Nelissen et al.
from sodium and benzophenone. Ethyl acetate was distilled
in vacuo and acetonitrile was distilled from sodium hydride.
All other solvents were used as received. Flash column
chromatography of cyclodextrin derivatives was performed on
silica gel (particle size <0.063 mm). The eluent was a mixture
of ethyl acetate, ethanol, and water, 50:2:1 (v/v). Addition of
0.4% toluene to this eluent gave a much better separation,
presumably because of inclusion of the toluene, which expels
the appended moiety from the cavity, making the difference
between a functionalized and nonfunctionalized cyclodextrin
larger. TLC’s were taken on precoated silica gel 60 F254 on glass
plates (Merck). Compounds containing cyclodextrins were
detected by spraying with a 10% H2SO4 solution in ethanol
followed by heating. Circular dichroism spectra were taken
at 25 °C in a standard quartz cuvette (2 × 10 × 45 mm). The
cyclodextrin-containing products showed no melting points, but
degraded at approximately 300 °C.
3.86-3.12 (m, 46H; H-2, H-3, H-4, H-5, H-6, CH2-NH, CH2-
O), 1.78 (quasi qui, 2H; CH2-CH2-NH). MS (FAB, m-ni-
trobenzyl alcohol, m/z): 2040 [M + Na + H].
Mon o(2-O-(3-a m in op r op yl))h ep t a k is(6-O-ter t-b u t yl-
d im eth ylsilyl)-â-CD (5). Cyclodextrin derivative 4 (560 mg,
0.28 mmol) and a catalytic amount of Pd(OH)2/C were slurried
in 50 mL of ethanol. A balloon filled with H2 gas was attached
to the 100-mL flask and the reaction mixture was stirred at
ambient temperature for 72 h. The solid Pd(OH)2/C was
filtered off and the filtrate was evaporated to dryness to yield
the white crystalline product. Yield: 557 mg (0.28 mmol,
1
100%). H NMR (500 MHz, CDCl3/CD3OD, 80:40 v/v): δ 4.86
3
(d, J (H,H) ) 3.3 Hz, 1H; H-1), 4.82 (m, 6H; H-1), 3.89-3.15
(m, 46H; H-2, H-3, H-4, H-5, H-6, CH2-NH, CH2-O), 1.79
(quasi qui, 2H; CH2-CH2-NH). MS (FAB, m-nitrobenzyl
alcohol, m/z): 2035 [M + 2Na].
(2,2′-Bip yr id in e)-4,4′-d ica r boxylic Acid (7a ). This com-
pound was synthesized from 4,4′-dimethyl-2,2′-bipyridine (1.5
g, 8.4 mmol) and KMnO4 (8.26 g, 6.2 equiv) according to a
procedure described by us before for 7b.14 Yield: 1.5 g (6.2
mmol, 75%). IR (KBr): ν 1720 cm-1 (CdO). 1H NMR (300 MHz,
D2O/NaOD): δ 8.65 (d, 3J (H,H) ) 5.1 Hz, 2H; bpy-H-6,6′), 8.27
N,N′-Bis[m on o(2-O-(3-a m in op r op yl)-â-CD]-4,4′-d ica r -
boxa m id e-2,2′-bip yr id in e (1). The synthesis of this com-
pound has already been briefly described in a previous paper.17
In 15 mL of THF was dissolved 210 mg (0.05 mmol) of 10a
and 1.0 mL of a 1.0 M solution of tetrabutylammonium fluoride
(TBAF) in THF was added. This solution was refluxed for 18
h after which the solvent was evaporated. The residue was
dissolved in a minimum amount of water and added dropwise
to ethanol (analytical grade). The resulting precipitate was
isolated by centrifugation. Repeating this procedure twice
afforded the pure dimer. Yield: 78 mg (0.03 mmol, 57%). IR
4
3
(s, 2H; bpy-H-3,3′), 7.74 (dd, J (H,H) ) 1.4 Hz, J (H,H) ) 5.1
Hz, 2H; bpy-H-5,5′).
(2,2′-Bip yr id in e)-4,4′-d ica r boxylic Acid Bis(N-h yd r oxy-
su ccin im id e) Ester (9a ). The diacid 7a (500 mg, 2.05 mmol)
was added to 20 mL of SOCl2 and the resulting mixture was
refluxed for 24 h. The excess SOCl2 was removed in vacuo and
20 mL of freshly distilled acetonitrile was added. Then 481
mg (2.04 equiv) of N-hydroxysuccinimide was added and after
this 625 µL (2.1 equiv) of Et3N via a syringe. The reaction
mixture became turbid and after 6 h an off-white precipitate
was isolated which was washed with acetonitrile. Yield: 484
mg (1.11 mmol, 54%). IR (KBr): ν 1737 cm-1 (CdO). 1H NMR
(300 MHz, DMSO-d6): δ 9.13 (d, 3J (H,H) ) 4.8, 2H; bpy-H-
1
(KBr): ν 1664 and 1540 cm-1 (amide I and II). H NMR (500
MHz, DMSO-d6): δ 9.02 (br t, 2H; NH), 8.91 (d, 3J (H,H) ) 4.9
3
Hz, 2H; bpy-H-6,6′), 8.89 (s, 2H; bpy-H-3,3′), 7.88 (d, J (H,H)
) 4.9 Hz, 2H; bpy-H-5,5′), 5.07 (br s, 2H; H-1A), 4.87 (br s,
12H; H-1B-G), 3.92-3.19 (m, 92H; H-2, H-3, H-4, H-5, H-6,
CH2-NH, CH2-O), 1.88 (br quasi qui, 4H; CH2-CH2-NH).
MS (FAB, glycerol, m/z): 2592 [M + 2H]+. Anal. Calcd for
3
C
102H158N4O72‚16H2O: C 42.51, H 6.65, N 1.95. Found:
C
6,6′), 8.96 (s, 2H; bpy-H-3,3′), 8.16 (d, J (H,H) ) 4.6 Hz, 2H;
42.25, H 6.19, N 2.06.
bpy-H-5,5′), 2.97 (s, 8H; CH2).
N,N′-Bis[m on o(2-O-(3-a m in op r op yl)-â-CD]-5,5′-d ica r -
boxa m id e-2,2′-bip yr id in e (2). This compound was synthe-
sized analogous to 1 from 40 mg of 10b (9.5 µmol) and 0.15
mL of a 1 M TBAF solution in THF. Yield: 10 mg (3.9 µmol,
41%). 1H NMR (500 MHz, DMSO-d6): δ 9.16 (s, 2H; bpy-H-
(2,2′-Bip yr id in e)-5,5′-d ica r boxylic Acid Bis(N-h yd r oxy-
su ccin im id e) Ester (9b). This compound was synthesized
from 7b (1.0 gr, 4.10 mmol) in the same way as described for
9a from 7a . Yield: 1.0 g (2.29 mmol, 56%). IR (KBr): ν 1734
cm-1 (CdO). 1H NMR (300 MHz, DMSO-d6): δ 9.44 (s, 2H;
bpy-H-6,6′), 8.78 (d, 3J (H,H) ) 8.2 Hz, 2H; bpy-H-4,4′), 8.74
3
6,6′), 8.84 (br t, 2H; NH), 8.56 (d, J (H,H) ) 8.1 Hz, 2H; bpy-
3
3
H-3,3′), 8.40 (d, J (H,H) ) 8.2 Hz, 2H; bpy-H-4,4′), 5.06 (br s,
(d, J (H,H) ) 8.4 Hz, 2H; bpy-H-3,3′), 2.97 (s, 8H; CH2).
2H; H-1A), 4.87 (br s, 12H; H-1B-G), 3.87-3.18 (m, 92H; H-2,
H-3, H-4, H-5, H-6, CH2-NH, CH2-O), 1.85 (br quasi qui, 4H;
CH2-CH2-NH). MS (ESI+, H2O/MeOH, 1:1, v/v, m/z): 1318
[M + 2Na]2+. Anal. Calcd for C102H158N4O72‚14H2O: C 43.05,
H 6.54, N 1.97. Found: C 43.28, H 6.24, N 1.86.
N,N′-Bis[m on o(2-O-(3-a m in op r op yl)h ep ta k is(6-O-ter t-
bu tyld im eth ylsilyl)-â-CD]-4,4′-d ica r boxa m id e-2,2′-bip yr -
id in e (10a ). A 780-mg (0.39 mmol) sample of 5 was dried in
vacuo (0.2 mbar, 80 °C, 2 h) and dissolved in 50 mL of THF in
a 100-mL Schlenk tube. After addition of 80 mg (0.45 equiv)
of diactive ester 9a the mixture was refluxed for 18 h. The
solvent was evaporated and the residue dissolved in ethyl
acetate (100 mL). After being washed with aqueous sodium
hydroxide (twice) and brine the organic layer was dried over
MgSO4 and evaporated to dryness. The crude product was
purified by column chromatography (100 g silica, eluent A).
Yield: 520 mg (0.12 mmol, 63%). MS (FAB, m-nitrobenzyl
alcohol, m/z): 4213 [M + Na + 2H]+.
Mon o(2-O-(3-a zid op r op yl))h ep t a k is(6-O-ter t-b u t yld i-
m eth ylsilyl)-â-CD (4). A 10-g (5.18 mmol) sample of silylated
â-cyclodextrin 3 was thoroughly dried in vacuo (0.2 mbar, 80
°C, 5 h) and dissolved in 250 mL of freshly distilled THF in a
500-mL Schlenk tube. After addition of 410 mg (2.1 equiv) of
sodium hydride (60% w/w dispersion in mineral oil) the turbid
reaction mixture was refluxed for 18 h after which it became
homogeneous. To the refluxing solution was added 1.4 g (1.1
equiv) of 3-azidopropyl tosylate and after 4 h the solvent was
removed. The residue was taken up in ethyl acetate (250 mL)
and washed with water (twice) and brine. The organic layer
was dried over MgSO4 and after evaporation of the solvent
the crude product was purified by column chromatography (1.5
kg silica). Yield: 2.1 g (1.02 mmol, 20%). In this way also 2 g
of pure silylated cyclodextrin 3 could be recovered. IR (KBr):
ν 2099 cm-1 (N3). 1H NMR (500 MHz, CDCl3/CD3OD, 80:40
v/v): δ 4.86 (d, 3J (H,H) ) 3.3 Hz, 1H; H-1), 4.82 (m, 6H; H-1),
N,N′-Bis[m on o(2-O-(3-a m in op r op yl)-â-CD]h ep ta k is(6-
O-ter t-bu tyld im eth ylsilyl)-5,5′-d ica r boxa m id e-2,2′-bip yr -
id in e (10b). This compound was synthesized from 9b and 5
as described for 10a from 9a and 5.
Ack n ow led gm en t. We thank the Dutch Technology
Foundation for financially supporting this research.
J O0256641
5906 J . Org. Chem., Vol. 67, No. 17, 2002