Design, synthesis and cation-binding properties of novel adamantane- and 2-oxaadamantane-containing crown ethers

Article abstract of DOI:10.1016/S0040-4020(00)01013-9

The synthesis of a series of adamantane- and 2-oxaadamantane-functionalized crown ethers 1-7 is described. Alkali metal picrate extraction profiles have been determined for these novel ionophores. The ability of crown ethers 1-7 to extract the alkali metal picrates was compared with that of benzo-15-crown-5 and 18-crown-6. Also, Na⁺- and K⁺-transport, the ability of ionophores 1-3 to transport Na⁺- and K⁺ across a bulk liquid membrane was measured. The results of alkali metal cation extraction experiments showed that the complexation properties of crown ethers 1 and 2 are comparable to that of benzo-15-crown-5 and 18-crown-6, respectively. Crown ether 3 showed enhanced extractability for all cations but lower selectivity compared to 18-crown-6. However, adamantano-crown ethers 4-7 showed almost negligible extraction capability toward any of the alkali cations. The observed differences among the complexation abilities of the ionophores 1-3 and 4-7 are rationalized on the basis of the results of a molecular modeling study of their corresponding K⁺ complexes.

Full text of DOI:10.1016/S0040-4020(00)01013-9

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 449±457
Design, synthesis and cation-binding properties of novel
adamantane- and 2-oxaadamantane-containing crown ethers
*
Kata Mlinaric-Majerski and Goran Kragol
Â
Ï
Department of Organic Chemistry and Biochemistry, Rudjer Boskovic Institute, P.O. Box 180, 10002 Zagreb, Croatia
Received 25 July 2000; accepted 25 October 2000
AbstractÐThe synthesis of a series of adamantane- and 2-oxaadamantane-functionalized crown ethers 1±7 is described. Alkali metal
picrate extraction pro®les have been determined for these novel ionophores. The ability of crown ethers 1±7 to extract the alkali metal
picrates was compared with that of benzo-15-crown-5 and 18-crown-6. Also, Na1- and K1-transport, the ability of ionophores l±3 to
transport Na1- and K1 across a bulk liquid membrane was measured. The results of alkali metal cation extraction experiments showed that
the complexation properties of crown ethers 1 and 2 are comparable to that of benzo-15-crown-5 and 18-crown-6, respectively. Crown ether
3 showed enhanced extractability for all cations but lower selectivity compared to 18-crown-6. However, adamantano-crown ethers 4±7
showed almost negligible extraction capability toward any of the alkali cations. The observed differences among the complexation abilities of
the ionophores 1±3 and 4±7 are rationalized on the basis of the results of a molecular modeling study of their corresponding K1 complexes.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
bridged adamantane and 2-oxaadamantane crown ethers
1±78 and investigated their binding ability and selectivity
towards alkali metal compared with that of benzo-15-
crown-5 and 18-crown-6. In addition, transport of sodium
and potassium picrates across a bulk chloroform membrane
containing crown ethers 1±3 as carriers was performed. The
difference between the complexation abilities of ionophores
1±3 and 4±7 can be understood on the basis of the results
obtained from a molecular modeling study of their corre-
sponding K1 complexes.
Synthetic macrocyclic polyethers that contain intramolecu-
lar cavities of the appropriate size and shape are interesting
complexing agents from the standpoint of their recognition
capabilities.1,2 Their structural features determine the
stability and the properties of their respective complexes
with inorganic and organic ions as well as with neutral
molecules.3,4 Although a vast literature has been accumu-
lated during the past thirty years, a relatively small number
of papers are concerned with crown ethers that incorporate a
polycyclic moiety as part of crown-backbone. The synthesis
and complexation properties of some macrocyclic poly-
ethers that contain cubane, pentacycloundecane or adaman-
tane moiety have been reviewed recently.5 Incorporation of
a rigid polycyclic moiety into crown ethers should affect
their conformational mobility and also their complexation
abilities. The lipophilic polycyclic moiety should increase
the solubility of the crown ethers in nonpolar solvent and
thereby increase their ability to perform selective ion extrac-
tion and ion transport via their complexation with metal
ions.
2. Results and discussion
2.1. Synthesis of ionophores 1±7
The 2-oxaadamantane-containing crown ethers 1, 2 and 3
were prepared from diol 8 by using an approach based upon
the Williamson ether synthesis (Scheme 1).
Thus, NaH promoted reaction of diol 8 with 1-tosyloxy-2-
benzyloxyethane in DMF afforded 9 in 40% yield. Subse-
quent hydrogenation of 9 produced the corresponding diol
10 quantitatively. The Na1-templated reaction of the conju-
gated base of diol 10 with ethylene glycol ditosylate resulted
in the formation of crown ether 1 in 33% yield. By using the
same conditions, condensation of diol 8 with tetraethylene
glycol ditosylate afforded crown ether 2 in 36% yield.
As a part of our extensive program which is involved with
the synthesis and complexation properties of adamantane-6
and 2-oxaadamantane-7 containing macrocyclic polyethers,
we have prepared a series of novel mono- and bis-1,3-
Keywords:
adamantane-crown-ethers;
oxaadamantane-crown-ethers;
Diol 10 was converted into the corresponding tosylate, 11,
in 98% yield via a standard procedure that employed
TsCl±pyridine. Subsequent Na1-templated, base promoted
extraction experiments; cation complexation; cation transport.
* Corresponding author. Tel.: 1385-1-46-80-196; fax: 1385-1-46-80-195;
e-mail: majerski@rudjer.irb.hr
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01013-9

Â
K. Mlinaric-Majerski, G. Kragol / Tetrahedron 57 (2001) 449±457
450
Scheme 1.
reaction of diol 8 with ditosylate 11 gave crown ether 3 in
30% yield.
spectroscopically (see Experimental). The structure of 3
was con®rmed by X-ray12 crystallographic analysis.
Novel 1,3-bis(hydroxymethyl)-2-oxaadamantane (8) was
prepared in 37% overall yield via vinylmagnezium bromide
addition to 7-exo-epoxymethylenebicyclo[3.3.1]nonan-3-
one9 followed by ozonization and reductive cleavage of
the intermediate ozonide by using BH3±SMe2 complex.10
2.2. Alkali metal ion selectivities of ionophores 1±7
In order to survey cation binding abilities of ionophores 1±
7, alkali metal picrate extraction experiments were carried
out. Since picrate ion concentration can be easily deter-
mined by UV, extractions of aqueous alkali picrates (Li1,
Na1, K1, Rb1 and Cs1; 5£1023 M) were carried out at 258C
with chloroform solutions of crown ethers 1±7 (5£1023 M),
and results were compared with those obtained by using
commercially available 18-crown-6 and benzo-15-crown-
5. In addition `blank' experiments in which CHCl3 con-
tained no crown ether were carried out for each alkali
metal picrate salt. The results are shown in Table 1.
Similarly, Na1-templated, base promoted condensation was
employed to prepare crown ethers 4±7 (Scheme 2). NaH
promoted condensation of diols 1211 and 136c with tetraethyl-
ene glycol ditosylate afforded crown ethers 4 and 5 in 40 and
25% yield, respectively.
NaH promoted reaction of diol 14 with diethylene glycol
ditosylate gave crown ether 6 in 57% yield. Base promoted
cyclization between diol 14 and the corresponding ditosyl-
ate, 15, afforded crown ether 7 in 32% yield.
As can be seen from the data in Table 1, the extractabilities
of oxaadamantano-crown ethers 1±3 toward alkali cations
are in good agreement with the generally accepted `ion-
cavity' concept.1,4 However, adamantano-crown ethers 4±7
showed almost negligible extractions toward any of the alkali
cations studied. Thus, the alkali metal cation complexation
and extraction properties displayed by 2-oxaadamantano-15-
crown-5 (1) and 2-oxaadamantano-18-crown-6 (2) are simi-
lar to those shown by benzo-15-crown-5 and 18-crown-6,
Hitherto unknown diol 14 was prepared in one step by Ag1-
promoted alkylation. Thus, reaction of 1,3-dibromoada-
mantane with ethylene glycol and two equivalents of
AgNO3 afforded the corresponding diol, 14, in 62% yield.
The structures of new compounds 1±7 were established

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K. Mlinaric-Majerski, G. Kragol / Tetrahedron 57 (2001) 449±457
451
Scheme 2.
respectively. However, ionophore 2 showed lower extracta-
bility toward K1 but somewhat increased extractability
toward Na1 and Cs1 ions compared to that of 18-crown-6.
of a relatively stable complex in which the metal cation
guest is surrounded additionally with two bulky groups.12b
It is generally believed that polyethers form a complex with
a cation guest by surrounding it with an electronegative
environment of oxygen atoms that screen the ion from the
surrounding nonpolar solvent.1 How extensively the cation
is complexed, and, hence, how effectively it is transported,
depend on how well it ®ts into the macrocyclic cavity and
also the facility with which the cation and anion depart from
the host carrier at the membrane interface. In order to obtain
Symmetrical bis(2-oxaadamantano)-18-crown-6 (3) showed
high extractability towards all alkali cations, particularly K1
and Rb1. Ionophore 3 displayed surprisingly high af®nity
toward Na1 or even Li1 cations when compared to parent
18-crown-6. One might assume that the unusual extraction
behavior of ionophore 3 could be attributed to the formation
Table 1. Extraction of alkali picrates with CHCl3 containing crown ethers
Ionophore
Extractability (%)a
Li1
Na1
K1
Rb1
Cs1
18-Crown-6
Benzo-15-crown-5
1 (OA15C5)
2 (OA18C6)
3 (DOA18C6)
4 (A18C5)
5 (A20C5)
6 (A16C5)
7 (DA20C6)
1.5^0.4
,1
1.3^0.7
,1
17.5^0.5
,1
,1
,1
3.6^0.4
4.0^0.6
8.1^0.3
6.8^0.6
9.8^0.3
21.7^0.3
1.2^0.2
,1
73.7^0.2
6.4^0.2
8.2^0.8
64.0^0.7
88.1^0.2
,1
,1
,1
,1
61.3^0.4
1.8^0.3
3.4^0.7
61.0^0.1
86.8^0.1
,1
,1
,1
,1
34.7^0.5
1.1^0.1
3.1^0.9
41.9^0.5
69.4^0.4
,1
,1
,1
,1
2.3^0.2
,1
a De®ned as percent of picrate extracted into organic phase. Each value is the average of three independent experiments.

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K. Mlinaric-Majerski, G. Kragol / Tetrahedron 57 (2001) 449±457
452
Table 2. Transport rate of Na1 and K1 picrate through chloroform
membrane containing crown ethers
Crownsa
(jc)b mol h21£1027
(n)c mol£1026 in 24 h
Na1
K1
Na1
K1
1 (OA15C5)
2 (OA18C6)
3(DOA18C6)
18-C-6
0.18
0.43
0.52
0.12
0.16
2.48
1.55
2.04
0.39
0.67
0.87
0.21
0.36
3.58
2.03
3.58
a Chloroform membrane contained 7.5´1024 mol of corresponding crown
ether. The molar ratio of crown ether:M-picrate was 1:10.
b Each value is the average of two or three independent measurements with
deviation less than ^5%.
c Measured value.
Figure 2. Transport of NaPy through CHCl3 membrane containing iono-
phores 1, 2, 3 or 18-crown-6.
convincing evidence regarding this point, we carried out a
series of ion transport studies. We studied the transport rates
(jc, in mol h21) through organic liquid membrane (H2O±
CHCl3±H2O) for sodium and potassium picrate by crown
ether 1, 2, 3, and 18-crown-6. The results are shown in
Table 2.
the other hand, if the complex is very stable, cations are not
released rapidly from the membrane into the receiving
phase.14c
A plot of moles of cation transported into aqueous phase vs
time was constructed for each carrier-containing system.
Linear increase in concentration in the receiving phase
with increasing time was observed through the ®rst 7 h
(see Figs. 1 and 2). In each case, the transport rate (jc)
could be obtained from the slope of the line. A similar linear
increase in salt concentration in the receiving phase with
increasing time was reported earlier.13
In order to better understand the remarkable difference
between the complexation abilities of the 2-oxaadamantane
ionophores 1±3 and adamantane crowns 4±7, we carried out
molecular modeling calculations for the corresponding
complexes with potassium ion. According to the results of
the molecular mechanics calculations, ionophore
3
possesses the ideal cavity size to complex K1. In addition,
ionophore 3 has reduced conformational mobility and there-
fore is better preorganized to complex K1 than is the less
symmetrical crown ether 2 or even the corresponding parent
18-crown-6.15 The complexation of potassium ion with six
ether oxygens stabilizes the macrocyclic ring.12c One bulky
oxaadamantane moiety is situated below and another above
the macrocyclic ring, and they provide additional `steric
support' to maintain potassium ion inside the cavity (Fig.
3a).
The transport rates of Na1 picrate with ionophores 1±3 are
in accord with their low extractability (Table 1). From the
data obtained for transport of K1 picrate (Table 2, Fig. 1), it
can be seen that ionophore 2 transports K1 picrate ca. 20%
faster than does the parent 18-crown-6. However, the trans-
port rate obtained by using crown ether 3 is approximately
25% lower than the corresponding transport rate of 18-
crown-6. Since crown ether 3 extracts .88% of K1 picrate,
it appears that the rate of cation-release is responsible for the
relatively low transport rate. It has been found that the trans-
port rate depends signi®cantly upon cation-carrier complex
stability.13,14a,b If the complex is unstable, cations are not
extracted from the source phase into the organic phase. On
The macrocyclic ring-cavity in adamantano-18-crown-5 (4)
can also accommodate K1. However in the resulting
complex, K1 is expelled from the cavity due its steric inter-
actions with the C±H bonds of adamantane moiety that are
directed toward the center of cavity (Fig. 3b). Raevsky et
al.16 have obtained similar results for an unsubstituted
18-crown-6 and 18-crown-5. On the other hand, diminished
binding of K1 can be rationalized on the replacement of
favorable O´´´K1 interaction by an unfavorable C±H´´´K1
interaction.
Adamantano-20-crown-5 (5) and bis(adamantano)-20-
crown-6 (7) showed no ability to complex alkali metal
cations (see Table 1). These observations are in agreement
with the results obtained by Ouchi et al.,17 who observed
that cation-binding abilities of the ring-extended crown
ethers showed a signi®cant shift in cation selectivity,
probably due to the enlarged cavity size. They found that
the cation-binding abilities of less symmetrical crown ethers
generally are lower than those displayed by common
symmetrical crown ethers. Contrary to 16-crown-5,17
adamantano-16-crown-5 (6) showed very low extractability
toward Na1 (Table 1). The molecular modeling studies
Figure 1. Transport of KPy through CHCl3 membrane containing iono-
phores 1, 2, 3 or 18-crown-6.

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K. Mlinaric-Majerski, G. Kragol / Tetrahedron 57 (2001) 449±457
453
Figure 3. Side view of CPK models (obtained from calculations): (a) K1 complex of bis(2-oxaadamantano)-18-crown-6 (3); (b) K1 complex of adamantano-
18-crown-5 (4).
Figure 4. Illustration of the most stable conformation of adamantano-16-crown-5 (6): (a) top view; (b) side view.
showed that oxygen-atoms, which are connected to the C1
and C3-atoms of adamantane units, have reduced cation-
binding abilities due to the steric effect of the C±H bonds
situated at the C2 carbon atom in adamantane (Fig. 4). The
adamantane-methylene group reduces the cavity size of
crown ether 6 and also makes it less symmetrical, thereby
impeding the potential binding interactions of all ®ve
oxygen-atoms with cation.
4. Experimental
4.1. General
1H and 13C NMR spectra were obtained by using Varian
Gemini 300 nuclear magnetic resonance spectrometer. IR
spectra were recorded on a Perkin±Elmer M-297 spectro-
photometer. UV-spectra were recorded on Philips P 8730
spectrophotometer. The purity of all compounds was deter-
mined by GLC and/or via 13C NMR spectral analysis. GLC
analyses were carried out on a Varian 3300 gas chromato-
graph equipped with a DB-210 capillary column. Melting
points were determined on Ko¯er apparatus and are uncor-
rected. Elemental analyses were performed at Central
Analytical Laboratory, IRB, Zagreb. Unless stated other-
wise, reagent grade solvents were employed.
3. Conclusions
A number of new adamantane and 2-oxaadamantane
containing crown ethers were synthesized, and their
cation-binding abilities were evaluated by using a solvent
extraction technique. The results of extraction experiments
that involved alkali metal cations indicate that the
complexation properties of crown ethers 1 and 2 are
comparable to those of benzo-15-crown-6 and 18-crown-
6, respectively. By way of comparison, crown ether 3
showed enhanced extractability for all cations, but 3
displayed lower selectivity when compared to 18-crown-6.
However, adamantano crown ethers 4±7 showed practically
no extraction capabilities toward any of the alkali metal
cations. The results of molecular modeling studies of the
various crown ethers studied and their corresponding K1
complexes indicate that the observed lower complexation
properties of crown ethers 4±7 may be due to steric
hindrance presented by the methylene group at the adaman-
tane C2 position. Transport of Na1 and K1 picrate, through
liquid membrane by ionophores l±3 and 18-crown-6
showed a linear increase in ion concentration in the
receiving phase with increasing time.
4.2. Molecular modeling studies
All molecular modeling studies were carried out with
complete geometry optimization by using HyperChem
5.0.18 To obtain the most stable conformer of the corre-
sponding crown ether the molecular mechanics calculations
were performed by using AMBER parameters.19 The charge
distribution was ®rst estimated by using PM3 semiempirical
method, then K1 was introduced into the crown ether-ring,
and the geometry of corresponding complex was optimized
by using the same AMBER parameters as had been
employed for the ligand.
4.3. General procedure for the synthesis of ionophores
1±7
Sodium hydride obtained as a 50% suspension of NaH in

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K. Mlinaric-Majerski, G. Kragol / Tetrahedron 57 (2001) 449±457
454
mineral oil (ca. 10 equiv. relative to the diol), was washed
with pentane (3£40 mL) under nitrogen to remove the
mineral oil. Pentane was decanted after the last washing,
and dry THF (250 mL) was added under nitrogen to the
residue. The resulting suspension then was heated to re¯ux,
and a solution of corresponding alcohol and ditosylate (1:1
ratio, ca. 1±2 mmol) in dry THF (150 mL) was added
dropwise during 16 h. The resulting mixture was re¯uxed
for an additional 5 days, and then was allowed to cool
gradually to ambient temperature. Excess of NaH was
destroyed via careful addition of water (ca. 1 mL), and the
resulting mixture was ®ltered. The ®ltrate was concentrated
in vacuo, water (500 mL) was added to the residue, and the
resulting aqueous suspension was extracted with CH2Cl2
(4£150 mL). The combined organic extracts were dried
(MgSO4) and ®ltered, and the ®ltrate was concentrated in
vacuo. The residue thereby obtained was puri®ed via
column chromatography.
reaction of diol 12 (400 mg, 2.02 mmol) with tetraethylene
glycol ditosylate (1.01 g, 2.02 mmol). The crude product
was puri®ed via column chromatography on silica gel by
eluting with 10!20% EtOAc in CH2Cl2. Pure 4 (285 mg,
40%) was thereby obtained as a colorless oil: IR (KBr)
1
2900, 2850, 1450, 1350, 1110 cm21; H NMR (CDCl3,
300 MHz) d 1.31 (d, Jˆ11.5 Hz, 4H), 1.55±1.65 (m, 8H),
2.03 (bs, 2H), 3.06 (s, 2H), 3.54±3.56 (m, 4H), 3.62±3.64
(m, 4H), 3.70 (s, 8H); 13C NMR (CDCl3, 75 MHz) d 28.0,
34.2, 37.1, 39.0, 40.9, 69.9, 70.2, 70.6, 70.8, 81.4. Anal.
Calcd for C20H34O5: C, 67.8; H, 9.7. Found: C, 67.61; H,
9.63.
4.3.5. 16,18-(1,3)Adamantano-20-crown-5 (5). By follow-
ing the general procedure, compound 5 was obtained via
reaction of diol 15 (225 mg, 1.00 mmol) with tetraethylene
glycol ditosylate (505 mg, 1.00 mmol). The crude product
was puri®ed via column chromatography on silica gel by
eluting with 10!20% EtOAc in CH2Cl2. Pure 5 (93 mg,
25%) was thereby obtained as a colorless oil: IR (KBr/
4.3.1. 2,15-[(1,3)2-Oxaadamantano]-15-crown-5 (1). By
following the general procedure, compound 1 was obtained
via reaction of diol 10 (500 mg, 1.76 mmol) with ethylene
glycol ditosylate (680 mg, 1.76 mmol). The crude product
was puri®ed by column chromatography on silica gel by
eluting with 0!2% MeOH in CH2Cl2. Pure 1 (180 mg,
33%) was thereby obtained as a colorless oil: IR (KBr/
®lm) 2900, 2850, 1450, 1350, 1110 cm21 1H NMR
;
(CDCl3, 300 MHz) d 1.29±1.48 (m, 14H), 1.56 (bs, 2H),
1.95 (bs, 2H), 3.49±3.66 (m, 20H); 13C NMR (CDCl3,
75 MHz) d 28.8, 32.2, 36.5, 42.4, 43.1, 45.3, 67.1, 70.2,
70.7, 70.8, 70.9. Anal. Calcd for C22H38O5: C, 69.08; H,
10.01. Found: C, 69.17; H, 9.94.
®lm) 2900, 2850, 1445, 1100 cm21 1H NMR (CDCl3,
;
300 MHz): d 1.43 (d, Jˆ9.5 Hz, 4H), 1.75±1.80 (m, 6H),
2.21 (bs, 2H), 3.30 (s, 4H), 3.65±3.75 (m, 12H); 13C NMR
(CDCl3, 75 MHz): d 26.8, 35.4, 36.2, 70.4, 71.3, 72.7, 78.5.
Anal. Calcd for C17H28O5: C, 65.36; H, 9.03. Found: C,
65.30; H, 9.11.
4.3.6. 14,16-(1,3)Adamantano-16-crown-5 (6). By follow-
ing the general procedure, compound 6 was obtained via
reaction of diol 14 (370 mg, 1.46 mmol) with diethylene
glycol ditosylate (610 mg, 1.46 mmol). The crude product
was puri®ed via column chromatography on silica gel by
eluting with 0!2% MeOH in CH2Cl2. Pure 6 (185 mg,
57%) was thereby obtained as a white crystals: mpˆ39±
4.3.2. 2,18-[(1,3)2-Oxaadamantano]-18-crown-6 (2). By
following the general procedure, compound 2 was obtained
via reaction of diol 8 (440 mg, 2.22 mmol) with tetraethyl-
ene glycol ditosylate (1.12 g, 2.22 mmol). The crude
product was puri®ed via column chromatography on silica
gel by eluting with 0!2% MeOH in CH2Cl2. Pure 2
(290 mg, 36%) was thereby obtained as a colorless oil: IR
418C. IR (KBr/®lm) 2910, 2860, 1450, 1100 cm21 1H
;
NMR (CDCl3, 300 MHz) d 1.49 (bs, 2H), 1.62±1.75 (m,
8H), 1.79 (bs, 2H), 2.30 (bs, 2H), 3.60 (bs, 8H), 3.67 (bs,
8H); 13C NMR (CDCl3, 75 MHz) d 30.5, 35.1, 40.3, 44.7,
59.7, 70.3, 70.4, 70.6, 74.2. Anal. Calcd for C18H30O5: C,
66.25; H, 9.25. Found: C, 66.41; H, 8.99.
1
(KBr/®lm) 2900, 2860, 1470, 1450, 1350, 1100 cm21; H
NMR (CDCl3, 300 MHz) d 1.43 (d, Jˆ12.2 Hz, 4H), 1.77±
1.81 (m, 6H), 2.22 (bs, 2H), 3.32 (s, 4H), 3.67±3.72 (m,
16H); 13C NMR (CDCl3, 75 MHz) d 26.8, 35.4, 36.1,
70.2, 70.6, 71.1, 72.5, 78.4. Anal. Calcd for C19H32O6: C,
64.02; H, 9.05. Found C, 63.91; H, 9.10.
4.3.7. 8,10:18,20-Bis[(1,3)adamantano]-20-crown-6 (7).
By following the general procedure, compound 7 was
obtained via reaction of diol 14 (410 mg, 1.61 mmol) with
ditosylate 13 (920 mg, 1.61 mmol). The crude product was
puri®ed via column chromatography on silica gel by eluting
with 0!2% MeOH in CH2Cl2. Pure 7 (230 mg, 32%) was
thereby obtained as a white crystals: mpˆ174±1768C; IR
(KBr) 2920, 2890, 2860, 1450, 1355, 1115, 1075,
4.3.3. 2,18:9,11-Bis[(1,3)2-oxaadamantano]-18-crown-6
(3). By following the general procedure, compound 3 was
obtained via reaction of diol 8 (300 mg, 1.52 mmol) with
ditosylate 11 (900 mg, 1.52 mmol). The crude product was
puri®ed via column chromatography on silica gel by eluting
with 10!20% EtOAc in CH2Cl2. Pure 3 (200 mg, 30%) was
thereby obtained as a white crystals: mpˆ210±2128C. IR
(KBr) 2920, 2900, 2850, 2815, 1440, 1130 cm21; 1H NMR
(CDCl3, 300 MHz) d 1.43 (d, Jˆ12.2 Hz, 8H), 1.78±1.85
(m, 12H), 2.22 (bs, 4H), 3.33 (s, 8H), 3.73 (s, 8H); 13C NMR
(CDCl3, 75 MHz) d 26.9, 35.5, 36.1, 71.3, 72.8, 78.0. Anal.
Calcd for C26H40O6: C, 69.61; H, 8.99. Found: C, 69.62; H,
9.16.
1
1000 cm21; H NMR (CDCl3, 300 MHz) d 1.50 (bs, 4H),
1.61 (d, Jˆ 11.5 Hz, 8H), 1.74 (d, Jˆ11.5 Hz, 8H), 1.86 (bs,
4H), 2.27 (bs, 4H), 3.57±3.63 (m, 16H); 13C NMR (CDCl3,
75 MHz) d 30.4, 35.1, 40.6, 44.0, 60.3, 70.9, 74.3. Anal.
Calcd for C28H44O6: C, 70.56; H, 9.30. Found: C, 70.47; H,
9.21.
4.3.8. 1,3-Bis(hydroxymethyl)-2-oxaadamantane (8).
Ozone was bubbled during 6 h through the solution of
1-hydroxymethyl-3-vinyl-2-oxaadamantane9b (6.41 g, 33.00
mmol) in CH2Cl2 (250 mL) at 2758C. The solution was
then allowed to warm up to room temperature, purged
with N2 for 30 min, and BH3£SMe2 (3£5 mL) was added
in the intervals of 15 min. The reaction mixture was stirred
4.3.4. 15,17-(1,3)Adamantano-18-crown-5 (4). By follow-
ing the general procedure, compound 4 was obtained via

Â
K. Mlinaric-Majerski, G. Kragol / Tetrahedron 57 (2001) 449±457
455
overnight at room temperature, then 5% HCl (10 mL) was
added, and stirring was continued for another 4 h. The
resulting suspension was dried over anhydrous MgSO4,
®ltered and the solvent was evaporated. The residue was
chromatographed on silica gel with 0!5% MeOH in
CH2Cl2 as the eluant, to give 4.10 g (63%) of 1,3-bis(hy-
droxymethyl)-2-oxaadamantane (8), mpˆ131±1348C. IR
(KBr): 3360, 3280, 2920, 2840, 1450, 1055, 1045,
mixture was stirred overnight at ,58C, diluted with water
(50 mL) and extracted with CH2Cl2 (4£40 mL). Organic
extracts were washed with 6M HCl (2£50 mL) and dried
over anhydrous MgSO4. The solvent was evaporated under
reduced pressure to give 1.66 g (98%) of 1,3-bis[(2-tosyloxy-
ethyloxy)methyl]-2-oxaadamantane (11) as colorless
viscous oil: IR (KBr/®lm) 3070, 3030, 2920, 2850, 1600,
1
1445, 1360 cm21; H NMR (CDCl3, 300 MHz) d 1.44 (d,
1
1025 cm21. H NMR (CDCl3): d 1.37 (d, Jˆ12.3 Hz, 4H),
Jˆ12.1 Hz, 4H), 1.58 (d, Jˆ12.1 Hz, 4H), 1.72 (bs, 2H),
2.17 (bs, 2H), 2.44 (s, 6H), 3.17 (s, 4H), 3.65±3.69 (m,
4H), 4.11±4.15 (m, 4H), 7.34 (d, Jˆ8.2 Hz, 4H), 7.79 (d,
Jˆ8.2 Hz, 4H); 13C NMR (CDCl3, 75 MHz) d 21.3, 26.7,
34.8, 36.3, 69.0, 69.3, 72.3, 78.8, 127.8, 129.7, 132.9, 144.7.
Anal. Calcd for C29H38O9S2: C, 58.57; H, 6.44. Found: C,
58.49; H, 6.70.
1.65±1.80 (m, 8H), 2.21 (bs, 2H), 3.32 (s, 4H), 3.74
(2£OH); 13C NMR (CDCl3) d 26.6, 35.4, 35.6, 69.8, 72.9.
Anal. Calcd for C11H18O3: C, 66.64; H, 9.15. Found: C,
66.66; H, 9.14.
4.3.9. 1,3-Bis[(2-benzyloxyethyloxy)methyl]-2-oxaada-
mantane (9). Solution of 1,3-bis(hydroxymethyl)-2-oxa-
adamantane (8, 3.63 g, 18.30 mmol) in dry DMF (25 mL)
was added to a stirred, cooled (ice/water) suspension of NaH
(3.50, 73.00 mmol; 50% in mineral oil) in dry DMF (50 mL)
under N2. The cooling bath was removed after 30 min, reac-
tion mixture was stirred on room temperature for 3 h and
cooled again with ice/water. To a cooled reaction mixture
solution of 2-benzyloxy-1-tosyloxyethane20 (12.30 g,
40.25 mmol) in dry DMF (15 mL) was added. The reaction
mixture was stirred for additional 48 h and then water
(250 mL) was added. The reaction mixture was extracted
with CH2Cl2 (3£100 mL). Organic extracts were dried over
anhydrous MgSO4. The solvent was evaporated and residue
was chromatographed on silica gel with 10!25% EtOAc in
pentane as the eluant, to give 3.35 g (40%) of 1,3-bis-
[(2-benzyloxyethyloxy)methyl]-2-oxaadamantane (9) as
colorless oil: IR (KBr/®lm) 3070, 3030, 2910, 2850, 1450,
4.3.11. 1,3-Bis(hydroxyethyloxy)adamantane (14). Stir-
red suspension of 1,3-dibromadamantane (16, 1.50 g, 5.00
mmol), dry ethylene glycol (7 mL) and AgNO3, (1.80 g,
10.6 mmol) was warmed up during 15 min to 1008C and
stirred for 30 min at that temperature. The reaction mixture
was then cooled to room temperature and diluted with
CH2Cl2 (25 mL). Insoluble part was ®ltered off and washed
with CH2Cl2 (100 mL). The ®ltrate was evaporated under
reduced pressure and the residue was diluted with water
(250 mL). Water solution was ®ltered, saturated with
NaCl, and extracted with CH2Cl2 (6£100 mL). The
combined extracts were dried over anhydrous MgSO4. The
solvent was evaporated and residue was chromatographed
on silica gel with 10% MeOH in CH2Cl2 as the eluant, to
give 790 mg (62%)21 of 1,3-bis(2-hydroxyethyloxy)ada-
mantane (14): mpˆ71±758C; IR (KBr) 3390, 2910, 2860,
1115, 1060, 1040 cm21; 1H NMR (CDCl3, 300 MHz) d 1.50
(bs, 2H), 1.65±1.72 (m, 8H), 1.78 (bs, 2H), 2.33 (bs, 2H),
3.53 (t, Jˆ4.6 Hz, 4H), 3.61 (s, 2£OH), 3.69 (t, Jˆ4.6 Hz,
4H); 13C NMR (CDCl3, 75 MHz) d 30.3, 34.8, 40.1, 45.1,
61.3, 61.7, 74.4. Anal. Calcd for C14H24O4: C, 65.60; H,
9.40. Found: C, 65.52; H, 9.34.
1
1270, 1100 cm21; H NMR (CDCl3, 300 MHz) d 1.58 (d,
Jˆ12.0 Hz, 4H), 1.70±1.77 (m, 6H), 2.23 (bs, 2H), 3.29 (s,
4H), 3.59±3.63 (m, 4H), 3.67±3.71 (m, 4H), 4.57 (s, 4H),
7.25±7.35 (m, 10H); 13C NMR (CDCl3, 75 MHz) d 26.5,
34.5, 36.3, 68.9, 70.8, 72.0, 72.6, 78.6, 127.0, 127.2, 127.9,
138.0. Anal. Calcd for C29H38O5: C, 74.65; H, 8.21. Found:
C, 74.45: H, 8.15.
4.3.12. 1,3-Bis(2-tosyloxyethyloxy)adamantane (15). To a
stirred, cooled (ice/water) solution of 1,3-bis(2-hydroxy-
ethyloxy)-adamantane (14, 540 mg, 2.13 mmol) in dry pyri-
dine (2.5 mL), tosyl chloride (830 mg, 4.35 mmol) was
added during 4 h. The reaction mixture was stirred over-
night at ,58C, diluted with water (50 mL) and extracted
with CH2Cl2 (4£35 mL). Organic extracts were washed
with 6 M HCl (2£50 mL) and dried over anhydrous
MgSO4. The solvent was evaporated under reduced pressure
to give 950 mg (80%) of 1,3-bis(2-tosyloxyethyloxy)ada-
mantane (15) as colorless viscous oil: IR (KBr) 3060,
3030, 2910, 2860, 1595, 1450, 1355, 1190, 1170, 1125,
4.3.10. 1,3-Bis[(2-hydroxyethyloxy)methyl]-2-oxaada-
mantane (10). Suspension of 1,3-bis[(2-benzyloxyethyl-
oxy)methyl]-2-oxaadamantane (9, 3.24 g, 6.95 mmol) and
10% Pd/C (1.20 g) in of dry ethanol (40 mL) was hydroge-
nated for 48 h. The reaction mixture was ®ltered and the
®ltrate was evaporated under reduced pressure to give
1.94 g (98%) of 1,3-bis[(2-hydroxyethyloxy)methyl]-2-
oxaadamantane (10) as colorless viscous oil. Analytically
pure sample was obtained by chromatography on alumina
(act. II/III) with 0!2% MeOH in CH2Cl2 as the eluant. IR
1
(KBr/®lm) 3370, 2910, 2850, 1445, 1120 cm21; H NMR
1095, 1010, 920 cm21 1H NMR (CDCl3, 300 MHz) d
;
(CDCl3, 300 MHz) d 1.43 (d, Jˆ12.0 Hz, 4H), 1.82±1.88
(m, 6H), 2.25 (bs, 2H), 3.32 (s, 4H), 3.58±3.62 (m, 4H),
3.67±3.71 (m, 4H), 4.09 (bs, 2£OH); 13C NMR (CDCl3,
75 MHz) d 26.5, 35.3, 35.9, 61.1, 73.1, 73.4, 77.8. Anal.
Calcd for C15H26O5: C, 62.91; H, 9.15. Found: C, 62.83; H,
9.29.
1.43 (bs, 2H), 1.45±1.65 (m, 10H), 2.26 (bs, 2H), 2.44 (s,
6H), 3.55±3.60 (m, 4H), 4.05±4.15 (m, 4H), 7.34 (d,
Jˆ7.95 Hz, 4H), 7.79 (d, Jˆ7.95 Hz, 4H); 13C NMR
(CDCl3, 75 MHz) d 21.3, 30.3, 34.8, 39.9, 44.9, 58.2,
69.7, 74.5, 127.8, 129.7, 133.0, 144.7. Anal. Calcd for
C28H36O8S2: C, 59.55; H, 6.43. Found: C, 59.35; H, 6.35.
4.3.11.
1,3-Bis[(2-tosyloxyethyloxy)methyl]-2-oxaada-
mantane (11). To a stirred, cooled (ice/water) solution of
1,3-bis[(2-hydroxyethyloxy)methyl]-2-oxaadamantane (10,
810 mg, 2.84 mmol) in dry pyridine (2.5 mL) tosyl chloride
(1.08 g, 5.68 mmol) was added during 3 h. The reaction
4.4. Alkali metal picrate extraction experiments
Alkali metal (Li1, Na1, K1, Rb1, and Cs1) picrates were
freshly prepared by reacting each of the respective alkali

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K. Mlinaric-Majerski, G. Kragol / Tetrahedron 57 (2001) 449±457
456
metal hydroxides, M1OH2, with picric acid.22 Due to its
high solubility in water and EtOH, Li1 picrate was prepared
and subsequently used in situ. All other alkali metal picrates
were isolated and dried prior to use. An aqueous solution
was prepared which was 5.0 mM in the alkali metal picrate.
Reagent grade CHCl3 was washed three times with
redistilled water and then utilized to prepare 5.0 mM
solution of crown ethers 1±7.
of this study. We also thank Prof. A. P. Marchand and Dr
T. D. Power for critical reading of the manuscript.
References
1. Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 7017±7036.
2. For the review see: (a) Gokel, G. W. Crown Ethers and
Cryptands; Royal Society of Chemistry: Cambridge, 1991.
A CHCl3 solution (0.5 mL) of the corresponding crown
ether was placed into a 5 mL screw-top vial, and the
aqueous solution of the alkali metal picrate (0.5 mL) was
added. Another portion of the metal picrate solution
(0.5 mL) was added to the second vial to the CHCl3
(0.5 mL), which contained no host (blank probe). The
vials were stoppered, shaken on a Termolyne Maxi-Mix
III Type 65800 mixer for 4 min, and then allowed to stand
at ambient temperature for 1 h. A 0.1 mL aliquot of the
aqueous phase was taken with automatic pippete and diluted
in volumetric ¯ask via addition of redistilled water to a total
volume of 10 mL. UV±Visible spectra were obtained for the
two solutions, and the percent of picrate extracted in each
case was calculated from the absorbance measured on
355 nm. For each combination of crown ether and alkali
metal picrate, the picrate extraction was conducted on
three different samples, and the average value of percent
picrate extracted was calculated. In the absence of crown
ether, no metal picrate extraction was detected.
È
(b) Vogtle, F. Supramolecular Chemistry; Wiley: New York,
1991. (c) Lehn, J. M. Suspramolecular Chemistry: Concepts
and Perspectives; VCH: Weinheim, 1995.
3. Izatt, R. M.; Pawlak, K.; Bradshaw, J. S. Chem. Rev. 1995, 95,
2529±2586.
4. Schneider, H.-J.; Yatsimirsky, A. Principles and Methods in
Supramolecular Chemistry; Wiley: Chichester, 2000.
Â
5. Mlinaric-Majerski, K.; Kragol, G. Kem. Ind. 2000, 49, 239±
247.
6. (a) Mlinaric-Majerski, K.; Pavlovic, D.; Luic, M.; Kojic-
Â
Â
Â
Â
Â
Prodic, B. Chem. Ber. 1994, 127, 1327±1329. (b) Marchand,
Â
A. P.; Alihodzic, S.; McKim, A. S.; Kumar, K. A.; Mlinaric-
Ï
Majerski, K.; Sumanovac, T.; Bott, S. G. Tetrahedron Lett.
1998, 39, 1861±1864. (c) Haashita, T.; Higuchi, T.; Sawano,
Â
H.; Marchand, A. P.; Kumar, K. A.; Bott, S. G.; Mlinaric-
Ï
Majerski, K.; Sumanovac, T.; Elkarim, N. S. A.; Hwang,
Ï Â
H.-S.; Talanova, G.; Bartsch, R. A.; Talanta 2000, 51, 385±
396.
Â
7. Marchand, A. P.; Kumar, K. A.; McKim, A. S.; Mlinaric-
Majerski, K.; Kragol, G. Tetrahedron 1997, 53, 3467±3474.
8. (a) According to the crown-ether nomenclature1 macrocyclic
polyethers 1±7 could be named: 2,15-[(1,3)2-oxaadaman-
tano]-15-crown-5 (1); 2,18-[(1,3)2-oksaadamantano]-18-
crown-6 (2); 2,18:9,11-bis [(1,3)2-oksaadamantano]-18-
crown-6 (3); 15,17-(1,3)adamantano-18-crown-5 (4); 16,18-
(1,3)adamantano-20-crown-5 (5); 14,16-(1,3)adamantano-16-
crown-5 (6) and 8,10:18,20-bis-[(1,3)adamantano]-20-
crown-6 (7); (b) According to the IUPAC recommendation,
Powell, W. H. Phane nomenclature. Pure Appl. Chem. 1998,
70, 1513±1545, new crown ethers could be named:
3,6,9,12-tetraoxa-1(1,3)-(2-oxaadamantana)cyclotridecaphane
(1); 3,6,9,12,15-pentaoxa-1(1,3)-(2-oxaadamantana)cyclo-
hexadecaphane (2); 3,6,10,13-tetraoxa-1,8(1,3)-bis(2-oxaada-
mantana)cyclotridecaphane (3); 3,6,9,12,15-pentaoxa-1(1,3)-
adamantana-cyclohexa-decaphane (4); 4,7,10,13,16-penta-
oxa-1(1,3)-adamantanacyclooctadecaphane (5); 2,5,8,11,14-
pentaoxa-1(1,3)-adamantanacyclotetradecaphane (6); 2,5,8,
10,13,16-hexaoxa-1,9(1,3)-diadamantanacyclohexadecaphane
(7).
4.5. Transport of alkali metal picrates across bulk
chloroform membranes
The transport studies were conducted at ambient tempera-
ture in `hollow-tube-within-a-vial' cells. A hollow glass
tube (20 mm ID) was suspended vertically within a glass
vial (40 mm ID) so that the bottom of the glass tube
extended below the surface of the CHCl3 membrane
which separated the aqueous source phase (7.5 mmol of
alkali metal picrate in 3 mL of redistilled water) from
aqueous receiving phase (10 mL of redistilled water). The
liquid membrane consisted of 0.75 mmol of crown ether in
10 mL of CHCl3. The molar ratio of crown ether to alkali
metal picrate was 1:10. The organic phase was stirred at ca.
200 rpm by means of internal small magnetic stirring bar.
During ®rst 7 h, aliquot of the aqueous receiving phase
(3 mL) was taken at 1 h intervals, and the concentration of
alkali metal picrate was determined by recording the
UV±visible spectra (percent of picrate transported was
calculated from the absorbance measured on 355 nm with
eˆ14400). Aliquot was returned to the receiving phase and
transport experiment was continued. Transport rate was
calculated as a slope of moles of picrate transported vs
time data, ®tted to a straight line. After ®rst 7 h transport
experiment was continued for another 17 h (total of 24 h),
and total amount of picrate transported in 24 h was deter-
mined.
9. (a) Stepanov, F. N.; Utochka, T. N.; Yurchenko, A. G. Zh.
Org. Khim. 1972, 8, 1183±1186. (b) For transannular cycli-
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Chem. 1989, 54, 1430±1432.
11. Landa, S.; Kamycek, Z. Collect. Czech. Chem. Comm. 1959,
24, 1320±1326.
 Ï
12. (a) Mlinaric-Majerski, K.; Visnjevac, A.; Kragol, G.; Kojic-
Â
Â
Prodic, B., J. Mol. Struct. 2000, 554, 277±285. (b) Ionophore
3 adopts crystallographic Ci symmetry, while in its potassium
picrato complex C1 symmetry is detected. (c) The potassium
ion reveals eight coordination in the shape of hexagonal bi-
pyramid. Six ether oxygens of the macrocyclic ring disposed
in chair-like conformation, are in equatorial position, whereas
Acknowledgements
We thank the Ministry of Science and Technology of the
Republic of Croatia (Grant 00980702) for ®nancial support

Â
K. Mlinaric-Majerski, G. Kragol / Tetrahedron 57 (2001) 449±457
457
phenol and para-nitrogroup of picrato anion are at the appical
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Christensen, J. J. J. Am. Chem. Soc. 1980, 102, 2452±2454,
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21. In addition to 14, if ethylene glycole isn't dried carefully, and
distilled just before use, 1-hidroxy-3-(2-hydroxyethyloxy)ada-
mantane is formed in 5±10% yield.
22. Ouchi, M.; Inoue, Y.; Wada, K.; Iketani, S.; Hakushi, T.;
Weber, E. J. Org. Chem. 1987, 52, 2420±2427.