Macrocyclic ligand design. A synthetic, solvent extraction, computational and NMR study of the effect of cryptand flexibility on sodium ion affinity

Article abstract of DOI:10.1039/b102585f

The rigidity of a series of cryptands incorporating an N₂O₆-donor has been shown to have a marked effect on the ability of such species to complex sodium ions. X-Ray and associated computational investigations, including molecular mechanics, semi-empirical (AM1) and ab initio (density functional) studies, coupled with the results of sodium picrate extraction experiments and NMR studies, have been employed to probe the conformational aspects influencing sodium ion complexation along the ligand series. It is concluded that the ease with which a cryptand is able to adopt an endo-endo conformation is an important factor affecting the occurrence of inclusive metal-ion binding in these systems.

Full text of DOI:10.1039/b102585f

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Macrocyclic ligand design. A synthetic, solvent extraction,
computational and NMR study of the effect of cryptand flexibility
on sodium ion affinity†
Kenneth R. Adam,a Ian M. Atkinson,a Jeong Kim,b,c Leonard F. Lindoy,*b Owen A. Matthews,a
George V. Meehan,a Fiona Raciti,a Brian W. Skelton,d Niels Svenstrupa and Allan H. Whited
a School of Biomedical and Molecular Science, James Cook University, Townsville, Qld. 4811,
Australia
b Centre for Heavy Metals Research, School of Chemistry, The University of Sydney, F11,
N.S.W. 2006, Australia. E-mail: lindoy@chem.usyd.edu.au
c Department of Chemistry, Seonam University, Namwon, 590–711, Korea
d Department of Chemistry, The University of Western Australia, Nedlands, W.A. 6009,
Australia
Received 20th March 2001, Accepted 22nd June 2001
First published as an Advance Article on the web 2nd August 2001
The rigidity of a series of cryptands incorporating an N2O6-donor has been shown to have a marked effect on the
ability of such species to complex sodium ions. X-Ray and associated computational investigations, including
molecular mechanics, semi-empirical (AM1) and ab initio (density functional) studies, coupled with the results of
sodium picrate extraction experiments and NMR studies, have been employed to probe the conformational aspects
influencing sodium ion complexation along the ligand series. It is concluded that the ease with which a cryptand is
able to adopt an endo–endo conformation is an important factor affecting the occurrence of inclusive metal-ion
binding in these systems.
(which lowers the energy barrier to complexation and decom-
Introduction
plexation) and rigidity (which confers selectivity, but can result
in inhibition of the ingress of a metal ion into the cavity).12 The
balance between rigidity and flexibility and its effect on the
complexation behaviour of cryptands is a central theme of the
work now presented. For this purpose, and as part of on-going
research aimed at developing and understanding new systems
for metal ion recognition,13 we have investigated the Naϩ com-
plexation behaviour of the cryptands 2–4 incorporating a grad-
ation in steric rigidity (and perhaps cavity size—see later) and
compared their behaviour with the flexible system 1; 2.2.2.9,10
Polyether cryptands were among the first fully synthetic
supramolecular host molecules to be synthesised and their
metal complexation behaviour has been studied in considerable
detail, with applications in catalysis, separations and in chem-
ical sensors being reported.1–3 A large number of such cryp-
tands have now been prepared4 and characteristically they
exhibit affinities for ‘hard’ metal ions such as the alkali and
alkaline earths; the latter ions bind via electrostatic interaction
with the dipolar ether functions, replacing solvent molecules
from the co-ordination sphere of the metal. Relative to their
single-ring analogues, bicyclic cryptands usually exhibit higher
formation constants for metal binding that can involve both
favourable entropy and/or enthalpy terms—depending on the
system—a phenomenon known as the Cryptate Effect.5–8
Cryptands, along with their two dimensional analogues, the
crown ethers, were the first cyclic ligands shown to be capable
of discriminating between ions from each of the above groups.
For example, the ‘classical’ cryptand 1 (2.2.2) has long been
known to bind potassium ions selectively in the presence of
other alkali metal ions.5,9,10 Such selectivity is characteristic of
many cryptands and largely depends on the number (and type)
of donor atoms present, as well as on the spatial and electronic
complementarity of the cryptand’s cavity for the metal ion
involved. The incorporation of rigidity in such systems, in the
form of fused benzo substituents, has been demonstrated to
enhance metal ion selectivity in particular cases by introducing
an element of preorganisation through restricting the possible
conformations that can be adopted. In this manner, better
complementarity between cavity and metal may be achieved.11
Nevertheless, to achieve optimal binding properties, it is
important to obtain just the right balance between flexibility
Results and discussion
Cryptand 1 (2.2.2) and cryptands 2–4 each share a common
N2O6 donor set, with the final member, 4, having a total of six
rigid benzo groups as part of its framework; in theory, the
nitrogen atoms in cryptands such as these can have their lone
1
† Electronic supplementary information (ESI) available: tables of H
and 13C NMR induced chemical shifts. See http://www.rsc.org/
suppdata/dt/b1/b102585f/
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J. Chem. Soc., Dalton Trans., 2001, 2388–2397
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102585f

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pairs pointing either in or out of the cavity, leading to possible
endo–endo, exo–exo isomerism (or even endo–exo isomerism).14
By analogy with the published behaviour of 1 (2.2.2) and
related all-aliphatic derivatives,5 it was anticipated that 2–4
might show a gradation in binding affinities for an alkali metal
(such as sodium). In turn, this would allow a systematic evalu-
ation of steric influences (and, in particular, increasing steric
rigidity) on complexation behaviour—while noting that there is
also a gradation in the hardness of the oxygen donors along the
series, as aromatic–aliphatic ethers replace all-aliphatic ones.
Further, it is expected that there will be a gradation in ligand
solvation energy along the ligand series as bulky benzo sub-
stituents are replaced by aliphatic moieties. Ligand desolvation
terms have been demonstrated to play a significant role in influ-
encing the relative free energies of complex formation for a
number of related azacrown ligand series.15
dialdehyde 5 (R = t-Bu) in two steps using standard functional
group interconversions; namely, borohydride reduction of the
dialdehyde 5 (R = t-Bu) to give the corresponding dialcohol in
96 percent yield. This was then converted to the dichloro deriv-
ative 8 (R = t-Bu) in 98 percent yield by treatment with thionyl
chloride in refluxing dichloromethane. The synthesis of 4
(R = t-Bu) involved dissolving the dichloro derivative 8 (R =
t-Bu) and 7 (R = t-Bu) in a 1 : 1 mixture of toluene and
acetonitrile and adding this solution dropwise over one hour to
a suspension of caesium carbonate in the same mixed solvent
at 40 ЊC. The reaction mixture was then heated under reflux for
72 hours to give 4 (R = t-Bu) in 85 percent yield.
The first of the cryptands of intermediate geometry, 2 (R = H
or t-Bu), were synthesised by bis-alkylation of commercially
available 1,10-diaza-18-crown-6 using the appropriately substi-
tuted dichloride of type 8 (R = H or t-Bu) in the presence of
sodium or caesium carbonate in acetonitrile. The products were
obtained in yields of 11 and 65 percent, respectively, after a
somewhat tedious purification procedure in each case (see
Experimental section).
In an alternative synthesis of 2 (R = t-Bu), paralleling a
procedure reported by Bradshaw et al.19 for the synthesis of
a related cryptand, the final ligand ‘strap’ was constructed by
bis-alkylation of ethylene glycol ditosylate with the required
bis(N,N Ј-methylenephenolate) derivative of 1,10-diaza-18-
crown-6. For this purpose N,NЈ-bis(4-tert-butylphenyl-2-yl-
methyl)diaza-18-crown-6 was prepared by means of a Mannich
reaction between 1,10-diaza-18-crown-6, 4-tert-butylphenol
and paraformaldehyde.20 This product was then converted to
the disodium salt by treatment with sodium ethoxide in
tetrahydrofuran/ethanol. Reaction with ethylene glycol ditosyl-
ate then yielded 2 (R = t-Bu) in 82 percent yield. Although this
two-reaction sequence gave 2 (R = t-Bu) in slightly lower overall
yield based on the precursor macrocycle than the one-step
procedure described above (59 percent overall compared to 65
percent for the previous case), the two-step route proved more
convenient since it produced a more readily purified crude
product than obtained from the first procedure.
The synthesis of 3 (R = H) involved bis-alkylation of the
N2O4-macrocycle 7 (R = H) using triethylene glycol ditosylate
under basic conditions. However, an initial attempt using
sodium carbonate as base led instead to the isolation of a spiro-
derivative of 7 in which dialkylation (that is, quaternisation)
had occurred at a single ring nitrogen. It is postulated that
complexation of sodium ion may have inhibited the triethylene
glycol moiety from spanning the co-ordination cavity and
alkylating the second nitrogen atom in this case. In order to
circumvent this possibility, triethylamine was employed as the
base. The subsequent synthesis then gave the desired product, 3
(R = H), in 28 percent yield.
In a prior investigation,16 we reported the preparation and
characterisation (including an X-ray structure and a prelimin-
ary computational study) of the free cage 4 (R = H). The struc-
ture showed that the bridgehead nitrogen lone pairs are orien-
tated exo, with the benzylic methylene groups directed into the
cage. In this configuration, a very restricted volume remains for
inclusion of a guest in the cavity. The preference of this cage
for an exo–exo arrangement was postulated to reflect steric
influences associated with the partial-rigidity and bulkiness
of the benzylic linkages present (the bridgehead essentially
corresponds to a substituted tribenzylamine).
Cage synthesis
The synthesis of 4 (R = H), as reported previously,16 involves
the 1 : 1 Schiff base condensation of dialdehyde 5 (R = H)
and related diamine precursor 6 (R = H) followed by in situ
sodium borohydride reduction of the intermediate diimine to
yield the corresponding diaza macrocycle 7 (R = H). Double
N-alkylation of this species with 2,2Ј-(ethylenedioxy)bis-
(benzyl chloride) 8 (R = H) in dry acetonitrile in the presence
of sodium or caesium carbonate gave 4 (R = H) in 42 per-
cent yield. Overall, the strategy employed is generally similar to
that used previously by Bradshaw et al.17 for other cryptand
syntheses.
Two alternative synthetic routes to 3 (R = t-Bu) were
developed. The first followed that just described and involved
reaction of the macrocyclic diamine 7 (R = t-Bu) with triethyl-
ene glycol ditosylate, caesium carbonate and tetrabutylam-
monium bromide in refluxing toluene/acetonitrile (1 : 1). After
purification, 3 (R = t-Bu) was isolated in 35 percent yield. The
second procedure involved the initial synthesis of the diaza-
crown 9 (R = t-Bu) using essentially the same methodology as
employed for 7 (R = t-Bu); see Experimental section. Double
n-alkylation of this crown with the dichloride 8 (R = t-Bu)
in acetonitrile containing a suspension of caesium carbonate
yielded 3 (R = t-Bu) in 70 percent yield after purification.
In the present study the preparation of the more lipophilic
cryptand 4 (R = t-Bu) followed that used for 4 (R = H),16 except
that the dialdehyde precursor was the tert-butyl derivative 1,2-
bis(4-tert-butyl-2-formylphenoxy)ethane, 5 (R = t-Bu).18 The
required diamine 6 (R = t-Bu) was obtained in two steps from
the dialdehyde 5 (R = t-Bu); treatment of the latter with
hydroxylamine in refluxing ethanol produced the correspond-
ing dioxime which was then reduced to 6 (R = t-Bu) in 77
percent yield using lithium aluminium hydride in refluxing
tetrahydrofuran. As before, condensation of the dialdehyde
and diamine, followed by sodium borohydride reduction, pro-
duced macrocycle 7 (R = t-Bu). The dichloro derivative 8 (R =
t-Bu) required for cage formation was also prepared from the
Variable temperature NMR study
In a previous study, Lehn et al.10 have used variable temperature
NMR studies of 1 (2.2.2) in CDCl3 to investigate an inter-
conversion process believed to involve two forms of d3-
symmetry in which the geminal NCH2 protons of this cryptand
are in different environments; this likely involves a twisting
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Table 1 2.2.2 cage torsion angles (degrees)
Compound
N–C
60, Ϫ179
(60, Ϫ179)
59, 178
61, Ϫ58
69, Ϫ58
59, 178
79, Ϫ156
C–C
C–O
177
(177)
149
176
176
149
Ϫ167
O–C
178
(178)
Ϫ176
Ϫ154
Ϫ154
Ϫ176
180
C–C
(2.2.2)ؒ2BH3a (2-symmetry) (exo–exo)
Ϫ93
(Ϫ93)
173
Ϫ73
Ϫ73
173
69
65
70
70
1 (2.2.2)a (1-symmetry) (exo–exo)
175
84, Ϫ145
82, Ϫ152
86, Ϫ144
68
77
69
Ϫ94
Ϫ90
Ϫ174
Ϫ175
Ϫ174
172
178
73, Ϫ161
72, Ϫ159
67
69
51(2)
Ϫ53(2)
53(2)
Ϫ51(2)
52(2)
Ϫ49(2)
13
Ϫ109
Ϫ155
Ϫ178
176
Ϫ179
Ϫ78(2)
Ϫ78(2)
Ϫ81(2)
Ϫ40
(2.2.2)ؒ2Hϩb (1-symmetry) (endo–endo)
[Na(2.2.2)]ϩc (32-symmetry) (endo–endo)
77, Ϫ156(2)
Ϫ72(2), 161(2)
73(2), Ϫ162(1)
Ϫ73(2), 161(2)
77(2), Ϫ156(2)
Ϫ72(2), 160(1)
105, Ϫ130
(105, Ϫ130)
168(2)
Ϫ78(2)
168(2)
Ϫ76(2)
169(1)
Ϫ81(2)
Ϫ130
180(2)
Ϫ152(2)
Ϫ178(2)
Ϫ153(2)
Ϫ178(1)
Ϫ149(2)
156
(13)
(Ϫ130)
(×3)
156
[K(2.2.2)]ϩd (2-symmetry) (endo–endo) (chirality of
64.3, Ϫ169.0
65.4, Ϫ168.2
65.4, Ϫ168.2
64.3, Ϫ169.0
65.2, Ϫ167.0
(65.2, Ϫ167.0)
100(3), Ϫ155(3)
90(3), Ϫ150(3)
57.6
55.0
55.0
57.6
55.9
(55.9)
55(4)
58(3)
Ϫ172.5
Ϫ169.9
Ϫ169.9
Ϫ172.5
Ϫ170.4
(Ϫ170.4)
72(4)
Ϫ179.3
Ϫ178.1
Ϫ178.1
Ϫ179.3
Ϫ177.8
(Ϫ177.8)
180(3)
Ϫ49.6
Ϫ49.6
this and the above Naϩ adduct inverted)
Ϫ52.5
63(3)
[NaL]ϩ (L = 3, R = H)e (the 2.2.2. string)
71(3)
Ϫ179(2)
Representative conformations found in structures incorporating ligand 1 (2.2.2) are presented. Presentation is in the form of the torsions throughout
each of the three strings in each complex, on two lines, thus:
Chiralities are presented in a common basis as far as possible; in designating the compounds, any substitution at the nitrogens is shown. Standard
uncertainities are cited where accessible. a Ref. 25. b Ref. 26. c Ref. 32; another (disordered) example is found as the iodide in ref. 30. d Ref. 31; the
conformations of the Rb, Cs analogues are closely similar — see ref. 29. e This work.
around the N ؒ ؒ ؒ N axis of the cage. Indeed, consideration of
torsions in the strings of the cage in a variety of its forms, as
tabulated in Table 1, suggests a variety of possible pathways for
such twists. The free energy of activation (∆G‡) was deter-
mined to be 27.2 kJ molϪ1 for this process. In the present
undertaken. The more lipophilic systems 2–4 (R = t-Bu) were
also synthesised with the aim of carrying out parallel extraction
experiments (together with the NMR induced shift studies
discussed below). However, preliminary experiments indicated
that there is a tendency for these tert-butyl derivatives
[especially 4 (R = t-Bu)] to extract picric acid under the con-
ditions employed for the metal extractions—a problem that
does not occur for the lower-lipophilic systems with R = H. In
view of this, no results for the systems with R = t-Bu are
presented here. The results of the sodium picrate extraction
(water/chloroform) experiments for 2–4 (R = H) and 1 (2.2.2)
are summarised in Fig. 1. While no extraction was observed for
4 (R = H) under the conditions employed, as the flexibility
increases along the series 3 (R = H), 2 (R = H) and 1 (2.2.2)
these cryptands become progressively better extractants of Naϩ.
1
investigation, a similar H NMR variable temperature study
was carried out for the six-benzo substituted cryptand, 4 (R =
H), in CDCl3. For this system a two-site interchange process
was also identified with a ∆G‡ value of ≈ 63 kJ molϪ1. This
significantly higher value relative to that reported for 2.2.2 is in
keeping with the reduced conformational flexibility expected
for 4 (R = H).
Metal ion extraction experiments
There are now many reports of the solvent extraction of alkali
metal picrates from water into an immiscible organic phase con-
taining a polyether crown or cryptand ligand.21 In such studies,
the complexed alkali metal is transferred to the organic phase
as an ion-pair with the picrate anion. The intense yellow colour
of the picrate ion makes spectrophotometric determination of
the degree of extraction into the organic phase possible. The
use of picrate almost always results in higher metal partition
coefficients than occurs with simple inorganic anions such as
chloride or nitrate. This is because the efficiency of metal ion
transfer is significantly influenced by the hydration energy of
the anion present,8,22 with picrate being weakly hydrated.
Despite the inability of cryptand 4 (R = H) to extract Naϩ, in
a separate series of experiments the corresponding monocyclic
precursor 7 (R = H) was found to be a good extractant for this
ion—in contradistinction to the behaviour predicted from
(sole) consideration of the cryptate effect. Further, it was
In the present study comparative solvent extractions of
sodium picrate from an aqueous phase to a chloroform phase
incorporating cryptands 2–4 (R = H) and 1 (2.2.2) have been
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Table 2 Calculated endo–endo Ϫ exo–exo conformational preferences for cryptands 1 (2.2.2) and 2–4 (R = H)
MM3 ∆ Steric energy/kJ molϪ1 AM1 ∆ Hf /kJ molϪ1 Local DFT ∆ Electronic energy/kJ molϪ1
4 endo–endo Ϫ exo–exo
3 endo–endo Ϫ exo–exo
2 endo–endo Ϫ exo–exo
1 endo–endo Ϫ exo–exo
Ϫ184.1
Ϫ113.0
Ϫ230.5a
Ϫ77.8b
Ϫ45.6b
Ϫ7.1b
Ϫ36.8
Ϫ20.1
Ϫ7.9
Ϫ12.6
Ϫ7.9
Ϫ3.8
a Single point calculations at the SVWN5/6-31G‡ level at the AM1 minimum. b Structure geometry optimised at the SVWN5/6-31G* level.
figuration on the overall cage conformations for 1 and 2–4
(R = H) were undertaken (without symmetry restriction) using
molecular mechanics (MM3), semi-empirical MO (AM1) and
local-density functional (SVWN5/VN*) methods. Calculations
were run using Spartan24 running on an SGI Power Challenge.
Specifically, geometry optimisations were performed in order to
obtain the energy differences between the respective minimised
endo–endo and exo–exo structures. The results are summarised
in Table 2. All three computational methods are in reasonable
agreement and confirm that 4 (R = H) is the least flexible
followed by 3 (R = H), 2 (R = H) then 1 (2.2.2). That is, the
respective endo–endo conformers become progressively more
Fig. 1 Relative sodium picrate extraction by 1, 2–4 (R = H) and 10
from water into chloroform (see Experimental section for details).
accessible along the series given by 4, 3, 2 (all R = H) and 1
(2.2.2). As mentioned already, the X-ray structure of 4
(R = H)16 shows that it has an exo–exo arrangement of its
observed that the N,NЈ-dibenzyl derivative of 7 (R = H),
namely 10 (R = H), a closer model for 4 (R = H), also extracts
Naϩ (albeit only to the extent of 6 percent) under the same
conditions employed for 1–4 (Fig. 1). Even though 10 contains
fewer potential donors than 4 (R = H), it is significant that it is
still able to extract sodium while 4 does not. Clearly in 10 the
nitrogen atoms are free to interconvert between their endo- and
exo-orientations and the observed ability of 10 to extract
Naϩ suggests that the tribenzylamine moieties participate in
binding to this ion—in contrast to the situation for 4 (R = H)
which, as mentioned already, appears to favour the adoption of
an exo–exo arrangement of its bridgehead nitrogens (with an
associated sterically crowded cryptand cavity).16 The above
observations are thus in accord with the lower accessibility
of the endo–endo form of cryptand 4 (R = H) inhibiting the
inclusive co-ordination of a sodium ion.
In view of the above results for sodium with 2–4 (R = H) and
1 (2.2.2), it was of interest to examine whether similar patterns
would be maintained for the adjacent Group 1 metal ions,
lithium and potassium. Accordingly, further solvent extraction
experiments involving these metal picrates were instigated using
related conditions to those employed for sodium picrate. Within
experimental error, no extraction was again observed for 4
(R = H) with either of these metal salts. As before, extraction
was observed to occur in both cases for 2 and 3 (R = H), with
the degree of extraction again increasing on passing from 2
(R = H) to 3 (R = H) for each metal system. That is, the Liϩ and
Kϩ extraction patterns along the series 2–4 (R = H) showed
the same overall trend as occurs for Naϩ (Fig. 1). Further, in
the case of Kϩ, flexible 2.2.2 was once again observed to be the
most efficient extraction reagent along the cryptand series (in
parallel to the results from the Naϩ extraction experiments);
however, this was not the case for Liϩ. For this ion, the extrac-
tion efficiency of 2.2.2 was lower than found for 2 (R = H).
While the origin of this is uncertain, it presumably reflects the
poorer complementarity of lithium (relative to sodium or potas-
sium) for the cavity of 2.2.2. In accord with this observation, it
has been well documented previously that the thermodynamic
stability of the lithium complex is significantly lower than that
of the corresponding sodium or potassium complex.5,23
nitrogens while in the corresponding solid state structure of
125 they are endo–endo (as is this cryptand in its diproton-
ated form).26 Table 1 tabulates the detailed conformations of
the associated strings of this cage in a variety of uncomplexed
and complexed structures for comparison with the correspond-
ing aliphatic string in the sodium complex of 3 (R = H) investi-
gated as part of the present study (see below). Clearly, the
degree of ‘preparedness’ of 1 (2.2.2) for co-ordination can differ
greatly—presumably in response to the respective associated
environments.
The relatively high calculated enthalpic difference between
the endo–endo and exo–exo forms of 4 (R = H) (Table 2)
indicates that adoption of the endo–endo form is clearly not
favoured. As mentioned already, the configurational inflexi-
bility of 4 (R = H) appears largely as a reflection of the
presence of the bulky tribenzylamine bridgehead groups, with
their semi-rigid N–C–C–C torsion angles. In contrast, the
calculated energy difference between the minimised endo–endo
and exo–exo structures of 2.2.2 is small using all three com-
putational techniques, confirming the previous observations
that inversion of the bridgehead nitrogen atoms in 2.2.2
between the exo–exo, exo–endo and endo–endo forms is
facile.10,27 Clearly, the computational results for the unbound
cryptands also confirm that configurational flexibility increases
along the series 4, 3, 2 (all R = H) and 1.
Computational studies on selected metal-containing cryptands
A series of local (SVWN5/VN*) and non-local (pBP86/VN*)
density functional calculations on selected cryptand complexes
of Liϩ, Naϩ and Kϩ have been performed using Spartan, with
little structural variation being observed between the two
methods. In an attempt to provide chemically reasonable start-
ing geometries on which to base the calculations, attempts were
made to grow crystals of alkali metal–cage complexes of 2–4
(R = H) that were suitable for X-ray analysis but, in general,
these attempts were unsuccessful. Nevertheless, poor quality
crystals of [NaL]picrateؒCH2Cl2 where L = 3 (R = H) were
obtained (from dichloromethane) which, subjected to a single
crystal X-ray study, yielded results definitive of the gross con-
formation and atom connectivity within the complex. The
structure (Fig. 2) clearly shows that the bridgehead nitrogens
adopt endo–endo configurations and that these nitrogens are
weakly co-ordinating, with Na–N distances of 2.85(4) and
2.95(4) Å. All six of the oxygen donors are co-ordinated to the
Computational studies for metal-free cryptands
In view of the above results, comparative gas-phase comput-
ational investigations of the effect of bridgehead nitrogen con-
J. Chem. Soc., Dalton Trans., 2001, 2388–2397
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Table 3 The sodium environment, [NaL]ϩ (L = 3, R = H)
Atom
r
O(8b)
O(8c)
O(3aЈ)
O(8bЈ)
O(8cЈ)
O(3a)
O(8b)
O(8c)
O(3aЈ)
O(8bЈ)
O(8cЈ)
2.33(2)
2.52(3)
2.53(2)
2.44(3)
2.62(2)
2.59(2)
104.2(9)
109.5(9)
105(1)
69.1(8)
173.3(9)
79.4(8)
83.6(8)
66.4(9)
166.0(8)
111(1)
165.2(9)
90.2(8)
62.9(8)
96.5(9)
105.4(9)
Na ؒ ؒ ؒ N(0,0Ј) are 2.85(4), 2.95(4) Å. r (Å) is the Na–O distance; other entries are the angles (degrees) subtended by the relevant atoms at the head of
the row and column.
Table 4 L = 3 (R = H) torsion angles (degrees)
Compound
N–C
C–C
C–C
C–O
O–C
C–C
4 (R = H)a
Ϫ80(4), 152(3)
Ϫ88(4), 148(3)
Ϫ77(3), 156(3)
Ϫ77(3), 159(3)
Ϫ75(4), 160(3)
Ϫ74(4), 165(3)
81(3), Ϫ171(3)
67(4), Ϫ174(3)
80(4), Ϫ172(3)
75(4), Ϫ165(3)
170(4)
167(3)
157(3)
167(3)
162(3)
156(4)
73(4)
74(3)
61(5)
74(4)
4(5)
3(5)
11(5)
10(6)
5(5)
7(6)
Ϫ9(4)
2(3)
Ϫ169(3)
Ϫ147(3)
Ϫ171(4)
Ϫ165(4)
Ϫ166(7)
Ϫ165(3)
147(3)
148(3)
132(4)
148(4)
171(3)
Ϫ178(3)
174(3)
170(4)
172(7)
Ϫ61(3)
Ϫ64(4)
Ϫ64(3)
Ϫ76(4)
Ϫ60(5)
176(3)
[NaL]ϩ (L = 3, R = H)b
(the 3.2.3 strings)
Ϫ157(3)
Ϫ176(3)
Ϫ172(4)
Ϫ166(3)
Ϫ1(6)
Ϫ1(5)
Presentation as in Table 1. a Ref. 16. b This work.
Table 5 Metal–donor atom contacts from non-local density functional calculations for the complexes of 3 (R = H)
Calculated (mean) metal–donor contacts/Å
Aliphatic ether–M
Aromatic ether–M
N–M
Pauling metal radius/Å
Liϩ
Naϩ
Kϩ
2.09a,b
2.44a
2.74b
2.63b
2.87b
3.20
3.06
3.08
0.60
0.95
1.33
2.700a
a Range of metal–aliphatic ether contacts (Å) from CSDS: Li–O, 1.72–2.65 Å (mean 2.03 Å); Na–O, 1.95–3.21 Å (mean 2.48 Å); K–O, 2.36–3.41 Å
(2.83 Å). b Range of metal–aromatic ether contacts (Å) from CSDS: Li–O, 2.007–2.54 Å (mean 2.11 Å)—see text; Na–O, 2.27–3.00 Å (mean 2.523
Å); K–O, 2.61–3.21 Å (mean 2.84 Å).
string is likewise unusual, the free 2.2.2 ligand conformations
(Table 1) again not being immediately precursive of that of the
complex at this level of detail. The present complex cation has
overall quasi-2 symmetry as is evident in its projection down
that quasi-axis in Fig. 2.
This X-ray determination provided a basis for setting the
starting structures for the calculations on the Liϩ, Naϩ and Kϩ
complexes incorporating L = 3 (R = H). A comparison between
the non-local-density functional minimised structure and the
(crude) X-ray data for the above sodium complex indicated that
reasonable accord (RMS differences: bond lengths = 0.078 Å,
angles = 4.95Њ, torsion angles = 5.45Њ) between the two struc-
tures was present. All calculations were run using the pBP86
functional and the VN* numeral basis set. The largest differ-
ences between the calculated and X-ray bond and torsion
angles appear to be associated with the disorder found in the
positions of individual carbons attached to the bridgehead
nitrogens.
As well as for the Naϩ complex 3 (R = H), geometry optimis-
ations were also performed for the corresponding Liϩ and Kϩ
species. Table 5 provides a comparison of selected mean metal–
Fig. 2 Projection of the [NaL]ϩ (L = 3, R = H) cation down its quasi-2
axis.
donor contact data for the minimised structures with related
data from the Cambridge Structural Database System (Version
5.19) (CSDS).28 The (mean) calculated aliphatic and aryloxy
sodium (Table 3) with a mean bond length of 2.5(1) Å [range:
2.33(2)–2.62(2) Å]. The conformations of the two 3.2.3 type
strings of the present structure differ from those previously
described in ligand 4 (the latter having overall quasi-3 sym-
metry) (Table 4) and, similarly, the conformation of the 2.2.2
(the latter refers to ethers in which one aryl and one aliphatic
group is attached to the oxygen) ether to metal values for the
Naϩ and Kϩ species all fall centrally in the observed range for
bonds of similar type listed in the CSDS, with the individual
contacts each lying well within the respective ranges. However,
2392
J. Chem. Soc., Dalton Trans., 2001, 2388–2397

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this is not the case for the lithium complex. While the aliphatic
ether to Liϩ contacts all lie within the ‘normal’ range (Table 5),
the mean value from Liϩ to the aromatic ether donors falls very
significantly above the corresponding literature range. This
result is perhaps best interpreted as implying that the lithium
ion is ‘too small’ for 3 (R = H) and that, as a consequence, there
is a tendency for the (weaker) aromatic ether donors to not
participate in binding to this metal. In this context, the calcu-
lated energies of the respective metal complexes of 3 (R = H),
after subtracting the energy of the cryptand and the particular
metal ion (and ignoring basic effects such as BSSE), were found
to fall in the order Liϩ > Naϩ > Kϩ—in keeping with lithium
being the least strongly bound of these three metals.
In part to provide additional validation of the above studies,
a set of parallel density functional calculations were under-
taken for the Liϩ, Naϩ and Kϩ complexes of 1 (2.2.2) for which
solution thermodynamic stability data have long been avail-
able 5 along with precise crystal structures for the sodium and
potassium complexes;29–32 with the X-ray structure30 of the
sodium complex again forming the basis for the starting
geometries for each calculation. In the case of the sodium
and potassium complexes, the minimised geometries were
in each case quite close to those found in the corresponding
X-ray structures.30,33 Clearly both of these metal ions are
accommodated well by 1. For the smaller lithium, as inferred
previously, it was anticipated that the conformational flexi-
bility of the cryptand arising from its all-aliphatic nature would
allow this ion to also occupy the central cavity but that its
‘fit’ would be poor. The calculated structure is in accord with
this expectation: a very non-symmetric geometry was predicted
with two long (mean: 3.14 Å) and one short (2.16 Å) Li–O
contacts, with the respective Li–N distances being 2.19 Å and
4.05 Å. While this (gas phase) result is thus in strong accord
with the previous assumption5 that there will be poor comple-
mentarity between the Liϩ ion and the cavity of this cryptand,
it needs to be emphasised that the solution behaviour will
of course involve a dynamic equilibrium over a range of
conformations/configurations and possible solvation patterns—
as demonstrated already for the alkali metal complexes of
this ligand using the molecular dynamics technique,34–36 and the
experimental data, presented in Table 1.
In contrast to the above, the Liϩ and Naϩ induced shifts in
both the 1H and 13C NMR spectra of the least flexible system 4
(R = t-Bu) in dimethylformamide-d6 were uniformly minimal,
amounting to not more than 0.02 ppm in the 1H spectrum and
0.53 ppm in the 13C spectrum. Such a result is thus in complete
accord with our earlier conclusions that the rigidity of this
ligand system inhibits metal binding. Unfortunately, as men-
tioned above, low solubilities prevented shifts being obtained
for the remaining alkali metals but little interaction with 4
(R = t-Bu) is expected in these cases also.
The induced chemical shifts for cryptand 2 (R = t-Bu), of
intermediate flexibility, in the presence of Liϩ, Naϩ and Kϩ
again followed the expected pattern. Minimal shifts [up to
0.01 ppm (1H) and Ϫ0.14 ppm (13C)] were induced by Liϩ
while both Naϩ and Kϩ yielded significant shifts [up to ϩ0.51
ppm (1H) and ϩ3.91 ppm (13C) for Naϩ and up to Ϫ0.29 (1H)
and ϩ3.72 ppm (13C) for Kϩ] in the case of particular reson-
ances. Again, such behaviour is in full accord with the results
discussed above.
Concluding remarks
A series of computational and experimental studies has been
performed to probe the effect of increasing rigidity on the con-
formational freedom of the diaza-polyether cryptands 1 and
2–4 (R = H). Clearly, both sets of results are in good agree-
ment concerning the effect that increasing benzylamine
incorporation has on the topological rigidity of the cryptands
investigated, namely, that increasing the number of benzyl
substituents on the bridgehead amine atoms hinders the adop-
tion of an endo–endo nitrogen conformation and in doing so
impedes metal ion complexation.
Experimental
1H and 13C NMR spectra were determined on a Bruker AM300
1
spectrometer at 300 and 75 MHz, respectively. The H NMR
variable temperature study was performed using the literature
procedure.38 Electrospray (ES) ionisation, electron impact (EI)
and liquid secondary ion (LSI) mass spectra were recorded on a
Kraytos M25RFA or a Bruker APEX 47e spectrometer, while
plasma desorption (PD) spectra were obtained on a Bio-Ion
20R instrument from Applied Biosystems. Melting points
are uncorrected. Unless stated otherwise, chromatographic
separations were performed using vacuum-assisted elution on
Merck silica gel 60H F254, 60 mesh (63–230 µm). Dialdehydes 5
(R = H)39 and 5 (R = t-Bu)18 together with the dichloro precur-
sor 8 (R = H),16 macrocycle 7 (R = H),16 cryptand 4 (R = H),16
triethylene glycol tritosylate40 and N,NЈ-bis(4-tert-butylphenol-
2-ylmethyl)diaza-18-crown-620 were prepared by the published
procedures.
In parallel to the published data for the experimentally
determined5 stability constants of the 1 : 1 (metal : 2.2.2) com-
plexes in solution, the calculated gas-phase stabilities of the
complexes investigated in the present study also follow a similar
order of Liϩ < Naϩ < Kϩ.
NMR induced chemical shift studies
Using the more lipophilic derivatives 2 (R = t-Bu) and 4 (R =
t-Bu) together with 1 (2.2.2) it has proved possible to obtain 1H
and 13C NMR induced chemical shift data for complex forma-
tion of each of these species with selected alkali metal nitrates.
A stoichiometric amount of the respective alkali metal nitrates
was added to each of the above cryptands dissolved in
dimethylformamide-d7 (ca. 0.10 mol dmϪ3) held in the NMR
tube. Despite the use of the more chloroform soluble deriv-
atives of 2 and 4 with R = t-Bu, under the conditions employed
metal complex precipitation was found to occur in the presence
of the heavier alkali metals, thus limiting the range of the
studies involving these latter systems.
While quite low induced shifts were observed for the inter-
action of Liϩ with the flexible cryptand 1 (in keeping with a
weak interaction occurring), shifts in the presence of both Naϩ
and Kϩ were generally higher in accord with the enhanced bind-
ing occurring for 2.2.2 with these ions5,37 while the correspond-
ing shifts in the presence of Rbϩ and Csϩ tended once again to
be lower. This pattern is thus in general agreement with that
reported5 for the binding affinities of 1 towards these alkali
metals.
Macrocycle and cryptand synthesis
Cryptand 2 (R ؍ H). 1,10-Diaza-18-crown-6 (218 mg, 0.83
mmol), dichloride 8 (R = H)16 (258 mg, 8.3 mmol) and sodium
carbonate (670 mg, 6.3 mmol) were stirred in HPLC grade
acetonitrile (20 cm3) at room temperature for 48 h. The solvent
was then evaporated, dichloromethane added and the resulting
suspension filtered. The precipitate was washed thoroughly
with dichloromethane (2 × 20 cm3) and the combined organic
fractions evaporated on a rotary evaporator. The resulting oil
was chromatographed (silica, eluent 5% methanol/chloroform)
to yield cryptand 2 (R = H) as a colourless solid (45 mg, 11%),
mp 137–139 ЊC. HR-MS (LSI) (M ϩ Hϩ) found 501.2971.
1
C28H41O6N2 requires 501.2964. H-NMR (CDCl3 at 320 K)
δ ≈ 2.5 (br s), ≈2.6 (br s), ≈3.1 (br s), ≈3.5 (br s), ≈3.6 (br s), 4.40
(s, CH2O, 4 H), 6.97 (dd, J = 2, 8 Hz, H-6Ј, 4 H), 7.09 (d, J = 8
Hz, H-3Ј, 4 H), 7.16 (dd, J = 2, 8 Hz, H-4Ј, 4 H). 13C-NMR
(CDCl3 at 320 K) δ 51.4, 56.0, 65.9, 66.8, 68.8, 114.8, 122.0,
126.9, 129.6, 132.4, 157.4.
J. Chem. Soc., Dalton Trans., 2001, 2388–2397
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Cryptand 3 (R ؍ H). A mixture of triethylamine (660 mg, 6.5
mmol), 7 (R = H)16 (265 mg, 0.52 mmol) and triethylene glycol
ditosylate40 (240 mg, 0.552 mmol) were dissolved in AR toluene
(20 cm3). The mixture was heated at 95 ЊC under a nitrogen
atmosphere for 8 days. The solvent was evaporated and the dark
brown mixture partitioned between dichloromethane (20 cm3)
and water (20 cm3). Further extraction with dichloromethane
(20 cm3) followed by routine work-up yielded a dark brown oil,
which was passed down a chromatography column (alumina,
eluted with dichloromethane). Concentration of the eluent
yielded 3 (R = H) as a colourless solid which was collected by
filtration and was washed with acetone; yield 90 mg (28%);
mp 224–227 ЊC. HR-MS (LSI) (M ϩ Hϩ) found 625.3265.
Lithium aluminium hydride (6.66 g, 0.175 mol) was added (gas
evolution) and the reaction was stirred at 0 ЊC for 10 min after
which it was allowed to warm to room temperature. The solu-
tion was refluxed for 4 h, then stirred at 50 ЊC for 16 h after
which it was allowed to cool to room temperature. Water (7
cm3) was added, followed by 20% NaOH (7 cm3) and then more
water (7 cm3) to quench the reaction. The granular precipitate
thus formed was filtered off and washed with dichloromethane
(3 × 50 cm3); the combined filtrates were evaporated, and the
residue was taken up in dichloromethane (250 cm3) and washed
with NaOH (4 mol dmϪ3, 2 × 50 cm3), water (2 × 50 cm3) and
dried (anhydrous Na2SO4). Evaporation of the solvent gave a
yellow solid which was taken up in ethanol (100 cm3); aqueous
60% HPF6 (20 cm3) was then added. The solution was then held
at 5 ЊC for 2 h. The crystals that formed were filtered off and
recrystallised from absolute ethanol to give the monohexa-
fluorophosphate salt of 1,2-bis(4-tert-butyl-2-aminomethyl-
phenoxy)ethane 6 (R = t-Bu) as colourless needles; yield 7.15 g
(77%); mp > 250 ЊC. The following procedure was employed to
produce the free amine. The hexafluorophosphate salt (1.55 g,
2.02 mmol) was suspended in dichloromethane (100 cm3) and
NaOH solution (6 mol dmϪ3, 40 cm3) was added. The resulting
two-phase system was stirred vigorously for 60 min, after which
the phases were separated. The aqueous phase was extracted
with dichloromethane (50 cm3), and the combined organic
phases were washed with NaOH solution (6 mol dmϪ3, 20 cm3)
then water (2 × 50 cm3). The chloroform phase was separated
and dried (anhydrous Na2SO4), then evaporated to give 1,2-
bis(4-tert-butyl-2-aminomethylphenoxy)ethane 6 (R = t-Bu) as
a white crystalline solid; yield 1.08 g (96%); mp 106–108 ЊC
(Found: C, 75.3; H, 9.8; N, 7.3. Calc. for C24H36N2O2: C, 74.96;
H, 9.44; N, 7.28%). MS (PD) m/z = 384.9 (Mϩ). 1H-NMR
(CDCl3) δ 7.29 (d, 2H, J = 3 Hz, arom. 3-H), 7.26 (dd, 2H,
J1 = 3 Hz, J2 = 9 Hz, arom. 5-H), 6.78 (d, 2H, J = 9 Hz, arom. 6-
H), 4.40 (s, 4H, OCH2CH2O), 3.86 (s, 4H, CH2NH2), 1.98 (br s,
4H, CH2NH2), 1.34 [s, 18H, C(CH3)3]. 13C-NMR (CDCl3)
δ 154.19, 143.82, 131.16, 126.08, 124.58, 110.86, 66.63, 43.00,
34.11, 31.69.
1
C38H45N2O6 requires 625.3277. H-NMR (CDCl3) δ 2.94 (t,
J = 6 Hz, CH2N, 4 H), 3.51 (s, CH2O, 4 H), 3.69 (t, J = 6 Hz,
CH2O, 4 H), 3.84 (d, Jab = 15 Hz, ArCHaCHbN, 4 H), 4.19 (d,
Jab = 15 Hz, ArCHaCHbN, 4 H), 4.31 (s, CH2O, 4 H), 6.91 (d,
J = 8 Hz, H-6Ј, 4 H), 7.02 (t, J = 7 Hz, H-4Ј, 4 H), 7.21 (t, J = 8
Hz, H-5Ј, 4 H), 7.73 (d, J = 7, H-3Ј, 4 H). 13C NMR (CDCl3)
δ 51.9, 52.3, 67.3, 69.0, 71.5, 112.2, 121.3, 127.3, 129.6, 129.7,
156.5.
Dibenzylated macrocycle 10. A mixture of caesium carbonate
(383 mg, 1.18 mmol), benzyl chloride (55 mg, 0.43 mmol) and 7
(R = H) (93 mg, 0.18 mmol) in acetonitrile (CaH2 dried) (20
cm3) was heated at reflux under nitrogen for 24 h. The solvent
was removed to yield a yellow solid. This was partitioned
between water (30 cm3) and dichloromethane (20 cm3) and the
pH of the aqueous phase was adjusted to 14 with NaOH solu-
tion (0.1 mol dmϪ3). The dichloromethane layer was separated
and the aqueous layer was again extracted with dichlorometh-
ane (3 × 20 cm3). The organic layers were combined, dried over
anhydrous sodium sulfate, and the solvent was removed on a
rotary evaporator to yield 10 as a yellow solid (120 mg, 95%);
mp 215 ЊC (Found: C, 79.6; H, 6.6; N, 4.15. Calc. for
1
C46H46N2O4: C, 79.97; H, 6.71; N, 4.05%). H-NMR (CDCl3)
δ 3.79 (s, 4H, ArCH2), 3.87 (s, 8H, ArCH2N), 4.25 (s, 8H,
CH2O), 6.85–7.91 (m, arom). 13C-NMR (CDCl3) δ 52.21
(ArCH2), 59.02 (CH2N), 66.40 (CH2O), 111.3, 121.3, 126.6,
127.1, 128.0, 128.1, 128.3, 129.1, 140.2 (arom).
1,2-Bis(4-tert-butyl-2-chloromethylphenoxy)ethane 8 (R ؍ t-
Bu). 1,2-Bis(4-tert-butyl-2-hydroxymethylphenoxy)ethane (850
mg, 2.21 mmol) was dissolved under N2 in dry dichloromethane
(50 cm3) in a 100 cm3 one-necked round-bottomed flask
equipped with magnetic stirring and a dropping funnel. The
clear solution was cooled to Ϫ78 ЊC using a solid CO2/acetone
cooling bath. Thionyl chloride (1.5 cm3 ≈245 mg, 20.6 mmol)
was added dropwise and the reaction solution was allowed to
warm to room temperature over a period of 45 min. The reac-
tion solution was heated at reflux for 10 min then stirred with-
out heating for 30 min after which it was cooled in an ice bath.
Water (15 cm3) was then added slowly to quench the reaction
solution. The mixture was allowed to warm to room temper-
ature and the phases were separated. The aqueous phase was
extracted with dichloromethane (50 cm3) and the combined
organic phases were washed with water (2 × 100 cm3), dried
(anhydrous Na2SO4), and evaporated to give the product 1,2-
bis(4-tert-butyl-2-chloromethylphenoxy)ethane 8 (R = t-Bu) as
a white crystalline solid; yield 91 mg (98%) (Found: C, 67.9, H,
7.3. Calc. for C24H32Cl2O2: C, 68.40, H, 7.65%). MS (PD)
1,2-Bis(4-tert-butyl-2-formylphenoxy)ethane
dioxime.
Hydroxylamine hydrochloride (10.82 g, 0.156 mol) was dis-
solved in aqueous NaOH (8.18 g, 0.205 mol in 40 cm3 of water).
The neutralised hydroxylamine solution was added to 1,2-bis(4-
tert-butyl-2-formylphenoxy)ethane (8.22 g, 21.5 mmol) in abso-
lute ethanol (100 cm3) contained in a 250 cm3 one-necked
round-bottomed flask equipped with magnetic stirring and
a reflux condenser. The resulting clear solution was refluxed
for 5 h (a white precipitate gradually formed). The reaction
mixture was cooled to room temperature, poured into HCl
(2 mol dmϪ3, 350 cm3), and allowed to stand in a refrigerator
overnight. The white precipitate of 1,2-bis(4-tert-butyl-2-
formylphenoxy)ethane dioxime that formed was filtered off and
dried in a vacuum oven at 75 ЊC; yield 7.33 g (17.4 mmol, 81%);
mp > 250 ЊC (Found: C, 70.1; H, 7.7; N, 6.6. Calc. for
C24H32N2O4: C, 69.88; H, 7.82; N, 6.79%). MS (PD) m/z = 412.2
(Mϩ). 1H-NMR (DMSO-d6): δ 8.26 (s, 2H, CH-NOH), 7.68 (d,
2H, J = 3 Hz, arom. 3-H), 7.37 (dd, 2H, J = 3 Hz, J = 9 Hz,
arom. 5-H), 6.90 (d, 2H, J = 9 Hz, arom. 6-H), 4.35 (s, 4H,
OCH2CH2O), 1.24 [s, 18H, C(CH3)3]. 13C-NMR (DMSO-d6)
δ 153.98, 143.46, 143.10, 127.80, 121.71, 120.60, 112.92, 67.28,
33.87, 31.22.
1
m/z = 421.8 (Mϩ). H-NMR (CDCl3) δ 7.35 (d, 2H, J = 3 Hz,
arom. 3-H), 7.30 (dd, 2H, J1 = 3 Hz, J2 = 9 Hz, arom. 5-H), 6.89
(d, 2H, J = 9 Hz, arom. 6-H), 4.62 (s, 4H, CH2Cl), 4.39 (s, 4H,
CH2O), 1.29 [s, 18H, C(CH3)3]. 13C-NMR (CDCl3) δ 154.28,
143.99, 127.75, 126.75, 125.64, 111.83, 67.21, 42.03, 34.14,
31.43.
1,2-Bis(4-tert-butyl-2-aminomethylphenoxy)ethane
6 (R ؍
t-Bu). 1,2-Bis(4-tert-butyl-2-formylphenoxy)ethane dioxime
(7.26 g, 17.6 mmol) (see above) was dissolved in dry tetrahydro-
furan (150 cm3) under N2 in a 250 cm3 one-necked round-
bottomed flask equipped with magnetic stirring and a reflux
condenser. The clear solution was cooled to 0 ЊC in an ice bath.
Cryptand 2 (R ؍ t-Bu). Method 1. Caesium carbonate (13.78
g, 42.3 mmol) was suspended in dry acetonitrile (60 cm3) in a
250 cm3 three-necked round-bottomed flask equipped with
magnetic stirring, a nitrogen bubbler and two 100 cm3 dropping
2394
J. Chem. Soc., Dalton Trans., 2001, 2388–2397

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funnels. 1,2-Bis(4-tert-butyl-2-chloromethylphenoxy)ethane 8
(R = t-Bu) (900 mg, 2.14 mmol) was dissolved in dry
acetonitrile (60 cm3) and transferred to the first dropping fun-
nel, while 1,10-diaza-18-crown-6 (553 mg, 2.11 mmol) was dis-
solved in dry acetonitrile (60 cm3) and transferred to the second
dropping funnel. The two solutions were added dropwise simul-
taneously to the reaction vessel over 45 min, and the resulting
suspension was stirred at room temperature for 72 h. The reac-
tion mixture was filtered to remove undissoled salts, these were
washed with acetonitrile, and the filtered solution was evapor-
ated under vacuum to give a residue which was subjected to
column chromatography on deactivated silica gel (column
packed in dichloromethane–ethanol–concentrated aqueous
ammonia 200 : 15 : 1, gradient elution from dichloromethane–
methanol–conc. aqueous ammonia 200 : 15 : 1 to 200 : 22 : 2).
Evaporation of the relevant fraction gave a colourless oil, which
hardened upon standing. The oil was redissolved in redistilled
chloroform (100 cm3) and subjected to continuous extraction
with distilled water (using a continuous extractor for liquid–
liquid extraction by upward displacement) for two days. The
phases were separated, and toluene (100 cm3) was added to the
organic phase. The solvent was removed under vacuum (with
concurrent drying by azeotropic distillation of the toluene).
After drying in a vacuum at 60 ЊC, the uncomplexed cryptand 2
(R = t-Bu) was obtained as a colourless glass which crystallised
upon standing to give a low-melting white solid; yield 840 mg
(65%).
Method 2. The macrocyclic Mannich base, N,NЈ-bis(4-tert-
butylphenol-2-ylmethyl)diaza-18-crown-620 (1.16 g, 1.98 mmol),
was dissolved in dry tetrahydrofuran (50 cm3) in a 100 cm3
round-bottomed flask under N2 and treated with a solution of
sodium (93 mg, 4.04 mmol) in dry ethanol (4 cm3). The solu-
tion, which at first became clear, soon turned cloudy, and a
white powder precipitated from the reaction mixture. This was
redissolved by the addition of dry ethanol (20 cm3) and the
resulting solution was stirred at room temperature for 20 min.
The solvent was evaporated under vacuum, and the resulting
semisolid was redissolved in dry dimethylformamide (50 cm3)
with gentle heating; ethylene glycol distosylate (741 mg, 2.00
mmol) was added. The resulting solution was heated at the
reflux for 24 h, the solvent was evaporated under vacuum, and
the resulting oily residue was purified by column chrom-
atography (SiO2; eluent dichloromethane–methanol–triethyl-
amine 50 : 5 : 1) to give a yellowish oil, which was purified by
continuous extraction with distilled water as described in
Method 1 (see above) to give the product 2 (R = t-Bu) as a white
low-melting crystalline solid; yield 1.00 g (82%) (Found:
C, 70.5; H. 9.1; N, 4.7. Calc. for C36H56N2O6: C, 70.55; H, 9.21;
N, 4.57%). MS (PD) m/z = 637.5 (M ϩ Naϩ). 1H-NMR
(CDCl3) δ 7.45 (d, 2H, J = 3 Hz, arom. 3-H), 7.20 (dd, 2H,
J1 = 3 Hz, J2 = 9 Hz, arom. 5-H), 6.81 (d, 2H, J = 9 Hz, arom.
6-H), 4.32 (s, 4H, ArOCH2), 3.89 (s, 4H, ArCH2N), 3.56 (m,
16H, CH2OCH2), 2.96 [symm. m, 8H, ArCH2NCH2], 1.31 [s,
18H, C(CH3)3]. 13C-NMR (CDCl3): δ 154.60, 143.56, 128.64,
127.85, 124.13, 111.28, 70.48, 69.85, 67.13, 54.63, 52.33, 34.00,
31.47.
dichloromethane (200 cm3) and washed with NaOH (2 mol
dmϪ3, 50 cm3), water (50 cm3), saturated aqueous NaCl (50 cm3)
and then evaporated to give 7 (R = t-Bu) as a white powder;
yield 1.44 g (95%); mp 219–220 ЊC.
Although this material was sufficiently pure for further reac-
tions, an analytical sample was prepared by chromatography
(deactivated SiO2, gradient elution from 5% methanol in
dichloromethane to 10% methanol in dichloromethane)
(Found: C, 78.6; H, 9.1. Calc. for C48H66N2O4: C, 78.43; H,
9.05%). HR-MS (EI) (Mϩ) found 734.5017. C48H66N2O4
1
requires 734.5023. H-NMR (CDCl3) δ 7.81 (d, 4H, J = 3 Hz,
arom. 3-H), 7.17 (dd, 4H, J1 = 3 Hz, J2 = 9 Hz, arom. 5-H), 6.81
(d, 4H, J = 9 Hz, arom. 6-H), 4.24 (s, 8H, CH2CH2O), 4.17 [d,
4H, Ja,b = 15 Hz, Ar(CHaHb)N], 3.84 [d, 4H, Ja,b = 15 Hz,
Ar(CHaHb)N], 3.65 (t, 4H, J = 6 Hz, NCH2CH2O), 3.50 (s,
4H, CH2OCH2CH2O), 2.93 (t, 4H, J = 6 Hz, NCH2CH2O), 1.30
[s, 36H, C(CH3)3]. 13C-NMR (CDCl3) δ 154.14, 143.57, 128.70,
124.27, 111.05, 66.37, 49.34, 34.14, 31.54.
Cryptand 3 (R ؍ t-Bu). Method 1. Tetrabutylammonium
bromide (25 mg) was added to caesium carbonate (5.0 g, 15
mmol) suspended in a 1 : 1 mixture of dry toluene and dry
acetonitrile (50 cm3) under N2 contained in a 500 cm3 three-
necked round-bottomed flask equipped with magnetic stirring,
a reflux condenser and two 100 cm3 dropping funnels. The macro-
cyclic diamine 7 (R = t-Bu) (432 mg, 0.59 mmol) in toluene–
acetonitrile (1 : 1, 80 cm3) was placed in one of the dropping
funnels, while triethylene glycol ditosylate (270 mg, 5.89 mmol)
in toluene–acetonitrile (1 : 1, 80 cm3) was placed in the
other. The caesium carbonate suspension was heated to reflux
with stirring and the above two solutions were added dropwise
simultaneously over a period of 2¹ h. The reaction mixture was
¯
²
refluxed for 72 h, after which it was allowed to cool to room
temperature and filtered through a sintered glass funnel. The
residue on the filter was washed with dichloromethane (2 × 50
cm3). Evaporation of the combined filtrates gave an oily res-
idue, which was taken up in dichloromethane (200 cm3) and
washed with water (3 × 100 cm3), dried (CaCl2), and evaporated
under vacuum. The residue was purified by chromatography
(SiO2, eluent 5% methanol in dichloromethane) to give 3 (R =
t-Bu) as a white low-melting crystalline solid which was dried
on a vacuum line then crystallised from cyclohexane; yield
170 mg (35%).
Method 2. Caesium carbonate (5.40 g, 16.6 mmol) was sus-
pended in dry acetonitrile (50 cm3) under N2 in a 250 cm3 three-
necked round-bottomed flask equipped with a magnetic stirrer,
a reflux condenser and two dropping funnels. The suspension
was warmed to 45 ЊC on an oil bath. 1,2-Bis(4-tert-butyl-2-
chloromethylphenoxy)ethane 8 (R = t-Bu) (436 mg, 1.03 mmol)
was dissolved in dry acetonitrile (50 cm3) and placed in the
first dropping funnel, while macrocycle 9 (534 mg, 1.07 mmol)
dissolved in dry acetonitrile (50 cm3) was placed in the second.
The two solutions were added dropwise simultaneously to the
reaction solution over 1 h. The resulting reaction mixture was
stirred at 45 ЊC for a further 48 h and then refluxed for 3 h.
The reaction mixture was filtered hot, after which the solvent
was removed under vacuum. The residue that remained was
dissolved in the minimum amount of dichloromethane and
chromatographed on deactivated silica (SiO2, packed with
dichloromethane–methanol–triethylamine 50 : 5 : 1 and gradient
eluted from dichloromethane–methanol 25 : 1 to dichloro-
methane–methanol–triethylamine 50 : 5 : 2). The resulting
residue was redissolved in chloroform (100 cm3) and subjected
to continuous extraction with distilled water (using a con-
tinuous extractor for liquid–liquid extraction by upward dis-
placement) for two days. The phases were then separated, and
toluene (100 cm3) was added to the organic phase. The solvent
was removed under vacuum (with concurrent drying by azeo-
tropic distillation of the toluene). After drying under vacuum at
60 ЊC, the uncomplexed cryptand 3 (R = t-Bu) was obtained as
Macrocycle 7 (R ؍ t-Bu). Bis(4-tert-butyl-2-aminomethyl-
phenoxy)ethane 6 (R = t-Bu) (794 mg, 2.06 mmol) in dry
methanol (50 cm3) and 1,2-bis(4-tert-butyl-2-formylphenoxy)-
ethane 5 (R = t-Bu) (788 mg, 2.06 mmol) in dry methanol were
added dropwise simultaneously into methanol (50 cm3) and 3X
molecular sieves (10 cm3) (under N2) in a 250 cm3 three-necked
round-bottomed flask equipped with magnetic stirring, two 50
cm3 dropping funnels, and a reflux condenser. After complete
addition (1 h), the solution was refluxed for 2 h, whereupon
NaBH4 (500 mg, 13.2 mmol) was added and the reaction
solution was heated at reflux for 90 min. The reaction mixture
was filtered through Celite to remove the molecular sieves,
the solvent was removed, and the residue was taken up in
J. Chem. Soc., Dalton Trans., 2001, 2388–2397
2395

View Article Online
a colourless glass; yield 612 mg (70%) (Found: C, 76.4; H, 9.1;
N, 3.35. Calc. for C54H76N2O6: C, 76.38; H, 9.02; N, 3.30%). MS
(PD) m/z = 871.9 (M ϩ Naϩ). 1H-NMR (CDCl3) δ 7.81 (d, 4H,
J = 3 Hz, arom. 3-H), 7.17 (dd, 4H, J1 = 3 Hz, J2 = 9 Hz, arom.
5-H), 6.81 (d, 4H, J = 9 Hz, arom. 6-H), 4.24 (s, 8H, OCH2-
CH2O), 4.17 [d, 4H, J = 15 Hz, RN(CHαHβ)2], 3.84 [d, 4H,
J = 15 Hz, RN(CHαHβ)2], 3.65 (t, 4H, J = 6 Hz, NCH2CH2O),
3.50 (s, 4H, CH2OCH2CH2OCH2), 2.93 (t, 4H, J = 6 Hz,
NCH2CH2O), 1.30 [s, 36H, C(CH3)3]. 13C-NMR (CDCl3)
δ 154.39, 143.95, 128.91, 126.23, 123.65, 111.78, 71.65, 68.84,
67.46, 52.01, 51.94, 34.14, 31.57.
in dry methanol (70 cm3) was placed in one dropping funnel,
while 1,2-bis(2-aminoethoxy)ethane (0.76 g, 5.15 mmol) in dry
methanol (70 cm3) was placed in the other. The solutions were
added dropwise simultaneously over a period of 50 min and the
reaction mixture was then refluxed for 2 h. NaBH4 pellets (1.29
g, 34 mmol) were added, and the resulting suspension was
refluxed for a further 5 h, after which it was filtered through a
bed of Celite to remove the molecular sieves. The latter were
washed with dichloromethane (2 × 50 cm3) and the combined
filtrates were evaporated in a rotary evaporator. The resulting
oily residue was redissolved in dichloromethane (200 cm3)
which was washed with water (2 × 100 cm3). Toluene (100 cm3)
was added to the organic phase and the solvent was removed
under vacuum (with concurrent drying by azeotropic distil-
lation of the toluene) to give the macrocycle as a colourless
residue; yield 2.34 g (92%).
Analytically pure material was obtained by subjecting the
above product to chromatography (either deactivated basic
Al2O3 with gradient elution from dichloromethane to 10%
methanol in dichloromethane or SiO2 using dichloromethane–
methanol–triethylamine 50 : 3 : 1 as eluent). The relevant frac-
tions were evaporated under high vacuum, and the residue
redissolved in chloroform. The chloroform solution was sub-
jected to continuous extraction with distilled water (using a
continuous extractor for liquid–liquid extraction by upward
displacement) for 72 h. The phases were separated, and toluene
(100 cm3) was added to the organic phase. The solvent was
removed under vacuum (with concurrent drying by azeotropic
distillation of the toluene). After drying under vacuum
at 60 ЊC for 72 h, the product was obtained as a colourless glass
(Found: C, 71.9; H, 9.2; N, 5.5. Calc. for C30H46N2O4: C, 72.25;
H, 9.30; N, 5.62%). MS (PD) m/z = 498.8 (Mϩ). 1H-NMR
(CDCl3) δ 7.30 (d, 2H, J = 3 H, arom. 3-H), 7.25 (dd, 2H, J1 = 3
Hz, J2 = 9 Hz, arom. 5-H), 6.85 (d, 2H, J = 9 Hz, arom.
6-H), 4.37 (s, 4H, OCH2CH2O), 3.87 (s, 4H, CH2OCH2CH2-
OCH2), 3.64 (t, 4H, J = 5 Hz, NCH2CH2O), 3.54 (s, 4H,
ArCH2NH), 3.10 (br s, 2H, NH), 2.77 (t, 4H, J = 5 Hz, OCH2-
CH2NH), 1.30 [s, 18H, C(CH3)3]. 13C-NMR (CDCl3) δ 154.77,
143.86, 127.80, 127.66, 125.04, 111.91, 70.07, 67.46, 49.64,
48.18, 33.93, 31.36.
Cryptand 4 (R ؍ t-Bu). Caesium carbonate (5.0 g, 15 mmol)
was suspended in a 1 : 1 mixture of dry toluene and dry
acetonitrile (100 cm3) under N2 in a 500 cm3 three-necked
round-bottomed flask equipped with magnetic stirring, a
reflux condenser and two 100 cm3 dropping funnels. The reac-
tion mixture was heated to 40 ЊC on an oil bath, and the
macrocyclic diamine 7 (R = t-Bu) (520 mg, 0.69 mmol) in
toluene–acetonitrile (1 : 1, 100 cm3) was placed in one dropping
funnel, while 1,2-bis(4-tert-butyl-2-chloromethylphenoxy)-
ethane 8 (R = t-Bu) (303 mg, 0.72 mmol) in toluene–acetonitrile
(1 : 1, 100 cm3) was placed in the other. The two solutions were
added dropwise simultaneously over 1 h after which the reac-
tion mixture was refluxed for 72 h. Upon allowing the solution
to cool to room temperature, the reaction mixture was filtered,
and the residue on the filter was washed with dichloromethane
(2 × 50 cm3). The combined filtrates were evaporated under
vacuum and the residue that remained was taken up in dichloro-
methane (300 cm3) and this solution washed with water
(3 × 100 cm3). The organic layer was separated, dried (CaCl2),
and evaporated under vacuum to give 4 (R = t-Bu) as a white
microcrystalline solid, which was dried under vacuum at 80 ЊC
for 48 h; yield 637 mg (85%); mp > 275 ЊC (Found: C, 79.85;
H, 9.07; N, 2.28. Calc. for C72H96N2O6: C, 79.66; H, 8.91;
N, 2.58%). HR-MS (EI) (Mϩ) found 1084.7255. C72H96N2O6
requires 1084.7268. 1H-NMR (CDCl3) δ 8.18 (d, 6H, J = 3 Hz,
arom. 3-H), 7.15 (dd, 6H, J1 = 3 Hz, J2 = 9 Hz, arom. 5-H), 6.78
(d, 6H, J = 9 Hz, arom. 6-H), 4.22 (s, 12H, OCH2CH2O), 3.99
[s, 12H, N(CH2)3], 1.28 [s, 54H, C(CH3)3]. 13C-NMR (CDCl3)
δ 154.05, 143.65, 128.26, 124.30, 123.02, 110.13, 66.15, 52.82,
34.22, 31.68.
Picrate extraction experiments
The extraction experiments were performed in 15 cm3 sealed
glass vials which were shaken on an oscillating shaker for 2 h
(at 22 ЊC) at 120 cycles per min. The extractions involved an
aqueous source phase (3 cm3) and a chloroform organic phase
(3 cm3). The aqueous phase was a standard solution of
sodium picrate which was prepared in distilled, deionised
water by neutralising (pH = 7.00 0.05) an aqueous solution
of picric acid with sodium hydroxide solution (0.1 mol dmϪ3).
The concentration of this standard solution (0.81 mmol dmϪ3)
was accurately determined using the aqueous molar absorp-
tivity of sodium picrate (ε356nm = 1.45 × 104 molϪ1 dm3).41 The
chloroform phase contained an accurately known concen-
tration of ligand (≈1 mmol dmϪ3). As part of each set of
experiments, control experiments (×3) using chloroform alone
were also run. The chloroform used for all extraction experi-
ments was first distilled and then saturated with water prior to
use.
After equilibration had been established, the concentration
of picrate in the aqueous phase was determined by spectro-
photometry. The percent extraction was calculated as (moles of
picrate in chloroform)/(moles of picrate corresponding to 100%
extraction).42 All spectrophotometric determinations were per-
formed using a Hewlett Packard 8451A Diode Array spectro-
photometer. All extractions were performed in triplicate with
the variation in the metal extraction being less than 10%.
Comparative extraction experiments were run in parallel under
identical conditions.
1,2-Bis(4-tert-butyl-2-hydroxymethylphenoxy)ethane. 1,2-Bis-
(4-tert-butyl-2-formylphenoxy)ethane 5 (R = t-Bu) (1.12 g, 2.94
mmol) was dissolved in dry ethanol (40 cm3) in a 100 cm3 one-
necked round-bottomed flask and NaBH4 (640 mg, 17 mmol)
was added. The clear solution was refluxed for 90 min, water
(100 cm3) was added, and the resulting mixture was refluxed for
5 min. After cooling the reaction mixture to room temperature,
it was extracted with ethylacetate (2 × 100 cm3); the combined
organic extracts were washed with NaHCO3 (2 × 100 cm3) and
water (100 cm3), then dried (anhydrous Na2SO4). Evaporation
of the solvent gave 1,2-bis(4-tert-butyl-2-hydroxymethylphen-
oxy)ethane as white crystals; yield 1.09 g (2.82 mmol, 96%); mp
123–124 ЊC (Found: C, 74.34; H, 9.10. Calc. for C24H34O4: C,
74.58; H, 8.87%). MS (EI): m/z = 386 (Mϩ). 1H-NMR (CDCl3)
δ 7.28 (d, 2H, J = Hz, arom. 3-H), 7.24 (dd, 2H, J1 = 3 Hz, J2 = 9
Hz, arom. 5-H), 6.84 (d, 2H, J = 9 Hz, arom. 6-H), 4.63 (s, 4H,
CH2OH), 4.37 (s, 4H, CH2CH2O), 3.20 (br s, 2H, CH2OH), 1.27
[s, 18H, C(CH3)3]. 13C-NMR (CDCl3) δ 154.16, 144.26, 128.98,
126.83, 125.50, 66.93, 62.08, 34.14, 31.43.
Unsymmetrical macrocycle 9. Dry methanol (50 cm3) and 3X
molecular sieves (20 cm3) were placed in a 500 cm3 three-necked
round-bottomed flask equipped with two 100 cm3 dropping
funnels, a reflux condenser and magnetic stirring. The mixture
was warmed to 50 ЊC (under N2) on an oil bath. 1,2-Bis(4-tert-
butyl-2-formylphenoxy)ethane 5 (R = t-Bu) (1.95 g, 5.10 mmol)
2396
J. Chem. Soc., Dalton Trans., 2001, 2388–2397

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11 X. X. Zhang, R. M. Izatt, J. S. Bradshaw and K. E. Krakowiak,
NMR induced chemical shift and relaxation studies
Coord. Chem. Rev., 1998, 174, 179.
1H and 13C NMR spectra for these studies were obtained on a
Varian Unity 400 spectrometer at 400 and 100 MHz, respect-
ively. The cryptand was dissolved in dimethylformamide-d7 (0.5
cm3) and placed in a 5 mm (o.d.) NMR tube. The cryptand
concentration was ca. 0.10 mol dmϪ3 in each case. To obtain the
induced chemical shift data, a stoichiometric amount of the
required metal nitrate was added directly to the tube con-
taining the cryptand solution and the mixture was shaken
until complete dissolution had ocurred. All metal nitrates
from lithium to caesium dissolved in the solution containing
1 (2.2.2), while rubidium and caesium nitrates yielded pre-
cipitates when added to the solution containing 2 (R = t-Bu)
and potassium, rubidium and caesium nitrates also produced a
precipitate on addition to the 4 (R = t-Bu) solution.
12 J.-M. Lehn, Acc. Chem. Res., 1978, 2, 49; C. Detellier, in
Comprehensive Supramolecular Chemistry, ed. J. L. Atwood, J. E. D.
Davies, D. D. MacNicol and F. Vögtle, Pergamon Press, Oxford,
1996, vol. 1, pp. 357–375.
13 T. W. Hambley, L. F. Lindoy, J. R. Reimers, P. Turner, G. Wei and
A. N. Widmer-Cooper, J. Chem. Soc., Dalton Trans., 2001, 614
and refs. therein.
14 R. W. Alder and S. P. East, Chem. Rev., 1996, 96, 2097.
15 H.-J. Buschmann, E. Schollmeyer, R. Trueltzsch and J. Beger,
Thermochim. Acta, 1993, 213, 11; V. P. Solov’ev, N. N. Strakhova,
O. A. Raevsky, V. Ruediger and H.-J. Schneider, J. Org. Chem., 1996,
61, 5221; A. Thaler, R. Bergter, T. Ossowski, B. G. Cox and H.
Schneider, Inorg. Chim. Acta, 1999, 285, 1; H.-J. Buschmann and E.
Schollmeyer, J. Inclusion Phenom. Macrocyclic Chem., 2000, 38, 85.
16 I. M. Atkinson, L. F. Lindoy, O. A. Matthews, G. V. Meehan, A. N.
Sobolev and A. H. White, Aust. J. Chem., 1994, 47, 1155.
17 K. E. Krakowiak, J. S. Bradshaw and D. J. Zamecka-Krakowiak,
Chem. Rev., 1989, 89, 929; K. E. Krakowiak and J. S. Bradshaw,
J. Org. Chem., 1991, 56, 3723.
Crystallographic data
᎐
18 L. F. Lindoy, G. V. Meehan and N. Svenstrup, Synthesis, 1998, 1029.
19 A. V. Bordunov, N. K. Dalley, X. Kou, J. S. Bradshaw and V. N.
Pastushok, J. Heterocyclic Chem., 1996, 33, 933.
20 K. W. Chi, H.-C. Wei, T. Kottke and R. J. Lagow, J. Org. Chem.,
1996, 61, 5684.
[NaL](picrate)ؒCH2Cl2 (L = 3 (R = H)) ᎐ C H N NaO ؒ
᎐
44 48
5
13
CH2Cl2, M = 961.8. Triclinic, space group P1 (Ci1, no. 2), a =
12.299(10), b = 14.264(11), c = 15.32(2) Å, α = 63.29(8),
β = 81.12(9), γ = 77.38(6)Њ, V = 2338 Å3. Dc (Z = 2) = 1.366
g
cmϪ3. µMo = 2.2 cmϪ1; specimen (capillary): 0.30 × 0.12 × 0.43
mm (no correction). Full sphere of single counter instrument
room temperature (T ca. 295 K) data (2θmax = 44Њ, 2θ/θ
scan mode; monochromatic Mo Kα radiation λ = 0.71073
Å) = 10081 reflections, merging to 5782 (Rint = 0.066) (no
absorption correction), 1228 (I > 3σ(I )) considered ‘observed’
and used in the full-matrix least-squares refinement (isotropic
non-hydrogen thermal parameter forms, (x, y, z, Uiso)H con-
strained at estimates; CH2Cl2 modelled as disordered, con-
strained geometry). Conventional R, RW (statistical weights) on
|F| 0.13, 0.14. Xtal 3.4 program system.43
21 See, for example: U. Olsher, H. Feinberg, F. Frolow and G. Shoham,
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Talanta, 1998, 47, 229; A. P. Marchang and H.-S. Chong,
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V. S. Talanov, R. E. Hanes, H.-S. Hwang, A. R. Bartsch and R. D.
Rogers, J. Am. Chem. Soc., 1999, 121, 11 281.
22 J. D. Lamb, J. J. Christensen, S. R. Izatt, K. Bedke, M. S. Astin and
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23 H.-J. Buschmann, Inorg. Chim. Acta, 1986, 125, 31.
24 Spartan Version 4.0, Wavefunction, Inc., 18401 Von Karman Ave.,
#370 Irvine, CA 92715, USA.
CCDC reference number 164829.
See http://www.rsc.org/suppdata/dt/b1/b102585f/ for crys-
tallographic data in CIF or other electronic format.
Acknowledgements
We acknowledge the support of the Australian Research
Council and thank Professor G. W. Everett and M.-A. Ahearn
for experimental assistance.
25 B. Metz, D. Moras and R. Weiss, J. Chem. Soc., Perkin Trans. 2,
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