Phenanthroline unit as a building block for carbohydrate receptors

Article abstract of DOI:10.1021/jo8005842

(Figure Presented) An acyclic receptor 1, containing phenanthroline- and aminopyridine-based recognition sites, has been established as a powerful carbohydrate receptor. Compared to the previously described acyclic receptors, compound 1 shows significantl

Full text of DOI:10.1021/jo8005842

Phenanthroline Unit as a Building Block for Carbohydrate
Receptors
Monika Mazik* and Andre` Hartmann
Institut fu¨r Organische Chemie der Technischen UniVersita¨t Braunschweig, Hagenring 30,
38106 Braunschweig, Germany
m.mazik@tu-bs.de
ReceiVed March 21, 2008
An acyclic receptor 1, containing phenanthroline- and aminopyridine-based recognition sites, has been
established as a powerful carbohydrate receptor. Compared to the previously described acyclic receptors,
compound 1 shows significantly higher binding affinities as well as selectivities, which are quite different
from those of the earlier systems. The phenanthroline unit has been established as a valuable building
block for the construction of effective and selective carbohydrate receptors.
Introduction
to provide insight into the molecular recognition phenomena,
but also to facilitate the development of new therapeutics or
chemosensors. As part of our program aimed at the development
of effective and selective carbohydrate receptors, we have
already analyzed the binding properties of receptors consisting
of pyridine-, pyrimidine-, indole-, imidazole-, benzimidazole-,
guanidinium-, carboxylate-, crown ether-, hydroxy-, amino-,
amide-, and oxime-based recognition groups.4 Depending on
the nature and number of recognition units and connecting
bridges used as the building blocks, a variety of structures with
Synthetic carbohydrate receptors operating through nonco-
valent interactions1–4 provide valuable model systems to study
the underlying principles of carbohydrate-based molecular
recognition processes. Advances in this area are likely not only
* To whom correspondence should be addressed. Phone: +49-531-391-5266.
Fax: +49-531-391-8185.
(1) (a) Davis, A. P.; James, T. D. In Functional Synthetic Receptors; Schrader,
T., Hamilton, A. D., Eds.; Wiley-VCH: Weinheim, Germany, 2005; pp 45-
109. (b) Davis, A. P.; Wareham, R. S. Angew. Chem., Int. Ed. 1999, 38, 2979–
2996. (c) Mazik, M., ChemBioChem 2008, 9, 1015-1017.
7444 J. Org. Chem. 2008, 73, 7444–7450
10.1021/jo8005842 CCC: $40.75 2008 American Chemical Society
Published on Web 06/25/2008

Phenanthroline as a Building Block for Carbohydrate Receptors
FIGURE 1. Receptor 1 and structures of sugars 2-9.
different binding properties could be obtained. The aim of this
study was to evaluate the potential of the phenanthroline unit
in the recognition of neutral carbohydrates. The potential of
phenanthroline-based receptors in the recognition of saccharides
through noncovalent interactions has not been explored so far.
The phenanthroline unit has mostly been incorporated into
different boronic acid-based receptors,3,5 using covalent interac-
tions for sugar binding. It should be noted that hydrogen-bonding
phenanthroline-based receptors have been designed to bind diols.
Complexation properties of such receptors toward cyclohexane
diols have been described by Anslyn and co-workers.6
As a starting point, we have examined the binding properties
of an acyclic phenanthroline/aminopyridine-based receptor 1 (see
Figure 1). To evaluate the recognition capabilities of this
receptor several sugars were selected as substrates, such as octyl
ꢀ-D-glucopyranoside (2a), methyl ꢀ-D-glucopyranoside (2b),
octyl R-D-glucopyranoside (3a), methyl R-D-glucopyranoside
(3b), octyl ꢀ-D-galactopyranoside (4a), methyl ꢀ-D-galactopy-
ranoside (4b), methyl R-D-galactopyranoside (5), methyl R-D-
mannopyranoside (6), N-acetyl-D-glucosamine (7), N-acetyl-D-
galactosamine (8), and L-fucose (9). The binding properties of
1 were compared with those of the symmetrical aminopyridine-
based analogue 10 (1,3,5-tris[(4,6-dimethylpyridin-2-yl)ami-
nomethyl]-2,4,6-triethylbenzene4l).7 The interactions of the
receptor 1 and the corresponding saccharides were investigated
(2) For some examples of carbohydrate receptors operating through nonco-
valent interactions, see (further examples are cited in refs 4a-c): (a) Ferrand,
Y.; Crump, M. P.; Davis, A. P. Science 2007, 318, 619-622, and references
cited therein. (b) Klein, E.; Crump, M. P.; Davis, A. P. Angew. Chem., Int. Ed.
2005, 44, 298–302. (c) Abe, H.; Aoyagi, Y.; Inouye, M. Org. Lett. 2005, 7,
59–61. (d) Welti, R.; Abel, Y.; Gramlich, V.; Diederich, F. HelV. Chim. Acta
2003, 86, 548–562. (e) Welti, R.; Diederich, F. HelV. Chim. Acta 2003, 86, 494–
503. (f) Wada, K.; Mizutani, T.; Kitagawa, S. J. Org. Chem. 2003, 68, 5123–
5131. (g) Segura, M.; Bricoli, B.; Casnati, A.; Mun˜oz, E. M.; Sansone, F.; Ungaro,
R.; Vicent, C. J. Org. Chem. 2003, 68, 6296–6303. (h) Ishi-I, T.; Mateos-
Timoneda, M. A.; Timmerman, P.; Crego-Calama, M.; Reinhoudt, D. N.; Shinkai,
S. Angew. Chem., Int. Ed. 2003, 42, 2300–2305. (i) Cho, H.-K.; Kim, H.-J.;
Lee, K. H.; Hong, J.-I. Bull. Korean Chem. Soc. 2004, 25, 1714–1716. (j) Tamaru,
S.-i.; Shinkai, S.; Khasanov, A. B.; Bell, T. W. Proc. Natl. Acad. Sci. U.S.A.
2002, 99, 4972–4976. (k) Ladomenou, K.; Bonar-Law, R. P. Chem. Commun.
2002, 2108–2109. (l) Bitta, J.; Kubik, S. Org. Lett. 2001, 3, 2637–2640. (m)
Kra´l, V.; Rusin, O.; Schmidtchen, F. P. Org. Lett. 2001, 3, 873–876. (n) Eblinger,
F.; Schneider, H.-J. Collect. Czech. Chem. Commun. 2000, 65, 667–672.
(3) Another strategy, which has been employed for the design of synthetic
carbohydrate receptors, involves exploitation of non-natural bonding interactions;
this strategy relies on the reversible formation of covalent bonds from diol units
and boronic acid. For reviews on boronic acid-based receptors, see: (a) James,
T. D.; Shinkai, S. Top. Curr. Chem. 2002, 218, 159–200. (b) Striegler, S. Curr.
Org. Chem. 2003, 7, 81–102. (c) James, T. D.; Sandanayake, K. R. A. S.; Shinkai,
S. Angew. Chem., Int. Ed. 1996, 35, 1910–1922.
(4) (a) Mazik, M.; Buthe, A. C. Org. Biomol. Chem. 2008, 6, 1558–1568.
(b) Mazik, M.; Kuschel, M. Chem. Eur. J. 2008, 14, 2405–2419. (c) Mazik, M.;
Kuschel, M. Eur. J. Org. Chem. 2008, 1517–1526. (d) Mazik, M.; Buthe, A. C.
J. Org. Chem. 2007, 72, 8319–8326. (e) Mazik, M.; Cavga, H. J. Org. Chem.
2007, 72, 831–838. (f) Mazik, M.; Ko¨nig, A. Eur. J. Org. Chem. 2007, 3271–
3276. (g) Mazik, M.; Cavga, H. Eur. J. Org. Chem. 2007, 3633–3638. (h) Mazik,
M.; Ko¨nig, A. J. Org. Chem. 2006, 71, 7854–7857. (i) Mazik, M.; Cavga, H. J.
Org. Chem. 2006, 71, 2957–2963. (j) Mazik, M.; Kuschel, M.; Sicking, W. Org.
Lett. 2006, 8, 855–858. (k) Mazik, M.; Cavga, H.; Jones, P. G. J. Am. Chem.
Soc. 2005, 127, 9045–9052. (l) Mazik, M.; Radunz, W.; Boese, R. J. Org. Chem.
2004, 69, 7448–7462. (m) Mazik, M.; Sicking, W. Tetrahedron Lett. 2004, 45,
3117–3121. (n) Mazik, M.; Radunz, W.; Sicking, W. Org. Lett. 2002, 4, 4579–
4582. (o) Mazik, M.; Sicking, W. Chem. Eur. J. 2001, 7, 664–670. (p) Mazik,
M.; Bandmann, H.; Sicking, W. Angew. Chem., Int. Ed. 2000, 39, 551–554.
(5) (a) For fluorescent sensing of uronic acids based on a cooperative action
of boronic acid and metal chelate, see: Takeuch, M.; Yamamoto, M.; Shinkai,
S. Chem. Commun. 1997, 1731–1732. For an example of metal-containing
phenanthroline-based chemosensor based on 1,3,5-triethylbenzene frame, see:
(b) Cabell, L. A.; Best, M. D.; Lavigne, J. J.; Schneider, S. E.; Perreault, D. M.;
Monahan, M.-K.; Anslyn, E. V. J. Chem. Soc., Perkin Trans. 2 2001, 315–323.
1
by H NMR titrations and extraction experiments. The studies
showed that the incorporation of a suitably positioned phenan-
throline unit into the receptor structure significantly affects the
binding properties of the new receptor.
Results and Discussion
The synthesis of compound 1 is outlined in Scheme 1. The
synthesis started from 1,3,5-tris(bromomethyl)-2,4,6-triethyl-
benzene (11),8 which was converted into compound 134b via a
reaction with 2 equiv of 2-amino-4,6-dimethylpyridine (12). The
treatment of 13 with aqueous ammonia gave the amino
derivative 14,4b which was converted into compound 1 through
a reaction with 1,10-phenanthroline-2-carbonyl chloride (19).9
The carbonyl chloride 19 was prepared via a reaction of 1,10-
phenanthroline-2-carboxylic acid (18) with thionyl chloride. The
synthesis of 18 started from phenanthroline (15), which was
oxidized with hydrogen peroxide to form 1,10-phenanthroline
(6) Bell, D. A.; Diaz, S. G.; Lynch, V. M.; Anslyn, E. V. Tetrahedron Lett.
1995, 36, 4155–4158.
(7) Our previous studies showed that receptors based on the 2,4,6-triethyl-
benzene frame display about 2-fold higher binding affinity toward neutral
monosaccharides than those based on the 2,4,6-trimethylbenzene unit, see ref
4l.
(8) Wallace, K. J.; Hanes, R.; Anslyn, E.; Morey, J.; Kilway, K. V.; Siegel,
J. J. Synthesis 2005, 2080–2083.
(9) (a) Corey, E. J.; Borror, A. L.; Foglia, T. J. Org. Chem. 1965, 30, 288–
289. (b) Su, W.-H.; Jie, S.; Zhang, W.; Song, Y.; Ma, H.; Chen, J.; Wedeking,
K.; Fro¨hlich, R. Organometallics 2006, 25, 666–677.
J. Org. Chem. Vol. 73, No. 19, 2008 7445

Mazik and Hartmann
SCHEME 1. Synthesis of Receptor 1a
a Reagents and conditions: (a) 2 equiv of 12, CH3CN/THF, K2CO3;4b (b) NH3/H2O;4b (c) N(Et)3, THF; (d) H2O2;9 (e) PhCOCl; KCN;9 (f) NaOH, H2O/
EtOH; (g) HCl;9 (h) SOCl2.
H2O · · · HNA,
2
×
HOH · · · N-phenanthroline, and
2
×
H2O· · ·HOH), as shown in Figure 2b.
1
The H NMR titration experiments with ꢀ- and R-glucopy-
ranoside, 2a and 3a, were carried out by adding increasing
amounts of the sugar to a solution of receptor 1. In addition,
inverse titrations were performed in which the concentration
of sugar 2a or 3a was held constant and that of the receptor
was varied. The interactions of receptor 1 with carbohydrates
were investigated in CDCl3, water-containing CDCl3, DMSO-
d6/CDCl3, and CD3OD/CDCl3 mixtures (0.1:9.9, 0.5:9.5, and
1:9 v/v). The complexation between receptor 1 and the glu-
copyranosides was evidenced by several changes in the NMR
spectra (see Figures 3 and 4, as well as Figures S1-S5 in the
Supporting Information).
The addition of ꢀ-glucopyranoside 2a to a CDCl3 solution
of receptor 1 caused significant downfield shift of the amine
NHA and amide NHD signals of 1 (indicating the participation
of these groups in the formation of intermolecular hydrogen
bonds; see Table 1), as well as changes of the chemical shifts
of the CH3G,H, CH2B,C, pyridine CHI,J, and phenantroline CH
resonances (for labeling, see Figure 1). The NHA and NHD
signals broadened significantly, became almost indistinguishable
from the baseline after the addition of only 0.1 equiv of 2a,
and finally became distinctly visible near the saturation that
FIGURE 2. (a) Crystal structure of 1 (two different representations,
C-Hs are omitted for clarity); three hydrogen-bonded water molecules
and one diethyl ether molecule are shown. (b) Schematic representation
of the hydrogen-bonding motifs in the binding pocket of 1.
1-oxide9 (16). The reaction of 16 with potassium cyanide and
benzoyl chloride gave 2-cyano-1,10-phenantroline (17), which
was further converted to the 1,10-phenanthroline-2-carboxylic
acid (18).
occurred after the addition of about 1 equiv of sugar 2a. The
G,H
CH3
signals of 1 moved up- and downfield, as shown in
B
Figure S1, Supporting Information, whereas the CH2 signal
moved upfield with broadening and splitting. Splitting of the
C
CH2 signal of 1 was observed after the addition of about 0.1
equiv of 2a (see Figure S1b in the Supporting Information).
The addition of R-glucopyranoside 3a to a CDCl3 solution
of 1 yielded similar NMR effects (see Figures 3, 4a, and S2,
Supporting Information); however, the spectral changes observed
in the titrations with the R-anomer 3a were more substantial
than those seen in the titrations with the ꢀ-anomer 2a (for
comparison, see Figure S1a in the Supporting Information and
The crystal structure of 1 is shown in Figure 2a (crystals were
grown by slow evaporation of the solvent from a diethyl
ether-chloroform solution of compound 1). The crystal structure
revealed the presence of three water molecules in the binding
pocket of 1; the receptor-water aggregate is stabilized by eight
hydrogen bonds (H2O · · · HND, HOH · · · N-pyridine, 2 ×
7446 J. Org. Chem. Vol. 73, No. 19, 2008

Phenanthroline as a Building Block for Carbohydrate Receptors
FIGURE 3. (a) Partial 1H NMR spectra (400 MHz) of receptor 1 after addition of (from bottom to top) 0.00-2.49 equiv of R-glucopyranoside 3a
1
([1] ) 1.02 mM): left, CDCl3; right, water-containing CDCl3 (0.04% H2O). (b) Partial H NMR spectra (500 MHz, CDCl3) of receptor 10 after
addition of 0.00-7.25 equiv of 3a ([10] ) 0.70 mM). Shown are chemical shifts of the pyridine methyl groups.
1
FIGURE 4. Partial H NMR spectra (400 MHz; CDCl3) of receptor 1 after addition of (a) 0.00-2.67 equiv of R-glucopyranoside 3a ([1] ) 0.86
mM) and (b) 0.00-1.80 equiv of ꢀ-galactopyranoside 4a ([1] ) 0.90 mM).
Figure 3a). In both cases, 1·2a and 1·3a, the shifts of the
aromatic CH’s and the CH3 protons were monitored for the
determination of the binding constants. The curve fitting of all
the titration data suggested the existence of 1:1 and 2:1
receptor-sugar complexes in chloroform solutions (this binding
model was further supported by the mole ratio plots; see Figure
S6 in the Supporting Information), with a stronger association
constant for the 1:1 binding and a weaker association constant
for the 2:1 receptor-sugar complex.10,11 The binding constants,
however, were too large to be accurately determined by the
NMR method12 (the association constants10b,11 for 1·2a amounted
to 334 600 (K11) and 13 970 M-1 (K21), those for 1·3a were
found to be K11 > 105 and K21 ≈ 104
M
-1; see Table 1). Similar
complexation behavior of receptor 1 could also be observed in
water-containing CDCl3 (0.04% H2O, see Table 1 and Figure
3a, as well as Figure S2b in the Supporting Information).
Compared with the previously described symmetrical receptor
10,4l receptor 1 shows significantly increased affinity to the both
anomers 2a and 3a (for comparison of the binding constants,
see Table 1). Receptor 1 displays not only higher efficiency,
but also an inverse selectivity since it binds the R-glucopyra-
noside better than the ꢀ-anomer. Comparison of parts a and b
of Figure 3 clearly reflects the strong differences in the
complexation ability of 1 and 10.
The binding studies in DMSO-d6/CDCl3 and CD3OD/CDCl3
mixtures showed that affinities of 1 for the glucopyranosides
2a and 3a decrease as solvent polarity increases. The motions
of the signals observed during the titrations of 1 with 2a or 3a
in 1%, 5%, and 10% DMSO-d6 in CDCl3 (see Figures S2 and
S3a, Supporting Information) were consistent with 1:1 and 2:1
receptor-sugar binding. After the addition of 1% DMSO-d6
the binding constants for 1·3a were still too large to be
accurately determined by the NMR method (K11 > 105 and K21
(10) (a) The binding studies were carried out in CDCl3, water-containing
CDCl3, CD3OD/CDCl3, and DMSO-d6/CDCl3 mixtures at 25°C. The titration
data were analyzed by nonlinear regression analysis, using the program
HOSTEST 5.6 (see ref 11). The stoichiometry of receptor--sugar complexes
was determined by the mole ratio method and by the curve-fitting analysis of
the titration data. For each system at least 3 titrations were carried out; for each
titration 16-20 samples were prepared. Dilution experiments show that receptor
1 does not self-aggregate in the used concentration range. (b) K11 corresponds
to the 1:1 association constant. K21 corresponds to the 2:1 receptor-sugar
association constant. K12 corresponds to the 1:2 receptor-sugar association
constant. ꢀ21 ) K11 × K21, ꢀ12 ) K11 × K12
.
≈ 104
M
-1; see Table 1). The binding constants for 1·3a in 5%
(11) Wilcox, C. S.; Glagovich, N. M. Program HOSTEST 5.6; University
of Pittsburgh: Pittsburgh, PA, 1994.
(12) For a review discussing the limitations of the NMR method, see:
Fielding, L. Tetrahedron 2000, 56, 6151–6170.
DMSO-d6 in CDCl3 were determined to be 107 700 (K11) and
8 540 M-1 (K21),10b whereas those for 1·2a amounted to 36 530
J. Org. Chem. Vol. 73, No. 19, 2008 7447

Mazik and Hartmann
TABLE 1. Association Constantsa b for Receptors 1 and 10 and Sugars 2a, 3a, and 4a
,
ꢀ21
)
j
K21 or
K11K21 or
k
n
receptor-
sugar complex
K11
K12
ꢀ12 ) K11K12
∆δobs
o
solvent
[M-1
]
[M-1
]
[M-2
]
(∆δmax) [ppm]
c
1·2a
CDCl3
105
104; j,l 109
NHA: 1.50; NHD: 1.40; CH3G: -0.06 (-0.06); CH3H: 0.04 (0.04); CHE:
0.09 (0.09); CHF: -0.04; CHJ: 0.05
c f
,
5% DMSO-d6/CDCl3
36530
2600; j 9.50 × 107
NHA: 1.56; NHD: 1.21; CH3G: -0.06 (-0.06); CH3H: 0.05 (0.05); CHE:
0.10 (0.10); CHF: -0.04; CHJ: 0.06
c
1·3a
CDCl3
>105
j, m
j, m
j,m
NHA: 1.90; NHD: 2.14; CH3G: -0.09 (-0.09); CH3H: 0.05; CHE: 0.09
(0.09); CHF: 0.12 (0.12); CHJ: 0.07
H2O-containingd CDCl3 >105
NHA: 0.90; NHD: 1.20; CH3G:-0.09 (-0.09); CHF: 0.15 (0.15); CHE:
0.07
c e
,
1% DMSO-d6/CDCl3
5% DMSO-d6/CDCl3
10% DMSO-d6/CDCl3
>105
NHA: 1.90; NHD: 2.12; CH3G: -0.09 (-0.09); CH3H: 0.05; CHE: 0.09;
CHF: 0.12 (0.12); CHJ: 0.07
c f
,
107700 8540; j 9.20 × 108
NHA: 1.75; NHD: 2.05; CH3G: -0.08 (-0.08); CH3H: 0.05; CHE: 0.08
(0.08); CHF: 0.12; CHJ: 0.07
c g
,
10500
41200
1390
840; j
8.82 × 106
NHA: 1.50; NHD: 1.93; CH3G: -0.08 (-0.08); CH3H: 0.05 (0.05); CHE:
0.07; CHF: 0.13; CHJ: 0.07
c h
,
1% CD3OD/CDCl3
5% CD3OD/CDCl3
4900; j 2.01 × 108
NHD: 0.78 (0.80); CH3G: -0.07 (-0.07); CH3H: 0.04; CHE: 0.04, CHF:
0.14 (0.14)
c i
,
NHD: 0.50 (0.67); CH3G: -0.05 (-0.07); CH3H: 0.05; CHE: 0.03, CHF:
0.12
c
1·4a
CDCl3
9550
1030; j 9.83 × 106
1320; k 6.42 × 107
NHA: 1.24; NHD: 1.14; CH3G: -0.04 (-0.05); CH3H: 0.03; CHE: 0.06;
CHF: 0.01; CHJ: 0.08
c
10·2ap
10·3ap
10·4ap
CDCl3
CDCl3
CDCl3
48630
1310
3070
NH: 1.31 (1.35)
NH: 1.16 (1.44)
NH: 1.15 (1.33)
c
c
470; k
1.44 × 106
a Average Ka values from multiple titrations. b Errors in Ka are less than 10%. c CDCl3 was stored over activated molecular sieves and deacidified
with Al2O3. ∼0.04% H2O. e DMSO-d6/CDCl3, 0.1:9.9 v/v. f DMSO-d6/CDCl3, 0.5:9.5 v/v. g DMSO-d6/CDCl3, 1:9 v/v. h CD3OD/CDCl3, 0.1:9.9 v/v.
d
i CD3OD/CDCl3, 0.5:9.5 v/v. K21 corresponds to 2:1 receptor-sugar association constant. K12 corresponds to 1:2 receptor-sugar association constant.
l Hostest program indicated “mixed” 1:1 and 2:1 receptor-sugar binding model with K11 ) 334600 and K21 ) 13970 M-1(ꢀ21 ) 4.67 × 109 M-2).
m Hostest program indicated “mixed” 1:1 and 2:1 receptor-sugar binding model with K11 > 105 and K21 ≈ 104; however, the binding constants were
too large to be accurately determined by the NMR method. n Largest change in chemical shift observed during the titration for receptor signals (the
concentration of receptor was kept constant and that of sugar varied). o Change in chemical shift at saturation binding, values provided by HOSTEST.
p Results from ref 4l. Compound 10: 1,3,5-tris[(4,6-dimethylpyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene.
j
k
(K11) and 2 600 M-1 (K21). Studies performed with the R-anomer
3a in 10% DMSO-d6 in CDCl3 revealed K11 ) 10 500 M-1
and K21 ) 840 M-1 (the complexation-induced shifts of the
receptor signals are given in Table 1). The spectral changes
observed during the titrations of 1 with 3a in methanol/
chloroform mixtures (see Figure S4 in the Supporting Informa-
tion) were less substantial than those observed during the
titrations in dimethyl sulfoxide-containing chloroform solutions
(see Figure S2, Supporting Information). The motions of the
signals observed during the titrations of 1 with 3a in 1% CD3OD
in CDCl3 (see Figure S4, Supporting Information) were again
consistent with 1:1 and 2:1 receptor-sugar binding; the binding
constants for 1·3a were determined to be 41 200 (K11) and 4 900
M-1 (K21). The curve fitting of the titration data obtained in
the presence of 5% CD3OD indicated the formation of com-
plexes with 1:1 receptor-sugar stoichiometry with K11 ) 1390
M-1. Thus, the interactions between 1 and 3a in CD3OD/CDCl3
mixtures are significantly weaker than those observed in the
presence of DMSO-d6.
In addition, the interactions between receptor 1 and
glucopyranosides 2a and 3a were investigated on the base
of inverse titrations in which the concentration of sugar 2a
or 3a was held constant and that of the receptor varied.
During the titrations of 2a or 3a with 1 the signals due to
the OH protons of the sugar shifted downfield with strong
broadening and were unobservable after the addition of only
0.1 equiv of the receptor, indicating an important contribution
of the OH groups to the complex formation. The complex-
ation between 2a/3a and 1 was further evidenced by
significant chemical shift changes of the CH units of the sugar
(upfield shifts, as shown for CH-1 in Figure S5, Supporting
Information). The results of the NMR spectroscopic titrations
indicate the participation of the sugar CH units in the CH · · ·π
interactions with the aromatic core of 1.
In both cases, 2a·1 and 3a·1, the best fit of the titration data
was obtained with the “mixed” 1:1 and 1:2 sugar-receptor
binding model; thus, the inverse titrations supported the exist-
ence of 1:1 and 2:1 receptor-sugar complexes in chloroform
solution, with a stronger association constant for the 1:1 binding
and a weaker association constant for the 2:1 receptor-sugar
complex. The association constants obtained on the basis of
these titrations are identical within the limits of uncertainty to
those determined from titrations where the role of receptor and
substrat was reversed.
Molecular modeling calculations (see Figure 5) also showed
that the binding pocket of 1 has the correct shape and size for
the encapsulation of glucopyranoside 2a or 3a; examples of
binding motifs indicated by molecular modeling are shown in
Figure 5, as well as Figure S8 in the Supporting Information.
The hydrogen-bonding motif shown in Figure 5c is similar to
that observed between the phenanthroline group and a water
molecule in the crystal structure of 1 (see Figure 2b).
Binding studies with ꢀ-galactopyranoside 4a showed that the
interactions of receptor 1 with this monosaccharide are less
favorable than those with glucopyranosides 2a and 3a. During
the titrations of 1 with 4a in CDCl3 the signals due to the amine
NHA and amide NHD of receptor 1 moved downfield and, in
contrast to the titrations with 2a and 3a, were still observable
even after the addition of 3 equiv of 4a (see Figure 4b and in
1
the Supporting Information Figure S3b). Furthermore, the H
NMR titrations of 1 with 4a produced chemical shift changes
of the CH2B,C,E, CH3F,G, pyridine CHH,I, as well as phenanthro-
7448 J. Org. Chem. Vol. 73, No. 19, 2008

Phenanthroline as a Building Block for Carbohydrate Receptors
1
FIGURE 6. Partial H NMR spectra (400 MHz) of receptor 1 before
(bottom) and after the extraction of solid methyl ꢀ-D-glucopyranoside
(2b), methyl R-D-glucopyranoside (3b), methyl ꢀ-D-galactopyranoside
(4b), methyl R-D-galactopyranoside (5), methyl R-D-mannopyranoside
(6), N-acetyl-D-glucosamine (7), N-acetyl-D-galactosamine (8), and
L-fucose (9) by a CDCl3-solution of receptor 1 (1.10 mM). Shown are
FIGURE 5. (a, b) Energy-minimized structure of the receptor 1 and
the 1:1 complex formed between receptor 1 and ꢀ-glucopyranoside 2a
(MacroModel V.8.5, OPLS-AA force field, MCMM, 50000 steps).
Color code: receptor C, blue; O, red; N, green; the sugar molecule is
highlighted in orange. (c-e) Examples of hydrogen-bonding motifs
indicated by molecular modeling studies in the 1:1 complex between
receptor 1 and R-glucopyranoside 3a.
G,H
chemical shifts of the CH3 signals of 1.
performs effective recognition of neutral carbohydrates through
multiple interactions. Both hydrogen bonding and interactions
of the sugar CH’s with the phenyl rings of the receptor13,14 (as
characterized by 1H NMR spectroscopy) contribute to the
stabilization of the receptor-sugar complexes. The comparison
of the binding properties of receptor 1 with those of the
previously described symmetrical pyridine-based analogue 104l
shows that combining phenanthroline- and aminopyridine-based
recognition units significantly affects the binding affinity and
selectivity of the new receptor (for comparison of the binding
constants, see Table 1). Compared to 10,4l receptor 1 exhibits
not only significantly higher binding affinities but also different
binding preferences. The phenanthroline unit has been estab-
lished as a valuable building block for the construction of
carbohydrate receptors. The results obtained with receptor 1
serve as a basis for the development of new phenantroline-based
receptors, incorporating both neutral and ionic hydrogen-bonding
sites for the recognition of saccharides in organic and aqueous
media.
line CH groups (see Table 1). In contrast to the titrations with
B
ꢀ- and R-glucopyranoside, 2a and 3a, no splitting of the CH2
C
and CH2 signals of 1 was observed after the addition of the
ꢀ-galactopyranoside 4a, as shown in Figure 4b. The curve fitting
of the titration data indicated again the formation of complexes
with 1:1 and 2:1 receptor-sugar stoichiometry (this binding
model was further supported by the mole ratio method); the
binding constants were determined to be 9550 (K11) and 1030
(K21) M-1 (see Table 1). Thus, the complexes formed between
receptor 1 and glucopyranosides 2a and 3a are much more stable
than those formed with the ꢀ-galactopyranoside 4a.
Further evidence for the strong complexation of R- and
ꢀ-glucoside and a weaker binding of ꢀ-galactoside by receptor
1 was provided by extraction experiments (extraction of sugars
from the solid state into a 1.1 mM CDCl3 solution of receptor
1; see Figure 6). Furthermore, these experiments indicated the
formation of strong complexes with R-galactoside and L-fucose.
Receptor 1 solubilized the tested sugars 2b, 3b, 4b, and 5-9
in CDCl3 to different extents (the 1H NMR signals of the
corresponding sugar were integrated with respect to the recep-
tor’s signals to provide the sugar-receptor ratio); the extract-
ability decreased in the sequence R-glucoside 3b > R-galacto-
side 5 > ꢀ-glucoside 2b > fucose 9 > ꢀ-galactoside 4b >
N-acetylgalactosamine 8 > R-mannoside 6 > N-acetylglu-
cosamine 7 (control experiments were performed in the absence
of 1). Receptor 1 was able to dissolve 1 equiv of R-glucoside
3b and R-galactoside 5, 0.5 equiv of ꢀ-galactoside 4b, and about
0.2 equiv of R-mannoside 6. The preference of 1 for R-glucoside
vs the ꢀ-anomer indicated by 1H NMR spectroscopic titrations
was also suggested by the extraction experiments. These
experiments indicated not only the R- vs ꢀ-anomer preference
in the recognition of glucopyranosides (3b vs 2b) but also that
in the recognition of galactopyranosides (5 vs 4b).
Experimental Section
1-[N-(1,10-Phenanthrolin-2-ylcarbonyl)aminomethyl]-3,5-
bis[(4,6-dimethylpyridin-2-yl)aminomethyl]-2,4,6-triethylben-
zene (1). (a) Synthesis of 19: A mixture of 1,10-phenantroline-2-
carboxylic acid (18)9 (0.30 g, 1.34 mmol) and thionyl chloride (20
mL) was refluxed for 6 h. The thionyl chloride was then removed
in vacuum. Afterward, THF (3 × 20 mL) was added and the solvent
was removed in vacuum. The crude product was used directly for
further reaction. (b) Synthesis of 1: A solution of 19 in THF/CH2Cl2
(1:1, v/v; 40 mL) was added dropwise to a solution of 1-aminom-
ethyl-3,5-bis[(4,6-dimethylpyridin-2-yl)aminomethyl]-2,4,6-trieth-
(13) For some discussions on carbohydrate-aromatic interactions, see: (a)
Terraneo, G.; Potenza, D.; Canales, A.; Jime´nez-Barbero, J.; Baldridge, K. K.;
Bernardi, A. J. Am. Chem. Soc. 2007, 129, 2890–2900. (b) Cha´vez, M. I.; Andreu,
C.; Vidal, P.; Aboitiz, N.; Freire, F.; Groves, P.; Asensio, J. L.; Asensio, G.;
Muraki, M.; Canˇada, F. J.; Jime´nez-Barbero, J. Chem. Eur. J. 2005, 11, 7060–
7074. (c) Kiehna, S. H.; Laughrey, Z. R.; Waters, M. L. Chem. Commun. 2007,
4026–4028. (d) Screen, J.; Stanca-Kaposta, E. C.; Gamblin, D. P.; Liu, B.;
Macleod, N. A.; Snoek, L. C.; Davis, B. G.; Simons, J. P. Angew. Chem., Int.
Ed. 2007, 46, 3644–3648. (e) Morales, J. C.; Penade´s, S. Angew. Chem., Int.
Ed. 1998, 37, 654–657.
Conclusions
The binding studies showed that acyclic receptor 1, containing
phenanthroline- and aminopyridine-based binding subunits,
(14) For examples of CH-π interactions in the crystal structures of the
complexes formed between artificial receptors and carbohydrates, see ref 4k.
J. Org. Chem. Vol. 73, No. 19, 2008 7449

Mazik and Hartmann
ylbenzene (14)4b (0.473 g, 1.03 mmol) and triethylamine (0.28 mL)
in THF/CH2Cl2 (50 mL). After complete addition, the mixture was
stirred at room temperature for 48 h. The reaction mixture was
then treated with water (15 mL) and stirred for 15 min, then the
organic solvents were removed in vacuum. The resulting precipitate
was filtered, washed with water, dried, and recrystallized from THF/
hexane. Yield 93%. Mp 129-130 °C. 1H NMR (400 MHz, CDCl3)
δ 1.19 (t, J ) 7.6 Hz, 3H), 1.22 (t, J ) 7.6 Hz, 6H), 2.14 (s, 6H),
2.26 (s, 6H), 2.71 (q, J ) 7.6 Hz, 2H), 2.82 (q, J ) 7.6 Hz, 4H),
4.34 (d, J ) 2.3 Hz, 4H), 4.55 (br s, 2H), 4.78 (d, J ) 4.6 Hz, 2H),
6.04 (s, 2H), 6.22 (s, 2H), 7.58 (m, 1H), 7.75 (s, 2H), 8.18 (dd, J
) 8.1/1.5 Hz, 1H), 8.32 (d, J ) 8.3 Hz, 1H), 8.54 (d, J ) 8.3 Hz,
1H), 9.06 (dd, J ) 4.5/1.5 Hz, 1H), 9.22 (br s, 1H). 13C NMR (100
MHz, CDCl3) δ 16.7, 16.9, 21.1, 22.9, 23.2, 23.9, 38.5, 40.7, 103.7,
113.7, 121.6, 123.4, 126.5, 127.8, 128.9, 130.0, 131.9, 132.9, 136.5,
137.4, 143.7, 144.1, 144.4, 145.6, 148.9, 149.9, 150.1, 156.3, 158.2,
164.5. HR-MS calcd for C42H47N7O 665.3837, found 665.3836. Rf
0.44 (aluminum oxide, diethyl ether/chloroform 15:1 v/v).
Acknowledgment. This work was supported by the Deutsche
Forschungsgemeinschaft. We thank Prof. Dr. Peter G. Jones
(Institut fu¨r Anorganische and Analytische Chemie der Tech-
nischen Universita¨t Braunschweig) for performing the X-ray
measurements.
Supporting Information Available: Further examples of 1H
NMR titrations (Figures S1-S5), representative mole ratio plots
(Figure S6), copies of the 1H and 13C NMR spectra of 1 (Figures
S9 and S10), and crystal data and structure refinement for
compound 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO8005842
7450 J. Org. Chem. Vol. 73, No. 19, 2008