Intramolecular complexation in modified β-cyclodextrins: 1 a preparative, nuclear magnetic resonance and pH titration study

Article abstract of DOI:10.1039/a909766j

The reactions of 4-nitrophenyl trinorbornane-2-acetate and 4-nitrophenyl noradamantane-1-carboxylate with 6^A-(6-aminohexyIamino)-6^A-deoxy-β-cyclodextrin l produce 6^A-{6-(bicyclo[2.2.l]heptan-2-ylacetylamino)hexylamino}-6 ^A-deoxy-β-cyclodextrin 2 (pK_a = 8.98) and 6^A-deoxy-6^A-{6-(tricyclo[3.3.1.0 ^3.7]nonan-3-ylcarbonylamino)-hexylamino}-β-cyclodextrin 4 (pK_a = 8.47), respectively, in good yield together with 4-nitrophenolate. The reaction of 2,3-dimethyl-1,8-bis-(4-nitrophenoxycarbonyl)cubane with two moles of 1 produces dimeric 1,8-bis-[6-(6^Adeoxy-β-cyclodextrin-6 ^A-ylamino)hexylaminocarbonyl]-2,3-dimethylcubane 7 (pK, = 8.80) in good yield together with two moles of 4-nitrophenolate. The pK_a in brackets are those of the single protonated amine functions of 2 and 4, and of both protonated amine functions of 7 which have identical pAT_as [in each case at 298.2 K and I = 0.10 mol dm^-3 (NaClO₄)]. ¹H NMR ROESY studies are consistent with the trinorbornyl, noradamantyl and dimethylcubyl entities of 2,4 and 7 complexing inside the βCD annuli in D₂O at pD ≥ 11. Under the same conditions, adamantane-1-carboxylate forms intermolecular complexes with 2,4 and 7 and displaces their trinorbornyl, noradamantyl and the dimethylcubyl entities from the β-cyclodextrin annulus to varying degrees depending on the relative size, shape and hydrophobicity of these groups. These data are compared with those for analogous modified β-cyclodextrins. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a909766j

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Intramolecular complexation in modified ꢀ-cyclodextrins:†
a preparative, nuclear magnetic resonance and pH titration study
Michael J. Field,a Bruce L. May,a Philip Clements,a John Tsanaktsidis,b Christopher J. Eastonc
and Stephen F. Lincolna*
1
a Department of Chemistry, University of Adelaide, Adelaide, SA 5005, Australia
b CSIRO Molecular Science, Private Bag 10, Clayton South MDC, Vic 3169, Australia
c Research School of Chemistry, Australian National University, Canberra, ACT 0200,
Australia
Received (in Cambridge, UK) 13th December 1999, Accepted 28th February 2000
Published on the Web 31st March 2000
The reactions of 4-nitrophenyl trinorbornane-2-acetate and 4-nitrophenyl noradamantane-1-carboxylate with
6A-(6-aminohexylamino)-6A-deoxy-β-cyclodextrin 1 produce 6A-{6-(bicyclo[2.2.1]heptan-2-ylacetylamino)hexyl-
amino}-6A-deoxy-β-cyclodextrin 2 (pKa = 8.98) and 6A-deoxy-6A-{6-(tricyclo[3.3.1.03,7]nonan-3-ylcarbonylamino)-
hexylamino}-β-cyclodextrin 4 (pKa = 8.47), respectively, in good yield together with 4-nitrophenolate. The reaction
of 2,3-dimethyl-1,8-bis-(4-nitrophenoxycarbonyl)cubane with two moles of 1 produces dimeric 1,8-bis-[6-(6A-
deoxy-β-cyclodextrin-6A-ylamino)hexylaminocarbonyl]-2,3-dimethylcubane 7 (pKa = 8.80) in good yield together
with two moles of 4-nitrophenolate. The pKas in brackets are those of the single protonated amine functions of 2 and
4, and of both protonated amine functions of 7 which have identical pKas [in each case at 298.2 K and I = 0.10 mol
dmϪ3 (NaClO4)]. 1H NMR ROESY studies are consistent with the trinorbornyl, noradamantyl and dimethylcubyl
entities of 2, 4 and 7 complexing inside the βCD annuli in D2O at pD ≥ 11. Under the same conditions, adamantane-
1-carboxylate forms intermolecular complexes with 2, 4 and 7 and displaces their trinorbornyl, noradamantyl and the
dimethylcubyl entities from the β-cyclodextrin annulus to varying degrees depending on the relative size, shape and
hydrophobicity of these groups. These data are compared with those for analogous modified β-cyclodextrins.
the substituents for intramolecular complexation in the βCD
annulus as is discussed below. The ability of the guest 8 to dis-
place the X entity from the annulus is dependent on the relative
size, shape and hydrophobicity of the polycyclic entity X.
Introduction
The intramolecular complexation of the 6-aminohexylamino
substituent in the β-cyclodextrin (βCD) annulus of 6A-(6-
aminohexylamino)-6A-deoxy-β-cyclodextrin (1, Fig. 1)1 pro-
vides the possibility of generating a range of intramolecularly
complexing modified βCDs through substitution of the prim-
ary nitrogen of 1 with a variety of entities, X.2,3 When the
precursor of the X substituent has either one or two groups
participating in this substitution, a modified βCD monomer
and a linked βCD dimer are obtained, respectively (Schemes 1
and 2, where the truncated cones represent the βCD annuli
where the secondary faces are delineated by 14 secondary
hydroxy groups and the primary faces are delineated by 6 prim-
ary hydroxy groups and a secondary amine group). We have
previously prepared such monomers where X is either a cubyl, a
dimethylcubyl or an adamantyl entity and a dimer where X
incorporates a cubyl entity (3 and its dimethylcubyl analogue,
5 and 6 in Fig. 1).2 We now report preparations where X
incorporates trinorbornyl and noradamantyl entities into the
modified βCD monomers (2 and 4 in Fig. 1 and Scheme 1), and
the dimethylcubyl entity into the βCD dimer (7 in Fig. 1 and
Scheme 2). The X entities of 2, 4 and 7 were selected on the
basis that they are hydrophobic and likely to enter the largely
hydrophobic βCD annulus to form intramolecular complexes
stabilised by a combination of secondary forces in aqueous
solution.4–10 The modified βCDs incorporating these X entities,
together with analogous species reported earlier, facilitate an
experimental assessment of the extent to which the size of X
places a mechanical constraint on its occupancy of the annuli
of the modified βCD monomers and dimers. Also shown
in Fig. 1 is adamantane-1-carboxylate, 8, which competes with
Results and discussion
The reaction of 4-nitrophenyl trinorbornane-2-acetate
9
and 4-nitrophenyl noradamantane-1-carboxylate 10 with 1
produced 6A-{6-(bicyclo[2.2.1]heptan-2-ylacetylamino)hexyl-
amino}-6A-deoxy-β-cyclodextrin
2
and 6A-deoxy-6A-{6-
(tricyclo[3.3.1.03,7]nonan-3-ylcarbonylamino)hexylamino}-β-
cyclodextrin 4 (Scheme 1), respectively, in good yield together
with 4-nitrophenolate 11. The reaction of 1,2-dimethyl-3,8-bis
(4-nitrophenoxycarbonyl)cubane 14 with two mole equiv.
of 1 produced 1,8-bis[6-(6A-deoxy-β-cyclodextrin-6A-ylamino)-
hexylaminocarbonyl]-2,3-dimethylcubane
7 in good yield
together with two moles of 11 (Scheme 2). These new modified
βCDs may either exist as 2, 4 and 7 with their substituents
outside the βCD annulus or as 2Ј, 4Ј and 7Ј where the substitu-
ents are intramolecularly complexed inside the βCD annulus.
The experimental evidence for the equilibria shown in
Schemes 1 and 2 depends on solution H and 13C NMR spec-
1
troscopy, of which the major aspects are presented below.
Detailed resonance assignments based on the COSY and
HSQC spectra of the new derivatives appear at the conclusion
of each of the preparative sections for 2, 4 and 7 in the Experi-
mental section.
6A-{6-(Bicyclo[2.2.1]heptan-2-ylacetylamino)hexylamino}-6A-
deoxy-ꢀ-cyclodextrin 2 and 6A-deoxy-6A-{6-(tricyclo[3.3.1.03,7]-
nonan-3-ylcarbonylamino)hexylamino}-ꢀ-cyclodextrin 4
The 1H ROESY NMR spectrum of 2/2Ј showed significant
cross-peaks arising from NOE interactions between the tri-
† β-Cyclodextrin = cycloheptamaltose.
DOI: 10.1039/a909766j
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This journal is © The Royal Society of Chemistry 2000
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Fig. 1 Structures of C-6-substituted βCDs, 1/1Ј–7/7Ј, where the
substituent is intramolecularly complexed in the primed species,
adamantane-1-carboxylate 8, showing the (mostly arbitrary) atom-
labelling schemes. The prefixes annular, hexyl, trinorbornyl, cubyl,
noradamantyl and adamantyl are used as appropriate in referring to 1H
and 13C resonances in the NMR spectra. The pKas ( 0.02) are those of
the protonated secondary amine function in each case at 298.2 K and
I = 0.10 mol dmϪ3 (NaClO4). In each case the amine groups of 6 and 7
have identical pKas.
Scheme 1
but these provide little information on complexation and are
not further considered.)
On addition of 8, new cross-peaks (Table 1) arising from the
NOE interactions of the adamantyl H-1- H-4 protons with the
annular H-3 and H-5 protons appeared, consistent with 8
competing with the intramolecularly complexed trinorbornyl
and noradamantyl entities to form the intermolecular com-
plexes 12 and 13 in Scheme 1. (The orientation of the carb-
oxylate group of 8 towards the secondary face of the βCD
annuli of 12 and 13 shown in Scheme 1 is consistent with
modelling studies of intermolecular complexes formed by 8
with βCD and 1.2,11,12) However, the cross-peaks arising from
the protons of the trinorbornyl and noradamantyl entities
remained, at a lower intensity, consistent with the intra-
molecular complexes 2Ј an 4Ј coexisting in solution with the
intermolecular complexes 12 and 13, respectively. The complex-
ation of the adamantyl group within the annuli of 2 and 4 in
competition with the trinorbornyl and noradamantyl groups,
respectively, is consistent with the measured values of the
formation constants for complexation of adamantane-1-
carboxylate, noradamantane-1-carboxylate and trinorbornane-
2-acetate within β-cyclodextrin (K = 4.2 × 104, 8.2 × 103 and
4.3 × 103 dm3 molϪ1 at pH 7.2, respectively).12 The stability of
the intramolecular complexes 2Ј and 4Ј is probably enhanced
by the favourable entropy contribution arising from the tether-
norbornyl protons and the annular H-3 and H-5 protons which
line the interior of the βCD annulus (Table 1). The analogous
spectrum of 4/4Ј showed cross-peaks between the noradam-
antyl protons and the annular H-3 and H-5 protons (Fig. 2 and
Table 1). This is consistent with intramolecular complexation
of the trinorbornyl and noradamantyl substituent in the annu-
lus of 2Ј and 4Ј as shown in Scheme 1. Usually, the annular H-3
and H-5 resonances occur at δ ≈3.8 and ≈3.5, respectively,
but in Fig. 2 they can neither be separately distinguished from
each other nor from the resonance of H-6 which lies on the
outside of the annulus. Hence the separate assignment of
cross-peaks arising from the annular H-3 and H-5 is not
possible. However, as the variations in the ROESY spectra
discussed herein are consistent with intra- and intermolecular
complexation in the βCD annulus, it seems unlikely that any of
the cross-peaks arise from NOE interactions of the protons of
complexed entities with H-6 on the outside of the βCD annulus.
(Cross-peaks also arise from interactions between protons
which are at small through-bond separations from each other,
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Scheme 2 A form of 7Ј where the hexyl entity is complexed in the second βCD annulus probably also exists but this is not shown in the Scheme.
ing of the trinorbornyl and noradamantyl groups to the βCD
entity.
trinorbornyl and noradamantyl entities of 2Ј and 4Ј to compete
with 8 for occupancy of the βCD annulus, whereas the
cubyl and dimethylcubyl entities of 3Ј and its dimethylcubyl
analogue 7Ј appear to be less effective,3 is consistent with a
decreasing strength of intramolecular retention in the βCD
annulus in the sequence: adamantyl > noradamantyl ≈
trinorbornyl > dimethylcubyl ≈ cubyl. This suggests that a
combination of closeness of fit and degree of hydrophobicity
of the substituent determines the relative stabilities of the
modified βCD intramolecular complexes. It is also consistent
with the closer fit of the adamantyl entity of 8, in combination
with its hydrophobicity, stabilising its intermolecular complex
with 3 by comparison with the intramolecular cubyl complex
3Ј. This interpretation is in accord with adamantan-1-ol,
adamantan-2-ol and adamantane-1-carboxylate competing
Similar intramolecular complexation of the cubyl and
adamantyl entities of 3 and 5 to form 3Ј and 5Ј, respectively, has
been reported.3 However, while 8 displaced the cubyl entity
from the annulus of 3Ј, it did not displace the adamantyl
entity from the annulus of 5Ј possibly because the intramolecu-
larly complexed adamantyl substituent of 5Ј has an entropic
advantage in competing with 8 for occupancy of the βCD
annulus. Alternatively, it may be that substitution of 1Ј through
the secondary face of the βCD annulus produces 5Ј and the
adamantyl entity is too large to pass through the primary face.
In the latter case, 5Ј is a mechanically constrained molecular
slip-knot. Despite uncertainty as to whether the entropic or the
mechanical constraint rationale is correct, the ability of the
J. Chem. Soc., Perkin Trans. 1, 2000, 1251–1258
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1
Table 1 600 MHz H NMR ROESY cross-peaks observed in D2O solution at pD ≥ 10 and identified as arising from intra- and intermolecular
complexation
System 2/2Ј
Annular protons
Trinorbornyl protons
Nor H-2
Nor H-5
Nor H-8
Nor H-8Ј
Nor Ha
H-3
H-5
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
System 2/2Ј ϩ 8
Trinorbornyl and adamantyl protons
Annular protons
Nor H-2
Nor H-5
Nor H-8
Not H-8Ј
Nor Ha
Adam 2
Adam 3
Adam 4
Adam 4Ј
H-3
H-5
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
System 4/4Ј
Annular protons
Noradamantyl protons
Norad H-3
Norad H-6
Norad Ha
H-3
H-5
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
System 4/4Ј ϩ 8
Noradamantyl and adamantyl protons
Annular protons
Norad H-3
Norad H-6
Norad Ha
Adam 2
Adam 3
Adam 4
H-3
H-5
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
System 7/7Ј
Annular protons
Hexyl and dimethylcubyl protons
Hexyl
H-2–H-5
Cubyl Ha
Cubyl Me
H-3
H-5
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
System 7/7Ј ϩ 8
Annular protons
Dimethylcubyl and adamantyl protons
Cubyl Me
Adam 2
Adam 3
Adam 4
Adam 4Ј
H-3
H-5
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
a Identification of individual resonances uncertain. Crosses indicate the presence of a cross-peak.
more effectively with the dansyl entity for occupancy of the
βCD annulus of Nα-dansyl--lysine-β-cyclodextrin than do
(Ϫ)-borneol, (ϩ)- and (Ϫ)-camphor and (ϩ) and (Ϫ)-fenchone
which are smaller.5 Intramolecular complexation of aromatic
substituents of modified βCDs is well established, particularly
in the case of those incorporating the dansyl entity.4–8
from the interaction of the hexyl H-2–H-5 protons with the
annular H-3 and H-5 protons, which is consistent with com-
plexation of a hexyl entity in the second βCD annulus. These
observations are consistent with exchange of the dimethylcubyl
entity between the two equivalent annular intramolecular
complexation sites of 7Ј (Scheme 2) occurring slowly on the
1H NMR timescale and resulting in an inequivalence of the
βCD entities. There was no detectable spectral differentiation
of the diastereomers of 7/7Ј in the 1H NMR spectra.
1,8-Bis[6-(6A-deoxy-ꢀ-cyclodextrin-6A-ylamino)hexylamino-
carbonyl]-2,3-dimethylcubane 7
On addition of two mol equiv. of 8, 1H NMR spectral
changes occurred consistent with step-wise intermolecular
complexation of 8 to give a symmetric 2:1 guest:host complex,
16, through the 1:1 intermediate complex 15. New cross-peaks
arose from the NOE interaction of the adamantyl protons H-1–
H-4 with the annular H-3 and H-5 protons of the inter-
molecular complex 16 (Scheme 2 and Table 1). The cross-peaks
from the hexyl H-2–H-5 protons disappeared, consistent with 8
displacing the hexyl entity from a βCD annulus. While the
The substituted βCD 7, prepared from the racemic diester 14
and homochiral 1, was a 1:1 mixture of diastereomers. The 1D
1H NMR spectrum of 7/7Ј showed three multiplet resonances
for the dimethylcubyl methine protons and a single resonance
for the methyl protons. The 1H ROESY NMR spectrum
showed cross-peaks arising from NOE interactions between the
dimethylcubyl methine and methyl protons and the annular H-3
and H-5 protons (Fig. 3 and Table 1). Cross-peaks also arise
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These interpretations are supported by 13C NMR studies. In
D2O solution, three carbonyl and five methyl 13C resonances
were observed, arising from both the asymmetry of 7Ј and some
spectral differentiation of the diastereomers of 7/7Ј. On addi-
tion of two mol equiv. of 8, only single carbonyl and methyl
13C resonances were observed, consistent with the domin-
ant formation of the symmetric 2:1 guest:host complex 16
(Scheme 2). In 7Ј, the distereomeric dimethylcubyl entities were
distinguished by two distinct pairs of methyl 13C resonances
arising from differing interactions of the methyl groups with the
homochiral βCD annulus. It appears that a combination of the
deep penetration of the methyl groups into the βCD annulus of
7Ј and the large chemical-shift scale for 13C was responsible for
this detection of chiral discrimination but no other evidence for
it was provided by either the 13C or 1H spectra.
pKa Studies
The pKas of the new modified βCDs 2, 4 and 7, and those of
their earlier reported analogues 3, 5 and 6, were determined
by pH titration (Fig. 1). The increased acidity of the proton-
ated amine group of the modified βCDs, by comparison
with that expected for simple aliphatic diamines, was similar
to that observed in other amino-substituted βCDs.13 This may
partially have arisen from either the electronic and steric
effects of the βCD entity, or a change in solvation experi-
enced by a protonated amine adjacent to the βCD annulus,
or combination of these factors. The pKa of the protonated
amine decreased as the size and hydrophobicity of the X
entity increased, consistent with an increasingly hydrophobic
environment destabilising the protonated amine. The βCD
dimers 6 and 7 were each characterised by identical pKas for
the two protonated amines, consistent with each amine being
sufficiently insulated from a change in the protonation state
of its twin to behave independently. This may also be
reflected through the identical pKas of 3 and 6. The proton-
ated amine groups of the modified βCDs experienced different
environments in their uncomplexed and intramolecularly com-
plexed forms. However, two distinct pKas were not observed,
consistent with either the intramolecular complex being greatly
dominant, or for exchange between it and its uncomplexed
analogue being sufficiently rapid to yield an averaged pKa, or a
combination of these effects. (Above pH 10 a time-dependent
pH change occurred for 3, which is thought to arise from
hydrolysis of the methyl ester.)
Fig. 2 600 MHz 1H NMR ROESY spectrum of 4/4Ј in D2O at
pH ≥ 11.
Experimental
Physical methods
Elemental analyses were carried out by the Microanalytical
Service of the University of Otago. Modified βCDs were
characterised as the hydrates by adding whole molecules of
water to the molecular formula to give the best fit to the
microanalytical data. Mps were determined using a Kofler
hot-stage apparatus under a Reichert microscope and are
uncorrected. As βCD derivatives generally decompose without
melting above 180 ЊC, mps were not determined for these
compounds. TLC was carried out on Kieselgel 60 F254 (Merck)
on aluminium backed plates. Unless otherwise stated, plates
were developed with 7:7:5:4 v/v ethyl acetate–propan-2-ol–
ammonium hydroxide–water for the analysis of all cyclodextrin
samples. Compounds bearing amino groups were visualised
by drying the plate then dipping it into a solution of 0.5%
ninhydrin in ethanol and heating it with a heat-gun. Modified
βCDs were further visualised by dipping the plate into a solu-
tion of 1% sulfuric acid in ethanol and heating it with a heat-
gun. Iodine vapour was also used to visualise cyclodextrins. The
value Rc represents the Rf of a modified βCD relative to the Rf
of βCD. Squat-column chromatography was carried out using
Kieselgel 60 F254 TLC-grade silica.14
Fig. 3 600 MHz 1H NMR ROESY spectrum of 7/7Ј in D2O at
pH ≥ 11.
observed changes in chemical shift rendered any change in the
cross-peaks arising from the dimethylcubyl methine protons
difficult to detect because of other overlapping cross-peaks, a
cross-peak arising from the methyl protons interacting with the
annular H-3 or H-5 protons remained. This is consistent with
the dimethylcubyl entity competing with 8 for occupancy of a
βCD annulus through the equilibria between 7Ј, 15 and 16
shown in Scheme 2. In the 1D 1H NMR spectrum, only a single
resonance was observed for the cubyl protons, consistent with
both βCD entities becoming equivalent and complexed by 8 in
16, the dominant species in solution. (Similar equilibria have
previously been reported for 6 and 6Ј.3)
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IR spectra were recorded on an ATI Mattson Genesis FT-IR.
The abbreviations strong (s), medium (m), weak (w) and broad
(b) are used in reporting the IR data. Electrospray mass spec-
troscopy (ESMS) was carried out at the Australian National
University. Samples were dissolved in 10% acetonitrile for
injection and the cone voltage was set to 120 V.
mass data: calculated for 9 (C15H18NO4) (M ϩ H)ϩ, 276.1236.
Found: m/z, 276.1249; δH (200 MHz; CDCl3) 8.27 (d, J 9.2 Hz,
2H, ArH), 7.28 (d, J 9.2 Hz, 2H, ArH), 2.0–2.5 (m, 5H), 1.0–1.6
(m, 8H); δC (50.4 MHz; CDCl ) 170.6 (C᎐O), 155.5, 145.1,
᎐
3
125.0, 122.4 (ArC), 41.1, 38.3, 38.1, 37.6, 36.7, 35.2, 29.6, 28.4;
νmax (film)/cmϪ1 3115w, 3088w, 2951s, 2871s, 1768s, 1706m,
1615m, 1593m, 1525s, 1490m, 1455w, 1347s, 1208s, 1162s,
1106s, 915m, 864m, 749w, 716w.
All 1H and 13C NMR spectra were run on solutions 0.10 mol
dmϪ3 in the cyclodextrin of interest using Varian Gemini 200
and 300 spectrometers except for the ROESY 1H NMR spectra
which were run on a Varian Inova 600 using a standard
sequence with a mixing time of 0.3 s.15 The modified βCDs 2, 4
and 7 (and 8 when present) were dissolved in D2O to give final
concentrations of 0.06 mol dmϪ3 of each component and a final
pH ≥ 11 adjusted with NaOD. The resultant solutions were fil-
tered (0.22 µm) and degassed by freeze–thawing before the spec-
tra were recorded. Resonances were assigned on the basis of
COSY and HSQC spectra. The spectral assignments presented
below with the preparative details of each modified βCD are
listed according to the (mostly arbitrary) atom labelling in
Fig. 1. All chemical shifts are referenced to aq. 3-(trimethyl-
silyl)propanesulfonic acid as external standard.
6A-{6-(2-Bicyclo[2.2.1]heptan-2-ylacetylamino)hexylamino}-6A-
deoxy-ꢀ-cyclodextrin 2
A mixture of 1 (0.565 g, 4.58 × 10Ϫ4 mol) and 9 (0.131 g, 4.76 ×
10Ϫ4 mol) in DMF (5 cm3) was stirred at room temperature for
3 h and then diluted with diethyl ether (100 cm3). The resultant
yellow precipitate was collected by vacuum filtration and
washed with diethyl ether (100 cm3). The solid was dissolved in
water (20 cm3) and the solution was acidified by the addition
of 3 mol dmϪ3 HCl (1 cm3). The solution was washed with
dichloromethane (3 × 20 cm3) and then treated with AG 4-X4-
anion-exchange resin (free-base-form, 10 g). The filtered solu-
tion was evaporated and the residue was dissolved in water (10
cm3) and loaded on to a BioRex 70 cation-exchange column
(NH4ϩ-form, 4.5 × 4.5 cm). The column was eluted with water
(100 cm3) and fractions containing the product were combined,
and evaporated under reduced pressure to give 2 as a white
powder (0.320 g, 51%), Rc = 1.4; ESMS m/z 1370 (M ϩ H)ϩ
[Found: C, 46.65; H, 7.22; N, 1.83. Calc. for Mؒ2.5H2O (C57-
H106N2O40): C, 46.91; H, 7.32; N, 1.92%]; δH (2/2Ј; 600 MHz;
D2O; pH ≥ 11) 4.89 (br s, 7H, H-1), 3.6–3.9 (m, 26H, H-3, -5,
-6), 3.2–3.5 (m, 14H, H-2, -4, hexyl H-6), 2.9–3.2 (m, 3H, H-4A,
-6A, hexyl H-6Ј), 2.67 (t, J 12.0 Hz, 1H, H-6AЈ), 2.51 (m, 1H,
hexyl H-1), 2.35 (br s, 1H, H-1), 2.24 (m, 1H, hexyl H-1Ј), 2.06
(m, 1H, trinorbornyl H-8), 1.95 (br s, 1H, trinorbornyl H-2),
1.74 (m, 1H, trinorbornyl H-8Ј), 0.9–1.7 (m, 17H, hexyl H-2–H-
5 ϩ trinorbornyl H); δC (2/2Ј; 75.4 MHz; D2O; pH ≥ 11) 176.7
pH Titrations were carried out using a Metrohm Dosimat
E665 titrimator, an Orion SA 720 potentiometer and an Orion
8172 Ross Sureflow combination pH electrode filled with 0.10
mol dmϪ3 NaClO4. Titration solutions were saturated with
nitrogen by passing a fine stream of bubbles (previously passed
through aqueous 0.10 mol dmϪ3 NaOH followed by 0.10 mol
dmϪ3 NaClO4) through them for at least 15 min before the
commencement of the titration. During the titrations a similar
stream of nitrogen bubbles was passed through the titration
solution which was magnetically stirred and held at 298.2 0.1
K in a water-jacketed 20 cm3 titration vessel which was closed
to the atmosphere except for a small exit for nitrogen. In all
titrations, standardised 0.100 mol dmϪ3 NaOH was titrated
against solutions which were 1 × 10Ϫ3 mol dmϪ3 in the species
of interest, 5 × 10Ϫ3 mol dmϪ3 in HClO4 and 9.5 × 10Ϫ2 mol
dmϪ3 in NaClO4 (I = 0.10). Values of Eo and pKw were deter-
mined by titration of a solution which was 1 × 10Ϫ4 mol dmϪ3 in
HClO4 and 9 × 10Ϫ4 mol dmϪ3 in NaClO4 against 0.100 mol
dmϪ3 NaOH. Values of pKa were determined using the program
SUPERQUAD.16 At least three runs were performed for each
system and at least two of these runs were averaged, the cri-
terion for selection for this averaging being that χ2 for each run
was <12.6 at the 95% confidence level.
(C᎐O), 105.9, 105.6 (C-1), 87.45 (C-4A), 85.1, 84.4 (C-4), 76.8,
᎐
76.6, 76.2, 75.9, 75.3, 74.8 (C-2, -3, -5), 70.3 (C-5A), 63.0
(C-6), 52.2 (C-6A), 49.4 (hexyl C-1), 46.4 (trinorbornyl C-8),
44.3, 42.2, 40.4, 39.3, 38.3, 38.2, 32.7, 31.4, 31.1, 30.7, 28.8,
27.3; δH (2/2Ј ϩ 1 mol equiv. 8; 600 MHz; D2O; pH ≥ 11) 4.89
(br s, 7H, H-1), 3.6–3.9 (m, 26H, H-3, -5, -6), 3.2 (br s, 13H,
H-2, -4), 2.9–3.2 (m, 4H, H-4A, -6A, hexyl H-6), 2.70 (m, 1H,
H-6AЈ), 2.50 (m, 1H, hexyl H-1), 2.30 (m, 1H, hexyl H-1Ј), 2.20
(br s, 1H, trinorbornyl H-5), 1.8–2.1 (m, 6H, trinorbornyl H-2
and -8, adamantyl H-3), 1.76 (s, 6H, adamantyl H-2), 0.8–1.7
(m, 23 H, adamantyl H-4, trinorbornyl H, hexyl H-2–H-5).
Preparations of modified ꢀ-cyclodextrins and their precursors
Literature methods were used to prepare 6A-(6-aminohexyl-
amino)-6A-deoxy-β-cyclodextrin13 and dimethyl 2,3-dimethyl-
cubane-1,8-dicarboxyate.17 Either standard procedures were
employed in the preparation of the other compounds used in
the preparations described below, or they were of good com-
mercial grade. CAUTION. While no instability was noted in the
cubyl-substituted βCDs prepared in this study, it should be
noted that cubanes are high-energy materials and should be
handled accordingly.
4-Nitrophenyl noradamantane-1-carboxylate 10
A solution of noradamantane-1-carboxylic acid (0.505 g,
3.04 × 10Ϫ3 mol), 4-nitrophenol (0.430 g, 3.09 × 10Ϫ3 mol) and
DCC (0.624 g, 3.03 × 10Ϫ3 mol) was stirred at room temper-
ature for 3 h. The reaction mixture was filtered and the filtrate
was washed successively with 5% aq. sodium hydrogen carbon-
ate (3 × 20 cm3) and brine (20 cm3) and dried over sodium
sulfate. The filtered solution was evaporated under reduced
pressure and the oily residue was suspended in 1:1 dichloro-
methane–hexane and loaded onto a squat column (4.5 cm i.d.;
30 g silica gel). Elution of the column was commenced with 1:1
dichloromethane–hexane and the proportion of dichlorometh-
ane was progressively increased. Fractions containing the
product were combined, and evaporated under reduced pres-
4-Nitrophenyl trinorbornane-2-acetate 9
A mixture of trinorbornane-2-acetic acid (0.571 g, 3.70 × 10Ϫ3
mol), 4-nitrophenol (0.516 g, 3.71 × 10Ϫ3 mol) and dicyclohexyl-
carbodiimide (DCC) (0.748 g, 3.63 × 10Ϫ3 mol) in dichloro-
methane (10 cm3) was stirred at room temperature for 18 h. The
reaction mixture was filtered through a pad of Celite and the
filtrate was evaporated under reduced pressure to give the crude
ester as a yellow oil. This material was further purified by
passage through a squat column eluted with dichloromethane.
Fractions containing the ester were combined and evaporated
to give the product as a colourless oil (0.830 g, 83%). An
attempt to further purify the ester by bulb-to-bulb distillation
(150 ЊC/0.05 mmHg) resulted in some decomposition. Accurate
sure to give the product as a colourless oil which solidified on
storage (0.812 g, 93%), mp 82–83 ЊC; EI-MS m/z 287 (Mϩ
)
ؒ
[Found: C, 66.81; H, 5.91; N, 4.99. Calculated for 10 (C16H17-
NO4): C, 66.89; H, 5.96; N, 4.87%]; δH (200 MHz; CDCl3) 8.26
(d, J 9.2 Hz, 2H, ArH), 7.28 (d, J 9.2 Hz, 2H, ArH), 2.86 (t,
J 6.6 Hz, 1H, H-7), 2.24 (m, 4H), 1.91 (m, 4H), 1.73 (m, 4H);
δ (50.4 MHz; CDCl ) 175.0 (C᎐O), 156.0, 145.1, 125.1, 122.4
᎐
C
3
(ArC), 54.1 (C-3), 46.8 (C-7), 44.5 (C-9), 43.5 (C-6), 37.4 (C-1),
1256
J. Chem. Soc., Perkin Trans. 1, 2000, 1251–1258

View Article Online
34.5 (C-2); νmax (Nujol)/cmϪ1 1747s, 1614m, 1591m, 1521s,
1346s, 1305m, 1274m, 1209m, 1182s, 1097m, 1074m, 1020m,
997m, 873m, 862m, 742m.
1,8-Bis[6-(6A-deoxy-ꢀ-cyclodextrin-6A-ylamino)hexylamino-
carbonyl]-2,3-dimethylcubane 7
A mixture of 1 (0.550 g, 4.46 × 10Ϫ4 mol) and 13 (0.098 g,
2.21 × 10Ϫ4 mol) in dry DMF (5 cm3) was stirred at room tem-
perature for 18 h. The yellow reaction mixture was diluted with
diethyl ether (100 cm3) and the resultant precipitate was col-
lected by vacuum filtration and washed with diethyl ether (100
cm3 in portions). The crude product was dissolved in water (20
cm3) and passed through an AG 4-X4 anion-exchange column
(free-base-form, 4.5 × 4.5 cm) and was further eluted with
water (150 cm3). The eluent was concentrated under reduced
pressure to ≈15 cm3 and this solution was loaded on to a
BioRex 70 cation-exchange column (NH4ϩ-form, 4.5 × 4.5 cm)
which was then eluted sequentially with water (150 cm3) and
0.05 mol dmϪ3 aq. ammonium hydrogen carbonate (200 cm3).
Fractions containing the product were combined and evapor-
ated under reduced pressure to give 7 as a white powder (0.340
g, 60%), Rc = 0.76; ESMS m/z 2651 (M ϩ Hϩ) [Found: C, 45.83;
H, 6.96; N, 2.06. Calc. for 7ؒ10H2O (C198H196N4O80): C, 45.83;
H, 6.98; N, 1.98%]; δH (7/7Ј; 600 MHz; D2O; pH ≥ 11) 4.88 (br
s, 14H, H-1), 4.30 (m, 1H, cubyl H), 4.10 (m, 2H, cubyl H), 3.80
(m, 1H, cubyl H), 3.5–3.8 (m, 52H, H-3, -5, -6), 3.3–3.5 (m,
26H, H-2, -4), 2.8–3.2 (m, 8H, hexyl H-6, H-4A, H-6A), 2.2–2.7
(m, 6H, H-6AЈ, hexyl H-1), 1.0–1.5 (m, 22H, hexyl H-2–H-5,
Me); δC (7/7Ј; 75.4 MHz; D2O; pH ≥ 11) 176.1, 175.7, 174.4
6A-Deoxy-6A-{6-(tricyclo[3.3.1.03,7]nonan-3-ylcarbonylamino)-
hexylamino}-ꢀ-cyclodextrin 4
A mixture of 1 (0.504 g, 4.09 × 10Ϫ4 mol) and 4-nitrophenyl
noradamantane-1-carboxylate (0.125 g, 4.36 × 10Ϫ4 mol) in
DMF (7 cm3) was stirred at room temperature for 3 h and then
diluted with diethyl ether (100 cm3). The resultant yellow pre-
cipitate was collected by vacuum filtration and washed with
diethyl ether (100 cm3). The solid was dissolved in water (20
cm3) and the solution was acidified by the addition of 3 mol
dmϪ3 HCl (1 cm3). The solution was washed with dichloro-
methane (3 × 20 cm3) and then treated with AG 4-X4 anion-
exchange resin (free-base-form, 10 g). The filtered solution was
evaporated and the residue was dissolved in water (10 cm3) and
loaded on to a BioRex 70 cation-exchange column (NH4ϩ-form,
4.5 × 4.5 cm). The column was eluted with water (100 cm3) and
fractions containing the product were combined, and evapor-
ated under reduced pressure to give 4 as a white powder (0.307
g, 54%), Rc = 1.4; ESMS m/z 1382 (M ϩ H)ϩ [Found: C, 46.46;
H, 7.30; N, 1.83. Calc. for Mؒ4ؒ7H2O (C58H110N2O42): C, 46.21;
H, 7.35; N, 1.86%]; δH (4/4Ј; 600 MHz; D2O; pH ≥ 11) 4.8 (m,
7H, H-1), 3.6–3.9 (m, 26H, H-3, -5, -6), 3.3–3.5 (m, 13H, H-2,
-4), 3.16 (br s, 2H, hexyl H-6), 3.10 (t, J 9.0 Hz, 1H, H-4A), 3.01
(d, J 13.0 Hz, 1H, H-6A), 2.67 (m, 2H, H-6AЈ, noradamantyl
H-6), 2.53 (m, 3H, hexyl H-1, noradamantyl H-3), 2.17 (m, 1H,
hexyl H-1Ј), 1.7–2.0 (m, 10H, noradamantyl H), 0.9–1.5 (m,
8H, hexyl H-2–H-5); δC (4/4Ј; 75.4 MHz; D2O; pH ≥ 11) 181.6
(C᎐O), 106.0, 105.7, 105.5, 105.2 (C-1), 87.3 (C-4A), 84.8, 84.7,
᎐
84.4 (C-4), 76.6, 75.8, 74.9, 74.8, 74.6 (C-2, -3, -5), 72.8, 72.5,
72.3, 69.9 (C-5A?), 63.1 (C-6), 59.6, 59.5, 58.8, 58.7, 58.5, 52.1,
51.3, 51.0, 49.5, 48.6, 46.3, 46.1, 41.9, 41.7, 40.3, 35.4, 33.5,
32.1, 31.5, 31.2, 31.1, 30.2, 30.l, 28.9, 28.8, 28.6, 28.1, 27.0
(C-6A, hexyl C-1–C-6, cubyl C), 16.0, 15.8, 14.7, 14.4, 13.7
(Me); δH (7/7Ј ϩ 2 mol equiv. 8; 600 MHz; D2O; pH ≥ 11 ϩ 2
equiv. 8) 4.86 (m, 14H, H-1), 3.86 (m, 2H, cubyl H), 3.84
(t, J 10.0 Hz, 2H, H-5A), 3.5–3.8 (m, 52H, H-3, -5, -6, cubyl H),
3.4 (m, 26H, H-2, -4), 3.1 (m, 6H, hexyl H-6, H-4A), 2.94 (d,
J 13.2 Hz, 2H, H-6A), 2.63 (m, 2H, H-6AЈ), 2.46 (m, 2H, hexyl
H-1), 2.27 (m, 2H, hexyl H-1Ј), 2.01 (br s, 6H, adamantyl
H-3), 1.79 (br s, 12H, adamantyl H-2), 1.72 (d, J 11.4 Hz, 6H,
adamantyl H-4), 1.47 (d, J 11.4 Hz, 6H, adamantyl H-4Ј),
1.0–1.4 (m, 22H, hexyl H-2–H-5, Me); δC (7/7Ј ϩ 2 mol equiv.
8 75.4 MHz; D2O; pH ≥ 11) 189.9 (CO2Ϫ), 176.0 (CONHR),
106.3, 106.0, 105.9, 105.3 (C-1), 87.7 (C-4A), 84.6, 84.5, 84.4,
84.1 (C-4), 76.8, 76.5, 76.4, 76.0, 75.0, 74.9, 74.7 (C-2, -3, -5),
72.3, 69.8 (C-5A?), 62.7 (C-6), 59.6, 58.8, 50.7, 49.5, 49.2, 46.1,
44.8, 42.4, 41.3, 39.8, 34.6, 31.3, 31.0, 30.6, 29.1, 28.5 (C-6A,
hexyl C-1–C6, adamantyl C, cubyl C), 13.7 (Me).
(C᎐O), 106.1, 106.0, 105.9 (C-1), 88.0 (C-4A), 85.1, 85.0, 84.9,
᎐
84.8, 84.7 (C-4), 76.7, 76.5, 76.4, 76.1, 75.9, 75.1, 75.0, 74.9,
74.8, 74.7 (C-2, -3, -5), 70.5 (C-5A), 63.4, 63.3, 63.0, 62.9,
62.8 (C-6), 57.9 (noradamantyl C-1), 52.4 (C-6A), 51.4, 50.8,
49.6 (hexyl C-1), 46.7, 46.5, 45.4 (noradamantyl C-6), 40.1, 39.9
(hexyl C-6, noradamantyl C-5), 36.7, 31.0, 30.8, 28.2, 26.1
(hexyl C-2–C-5); δH (4/4Ј ϩ 1 mol equiv. 8; 600 MHz; D2O;
pH ≥ 11) 4.8 (m, 7H, H-1), 3.6–3.9 (m, 26H, H-3, -5, -6), 3.3–
3.5 (m, 13H, H-2, -4), 3.15 (m, 3H, H-4A, hexyl H-6), 2.96 (d,
J 13.0 Hz, 1H, H-6A), 2.70 (dd, J 9.0, 13.0 Hz, 1H, H-6AЈ), 2.60
(m, 1H, noradamantyl H-6), 2.50 (m, 1H, hexyl H-1), 2.28 (br s,
2H, noradamantyl H-5), 2.26 (m, 1H, hexyl H-1Ј), 1.95 (s, 3H,
adamantyl H-3), 1.5–1.9 (m, 22H, adamantyl H, noradamantyl
H), 1.0–1.5 (m, 8H, hexyl H-2–H-5).
2,3-Dimethyl-1,8-bis(4-nitrophenoxycarbonyl)cubane 14
A mixture of 2,3-dimethylcubane-1,8-dicarboxylic acid (0.320
g, 1.45 × 10Ϫ3 mol), 4-nitrophenol (0.409 g, 2.94 × 10Ϫ3 mol)
and DCC (0.613 g, 2.98 × 10Ϫ3 mol) in dichloromethane (8 cm3)
was stirred at room temperature for 18 h. The reaction mixture
was filtered and the collected solid was washed with dichloro-
methane (3 × 10 cm3). The combined filtrate was washed with
5% aq. sodium hydrogen carbonate (3 × 20 cm3) and dried over
sodium sulfate. The solution was concentrated to approx. 20
cm3 and loaded onto a squat column (30 g silica gel; 4.5 cm i.d.)
and the column was eluted successively with dichloromethane
(3 × 25 cm3) and chloroform (3 × 25 cm3). Fractions contain-
ing the product were combined and evaporated to give the
diester as a white powder (0.451 g, 67%). A portion of this
material was recrystallised from dichloromethane–hexane,
mp 202–204 ЊC [Found: C, 62.32; H, 3.90; N, 6.08. Calc. for 14
(C24H18N2O8): C, 62.34; H, 3.92; N, 6.06%]; δH (200 MHz;
CDCl3) 8.31 (d, J 8.4 Hz, 4H, ArH), 7.29 (d, J 8.4 Hz, 4H,
ArH), 4.38 (t, J 4.0 Hz, 2H, cubyl H), 4.12 (t, J 4.0 Hz, 2H,
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1319s, 1203s, 1187s, 1155s, 1108s, 1095s, 995s, 873m, 860m,
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J. Chem. Soc., Perkin Trans. 1, 2000, 1251–1258