Crown ethers derived from cyclohexane. Influence of their stereochemistry in complexation and transport

Article abstract of DOI:10.1016/S0040-4020(02)00681-6

Crown ethers derived from cyclohexane have been prepared. The trans stereochemistry of the substituents on the carbocyclic ring makes that only one conformation can complex cations. The influence of the stereochemistry in complexation has been studied.

Full text of DOI:10.1016/S0040-4020(02)00681-6

Tetrahedron 58 (2002) 6729–6734
Crown ethers derived from cyclohexane. Influence of their
stereochemistry in complexation and transport
*
Ana M. Costero, J. Pablo Villarroya, Salvador Gil, M. Jose Aurell
´
and M. Carmen Ramirez de Arellano
´ ´ ´ ´
Departamento de Quımica Organica, Universidad de Valencia, Doctor Moliner 50, Vicente Andres Estelles s/n, 46100-Burjassot,
Valencia, Spain
Received 19 February 2002; revised 7 May 2002; accepted 17 June 2002
Abstract—Crown ethers derived from cyclohexane have been prepared. The trans stereochemistry of the substituents on the carbocyclic ring
makes that only one conformation can complex cations. The influence of the stereochemistry in complexation has been studied. q 2002
Elsevier Science Ltd. All rights reserved.
Our research group has been interested for several years in
the preparation of crown ether derives from cyclohexane.
The rigidity shown by the crown ether directly bound to a
cyclohexyl moiety has been previously used by our
research group in controlling the ability of ligands to
complex and transport cations.1 Thus, the negative allosteric
cooperativity observed in compounds 1 and 2 (Chart 1)
greatly increased the transport of cations through organic
membranes. The allosteric behaviour observed in these
ligands was due to the stereochemistry of the cyclohexane
derivative in which only one site at a time has a favourable
conformation for binding. On the other hand, the rigidity of
the cyclohexyl system provides a direct connection between
the crown ether and the substituents on the cyclohexane.
Thus, it has been reported that in trans-cyclohexyl crown
ethers with a bulky substituent in position 3, conformations
with the equatorial substituent are more stable than those
with the axial disposition.2 Making use of the same
principle, we prepared compound 3 which showed different
conformation of the cyclohexane system depending on the
pH of the medium. Because of its stereochemistry
compound 3 is only able to complex cations if the crown
ether moiety adopts a trans-diequatorial conformation (lone
pair on the oxygen atoms directed toward the centre of the
cavity). In addition, the rigidity of the cyclohexyl moiety
fixes the conformation in such a way that compound 3 is
able to form more stable complexes under basic conditions
rather than in an acid medium.3
In the course of these studies, several crown ethers derived
from cyclohexane have been prepared. These compounds do
not only show different stereochemistry but can also present
two conformations in the cyclohexane moiety. These two
factors can affect their complexation and transport
properties.
1. Synthesis and conformational studies
Compounds 7 and 7b were synthesised as shown in Scheme
1. Compound 4 was prepared using a Diels–Alder reaction
between diethyl fumarate and butadiene sulfone.4 Epoxida-
tion of 4 under standard conditions gave compound 55 that
was transformed into diol 6 by reaction with ethyleneglycol
in the presence of sulfuric acid.1b Compound 6 was the main
product in this reaction but the other diasteroisomer, 6a, was
Chart 1.
Keywords: complexation; cyclohexyl-crown ethers; conformational regulation.
*
Corresponding author. Fax: þ34-96-398-31-52; e-mail: ana.costero@uv.es
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00681-6

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A. M. Costero et al. / Tetrahedron 58 (2002) 6729–6734
Scheme 1.
also detected but in such a small amount that it was
impossible to carry out its identification at this step.
conformation is related to the possibility of the compound to
form intra or intermolecular hydrogen bonds. In chloroform,
the intramolecular hydrogen bond is more favourable than
in acetone and for this reason conformation 6I was the most
abundant conformation in this solvent. Computational
studies carried out using a PM3 semiempirical method,6
implemented in the MOPAC program7 showed that
conformation 6I was stabilised by intramolecular hydrogen
bonds to a higher level than conformation 6II. In contrast,
conformation 6II became around 4 kcal mol21 more stable
than conformation 6I when intermolecular hydrogen bonds
with acetone were considered. In all these studies several
conformations related to the rotation around the single
bonds have been considered and the reported results
correspond to the most stable ones.
On the other hand, 1H NMR studies carried out with
compound 6, showed that the conformation of this
compound in solution depends on the solvent. Thus,
conformation 6I was mainly present in chloroform and
conformation 6II was present in acetone (Chart 2). Even
though coupling constants would give more information
about the spacial disposition, unfortunately slow exchange
on the NMR time scale led to broad signals (even over a
range of temperatures) making difficult the determination of
coupling constants. Therefore, the intensity of the cross-
peaks in COSY experiments turned out to be the most
reliable proof of the preferred conformational arrangement.
Thus, in chloroform, strong correlations were observed
0
0
between Hax and Hd, and between Hax and Hd ; in addition,
cross-peaks due to the simultaneous coupling between Heq–
Cyclization to give compound 7 was carried out using 6 and
tri(ethyleneglycol) ditosilate in a basic medium. When this
reaction was directly carried out with the mixture of
compound 6 and 6a obtained in the former step, compounds
7 and 7a could be isolated. 1H NMR studies carried out with
compound 7 showed that 7II was the most stable
conformation not only in acetone but also in chloroform.
Thus, strong correlations between Hax and Hc were observed
0
Hc and Heq–Hc (vecinal and W coupling, respectively) and
Heq –Hc and Heq –Hc were also detected. In contrast, in
acetone, the strongest correlations were observed between
0
Hax and Hc and Hax and Hc , whereas weaker interactions
0
were observed between Heq–Hd; Heq–Hd and Heq –Hd;
0
0
0
0
0
0
Heq –Hd , respectively. The influence of the solvent on
0
Chart 2.

A. M. Costero et al. / Tetrahedron 58 (2002) 6729–6734
6731
stereochemistry. On the other hand, comparison between
ligands 7 and 11 allowed to affirm that the presence of the
ethoxycarbonyl groups in the carbocyclic ring makes
compound 7 a better ligand than 11 probably due to
lipophilic reasons. Finally, it is very interesting to note that
podand compound 8 show values higher than these observed
for the related macrocyclic system 11. A reason for this
behaviour can be found in the more open structure of 11 that
is not modified by the trans stereochemistry. This
favourable effect seems to compensate the absence of the
macrocyclic effect. In fact, association constants for
compound 8 are similar to those obtained for the substituted
cyclic ligand 7.
Scheme 2.
and, in addition, correlations were also detected between
Heq and Hd. On the other hand, several conformations in the
crown chain must be present because in the 1H NMR
spectrum several signals corresponding to the ethoxycar-
bonyl groups appear. These signals collapsed to one when
the experiment was carried out at high temperature.
Compound 7a was isolated as a minoritary product and
was also spectroscopically studied. As expected, a single
conformation for the cyclohexane moiety was observed (the
one with the four groups in equatorial position).
3. X-Ray studies
Computational calculations were carried out in order to
have additional information on the stability of the different
conformations. Thus, the difference of stability between 7II
and 7I was around 3 kcal mol21 conformation 7II being the
most stable. On the other hand, compound 7a in its most
stable conformation was around 2 kcal mol21 more stable
than 7II and around 5 kcal mol21 more stable than 7I.
Complex 9, obtained from 7 and Hg(SCN)2 has been studied
by X-ray analysis (Fig. 1). First of all, the obtained data
confirm the trans–anti–trans stereochemistry of compound
7. On the other hand, the structure shows that the
cyclohexane moiety presents a chair conformation without
strong distortions; only angles C(12)–C(13)–C(14) and
C(15)–C(16)–C(11) have values slightly higher than the
ideal ones (115.0 and 114.2, respectively). In the crown
moiety, the oxygen atoms are not symmetrically arranged
with respect to the mercury atom. The metal centre is
Complementary studies were carried out with podand 8.
This compound was prepared as shown in Scheme 2 in order
to have information on the influence of the macrocyclic
effect in systems derived from cyclohexane showing a trans
configuration. Compound 8 is related to the ligands studied
by Raban et al. and described as sterically switched
ionophores.8
˚
close to O(2) (Hg–O(2) 2.748 A) and far from O(6)
˚
(Hg–O(6) 2.900 A). The four remaining oxygen atoms are
placed approximately equidistant from the mercury atom
˚
(on an average 2.845 A).
Stronger distortions are observed in the ethoxycarbonyl
groups. Firstly, angles C(14)–C(17)–O(8) and C(15)–
C(20)–O(10) with values of 110.0 and 109.6, respectively,
are far from the ideal situation. Additionally, the ethyl
groups show a pronounced asymmetry one of them being in
antiperiplanar conformation (dihedral angles C(20)–
O(10)–C(21)–C(22) and C(14)–C(15)–C(20)–O(10) of
177.7 and 175.1, respectively) and the other in anticlinal
conformation (C(17)–O(8)–C(18)–C(19) and C(15)–
C(14)–C(17)–O(8) 80.1 and 259.7, respectively). One of
the carbonyl groups (C(17)–O(7)) is practically eclipsed
with C(14)–C(13) bond while the other one (C(20)–O(9))
2. Complexation studies
Firstly, complexation of ligand 7 and Hg(SCN)2 was
studied. The corresponding 1:1 complex (9) could be
isolated and the complexation constant determined by
using NMR techniques (log K¼4.3); the use of this
technique for the determination of the constant led to
excellent results because a slow exchange occurred on the
NMR time scale.
Additionally, association constants of ligand 7 with several
alkaline and alkaline-earth cations have been evaluated9 and
compared with compound 8, dicyclohexyl-18-crown-6
(10)10 (commercial) and trans-cyclohexyl-18-crown-6 (11)
(previously described in the literature1b). Data in Table 1
show that stereochemistry is very important in complexa-
tion. Thus, macrocyclic compounds derived from cyclo-
hexane with a trans stereochemistry (7, 11) make
complexes with lower association constant than those
observed in the case of compound 10 which presents a cis
Table 1. log K determined by UV methods (picrate salts)
Ligand
Liþ
Naþ
Kþ
Rbþ
Csþ
Mg2þ
Sr2þ
7
8
10
11
4.27
3.95
5.28
4.67
4.14
6.37
3.71
5.92
4.30
8.30
3.99
6.81
3.91
6.70
4.47
3.59
6.25
2.92
2.16
1.65
1.54
Figure 1. Ellipsoid plot of compound 9.

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A. M. Costero et al. / Tetrahedron 58 (2002) 6729–6734
is eclipsed with the C(14)–C(15) bond. Finally, both SCN
groups are placed close to the ideal positions.
In conclusion, it has been established that the stereo-
chemistry of crown ethers substituted by a cyclohexane
moiety has a strong influence on the cation complexation
and the transport efficacy. This behaviour can be related to
the size of the crown cavity that depends on the
stereochemistry of the compound. The relationship between
the capacity of the ligand to bind the cation in the source
phase and to release it in the receiving phase is also
important. Additionally, it has been observed that the
conformation of the cyclohexane and consequently the
conformation of the crown cavity depend on a high number
of factors.
4. Transport experiments
Transport experiments were carried out in a U-tube where
two aqueous phases were separated through an organic
membrane (CHCl3) and different alkali and alkaline-earth
cations were studied.11 The use of ligands 7 and 7a allowed
to study the influence of the ether configuration on the
transport processes. The results observed in these experi-
ments are shown in Table 2. Several interesting results are
noteworthy. Thus, as expected, the ligand with a higher
association constant does not always induce a higher
transport. For example, ligand 7 shows values of association
constant of log Ka¼4.67, 5.92 and 6.81 for Naþ, Kþ and
Rbþ, respectively but the efficiency in transport (after 24 h)
is 38.3, 160.7 and 69.6, respectively. Similarly, ligand 10
transports Naþ more than Kþ (135 and 46, respectively)
while the corresponding association constants are in
opposite relationship (log K for Naþ 6.37 and for Kþ
8.30). This behaviour clearly shows that transport depends
on the relationship between complexing in the source phase
and releasing in the receptor phase.
5. Experimental
5.1. Data for compounds
5.1.1. Synthesis of trans-1,2-bis(ethoxycarbonyl)-4-cyclo-
hexane (4). Butadiene sulfone (10 g, 0.0846 mol), diethyl
fumarate (13.6 g, 0.0846 mol) and hydroquinone (116 mg,
1 mmol) were dissolved in ethanol (20 ml). The mixture
was kept in a sealed reactor at 1208C for 16 h. After cooling,
150 ml of a solution of NaHCO3 (10%) was added and the
reaction was extracted with dichloromethane (3£50 ml).
The organic phase was dried with anhydrous Na2SO4 and
the solvent evaporated to give 4 as a pale yellow oil (97%).
1H NMR (250 MHz, CDCl3) d 5.68 (m, 2H), 4.15 (q, 4H,
J¼7.12 Hz), 2.82 (m, 2H), 2.39 (m, 2H), 2.21 (m, 2H), 1.25
(t, 6H, J¼7.12 Hz). 13C NMR (62.5 MHz, CDCl3) d 174.7
(s), 124.8 (d), 60.4 (t), 41.1 (d), 27.8 (t), 14.0 (q). HRMS
(IEþ) calcd for C12H18O4 m/z 226.1205; found 226.1210.
More interesting results are those related to the influence of
stereochemistry in transport. It seems that the stereo-
chemistry of the ligands gives rise to different cavity sizes
and for this reason the same cation can be transported with
very different efficacy depending on the ligand used. Thus,
the sodium cation is transported by ligand 7a with an
efficiency that is around four times that shown by ligand 7.
On the other hand, strong differences between Mg2þ and
Sr2þ were found for compound 7 which transports around
200 times more Sr2þ than Mg2þ. In addition, some
differences between Naþ and Sr2þ (Naþ/Sr2þ¼2.2) were
also observed. This is important because there are not many
ligands useful for separating Naþ from Sr2þ. Finally,
complexation of Mg2þ and Sr2þ with ligand 7 and 7a
shows an opposite tendency. Thus ligand 7a transports 77.5
times more Mg2þ than 7 but this ligand transports three
times more Sr2þ than ligand 7a.
5.1.2. Synthesis of trans-4,5-bis(ethoxycarbonyl)-epoxy-
cyclohexane (5). 18.33 g (0.08 mol) of 4 were dissolved in
100 ml of dichloromethane. The solution was cooled to 08C
and then a solution of m-CPBA (70%), 30 g (0.12 mol) in
300 ml of dichloromethane was added dropwise. The
reaction was kept at this temperature for 20 h and then a
solution of Na2CO3 (10%) (125 ml) was added. The mixture
was stirred for 10 min and the organic phase was washed
three times with the solution of Na2CO3 (10%). The organic
phase was dried with anhydrous Na2SO4 and the solvent
evaporated to give compound 5 as a transparent oil (96%).
1H NMR (250 MHz, CDCl3) d 4.10 (q, 4H, J¼7.2 Hz), 3.24
(m, 2H), 2.80 (m, 1H), 2.00 (m, 1H), 2.31 (m, 2H), 2.03 (m,
2H), 1.23 (t, 6H, J¼7.2 Hz). 13C NMR (62.5 MHz, CDCl3)
d 174.0 (s), 173.2 (s), 60.1 (t), 51.3 (d), 49.7 (d), 39.6 (d),
37.3 (d), 26.8 (t), 25.7 (t), 13.3 (q). HRMS (EIþ) calcd for
C12H18O5 m/z 242.1154; found 242.1153.
In addition, comparative studies were carried out with the
commercial dicyclohexyl-18-crown-6 (10) that has
traditionally been reported as a good Sr2þ extractant.12
However, ligand 7 transports 6.3 times more strontium than
10 and even podand 8 shows an efficacy 3.3 times higher for
the same cation. Probably the observed behaviour for
compound 10 is due to the high association constant values
that this ligand shows and the release of the cation at the
receiving phase is difficult.
5.1.3. Synthesis of compounds 6 and 6a. A solution of 5
(10 g, 1.65 mol) in 100 ml of chloroform was added to
diethyleneglycol (175 g, 1.65 mol). The mixture was stirred
and then 60 ml of H2SO4 were added. The reaction was kept
under reflux for 20 h and then cooled and washed with
water. The organic phase was dried with anhydrous MgSO4
and the crude was purified by distillation to give a mixture
of both diastereoisomers 6 and 6a (80%). 1H NMR
(250 MHz, CDCl3) d 4.11 (q, 4H, J¼7.0 Hz), 3.77 (m,
1H), 3.58 (m, 8H), 3.38 (m, 1H), 3.04 (m, 2H), 2.07 (m, 2H),
1.77 (m, 2H), 1.20 (t, 6H, J¼7.0 Hz). 13C NMR d
(62.5 MHz, CDCl3) d 174.4 (s), 78.1 (d), 73.5 (t), 70.7 (t),
Table 2. Transport efficacy after 24 h with ligands 7 and 7a, 8 and 10
Liþ
Naþ
Kþ
Rbþ
Csþ
Mg2þ
Sr2þ
NHþ4
7
7a
8
9.0
35.0
,1
46
38.3
152.1
27
160.7
148.6
43
69.6
77.0
28
52.2
70.9
20
0.4
31.1
35
82.8
27.8
44
89.7
65.9
19
10
135
46
51
–
21
13.1
29
All the salts were picrates.

A. M. Costero et al. / Tetrahedron 58 (2002) 6729–6734
6733
68.4 (t), 68.0 (t), 61.6 (t), 60.8 (t), 39.7 (d), 39.4 (d), 30.5 (t),
27.2 (t), 14.1 (q). HRMS (EIþ) (M2H2O) calcd for
C16H26O7 m/z 330.1678; found 330.1691.
5.3. Transport experiments
Transport experiments were done in a U-tube cell at 258C. A
solution 0.003 M of the ligand in free-ethanol chloroform
(12 ml) was placed at the bottom of the cell, and two
portions of aqueous solutions (2 ml) were carefully added
on top of them. The source phase was a 0.01 M aqueous of
the corresponding salt and the receiving phase was
desionized water. Both surface areas were 1.75 cm2. The
organic phase was magnetically stirred at 500 rpm. The
concentration of the picrate anion after 24 h was obtained by
calculation based on the absorption of 354.0 nm for KPic
and 356.0 nm for SrPic2 in the UV spectrum. Each
experiment was repeated at least three times, and the results
are reported as the average of the three determinations.
5.1.4. Synthesis of compounds 7 and 7a. A suspension of a
mixture of 6 and 6a (4 g, 0.0115 mol) and NaH (827 mg,
0.034 mol) in THF (150 ml) was heated at reflux under inert
atmosphere for 2 h. Then, a solution of triethylene glycol di-
p-tosylate (5.22 g, 0.0115 mol) in anhydrous THF (70 ml)
was added dropwise during 4 h. After the addition, the
reaction was additionally heated for 48 h. The solvent was
removed and the product was dissolved in water. The
aqueous phase was acidified with HCl (10%) and extracted
with chloroform and ethyl acetate several times. All the
organic phases were dried with anhydrous Na2SO4 and the
solvent was evaporated to give an oil. Purification by
column chromatography (silicagel, hexane/ethyl acetate
1:3) allowed to separate both diasteroisomers 7 (transparent
oil, 17%) and 7a (transparent oil, 3%). 7 1H NMR
(250 MHz, CDCl3) d 4.09 (q, 4H, J¼7.12 Hz), 3.74 (m,
2H), 3.62 (m, 20H), 2.86 (m, 2H), 1.98 (m, 2H), 1.79 (m,
2H), 1.19 (t, 6H, J¼7.12 Hz). 13C NMR d (62.5 MHz,
CDCl3) d 175.0 (s), 74.2 (d), 71.2 (t), 70.6 (t), 68.0 (t), 60.3
(d), 38.9 (d), 27.5 (t), 14.1 (q). HRMS (FABþ) (MþH) calcd
for C22H30O10 m/z 463.2543; found 463.2546. Combustion
analysis calcd for C22H30O10·H2O: 55.00% C, 8.33% H;
found 55.02% C, 8.34% H. 7a 1H NMR (250 MHz,
CDCl3) d 4.09 (q, 4H, J¼7.10 Hz), 3.80 (m, 2H), 3.67
(m, 20H), 3.25 (m, 2H), 2.60 (d, 2H, J¼12.3 Hz), 2.30 (d,
2H, J¼12.3 Hz), 1.19 (t, 6H, J¼7.10 Hz). 13C NMR
(62.5 MHz, CDCl3) d 174.3 (s), 80.6 (d), 71.2 (t), 70.7–
69.7 (t), 60.6 (t), 42.8 (d), 32.1 (t), 13.1 (q). HRMS (FABþ)
(MþNa) calcd for C22H30O10Na m/z 485.2362; found
485.2376.
5.4. X-Ray crystal structure determination of 9
A colourless lath of 0.62£0.24£0.07 mm3 size grown by
n-hexane/methanol diffusion, monoclinic, space group
˚
P21/n, a¼8.369 (2), b¼16.764 (3), c¼21.638 (4) A,
3
˚
b¼93.26 (3)8, V¼3031 (11) A , Z¼4, 2umax¼508, diffrac-
˚
tometre Nonius CAD4, Mo Ka (l¼0.71073 A), v-scan,
T¼293 (2) K, 5961 reflections collected of which 5302
(Rint¼0.03) were independent, heavy atom method primary
solution and refinement on F 2 using SHELX97 program,13
342 refined parameters. Hydrogen atoms were included
P
P
using
a
riding model. R1[ llFol2lFcll/ lFol,
23
˚
I.2s(I )]¼0.0548, max D/s¼0.001, max Dr¼1.03 e A
.
Crystallographic data (excluding structure factors) for the
structure in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 167759. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK (fax þ44(0)-1223-
336033 or e-mail deposit@ccdc.cam.ac.uk).
5.1.5. Synthesis of compound 8. 7.6 g (26.6 mmol) of
diethyleneglycol monoethylether tosilate were added to a
suspension of NaH in DMSO (8.5%, 6 ml) and 1.6 g
(13.5 mmol) of trans-cyclohexanediol. The mixture was
heated at 458C for 20 h. Then, 25 ml of water were added
and the mixture was extracted with ethyl acetate (3£25 ml).
The organic phase was dried and the product was purified by
column chromatography (silicagel, hexane/ethyl acetate
Acknowledgments
We acknowledge the support of the EC, project
FI4WCT960022 and DGICYT, project PB98-1429. M. C.
R. A. thanks the Generalitat Valenciana for a project
(GVDOC-99-22). The authors are very thankful to Dr L. R.
Domingo for his useful suggestions on the computational
studies.
1
1:1) to give compound 8 (65%) as a light yellow oil. H
NMR (250 MHz, CDCl3) d 3.49–3.70 (m, 16H), 3.47 (q,
4H, J¼7 Hz), 3.13 (m, 2H), 1.90 (m, 2H), 1.54 (m, 2H), 1.19
(m, 4H), 1.11 (t, 6H, J¼7 Hz). 13C NMR (62.5 MHz,
CDCl3) d 82.2 (d), 69.1–70.8 (t), 66.8 (t), 30.5 (t), 23.8 (t),
15.4 (q). HRMS (FABþ) (Mþ) calcd for C18H37O6 m/z
349.2590; found 349.2578.
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for 24 h. After this time 9 was separated by filtration.
Suitable crystals for X-ray were obtained by diffusion in
MeOH/hexane.
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