Synthesis of calix[4]crowns containing soft donor atoms and a study of their metal-cation binding properties: Highly selective receptors for Cu2+

Article abstract of DOI:10.1039/b205436a

Two new calix[4]arenethiacrown derivatives 1 and 2 in the cone conformation were synthesized by two different pathways in good yield. Their complexation properties toward alkali, alkaline earth and transition metal cations were studied in acetonitrile at 298.15 K using a conductometric titration technique. The selectivity for Cu²⁺ over other cations with these novel ligands was excellent.

Full text of DOI:10.1039/b205436a

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Synthesis of calix[4]crowns containing soft donor atoms and a
study of their metal–cation binding properties: highly selective
receptors for Cu2؉
2
Muhammad Ashram*
Chemistry Department, Mu’Tah University, Al-Karak, Jordan. E-mail: ashram@mutah.edu.jo
Received (in Cambridge, UK) 6th June 2002, Accepted 29th July 2002
First published as an Advance Article on the web 13th September 2002
Two new calix[4]arenethiacrown derivatives 1 and 2 in the cone conformation were synthesized by two different
pathways in good yield. Their complexation properties toward alkali, alkaline earth and transition metal cations were
studied in acetonitrile at 298.15 K using a conductometric titration technique. The selectivity for Cu2ϩ over other
cations with these novel ligands was excellent.
was carried out by following two different pathways (Schemes 1
and 2) while p-tert-butylcalix[4]dithiadioxadibenzocrown 1 was
obtained as shown in Scheme 1. Salicylaldehyde was reacted
with an equimolar amount of ethyl bromoacetate in the
Introduction
Many macrocyclic ligands possessing different donor atoms
have been developed and their complexation properties have
been extensively studied.1,2 Those macrocycles containing hard
presence of one equiv. of anhydrous K2CO3 in refluxing CH3-
donor atoms such as O atoms or N atoms mainly complex
alkali or alkaline earth metal ions, whereas those containing
CN (3–4 h) to afford a yellow oily mixture of compounds 3 and
4 (Scheme 1). With longer reaction times, the benzofuran 414
soft donor atoms such as thioether S atoms or phosphine P
was obtained exclusively. When salicylaldehyde was treated
with ethyl bromoacetate in the presence of K2CO3 in refluxing
anhydrous acetone for 3–4 h however, 3 could be obtained in
atoms bind transition metal ions.1,2 Interest in the study of the
complexation of heavy metals with macrocycles is mainly due
to the importance of such ions in biological and environmental
88% yield. Trace amounts of remaining starting material could
processes. An important parameter in the study of macrocyclic
easily be removed by washing the ether solution of the crude
ligand–metal complexes is the stability constant, Kassoc
.
product with aqueous 5% NaOH. Reduction of 3 using NaBH4
in MeOH at room temperature afforded a mixture of 5 and 6.
With longer reaction times (6–7 h) 3 was completely converted
to 6. However, when the reduction was conducted at Ϫ5–0 ЊC
for only 10–15 min, 5 was obtained in 95% yield. Treatment
of 5 with freshly distilled SOCl2 at 0 ЊC for 15 min produced 7
(92%) which, under basic conditions with ethanedithiol or
2-mercaptoethyl sulfide, afforded 8 and 9 respectively, in quanti-
tative yields. Lithium aluminium hydride reduction of 8 or 9 in
THF at room temperature afforded 10 and 11 respectively, in
98% yield. Reaction of 10 or 11 with p-TsCl and KOH in ether
at 0 ЊC successfully produced 12 and 13 respectively, also in
good yields, after column chromatographic purification.
p-tert-Butylcalix[4]dithiadioxadibenzocrown 1 and p-tert-butyl-
calix[4]trithiadioxadibenzocrown 2 were prepared by coupling
of p-tert-butylcalix[4]arene with an equimolar amount of 12
or 13 respectively, in the presence of excess anhydrous K2CO3
in refluxing anhydrous CH3CN for 7 d. Each of the resulting
reaction products was purified by column chromatography to
give 1 or 2 as colourless solids, in 30 and 39% yields, respec-
tively. Further purification was achieved by washing the solids
with diethyl ether. Compounds 1 and 2 were fully characterized,
and established to be in cone conformations by the presence of
The magnitudes of these stability constants depend on several
factors, including the relative size of the cation and the macro-
cyclic cavity, the number and the nature of binding sites,
the acid–base character of metal ions and the nature of the
solvent.3 All of these factors also affect the selectivity of
the macrocyclic ligands towards cations. A group of such
compounds that are currently under intensive study are the
calixarenes, and calix[4]arenes in particular.4 More commonly,
however, calixarenes modified on their lower rims represent
simple, though effective and versatile means of producing
receptors with very selective cation binding properties.
Most calixarene derivatives with pendant ether,5 ester,6 ketone,7
carboxylic acid,8 amide9 or crown ether10 groups complex
alkali and alkaline earth metal cations. Calixarene ligands
which are better for “softer” transition metals can be derived by
incorporating “softer” N and/or S atoms into the lower rim.
Schiff base,11 thioamide12 and thioether13 derivatives are able to
extract Agϩ, Pb2ϩ, Cu2ϩand Hg2ϩ ions for example, but among
such calix[4]arene derivatives that have been reported, the
selectivity for these transition metals was not very pronounced.
In order to enhance the selectivity toward transition metal
ions by controlling the cavity size of the calix[4]arene crown
derivatives, and also the rigidity of the crown tether we report
herein the synthesis of two new calix[4]thiacrown derivatives.
1
two sets of doublet signals in their H NMR spectra at δ 3.31
and 4.38 ppm, and at δ 3.31 and 4.45 ppm respectively, due
to the methylene bridge protons (ArCH2Ar), as well as by the
presence of two singlet signals due to the tert-butyl groups at
δ 0.98 and 1.30 ppm and at δ 0.8 and 1.30 ppm, respectively.
Alternatively, 2 could also be prepared in 74% yield using
the shorter reaction pathway shown in Scheme 2. Alkylation
of salicylaldehyde with an excess of 1,2-dibromoethane in
the presence of 2 equiv. of anhydrous K2CO3 in refluxing
anhydrous CH3CN afforded, after column chromatographic
purification, 14 as a pale yellow solid in 66% yield, along with a
These derivatives, calix[4]dithiadioxadibenzocrown
1 and
calix[4]trithiadioxadibenzocrown 2 were shown to exist in cone
conformations, and a preliminary investigation of their metal
ion binding properties is also reported herein.
Results and discussion
Synthesis
The synthesis of p-tert-butylcalix[4]trithiadioxadibenzocrown 2
1662
J. Chem. Soc., Perkin Trans. 2, 2002, 1662–1668
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b205436a

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Scheme 1
minor product (<10%) 14a whose melting point was identical
after column chromatographic purification, 17 in 58% yield.
Base-mediated coupling of equimolar amounts of 17 and
2-mercaptoethyl sulfide afforded 2 in 74% yield.
to that reported in the literature.15 The 1,3-dialdehyde 15 was
prepared by alkylation of p-tert-butylcalix[4]arene with 2
equiv. of compound 14 in refluxing anhydrous CH3CN contain-
ing 1 equiv. of anhydrous K2CO3. Compound 15 was formed
as a colourless solid in 75% yield after washing the crude
product with diethyl ether. Reduction of 15 using NaBH4 in
MeOH at room temperature afforded 16 in quantitative yield.
Treatment of 16 with freshly distilled SOCl2 at room temper-
ature in anhydrous benzene or CH2Cl2 for 15 min afforded,
Conductometric titrations
In principle, measurements of the variation of electrical con-
ductance with the concentration of metal salts and receptors
can be used to determine the strength, stoichiometry and
stability constants of complex formation and to assess the
J. Chem. Soc., Perkin Trans. 2, 2002, 1662–1668
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Scheme 2
nature of the interactions taking place.16,17 We employed such
measurements to establish the stoichiometry of the complexes
formed between several individual metal cations and 1 and 2,
and to assess qualitatively the strength of the complexes from
the shape of the conductometric titration curves, and also to
determine the stability constants of these complexes. Plots
showing no or very slight slopes indicate very little or no com-
plexation at any given mole ratio. For complexes of moderate
stability, plots with well-defined changes in curvature at the
stoichiometric ratios of the reaction were obtained. Plots in
which two straight lines intersect at the stoichiometric ratios of
the reaction are indicative of strong complexation. The molar
conductance versus [L]T/[M]T plots in acetonitrile at 25 ЊC are
given in Figs. 1 and 2. [L]T and [M]T are the total concentrations
of the ligands 1 or 2 and of the metal cations respectively.
As can be seen, in Fig. 1 the addition of calixthiacrown 1 to
solutions of Cu2ϩ or Agϩ, but not of Mg2ϩ or Csϩ, result
in continuous decreases in the molar conductances of the
resulting solutions. Also, as shown in Fig. 2, addition of calix-
thiacrown 2 to solutions of Cu2ϩ or Agϩ, but not of Mg2ϩ or
Csϩ, result in continuous decreases in the molar conductances
of the resulting solutions. These decreases indicate lower
mobilities of the metal–ligand complexes as compared to the
solvated cations alone. The decreases in molar conductances for
Fig. 1
Cu2ϩ and Agϩ, which are shown in Figs. 1 and 2 start to level off
at a mole ratio of 1. The corresponding slopes of the plots
for these cations also change at the point where the calixthia-
crown-to-cation mole ratio is 1, implying the formation of 1 : 1
complexes. It is noteworthy that the sharp decreases of the
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Table 1 Kassoc (in dm3 molϪ1) for complexation of Cu2ϩ and Agϩ with
1 and 2 in acetonitrile at 25 ЊC
the suppliers indicated: LiClO4 (Aldrich, 95%), NaClO4 (Sigma,
99%), KClO4 (Fluka, Chemica, >99.5%), RbClO4 (Aldrich),
CsNO3 (Aldrich, 99%), AgNO3 (GCC, 99%), HgBr2 (BDH,
98%), Cu(ClO4)2ؒ6H2O (Aldrich), Zn(ClO4)2ؒ6H2O (Aldrich),
Cd(ClO4)2 (Aldrich), MnCl2ؒ4H2O (Aldrich), Cr(NO3)3ؒ9H2O
(Aldrich), Pb(ClO4)2ؒ3H2O (Aldrich), Co(ClO4)2ؒ6H2O (Alfa),
Ni(NO3)2ؒ6H2O (BDH, 99%), Mg(ClO4)2 (Aldrich). Chroma-
tographic separations were performed on silica gel columns
(60–120 mesh, CDH). Thin layer chromatography (TLC) was
carried out using silica gel GF254 (Fluka). Unless otherwise
noted, all reactions were carried out under dry nitrogen.
Compound
Cu2ϩ
Agϩ
1
2
5.77 0.28
5.58 0.27
3.39 0.16
4.50 0.22
Synthesis: pathway A
o-(Ethoxycarbonylmethoxy)benzaldehyde (3) and ethyl 1-
benzofuran-2-carboxylate (4). In a 100 ml two-necked flask
equipped with a magnetic stirrer bar and a reflux condenser,
salicylaldehyde (2.50 g, 0.021 mol), ethyl bromoacetate (3.75 g,
0.021 mol) and anhydrous K2CO3 (3.06 g, 0.021 mol) were
mixed in anhydrous CH3CN (75 ml). The mixture was refluxed
for 3–4 h and then allowed to cool to room temperature. The
solid was separated by filtration and washed with acetonitrile.
The combined organic solution was then evaporated to dryness
to obtain a yellow oily residue. The crude product was purified
by column chromatography using ethyl acetate–hexane (2 : 8) to
give in order of increasing Rf values: 4 as a yellow oil (1.41 g,
Fig. 2
1
slopes for calixthiacrown–Cu2ϩ complexes of 1 or 2 indicate
that these complexes are more stable than the corresponding
calixthiacrown–Agϩ complexes and that the stability constants
of the calixthiacrown–Cu2ϩ complexes of 1 or 2 are higher
than those of the Agϩ–calixthiacrown complexes (Table 1).
Furthermore, it can also be seen that the strength of the calix-
thiacrown 1–Cu2ϩ complex is higher than that of the calixthia-
crown 2–Cu2ϩ complex, while that of the calixthiacrown 2–Agϩ
complex is higher than that of the calixthiacrown 1–Agϩ
complex. Figs. 1 and 2 also reveal that despite increases in the
calixthiacrown concentrations of 1 or 2, no detectable changes
in molar conductances were found for Mg2ϩ and Csϩ, for
example. Similar negligible changes in molar conductances
37%), H NMR δH 1.45 (t, J = 8 Hz, 3H, OCH2CH3), 4.46
(q, J = 8 Hz, 2H, OCH2CH3), 7.27–7.72 (m, 5H, aromatic); 13
C
NMR δC 14.1, 61.4, 112.4, 113.8, 122.8, 123.7, 127.0, 128.6,
145.8, 155.5, 159.1; ϩAPCI HRMS calcd for C11H11O3 (M ϩ
1)ϩ 191.071, found 191.15. Compound 3 was obtained as pale
1
yellow solid (1.81 g, 61%), mp 39–40 ЊC; H NMR δH 1.31 (t,
J = 8 Hz, 3H, OCH2CH3), 4.33 (q, J = 8 Hz, 2H, OCH2CH3),
4.81 (s, 2H, OCH2CO), 6.91 (d, J = 4 Hz, 1H), 7.12 (t, J = 4 Hz,
1H), 7.56 (t, J = 4 Hz, 1H), 7.91 (d, J = 4 Hz, 1H), 10.61 (s, 1H,
CHO); 13C NMR δC 14.0, 61.2, 65.3, 112.5, 121.2, 125.0, 128.0,
135.5, 159.8, 168.0, 189.5; ϩAPCI HRMS calcd for C11H13O4
(M ϩ 1)ϩ 209.081, found 209.15. Longer reaction times (36 h)
produced 4 in 78% yield. When acetonitrile was replaced with
anhydrous acetone only 3 was produced (88%) yield in addition
to a trace amount of salicylaldehyde. Purification was con-
ducted by dissolving the crude product in diethyl ether and
washing with aqueous 5% NaOH followed by water until the
aqueous washes were neutral to pH paper.
were also found for Mnϩ = Naϩ, Kϩ, Rbϩ, Cr3ϩ, Mn2ϩ, Fe2ϩ
,
Co2ϩ, Ni2ϩ, Zn2ϩ and Cd2ϩ. Determinations of their complex
formation constants with calixthiacrowns 1 and 2 were there-
fore not possible. Such behavior can indicate that no com-
plexation takes place between calixthiacrowns 1 or 2 and the
above mentioned metal cations other than Cu2ϩ and Agϩ.
In conclusion, two new calix[4]thiacrowns 1 and 2 have been
synthesized in good yields by two different pathways. These two
receptors showed highest complexation ability and selectivity
for Cu2ϩ among all of the metal cations studied. Conductance
data indicated well-defined breaks in the titration curves for
Cu2ϩ and Agϩ with 1 and 2, indicative of the formation of 1 : 1
complexes in acetonitrile at 25 ЊC. Since no detectable changes
were observed in the shapes of the conductance titration curves
determined for various metal cations, other than Cu2ϩ and Agϩ,
no complexation apparently occurred with these cations. A
follow-up study on other thermodynamic parameters and the
effect of solvent changes on these parameters will be reported
in due course.18
o-(Ethoxycarbonylmethoxy)benzyl alcohol (5). To a solution
of 3 (0.30 g, 1.44 mmol) in MeOH (10 ml) was added NaBH4
(30 mg, 72 mmol) at Ϫ5–0 ЊC. The reaction was stirred for 15
min and then quenched by adding 2 ml of cold water, followed
by aqueous 5% HCl until the solution become acidic to pH
paper. The mixture was extracted with CHCl3. The organic
layer was dried over anhydrous MgSO4 and evaporated to give
1
5 as a colorless oil in 95% yield; H NMR δH 1.3 (t, J = 6 Hz,
3H, OCH2CH3), 3.43 (t, 1H, OH), 4.25 (q, J = 6 Hz, 2H,
OCH2CH3), 4.71 (2s, 4H, CH2OH and OCH2CO), 6.79 (d, J = 4
Hz, 1H), 6.95 (t, J = 6 Hz, 1H), 7.18–7.30 (m, 2H); 13C NMR
δC 14.1, 61.5, 62.0, 65.5, 112.0, 122.0, 129.1, 129.6, 130.2, 155.5,
169.1; ϩ APCI MS (m/z): 193.15 (Mϩ Ϫ OH).
o-(Ethoxycarbonylmethoxy)benzyl chloride (7). To a solution
of 5 (3.05 g, 15 mmol) in dry CH2Cl2 (150 ml) at 0 ЊC was added
freshly distilled SOCl2 (2.1 ml, 29 mmol). The reaction mixture
was stirred at 0 ЊC for 15 min and then was quenched by adding
20 ml of cold water. The organic layer was washed with water
until the aqueous layer was neutral to pH paper. The organic
layer was dried over anhydrous MgSO4 and evaporated to give 7
as a pale yellow oil in 92% yield; 1H NMR δH 1.3 (t, J = 6 Hz,
3H, OCH2CH3), 4.23 (q, J = 6 Hz, 2H, OCH2CH3), 4.71 (s, 2H,
CH2Cl), 4.76 (s, 2H, OCH2CO), 6.29 (d, J = 4 Hz, 1H), 6.97
(t, J = 4 Hz, 1H), 7.28 (t, J = 4 Hz, 1H), 7.38 (d, J = 4 Hz, 1H);
Experimental
Melting points are uncorrected. 1H NMR spectra were
recorded on a 200 MHz spectrometer. In all cases, samples were
dissolved in CDCl3 using TMS as internal standard. Infrared
(IR) spectra were determined on an FT-IR spectrometer.
All materials were analytical grade and used without further
purification. For conductivity experiments, acetonitrile (HPLC
grade, GCC, assay 99.8%) was dried over calcium hydride
and then double-distilled fractionally to give anhydrous solvent
(<3 × 10Ϫ7 S cmϪ1). The following salts were obtained from
J. Chem. Soc., Perkin Trans. 2, 2002, 1662–1668
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13C NMR δC 14.5, 41.7, 61.5, 66.0, 112.1, 122.0, 126.8, 130.2,
131.0, 156.0, 169.0, ϩAPCI MS (m/z): 193.15 (Mϩ Ϫ 35Cl).
water until the aqueous washes became neutral to pH paper.
After drying in air 12 was obtained in 52% yield, mp 108–109
1
ЊC; H NMR δH 2.42 (s, 6H, CH3), 2.50 (s, 4H, SCH2CH2S),
Base-mediated coupling of 7 with ethanedithiol to give 8. To a
suspension of ethanedithiol (0.88 g, 9.36 mmol) in 95% ethanol
(100 ml) at room temperature was added KOH (1.10 g, 20
mmol). The reaction was left to stir for 1 h. A solution of 7
(4.14 g, 18.72 mmol) in benzene (50 ml) was added dropwise.
The reaction was stirred for an additional 1 h and then the
mixture was filtered. The filtrate was added to CHCl3 (100 ml)
and then washed with water. The organic layer was dried over
anhydrous MgSO4 and evaporated to give 8 as a colorless solid
in quantitative yield. The sample was pure enough for use in
the subsequent reaction. An analytical sample was purified by
TLC using ethyl acetate–hexane (3 : 7), mp 74–75 ЊC; 1H NMR
δH 1.3 (t, J = 4 Hz, 6H, OCH2CH3), 2.72 (s, 4H, SCH2CH2S),
3.85 (s, 4H, ArCH2S), 4.15 (q, J = 4 Hz, 4H, OCH2CH3), 4.68
(s, 4H, OCH2CO), 6.72 (d, J = 4 Hz, 2H), 6.92 (t, J = 4 Hz, 2H),
7.15–7.28 (m, 4H); 13C NMR δC 9.4, 30.1, 31.8, 38.6, 61.5, 66.0,
112.0, 122.0, 127.8, 128.0, 131.0,169.0; ϩAPCI HRMS calcd
for C24H31S2O6 (M ϩ 1)ϩ 479.156, found 479.20.
3.61 (s, 4H, ArCH2S), 4.18 (t, J = 4 Hz, 4H, OCH2CH2O), 4.38
(t, J = 4 Hz, 4H, OCH2CH2O), 6.72 (d, J = 4 Hz, 2H), 6.91
(t, J = 4 Hz, 2H), 7.18 (t, J = 4 Hz, 2H), 7.12–7.20 (m, 4H), 7,33
(d, J = 8 Hz, 4H), 7.83 (d, J = 8 Hz, 4H); 13C NMR δC 22.0, 30.2,
31.6, 65.8, 68.4, 112.0, 121.5, 127.7, 128.1, 128.6, 130.0, 130.5,
145.0, 156.5; ϩAPCI HRMS calcd for C34H39S4O8 (M ϩ 1)ϩ
703.153, found 703.40.
Bis(tolylsulfonyloxy) compound 13. Compound 11 (1.02 g,
2.20 mmol) was subjected to the same conditions as 10 to afford
13 as a viscous product in 80% yield after column chromato-
graphic purification using ethyl acetate–hexane (7 : 3); 1H NMR
δH 2.45 (s, 6H, CH3), 2.57 (s, 8H, SCH2CH2S), 3.64 (s, 4H,
ArCH2S), 4.20 (m, 4H,OCH2CH2O), 4.38 (m, 4H, OCH2-
CH2O), 6.76 (d, J = 4 Hz, 2H), 6.93 (d, J = 4 Hz, 2H), 7.14–7.23
(m, 4H), 7.32 (d, J = 8 Hz, 4H), 7.84 (d, J = 8 Hz, 4H); 13C
NMR δC 21.8, 29.9, 30.0, 32.0, 32.1, 66.0, 68.2, 112.0, 121.5,
127.5, 128.0, 128.6, 130.0, 130.6, 144.9, 155.2; ϩAPCI HRMS
calcd for C36H43S5O8 (M ϩ 1)ϩ 763.150, found 763.50.
Base-mediated coupling of 7 with 2-mercaptoethyl sulfide
to give 9. Mercaptoethyl sulfide (1.22 g, 7.92 mmol) in 95%
ethanol (100 ml), KOH (0.93 g, 16.6 mmol) and 7 (3.33 g,
15.8 mmol) in benzene (40 ml) were subjected to the same reac-
tion conditions as 8 to afford 9 as a colorless oil in quantitative
yield. The sample was pure enough for use in the subsequent
reaction. An analytical sample was purified by TLC using ethyl
25,27-O-[Ethylenedithiodimethylenedi-o-phenylenedioxy-
diethylene]-p-tert-butylcalix[4]arene 1. In a 500 ml two-necked
flask equipped with a magnetic stirrer bar and a reflux con-
denser, p-tert-butylcalix[4]arene (3.2 g, 4.93 mmol) and
anhydrous K2CO3 (7.04 g, 51.0 mmol) were mixed in anhydrous
CH3CN (150 ml). The mixture was stirred at room temperature
for 3 h and then heated to reflux. To the refluxing solution, a
solution of 12 (3.5 g, 4.93 mmol) in anhydrous CH3CN (150 ml)
was added dropwise over a period of 10 h. The reaction mixture
was refluxed with stirring for 7 d after which time the CH3CN
was evaporated and the residue was dissolved in CHCl3 (100
ml). Aqueous 5% HCl was added until the aqueous become
slightly acidic. The organic layer was dried over anhydrous
MgSO4 and then evaporated. The crude product was chromato-
graphed on silica gel using ethyl acetate–hexane (1 : 9) as eluent
to give 1 as a colorless solid (1.51 g, 30%). The product was
further purified by washing with diethyl ether, mp 269–271 ЊC;
1H NMR δH 0.98 (s, 18H, t-But), 1.30 (s, 18H, t-But), 2.70
(s, 4H, SCH2CH2S), 3.31 (d, J = 12 Hz, 4H, ArCH2Ar), 3.99 (s,
4H, ArCH2S), 4.35–4.53 (m, 12H, OCH2CH2O and ArCH2Ar),
6.81 (s, 4H), 6.83–7.0 (m, 4H), 7.04 (s, 4H), 7.28 (s, 2H, OH),
7.18–7.32 (m, 4H);13C NMR δC 29.6, 31.1, 31.8, 32.0, 34.1, 66.5,
74.7, 111.5, 121.6, 125.3, 125.8, 128.0, 128.2, 128.5, 131.2,
132.6, 141.2, 147.1, 150.0, 150.6, 151.0, 156.5; ϩAPCI HRMS
calcd for C64H79S2O6 (M ϩ 1)ϩ 1007.531, found 1007.9. Anal.
calcd for C64H78S2O6.(CH3CN)4: C, 73.81; H, 7.74; S, 5.47,
found: C, 72.51; H, 7.37; S, 5.46%.
1
acetate–hexane (3 : 7); H NMR δH 1.31 (t, J = 4 Hz, 6H,
OCH2CH3), 2.65 (m, 8H, SCH2CH2S), 3.85 (s, 4H, ArCH2S),
4.31 (q, J = 4 Hz, 4H, OCH2CH3), 4.70 (s, 4 H, OCH2CO), 6.73
(d, J = 4 Hz, 2H), 6.86 (t, J = 4 Hz, 2H), 7.14–7.30 (m, 4H); 13
C
NMR δC 14.5, 30.0, 31.6, 32.2, 61.5, 66.0, 112.0, 121.9, 128.0,
128.5, 131.0, 155.7 169.0; ϩAPCI HRMS calcd for C26H34S3O6
(M ϩ 1)ϩ 539.160, found 539.50.
LAH reduction of 8. To a suspension of LAH (0.3 g,
7.8 mmol) in anhydrous THF (50 ml) was added a solution of
8 (0.93 g, 1.95 mmol) in anhydrous THF (25 ml) at room
temperature. The reaction mixture was stirred for 5 min and
then was quenched by adding the mixture into wet diethyl ether
(100 ml) at 0 ЊC. The mixture was then acidified with aqueous
5% HCl. The organic layer was separated and the aqueous layer
was extracted with diethyl ether (50 ml). The combined organic
layers were dried over anhydrous MgSO4 and evaporated to give
10 as a colourless oil in near 98% yield; 1H NMR δH 2.65 (s, 4H,
SCH2CH2S), 3.32 (br, 2H, OH), 3.78 (s, 4H, ArCH2S), 3.92
(br, 4H, OCH2CH2O), 4.18 (s, 4H, OCH2CH2O), 6.81–6.92
(m, 4H), 7.12–7.28 (m, 4H); 13C NMR δC 31.0, 31.2, 61.2,
69.9, 112.1, 121.0, 126.8, 129.0, 130.8, 156.5; ϩAPCI HRMS
calcd for C20H26S2O6 (M ϩ 1)ϩ 395.135, found 395.20.
25,27-O-[Thiodiethylenedithiodimethylenedi-o-phenylene-
dioxydiethylene]-p-tert-butylcalix[4]arene 2. Compound 13
(3.0 g, 3.94 mmol) was subjected to the same reaction con-
ditions as 12 to afford 2 as a colourless solid (1.6 g, 39%). The
product was further purified by washing with diethyl ether,
mp 248–250 ЊC; 1H NMR δH 0.80 (s, 18H, t-But), 1.30 (s, 18H,
t-But), 2.51 (s, 8H, SCH2CH2S), 3.31 (d, J = 14 Hz, 4H,
ArCH2Ar), 3.90 (s, 4H, ArCH2S), 4.30–4.45 (m, 12H, OCH2-
CH2O and ArCH2Ar), 6.75 (s, 4H), 6.88 (s, 2H, OH), 6.86–6.98
(m, 4H), 7.06 (s, 4H), 7.15–7.35 (m, 4H); 13C NMR δC 29.5,
31.1, 31.5, 31.8, 31.9, 32.0, 34.0, 66.9, 74.8, 111.5, 121.2, 125.1,
125.6, 127.6, 128.0, 128.1, 131.0, 132.4, 141.5, 146.9, 149.8,
150.5, 156.5; ϩAPCI HRMS calcd for C66H83S3O6 (M ϩ 1)ϩ
1067.535, found 1067.90. Anal. calcd for C66H82S3O6: C, 74.12;
H, 7.74; S, 8.99, found: C, 74.24; H, 7.82; S, 9.11%.
LAH reduction of 9. Compound 9 (2.01 g, 3.71 mmol) was
subjected to the same conditions as 8 to afford 11 as a colorless
1
oil in 97% yield; H NMR δH 2.61 (s, 8H, SCH2CH2S), 3.13
(br, 2H, OH), 3.80 (s, 4H, ArCH2S), 3.92 (br, 4H,OCH2CH2O),
4.18 (s, 4H, OCH2CH2O), 6.85–6.95 (m, 4H), 7.17–7.29 (m,
4H); 13C NMR δC 31.8, 31.9, 32.0, 61.5, 69.9, 112.1, 121.0,
126.8, 126.1, 129.0, 131.0, 156.1; ϩAPCI HRMS calcd for
C22H31S3O4 (M ϩ 1)ϩ 455.138, found 455.30.
Bis(tolylsulfonyloxy) compound 12. To a mixture of freshly
purified toluene-p-sulfonyl chloride (0.84 g, 4.45 mmol) and
diol 10 (0.70 g, 1.78 mmol) in anhydrous diethyl ether (60 ml)
was added freshly machine-powdered KOH (1.25 g, 22.25
mmol) with vigorous stirring and cooling at Ϫ5–0 ЊC. Stirring
with cooling at 0 ЊC was continued for 3 h. The mixture was
then poured into ice–water (30 g). After vigorous stirring, a
colorless solid was filtered off and washed several times with
Pathway B
o-(2-Bromoethoxy)benzaldehyde (14). In a 250 ml two-necked
flask equipped with a magnetic stirrer bar and a reflux con-
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denser, salicylaldehyde (3.90 g, 32 mmol), 1,2-dibromoethane
(60.1 g, 320 mmol) and anhydrous K2CO3 (8.83 g, 64.0 mmol)
were mixed with anhydrous CH3CN (200 ml). The mixture
was refluxed for 30 h and then cooled to room temperature,
filtered and the solid was washed with CH3CN. The filtrate
was evaporated to dryness. The crude product was purified by
column chromatography on silica gel using CHCl3–hexane
(8 : 2) to give 14 as a pale yellow solid (4.81 g, 66%), mp 51–52
ЊC; 1H NMR δH 3.61 (t, 2H, OCH2CH2Br), 4.34 (t, 2H, OCH2-
HRMS calcd for C62H74Cl2O6 (M ϩ 1)ϩ 984.486, found
985.80.
Base-mediated coupling of 17 with 2-mercaptoethyl sulfide to
give 2. To a solution of KOH (0.12 g) in 95% ethanol (60 ml)
was added a solution of 17 (0.54 g, 0.548 mmol) and 2-mer-
captoethyl sulfide (0.084 g, 0.548 mmol) in benzene (30 ml)
dropwise over 3 h. The reaction was stirred for an additional 3 h
and then the organic solvents were evaporated. The residue
was dissolved in CH2Cl2 (20 ml) and washed with aqueous 5%
HCl. The organic layer was dried over anhydrous MgSO4 and
evaporated. The crude product was washed with diethyl ether to
afford a colorless solid (0.43 g, 74%) whose mp and spectro-
scopic properties were identical to those of 2 as obtained by
pathway A.
CH2Br), 6.88 (d, 1H), 6.98 (t, 1H), 7.45 (t, 1H), 7.81 (d, 1H); 13
C
NMR δC 29.1, 68.0, 103.0, 121.8, 125.2, 128.7, 136.0, 160.5,
189.8; ϩAPCI HRMS calcd for C9H10BrO2 (M ϩ 1)ϩ 228.9864,
found 228.95.
25,27-O-Bis(2-formylphenoxyethyl)-p-tert-butylcalix[4]arene
(15). In a 100 ml two-necked flask equipped with a magnetic
stirrer bar and a reflux condenser, p-tert-butylcalix[4]arene
(0.40 g, 0.62 mmol), and anhydrous K2CO3 (0.09 g, 0.62 mmol)
were mixed with anhydrous CH3CN (20 ml) and refluxed for
1 h. At the reflux temperature, a solution of 14 (0.282 g,
1.24 mmol) in CH3CN (5 ml) was added dropwise. The mixture
was further refluxed for 4 days and then cooled, filtered and the
solid was washed with CH3CN. The combined filtrate was
evaporated to dryness. The residue was dissolved with CHCl3
and washed with aqueous 5% HCl. After drying and evapor-
ation of the organic solvent the crude product was washed
with diethyl ether to afford a 15 as a colourless solid, (0.45 g,
75%), mp 93–95 ЊC; IR (KBr, ν/cmϪ1) 1684 (CHO), 3459 (OH);
1H NMR δH 1.03 (s, 18H, t-But), 1.28 (s, 18H, t-But),
3.31 (d, J = 12 Hz, 4H, ArCH2Ar), 4.33 (d, J = 12 Hz, 4H, Ar-
CH2Ar), 4.42 (m, 8H, OCH2CH2O), 6.88 (s, 4H), 7.0 (s, 4H),
6.96–7.04 (m, 4H), 7.42–7.52 (m, 4H, aromatic and OH), 7.82
(d, J = 8 Hz, 2H), 10.48 (s, 2H, CHO); 13C NMR δC 29.8, 31.0,
31.5, 31.6, 34.0, 67.7, 73.8, 112.6, 121.1, 125.2, 126.0, 128.0,
128.2, 133.0, 136.0, 141.9, 147.5, 150.0, 150.6, 161.0, 190.2;
ϩAPCI HRMS calcd for C62H73O8 (M ϩ 1)ϩ 945.531, found
945.90.
Conductance measurements
Solutions having metal ion concentrations of approximately
1.0–1.10 × 10Ϫ4 M were prepared by dissolving a known
amount of each salt in anhydrous acetonitrile. These solutions
were also used as solvents for preparing the calix[4]thiacrowns
with concentrations of approximately 1.5–1.6 × 10Ϫ3 M in order
to keep the electrolyte concentration constant during the
titration. Conductance measurements were carried out with
a
microprocessor conductivity meter (WTW/LF537). A
calibrated cell (WTW/Tetracon 96) having cell constant of
0.609 cmϪ1 was used. The cell was calibrated using analytical
grade KCl (Merck) in triply-distilled deionized water. The
temperature of the solution was controlled to 0.1 ЊC using a
thermostatted circulator water bath (HAAKE D1) equipped
with a refrigeration unit. In order to determine the complex
formation constant with the different metal cations used, 50 ml
of the desired salt solution were placed in a specially-designed
water-jacketed cell (150 ml, Pyrex®) which was equipped
with a magnetic stirrer and was connected to the thermostatted
circulator water bath at 25 ЊC. The conductances of the
solutions were measured at 25 ЊC. Known amounts (0.5 ml of
solutions of calix[4]thiacrown 1 or 2) were added in a stepwise
manner using a calibrated micro-pipette. The conductivity of
the mixture was then measured after stirring and temperature
equilibration. This procedure was repeated in the same manner
for each addition. Addition of the ligand was continued
until the desired ligand-to-cation mole ratio was achieved.
Mathematical calculation of the stability constant K value from
the conductivity data was achieved by means of the simplex
program listed elsewhere.19 The conductometric measurements
showed that the anhydrous acetonitrile solutions of the ligands
1 or 2 behave as non-electrolytes (0.0 S cmϪ1).
25,27-O-Bis[2-(hydroxymethyl)phenoxyethyl]-p-tert-butyl-
calix[4]arene (16). To a solution of 15 (0.301 g, 0.317 mmol) in
THF (10 ml) at room temperature was added NaBH4 (50 mg,
1.27 mmol). After 10 min the reaction was quenched by adding
5 ml of cold water followed by 5 ml of aqueous 5% HCl. The
mixture was extracted with CHCl3 (20 ml). The organic layer
was dried over anhydrous MgSO4 and then evaporated to afford
16 as a colourless solid in 100% yield, mp 205–207 ЊC; 1H NMR
δH 1.16 (s, 18H, t-But), 1.24 (s, 18H, t-But), 3.39 (d, J = 10 Hz,
4H, ArCH2Ar), 4.28–4.38 (m, 12H, OCH2CH2O and ArCH2-
Ar), 4.63–4.82 (m, 6H, CH2OH), 6.65 (d, J = 6 Hz, 2H), 6.88–
7.35 (m, 14H), 8.94 (s, 2H, OH); 13C NMR δC 31.0, 31.1, 31.7,
32.2, 61.2, 66.9, 74.8, 111.1, 121.0, 125.7, 126.1, 128.2, 129.6,
130.0, 130.8, 133.6, 142.7, 148.0, 149.6; ϩAPCI HRMS calcd
for C62H77O8 (M ϩ 1)ϩ 949.562, found 949.90.
Acknowledgements
Professor Paris E. Georghiou at the Memorial University of
Newfoundland, Canada, is thanked for his critical review and
suggestions. Ms Linda Winsor at the Memorial University of
Newfoundland, Canada, is also thanked for recording the mass
spectra reported herein.
25,27-O-Bis[2-(chloromethyl)phenoxyethyl]-p-tert-butylcalix-
[4]arene (17). To a solution of 16 (0.55 g, 0.58 mmol)
in anhydrous benzene (50 ml) was added freshly distilled
SOCl2 (0.16 ml, 2.32 mmol) at room temperature. The reaction
was stirred for 15 min and then cold water was added.
The organic layer was separated and washed with water, dried
and evaporated. The crude product was purified by column
chromatography using ethyl acetate–hexane (2 : 8) to afford 17
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1
as a colorless solid (0.33 g, 58%), mp 197–198 ЊC; H NMR
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