Silica-attached molecular receptor complexes for benzoates and naphthoates

Article abstract of DOI:10.1007/s10847-010-9782-8

A series of cyclen (1,4,7,10-tetraazacyclododecane) derived molecular receptors for aromatic oxoanions, that are activated by complexation with Cd(II), have been covalently linked to 3-(glycidoxy)propyl-functionalised silica gel (70-230 mesh). These immob

Full text of DOI:10.1007/s10847-010-9782-8

J Incl Phenom Macrocycl Chem (2010) 68:261–270
DOI 10.1007/s10847-010-9782-8
ORIGINAL ARTICLE
Silica-attached molecular receptor complexes for benzoates
and naphthoates
•
Jozef A. Z. Hodyl Stephen F. Lincoln
•
Kevin P. Wainwright
Received: 5 January 2010 / Accepted: 1 April 2010 / Published online: 18 April 2010
Ó Springer Science+Business Media B.V. 2010
Abstract A series of cyclen (1,4,7,10-tetraazacyclod-
odecane) derived molecular receptors for aromatic oxoa-
nions, that are activated by complexation with Cd(II), have
been covalently linked to 3-(glycidoxy)propyl-functional-
ised silica gel (70–230 mesh). These immobilised receptor
complexes are highly effective for the sequestration of
o-hydroxybenzoates and 2-naphthoate from aqueous solu-
tion, achieving a [80% saturation level by stirring the
material in the aqueous solution for 1 h at pH 7.00 and
298 K. Examination of the uptake levels of a variety of
different benzoates and naphthoates suggests that the
retention mechanism involves a combination of classical
hydrogen bonding and non-classical, water mediated,
O–HÁÁÁp hydrogen bonding. Contrary to expectations,
attachment of hydroxy terminated polyether chains to the
periphery of the receptor complex diminished the level of
uptake.
Introduction
In earlier work we have described a range of pendant arm
macrocyclic ligands which when complexed to an eight-
coordinating metal ion, such as Cd(II), form receptor
complexes that contain a hydrophobic pocket suitable for
the sequestration of aromatic oxoanions through the for-
mation of receptor host–guest complexes [1–5]. Examples
can be seen in Fig. 1a and b where the guest molecules are,
respectively, p-aminobenzoate and 2,6-dihydroxybenzoate,
and the walls of the pocket are defined by four or three
phenoxy moieties. In each case the anion is primarily
retained by four classical O–H hydrogen bond forming
donor groups that converge from the base of the pocket and
serve to capture any appropriately hydrophobic, hydrogen
bond acceptor guest molecule that moves into their vicin-
ity. We have also found that in certain instances, such as
when ortho-substituted benzoates are retained, this classi-
cal hydrogen bonding may be augmented by water medi-
ated non-classical hydrogen bonding to the walls of the
pocket, as shown in Fig. 1b [5, 6]. In cases where both
hydrogen bonding mechanisms can operate association
constants have been determined that exceed 107 M-1 [5].
Modification of the receptor complexes shown in Fig. 1
so that one arm carries an anthracenyl [5], or dansyl [7],
fluorescent probe has enabled us, with some guests, to elicit
an observable fluorescence perturbation when the guest
molecule moves into the receptor pocket, for which the
aromatic fluorophore now forms one of the walls. This has
taken us some way towards producing useful sensor
materials for aromatic oxoanions [5]. However, until now
we have conducted these sequestration reactions with both
the receptor complex and the guest molecule in the same
solution, thereby unavoidably contaminating the seques-
tration medium with the receptor complex. We have now
Keywords Inclusion complex Á Hydroxybenzoates Á
Naphthoates Á Cyclen derivatives Á Silica attachment
Electronic supplementary material The online version of this
article (doi:10.1007/s10847-010-9782-8) contains supplementary
material, which is available to authorized users.
J. A. Z. Hodyl Á K. P. Wainwright (&)
School of Chemistry, Physics and Earth Sciences, Flinders
University, GPO Box 2100, Adelaide, SA 5001, Australia
e-mail: Kevin.Wainwright@flinders.edu.au
S. F. Lincoln
School of Chemistry and Physics, University of Adelaide,
Adelaide, SA 5005, Australia
123

262
J Incl Phenom Macrocycl Chem (2010) 68:261–270
Fig. 1 a X-ray determined
structure of a four walled
receptor host–guest complex
where the guest is retained by
classical H-bonding alone [3].
b Presumed structure of a three
walled receptor host–guest
complex, with a guest capable
of water mediated O–HÁÁÁp
hydrogen bonding (for clarity,
shown for only one O–H group)
as well as classical H-bond
acceptance [6]
Water mediated O-H...π H-bonding
H
O
H
O
N
H
OH
O
O
O
H
H
O
O
-
H
O
O
O
H
O
H
H
O
O
H
H
O
O
O
Classical
H-bonding
O
O
H
H
O
O
Me
Cd2+
O
Cd2+
N
N
N
N
N
-
-
ClO4
ClO4
N
N
N
1
(b)
(a)
turned our attention towards immobilizing these receptor
complexes by covalently attaching them to silica gel.
Immobilisation in this way has been used in the past for
macrocyclic ligands designed to remove metal ions from
aqueous solution [8–13]. It allows isolation of the receptor
from the guest-containing solution without preventing
sequestration, even though in these circumstances it must
occur across a solid–liquid interface. In this paper we
report on the consequences for aromatic oxoanion uptake
from water of modifying and using our receptor complexes
in this way.
previously reported three-armed macrocycle, 2 [5], or a
hydroxy terminated polyether variant of it (3 or 4) as
shown in Scheme 1.
Characterisation of 5–7, following Soxhlet extraction of
the siliceous product with MeOH, to remove any residual,
adsorbed macrocycle, was performed qualitatively by both
13C solid state NMR spectroscopy and DRIFT (infrared)
spectroscopy. In both cases, signals associated with the
aromatic moieties, in particular, belonging to the macro-
cycle, were clearly evident indicating that covalent
attachment of the receptor ligand had occurred. The load-
ing of the receptor ligand on the silica was quantified by
microanalysis of the carbon and nitrogen content [8, 10],
and confirmed by thermal decomposition [20], as being
0.31, 0.17 and 0.10 mmol g-1 5% for 5–7, respectively.
A comparison of these loadings with the loading of the
3-(glycidoxy)propyl linker moiety on the silica, which was
The materials used for the investigation are those shown
as 8–10 in Scheme 1. Receptor complex 8 is an adaptation
of receptor complex 1, shown in Fig. 1b, and some of the
guest anion uptake levels obtained using it under aqueous
conditions will be discussed in terms of the solution
association constant values previously measured using 1,
which serves as a soluble model, in aqueous acetonitrile
[6]. Receptor complexes 9 and 10 are similar to 8, but
carry hydroxy terminated polyether (HTPE) chains at
their periphery. These were added to allow for an investi-
gation of their ability to improve anion uptake across
the solid–liquid interface by improving the contact between
the receptor complex and the aqueous phase [14–17],
compared to 8.
determined in the same way to be 1.1 3% mmol g-1
,
shows that the more bulky the receptor ligand becomes the
fewer the number of linker moieties that are accessible to
it. Loadings of receptor ligand 2 on two higher surface area
forms of silica, namely 230–400 mesh silica gel and MCM-
41, with the 3-(glycidoxy)propyl linker covalently attached
at loadings of 0.88 and 1.70 mmol g-1 3%, respec-
tively, were also investigated. In both cases these were
inferior, being 0.27 and 0.22 mmol g-1 5%, respec-
tively and consequently the following work was conducted
using the 70–230 mesh silica gel derived materials.
Results and discussion
For receptor ligands such as 5–7 to behave as receptors
they must first be activated by complexation with an eight-
coordinating metal ion [1]. This causes the receptor ligand to
develop a partially rigid three-dimensional structure in
which the binding pocket is formed from the juxtaposed
aromatic moieties on the coordinated pendant arms, as
shown in Fig. 1 and Scheme 1. Metal ion uptake was
investigated with the potentially eight-coordinating metal
Synthesis of the silica-attached receptor complexes
Synthesis of the silica-attached receptor complexes was
achieved using racemic 3-(glycidoxy)propyl-functionalised
silica gel (70–230 mesh), prepared according to an estab-
lished method [10, 18, 19], in conjunction with the
123

J Incl Phenom Macrocycl Chem (2010) 68:261–270
263
Scheme 1 Synthesis of the
silica-attached receptor
complexes 8–10
H
OH
H
RC6H4OCH2
CH2OC6H4R
O
N
N
N
N
OH
O
O
O
Si
+
O
H
Silica Surface
H
HO
CH2OC6H4R
2: R = H
3: R = (OCH2CH2)2OH
4: R = (OCH2CH2)3OH
toluene (2) or
acetonitilrile (3,4)
60o / 2 - 3 d
R
R
R
O
O
O
O
O
H
O
O
O
O
Si
H
H
H
O
O
N
N
5: R = H
N
N
Silica Surface
6: R = (OCH2CH2)2OH
7: R = (OCH2CH2)3OH
Cd(ClO4)2
pH 5
15 min
R
R
R
O
O
O
H
H
O
O
H
H
O
O
O
O
Si
O
O
Cd2+
N
N
N
N
-
Silica Surface
2ClO4
8: R = H
9: R = (OCH2CH2)2OH
10: R = (OCH2CH2)3OH
Aromatic oxoanion uptake studies
ions Cd(II), Pb(II) and Ca(II) as well as Cu(II) and Zn(II) by
suspending 100 mg of 5, 6 or 7 in 10 cm3 of an aqueous
solution 2 9 10-2 mol dm-3 in the appropriate metal
nitrate at pH 5 (HEPES), and then periodically measuring
the reduced concentration of the free metal ion by atomic
absorption spectroscopy. The results of this investigation
were similar for 5, 6 and 7 and are shown for 5 in Fig. 2.
There it can be seen that whilst the uptake of Ca(II) is
somewhat slower, 100% uptake of all the other metal ions is
complete in 1 h or less. Accordingly, receptor ligands 5–7
were loaded with Cd(II) by treatment with Cd(ClO4)2Á6H2O
to form the silica-attached receptor complexes 8–10 for use
in aromatic oxoanion binding studies.
Aromatic oxoanion uptake studies were conducted using the
collection of sodium benzoates and naphthoates listed in
Table 1. These were chosen since they were mostly known
from earlier studies of related, but non-silica attached
receptor complexes, to show good affinity in solution for this
class of receptor [1–6]. In each case 100 mg of receptor
complex material (\0.03 mmol of receptor complex) was
suspended in 10 cm3 of a 5 9 10-3 mol dm-3 aqueous
solution of the guest (0.05 mmol) at pH 7.00 (0.01 mol
dm-3 HEPES) and stirred for 1 h at 298 K. After filtering off
the expended receptor complex material the concentration of
123

264
J Incl Phenom Macrocycl Chem (2010) 68:261–270
complex, 1, with very high uptakes occurring for o-hy-
droxybenzoates where water mediated O–HÁÁÁp hydrogen
bonding could be expected to be most effective. Further
evidence for the existence of O–HÁÁÁp hydrogen bonding,
and its importance to the uptake process, can be seen from
the data for the Group B guests. Here the hydroxy group
has been replaced with a methoxy group to eliminate all
possibility of O–HÁÁÁp hydrogen bonding and not only is
there now a much lower level of uptake for the o-substi-
tuted compounds, but also the ordering of the uptake fol-
lows the decline in basicity of the guest, as expected if only
the classical hydrogen bonding retention mechanism is
operative. Interestingly for the p-methoxy and to a lesser
extent the m-methoxy benzoates there is an increase in
uptake compared to the corresponding hydroxy-guests.
This is probably a manifestation of the hydrophobic effect
[23], whereby the methoxy guests are excluded from the
aqueous phase and retreat into the pocket whilst the
hydrophilic hydroxy guests tend to be extracted from it by
the solvent. The uptake of the Group C guests (Table 1)
support the same dual retention mechanism: It can be seen
that as the number of o-OH groups (those in the 2 or
6-positions) increases the uptake goes up, whilst 3,4,5-tri-
hydroxybenzoate (gallate) has a lower uptake despite it
being more basic.
Fig. 2 Metal ion uptake by receptor 5 from metal(II) nitrate solutions
residual guest was determined by UV spectroscopy and the
uptake calculated as the percentage of the available receptor
complex sites filled, on the basis of there being one guest
molecule per receptor complex, as demonstrated in earlier
work through the construction of Job’s plots [6]. In cases
where the guest uptake exceeded 60% the 13C solid state
NMR spectrum of the thoroughly washed, expended receptor
complex displayed easily seen resonances attributable to
both the receptor complex and the guest, thus qualitatively
confirming the uptake and that the Cd(II) is not lost from the
receptor complex during the uptake process. A typical
montage is displayed as Fig. 3, the remainder are provided as
supplementary information.
The effect on the guest uptake level of attaching the
HTPE chains to the periphery of the receptor complex, to
improve its hydrophilicity, was investigated with the group
A guests using 9 and 10. It can be seen from the Table that
for the four guests examined there was no improvement in
their uptake. In fact the general pattern was one of
diminishment, with a clear deterioration as the length of
the HTPE chain increased. We interpret this as evidence
of the HTPE chain inserting itself into the binding pocket
of the receptor complex and hydrogen bonding to the O–H
groups at its base, thereby blocking access to it and
thwarting the objective of HTPE attachment.
The uptake of the series of hydroxybenzoates identified
as Group A in Table 1 has been of interest to us for some
time owing to the observation that in aqueous conditions,
with this class of receptor, the association constant
increases quite markedly as the hydroxy substituent moves
from the para- to the ortho-position [5, 6]. This was ini-
tially unexpected since the diminishing basicity of the
anions along this progression should diminish the strength
of the hydrogen bonding between the benzoate and the
hydroxy groups at the base of the binding pocket and
consequently lower the association constant. We have
explained this trend by suggesting that non-classical
hydrogen bonding of the O–HÁÁÁp type [22], shown in
Fig. 1b, increasingly comes into play as the O–H group(s)
on the benzoate moves closer to the carboxylate, and hence
deeper into the binding pocket, where interaction of the
O–H group(s) with the aromatic moieties that constitute the
pocket wall becomes geometrically possible, especially if
mediated by water (as seems likely since this phenomenon
is not seen in anhydrous solvents [6]). In the present study
we see that the uptake trend for these guests mirrors the
association constant trend seen with the model receptor
The Group D guests provide another opportunity to
examine a group some of which, the amines, can poten-
tially N–HÁÁÁp hydrogen bond to the cavity wall, compared
to a group that cannot, the nitro compounds. The group of
amines again show higher uptake when the amine is ortho
to the carboxylate, but the level of uptake is much less than
for the corresponding class A compound, consistent with
much weaker N–HÁÁÁp hydrogen bonding [22]. It is none-
theless interesting to note that the least basic amine still has
the highest uptake, supporting the presence of N–HÁÁÁp
hydrogen bonding, whereas the uptake trend for the nitro
compounds simply follows their basicity.
Amongst the Group E guests the 1- and 2-naphthoates
are particularly interesting since they have high and very
high uptakes, respectively. This again suggests that a sec-
ond type of retention force is operating that augments
123

J Incl Phenom Macrocycl Chem (2010) 68:261–270
265
Table 1 % Uptake ( 7%) by
Group
A
Benzoate or
naphthoate
% Uptake
by 8
% Uptake
by 9
% Uptake
by 10
Log(Kassoc/M-1) in 20%
D2O/CD3CN using 1a
pKba
receptors 8–10 of sodium
benzoates and naphthoates from
aqueous solution at pH 7.00
(HEPES) and 298 K
Benzoate
p-OH
30
32
48
50
81
95
60
55
29
23
82
94
73
22
12
43
16
23
12
43
33
38
19
76
98
3.1
3.2
3.5
4.19
4.54
4.30
4.04
2.97
1.05
4.47
4.09
3.90
3.44
2.95
1.68
4.41
2.38
3.07
2.14
3.44
3.46
2.47
4.37
4.14
3.98
3.77
3.60
4.17
50
45
31
30
m-OH
3,5-di-OH
o-OH
76
92
45
46
3.7
4.6
2,6-di-OH
p-OMe
B
C
D
m-OMe
o-OMe
2,6-di-OMe
2,5-di-OH
2,4,6-tri-OH
3,4,5-tri-OH
p-NH2
m-NH2
o-NH2
p-NO2
m-NO2
o-NO2
p-CH3
p-F
E
p-Cl
a
Data taken from [6]
p-CHO
b
pKa of the acid conjugate to
the benzoate or naphthoate, data
taken from [21]
1-naphthoate
2-naphthoate
OH
5
4
4
3
3
2
HO
OH
2
1
3, 4, 5
1
O
O
A
Anionic Guest
B
C
Receptor Complex
Receptor Host-Guest
Complex
Fig. 3 13C CPMAS NMR spectra for (top) sodium 2,4,6-trihydroxybenzoate (middle) receptor complex 8, and (bottom) receptor complex 8 with
94% loading of 2,4,6-trihydroxybenzoate
hydrogen bonding at the base of the cavity, since benzoate,
which has a similar basicity to 2-naphthoate but lacks the
second aromatic ring, shows less than one-third the level of
uptake. The high level of uptake for both naphthoates may
be due to an enhanced hydrophobic effect compared to
benzoate, but this should be more pronounced for
1-naphthoate, which on spatial grounds, as shown in Fig. 4,
should sit lower in the binding pocket than 2-naphthoate. It
is also possible a similar type of non-classical hydrogen
bonding interaction to that seen when O–HÁÁÁp hydrogen
123

266
J Incl Phenom Macrocycl Chem (2010) 68:261–270
O
H
O
H
H
H
H
H
H
H
H
H
C
C
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
O
O
H
O
O
O
H
O
H
H
H
H
H
O
O
Si
O
Si
O
O
O
Cd2+
Cd2+
N
N
N
N
N
N
N
N
-
Silica Surface
-
Silica Surface
ClO4
ClO4
Fig. 4 Representation of the possible hydrogen bonding interactions responsible for the high level of uptake of 1- (left) and 2-naphthoate (right)
bonding was first substantiated by X-ray crystallography
occurs [24], whereby a water molecule bridges between
two aromatic rings, engaging in O–HÁÁÁp hydrogen bonding
with each of them. This is suggested in Fig. 4, however, on
spatial grounds again this would appear to favour 1-naph-
thoate over 2-naphthoate where the additional aromatic
ring, compared to benzoate, is in closer proximity to the
walls of the pocket. It appears that whilst either or both of
these two factors must contribute significantly to the
binding strength of both naphthoates, since neither is likely
to favour 2-naphthoate it is ultimately the higher basicity of
2-naphthoate that is the determining factor responsible for
its higher uptake level.
NMR chemical shifts were referenced to the residual non-
deuterated solvent peak at d 7.26 for CDCl3. 13C CPMAS
NMR spectra were recorded on a Bruker 400 Avance
spectrometer at an operating frequency of 100.61 MHz
with TOSS (TOtal Suppression of Spinning Side-bands)
software in a 4 mm zirconium oxide rotor with a Kel-F
end-cap. The samples were spun at 5 kHz and a contact
time of 1 ms with a recycle delay time of 4 s. Chemical
shift values were referenced to external glycine. DRIFT
spectra were recorded using finely ground mixtures of the
compound and KBr held in aluminium sample cups on a
Nicolet Nexus 8700 FTIR Spectrophotometer fitted with a
Smart Collector DRIFT accessory. Optical rotations were
measured using a PolAAr polarimeter. Thermal combus-
tion determinations of receptor ligand loading levels on
silica gel were conducted in 15 cm3 crucibles at 1073 K in
a C muffle furnace (H. B. Selby and Co.).
Conclusion
We have demonstrated that it is possible to attach our metal
ion activated receptor complexes to silica in a manner that
retains their ability to sequester benzoates from aqueous
solution. In cases where the guest benzoate has two
hydroxy moieties both ortho to the carboxylate the uptake
level exceeds 90 or 80% if there is just one. For 2-naph-
thoate the impressively high level of sequestration, and
hence selectivity over most of the other guests examined,
of 98% was measured.
Synthesis of compounds 3 and 4
Ligands 3 and 4 were prepared by the procedure outlined in
Scheme 2. 4-Benzyloxyphenol, 11, and S-glycidyl tosylate,
16, were purchased from Sigma-Aldrich. Compounds 12
and 13 were prepared following the literature procedure
[25], as was 19 [26].
1-[2-(2-hydroxyethoxy)ethoxy]-4-
benzyloxybenzeneÁ0.5H2O, 14
Experimental
This compound was synthesised by a procedure modified
from Amabilino and co-workers [27]. A solution of
4-(benzyloxy)phenol, 11 (2.34 g, 11.70 mmol), dissolved
in anhydrous DMF (10 cm3) was added slowly over
10 min to a stirring suspension of finely ground anhydrous
K2CO3 (4.04 g, 29.30 mmol), in anhydrous DMF (5 cm3).
The mixture was stirred at 80 °C for 1 h in an atmosphere
of nitrogen. A solution of the tosylate 12 (3.10 g, 11.90
mmol), dissolved in dry DMF (10 cm3) was then added
dropwise and the mixture stirred for 4 days at 80 °C. The
mixture was diluted with water (200 cm3), and extracted
with CH2Cl2 (5 9 100 cm3). The CH2Cl2 extracts were
General
All reactions were performed under an atmosphere of
nitrogen. Solvents were pre-dried and purified using known
literature methods. Microanalyses and high resolution mass
spectra acquisition were carried out at the University of
Otago, New Zealand. H and 13C NMR solution spectra
1
were obtained using a Bruker Avance 400 MHz spec-
trometer. Referencing of the 13C NMR chemical shifts was
to the central resonance of the solvent multiplet: d 77.00
for CDCl3, 118.10 for CD3CN and d 49.00 for CD3OD. 1H
123

J Incl Phenom Macrocycl Chem (2010) 68:261–270
267
(2.6 g, 76%). 1H NMR (CDCl3): d 7.38–7.30 (5H, m,
Bn–H); 6.92–6.85 (4H, m, Ar–H); 5.01 (2H, s, Bn–CH2–);
4.10–3.84 (2H, m, –OCH2); 3.78–3.76 (2H, m, –OCH2);
3.76–3.66 (4H, m, –OCH2); 2.10 (1H, br s, –OH). 13C
NMR (CDCl3): 153.19 (1C, Ar, para); 152.94 (1C, Ar,
ipso); 137.18 (1C, Bn, ipso);128.48 (2C, Bn, meta); 127.83
(1C, Bn, para); 127.41 (2C, Bn, ortho); 115.80 (2C, Ar,
ortho); 115.59 (2C, Ar, meta); 72.52 (1C, –CH2–OAr);
70.60 (2C, –CH2–Bn); 69.72 (1C, –CH2–CH2–OAr); 68.03
(1C, –CH2–OAr); 61.71 (1C, –CH2–OH). (Found: C,
70.54; H, 7.56. C17H20O4Á0.5H2O requires C, 70.57; H,
7.32%).
+
Ts
O
PhCH2O
OH
OH
n
11
12: n = 2
13: n = 3
K2CO3
DMF
PhCH2O
O
OH
n
14: n = 2
15: n = 3
H2
Pd/C
OTs
1-[2-(2-(2-hydroxyethoxy)ethoxy)ethoxy]-4-
+
HO
O
OH
n
O
benzyloxybenzene, 15
16
17: n = 2
18: n = 3
NaH / DMF
Preparation of this compound was by a method analogous
to that used for the preparation of 14 from 4-(benzyl-
oxy)phenol, 11 (3.25 g, 16.23 mmol), K2CO3 (5.6 g,
40.60 mmol), and 13 (5.01 g, 16.45 mmol) (rf: 0.18), to
obtain 15 as an off-white oil which solidified overnight into
a white, waxy solid (4.6 g, 85%). 1H NMR (CDCl3): 7.44–
7.31 (5H, m, Bn–H); 6.92–6.84 (4H, m, Ar–H); 5.01 (2H, s,
Bn–CH2–); 4.10–4.07 (2H, m, –OCH2–); 3.86–3.82 (2H,
m, –OCH2–); 3.75–3.70 (6H, m, –OCH2–); 3.63–3.60 (2H,
m, –OCH2–); 2.52 (1H, br s, OH). 13C NMR (CDCl3): d
153.12 (1C, Ar, para); 153.01 (1C, Ar, ipso); 137.21 (1C,
Bn, ipso); 128.46 (2C, Bn, meta); 127.79 (1C, Bn, para);
127.39 (2C, Bn, ortho); 115.75 (2C, Ar, ortho); 115.57
(2C, Ar, meta); 72.43 (1C, –CH2–CH2OH); 70.72 (1C,
–CH2OCH2CH2OH; 70.59 (1C, –CH2–Bn); 70.32 (1C,
–CH2OCH2CH2OAr); 69.79 (1C, –CH2–CH2OAr); 67.97
(1C, –CH2–OAr, 61.69 (1C, –CH2–OH). (Found: C, 68.60;
H, 7.24. C19H24O5 requires C, 68.66; H, 7.28%).
HN NH
NH
OH
O
O
+
O
n
O
N
20: n = 2
21: n = 3
O
19
EtOH
H
RC6H4OCH2
H
OH
CH2OC6H4R
N
N
N
OH
O
N
O
H
HO
CH2OC6H4R
cyclohexene
10% Pd/C
22: R = (OCH2CH2)2OH
23: R = (OCH2CH2)3OH
H
RC6H4OCH2
H
OH
CH2OC6H4R
1-[2-(2-hydroxyethoxy)ethoxy]-4-hydroxybenzene, 17
N
N
N
OH
A solution of 14 (2.5 g, 8.67 mmol), dissolved in anhy-
drous DCM (25 cm3) was added to a suspension of Pd/C
(10%, 0.30 g), in anhydrous MeOH (25 cm3) and stirred at
ambient temperature under an atmosphere of H2 for 2 days.
The catalyst was removed by filtration through Celite. The
solvent was removed in vacuo to yield 17 as a brown oil in
HN
H
HO
CH2OC6H4R
3: R = (OCH2CH2)2OH
4: R = (OCH2CH2)3OH
1
quantitative yield. H NMR (CD3OD/CDCl3): 6.68–6.61
Scheme 2 Synthesis of receptor ligands 3 and 4
(4H, m, Ar–H); 4.06 (2H, br s, 2 x –OH); 3.95–3.93 (2H,
m, –OCH2); 3.70–3.67 (2H, m, –OCH2); 3.62–3.59 (2H, m
–OCH2); 3.53–3.50 (2H, m, –OCH2). 13C NMR (CD3OD/
CDCl3): 151.42 (1C, Ar, para); 150.56 (1C, Ar, ipso);
115.32 (2C, Ar, meta); 115.31 (2C, Ar, ortho); 72.10 (1C,
–CH2–CH2OH); 69.12 (1C, –CH2–CH2OAr); 68.11 (1C,
–CH2–OAr); 61.08 (1C, –CH2–OH); (m/z) HRMS (ESI?):
calculated 221.0784 for C10H14NaO4 (M ? Na)?, found
221.0774.
combined and washed with 1 mol dm-3 KHSO4 (3 9
100 cm3), brine (3 9 100 cm3), and water (3 9 100 cm3),
and then dried over MgSO4. The solvent was removed in
vacuo to yield a brown oil which was purified by column
chromatography on silica (eluent 40% EtOAc/DCM, rf:
0.35), and concentrated in vacuo to obtain 14 as an off-
white oil that solidified overnight into a white waxy solid
123

268
J Incl Phenom Macrocycl Chem (2010) 68:261–270
1-[2-(2-(2-hydroxyethoxy)ethoxy)ethoxy]-4-
43.5 mmol), and 16 (3.97 g, 17.39 mmol), to yield 21 as a
pale yellow oil (3.71 g, 74%), rf: 0.21. 1H NMR (CDCl3): d
6.82 (4H, s, Ar–H); 4.14 (1H, dd, J = 3.2, 11.04 Hz,
–CH2OAr); 4.05 (2H, m, –OCH2–); 3.86 (1H, dd, J = 5.7,
11.04 Hz, –CH2OAr); 3.81 (2H, m, –OCH2–); 3.71–3.64
(6H, m, –OCH2–); 3.58 (2H, m, –OCH2–); 3.30 (1H, m,
–CHO–); 2.87 (1H, t, J = 4.48 Hz, –HCH–O–); 2.71 (1H,
hydroxybenzene, 18
Deprotection of this compound was analogous to the prep-
aration of 17 using 15 (3.6 g, 10.83 mmol), and Pd/C (10%,
0.40 g), to obtain 18 as a brown oil in quantitative yield. 1H
NMR (CD3OD/CDCl3): 6.70–6.64 (4H, m, Ar–H); 4.68
(2H, br s, 2x –OH); 3.95–3.93 (2H, m, –OCH2–); 3.75–3.72
(2H, m, –OCH2–); 3.69–3.64 (4H, m, –OCH2–); 3.62–3.60
(2H, m, –OCH2–); 3.55 (2H, m, –OCH2–) 13C NMR
(CD3OD/CDCl3): 152.37 (1C, Ar, para); 150.14 (1C, Ar,
ipso); 116.07 (2C, Ar meta); 115.66 (2C, Ar, ortho); 72.50
(1C, –CH2–CH2OH); 70.73 (1C, –CH2–OCH2CH2OH);
70.21 (1C, –CH2–CH2CH2OAr; 69.88 (1C, CH2–CH2OAr;
67.85 (1C, –CH2–OAr; 61.68 (1C, –CH2–OH); (m/z) HRMS
(ESI?): calculated 265.1052 for C12H18NaO5 (M ? Na)?,
found 265.1059.
dd, J = 2.68, 4.91 Hz, –HCHO–); 2.15 (1H, br s, OH). 13
C
NMR (CDCl3): d 153.15 (1C, Ar); 152.75 (1C, Ar); 115.53
(2C, Ar); 115.48 (2C, Ar); 72.39 (1C); 70.66 (1C); 70.24
(1C); 69.71 (1C); 69.35 (1C); 67.87 (1C); 61.61 (1C);
50.14 (1C, epoxide); 44.56 (1C, epoxide). [a]2D5 = ? 2.35°
(c 2.13, MeOH); (m/z) HRMS (ESI?): calculated 321.1314
for C15H22NaO6 (M ? Na)?, found 321.1309.
1-(benzyloxycarbonyl)-4,7,10-tris(2S)-2-hydroxy-3-[4-
(2-(2-hydroxyethoxy)ethoxy)phenoxypropyl]-1,4,7,10-
tetraazacyclododecane, 22
(2S)-(?)-3-(phenoxy-4-[2-(2-hydroxyethoxy)ethoxy]-
1,2-epoxypropane, 20
Synthesis of this compound was by a method analogous to
that used for the preparation of the HTPE free variant, [5]
using 1-benzyloxycarbonyl)-1,4,7,10-tetraazacyclodode-
cane, 19 (415 mg, 1.35 mmol) and 20 (1.04 g, 4.08 mmol),
to give 22 as a thick brown oil (1.44 g, quantitative). 13C
NMR (CDCl3): d 156.26 (1C, C=O); 152.95 (3C, Ph);
152.77 (3C, Ph); 136.54 (1C, Bn, ipso); 128.29 (1C, Bn);
127.80 (1C, Bn); 127.77 (1C, Bn); 127.70 (2C, Bn); 115.40
(6C, Ph); 115.33 (6C, Ph); 72.46 (3C); 71.23 (1C); 70.42
(1C); 70.30 (1C); 69.47 (3C); 67.86 (3C); 66.93 (2C);
66.72 (1C); 65.98 (1C); 61.28 (3C); 59.15 (3C); 52.76 (2C,
cyclen); 50.05(2C, cyclen); 47.50 (2C, cyclen); 44.43 (2C,
cyclen); (m/z) HRMS (ESI?): calculated 1069.5591 for
C55H81N4O17 (M ? H)?, found 1069.5568.
A solution of 17 (2.00 g, 10.1 mmol), was added slowly over
20 min to a stirring suspension of anhydrous K2CO3 (3.5 g,
25.3 mmol), in anhydrous DMF (10 cm3). The mixture was
stirred at 50 °C for 2 h. (2S)-(?)-glycidyl tosylate, 16
(2.30 g, 10.0 mmol), dissolved in anhydrous DMF (10 cm3)
was then added dropwise and the mixture was stirred at
50 °C for 4 days. The reaction was quenched with saturated
NH4Cl (10 cm3) and then diluted with water (200 cm3). The
product was extracted with CH2Cl2 (4 9 150 cm3). The
organic extracts were combined and then washed with brine
(2 9 100 cm3) and water (1 9 100 cm3), concentrated in
vacuo and purified by column chromatography on silica
(eluent 40% EtOAc/DCM, rf: 0.20). The pure product was
concentrated in vacuo to yield 20 (1.73 g, 68%) as a pale
yellow oil. 1H NMR (CDCl3): d 6.81 (4H, s, Ar–H); 4.13 (1H,
dd, J = 3.0, 11.5 Hz, –CH2OAr); 4.03 (2H, m, –OCH2–);
3.84 (1H, dd, J = 5.7, 11.5 Hz, –CH2OAr); 3.78 (2H, m,
–OCH2–); 3.70 (2H, br s, –OCH2–); 3.61 (2H, m, –OCH2–);
3.29 (1H, m, –CHO–); 2.90 (1H, br s, –OH); 2.85 (1H, t,
J = 4.5 Hz, –HCHO–); 2.70 (1H, dd, J = 2.7, 4.8 –HCHO–
). 13C NMR (CDCl3): d 153.04 (1C); 152.75 (1C); 115.52
(2C); 115.47 (2C); 72.48 (1C); 69.55 (1C); 69.29 (1C); 67.87
(1C); 61.53 (1C); 50.09 (1C, epoxide); 44.48 (1C, epoxide).
[a]2D5 = ? 4.21° (c 2.19, MeOH); (m/z) HRMS (ESI?):
calculated 277.1052 for C13H18NaO5 (M ? Na)?, found
277.1049.
1-(benzyloxycarbonyl)-4,7,10-tris(2S)-2-hydroxy-3-[4-
(2-(2-(2-hydroxyethoxy)-ethoxy)ethoxy)
phenoxypropyl]-1,4,7,10-tetraazacyclododecane, 23
Synthesis of this compound was by a method analogous to
that used for the preparation of 22 using 19 (503 mg,
1.64 mmol), and 21 (1.50 g, 4.94 mmol), to give 23 as a
thick brown oil (1.93 g, quantitative). 13C NMR (CDCl3): d
156.18 (1C, C=O); 152.89 (3C, Ph); 152.74 (3C, Ph);
136.49 (1C, Bn, ipso); 128.26 (1C, Bn); 127.75 (4C, Bn);
115.37 (6C, Ph); 115.27 (6C, Ph); 72.34 (3C); 70.47 (3C);
70.31 (1C); 70.03 (3C); 69.53 (3C); 67.76 (3C); 66.91
(2C); 66.80 (1C) 66.02 (3C); 61.33 (3C); 59.08 (2C); 58.00
(1C); 53.61 (2C, cyclen); 52.68 (2C, cyclen); 50.61 (2C,
cyclen); 47.47 (2C, cyclen); (m/z) HRMS (ESI?): calcu-
lated 1201.6378 for C61H93N4O20 (M ? H)?, found
1201.6383.
(2S)-(?)-3-(phenoxy-4-[2-(2-(2-
hydroxyethoxy)ethoxy)ethoxy]-1,2-epoxypropane, 21
The preparation of this compound was by the same method
as for 20 using 18 (4.21 g, 17.40 mmol), K2CO3 (6.01 g,
123

J Incl Phenom Macrocycl Chem (2010) 68:261–270
269
2875 cm-1; m(C=C) 1602 cm-1, 1497 cm-1; d(Ar–H) 752
1,4,7-tris(2S)-2-hydroxy-3-[4-(2-(2-
hydroxyethoxy)ethoxy)phenoxypropyl]-1,4,7,10-
tetraazacyclododecane, 3
cm-1, 690 cm-1
.
Receptor complex 6
Synthesis of this compound was by a method analogous to
that used for the preparation of 2 [5], using 22 (396 mg,
0.37 mmol), and, cyclohexene (158 mg, 1.92 mmol), to
give 3 as a thick brown oil (345 mg, quantitative). 13C
NMR (CD3CN): d 153.35 (3C, Ph); 153.19 (3C, Ph);
115.85 (12C); 72.93 (3C); 71.67 (1C); 71.13 (2C); 69.92
(3C); 68.30 (3C); 67.11 (3C); 61.66 (3C); 59.10 (3C);
52.50 (2C, cyclen); 51.80 (2C, cyclen); 50.20 (2C, cyclen);
44.20 (2C, cyclen); (m/z) HRMS (ESI?): calculated
935.5223 for C47H75N4O15 (M ? H)?, found 935.5187.
To a stirred suspension of racemic 3-(glycidoxy)propyl-
functionalised silica gel (70–230 mesh) (2.0 g, 1.1 mmol
g-1) in dry acetonitrile (30 cm3) a solution of 3 (6.2 g,
6.6 mmol) dissolved in dry acetonitrile (5 cm3) was added
and the mixture was stirred at 60 °C for 3 days. The sus-
pension was filtered, washed with dry acetonitrile and sub-
jected to soxhlet extraction with MeOH for 4 h to obtain 6 as
a light brown powder. Found: C, 14.89; H, 2.47; N, 0.93%
corresponding to a loading of 0.17 mmol g-1 13C NMR
.
(CPMAS): d157.5 (3C), 128.0–107.5br (15C), 77.5–55.0, br
(33C), 26.9 (1C), 12.5 (1C). IR (KBr, DRIFT): m(C–H)
1,4,7-tris(2S)-2-hydroxy-3-[4-(2-(2-(2-
hydroxyethoxy)ethoxy)-ethoxy)phenoxypropyl]-
1,4,7,10-tetraazacyclododecane, 4
2981 cm-1, 2888 cm-1; m(C=C) 1509 cm-1, 1458 cm-1
;
m
(Si–O–Si) 955 cm-1, d(Ar–H) 794 cm-1
.
Synthesis of this compound was by a method analogous to
that used for the preparation of 3 using 23 (457 mg,
0.39 mmol), and, cyclohexene (183 mg, 2.22 mmol), to
give 4 as a thick brown oil (415 mg, quantitative). 13C
NMR (CD3CN): d 153.15 (1C, Ph); 153.09 (1C, Ph);
153.05 (1C, Ph); 152.98 (1C, Ph); 152.91 (1C, Ph); 152.85
(1C, Ph); 115.63 (2C, Ph); 115.59 (4C, Ph); 115.48 (6C,
Ph); 72.54 (2C); 72.51 (1C); 70.72 (2C); 70.70 (1C); 69.78
(3C); 67.96 (3C) 61.56 (2C); 61.50 (3C); 71.27 (2C); 70.27
(1C); 69.66 (2C); 69.42 (1C); 59.00 (2C); 58.45 (1C);
50.10 (4C, cyclen); 44.05 (4C, cyclen).
Receptor complex 7
Thiswaspreparedbythesamemethodasusedfor, 6, but using
racemic 3-(glycidoxy)propyl-functionalised silica gel
(70–230 mesh) (2.0 g, 1.1 mmol g-1) and 4 (7.04 g,
6.6 mmol). Found: C, 11.85; H, 2.25; 0.54% N corresponding
to a loading of 0.10 mmol g-1 13
(3C), 128.0–108 0.5 br (15C), 76.0–54.5, br (39C), 27.5 (1C),
12.5 (1C). IR (KBr, DRIFT): m(C–H) 2981 cm-1, 2888 cm-1
m(C=C) 1508 cm-1, 1457 cm-1; m(Si–O–Si) 953 cm-1, d(Ar–H)
796 cm-1
. C NMR (CPMAS): d 157.5
;
.
Acknowledgement We are grateful to the Australian Research
Council for the support of this work.
Synthesis of receptor complex materials
Racemic 3-(glycidoxy)propyl-functionalised silica gel (70–
230 mesh) was prepared by a literature procedure [19], as
was 1,4,7-tris((2S)-2-hydroxy-3-phenoxypropyl)-1,4,7,10-
tetraazacyclododecane, 2 [5].
References
1. Smith, C.B., Wallwork, K.S., Weeks, J.M., Buntine, M.A., Lin-
coln, S.F., Taylor, M.R., Wainwright, K.P.: Metal ion dependent
molecular inclusion chemistry: inclusion of p-toluenesulfonate
and p-nitrophenolate within the structure of coordinated 1,4,7,
10-tetrakis((S)-2-hydroxy-3-phenoxypropyl)-1,4,7,10-tetraazacy-
clododecane. Inorg. Chem. 38, 4986–4992 (1999)
2. Wainwright, K.P.: Applications for polyaza macrocycles with
nitrogen-attached pendant arms. Adv. Inorg. Chem. 52, 293–334
(2001)
3. Smith, C.B., Stephens, A.K.W., Wallwork, K.S., Lincoln, S.F.,
Taylor, M.R., Wainwright, K.P.: Metal ion-dependent molecular
inclusion chemistry: inclusion of aromatic anions by coordinated
1,4,7,10-tetrakis((S)-2-hydroxy-3-phenoxypropyl)-1,4,7,10-tetra-
azacyclododecane. Inorg. Chem. 41, 1093–1100 (2002)
4. Robinson, T.S., Wyness, O., Lincoln, S.F., Taylor, M.R., Tiekink,
E.R.T., Wainwright, K.P.: A structural study of the synergic
envelopment of acetonitrile by a Cd(II) activated molecular
receptor formed from cyclen with appended 2-hydroxy-3-phen-
ylpropyl moieties. Inorg. Chim. Acta 359, 1413–1420 (2006)
Receptor complex 5
To a stirred suspension of racemic 3-(glycidoxy)propyl-
functionalised silica gel (70–230 mesh) (1.5 g, 1.1 mmol
GPS g-1 material) in dry toluene (40 cm3) a solution of 2
(2.57 g, 4.13 mmol) dissolved in dry toluene (10 cm3) was
added and the mixture was stirred at 60 °C for 2 days. The
suspension was filtered, washed with dry toluene and
subjected to soxhlet extraction with MeOH for 4 h to
obtain 5 as a light brown powder. Residual 2 was recovered
by evaporating the washing and soxhlet solvents. Found: C,
18.09; H, 2.67; N, 1.75% corresponding to a loading of
0.31 mmol g-1
(6C), 120.0 (3C), 114.8 (6C), 72.5–51.1, br (21C), 23.2
(1C), 8.8 (1C). IR (KBr, DRIFT): m(C–H) 2942 cm-1
.
13C NMR (CPMAS): d 159.7 (3C), 129.4
,
123

270
J Incl Phenom Macrocycl Chem (2010) 68:261–270
5. Bradbury, A.J., Lincoln, S.F., Wainwright, K.P.: Fluorescent
use with microstamped substrates in neuronal cell culture. Bio-
materials 22, 1035–1047 (2001)
17. Wang, R., Zhang, Y., Ma, G., Su, Z.: Modification of
poly(glycidyl methacrylate-divinylbenzene) porous microspheres
with polyethylene glycol and their adsorption property of protein.
Colloids Surf. B Biointerfaces 51, 93–99 (2006)
18. Bagnoud, M.A., Haerdi, W., Veuthey, J.L.: Outer-sphere ligand-
exchange chromatography with copper-loaded macrocyclic-bon-
ded silica column. Chromatographia 29, 495–499 (1990)
19. Subba Rao, Y.V., De Vos, D.E., Bein, T., Jacobs, P.A.: Practical
heterogenisation of an active manganese triazacyclononane
epoxidation catalyst via surface glycidylation. Chem. Commun.
355–356 (1997)
20. Mahmoud, M.E., El-Essawi, M.M., Kholeif, S.A., Fathalla,
E.M.I.: Aspects of surface modification, structure characteriza-
tion, thermal stability and metal selectivity properties of silica gel
phases-immobilized-amine derivatives. Anal. Chim. Acta 525,
123–132 (2004)
signaling provides deeper insight into aromatic anion uptake
by metal-ion activated molecular receptors. New J. Chem. 32,
1500–1508 (2008)
6. Hodyl, J.A.Z., Lincoln, S.F., Wainwright, K.P.: Solvent induced
selectivity switching in aromatic-anion binding molecular recep-
tors. J. Incl. Phenom. Macrocycl. Chem. (2010). doi:10.1007/
s10847-009-9725-4
7. Kadidae, L. O., Lincoln, S. F., Wainwright, K. P.: Unpublished work
8. Dudler, V., Lindoy, L.F., Sallin, D., Schlaepfer, C.W.: An oxy-
gen-nitrogen donor macrocycle immobilized on silica gel. A
reagent showing high selectivity for Copper(II) in the presence of
Cobalt(II), Nickel(II), Zinc(II) or Cadmium(II). Aust. J. Chem.
40, 1557–1563 (1987)
9. Bradshaw, J.S., Bruening, R.L., Krakowiak, K.E., Tarbet, B.J.,
Bruening, M.L., Izatt, R.M., Christensen, J.J.: Preparation of
silica gel-bound macrocycles and their cation-binding properties.
J. Chem. Soc. Chem. Commun. 812–814 (1988)
`
10. Gros, C., Rabiet, F., Denat, F., Brandes, S., Chollet, H., Guilard
21. Howard, P., Meylan, W.: Physical Properties Database. Syracuse
Research Corporation, Environmental Science Center, North
Syracuse, NY (1999)
22. Desiraju, G.R., Steiner, T.: The Weak Hydrogen Bond in Struc-
tural Chemistry and Biology. Oxford University Press, New York
(1999)
23. Lindoy, L.F., Atkinson I.M.: Self-assembly in Supramolecular
Systems, p. 17. Royal Society of Chemistry, Cambridge (2000)
24. Atwood, J.L., Hamada, F., Robinson, K.D., Orr, G.W., Vincent,
R.L.: X-ray diffraction evidence for aromatic p hydrogen bonding
to water. Nature 349, 683–684 (1991)
25. Van Ameijde, J., Liskamp, R.M.J.: Synthesis of novel trivalent
amino acid glycoconjugates based on the cyclotriveratrylene
(CTV) scaffold. Org. Biomol. Chem. 1, 2661–2669 (2003)
26. Yoo, J., Reichert, D. E., Welch, M. J.: Regioselective N-substi-
tution of cyclen with two different alkyl groups: synthesis of all
possible isomers. Chem. Commun. 766-767 (2003)
R.: New silica-gel-bound polyazacycloalkanes and characteriza-
tion of their copper(II) complexes using electron spin resonance
spectroscopy. J. Chem. Soc. Dalton Trans. 1209–1214 (1996)
`
11. Dubois, G., Tripier, R., Brandes, S., Denat, F., Guilard, R.:
Cyclam complexes containing silica gels for dioxygen adsorp-
tion. J. Mater. Chem. 12, 2255–2261 (2002)
12. Barbette, F., Rascalou, F., Chollet, H., Babouhot, J.L., Denat, F.,
Guilard, R.: Extraction of uranyl ions from aqueous solutions
using silica-gel-bound macrocycles for alpha contaminated waste
water treatment. Anal. Chim. Acta 502, 179–187 (2004)
13. Jal, P.K., Patel, S., Mishra, B.K.: Chemical modification of silica
surface by immobilization of functional groups for extractive
concentration of metal ions. Talanta 62, 1005–1028 (2004)
14. Harris, J.M., Struck, E.C., Case, M.G., Paley, M.S., Yalpini, M.,
Van Alstine, J.M., Brooks, D.E.: Synthesis and characterization of
poly(ethylene glycol) derivatives. J. Polym. Sci. A 22, 341–352
(1984)
´
27. Amabilino, D.B., Anelli, P., Ashton, P.R., Brown, G.R., Cordova,
15. Suggs, L.J., Shive, M.S., Garcia, C.A., Anderson, J.M., Mikos,
A.G.: In vitro cytotoxicity and in vivo biocompatibility of
poly(propylene fumarate-co-ethylene glycol) hydrogels. J. Biomed.
Mater. Res. 46, 22–32 (1999)
16. Branch, D.W., Wheeler, B.C., Brewer, G.J., Leckband, D.E.:
Long-term stability of grafted polyethylene glycol surfaces for
E., Godinez, L.A., Hayes, W., Kaifer, A.E., Philp, D., Slawin,
A.M.Z., Spencer, N., Stoddart, J.F., Tolley, M.S., Williams, D.J.:
Molecular Meccano. 3. Constitutional and translational isomer-
ism in [2]Catenanes and [n]Pseudorotaxanes. J. Am. Chem. Soc.
117, 11142–11170 (1995)
123