spectroscopic titrations indicate the participation of the
sugar CH units in the CH···p interactions with the phenyl
ring of the receptor. The formation of these interactions was
also suggested by molecular-modelling calculations (for ex-
amples of binding motifs indicated by molecular modelling,
see Table 2). The character of carbohydrate–aromatic inter-
actions is still a subject of controversy;[7,18] thus, the studies
H,I
and downfield shifts in the range of 0.03–0.15 ppm), CH
and CH3 (up- and downfield shifts in the range of 0.02–
F,G
0.06 ppm) resonances of 3. The best fit of the titration data
was obtained with the 1:1 binding model; the binding con-
stant for 3·6 was found to be 2300mÀ1 and that for 3·7 was
determined to be 4100mÀ1.
The spectral changes observed during the titrations of the
receptor 4, including the 1-imidazolyl unit, with b-glucopyra-
noside 5 (see Figure S4 in the Supporting Information and
Figure 13b and c) are less substantial than those observed
during the titrations of 1 with 5. The spectroscopic changes
indicated 1:1 binding followed by an association of the
second sugar molecule (mixed 1:1 and 1:2 receptor–sugar
binding model; this is a different binding model as that de-
termined for the complexation of 1 with 5). The binding
constants for 4·5 were found to be 3560mÀ1 (K11) and
1300mÀ1 (K12; b12 =4.87”106 mÀ2). Thus, the interactions be-
tween 4 and 5 are significantly weaker than those observed
with the receptors 1 and 2.
Conclusion
The analysis of the binding motifs in the protein–carbohy-
drate complexes (for examples, see Figure 1) has inspired
the design of receptors that include suitable substituted imi-
dazole or indole units, which represent the entities used in
nature, and 2-aminopyridine groups, which act as heterocy-
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Artificial Acyclic Carbohydrate Receptors
FULL PAPER
838C; 1H NMR (300 MHz, [D6]DMSO) d=1.22 (t, J=7.3 Hz, 3H), 1.23
(t, J=7.4 Hz, 6H), 2.23 (s, 6H), 2.36 (s, 6H), 2.72 (q, J=7.3 Hz, 2H),
2.80 (q, J=7.4 Hz, 4H), 3.92 (s, 2H), 4.36 (s, 6H), 6.10 (s, 2H), 6.34 ppm
(s, 2H); 13C NMR (100 MHz, CDCl3) d=16.76, 16.81, 21.15, 22.48, 22.76,
23.97, 39.47, 40.63, 103.61, 113.82, 133.15, 135.02, 142.07, 142.60, 155.22,
158.27 ppm; HRMS (EI): m/z: calcd for C29H41N5: 459.3362; found
459.3352; Rf =0.17 (CHCl3/CH3OH 7:1v/v).
with suitable model systems provide important insights on
the origin of the carbohydrate–aromatic interactions.
Comparative binding studies showed that the replacement
of the 4(5)-imidazolyl unit by a 2-pyrrolyl group (compound
3) does not reduce the binding affinity of the receptor, indi-
cating a less important contribution of the imidazole 3-N of
1 to the stabilisation of the complex 1·5 (as also indicated by
molecular modelling, see Figure 8). In contrast, the incorpo-
ration of a 1-imidazolyl unit into the receptor structure
(compound 4) causes both the change of the binding model
and a substantial drop in the binding affinity. Similar to the
receptors 1 and 2, the receptor 3 shows much higher affinity
for the b-glucopyranoside 5 than for the a-glucopyranoside
6 and b-galactopyranoside 7 (see Table 1).
The binding studies show that the mimicking of the bind-
ing motifs found in the crystal structures of protein–carbo-
hydrate complexes (by using natural recognition groups or
their analogues) represents a powerful strategy for the
design of effective and selective carbohydrate receptors. The
binding of sugars with artificial receptors in a medium with
a lower dielectric constant (see also reference [8]) provides
important information about the factors that contribute to
the affinity between receptors and saccharides and offers an
important screen for effective recognition motifs for carbo-
hydrates. The simple acyclic structure of 1–4 gives the possi-
bility of an easy variation of the receptor structure, provid-
ing a base for systematic studies towards recognition motifs
for carbohydrates.
General procedure for the synthesis of compounds 1–3: The carbalde-
hyde (4(5)-imidazole-, 3-indole- or 2-pyrrole-carbaldehyde; 0.76 mmol)
was dissolved in methanol (5 mL) and added to a solution of compound
12 (0.76 mmol) in methanol (20 mL). The reaction mixture was stirred
for 12 h. The solution was cooled to 08C and NaBH4 (0.76 mmol) was
added. The reaction mixture was then stirred for 1h at 0 8C and for an
additional 2 h at room temperature. The solvent was removed and the
residue taken up in chloroform/water (20 mL, 1:1) The aqueous phase
was washed twice with chloroform and the combined organic phases
were dried over magnesium sulfate and the solvent was removed. The
crude product was purified by column chromatography (CHCl3/CH3OH
5:1or 7:1v/v).
1-[(4-Imidazolyl-methyl)aminomethyl]-3,5-bis[(4,6-dimethylpyridin-2-
yl)aminomethyl]-2,4,6-triethylbenzene (1): Yield: 32%; m.p. 103–1048C;
1H NMR (400 MHz, CDCl3) d=1.13 (t, J=7.5 Hz, 6H), 1.19 (t, J=
7.5 Hz, 3H), 2.21(s, 6H), 2.33 (s, 6H), 2.68 (q, J=7.5 Hz, 6H), 3.75 (s,
2H), 3.87 (s, 2H), 4.31(s, 4H), 4.40 (brs, 2H), 6.10 (s, 2H), 6.32 (s, 2H),
6.89 (d, J=0.6 Hz, 1H), 7.40 ppm (d, J=0.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d=16.68, 16.71, 21.03, 22.66, 22.76, 23.92, 40.53, 46.03,
46.42, 103.61, 113.78, 118.65 135.28, 132.63, 133.87, 142.96, 143.18, 148.92,
156.27, 158.14 ppm; HRMS (ESI): m/z: calcd for C33H46N7: 540.3809;
found 540.3804; Rf =0.06 (CHCl3/CH3OH, 7:1v/v).
1-[(3-Indolylmethyl)aminomethyl]-3,5-bis[(4,6-dimethylpyridin-2-yl)ami-
nomethyl]-2,4,6-triethylbenzene (2): Yield: 36%; m. p. 97–988C;
1H NMR (400 MHz, CDCl3) d=1.09 (t, J=7.5 Hz, 6H), 1.17 (t, J=
7.5 Hz, 3H), 2.18 (s, 6H), 2.34 (s, 6H), 2.67 (q, J=7.5 Hz, 6H), 3.82 (s,
2H), 4.11 (s, 2H), 4.22 (brs, 2H), 4.32 (d, J=3.8 Hz, 4H), 6.01(s, 2H),
6.31(s, 2H), 7.13 (m, 3H), 7.30 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz,
1H), 8.44 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3) d=16.70, 16.79,
21.04, 22.76, 22.82, 24.13, 40.55, 45.11, 46.89, 103.74, 111.14, 113.70,
118.84, 119.62, 122.09, 125.07, 127.19, 128.23, 132.77, 136.35, 143.05,
143.34, 148.70, 156.48, 158.20 ppm; HRMS (ESI): m/z: calcd for
C38H48N6: 589.4013; found 589.4014; Rf =0.09 (CHCl3/CH3OH 7:1v/v).
Experimental Section
Analytical TLC was carried out on silica gel 60 F254 plates with ethyl ace-
tate/toluene (3:1v/v) or chloroform/methanol (7:1v/v) as the mobile
phase. Melting points are uncorrected. Octyl b-d-glucopyranoside (5),
octyl a-d-glucopyranoside (6), octyl b-d-glucopyranoside (7), dodecyl b-
d-maltoside (8) and dodecyl a-d-maltoside (9) are commercially avail-
able.
1-[(2-Pyrrolylmethyl)aminomethyl]-3,5-bis[(4,6-dimethylpyridin-2-yl)ami-
1
nomethyl]-2,4,6-triethylbenzene (3): Yield: 42%; m.p. 79–808C; H NMR
(400 MHz, CDCl3) d=1.16 (t, J=7.5 Hz, 6H), 1.19 (t, J=7.4 Hz, 3H),
2.21(s, 6H), 2.34 (s, 6H), 2.68 (q, J=7.4 Hz, 2H), 2.69 (q, J=7.5 Hz,
4H), 3.75 (s, 2H), 3.89 (s, 2H), 4.24 (brs, 2H), 4.34 (d, J=4.1Hz, 4H),
6.07 (s, 2H), 6.11 (m, 2H), 6.33 (s, 2H), 6.68 (m, 1H), 8.86 ppm (brs,
1H); 13C NMR (100 MHz, CDCl3) d=16.76, 16.80, 21.05, 22.78, 22.85,
24.11, 40.56, 46.45, 46.87, 103.57, 106.94, 108.04, 113.78, 117.57, 130.13,
132.91, 143.18, 143.25, 148.72, 156.55, 158.20 ppm; HRMS (EI): m/z:
calcd for C34H46N6: 538.3778; found 538.3780; Rf =0.11 (CHCl3/CH3OH
7:1v/v).
1-Bromomethyl-3,5-bis[(4,6-dimethylpyridin-2-yl)aminomethyl]-2,4,6-tri-
ACHTREUNG
AHCTREUNG
ACHTREUNG
(3.76 g, 27.20 mmol) in CH3CN/THF (1:1 v/v; 40 mL). The mixture was
stirred at room temperature for 48 h. After filtration and evaporation of
the solvents, the crude product was purified by column chromatography
(ethyl acetate/toluene, 1:3 v/v). Yield: 30%; m.p. 78–79 8C; 1H NMR
(400 MHz, CDCl3): d=1.22 (t, J=7.5 Hz, 3H), 1.29 (t, J=7.5 Hz, 6H),
2.24 (s, 6H), 2.36 (s, 6H), 2.73 (q, J=7.5 Hz, 2H), 2.85 (q, J=7.5 Hz,
4H), 4.23 (brs, 2H), 4.37 (d, J=4.2 Hz, 4H,), 4.62 (s, 2H), 6.10 (s, 2H),
6.35 ppm (s, 2H); 13C NMR (100 MHz, CDCl3) d=16.4, 16.7, 21.1, 22.8,
23.0, 24.1, 29.6, 40.5, 103.6, 113.9, 131.9, 133.4, 143.8, 144.9, 148.9, 156.5,
158.0 ppm; HRMS (EI): m/z: calcd for C29H39BrN4: 522.2353; found:
522.2360; Rf =0.12 (ethyl acetate/toluene, 1:3 v/v).
1-[(1-Imidazolyl)methyl]-3,5-bis[(4,6-dimethylpyridin-2-yl)aminomethyl]-
2,4,6-triethylbenzene (4):
0.96 mmol) in THF (10 mL) was added dropwise to a mixture of imid-
azole (65 mg, 0.96 mmol) and K2CO3 (132 mg, 0.96 mmol) in THF
A
solution of compound 11 (500 mg,
AHCTREUNG
(20 mL). The mixture was stirred at room temperature for 24 h. After fil-
tration and evaporation of solvents, the crude product was purified by
column chromatography (silica gel, chloroform/methanol 20:1and 7:1v/
v). Yield: 30%; m.p. 68–698C; 1H NMR (400 MHz, CDCl3) d=1.12 (t,
J=7.5 Hz, 6H), 1.25 (t, J=7.5 Hz, 3H), 2.23 (s, 6H), 2.35 (s, 6H), 2.69
(q, J=7.5 Hz, 4H), 2.77 (q, J=7.5 Hz, 2H), 4.20 (t, J=4.0 Hz, 2H), 4.39
(d, J=4.0 Hz, 4H), 5.18 (s, 2H), 6.10 (s, 2H), 6.35 (s, 2H), 6.75 (t, J=
1.1 Hz, 1H), 7.02 (t, J=1.1Hz, 1H), 7.39 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3) d=16.09, 16.70, 21.02, 22.93, 24.09, 40.44, 44.66,
103.46, 114.00, 118.55 128.74, 129.30, 133.69, 136.41, 143.79, 145.07,
148.77, 156.64, 158.01 ppm; HRMS (EI): m/z: calcd for C32H42N6:
510.3465; found 510.3466; Rf =0.32 (CHCl3/CH3OH 7:1v/v).
1-Aminomethyl-3,5-bis[(4,6-dimethylpyridin-2-yl)aminomethyl]-2,4,6-tri-
A
added to a solution of 11 (776 mg, 1.48 mmol) in THF/MeOH (1:1, v/v,
20 mL). This mixture was stirred at room temperature for 12 h. After
evaporation of the solvents, water (20 mL) was added and the solution
was extracted with CHCl3 (3”20 mL). The combined organic phases
were washed with brine (20 mL), dried over MgSO4 and the solvent was
removed under reduced pressure. The crude product was purified by
column chromatography (CHCl3/MeOH, 7:1v/v). Yield: 72%; m.p. 82–
Chem. Eur. J. 2008, 14, 2405 – 2419
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2417

M. Mazik and M. Kuschel
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Supporting information for this article is available on the WWW under
http://www.chemeurj.org/ or from the author and contains 1H und
13C NMR spectra of compounds 1–4, IR data of compounds 1–4, exam-
ples of 1H NMR titrations of receptor 3 and 4 with b-glucopyranoside 5,
an example of 1H NMR titration of b-glucopyranoside 5 with receptor 3
(inverse titration), further examples of titration curves, representative
mole-ratio plots and X-ray data for compound 11.
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft is gratefully
acknowledged. We thank Prof. Dr. Peter G. Jones (Institut für Anorgani-
sche and Analytische Chemie der Technischen Universität Braunschweig)
for performing the X-ray measurements of 11.
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A
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Chem. Eur. J. 2008, 14, 2405 – 2419

Artificial Acyclic Carbohydrate Receptors
FULL PAPER
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each titration 15–20 samples were prepared. b) The error in Ka was
less than 10%; c) K11 corresponds to the 1:1 association constant.
K21 corresponds to the 2:1receptor–sugar association constant. K12
corresponds to the 1:2 receptor–sugar association constant. b21
K11 ”K21, b12 =K11 ”K12.
=
[15] a) For each system, at least two fluorescence titrations were carried
out; for each titration, 20 samples were prepared. b) The error in a
single Ka estimation was less than 15%.
[10] C. S. Wilcox, N. M. Glagovich, Program HOSTEST 5.6, University
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[14] a) The binding constants were determined in chloroform at 258C by
titration experiments (CDCl3 was stored over activated molecular
sieves and deacidified with Al2O3). Dilution experiments show that
receptors do not self-aggregate in the used concentration range. For
each system at least three 1H NMR titrations were carried out; for
Received: August 15, 2007
Published online: January 18, 2008
Chem. Eur. J. 2008, 14, 2405 – 2419
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2419