Synthesis, Optical Resolution and Complexation Properties of Inherently Chiral Monoalkylated p-tert-Butyl-(1,2)-calix[4]crown Ethers

Article abstract of DOI:10.1021/jo970934e

Reaction of mono-O-alkylated calix[4]arenes 2 with tri- to pentaethylene glycol ditosylates and K₂CO₃ affords asymmetrical (1,2)-calix[4]crown ether derivatives 3 as the main product, along with minor amounts of calix[4]arene dimers 4 and mixed syn-distal di-O-alkylated calix[4]arenes 5. A reaction mechanism for the formation of 3-5 is proposed, and the NMR spectral features of these products are briefly discussed. Evidence of the chirality of 3 was provided by diastereomeric interaction with enantiopure alkylammonium salts. The enantiomeric resolution of racemates 3 was achieved by direct HPLC separation, using chiral stationary phases. A screening of the complexing abilities of pyridino-(1,2)-calix[4]crown ethers 3a-c by extraction studies from water into CH₂Cl₂ showed a low extraction level of alkali, alkaline earth, and heavy metal picrates, while up to 25% extraction was found for Ag⁺. UV and pH-metric measurements of 3a-c with silver picrate in THF indicate the formation of 1:1:1 (metal:ligand:picrate) species, with log K's in the range 3.1-3.7.

Full text of DOI:10.1021/jo970934e

J . Org. Chem. 1997, 62, 8041-8048
8041
Syn th esis, Op tica l Resolu tion a n d Com p lexa tion P r op er ties of
In h er en tly Ch ir a l Mon oa lk yla ted p-ter t-Bu tyl-(1,2)-ca lix[4]cr ow n
Eth er s
Francoise Arnaud-Neu,† Salvatore Caccamese,‡ Saowarux Fuangswasdi,†
Sebastiano Pappalardo,*,‡ Melchiorre F. Parisi,§ Ada Petringa,§ and Grazia Principato‡
Laboratoire de Chimie-Physique de l'ECPM, URA 405 au CNRS, Universite´ Louis Pasteur, 1, rue Blaise
Pascal, 67000 Strasbourg, France, Dipartimento di Scienze Chimiche, Universita` di Catania, Viale A.
Doria 6, I-95125 Catania, Italy, and Dipartimento di Chimica Organica e Biologica, Universita` di
Messina, Salita Sperone 31, I-98166 Vill. S. Agata, Messina, Italy
Received May 28, 1997X
Reaction of mono-O-alkylated calix[4]arenes 2 with tri- to pentaethylene glycol ditosylates and
K2CO3 affords asymmetrical (1,2)-calix[4]crown ether derivatives 3 as the main product, along with
minor amounts of calix[4]arene dimers 4 and mixed syn-distal di-O-alkylated calix[4]arenes 5. A
reaction mechanism for the formation of 3-5 is proposed, and the NMR spectral features of these
products are briefly discussed. Evidence of the chirality of 3 was provided by diastereomeric
interaction with enantiopure alkylammonium salts. The enantiomeric resolution of racemates 3
was achieved by direct HPLC separation, using chiral stationary phases. A screening of the
complexing abilities of pyridino-(1,2)-calix[4]crown ethers 3a -c by extraction studies from water
into CH2Cl2 showed a low extraction level of alkali, alkaline earth, and heavy metal picrates, while
up to 25% extraction was found for Ag+. UV and pH-metric measurements of 3a -c with silver
picrate in THF indicate the formation of 1:1:1 (metal:ligand:picrate) species, with log K’s in the
range 3.1-3.7.
In tr od u ction
inherently chiral derivatives: these precursors possess
only one plane of symmetry, which is lost by appropriate
lower rim functionalization.6
Calix[4]arenes have become very popular as three-
dimensional molecular platforms for the design of arti-
ficial molecular receptors, owing to the ready availability
of native calix[4]arenes and their ability to provide
different stereochemical arrangements of binding sites.1
In a preliminary paper we reported that the reaction
of mono-O-alkylated calix[4]arenes with oligoethylene
glycol ditosylates affords inherently chiral (1,2)-calix[4]-
crown ethers.7 Here we report the synthesis and char-
acterization of these racemates and their enantiomeric
resolution by enantioselective HPLC. Owing to the lack
of information about the coordinating behavior of (1,2)-
calix[4]crown ethers,1c the binding properties of the
pyridino derivatives toward a variety of metal cations
have also been explored.
The quest for receptors with chiral discriminating
ability has led to interest in chiral calix[4]arenes. Chiral
calixarenes can be obtained by simply attaching chiral
residues at the upper2 or lower rim.3 However, a more
challenging approach to introducing chirality is to make
the calixarene “inherently” chiral by exploiting the non-
planarity of the molecule in conjunction with an asym-
metric substitution of the macrocycle (creation of molec-
ular asymmetry). The basic concepts and methods
available for the synthesis of atropisomeric inherently
chiral calixarenes have been recently reviewed.4 Among
other possibilities,5 mono- and 1,2-di-O-alkylated calix-
[4]arenes have been shown to provide a useful source of
Resu lts a n d Discu ssion
Syn th eses. A two-step synthesis of racemic calix[4]-
crown ethers 3 is depicted in Scheme 1. The pivotal
mono-O-alkylated calix[4]arenes 2 were prepared in 23-
50% yield by direct alkylation of p-tert-butylcalix[4]arene
1 with 1 equiv of the appropriate electrophile and 1 equiv
of NaH [2 equiv in the case of the hydrochloride salts of
2-(chloromethyl)pyridine or 2-(chloromethyl)quinoline] in
†Universite´ Louis Pasteur.
‡Universita` di Catania.
1
§ Universita` di Messina.
anhydrous toluene at 70 °C. The H NMR spectra of 2
X Abstract published in Advance ACS Abstracts, October 1, 1997.
(1) (a) Gutsche, C. D. Calixarenes; Stoddart, J . F., Ed.; Monographs
in Supramolecular Chemistry; The Royal Society of Chemistry: Cam-
bridge, 1989, Vol. 1. (b) Calixarenes, a Versatile Class of Macrocyclic
Compounds; Vicens, J ., Bohmer, V., Ed.; Kluwer: Dordrecht, 1991.
(c) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713.
(2) Gutsche, C. D.; Nam, K. C. J . Am. Chem. Soc. 1988, 110, 6153.
(3) Muthukrishnan, R.; Gutsche, C. D. J . Org. Chem. 1979, 44, 3962.
Arimura, T.; Kawabata, H.; Matsuda, T.; Muramatsu, T.; Satoh, H.;
Fujio, K.; Manabe, O.; Shinkai, S. J . Org. Chem. 1991, 56, 301. Marra,
A.; Schermann, M.-C.; Dondoni, A.; Casnati, A.; Minari, P.; Ungaro,
R. Angew. Chem., Int. Ed. Engl. 1994, 33, 2479. Neri, P.; Bottino, A.;
Geraci, C.; Piattelli, M. Tetrahedron Asymm. 1996, 7, 17. Kubo, Y.;
Maeda, S. K.; Tokita, S.; Kubo, M. Nature 1996, 382, 522.
(4) Bo¨hmer, V.; Kraft, D.; Tabatabai, M. J . Inclusion Phenom. 1994,
19, 17.
display for the calixarene skeleton the expected sym-
metry for a monoalkylated derivative in a fixed cone
conformation, i.e. two AX systems (J ) 13.4 ( 0.4 Hz)
for ArCH2Ar protons, two singlets and an AB quartet
(ratio 1:1:2) for the aromatic protons, and two sharp
singlets for OH groups (ratio 2:1) (a broad singlet for
calixarenes 2a and 2e) at very low field (9.1-10.0 ppm).
Subsequent reaction of 2 with the appropriate oligo-
ethylene glycol ditosylate (1 equiv) was carried out in
(6) (a) Pappalardo, S.; Caccamese, S.; Giunta, L. Tetrahedron Lett.
1991, 32, 7747. (b) Iwamoto, K.; Shimizu, H.; Araki, K.; Shinkai, S. J .
Am. Chem. Soc. 1993, 115, 3997. (c) Ferguson, G.; Gallagher, J . F.;
Giunta, L.; Neri, P.; Pappalardo, S.; Parisi, M. J . Org. Chem. 1994,
59, 42.
(5) Verboom, W.; Bodewes, P. J .; van Essen, G.; Timmerman, P.;
van Hummel, G. J .; Harkema, S.; Reinhoudt, D. N. Tetrahedron 1995,
51, 499. Ikeda, A.; Yoshimura, M.; Lhotak, P.; Shinkai, S. J . Chem.
Soc., Perkin Trans. 1 1996, 1945.
(7) Pappalardo, S.; Parisi, M. F. Tetrahedron Lett. 1996, 37, 1493.
S0022-3263(97)00934-1 CCC: $14.00 © 1997 American Chemical Society

8042 J . Org. Chem., Vol. 62, No. 23, 1997
Arnaud-Neu et al.
Sch em e 1
Sch em e 2
anhydrous DMF in the presence of a large excess of
K2CO3 (10 equiv) for 48 h at 70 °C. After careful column
chromatography of the reaction mixture, inherently
chiral (1,2)-calix[4]crown ethers 3 were isolated as the
main product (30-41%), along with minor amounts of
calix[4]arene dimers 4, mixed syn-distal calix[4]arenes
5, and unreacted 2 (20-25%) (Scheme 1). Attempts to
synthesize by the same strategy analogous (1,2)-calix[4]-
crown ethers endowed with larger (3,5-dinitrobenzyl,
2-naphthylmethyl, or 2-quinolylmethyl) pendant groups
failed, probably due to the deleterious role played by
these bulky substituents during the crucial crown ether
cyclization step.
A possible reaction pathway to explain the formation
of compounds 3-5 is shown in Scheme 2. Deprotonation
of the distal OH group of 2 by the weak base K2CO3,
followed by reaction of the resulting monoanion 2A with
the bifunctional electrophile, produces the key monoto-
sylated intermediate 6.8 Subsequently, 6 undergoes (i)
intramolecular cyclization (with K+ acting as a template)
to afford crown ethers 3 as the main product, (ii)
F igu r e 1. Aromatic and oxymethylene regions of (a) 1H NMR
(CDCl3, 300 MHz) and (b) BB decoupled 13C NMR spectra
(CDCl3, 75.5 MHz) of 3b.
nucleophilic displacement by the monoanion 2A to give
calix[4]arene dimers 4, or alternatively (iii) hydrolysis
to produce 5. The product distribution is in full agree-
ment with the general mechanism of stepwise alkylation
of calix[4]arenes with weak bases (only the phenoxyde
anion stabilized by hydrogen bonding with the two
flanking OH is formed).9 Furthermore, the complete
absence, in the reaction mixtures, of the achiral regio-
isomeric (1,3)-calix[4]crown ethers confirms the mecha-
nism proposed.
NMR Stu d ies. The absence of symmetry elements in
compounds 3 is evident from their complex NMR spectra,
which show characteristic line patterns for the chiral
calix[4]arene skeleton and the groups attached to it. The
NMR spectra of 3 are quite uniform and here we will
discuss the 1H and 13C NMR spectra of crown-5 derivative
3b, typical of this class of compounds.
(8) Although 6 was not detected in the reaction mixtures, it was
possible to isolate and characterize compound 6a [Z ) (CH2OCH2)2]
during an alkylation of 2a with a limited amount of triethylene glycol
ditosylate. 6a : 1H NMR δ 0.93, 0.95, 1.29 (s, ratio 1:1:2, 36 H), 2.41
(s, 3 H), 3.29, 4.29 (d, J ) 13.3 Hz, 4 H), 3.30, 4.32 (d, J ) 13.1 Hz, 4
H), 3.54-4.15 (m, 12 H), 5.13 (s, 2 H), 6.77, 6.79, 7.05 (s, ratio 1:1:2,
8 H), 7.06 (m, 1 H), 7.16 (s, 2 H), 7.29, 7.75 (d, J ) 7.7 and 8.4 Hz,
respectively, 2 H each), 7.84 (td, J ) 7.7, 1.7 Hz, 1 H), 8.18 (d, J ) 7.7
Hz, 1 H), and 8.59 (dt, J ) 4.7, 0.9 Hz, 1 H); FAB (+) MS, m/z 1026
(100, MH+).
1
The H NMR spectrum of 3b shows (Figure 1a) four
singlets for tert-butyl groups (not shown), four partly
overlapping AX systems (J ) 12.6-13.5 Hz) for the
(9) van Loon, J .-D.; Verboom, W.; Reinhoudt, D. N. Org. Prepr. Proc.
Int. 1992, 24, 437.

Monoalkylated p-tert-Butyl-(1,2)-calix[4]crown Ethers
J . Org. Chem., Vol. 62, No. 23, 1997 8043
bridging methylenes, a complex pattern for the polyether
chain in the range 3.4-4.4 ppm, an AB system (J ) 12.3
Hz) for the diastereotopic protons of the OCH2Py group,
an upfield resonance for the residual OH group at δ 5.96
ppm, three AB systems (J ) 2.4-2.5 Hz) and a (pseudo)
singlet for the aromatic protons of the calix[4]arene
skeleton, and a four-spin system for the 2-substituted
pyridine ring. A chemical shift difference (∆δ) >1 ppm
between the four pairs of signals due to the bridging
methylene protons (CHexo and CHendo) is suggestive of a
cone conformation for 3b.1a
The cone structure for 3b is further confirmed by the
13C NMR spectrum (Figure 1b), which shows resonances
around 31 ppm (partly buried under the t-Bu signals) for
the ArCH2Ar carbons, considered of diagnostic value for
such a conformation.10 Due to the greater dispersion of
1
the 13C scale as compared to that of H, very often the
number of observed resonances coincide with those
expected, as can be seen for the nine lines of roughly
equal intensity present in the oxymethylene region (68-
78 ppm) and for the eight-line pattern for the bridgehead
carbons in the range 128-136 ppm (Figure 1b). The
NMR spectra of the other inherently chiral calix[4]crown
ethers show a similar trend (see Experimental Section),
so that these compounds are believed to adopt a fixed
cone conformation as well.
F igu r e 2. Aromatic and tert-butyl regions of the 1H NMR
spectrum (CDCl3, 300 MHz) of 3c (a) and spectral changes
upon addition of (b) 0.25, (c) 0.5, and (d) 1 equiv amount of
(R)-R-methylbenzylammonium picrate. The two regions are
plotted in different scales.
experiment at low temperatures (223 K), suggesting that
no discrimination between the two enantiomers is taking
place. On the other hand, compounds 3c and 3d do not
give any diastereomeric interaction with the more en-
cumbered (R)- or (S)-R-methyl-o-methoxybenzylammo-
nium picrates, which presumably cannot approach the
crown ether portion in a favorable manner from either
side (vide infra).
The NMR analysis of the achiral byproducts 4 and 5
is much more straightforward, owing to the persistence
of at least one plane of symmetry in the molecule after
derivatization of 2. Their spectra show the presence of
three resonances for the tert-butyl groups and for the
aromatic protons in the ratio 1:1:2, respectively, and two
AX systems for the bridging methylenes. Also in this
case a ∆δ > 1 ppm for the geminal ArCH2Ar protons of
4 and 5 is suggestive of a cone conformation. The NMR
pattern for the polyether bridge is symmetrical for calix-
[4]arene dimers 4 and quite complex for mixed syn-distal
di-O-alkylated calix[4]arenes 5, due to the presence of
an asymmetrical glycolic chain. Compounds 5a and 5b
were isolated as DMF solvates with stoichiometry 1:1
(NMR and elemental analyses).
To prove that complexation occurs inside the hydro-
philic pocket generated by the substituents attached at
the lower rim of the calix[4]arene, a CDCl3 solution of
pyridino compound 3c was protonated with CF3COOH
(1.2 equiv) to give the corresponding pyridinium salt
3c‚H+ (as supported by a significant to large downfield
shift experienced by the pyridinyloxy protons; see ex-
1
perimental section for the H NMR spectrum of 3c‚H+).
Evidence of chirality for asymmetrical (1,2)-calix[4]-
crown ethers synthesized was provided by titration
experiments of CDCl3 solutions of 3 (containing one drop
of CD3OD) with both (R)- and (S)-R-methylbenzylammo-
Upon titration with 1 equiv of the (R)-salt, the chemical
shifts of most protons remained unvaried, with the
exception of the tert-butyl region, which underwent some
changes. The two downfield resonances coalesced to a
broad singlet, while the remaining two singlets split into
two doublets. The invariability of the other signals in
1
nium picrates. Whereas the H NMR spectra of crown-4
and crown-5 derivatives 3a and 3b did not show any
appreciable change upon titration with 1 equiv of the
chiral salt, splitting and doubling of signals occurred in
every region of the spectra of crown-6 derivatives 3c and
3d from the addition of the first aliquot (0.25 equiv) of
each chiral salt. Illustrative regions of the 1H NMR
spectrum of receptor 3c, without and with increasing
amounts of the (R)-salt, are shown in Figure 2. The
spectra did not change further by adding an excess of
the salt, suggesting that the diastereomeric 1:1 complexes
had formed. These results confirm that a crown-6 moiety
is likely to be a prerequisite for anchoring the NH3+ group
of the primary ammonium cation into its crown ether-
cavity via N-H‚‚‚O hydrogen bonds.11 It is worth noting
that the signals due to the diastereomeric complexes
show comparable intensities, even by performing the
+
the spectrum suggests that the R-NH3 cation is im-
peded from entering the hydrophilic pocket of 3c‚H +
(internal approach), due to a strong electrostatic repul-
sion with the pendant pyridinium group (complexa-
tion is switched off by protonation); therefore, the inter-
action with the crown ether moiety necessarily occurs on
the side exterior to the hydrophilic cavity (external
approach).
Ch r om a togr a p h ic En a n tiosep a r a tion . Racemic
calix[4]crown ethers 3a -d were resolved on at least one
of the chiral stationary phases (CSPs), as shown in Table
1. The Chiralpak AD CSP [amylose tris(3,5-dimeth-
ylphenylcarbamate)] was effective in the enantiomeric
resolution of all compounds, while the Chiralcel OD
[cellulose tris(3,5-dimethylphenylcarbamate)] gave no
resolution for compounds 3a and 3c. The difference in
chiral recognition of cellulose and amylose derivatives is
probably due to the different chiral environment around
the carbamate residue and to the wider and more
(10) J aime, C.; de Mendoza, J .; Prados, P.; Nieto, P. M.; Sanchez,
C. J . Org. Chem. 1991, 56, 3372.
(11) Lehn, J .-M. Angew. Chem., Int. Ed. Engl., 1988, 27, 89. Cram,
D. J . Angew. Chem., Int. Ed. Engl. 1988, 27, 1009.

8044 J . Org. Chem., Vol. 62, No. 23, 1997
Arnaud-Neu et al.
Ta ble 1. HP LC CSP Resolu tion of In h er en tly Ch ir a l
When the OH group in 3b was replaced by a propoxy
substituent as in 7 (obtained in 70% yield by reaction of
3b with n-propyl iodide and NaH in dry THF), chiral
discrimination with Chiralpak AD was less effective,
while no separation at all occurred with the less efficient
Chiralcel OD phase (Table 1). Similar behavior has
previously been observed for other chiral calix[4]arenes.16
Ca lix[4]cr ow n Eth er s 3a -d a n d 7
c
compd
column
A (%)a
FRb
k′1
a
Rs
3a
AD
AD
AD
OD
AD
AD
AD
OD
AD
AD
AD
OD
AD
AD
AD
OD
AD
AD
AD
OD
10
5
5
10
10
5
0.5
0.5
1
0.5
0.5
0.5
1
0.5
0.5
0.5
1
0.5
0.5
0.5
1
0.113
0.239
0.320
0.173
0.214
0.437
0.425
0.164
0.286
0.473
0.669
0.322
0.196
0.336
0.437
0.379
0.147
0.252
0.254
0.150
3.57
3.49
2.65
NSd
2.60
2.55
2.46
1.80
1.20
1.24
1.21
NSd
1.20
1.35
1.26
1.32
1.99
1.98
1.97
NSd
2.9
4.5
3.3
3b
3c
3d
7
3.0
4.7
3.8
1.0
0.7
1.1
0.9
5
10
10
5
5
10
10
5
0.8
1.3
1.1
0.6
1.9
2.5
2.4
5
10
10
5
5
10
0.5
0.5
0.5
1
Com p lexa tion Stu d ies w ith Alk a li Meta l Ca tion s.
As shown in Table 2, compounds 3a -c do not signifi-
cantly extract alkali picrates from water into CH2Cl2.
Under our experimental conditions, the highest extrac-
tion percentage (%E) obtained is hardly higher than 2
(i.e., K+ and 3c).
0.5
a
b
Percentage of 2-propanol in n-hexane. Flow rate (mL/min);
FR ) 1, t0 ) 3.4 min; FR ) 0.5, t0 ) 7.1 min. c Capacity factor of
d
the first-eluted enantiomer. Not separated.
However, complexation of a number of alkali cations
could be detected from spectrophotometric measurements
in MeOH with ligands 3b and 3c. Analysis of the UV
spectra showed the formation of 1:1 species (Table 3). The
results indicate a low level of complexationsâ values
never exceeding 2.2 log unitssin comparison with other
calixarene-based receptors17 and, more specifically, with
1,3-dialkoxy calix[4]-crowns18 and calix[4]-bis-crowns.19
The crown-5 derivative 3b appears to be selective for K+
(log â ) 2.2): it is not efficient for the smaller Li+ and
Na+ cations, with which no spectral modifications were
recorded, or for the larger Rb+ and Cs+ cations, which
produced only small and uninterpretable spectral changes.
The crown-6 derivative 3c is less discriminating as it
accommodates the three cations Na+, K+, and Rb+ to the
same extent. Little or no complexation is again observed
for Li+ and Cs+ with this ligand. No data could be
obtained with 3a due to solubility limitations in MeOH.
Additional extraction tests showed that these ligands
were also inefficient for alkaline earth cations, as well
as for Zn2+, Pb2+, and Cd2+. Only Ag+ is to some extent
extracted by the three ligands, 3a being the most efficient
(%E ) 25). The lower and comparable efficiencies shown
by 3b and 3c are consistent with their log â values (3.58
and 3.44, respectively), determined by spectrophotometric
measurements in MeOH. The value for 3b was con-
firmed by pH-metric measurements (Table 4). A very
similar value of 3.28 was obtained with Zn2+ and the
same ligand, although no extraction could be detected in
this case. With Ag+ and especially with Zn2+, titration
curves (Figure 4) show that deprotonation of the phenol
and/or solvolysis of the cation or the complex may occur
at higher pH.
(b)
(c)
(a)
F igu r e 3. HPLC separation on Chiralpak AD (mobile phase
n-hexane/2-propanol 9:1 at 0.5 mL/min) of the enantiomeric
pairs of (a) 3a , (b) 3b, and (c) 3c.
compact helix of the amylose derivative. Zugenmaier et
al., in fact, proposed left-handed 3/2 and 4/1 helical
structure for cellulose tris(phenylcarbamate)12 and amy-
lose tris(phenylcarbamate),13 respectively. Comprehen-
sive surveys on chiral discrimination by using polysac-
charide derivatives have recently appeared.14
The separation factors (R) and resolution factors (Rs)
with Chiralpak AD (Table 1) are much better for 3a than
for 3b-d , indicating a possible influence of the size of
the crown ether moiety on the chiral recognition mech-
anism. An increase of the polarity of the mobile phase
has a detrimental effect on Rs, whereas a decrease in the
flow rate of the mobile phase has a beneficial effect on
R. Moreover, the very low capacity factor (k′1) and good
R and Rs values may allow a semipreparative-scale
isolation of the single enantiomers of 3a and 3b. Figure
3 shows typical chromatograms of the resolution of
racemic crown ethers 3a -c. In the absence of the diode
array detector, the area ratio of the peaks was measured
(in a number of different experiments) with the UV
detector set at different wavelengths (240, 265, and 280
nm). As expected for an enantiomeric pair, these area
ratios were equal.15
To compare the efficiencies of the three ligands toward
Ag+, spectrophotometric measurements were carried out
(15) Pirkle, W. H.; Welch, C. J .; Yang, Q. J . Chromatogr. 1993, 639,
329.
(16) Caccamese, S.; Pappalardo, S. Chirality 1993, 5, 159.
(17) McKervey, M. A.; Schwing-Weill, M. J .; Arnaud-Neu, F. In
Comprehensive Supramolecular Chemistry; Lehn, J . M., Gockel, G. W.,
Eds.; 1996; Vol. 1, pp 537-603.
(18) Casnati, A.; Pochini, A.; Ungaro, R.; Ugozzoli, F.; Arnaud, F.;
Fanni, S.; Schwing, M. J .; Egberink, R. J . M.; de J ong, F.; Reinhoudt,
D. N. J . Am. Chem. Soc. 1995, 117, 2767.
(12) Vogt, U.; Zugenmaier, P. Ber. Bunsen-Ges. Phys. Chem. 1985,
89, 1217.
(13) Vogt, U.; Zugenmaier, P. European Science Foundation Work-
shop on Specific Interaction in Polysaccharide Systems, Uppsala, 1983.
(14) Yashima, E.; Okamoto, Y. Bull. Chem. Soc. J pn. 1995, 68, 3289.
Okamoto, Y.; Kaido Y. J . Chromatogr. 1994, 666, 403.
(19) Arnaud-Neu, F.; Asfari, Z.; Souley, B.; Vicens, J . New J . Chem.
1996, 20, 453.

Monoalkylated p-tert-Butyl-(1,2)-calix[4]crown Ethers
J . Org. Chem., Vol. 62, No. 23, 1997 8045
Ta ble 2. Extr a ction P er cen ta ge (%E) of Meta l P icr a tes fr om Wa ter in to CH2Cl2 by Com p ou n d s 3 a t 20 °Ca
ligand
Li+
Na+
K+
Rb+
Cs+
Ca2+
Sr2+
Ba2+
Ag+
Zn2+
Pb2+
Cd2+
3a
3b
3c
b
0.2
0.8
0.9
0.4
1.0
0.4
0.7
2.1
0.5
0.6
1.8
0.4
0.5
1.4
0.1
0.4
0.6
0.1
0.1
0.6
b
0.2
0.6
25.0
12.6
11.4
b
b
0.8
0.5
0.8
0.5
0.2
0.2
0.6
a
Standard deviation on the mean of several experiments: σn-1 e 0.7. bNot detected.
Ta ble 3. Sta bility Con sta n ts (log â) of Meta l Com p lexes of Com p ou n d s 3 in MeOH a t 25 °C, I ) 0.01 M (Et4NClO4 or
Et4NCl)a
ligand
Li+
Na+
K+
Rb+
Cs+
Ag+
Zn2+
3b
3c
b
b
b
2.20 ( 0.06
2.12 ( 0.09
e1c
2.09 ( 0.01
e1c
e1c
3.58 ( 0.02 (3.43)d
3.44 ( 0.01
2.9 ( 0.4 (3.28)d
2.90 ( 0.01
2.18 ( 0.05
a
b
Spectrophotometric determinations; standard deviation σn-1 on the mean of two experiments. No spectral changes. c Very small
d
spectral changes. pH-metric determinations.
Ta ble 4. Associa tion Con sta n ts (log K) of Ag+P ic- w ith
Com p ou n d s 3a -c in THF a n d Ba th och r om ic Sh ifts [∆λ
(n m )] vs Ag+P ic-
ligand
log Ka
∆λb
3a
3b
3c
3.7 ( 0.1
3.14 ( 0.09
3.54 ( 0.08
11
11
2
a
Standard deviation σn-1 on the mean of at least four experi-
b
ments. Precision: (2 nm.
F igu r e 5. Spectral changes observed for Ag+Pic- in the
presence of increasing amounts of ligand 3a in THF ([Pic-] )
1.0 × 10-4 M, 0 e [Pic-]/[L] e 4).
separation of the ion pair. For comparison, Ag+Pic- has
been found to undergo a very large shift of 31 nm in the
presence of calix[4]-bis-crown-5, corresponding to a fully
separated ion absorbing at 380 nm.23 On the other hand,
ligand 3c gives rise to a much smaller shift (∆λ ) 2 nm),
suggesting an external solvation of the ion pair by the
ligand. The relatively high association constant found
with 3a , and the rather large ∆λ and %E values,
demonstrate that this ligand is the best adapted for Ag+.
However, with the three ligands the picrate anion is
involved in the complexation of Ag+ in THF.
F igu r e 4. Titration curves of 3b (3), and 3b in the presence
of equimolar amounts of Ag+ (O) and Zn2+ (b).
in THF, where no solubility limitations were met. In
such a low polarity solvent, complexation may lead to an
increase in the interionic distance between the cation and
the anion and to the conversion of a tight ion pair into a
loose or ligand separated ion pair, as previously shown
for alkali picrates with crown ethers20 and calixarene
derivatives.21-23 The resulting bathochromic shift of the
main absorption band of the metal picrate ion pair has
been used as a measure of this separation. The three
ligands are able to separate the tight silver picrate
(Ag+Pic-) ion pair by forming 1:1:1 (metal:ligand:picrate)
species only, as suggested by the observation of the
spectra and the isosbestic points (Figure 5) and further
confirmed by numerical treatment of the absorbances.
The association constants of the loose ion pairs are given
in Table 4 as well as the bathochromic shifts with respect
to Ag+Pic-. Compounds 3a and 3b induce strong shifts
(∆λ ) 11 nm), indicating a significant but incomplete
Con clu sion s
In conclusion, we have developed a two-step synthesis
of inherently chiral (1,2)-calix[4]crown ethers 3 starting
from p-tert-butylcalix[4]arene 1. All racemates have been
resolved into their enantiomers by direct HPLC, using
chiral stationary phases. The results obtained with
Chiralpak AD are very promising for a fast semiprepara-
tive-scale separation of the pure enantiomers. This will
make it possible to explore the chiral discrimination
properties of this new class of calixarene-based chiral
receptors. The complexing properties of 3 toward alkali,
alkaline earth, and heavy metal cations, with the excep-
tion of Ag+ and Zn2+, appear to be modest in comparison
with those of (1,3)calix[4]crown ethers.
Exp er im en ta l Section 24
1H and 13C NMR spectra were taken in CDCl3 at 300 and
75.5 MHz, respectively. p-tert-Butylcalix[4]arene‚toluene 1:1
(20) Bourgoin, M.; Wong, K. H.; Hui, J . Y.; Smid, J . J . Am. Chem.
Soc. 1975, 97, 3462.
(21) Arduini, A.; Pochini, A.; Reverberi, S.; Ungaro, R.; Andreetti,
G. D.; Ugozzoli, F. Tetrahedron 1986, 42, 2089.
(22) Arimura, T.; Kubota, M.; Matsuda, T.; Manabe, O.; Shinkai, S.
Bull. Chem. Soc. J pn. 1989, 62, 1674.
(23) Arnaud-Neu, F.; Asfari, Z.; Souley, B.; Vicens, J . In preparation.
(24) For characterization techniques and instrumentation, see:
Pappalardo, S.; Ferguson, G.; Neri, P.; Rocco, C. J . Org. Chem. 1995,
60, 4576.

8046 J . Org. Chem., Vol. 62, No. 23, 1997
Arnaud-Neu et al.
complex 1 was prepared by a literature procedure.25 The
HPLC system used for the enantiomeric separations has been
previously described.16 The columns (25 cm × 4.6 mm) were
packed with Chiralpak AD or Chiralcel OD coated on 10 µm
silica gel. Column void time (t0) was measured by injection of
tri-tert-butylbenzene as a nonretained compound.26 Retention
times for each pair of enantiomers (t1 and t2) are mean values
of two replicate determinations. HPLC chromatographic
parameters are given as usual.27
Con ver sion of 1 in t o Mon o-O-a lk yla t ed 2. Gen er a l
P r oced u r e. A slight modification of Shinkai’s procedure was
used.28 A stirred mixture of 1 (4.44 g, 6 mmol), the appropriate
electrophile RCH2X (1 equiv), and NaH (1 equiv) (2 equiv in
the case of 2-(chloromethyl)pyridine or 2-(chloromethyl)quino-
line hydrochlorides) in anhydrous toluene was heated at 70
°C for 7-12 h. The reaction was monitored by TLC (cyclo-
hexane-AcOEt 5:1), and quenched by addition of MeOH (1
mL) as soon as the di-O-alkylated product(s) started to form.
The solvent was evaporated in vacuo, and the residue was
partitioned between 1 N HCl and CHCl3. The organic extract
was washed with water, dried (MgSO4), and concentrated. The
solid was treated with AcOEt (30-40 mL) to leave unreacted
1 as an insoluble material. The solution was concentrated to
dryness and subjected to column chromatography on silica gel,
by eluting with cyclohexane-CH2Cl2 1:1 (to remove residual
1), and then with CH2Cl2. The fractions containing 2 were
further purified by recrystallization from an appropriate
solvent.
9 H each), 3.17, 3.23, 3.29 (d, J ) 12.6, 13.4, and 13.4 Hz,
respectively, ratio 2:1:1, 4 H), 3.57-4.35 (m, 12 H), 4.26, 4.31,
4.49, 4.50 (d, J ) 13.5, 12.7, 13.0, and 12.4 Hz, respectively, 1
H each), 4.94, 5.00 (ABq, J ) 11.9 Hz, 2 H), 5.84 (s, 1 H), 6.48
(s, 2 H), 6.58, 6.64 (ABq, J ) 2.4 Hz, 2 H), 7.05, 7.08 (ABq, J
) 2.4 Hz, 2 H), 7.14, 7.16 (ABq, J ) 2.5 Hz, 2 H), 7.27 (m, 1
H), 7.78 (td, J ) 7.6, 1.8 Hz, 1 H), 7.88 (d, J ) 7.7 Hz, 1 H),
and 8.62 (d, J ) 4.1 Hz, 1 H); 13C NMR δ 30.36, 31.18, 31.51
(t), 31.02, 31.68 (q), 33.84, 34.14(s), 69.40, 69.77, 70.19, 71.34,
72.50, 75.31, 78.68 (t), 122.76, 123.04, 124.80, 125.12, 125.41,
125.62, 125.76 (d), 128.35, 129.53, 131.56, 131.89, 132.02,
132.71, 135.72, 135.93 (s), 136.64 (d), 141.50, 145.27, 145.85
(s), 149.20 (d), 150.45, 150.71, 151.64, 153.55, and 157.58 (s);
FAB (+) MS, m/z 854 (100, MH+). Anal. Calcd for C56H71
-
NO6: C, 78.74; H, 8.38; N, 1.64. Found: C, 79.14; H, 8.54; N,
1.79.
Ca lix[4]a r en e d im er (4a ): ca. 1% yield; Rf ) 0.31 (cyclo-
hexane-AcOEt 2:1); 1H NMR δ 0.93, 0.96, 1.28 (s, ratio 1:1:2,
72 H), 3.26, 3.28 (d, J ) 13.2 and 13.1 Hz, respectively, 4 H
each), 3.81 (s, 4H), 3.91 (t, J ) 4.5 Hz, 4H), 4.04 (dd, J ) 5.4,
3.6 Hz, 4H), 4.28, 4.30 (d, J ) 12.9 and 13.1 Hz, respectively,
4 H each), 5.11 (s, 4 H), 6.77, 6.78, 7.04 (s, ratio 1:1:2, 16 H),
7.19 (m, 2 H), 7.22 (s, 4 H), 7.83 (td, J ) 7.7, 1.7 Hz, 2 H), 8.20
(d, J ) 7.7 Hz, 2 H), and 8.55 (dt, J ) 5.0, 0.9 Hz, 2 H); 13C
NMR δ 30.99, 31.71 (q), 31.52 (t), 33.81, 33.92 (s), 70.03, 70.51,
70.63, 71.04, 75.37, 78.21 (t), 121.63, 122.70, 125.03, 125.52,
125.54, 125.60 (d), 127.59, 127.76, 132.44, 132.51 (s), 137.13
(d), 141.42, 146.97, 147.01 (s), 148.89 (d), 149.50, 149.72,
150.60, and 157.48 (s); FAB (+) MS, m/z 1593 (100, MH+).
p -ter t-Bu t yl-25-[(3,5-d in it r ob en zyl)oxy]-26,27,28-t r i-
h yd r oxyca lix[4]a r en e (2c): 32% yield; mp 143-145 °C
(MeOH); 1H NMR δ 1.21, (s, 36 H), 3.44, 4.22 (d, J ) 13.8 Hz,
4 H), 3.50, 4.25 (d, J ) 13.0 Hz, 4 H), 5.29 (s, 2 H), 7.00, 7.06
(ABq, J ) 2.4 Hz, 4 H), 7.04, 7.15 (s, 2 H each), 9.10 [m, 3 H],
9.14 and 9.66 (s, ratio 2:1, 3 H); FAB (+) MS, m/z 825 (100,
MH+). Anal. Calcd for C51H60N2O8: C, 73.89; H, 7.29; N, 3.38.
Found: C, 73.86; H, 7.49; N, 3.60.
Anal. Calcd for C106H132N2O10
: C, 79.86; H, 8.35; N, 1.76.
Found: C, 59.61; H, 8.45; N, 1.80.
Syn -d ista l p-ter t-bu tyl-25-[(2-p yr id ylm eth yl)oxy]-27-
[(1-h yd r oxy-3,6-d ioxa oct-8-yl)oxy]-26,28-d ih yd r oxyca lix-
[4]a r en e (5a ): 11% yield; mp 111-113 °C; Rf ) 0.15 (cyclo-
hexane-AcOEt 1:1); 1H NMR δ 0.93, 0.95, 1.29 (s, ratio 1:1:2,
36 H), 2.85, 2.89 (s, 3 H each), 3.31 (d, J ) 12.8 Hz, 4 H), 3.52
(m, 2 H), 3.61 (m, 2 H), 3.65 (m, 2 H), 3.75 (t, J ) 5.4 Hz, 1 H),
3.84 (dd, J ) 5.6, 3.7 Hz, 2 H), 3.99 (t, J ) 4.5 Hz, 2 H), 4.16
(dd, J ) 5.5, 3.5 Hz, 2 H), 4.32 (t, J ) 12.5 Hz, 4 H), 5.15 (s,
2 H), 6.78, 6.79, 7.06 (s, ratio 1:1:2, 8 H), 7.19 (s, 2 H), 7.28
(m, 1 H), 7.86 (td, J ) 7.7, 1.7 Hz, 1 H), 7.99 (s, 1 H), 8.18 (d,
J ) 7.8 Hz, 1 H), and 8.61 (dt, J ) 4.9, 0.8 Hz, 1 H); FAB (+)
MS, m/z 872 (100, MH+). Anal. Calcd for C56H73NO7 ‚C3H7-
NO: C, 74.96; H, 8.53; N, 2.96. Found: C, 74.68; H, 8.45; N,
2.48.
p -t er t -Bu t yl-25-(â-n a p h t h ylm e t h yloxy)-26,27,28-t r i-
h yd r oxyca lix[4]a r en e (2d ): 30% yield; mp 140-143 °C (2-
propanol); 1H NMR δ 1.19, 1.20, 1.22 (s, ratio 2:1:1, 36 H), 3.38,
4.20 (d, J ) 13.7 Hz, 4 H), 3.41, 4.39 (d, J ) 12.9 Hz, 4 H),
5.33 (s, 2 H), 6.95, 7.04 (ABq, J ) 2.4 Hz, 4 H), 7.02, 7.12 (s,
2 H each), 7.5-8.1 (m, 7 H), 9.46, and 10.03 (s, ratio 2:1, 3 H);
FAB (+) MS, m/z 785 (100, MH+). Anal. Calcd for
C55H60O4‚1.5H2O: C, 80.94; H, 8.27. Found: C, 81.17; H, 8.17.
p -ter t-Bu t yl-25-[2-(q u in olylm et h yl)oxy]-26,27,28-t r i-
h yd r oxyca lix[4]a r en e (2e): 38% yield; mp 170-173 °C
Rea ction of 2a w ith Tetr a eth ylen e Glycol Ditosyla te.
The reaction was carried out under the above-described
procedure. Usual workup, followed by chromatography af-
forded the following components:
1
(MeCN); H NMR δ 1.21, 1.23 (s, ratio 3:1, 36 H), 3.43 (bd, J
) 13.0 Hz, 4 H), 4.28, 4.63 (d, J ) 13.6 and 12.9 Hz,
respectively, 2 H each) 5.52 (s, 2 H), 6.98, 7.09 (ABq, J ) 2.3
Hz, 4 H), 7.06, 7.12 (s, 2 H each), 7.59 (bt, J ) 7.2 Hz, 1 H),
7.75 (bt, J ) 6.9 Hz, 1 H), 7.90 (d, J ) 8.4 Hz, 2 H), 8.24 (d, J
) 8.4 Hz, 1 H), 8.34 (d, J ) 8.5 Hz, 1 H), and 9.95 (bs, 3 H);
3-[2-(P yr idylm eth yl)oxy]-p-ter t-bu tylcalix[4]ar en e-(1,2)-
cr ow n -5 (3b): 35% yield; mp 256-258 °C (MeOH); Rf ) 0.27
(cyclohexane-AcOEt 5:1); 1H NMR δ 0.77, 0.88, 1.33, 1.34 (s,
9 H each), 3.17, 3.20, 3.22, 3.26 (d, J ) 12.7-13.2 Hz, 1 H
each), 3.48-4.34 (m, 16 H), 4.36, 4.39, 4.42, 4.53 (d, J ) 12.6,
12.7, 13.5, and 13.0 Hz, respectively, 1 H each), 4.90, 5.03
(ABq, J ) 12.3 Hz, 2 H), 5.96 (s, 1 H), 6.45 (s, 2 H), 6.59, 6.61
(ABq, J ) 2.5 Hz, 2 H), 7.06, 7.09 (ABq, J ) 2.4 Hz, 2 H),
7.13, 7.15 (ABq, J ) 2.5 Hz, 2 H), 7.26 (m, 1 H), 7.77 (td, J )
7.7, 1.7 Hz, 1 H), 7.95 (d, J ) 7.8 Hz, 1 H), and 8.61 (d, J )
4.5 Hz, 1 H); 13C NMR δ 30.92, 31.28 (t), 31.03, 31.68, 31.77
(q), 33.61, 33.76, 33.85, 34.15 (s), 68.41, 69.52, 69.81, 70.38,
70.95, 71.71, 72.15, 76.26, 78.51 (t), 122.62, 122.86, 124.76,
124.86, 124.94, 125.06, 125.37, 125.56, 125.80 (d), 128.47,
129.56, 131.67, 131.82, 131.87, 132.54, 135.58, 136.01 (s),
136.70 (d), 141.33, 145.10 145.85, 145.93, (s), 149.13 (d),
150.73, 150.81, 152.03, 153.61, and 157.97 (s); FAB (+) MS,
m/z 898 (100, MH+). Anal. Calcd for C58H75NO7: C, 77.56; H,
8.42; N, 1.56. Found: C, 77.89; H, 8.61; N, 1.72.
Ca lix[4]a r en e d im er (4b): 2% yield; mp 130-132 °C
(MeOH); Rf ) 0.21 (cyclohexane-AcOEt 2:1); 1H NMR δ 097,
1.02, 1.27 (s, ratio 1:1:2, 72 H), 3.31 (t, J ) 12.3 Hz, 8 H), 3.70
(m, 8 H), 4.00 (dd, J ) 4.4, 4.0 Hz, 4 H), 4.17 (dd, J ) 4.4, 3.7
Hz, 4 H), 4.32, 4.34 (d, J ) 13.0 Hz, 4 H each), 5.17 (s, 4 H),
6.82, 6.89 (s, ratio 1:1, 4 H each), 7.03, 7.05 (ABq, J ) 2.4 Hz,
8 H), 7.28 (m, 2 H), 7.79 (s, 4 H), 7.85 (td, J ) 7.7, 1.8 Hz, 2
H), 8.10 (d, J ) 7.9 Hz, 2 H), and 8.61 (dt, J ) 4.9, 0.8 Hz, 2
FAB (+) MS, m/z 786 (100, MH+). Anal. Calcd for C54H59
-
NO4‚H2O: C, 81.63; H, 7.55; N, 1.76. Found: C, 81.76; H, 7.88;
N, 1.92.
Rea ction of Mon oa lk yla ted Ca lix[4]a r en e 2a w ith
Tr ieth ylen e Glycol Ditosyla te. Gen er a l P r oced u r e.
A
solution of 2a (0.44 g, 0.6 mmol) in DMF (20 mL) was slowly
added to a stirred solution of triethylene glycol ditosylate
(0.275 g, 0.6 mmol) in DMF (30 mL) in the presence of K2CO3
(0.83 g, 6 mmol). The mixture was kept at 60-70 °C under
stirring for 2 days. After evaporation of the solvent, the
residue was partitioned between water and CH2Cl2. The
organic layer was dried (MgSO4) and concentrated. The crude
product was redissolved in CH2Cl2 and column chromato-
graphed on silica gel, by eluting with a gradient of AcOEt in
cyclohexane to give compounds 3a -5a .
3-[2-(P yr idylm eth yl)oxy]-p-ter t-bu tylcalix[4]ar en e-(1,2)-
cr ow n -4 (3a ): 38% yield; mp 278-281 °C (MeOH); Rf ) 0.34
(cyclohexane-AcOEt 5:1); 1H NMR δ 0.79, 0.88, 1.33, 1.34 (s,
(25) Gutsche, C. D.; Iqbal, M. Org. Synth. 1989, 68, 234.
(26) Pirkle, W. H.; Welch, C. J . J . Liq. Chromatogr. 1991, 14, 1.
(27) Allenmark, S. Chromatographic Enantioseparation. Methods
and Applications; Ellis Horwood: New York, 1991; Chapter 4.
(28) Iwamoto, K.; Araki, K.; Shinkai, S. Tetrahedron 1991, 47, 4325.

Monoalkylated p-tert-Butyl-(1,2)-calix[4]crown Ethers
J . Org. Chem., Vol. 62, No. 23, 1997 8047
H); 13C NMR δ 28.69, 31.61 (t), 31.01, 31.05, 31.66 (q), 33.81
(s), 61.81, 69.81, 73.06, 75.07, 78.65 (t), 122.46, 122.71, 125.01,
125.27, 125.62, 125.73 (d), 127.41, 128.14, 132.67, 132.97 (s),
136.96 (d), 141.74, 146.89, 147.38 (s), 148.93 (d), 149.09,
150.10, and 157.16 (s); FAB (+) MS, m/z 1637 (100, MH+).
5.3, 3.8 Hz, 2 H), 4.30, 4.34 (d, J ) 13.0 Hz, 2 H each), 5.14 (s,
2 H), 6.82, 7.06 (s, 4 H each), 7.27 (s, 2 H), 7.29 (m, 1 H), 7.89
(td, J ) 7.7, 1.8 Hz, 1 H), 8.24 (d, J ) 7.7 Hz, 1 H), and 8.60
(d, J ) 4.0 Hz, 1 H); FAB (+) MS, m/z 960 (100, MH+). Anal.
Calcd for C60H81NO9: C, 75.04; H, 8.50; N, 1.46. Found: C,
75.26; H, 8.34; N, 1.55.
Anal. Calcd for C108H106N2O11
: C, 79.18; H, 8.37; N, 1.71.
Found: C, 77.57; H, 8.60; N, 1.78.
Rea ction of 2b w ith P en ta eth ylen e Glycol Ditosyla te.
The reaction was carried out under the above-described
procedure. Usual workup, followed by chromatography af-
forded the following components:
Syn -d ista l p-ter t-bu tyl-25-[(2-p yr id ylm eth yl)oxy]-27-
[(1-h yd r oxy-3,6,9-t r ioxa u n d e c-11-yl)oxy]-26,28-d ih y-
d r oxyca lix[4]a r en e (5b): pale yellow oil, 8% yield; Rf ) 0.04
(cyclohexane-AcOEt 1:1); 1H NMR δ 0.94, 0.95, 1.29 (s, ratio
1:1:2, 36 H], 2.87, 2.94 (s, 3 H each), 3.31 (d, J ) 13.0 Hz, 4
H), 3.50-3.70 (m, 11 H), 3.83 (dd, J ) 5.6, 3.6 Hz, 2 H), 3.99
(t, J ) 4.6 Hz, 2 H), 4.16 (dd, J ) 5.7, 3.5 Hz, 2 H), 4.30, 4.34
(d, J ) 12.7 and 12.8 Hz, respectively, 2 H each), 5.14 (s, 2 H),
6.79, 7.06 (s, 4 H each), 7.21 (s, 2 H), 7.27 (m, 1 H), 7.87 (td,
J ) 7.7, 1.8 Hz, 1 H), 8.01 (s, 1 H), 8.23 (d, J ) 7.9 Hz, 1 H),
and 8.60 (ddd, J ) 4.9, 1.7, 0.9 Hz, 1 H); FAB (+) MS, m/z 916
(100, MH+). Anal. Calcd for C58H77NO8‚C3H7NO: C, 74.05;
H, 8.56; N, 2.83. Found: C, 73.82; H, 8.38; N, 2.53.
3-(Ben zyloxy)-p -ter t-b u t ylca lix[4]a r en e-(1,2)cr ow n -6
(3d ): 26% yield; mp 176-178 °C (MeOH); Rf ) 0.09 (cyclo-
1
hexane-AcOEt 5:1); H NMR δ 0.81, 0.83, 1.33, 1.34 (s, 9 H
each), 3.14, 3.15, 3.23, 3.26 (d, J ) 12.7, 12.6, 13.4, and 13.0
Hz, respectively, 1 H each), 3.18-4.17 (m, 20 H), 4.25, 4.34,
4.43, 4.44 (d, J ) 13.2, 12.5, 13.1, and 12.5 Hz, respectively, 1
H each), 4.81 (s, 2 H), 5.62 (s, 1 H), 6.51, 6.54 (s, 2 H each),
7.05, 7.07 (ABq, J ) 2.4 Hz, 2 H), 7.13 (t, J ) 2.8 Hz, 2 H),
7.30-7.42 (m, 3 H), and 7.55-7.58 (m, 2 H); 13C NMR δ 30.87,
31.34 (t), 31.00, 31.66, 31.74 (q), 33.65, 33.83, 34.12 (s), 69.14,
69.69, 70.35, 70.55, 70.68, 70.95, 71.56, 74.78, 78.14 (t), 124.71,
124.77, 124.93, 124.96, 125.03, 125.09, 125.55, 125.62, 127.91,
128.46, 128.95 (d), 128.86, 129.28, 131.82, 131.88, 132.19,
132.50, 135.80, 135.88, 137.52 (s), 141.45, 145.34, 145.52,
145.77, 150.61, 151.06, 151.37, and 153.84 (s); FAB (+) MS,
m/z 941 (100, MH+). Anal. Calcd for C61H80O8: C, 77.83; H,
8.57. Found: C, 77.63; H, 8.58.
Rea ction of 2a w ith P en ta eth ylen e Glycol Ditosyla te.
The reaction was carried out under the above-described
procedure. Usual workup, followed by chromatography af-
forded the following components:
3-[2-(P yr idylm eth yl)oxy]-p-ter t-bu tylcalix[4]ar en e-(1,2)-
cr ow n -6 (3c): 41% yield; mp 173-175 °C (MeOH); Rf ) 0.09
(cyclohexane-AcOEt 5:1); 1H NMR δ 0.80, 0.86, 1.33, 1.34 (s,
9 H each), 3.16, 3.20, 3.22, 3.29 (d, J ) 12.7, 12.4, 13.0, and
13.4 Hz, respectively, 1 H each), 3.30-4.21 (m, 20 H), 4.25,
4.40, 4.44, 4.47 (d, J ) 13.2, 13.0, 14.0, and 12.5 Hz,
respectively, 1 H each), 4.91, 5.06 (ABq, J ) 12.6 Hz, 2 H),
5.67 (s, 1 H), 6.50 (s, 2 H), 6.58 (t, J ) 2.9 Hz, 2 H), 7.06, 7.08
(ABq, J ) 2.4 Hz, 2 H), 7.13, 7.15 (ABq, J ) 2.5 Hz, 2 H), 7.25
(m, 1 H), 7.79 (td, J ) 7.7, 1.8 Hz, 1 H), 8.00 (d, J ) 7.9 Hz, 1
H), and 8.60 (dt, J ) 4.8, 0.9 Hz, 1 H); 13C NMR δ 31.33, 31.48
(t), 31.01, 31.67, 31.74 (q), 33.65, 33.72, 33.86, 34.14 (s), 69.30,
69.69, 70.34, 70.59, 70.72, 71.06, 71.58, 74.93, 78.41 (t), 122.56,
124.87, 125.10, 125.26, 125.61, 125.66 (d), 128.73, 129.67,
131.54, 131.83, 132.08, 132.70, 135.65, 135.96 (s), 136.80 (d),
141.66, 145.35, 145.83 (s), 149.03 (d), 150.59, 150.80, 151.61,
153.59, and 157.94 (s); FAB (+) MS, m/z 942 (100, MH+). Anal.
Calcd for C60H79NO8: C, 76.48; H, 8.45; N, 1.49. Found: C,
76.28; H, 8.62; N, 1.64.
Ca lix[4]a r en e d im er (4d ): 8% yield; mp 148-150 °C (CH2-
Cl2-MeOH); Rf ) 0.31 (cyclohexane-AcOEt 5:1); 1H NMR δ
0.96, 0.97, 1.27 (s, ratio 1:1:2, 72 H), 3.27 (d, J ) 13.0 Hz, 8
H), 3.51 (s, 4H), 3.55 (dd, J ) 5.6, 3.6 Hz, 4H), 3.75 (dd, J )
5.6, 3.6 Hz, 4H), 3.91 (t, J ) 4.8 Hz, 4H), 4.11 (t, J ) 4.8 Hz,
4H), 4.30, 4.33 (d, J ) 12.7 and 13.0 Hz, respectively, 8 H
each), 5.00 (s, 4 H), 6.78, 6.80, 7.03 (s, ratio 1:1:2, 16 H), 7.32
(s, 4 H), 7.36-7.44 (m, 6 H), and 7.64-7.67 (m, 4 H); 13C NMR
δ 31.02, 31.71 (q), 31.57 (t), 33.79, 33.93 (s), 69.92, 70.44, 70.65,
71.08, 75.49, 78.21 (t), 124.95, 125.04, 125.47, 125.51, 127.91,
128.07, 128.50 (d), 127.71, 132.63, 132.69, 137.06 (s), 141.24,
146.81, 146.87, 149.63, 149.82, and 150.67 (s); FAB (+) MS,
m/z 1701 (100, MNa+). Anal. Calcd for C112H142O12‚1.5H2O:
C, 78.79; H, 8.56. Found: C, 78.65; H, 8.51.
Syn -d ista l p-ter t-Bu tyl-25-(ben zyloxy)-27-[(1-h yd r oxy-
3,6,9,12-tetr aoxatetr adec-14-yl)oxy]-26,28-dih ydr oxycalix-
[4]a r en e (5d ): 18% yield; pale yellow oil, which crystallizes
on standing, mp 50-52 °C; Rf ) 0.15 (cyclohexane-AcOEt
P yr id in iu m tr iflu or oa ceta te 3c‚H+: 1H NMR (CDCl3 with
1 drop CD3OD) δ 0.80, 0.89, 1.30, 1.31 (s, 9 H each), 3.18, 3.19,
3.22, 3.31 (d, J ) 11.7, 13.1, 11.9, and 13.5 Hz, respectively, 1
H each), 3.4-4.2 (m, 20 H), 4.19, 4.31, 4.33, 4.47 (d, J ) 13.6,
12.9, 12.6 and 12.5 Hz, respectively, 1 H each), 5.02, 5.26 (ABq,
J ) 14.3 Hz, 2 H), 6.50, 6.52 (ABq, J ) 2.5 Hz, 2 H), 6.63,
6.66 (ABq, J ) 2.4 Hz, 2 H), 7.03, 7.07 (ABq, J ) 2.4 Hz, 2 H),
7.11, 7.125 (ABq, J ) 2.4 Hz, 2 H), 7.55 (m, 1 H), 8.20 (td, J
) 7.9, 1.6 Hz, 1 H), 8.42 (d, J ) 7.8 Hz, 1 H), and 8.78 (dd, J
) 4.5, 0.9 Hz, 1 H).
Ca lix[4]a r en e d im er (4c): 5% yield; mp 264-266 °C
(CH2Cl2-MeOH); Rf ) 0.28 (cyclohexane-AcOEt 1:1); 1H NMR
δ 0.94, 0.95, 1.28 (s, ratio 1:1:2, 72 H), 3.30, 3.31 (d, J ) 13.2
and 13.0 Hz, respectively, 4 H each), 3.49 (s, 4H), 3.58 (dd, J
) 5.6, 3.8 Hz, 4H), 3.79 (dd, J ) 5.6, 3.8 Hz, 4H), 3.97 (t, J )
4.7 Hz, 4H), 4.14 (t, J ) 4.7 Hz, 4H), 4.29, 4.33 (d, J ) 13.0
Hz, 4 H each), 5.13 (s, 4 H), 6.79, 7.05 (s, 8 H each), 7.20 (s, 4
H), 7.26 (m, 2 H), 7.86 (td, J ) 7.7, 1.8 Hz, 2 H), 8.23 (d, J )
7.9 Hz, 2 H), and 8.58 (dt, J ) 4.8, 0.8 Hz, 2 H); 13C NMR δ
30.99, 31.71 (q), 31.52 (t), 33.81, 33.92 (s), 70.03, 70.51, 70.63,
71.04, 75.37, 78.21 (t), 121.63, 122.70, 125.03, 125.52, 125.54,
125.60 (d), 127.59, 127.76, 132.44, 132.51 (s), 137.13 (d),
141.42, 146.97, 147.01 (s), 148.89 (d), 149.50, 149.72, 150.60,
and 157.48 (s); FAB (+) MS, m/z 1703 (100, MNa+). Anal.
Calcd for C110H140N2O12‚1.5H2O: C, 77.29; H, 8.43; N, 1.64.
Found: C, 77.15; H, 8.42; N, 1.82.
1
1:1); H NMR δ 0.957, 0.959, 1.28 (s, ratio 1:1:2, 36 H), 2.85,
2.88 (s, 3 H each), 3.27 (d, J ) 13.2 Hz, 4 H), 3.53-3.80 (m, 17
H), 3.93 (t, J ) 4.6 Hz, 2 H), 4.12 (t, J ) 4.6 Hz, 2 H), 4.30,
4.32 (d, J ) 13.0 and 13.1 Hz, respectively, 2 H each), 5.01 (s,
2 H), 6.79, 6.80, 7.04 (s, ratio 1:1:2, 8 H), 7.32 (s, 2 H), 7.37-
7.44 (m, 3 H), 7.67 (d, J ) 6.8 Hz, 2 H), and 7.99 (s, 1 H); FAB
(+) MS, m/z 959 (100, MH+). Anal. Calcd for C61H82O9‚C3H7-
NO: C, 74.46; H, 8.69; N, 1.36. Found: C, 74.58; H, 8.70; N,
1.26.
3-[2-(P yr id ylm eth yl)oxy]-4-p r op oxy-p-ter t-bu tylca lix-
[4]a r en e-(1,2)cr ow n -5 (7): A mixture of 3b (90 mg, 0.1
mmol) and NaH (5 mg, 0.2 mmol) in anhydrous THF (5 mL)
was stirred at rt for 0.5 h. n-Propyl iodide (34 mg, 0.2 mmol)
was then added, and the reaction mixture was refluxed for 6
h. The excess NaH was destroyed by addition of MeOH (0.5
mL), and the solvent was evaporated. The residue was
partitioned between water and CH2Cl2. The organic layer was
washed with 1 N Na2S2O4 and then with water, dried (MgSO4),
and evaporated. The crude product was passed through a
short column (neutral alumina, eluent Et2O). Evaporation of
the solvent afforded propyl ether 7 (66 mg, 70%) as colorless
crystals: mp 221-224 °C (hexane); 1H NMR δ 0.81 (t, J ) 7.5
Hz, 3 H), 1.044, 1.051, 1.139, 1.145 (s, 9 H each), 1.85 (m, 2
H), 3.12, 3.13, 3.14, 3.16 (d, J ) 12.3-12.7, 1 H each), 3.57-
4.12 (m, 18 H), 4.37, 4.41, 4.45, 4.53 (d, J ) 12.3-12.7 Hz, 1
H each), 5.00, 5.07 (ABq, J ) 12.1 Hz, 2 H), 6.72-6.90 (m, 8
H), 7.28 (ddd, J ) 7.7, 4.8, 1.2 Hz, 1 H), 7.89 (td, J ) 7.7, 1.8
Hz, 1 H), 8.06 (d, J ) 7.9 Hz, 1 H), and 8.61 (dd, J ) 5.0, 1.0
Hz, 1 H); 13C NMR δ 10.11 (q), 22.96 (t), 30.69, 30.92, 30.96,
31.11 (t,), 31.37, 31.49 (q), 33.76, 33.78, 33.87 (s), 70.06, 70.37,
70.57, 70.66, 70.96, 71.03, 73.24, 73.72, 76.85, 78.37 (t), 122.45,
Syn -d ista l p-ter t-bu tyl-25-[(2-p yr id ylm eth yl)oxy]-27-
[(1-h yd r oxy-3,6,9,12-t et r a oxa t et r a d ec-14-yl)oxy]-26,28-
d ih yd r oxyca lix[4]a r en e (5c): pale yellow oil, 4% yield; Rf
1
) 0.05 (cyclohexane-AcOEt 1:1); H NMR δ 0.96, 0.97, 1.28
(s, ratio 1:1:2, 36 H), 3.31, 3.32 (d, J ) 13.2 Hz, 2 H each),
3.50-3.66 (m, 13 H), 3.70 (dd, J ) 5.4, 3.6 Hz, 2 H), 3.83 (dd,
J ) 5.5, 3.7 Hz, 2 H), 3.99 (t, J ) 4.5 Hz, 2 H), 4.16 (dd, J )

8048 J . Org. Chem., Vol. 62, No. 23, 1997
Arnaud-Neu et al.
123.58, 124.74, 124.98, 125.00, 125.03, 125.05, 125.09, 125.23
(d), 133.13, 133.28, 133.34, 133.67, 133.90, 134.17, 134.20,
134.42 (s, bridgehead-C), 136.59 (d), 144.35, 144.45, 144.62,
144.68 (s), 149.13 (d), 152.80, 153.18, 153.36, 153.60, and
158.35 (s); FAB (+) MS, m/z 940 (100, MH+). Anal. Calcd for
C61H81NO7: C, 77.92; H, 8.68; N, 1.49. Found: C, 77.55; H,
8.38; N, 1.60.
Com p lexa tion Stu d ies. Extraction experiments were
performed using the Pedersen method:29 equal volumes (5 mL)
of the aqueous phase (2.5 × 10-4 M metal picrate in bidis-
tilled water) and the organic phase (2.5 × 10-4 M calixarene
in CH2Cl2) were placed in stoppered glass tubes and shaken
were determined by UV absorption spectrophotometry or by
pH-metry according to the procedures already described.30,31
The ionic strength was maintained at 0.01 by using Et4NCl
or Et4NClO4. The metal salts used were the alkali chlorides
and silver and zinc perchlorates.
Association constants Ka of ligands 3a -c with Ag+Pic- in
THF, corresponding to the equilibrium Ag+Pic- + LH H
Ag+LHPic-, were determined by following the change in the
absorption spectra of solutions of the metal picrate in this
solvent upon addition of increasing amounts of ligand.
Spectrophotometric and pH-metric data were treated with
the program Sirko.32
with
a mechanical vibrator for 4 min and then stirred
magnetically for 1 h. The percentages of cation extracted (%E)
were calculated from the spectrophotometric determination at
355 nm of the concentration of picrate anion remaining in the
aqueous phase after separation of the two phases. The
experimental details and the preparation of the metal picrates
have been described earlier.30
Ack n ow led gm en t . The Italian authors thank
M.U.R.S.T. for financial support of this work.
J O970934E
(30) Arnaud-Neu, F.; Schwing-Weill, M. J .; Ziat, K.; Cremin, S.;
Harris, S. J .; McKervey, M. A. New J . Chem. 1991, 15, 33.
(31) Arnaud-Neu, F.; Barrett, G.; Harris, S. J .; Owens, M.; McK-
ervey, M. A.; Schwing-Weill, M. J .; Schwinte, P. Inorg. Chem. 1993,
32, 2644.
Stability constants â in MeOH, referring to the equilibrium
Mn+ + LH H MLHn+ (LH being the phenolic form of the ligand)
(29) Pedersen, C. J . Fed. Proc. Fed. Am. Soc. Expl. Biol. 1968, 27,
1305.
(32) Vetrogon, V. I.; Lukyanenko, N. G.; Schwing-Weill, M. J .;
Arnaud-Neu, F. Talanta 1994, 41, 2105.