Ligational properties of two new phenolic aza cages towards proton and alkali metal ions - A theoretical and an experimental approach

Article abstract of DOI:10.1002/1099-0682(200107)2001:7<1763::AID-EJIC1763>3.0.CO;2-F

Molecular Dynamics (MD) simulations were performed on several species (anion, zwitterion, and neutral metal complexes) of two phenolic aza cages (L1 and L2) in aqueous solution. The anionic species of the smaller L1 ligand appears to be able to selectivel

Full text of DOI:10.1002/1099-0682(200107)2001:7<1763::AID-EJIC1763>3.0.CO;2-F

FULL PAPER
Ligational Properties of Two New Phenolic Aza Cages towards Proton and
Alkali Metal Ions ؊ a Theoretical and an Experimental Approach
Paolo Dapporto,[a] Mauro Formica,[b] Vieri Fusi,*[b] Luca Giorgi,[b] Mauro Micheloni,*[b]
Roberto Pontellini,[b] Paola Paoli,*[a] and Patrizia Rossi[a]
Keywords: Synthesis / Aza cages / Crystal structures / Thermodynamics / Molecular dynamics
Molecular Dynamics (MD) simulations were performed on
logK2 = 7.39(5), logK3 = 1.4(1) for L1 and logK1 = 11.76(5),
several species (anion, zwitterion, and neutral metal com- logK2 = 8.24(5), logK3 = 2.9(2) for L2. The last proton cannot
plexes) of two phenolic aza cages (L1 and L2) in aqueous
solution. The anionic species of the smaller L1 ligand appears
be removed because both compounds are strongly basic un-
der the experimental conditions studied. Proton localization
to be able to selectively encapsulate Li+, while the other al- was studied by UV/Vis and NMR spectroscopy, both in water
kaline metal ions tested (Na+ and K+) are too large to be en-
capsulated. The larger cage L2 does not show any selectivity; [HL1](ClO4) and [NaL2](ClO4) were determined by X-ray
the anion binds all the alkaline metal ions. The two aza cages analysis. The crystals of [HL1](ClO4) are triclinic, space
and nonaqueous solutions. The crystal structures of
¯
L1 and L2 were synthesized. Both basicity and alkali metal group P(1); cell parameters are a = 10.3628(8), b = 11.938(1),
˚
complex formation were studied in aqueous solution at 25 °C
in 0.15 mol dm−3 Me4NCl, using potentiometric, UV/Vis- and
NMR-spectroscopic techniques. Both cages behave as trip-
c = 12.201(4) A, α = 117.53(1), β = 101.25(1), γ = 102.774°. The
crystals of [NaL2](ClO4) are monoclinic, space group P21/n;
cell parameters are a = 10.6154(7), b = 17.0418(9), c =
˚
rotic bases in the pH range investigated; logK1 = 12.15(6), 14.9452(9) A, β = 95.634(6)°.
Introduction
in our laboratories thus far is compound L (see
Scheme 1).[27] The ligand is able to selectively encapsulate
the lithium ion, a logK Ͼ3 is expected for the complexation
process Liϩ ϩ [HϪ1L]Ϫ ϭ [LiHϪ1L].[27] At 300 K the mole-
cule, both in the [H2L]2ϩ [27] and the [HϪ1L]Ϫ species, ap-
peared rather rigid in the MD simulations performed in
aqueous solution [the solvent was mimicked by using a dis-
tance-dependent dielectric constant ε(r) ϭ 80r, unpublished
results]. In particular, the phenolic moiety does not change
its orientation with respect to the [12]aneN4 ring. It is al-
most parallel to the trans-dimethylated tetraazamacrocycle
with the oxygen atom pointing ‘‘outside’’ the macrobicyclic
cavity. We designed the trial molecules L1 and L2 (see
Scheme 1) starting from this molecule, with the aim to ob-
tain a more flexible macrobicyclic skeleton which can better
accommodate the donors around the metal guest. The
promising theoretical results obtained encouraged us to
synthesize these two new molecules. Their ligational proper-
ties towards proton (i.e. their basicity) and alkali metal ions
were investigated both in solution (by potentiometric titra-
tions, UV/Vis and NMR spectra) and in the solid state (by
The design of macrocyclic molecules to achieve selective
host recognition is a widely used synthetic strategy.[1Ϫ6] To
complex small, spherical guests such as metal ions, only
macropolycyclic hosts are able to provide many binding
sites directed towards the guest in a convergent manner,
thus making the resulting metal complex thermodyn-
amically stable. A further advantage of cage-like hosts is
that solvation inside the cavity is weaker than with hosts
where the binding sites are more exposed to the solvent.[7]
Alkali and alkaline earth cations are the simplest guests;
they are spherical in shape and utilize only electrostatic
forces for binding. In order to achieve selectivity among the
alkali metal ions the size of the cavity of the macropoly-
cyclic host should exactly match that of the alkali metal ion.
In our laboratory we have synthesized many small aza
cages,[8Ϫ22] some of which are able to selectively encapsulate
the lithium ion.[11,13,15,17,18] In some cases these molecules
behave as ‘‘fast proton sponges’’,[8,9,11,12,19] indicating that
the smallest cation, the proton, is also selectively encapsul-
ated. In order to gain spectroscopic information about the
binding event, chromoionophores such as nitro and/or
phenolic groups have been inserted into the molecular
frameworks.[23Ϫ26] One of the latest small aza cages studied
[a]
‘‘Sergio Stecco’’ Department of Energy Engineering, University
of Florence,
Via S. Marta No. 3, 50139 Florence, Italy
[b]
Institute of Chemical Sciences, University of Urbino,
Piazza Rinascimento No. 6, 61029 Urbino, Italy
Fax: (internat.) ϩ 39-0722/350032
E-mail: mauro@chim.uniurb.it
Scheme 1. Drawing of the ligands
Eur. J. Inorg. Chem. 2001, 1763Ϫ1774
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
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1763

V. Fusi, M. Micheloni, P. Paoli et al.
FULL PAPER
˚
X-ray diffraction), and then compared with the modeled be-
havior.
Table 1. Mean X (center of donors)Ϫdonor atoms distances [A]
obtained from MD simulations and mean metalϪdonor bond
˚
lengths [A] obtained from the crystal structures of the metal (M ϭ
Liϩ, Naϩ, and Kϩ) complexes having nitrogen and/or oxygen
atoms as donors deposited at the CCDC
Results and Discussion
Molecular Dynamics Simulations
(i) Anion Species
[HϪ1L1]Ϫ
[HϪ1L2]Ϫ
Liϩ donor Naϩ donor Kϩ donor
XϪO1 2.78 XϪO1 2.61 LiϪN 2.2 NaϪN 2.5 KϪN 2.8
XϪN1 2.21 XϪN1 2.63 LiϪO 2.1
XϪN2 2.16 XϪN2 2.80
XϪN3 2.15 XϪN3 2.95
XϪN4 2.71 XϪN4 2.72
XϪN5 3.05
NaϪO 2.4
KϪO 2.8
During the MD simulation of [HϪ1L1]Ϫ, the dominant
conformation was found to be characterized by a phenolate
group which is nearly parallel to the mean plane described
by the four nitrogen atoms. In this case, the oxygen atom
of the bridging unit is always directed towards the methyl
moiety disposed above the trans-dimethylated cyclen ring.
As a consequence, during the MD run at least one
atom itself were calculated throughout the simulations.
Table 1 lists these average distances for the [HϪ1L1]Ϫ and
[HϪ1L2]Ϫ species, as well as an estimate of the
metalϪdonor bond lengths obtained from crystal structures
of metal (M ϭ Liϩ, Naϩ, and Kϩ) complexes having nitro-
gen and/or oxygen atoms as donors, which have been depos-
ited at the CCDC.[28] With regard to the [HϪ1L1]Ϫ ligand,
comparison between the distance values reported in Table 1
seems to indicate that the molecular cavity is too small to
encapsulate the sodium and potassium ions, whereas it is
well suited to the size of the Liϩ ion. On the contrary, the
donors of the larger [H-1L2]Ϫ host appear to be suitable to
bind the sodium and potassium cations, while the lighter
lithium is probably too small.
˚
ϪCH3···O intramolecular interaction (Ͻ 2.7 A) takes place.
The two trans-disposed methyl groups point in opposite dir-
ections with respect to the [12]aneN4 mean plane, with the
exception of just a few conformations. Figure 1 (a) reports
the average structure from snapshots of the coordinates for
[HϪ1L1]Ϫ. However, during the simulation time a few con-
formations were observed to have the phenolate moiety al-
most perpendicular to the [12]aneN4 ring. As expected, the
propyl chains allow the phenolate ring greater conforma-
tional freedom relative to the ligand L. In this regard the
[HϪ1L2]Ϫ anion is more rigid, with the benzene ring always
in the same orientation with respect to the 15-membered
ring. Thus, the lengthening of the polyaza ring does not
provide greater conformational freedom of the bridging
moiety. As in L and L1, the phenolate ring of L2 is almost
parallel to the N5 mean plane and the oxygen atom is ori-
ented towards the longer chain bearing the two methyl
groups of the [15]aneN5 base. The latter groups are always
pointing in the opposite direction to the [15]aneN5 ring,
while the third methyl group is always positioned below the
mean plane. Figure 1 shows the average conformation re-
sulting from MD. Furthermore, the collected conforma-
tions show at least one intramolecular interaction between
the phenolic oxygen atom and a hydrogen atom of a
methyl group.
(ii) Neutral Species
Both cages in their neutral form still contain one proton
and are zwitterions. The acidic hydrogen atom (H1) was
bound to a bridgehead nitrogen atom, as found in previous
work involving similar monoprotonated cages.[29] Once
again, during the MD runs the phenolate ring is almost
coplanar to the N4 and N5 mean planes of L1 and L2, re-
spectively. However, in L1 the propyl chains connecting the
phenolate group to the [12]aneN4 are more stretched out
than in the anionic form. As a result, the phenolic oxygen
atom is further from the mean N4 plane in L1 than in
[H؊1L1]Ϫ (see Figure 2, a), and the stabilization of the zwit-
terion can be entirely ascribed to the nitrogen atoms (vide
infra). Conversely, the introduction of an acidic proton
within the molecular framework of [H؊1L2]؊ does not sig-
nificantly affect the overall shape of the molecule, the only
noteworthy difference is that the two adjacent methylated
nitrogen atoms are always pointing above the N5 mean
plane (see Figure 2, b).
In order to gain some information concerning the relative
basicity of both compounds in the reaction [HϪ1L]Ϫ ϩ Hϩ
Ǟ L, the inter-atomic distances of the H···donor atoms
were collected during the simulations. In both zwitterions,
the acidic proton appears to be involved in essentially two
H-bonding interactions (see Table 2). In L1 the acidic hy-
Figure 1. Average conformation from snapshots of coordinates for
(a) [HϪ1L1]Ϫ, (b) [HϪ1L2]Ϫ
In order to evaluate the approximate size of the three- drogen atom interacts more closely with the two methylated
dimensional cavity inside the two macrocyclic ligands that nitrogen atoms. The interaction with the phenolic oxygen
is able to accommodate the cation, the distances between atom is weaker as it is more distant. Most conformations
the geometric center defined by the donors and each donor of the larger compound L2, show an NϪH···O hydrogen
1764
Eur. J. Inorg. Chem. 2001, 1763Ϫ1774

Ligational Properties of Phenolic Aza Cages towards Proton and Alkali Metal Ions
FULL PAPER
donor atoms were nitrogen atoms and the LiϪN distances
˚
were shorter (mean 2.04 A) than in [LiHϪ1L1]. Further-
more, in the lithium complex with 4,7,13-trioxa-1,10-diaza-
bicyclo[8.5.5]icosane (FENHIP[30]), whose chain lengths are
comparable with those of L2, the coordination distances are
very similar to those observed during the MD simulation of
[LiHϪ1L2] (vide infra).
˚
Table 3. Mean MϪdonor atoms distances [A] obtained from MD
simulations
H
Ϫ1L1
LiHϪ1L2
Figure 2. Average conformation from snapshots of coordinates for
(a) [L1], (b) [L2]
LiϪO1 1.75
LiϪN1 2.34
LiϪN2 2.09
LiϪN3 2.21
LiϪN4 2.13
LiϪO1 1.81
LiϪN1 2.79
LiϪN2 2.29
LiϪN3 2.44
LiϪN4 2.17
LiϪN5 2.90
˚
Table 2. Mean HϪdonor atoms distances [A] obtained from MD
simulations
L1
L2
NaHϪ1L2
KHϪ1L2
HϪO1 4.15
HϪN1 3.61
HϪN2 2.41
HϪN4 2.62
HϪO1 2.34
HϪN2 3.92
HϪN3 3.92
HϪN4 4.46
HϪN5 2.66
NaϪO1 2.15
NaϪN1 2.66
NaϪN2 2.47
NaϪN3 2.59
NaϪN4 2.63
NaϪN5 2.44
KϪO1 2.51
KϪN1 2.76
KϪN2 2.72
KϪN3 2.72
KϪN4 2.71
KϪN5 2.63
bond and an interaction involving the closer methylated ni-
trogen atom N5 belonging to the longer arm of the
[15]aneN5 ring. In both forms the mean H···acceptor dis-
tances are very similar; as a result, we can infer that the
basicity properties of the two polyaminic bases should be
similar.
(iii)؊(iv) Metal Complexes
The results from the simulations performed in the two
media studied are practically identical. Table 3 reports the
average distances of the MϪdonors extracted from the MD
simulations. In both cases [H؊1L1]؊ appears to be able to
bind only the smallest alkaline cation. The sodium ion
comes out from the molecular cavity, remaining close to the
phenolic oxygen atom throughout the entire simulation
Figure 3. Average conformation from snapshots of coordinates for
(a) [LiL1], (b) [LiL2]
˚
time (mean NaϪO distance 2.22 A). The largest ion, potas-
The [HϪ1L2] species behaved in a similar manner towards
sium, moves away from the macrocycle very quickly, thus the lithium, sodium, and potassium cations. During the
confirming the results of the preliminary studies concerning MD runs the cation was encapsulated within the ligand cav-
the cavity size of the ligands in the anionic form. The mean ity in all cases. These results seem to indicate that the larger
LiϪN distances monitored during the MD run ranged from ligand is not a selective binder of the lithium ion. In the
˚
2.09 to 2.34 A. The phenolic oxygen atom interacts strongly [LiHϪ1L2] complex the mean LiϪN distances range from
˚
˚
˚
with the lithium cation. The mean LiϪO distance is 1.75 A, 2.2 to 2.9 A, with a mean LiϪO bond length of 1.8 A (see
with the LiϪO bond pointing inside the molecular cavity. Table 3). Essentially, the molecular cavity appears to be too
As a result of this interaction, the phenyl ring is almost large to accommodate the smallest alkaline cation, while
perpendicular to the N4 ring and the overall shape of the the monitored MϪdonor distances for the sodium and pot-
metal complex is different from that observed for the anion assium complexes are in agreement with the corresponding
and the zwitterion (see Figure 3, a). The coordination geo- experimental values retrieved from the CCDC. In terms of
metry around the metal guest is trigonal-bipyramidal, with bond lengths, the coordination of the lithium ion appears
the bridgehead nitrogen atoms occupying the axial posi- to be of the 4ϩ2 type which is in agreement with the trend
tions, as already found in the solid-state X-ray structures of observed in the solid-state structures of hexacoordinated
analogous tbp macrobicycleϪLiϩ complexes (SEKSAC[15a] LiϩϪmacrobicyclic complexes with nitrogen and/or oxygen
and SONJAC[17] refcode). In the latter complexes, all the donor atoms, retrieved from the CCDC.
Eur. J. Inorg. Chem. 2001, 1763Ϫ1774
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V. Fusi, M. Micheloni, P. Paoli et al.
FULL PAPER
The phenyl ring gradually changes its orientation with from 10 using a classic elongation method of an alkyl chain.
respect to the N5 mean plane, in the lithium complex it is The cyclization of 15 with the macrocyclic aza base 17,
almost perpendicular, while in the potassium one it is al- gives the phenol-protected cage 19. For both ligands 18 and
most coplanar (see Figure 3, b, and Figure 4).
19, no template effect was found in the cyclization step;
moreover, they were deprotected in the same way, with so-
dium ethanethiolate in DMF. This afforded the phenolic
aza cages L1 and L2, after the purification steps.
Figure 4. Average conformation from snapshots of coordinates for
(a) [NaL2], (b) [KL2]
Figure 6. Synthetic procedure to obtain macrocycle 7
Synthesis
The cages L1 and L2 were prepared according to the syn-
thetic procedures depicted in Figure 5. The two cages were
obtained by following the synthetic procedure reported for
the analogous phenolic aza cage L.[25] This procedure in-
volves the use of a dimesyl derivative of 2,6-dimethylani-
sole, and of an aza crown base as the reactants to increase
the 1 ϩ 1 product in the final cyclization. In order to obtain
L2, the new aza crown base 7 was synthesized (see Fig-
ure 6). The synthesis of 7, according to the RichmanϪ
Atkins method, requires the use of the ditosylated polyam-
ine 3, obtained by the extension of N,NЈ-dimethylethylendi-
amine (1) with 2 equiv. of N-(p-tolylsulfonyl)aziridine (2).
The reaction of the disodium salt of 3 with bis(2-chloro-
ethyl)methylamine (5) in DMF leads to the ditosylated
macrocycle 6, which was detosylated with strong acid giving
7. By treating the aza base
7 with methyl 2-[2-
methoxy-3-(2-methylsulfonyloxyethyl)phenyl]ethane-
sulfonate (16) in acetonitrile in the presence of an alkaline
carbonate base, we obtained the phenol-protected cage 18
(see Figure 5). To synthesize the cage L1, a longer dimesyl
derivative 15 of 2,6-dimethylanisole was prepared (see Fig-
ure 7). In order to obtain reagent 10, which is the starting
material used to prepare 15, we followed a different syn-
thetic scheme than that reported previously,[31] thus achiev-
ing a higher reaction yield. Compound 15 was obtained
Figure 7. Synthetic procedure to obtain intermediate compounds
for the synthesis of L1
Protonation and Complex Formation Equilibria
Table 4 reports the protonation constants of L1 and L2.
The ligands have a total of five and six protonation sites
respectively, and all of the nitrogen atoms are tertiary. Both
cages accept three protons under the experimental condi-
tions employed. It should be noted that both cages in their
neutral species still contain one proton. This proton cannot
be removed in the pH range investigated because the fully
Figure 5. Synthetic pathway used to obtain compounds L1 and L2 deprotonated species [HϪ1L1]Ϫ and [HϪ1L2]Ϫ are strongly
1766 Eur. J. Inorg. Chem. 2001, 1763Ϫ1774

Ligational Properties of Phenolic Aza Cages towards Proton and Alkali Metal Ions
FULL PAPER
basic. As expected, the molecular topology strongly influ- chargeϪcharge separation in water is successful, however,
ences the basicity behavior of L1 and L2; both compounds in methanol it is not. Nevertheless, it was possible to record
are much stronger bases than both the phenolate and the the spectrum of the [HL1]ϩ species in methanol which
polyaminic tertiary nitrogen atom.[32]
shows a different absorption spectrum from the previous
ones. Two bands appear at λmax ϭ 236 nm (ελmax ϭ 4300
Ϫ1 cmϪ1) and λmax ϭ 292 nm (ελmax ϭ 700 Ϫ1 cmϪ1).
The spectrum is similar to that recorded in aqueous solu-
tion at an alkaline pH value, highlighting the presence of
the phenolate form in the [HL1]ϩ species in methanol.
1H and 13C NMR spectra were recorded to better analyze
Table 4. Protonation constants of L1 and L2 (log K) determined
by potentiometry in 0.15 mol dmϪ3 Me4NCl aqueous solution at
298Ϯ0.1 K
Reaction
L1
L2
1
the [HL1]ϩ species in solution. The H NMR spectrum of
L ϩ Hϩ ϭ HLϩ
HLϩ ϩ Hϩ ϭ H2L2ϩ
H2L2ϩ ϩ Hϩ ϭ H3L3ϩ
12.15(6)[a]
7.39(5)
1.4(1)
11.76(5)
8.24(5)
2.9(2)
the [HL1]ϩ species, carried out in CDCl3, is shown in Fig-
ure 8a. It shows a broad deshielded resonance at δ ϭ 9.97
integrating for two protons which can be assigned to the
acidic protons of the ligand. After the addition of a small
amount of H2O or CH3OH to the chloroform solution, the
[a] Values in parentheses are the standard deviation to the last signi-
ficant figure.
In order to understand how the phenolic moiety is in- signal remains. This indicates a slow exchange, on the NMR
volved in the protonation steps, absorption electronic spec- time scale, of the two protons with the mobile protons of
tra and NMR experiments were performed on the com- the solvent. However, when D2O or CD3OD was added the
pounds L1 and L2 in water and in nonaqueous solvents. resonance disappeared. These experimental data suggest
For both ligands, the absorption and NMR spectra show that the two protons are positioned inside the macrocyclic
the involvement of the phenolic group in the protonation cavity and are stabilized by a strong hydrogen-bonding net-
steps. For example, the UV spectra of L1 recorded in aque- work involving the donor functions. This is in agreement
1
ous solution, are different in acidic and basic solution. The with the X-ray structure (vide infra). The H NMR spec-
spectrum shows a band with λmax ϭ 272 nm (ελmax ϭ 950 trum of the same species recorded in CD3OD (Figure 8, b)
Ϫ1 cmϪ1) in the acidic region, while at a pH value slightly reveals the disappearance of the deshielded resonance, while
over 12, where the neutral species is prevalent in solution, the pattern of the other resonances remain quite similar.
two bands appear in the spectra at λmax ϭ 239 (ελmax
ϭ
The addition of Me4NOH to the species [HL1]ϩ in CD3OD
5900 Ϫ1 cmϪ1) and 295 nm (ελmax ϭ 2600 Ϫ1 cmϪ1). This solution (Figure 8, c) leads to a downfield shift of the triplet
latter spectrum is also maintained at more alkaline pH
values. The different behavior of the chromophore in the
acidic and basic solution is due to the presence of the
phenol hydroxy form at low pH values and to the phenolate
form at high pH values. This spectral feature suggests that
in the neutral species the ligand is in the zwitterionic form
in aqueous solution, with the acidic proton located on the
aza base. 1H NMR spectra of L1 recorded in aqueous solu-
tion, confirmed this hypothesis. The spectrum at pH ϭ 2 in
fact shows broad resonances in the aliphatic field, while the
aromatic protons give rise to a doublet at δ ϭ 7.15 integrat-
ing for two protons (the aromatic protons in meta position),
and a triplet at δ ϭ 7.00 integrating for one proton (the
aromatic proton in para position). These resonances un-
dergo an upfield shift in the spectrum recorded at pH ϭ 12,
resonating at δ ϭ 6.86 and 6.38 for the doublet and the
triplet, respectively. This indicates the deprotonation of the
phenolic group at alkaline pH values. Compound L2 shows
a similar behavior with very small differences in wave-
lengths and in chemical shifts.
The behavior of L1 and L2 is different in methanol. The
absorption spectra for the phenolic group do not change
significantly in acidic or strong alkaline solution, the max-
imum wavelength and molar absorptivity remain the same
[one band with λmax ϭ 276 nm (ε ϭ 1400 Ϫ1 cmϪ1)]. In
other words, the phenolic group appears in its hydroxy form
1
1
Figure 8. (a) The H NMR spectrum of [HL1]ϩ in CDCl3, (b) H
even in the neutral species. This behavior was also found
NMR spectrum of [HL1]ϩ in CD3OD, (c) 1H NMR spectrum after
the addition of Me4NOH, (d) H NMR spectrum of [LiH-1L1] in
for L, as already reported,[27] and can be explained by the
1
different solvating power of the two media; the CD3OD
Eur. J. Inorg. Chem. 2001, 1763Ϫ1774
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V. Fusi, M. Micheloni, P. Paoli et al.
FULL PAPER
due to the aromatic proton in the para position, together free lithium. The independence of the 7Li chemical shift
with an upfield shift of almost all the aliphatic resonances, from the solvent, and the slow exchange on the NMR time
thus indicating the loss of positive charge density on the scale between the free and bound lithium ion suggest that
amine groups and the protonation of the phenolate oxygen it is encapsulated inside the macrocyclic cavity and hence is
atom. This is in agreement with the UV spectra. In conclu- quite isolated from the medium. The 1H NMR spectrum of
sion we can say that in the [HL1]ϩ species, the nature of the [LiHϪ1L1] in CD3OD (see Figure 8 spectrum d) shows a
the acidic proton, in water and in organic solvents, seems marked upfield shift of the triplet signal due to the aromatic
to be the same as that found in the solid state. In organic proton in the para position relative to that of the neutral
solvents the removal of one proton results in the redistribu- species (see Figure 8 spectrum c). This suggests the depro-
tion of the last acidic proton, it is located on the oxygen tonation of the phenol group with lithium complexation.
atom. However, in aqueous solution the last acidic proton The 1H NMR spectrum of the lithium complex recorded in
remains on the aza base. The 13C NMR spectra recorded aqueous solution shows broader signals with approximately
in the same solvents, also support this hypothesis. More- the same chemical shifts in the resonances. The UV spectra
over, L2 and the smallest compound L display similar be- recorded in water and in methanol of the lithium complex
havior.[27]
show the two characteristic bands of the phenolate form
with an increased molar absorptivity in water with respect
to the free ligand at the same pH values [λmax ϭ 241 nm
(ελmax ϭ 8250 Ϫ1 cmϪ1), λmax ϭ 296 nm (ελmax ϭ 4200
Alkali Metal Ions Complexation
The coordination of the alkali metal ions by ligands L1 Ϫ1 cmϪ1)].
and L2 was also investigated by H, 13C, and Li NMR
spectroscopy and by UV/Vis absorption electronic spectra
in water and in organic solvents. Potentiometry was also
employed to investigate the formation equilibria of alkali
metal complexes (see Table 5). The equilibrium constants
reported in Table 5 refer to an overall process in which the
alkali metal ion Mϩ is bound and, at the same time, the
last proton present in the cages is removed, yielding a neut-
ral species MHϪ1L [Mϩ ϩ L ϭ MHϪ1L ϩ Hϩ]. The
stability constants relative to the net complexation process
1
7
Table 5. Logarithms of the equilibrium constants determined in
0.15 mol dmϪ3 Me4NCl at 298.1 K for the complexation reactions
of L1 and L2 with Liϩ, Naϩ, and Kϩ ions
Liϩ
Naϩ
Kϩ
Mϩ ϩ L1 ϭ MHϪ1L1 ϩ Hϩ
Mϩ ϩ L2 ϭ MHϪ1L2 ϩ Hϩ
Ϫ8.03
Ϫ8.91
Ϫ
Ϫ8.33
Ϫ
Ϫ8.65
A different behavior is shown by the larger compound
Mϩ ϩ HϪ1LϪ ϭ MHϪ1L can only be estimated since the L2. No selectivity was found in aqueous solution by the
first protonation constant for both cages L1 and L2 is too spectroscopic techniques which is in agreement with the
high to be measured under the chosen experimental condi- MD simulations. However, some interesting aspects were
7
tions. The logK value for the first protonation step Hϩ
ϩ
revealed. The Li NMR spectra recorded in aqueous solu-
H
Ϫ1L ϭ L should be greater than 12.15 and 11.76 for L1 tion and in methanol show only one signal that rapidly in-
and L2, respectively. Also, logK Ͼ 4 and logK Ͼ 3 are ex- terchanges with the free lithium ion, thus denoting the easy
pected for the net complexation process (Liϩ ϩ HϪ1LϪ
access of the solvent to the ion sphere, together with the
ϭ
LiL) for L1 and L2, respectively, since the values for the poor fit of the ion in the macrocyclic cavity as previously
complexation of Liϩ (8.03 and 8.91, see Table 5) should be inferred from MD simulation results. In both media, the 1H
subtracted. For cage L2 all three metal ions can be com- NMR spectra of the [MH-1L2] metal complexes reveal the
plexed, potentiometric studies show that the estimated lack of selectivity of the ligand; for example, the spectrum
stability constants are very similar (see Table 5). For ligand of each complex can also be obtained by adding a small
L1, the spectroscopic experiments do not reveal any com- excess of the metal ion to a solution of another complex.
plex formation with sodium and potassium ions in water or However, some interesting results were found in the case of
in the alcohol solution. L1 does form a complex with the the sodium complexes. Solution studies performed in meth-
smallest ion Liϩ and the complex was also isolated in the anol in fact reveal that the [NaL2]ϩ species, which is prob-
solid state. As is often the case with aza cage lithium com- ably in a conformation similar to that found in the crystal
plexes,[11,13,15,17,18] the solid complex is soluble in organic structure, rapidly evolves into another species upon addi-
7
solvents such as CDCl3. The Li NMR spectrum shows a tion of a small amount of a base. This is well depicted by
1
sharp peak which is shifted downfield (0.53 ppm) with re- monitoring the aromatic region of the H NMR spectra of
spect to that of the free Liϩ ion. The spectra of [LiHϪ1L1] [NaL2]ϩ and the UV/Vis absorption electronic spectra of
show the same signal with an approximately equal chemical these species (Figure 9). The new species corresponds to
shift both in water and in methanol. When an excess that of the [NaHϪ1L2] sodium complex which is isolated in
amount of Liϩ is added to the solution of the complex, the the solid state as reported in the Exp. Sect. As depicted in
7Li NMR spectrum shows the appearance of a new sharp the aromatic part of the 1H NMR spectrum of the
peak at δ ϭ 0 due to the free lithium ion, together with that [NaHϪ1L2] species, there are two stable conformers on the
of the complexed lithium ion. The simultaneous presence NMR time scale that give rise to a high number of signals
of two peaks in the spectrum denotes a slow exchange (on in the 13C NMR spectra as well (see Exp. Sect.). However,
the NMR time scale) of the complexed lithium ion with the in both conformers, the upfield shift of the proton located
1768
Eur. J. Inorg. Chem. 2001, 1763Ϫ1774

Ligational Properties of Phenolic Aza Cages towards Proton and Alkali Metal Ions
FULL PAPER
in the para position, as compared with that in the [NaL2]ϩ group. The nitrogen atoms N2 and N4 are on the opposite
spectrum, suggests the deprotonation of the phenolic group side of the N4 mean plane, with their bonded methyl groups
of L2 due to metal complexation. This hypothesis was con- equatorial and axial with respect to the N4 mean plane,
firmed by the comparison of the UV spectra of the [NaL2]ϩ respectively. In the crystal there are no strong intermolecu-
and [NaHϪ1L2] complexes, each of which has the spectral lar interactions. The conformation assumed by the
characteristics of one of the two forms of the phenol, thus [12]aneN4 ring is of the [2424] C-corners type.[34] This is not
suggesting a conformation of [NaL2]ϩin solution which is a very common conformation for this class of compounds;
similar to that found in the solid state and leading to the in fact, the analysis of the solid-state structures collected in
deprotonation of the ligand in more basic solutions.
the Cambridge Structural Database v.5.19 revealed that the
most common conformation assumed by [12]aneN4 dipro-
tonated rings is [3333].
Figure 10. ORTEP view of the [HL1]ϩ cation
Figure 9. (a) The 1H NMR spectra of the Naϩ/L2 system, (b) UV/
Vis absorption electronic spectra of [NaL2]ϩ and [NaHϪ1L2]
Table 6. Crystal data and structure refinement for [HL1](ClO4)
and [NaL2](ClO4)
Empirical formula
Molecular mass
Temperature [K]
C22H39ClN4O5 C23H41ClN5NaO5
X-ray Structures
[HL1]؉(ClO4)؊
The crystal structure consists of [HL1]ϩ cations and
(ClO4)Ϫ anions. Figure 10 shows an ORTEP[33] view of the
[HL1]ϩ cation with the atom labelling. Crystal and struc-
ture refinement data are reported in Table 6. With regard
to the protonation sites, the two acidic hydrogen atoms are
bound to the bridgehead nitrogen atoms N1 and N3 and
form short hydrogen bonds with the oxygen atom O1
475.02
293
1.5418
526.05
293
1.5418
monoclinic, P21/n
˚
λ [A]
¯
Crystal system, space group triclinic, P(1)
˚
Unit cell dimensions[A, °]
a ϭ 10.3628(8), a ϭ 10.6154(7)
α ϭ 117.53(1)
b ϭ 11.938(1),
β ϭ 101.25(1)
c ϭ 12.201(4),
γ ϭ 102.774(9)
1225.9(9)
b ϭ 17.0418(9),
β ϭ 95.634(6)
c ϭ 14.9452(9)
3
˚
Volume [A ]
2690.6(2)
4
˚
[H1N···O1 1.70(7), H3N···O1 1.79(6) A]. The interactions
Z
2
Calculated density [g/cm3]
1.287
1.706
1.299
1.763
between these hydrogen atoms and the other two donor
atoms (N2 and N4) are significantly weaker than those in-
volving the oxygen atom with distances 2.56(7) and 2.90(7)
µ [mmϪ1
]
Final R indices [I Ͼ 2σ(I)]
R1 ϭ 0.0519,
wR2 ϭ 0.1408
R1 ϭ 0.0653,
wR2 ϭ 0.1564
R1 ϭ 0.0682,
wR2 ϭ 0.1948
R1 ϭ 0.0848,
wR2 ϭ 0.2135
˚
A for [H3N···N2] and [H1N···N2], respectively, and 2.67(5)
R indices (all data)
˚
and 2.79(5) A for [H1N···N4] and [H3N···N4], respectively.
The atoms N1 and N3 are pointing toward the phenolic
Eur. J. Inorg. Chem. 2001, 1763Ϫ1774
1769

V. Fusi, M. Micheloni, P. Paoli et al.
FULL PAPER
[NaL2]؉(ClO4)؊
ϩ
˚
Table 7. Selected bonds lengths [A] and angles [°] for [NaL2]
The structure consists of [NaL2]ϩ cations and of (ClO4)Ϫ
anions. Figure 11 shows a perspective view of the complex
cation. In Table 6 crystal and structure refinement data are
reported. Selected bond lengths and angles are given in
Table 7. The sodium ion is bound to the five nitrogen atoms
of the ligand and to the oxygen atom of the phenol group.
The coordination geometry around the sodium ion can be
described as a strongly distorted pyramid having a penta-
gonal base, with the apex occupied by the oxygen atom.
The five nitrogen atoms at the corners of the pentagonal
base are not in a plane as seen by the deviations from the
mean plane passing through them [minimum deviation
NaϪO(1)
NaϪN(4)
NaϪN(2)
NaϪN(5)
NaϪN(1)
NaϪN(3)
2.301(3)
2.455(3)
2.473(3)
2.504(3)
2.667(3)
2.731(3)
O(1)ϪNaϪN(4)
O(1)ϪNaϪN(2)
N(4)ϪNaϪN(2)
O(1)ϪNaϪN(5)
N(4)ϪNaϪN(5)
N(2)ϪNaϪN(5)
O(1)ϪNaϪN(1)
N(4)ϪNaϪN(1)
N(2)ϪNaϪN(1)
N(5)ϪNaϪN(1)
O(1)ϪNaϪN(3)
N(4)ϪNaϪN(3)
N(2)ϪNaϪN(3)
N(5)ϪNaϪN(3)
N(1)ϪNaϪN(3)
109.61(11)
132.82(10)
108.91(12)
94.87(12)
73.05(16)
121.84(13)
91.30(11)
141.78(14)
74.24(12)
73.62(15)
93.60(10)
72.59(13)
73.15(11)
145.49(15)
139.54(13)
˚
˚
0.045(3) A (N5), maximum deviation 0.750(3) A (N3),
˚
˚
mean deviation 0.507(3) A]. The NaϪN distances range
from 2.455(3) to 2.731(3) A. It is worthy to note that the
two bridgehead nitrogen atoms are significantly further (see
Table 7), perhaps because of the conformational require-
ments of the ethylenic chains connecting the phenol ring to
the 15-membered macrocycle. The complex cation possesses
a pseudo-symmetry plane crossing the phenol moiety and
the bond between the C17 and C18 atoms. In this plane
lie the Na, N2, and O1 atoms. An examination of the
dihedral angles of the macrobicycle shows that the greatest
deviation from this pseudo-symmetry is due to the
N4ϪC17ϪC18ϪN5 fragment; the dihedral angle around
N4ϪC17 is Ϫ175°, versus a value of 96° for the angle about
the N5ϪC18 bond. The phenol ring forms an angle of
18.4(1)° with the N5 mean plane. Both the methyl groups
bound to N4 and N5 are pointing towards the same side of
the N5 ring, with the other methyl group (bound to N2)
pointing in the opposite direction. This is in agreement with
the results of MD simulations performed on the zwitter-
ionic species. No interesting intramolecular interactions
were observed, while a short intermolecular interaction be-
tween the hydrogen atom of the phenol group and an oxy-
gen atom of the perchlorate anion was observed
˚
[O1ϪH10····O2 ϭ 2.09(4) A].
Experimental Section
General Remarks: 1H, 13C, and 7Li NMR spectra were recorded
with a Bruker AC-200 instrument, operating at 200.13, 50.33, and
77.78 MHz, respectively. In the 1H NMR experiments peak posi-
tions are reported in relation to HOD (δ ϭ 4.75) and dioxane was
used as the reference in the 13C NMR spectra (δ ϭ 67.4). 7Li peaks
are reported in relation to free LiClO4. 1H-1H and 1H-13C correla-
tion experiments were performed to assign the signals. Solvents and
starting products were used as purchased.
Molecular Dynamics (MD) Simulation Protocol: The studied spe-
cies were the anions [HϪ1L1]Ϫ and [HϪ1L2]Ϫ, the neutral ligands
L1 and L2 (zwitterionic forms) and the neutral metal complexes
M[HϪ1L1] and M[HϪ1L2] (M ϭ Liϩ, Naϩ, and Kϩ). The MSI
software programs InsightII and Discover version 98.0[35] were used
for all the molecular modeling studies. Based on the good results
of a previous computational study performed on monoprotonated
macrocyclic compounds[29] of the same family, the Amber[36] force
field was used (all the 1Ϫ4 nonbonding interactions were scaled
by a factor of 0.5). Atomic charge distributions were calculated
according to the ChelpG scheme at the single point 6Ϫ31G* level
of theory using Guassian94 (revision D3).[37] As initial geometries
for each species in vacuo, fully optimized model-built structures
were used. In addition, before starting with the MD procedures the
initial molecular assembly was further optimized until the conver-
gence criterion was met (Ͻ 0.01 kcal molϪ1). The MD simulation
temperature was set at 298 K and the Verlet leapfrog algorithm,
with a time step of 1 fs, was used for integration of equations of
˚
motion in all simulations. In energy calculations 9.5 and 12.5 A
˚
nonbonded cutoff distances (buffer width 0.5 A) were employed for
van der Waals and Coulomb terms, respectively. In a preliminary
Figure 11. ORTEP view of the [NaL2]ϩ complex
1770
Eur. J. Inorg. Chem. 2001, 1763Ϫ1774

Ligational Properties of Phenolic Aza Cages towards Proton and Alkali Metal Ions
FULL PAPER
MD study (i) on the [H؊1L1]Ϫ and [H؊1L2]Ϫ species, performed
to evaluate the molecular cavity, the system was allowed to equilib-
rate for 8 ps, then MD simulations were run for 80 ps with snapshot
conformations saved every ps, and a distance-dependent dielectric
constant [ε(r) ϭ 80r] was used. The dynamic behavior of the zwit-
der reduced pressure. The solid residue was dissolved in dry DMF
(50 mL) and to the resulting solution, heated at 110 °C, a solution
of bis(2-chloroethyl)methylamine (5) (1.6 g, 0.01 mol), dissolved in
100 mL of dry DMF, was added. The reaction mixture was stirred
over a period of 4 h. It was kept at 110 °C for a further 2 h. The
terionic ligand forms, L1 and L2, (ii) was investigated by placing suspension was then cooled, filtered, and concentrated under re-
˚
the studied species in a cubic cell (25 A edge) containing SPC
duced pressure to give a yellowish solid, which was chromato-
model water molecules (equilibration time 8 ps, data collection time graphed on neutral alumina using CHCl3 as the eluent. The eluted
80 ps, snapshot conformations saved every ps). The geometry of the fractions containing the product having Rf ϭ 0.77 were collected
water molecules was fixed by means of the rattle option. Periodic and concentrated to dryness, affording 6 as a white solid. Yield:
boundary conditions were applied. In addition, calculations on
3.1 g (55%). Ϫ C27H43N5O4S2 (565.8): calcd. C 57.32, H 7.66, N
M[H؊1L1] and M[HϪ1L2] were performed both by mimicking the 12.38; found C 57.5, H 7.7, N 12.5. Ϫ MS (FAB): 567 [M ϩ Hϩ].
1
solvent with a distance-dependent dielectric constant ε(r) ϭ 80r
[equilibration time 20 ps, data collection time 200 ps, (iii)] and by
surrounding the solute species with water molecules occupying the
Ϫ H NMR (CDCl3, 25 °C): δ ϭ 2.14 (s, 6 H), 2.37 (s, 3 H), 2.42
(s, 6 H), 2.54 (t, 4 H), 2.67 (t, 4 H), 2.96 (s, 4 H), 3.28 (m, 8 H)
7.28 (d, 4 H), 7.68 (d, 4 H). Ϫ 13C NMR (CDCl3, 25 °C): δ ϭ 21.5,
42.5, 43.7, 46.9, 47.4, 55.6, 56.4, 58.4 127.1, 129.7, 136.7, 143.2.
˚
volume of a cube (25 A edge) as previously reported (iv).
Spectrophotometric Measurements: Absorption spectra were re-
corded at 298 K with a Varian Cary-100 spectrophotometer,
equipped with a temperature control unit.
1,7,10-Trimethyl-1,4,7,10,13-pentaazacyclopentadecane (7): A solu-
tion of 6 (3.0 g, 0.005 mol) was dissolved in 8 mL of 96% H2SO4
and the resulting solution kept at 100 °C for 72 h. The solution was
cooled and added to 200 mL of diethyl ether with stirring. It gave
a brown solid, which was filtered and washed with diethyl ether.
The residue was dissolved in the minimum amount of water and
made alkaline with concentrated aqueous NaOH. The Na2SO4 pre-
cipitate was filtered off and the alkaline solution was extracted with
CHCl3 (6 ϫ 100 mL). The organic solutions were combined, dried
with Na2SO4 and concentrated under reduced pressure to obtain 7
as a colorless oil. Yield: 1.2 g (88%). Ϫ C13H31N5 (257.4): calcd. C
60.66, H 12.14, N 27.21; found C 60.5, H 12.3, N 27.0. Ϫ 1H NMR
(CDCl3, 25 °C): δ ϭ 2.13 (s, 6 H), 2.24 (s, 3 H), 2.41 (m, 8 H), 2.51
(t, 4 H), 2.67 (t, 4 H), 2.76 (s, 4 H),. Ϫ 13C NMR (CDCl3, 25 °C):
δ ϭ 42.1, 42.4, 47.1, 47.2, 55.6, 57.0, 57.5.
Potentiometric Measurements: All potentiometric measurements
were carried out in 0.15 mol dmϪ3 Me4NCl at 298.0Ϯ0.1 K, in the
pH range 2.4Ϫ10.5, using the fully automatic equipment that has
already been described.[38] The emf data were acquired with the
PASAT computer program.[38] The electrode was calibrated as a
hydrogen concentration probe by titrating known amounts of HCl
with CO2-free Me4NOH solutions and determining the equivalent
point by Gran’s method,[39] which gives the standard potential E°
and the ionic product of water Kw. At least two to three measure-
ments were performed for each ligand. The HYPERQUAD[40]
computer programs were used to process the potentiometric data
and calculate the protonation constants.
Diethyl
2-{3-[2,2-Bis(ethoxycarbonyl)ethyl]-2-methoxybenzyl}-
Ligand Synthesis: The precursor reagents 7 and 15 were synthesized
as depicted in Figure 6 and Figure 7, respectively. Ligands L1 and
L2 were obtained according to the synthetic procedure reported in
Figure 5. N-(p-Tolylsulfonyl)aziridine (2),[41] bis(2-chloroethyl)me-
thylamine (5),[42] 2,6-bis(bromomethyl)anisole (8),[43] and 16[43]
were prepared as previously described. The solvents and the start-
ing materials not mentioned were used as purchased. All reactions
were carried out under nitrogen.
malonate (10): A solution of 8 (11.8 g, 0.04 mol) in 150 mL of
acetonitrile was added to a refluxing suspension of 9 (12.8 g, 0.08
mol) and K2CO3 (27.6 g, 0.2 mol) in 300 mL of acetonitrile over a
period of 1 h. The reaction mixture was maintained under reflux
for a further 3 d. The mixture was then cooled to room temperature
and the resulting suspension was filtered and the solution concen-
trated under reduced pressure, giving the crude product, which was
chromatographed on neutral alumina (CHCl3). The eluted frac-
tions (Rf ϭ 0.79) were collected and concentrated to dryness, af-
fording 10 as a colorless oil. Yield: 16.7 g (92%). Ϫ C23H32O9
4,7-Dimethyl-1,10-bis(p-tolylsulfonyl)-1,4,7,10-tetraazadecane (3): A
solution of N-(p-tolylsulfonyl)aziridine (6.7 g, 0.034 mol) in anhyd-
rous benzene (200 mL) was added dropwise at room temperature to
a stirred solution of N,NЈ-dimethyl-1,2-ethylendiamine (3.0 g, 0.034
mol) in anhydrous benzene (400 mL) over a period of 7 h. The
resulting solution was kept at room temperature for ca. 12 h and
then a further 6.7 g (0.0034 mol) of 2 in 200 mL of benzene was
added under the same experimental conditions. After 12 h, the tur-
bid solution was filtered and concentrated under reduced pressure
to give the crude compound 3 as a yellowish solid. The product
was dissolved in 150 mL of ethanol and an excess of 37% HCl was
added to the solution, obtaining 3 as the dihydrochloride salt.
Yield: 14.7 g (78%). Ϫ C22H36Cl2N4O4S2 (555.6): calcd. C 47.56, H
1
(452.5): calcd. C 61.05, H 7.13; found C 60.9, H 7.2. Ϫ H NMR
(CDCl3, 25 °C): δ ϭ 1.20 (t, 12 H), 3.22 (d, 4 H) 3.79 (t, 2 H), 3.81
(s, 3 H), 4.14 (q, 8 H), 6.92(t, 1 H), 7.08 (d, 2 H). Ϫ 13C NMR
(CDCl3, 25 °C): δ ϭ 13.9, 29.5, 52.1, 60.7, 60.9, 124.1, 129.6, 131.4,
157.7, 169.1.
2-[3-(2,2-Dicarboxyethyl)-2-methoxybenzyl]malonic Acid (11): A so-
lution of 10 (9.0 g, 0.02 mol) and NaOH (12.0 g, 0.3 mol) in 100
mL of ethanol was refluxed for 7 h. The mixture was cooled, 50
mL of ethanol was added. The solution was maintained under stir-
ring for further 12 h. Acetonitrile (80 mL) was added to the re-
sulting deliquescent mixture until the complete precipitation of a
white solid was obtained. The dried solid was dissolved in the min-
imum amount of water and the solution, made acidic with 37%
HCl, was extracted with ethyl ether (5 ϫ 30 mL). The organic solu-
tions were combined, dried with Na2SO4 and concentrated under
1
6.53, N 10.08; found C 47.6, H 6.6, N 10.0. Ϫ H NMR (D2O, 25
°C): δ ϭ 2.34 (s, 6 H), 2.94 (s, 6 H), 3.23 (t, 4 H), 3.36 (t, 4 H),
3.67 (s, 4 H), 7.38 (d, 4 H), 7.69 (d, 4 H). Ϫ 13C NMR (D2O, 25
°C): δ ϭ 21.9, 38.7, 42.3, 50.6, 57.1, 128.1, 131.5, 135.1, 146.9.
1,7,10-Trimethyl-4,13-bis(p-tolylsulfonyl)-1,4,7,10,13-pentaaza- reduced pressure to obtain 11 as a colorless oil. Yield: 5.4 g (79%).
cyclopentadecane (6): A solution of sodium (0.96 g, 0.042 mol) in Ϫ C15H16O9 (340.3): calcd. C 52.95, H 4.74; found C 53.1, H 4.8.
1
dry ethanol (50 mL) was added to a hot solution of 3·2HCl (5.6 g,
0.01 mol) in dry ethanol (100 mL). The resulting suspension was
Ϫ H NMR (CDCl3, 25 °C): δ ϭ 3.10 (d, 4 H) 3.67 (s, 3 H), 3.77
(t, 2 H), 6.92(t, 1 H), 7.00 (d, 2 H). Ϫ 13C NMR (CDCl3, 25 °C):
refluxed for 30 min, after which time the solvent was removed un- δ ϭ 30.3, 53.5, 62.3, 126.1, 130.8, 132.2, 158.2, 174.2.
Eur. J. Inorg. Chem. 2001, 1763Ϫ1774
1771

V. Fusi, M. Micheloni, P. Paoli et al.
FULL PAPER
3-[3-(2-Carboxyethyl)-2-methoxyphenyl]propionic Acid (12): A solu-
fractions were collected and concentrated to yield an oil, which was
tion of 11 (6.8 g, 0.02 mol) and diphenyl ether (150 g) was refluxed dissolved in ethanol and treated with 37% hydrochloride acid to
for 2 h. The solution was cooled and 50 mL of CHCl3 was added.
give 18 as a tetrahydrochloride salt (1.2 g, 42%). Ϫ C24H47Cl4N5O
This solution was then washed with 0.1 mol dmϪ3 NaOH (6 ϫ 25 (18·4HCl: 563.5): calcd. C 51.16, H 8.41, N 12.43; found C 51.1,
mL). The collected aqueous part was acidified with 96% H2SO4
and the solution extracted with diethyl ether (6 ϫ 25 mL). The
organic solutions were combined, dried with Na2SO4 and concen-
trated under reduced pressure to obtain 12 as a yellowish solid.
Yield: 3.9 g (77%). Ϫ C13H16O5 (252.3): calcd. C 61.90, H 6.39;
H 8.3, N 12.3. Ϫ MS (FAB), m/z: 419 [M ϩ Hϩ]. Ϫ 13C NMR:
δ ϭ 25.8, 29.7, 43.2, 43.3, 44.6, 52.3, 52.7, 53.8, 55.3, 56.1, 62.0,
64.1, 127.2, 128.3, 129.6, 131.5, 135.3, 157.5, 158.2.
Cryptand L2 (L2·4HCl): A solution of cryptand 18·4HCl (1.1 g,
2 mmol), EtSNa (1.7 g, 20 mmol) and LiBr (0.51 g, 6 mmol) in dry
DMF (50 mL) was heated at 150 °C for 6 h. The solvent was then
vacuum-evaporated and the residue was suspended in CH2Cl2 and
filtered. The organic layer was concentrated and the crude product
was chromatographed on neutral alumina (CH2Cl2/MeOH, 100:1).
The eluted fractions were collected and concentrated to dryness.
The crude product was dissolved in ethanol and treated with 37%
hydrochloric acid to give the L2 tetrahydrochloride salt as a white
1
found C 61.8, H 6.3. Ϫ H NMR (CDCl3, 25 °C): δ ϭ 2.70 (t, 4
H) 2.99 (t, 4 H), 3.78 (s, 3 H), 7.08 (m, 3 H), 10.32 (b, 2 H). Ϫ 13C
NMR (CDCl3, 25 °C): δ ϭ 25.2, 34.5, 61.0, 124.5, 128.4, 133.4,
157.1, 179.4.
Ethyl
3-[3-(2-Ethoxycarbonylethyl)-2-methoxyphenyl]propionate
(13): A solution of 12 (7.6 g, 0.03 mol) and p-toluenesulfonic acid
(8.6 g, 0.045 mol) in 100 mL of ethanol was kept under reflux for
a period of 12 h. An aqueous solution of NaHCO3 was added to solid (0.69 g, 63%). Ϫ C23H45Cl4N5O (L2·4HCl: 549.5): calcd. C
1
the reaction mixture (cooled to room temperature) until neutraliza-
50.28, H 8.25, N 12.75; found C 55.3, H 8.4, N 12.6. Ϫ H NMR
tion was achieved. The mixture was extracted with CH2Cl2 (3 ϫ 50 (D2O, pH ϭ 7): δ ϭ 2.32 (s, 3 H) 2.63 (s, 6 H), 3.28 (b, 28 H), 6.72
mL), and the organic layer was combined, dried with Na2SO4 and (t, 1 H), 7.02 (d, 2 H). Ϫ 13C NMR (D2O, pH ϭ 7): δ ϭ 30.4, 41.5,
concentrated under reduced pressure to obtain 13 as an oil. Yield:
8.2 g (89%). Ϫ C17H24O5 (308.4): calcd. C 66.21, H 7.84; found C
66.0, H 7.9. Ϫ H NMR (CDCl3, 25 °C): δ ϭ 1.25 (t, 6 H), 2.62
41.7, 52.1, 54.9, 55.3, 56.0, 58.8, 120.7, 129.1, 131.7, 156.5.
Cryptand 19 (19·2HClO4): This compound was synthesized from
amine 17 (2.0 g, 0.01 mol), Na2CO3 (5.3 g, 0.05 mol) and 15 (3.5 g,
0.01 mol) according to the same procedure reported for 18. The
crude product 17 was dissolved in ethanol and treated with 65%
perchloric acid to give the diperchlorate salt as a white solid (2.3 g,
39%). Ϫ C23H42Cl2N4O9 (19·2HClO4: 589.5): calcd. C 48.86, H
1
(t, 4 H), 2.98 (t, 4 H), 3.77 (s, 3 H), 4.14 (q, 4 H), 7.02 (m, 3 H).
Ϫ
13C NMR (CDCl3, 25 °C): δ ϭ 14.2, 25.5, 34.9, 60.4, 61.3, 124.3,
128.2, 133.8, 157.3, 173.2.
3-[3-(3-Hydroxypropyl)-2-methoxyphenyl]propanol (14): A solution
of 13 (6.2 g, 0.02 mol) in 50 mL of anhydrous diethyl ether was
7.18, N 9.50; found C 48.9, H 7.1, N 9.4. Ϫ MS (FAB), m/z: 390
carefully added to a suspension of LiAlH4 in 100 mL of anhydrous [M ϩ Hϩ]. Ϫ H NMR (D2O, pH ϭ 7, 25° C): δ ϭ 2.14 (b, 4 H),
1
ethyl ether. The mixture was allowed to react for 3 h at room tem-
perature. An aqueous solution of NaHCO3 was added to the mix-
2.36 (s, 6 H), 2.83 (b, 16 H), 3.19 (b, 4 H), 3.39 (b, 4 H), 3.80 (s, 3
H), 7.27 (m, 3 H). Ϫ 13C NMR (D2O, pH ϭ 7, 25° C): δ ϭ 25.2,
ture until excess LiAlH4 was completely destroyed. The suspension 29.0, 43.6, 45.2, 49.4, 52.8, 53.4, 54.0, 55.6, 62.2, 127.1, 130.2,
was extracted with CHCl3 (6 ϫ 50 mL) and the organic solutions 136.1, 157.2.
were combined, dried with Na2SO4 and concentrated under re-
Cryptand L1 (L1·3HCl): This compound was synthesized from
duced pressure to obtain 14 as a yellowish oil. Yield: 4.1 g (91%).
cryptand 19·2HClO4 (1.2 g, 2 mmol), according to the same pro-
Ϫ C13H20O3 (224.3): calcd. C 69.61, H 8.99; found C 69.7, H 9.1.
cedure reported for L2. The crude product L1 was dissolved in
1
Ϫ H NMR (CDCl3, 25 °C): δ ϭ 1.87 (q, 4 H), 2.34 (s, 2 H), 2.75
ethanol and treated with 37% hydrochloric acid to give the trihyd-
rochloride salt as a white solid (0.57 g, 59%). Ϫ C22H41Cl3N4O
(L1·3HCl: 484.0): calcd. C 54.60, H 8.54, N 11.58; found C 54.5,
H 8.7, N 11.4. Ϫ 1H NMR (D2O, pH ϭ 3): δ ϭ 2.03 (m, 4 H) 2.66
(s, 6 H), 2.76 (m, 16 H), 3.16 (m, 8 H), 6.99 (t, 1 H), 7.14 (d, 2 H).
(t, 4 H), 3.58 (t, 4 H), 3.78 (s, 3 H), 7.05 (m, 3 H). Ϫ 13C NMR
(CDCl3, 25 °C): δ ϭ 25.7, 33.5, 61.4, 61.6, 124.8, 128.3, 134.5,
156.5.
Methyl 3-[2-Methoxy-3-(3-methylsulfonyloxypropyl)phenyl]propyl-
sulfonate (15): A solution of methylsulfonyl chloride in anhydrous
CH2Cl2 (40 mL) was added to an ice-cold solution of 14 (4.0 g,
0.018 mol) and triethylamine in 50 mL of anhydrous CH2Cl2, over
a period of 1 h. The solution was kept at this temperature for a
further 2 h, and then washed with 5% HCl aqueous solution (3 ϫ
50 mL), 10% NaHCO3 aqueous solution (3 ϫ 50 mL) and water
(3 ϫ 50 mL). The organic part was dried with Na2SO4 and concen-
trated under reduced pressure to give 15 as an oil. Yield: 6.5 g
(95%). Ϫ C15H24O7S2 (380.5): calcd. C 47.35, H 6.36; found C 47.2,
Ϫ
13C NMR (D2O, pH ϭ 3): δ ϭ 25.7, 29.4, 44.6, 49.8, 53.7, 54.4,
124.3, 130.2, 132.6, 156.2.
Preparation of the Complexes. ؊ [LiH؊1L1]: A solution of LiOH
(10 mg, 0.44 mmol) in 15 mL of methanol was added to a solution
of L1·3HCl3 (48 mg, 0.1 mmol) in methanol (15 mL). The reaction
mixture was stirred for 15 min and then concentrated to dryness.
The solid was suspended in 20 mL of CHCl3 and the mixture fil-
tered to separate the inorganic excess. The organic solution was
dried with Na2SO4. On addition of cyclohexane (25 mL) a white
precipitate formed. Yield 31 mg (81%). Ϫ C22H37LiN4O (380.5):
calcd. C 69.45, H 9.80, N 14.72; found C 69.3, H 9.7, N 14.6. Ϫ
13C NMR (CDCl3): δ ϭ 29.9, 34.2, 43.7, 54.3, 55.5, 59.3, 119.5,
129.4, 132.7, 160.4. Ϫ [NaL2]: An excess of NaClO4 was added to
a solution of L2·4HCl (165 mg, 0.3 mmol) in 50 mL of water. A
1
H 6.5. Ϫ H NMR (CDCl3, 25 °C): δ ϭ 2.09 (q, 4 H), 2.77 (t, 4
H), 3.01 (s, 6 H), 3.74 (s, 3 H), 4.24 (t, 4 H), 7.06 (m, 3 H). Ϫ 13C
NMR (CDCl3, 25 °C): δ ϭ 26.0, 29.9, 37.3, 61.2, 69.6, 124.5, 128.6,
133.7, 156.7.
Cryptand 18 (18·4HCl): Amine 7 (1.3 g, 5 mmol) and Na2CO3
(2.65 g, 25 mmol) were suspended in refluxing CH3CN (100 mL). 0.1 mol dmϪ3 NaOH solution was added until complete precipita-
To this mixture, a solution of 15 (1.8 g, 5 mmol) in CH3CN (100 tion of a white precipitate was obtained. The solid was then sus-
mL) was added dropwise over 6 h, after which the suspension was
refluxed for 72 h and then filtered. The solution was concentrated
under vacuum to yield the crude product, which was chromato-
pended in 20 mL of CHCl3 and the mixture filtered. The liquid
part was dried with Na2SO4 and concentrated to dryness. The solid
was recrystallized by slow concentration of a mixture of CHCl3/
graphed on neutral alumina (CHCl3/CH3OH, 100:4). The eluted cyclohexane, obtaining white crystals suitable for X-ray analysis.
1772 Eur. J. Inorg. Chem. 2001, 1763Ϫ1774

Ligational Properties of Phenolic Aza Cages towards Proton and Alkali Metal Ions
FULL PAPER
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A. Bianchi, M. Micheloni, P. Paoletti, Coord. Chem. Rev. 1991,
101, 17.
J. S. Bradshaw, Aza-Crown Macrocycles, Wiley, New York,
1993. Ϫ [4b] R. M. Izatt, K. Pawlak, J. S. Bradshaw, R. L. Bru-
ening, Chem. Rev. 1991, 91, 1721.
Yield 60 mg (38%). Ϫ C23H41ClN5NaO5 (526.1): calcd. C 52.51, H
7.86, N 13.31; found C 52.6, H 7.9, N 13.2. Ϫ 13C NMR (CDCl3):
δ ϭ 30.6, 42.7, 42.9, 55.3, 56.7, 58.3, 58.6, 63.0, 121.1, 127.4, 133.0,
153.8. Ϫ [NaH؊1L2]: This compound was synthesized from [NaL2]
(53 mg, 0.1 mmol) according to the same procedure reported for
[LiHϪ1L1], giving [NaHϪ1L2] as a white solid. Yield: 30 mg, 69%).
Ϫ C23H40N5NaO (425.6): calcd. C 64.91, H 9.47, N 16.46; found
C 64.3, H 9.3, N 16.4. Ϫ 13C NMR (CD3OD): δ ϭ 29.1, 31.3, 41.2,
41.8, 43.1, 43.2, 52.6, 54.4, 54.5, 57.1, 57.2, 57.3, 57.5, 58.2, 59.3,
60.9, 66.7, 111.2, 114.69, 127.2, 128.7, 130.7, 132.4, 163.2, 163.4.
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Cambridge Structural Database Search: The Cambridge Structural
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sodium and potassium by nitrogen and/or oxygen atoms. The
VISTA V2.1 software was used to analyze the retrieved fragments.
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[9]
meter, using graphite-monochromated Cu-Kα radiation (λ
ϭ
˚
1.54184 A). Cell parameters were determined by least-squares fit-
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with those of the linked atoms [overall isotropic temperature factor
[10]
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2
˚
[15b]
U ϭ 0.048(2) A ]. The H10 atom of compound L2 was found in a
difference synthesis and its position was refined, as well as its ther-
mal parameter. The other hydrogen atoms of the complex were
introduced in calculated positions and their coordinates refined in
A.
[16]
[17]
2
˚
agreement with those of the linked atoms [U ϭ 0.0126(3) A ]. All
the non-hydrogen atoms of the two structures were refined aniso-
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was produced by the ORTEP program.[33] Crystallographic data
(excluding structural factors) for the structures reported in this pa-
per have been deposited at the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-152533 and
-152534 for [HL1](ClO4) and [NaL2](ClO4), respectively. Copies
may be obtained without charge from CCDC, Union Road, Cam-
bridge CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
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Acknowledgments
`
Support for this research from MURST (Ministero per l’Universita
e la Ricerca Scientifica e Tecnologica, COFIN98) and CNR (Con-
siglio Nazionale delle Ricerche) is gratefully acknowledged.
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1774
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