Mono-, bis-, and tris(crown ether)s assembled around 1,3,5-triaroylbenzene scaffolds

Article abstract of DOI:10.1021/jo7026867

(Chemical Equation Presented) A concise and experimentally straightforward method for assembling multiple benzo(crown ether) units around 1,3,5-triaroylbenzene scaffolds has been developed. Symmetrical tris(crown ether)s possessing three benzo(15-crown-5)

Full text of DOI:10.1021/jo7026867

Mono-, Bis-, and Tris(crown ether)s Assembled around
1,3,5-Triaroylbenzene Scaffolds
F. Christopher Pigge,*,† Mayuri K. Dighe,† and Jon C. D. Houtman‡
Department of Chemistry, and Department of Microbiology, CarVer College of Medicine,
UniVersity of Iowa, Iowa City, Iowa 52242
chris-pigge@uiowa.edu
ReceiVed December 18, 2007
A concise and experimentally straightforward method for assembling multiple benzo(crown ether) units
around 1,3,5-triaroylbenzene scaffolds has been developed. Symmetrical tris(crown ether)s possessing
three benzo(15-crown-5) or three benzo(18-crown-6) peripheral substituents have been prepared in good
yield via cyclotrimerization of monomeric enaminones. Efficient cross-cyclotrimerizations have also been
demonstrated through construction of unsymmetrical triaroylbenzenes functionalized with only one or
two benzo(15-crown-5) moieties. The alkali cation-binding abilities of these mono- and polytopic crown
ethers have been probed through picrate extraction experiments and isothermal titration calorimetry.
Thermodynamic binding parameters uncovered using the latter technique reveal increasing K+/Na+
selectivity in the benzo(15-crown-5) series of compounds as a function of increasing numbers of benzo-
(crown) units. The data also indicate that the triaroylbenzene-derived bis- and tris-crown ethers do not
engage in intramolecular chelation of cations too large to be accommodated by individual crown
macrorings. Instead, cation/triaroylbenzene stoichiometries and binding profiles indicate formation of
alkali metal-bridged dimers.
Introduction
thermore, polytopic receptors featuring multiple structurally
distinct substrate-binding sites may be capable of complexing
two (or more) non-identical guest moieties (i.e., heteropolytopic
receptors).3
Crown ethers are well-recognized as effective alkali and
alkaline cation-binding agents, and, in many respects, their
discovery by Pedersen represents the genesis of modern supra-
molecular chemistry.4 In general, the cation selectivity exhibited
by simple crown ethers can be estimated according to the “hole-
size” principle. That is, size-complementarity between the crown
ether macrocycle and guest cation facilitates formation of ion-
crown complexes. Steric factors alone do not account for the
Host-guest interactions are a fascinating topic of study within
the field of supramolecular chemistry. Inspired largely by nature,
researchers over the last several decades have achieved a greater
understanding and control over the various intermolecular
interactions that govern supramolecular assembly in artificial
systems.1 An emerging area of contemporary interest concerns
the design, synthesis, and evaluation of molecular receptors
possessing multiple binding sites for targeted guest species.
Polytopic receptors capable of binding two or more substrates
not only may display altered guest affinities and selectivities
relative to their monotopic components (for example, due to
cooperative host-guest interactions and/or formation of chelated
host-guest assemblies) but also may provide the means to
explore multivalent interactions in synthetic systems.2 Fur-
(2) (a) Badjic´, J. D.; Nelson, A.; Cantrill, S. J.; Turnbull, W. B.; Stoddart,
J. F. Acc. Chem. Res. 2005, 38, 723. (b) Mulder, A.; Huskens, J.; Reinhoudt,
D. N. Org. Biomol. Chem. 2004, 2, 3409.
(3) (a) Kirkovits, G. J.; Shriver, J. A.; Gale, P. A.; Sessler, J. L. J.
Inclusion Phenom. Macrocycl. Chem. 2001, 41, 69. (b) Itsikson, N. A.;
Zyryanov, G. V.; Chupakhin, O. N.; Matern, A. I. Russ. Chem. ReV. 2005,
74, 747.
† Department of Chemistry.
‡ Department of Microbiology.
(1) Steed, J. W.; Atwood, J. L. Supramolecular Chemistry; John Wiley
& Sons: Chichester, 2000.
(4) Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 7017.
10.1021/jo7026867 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/11/2008
2760
J. Org. Chem. 2008, 73, 2760-2767

Mono-, Bis-, and Tris(crown ether)s
ionophoric activity of crown ethers, however, as cations
nominally too large or too small to fit within a given crown
may still display significant affinities.5
extreme example of the hole-size principle). This prompted us
to consider incorporating more conventional and established
crown ether units into future ionophoric receptors. Specifically,
we envision using the convergency inherent in enaminone-
directed cross-cyclotrimerization reactions to construct hetero-
topic receptors along the lines indicated in eq 1, in which
individual cation- and anion-binding substituents (CB and AB,
respectively) are arrayed about a common triaroylbenzene core.
Incorporation of crown ethers into oligomeric assemblies can
result in binding of multiple cation substrates. In addition, cation
affinities and guest selectivities exhibited by crown oligomers
may differ significantly from those manifested by the individual
monomeric crown ether units.6 Using bis(crown ether)s as an
example, ionophores derived from 15-crown-5 units may display
enhanced selectivity for the binding of K+ and Rb+ (ions too
large to fit within individual 15-crown-5 rings) over that of Na+
(an ion that is accommodated by a single 15-crown-5 moiety)
due to the formation of chelated sandwich-type crown-cation
complexes. Likewise, bis(18-crown-6) derivatives may display
enhanced Cs+/K+ selectivity relative to simpler mono(18-crown-
6) congeners.7
We have recently demonstrated the utility of alkyne/enami-
none cyclotrimerization processes in the construction of struc-
turally elaborate 1,3,5-triaroylbenzene (TAB) derivatives. In
Such receptors may function as discrete unimolecular salt-
binding ionophores or as components of multi-molecular
constructs formed via self-assembly in the presence of suitable
cation/anion combinations. This latter possibility offers an
opportunity to potentially tune the cation and/or anion specifici-
ties of these receptors beyond those exhibited by the individual
cation-binding and anion-binding units via polyvalent host-
guest interactions. As a prelude to the construction of such salt-
binding heterotopic receptors and their associated assemblies,
we sought to determine the ionophoric properties of simpler
homotopic TAB’s decorated with benzo(crown ether) moieties.
To that end, we report the synthesis of symmetrical triaroyl-
benzenes possessing three benzo(15-C-5) or three benzo(18-C-
6) groups as peripheral arene substituents. Additionally, un-
symmetrical TAB’s incorporating one or two benzo(15-C-5)
rings have also been prepared. The alkali cation-binding abilities
and cation selectivities of these receptors have been examined
using picrate extraction experiments and isothermal titration
calorimetry (ITC).
particular, dendritic-like triaroylbenzenes have been prepared
via cyclotrimerization of linked enaminones,8 while bis(aryl
ethynyl ketones) have been shown to participate in con-
comitant trimerization-macrocyclization reactions.9 This latter
transformation was subsequently employed to prepare a series
of crownophanes (1).10 It was originally envisaged that 1 would
provide the basis for construction of new heteroditopic salt-
binding receptors with the crownophane portion serving as the
site for cation association.11 Unfortunately, none of the crowno-
phanes prepared in the course of this study exhibited any cation-
binding ability, presumably because the crown portions of these
cyclophanes are too large and rigid to trap alkali cations (an
Results and Discussion
The initial synthetic targets of this study were symmetrical
triaroylbenzenes functionalized with either benzo(15-C-5) or
benzo(18-C-6) groups along the periphery. Although in principle
the targeted receptors could be constructed in a single step via
3-fold Friedel-Crafts acylation of benzo(crown ether)s with
trimesic acid chloride, we opted to develop a convergent
trimerization route in anticipation of preparing unsymmetrical
triaroylbenzene-based receptors in the future. The synthesis of
these tris(crown ether)s is illustrated in Scheme 1. The 4-acetyl
benzocrown derivatives were treated with N,N-dimethyl for-
mamide dimethyl acetal to afford the corresponding enaminones
2 and 3. Cyclotrimerization was then effected using established
conditions that involve heating the enaminone in a solution of
acetic acid and pyridine.12 The desired tris(benzo(15-C-5)) and
tris(benzo(18-C-6)) derivatives 4 (TB15C5) and 5 (TB18C6)
were obtained in excellent yields without the need for chro-
matographic purification.
(5) Gokel, G. W. Crown Ethers & Cryptands; Royal Society of
Chemistry: Cambridge, 1991.
(6) An, H.; Bradshaw, J. S.; Izatt, R. M.; Yan, Z. Chem. ReV. 1994, 94,
939.
(7) Selected examples: (a) Bourgoin, M.; Wong, K. H.; Hui, J. Y.; Smid,
J. J. Am. Chem. Soc. 1975, 97, 3462. (b) Kikukawa, K.; He, G.-X.; Abe,
A.; Goto, T.; Arata, R.; Ikeda, T.; Wada, F.; Matsuda, T. J. Chem. Soc.,
Perkin Trans. 2 1987, 135. (c) Bereczki, R.; AÄ gai, B.; Bitter, I.; To¨ke, L.;
To´th, K. J. Inclusion Phenom. Macrocycl. Chem. 2003, 45, 45. (d) Hudson,
M. R.; Gallucci, J. C.; Parquette, J. R. Supramol. Chem. 2003, 15, 557. (e)
Inokuma, S.; Funaki, T.; Kondo, S.; Nishimura, J. Tetrahedron 2004, 60,
2043. (f) An, H.; Wu, Y.; Zhang, Z.; Izatt, R. M.; Bradshaw, J. S. J.
Inclusion Phenom. Mol. Recognit. Chem. 1991, 11, 303.
(8) Pigge, F. C.; Ghasedi, F. Tetrahedron Lett. 2000, 41, 6545.
(9) Pigge, F. C.; Ghasedi, F.; Rath, N. P. J. Org. Chem. 2002, 67, 4547.
(10) Pigge, F. C.; Ghasedi, F.; Schmitt, A. V.; Dighe, M. K.; Rath, N.
P. Tetrahedron 2005, 61, 5363.
The preparation of unsymmetrical triaroylbenzenes was next
examined. In previous studies involving the construction of
dendritic and macrocyclic TAB’s,8-10 we used preformed
(11) For recent examples of ion pair receptors, see: (a) Cametti, M.;
Nissinen, M.; Dalla Cort, A.; Mandolini, L.; Rissanen, K. J. Am. Chem.
Soc. 2005, 127, 3831 and references cited. (b) Mahoney, J. M.; Stucker, K.
A.; Jiang, H.; Carmichael, I.; Brinkmann, N. R.; Beatty, A. M.; Noll, B.
C.; Smith, B. D. J. Am. Chem. Soc. 2005, 127, 2922.
(12) Elghamry, I. Synthesis 2003, 2301.
J. Org. Chem, Vol. 73, No. 7, 2008 2761

Pigge et al.
SCHEME 2. Preparation of Unsymmetrical TAB-Based
SCHEME 1. Preparation of Tris[benzo(crown ether)s]
Mono- and Bis-benzo(crown ether)s
enaminones as triggers to initiate cyclotrimerization in the
presence of excess aryl ethynyl ketone reactants.13 Application
of this method for the synthesis of bis(benzocrown)-function-
alized TAB’s would thus require preparation of benzo(crown
ether) ethynyl ketone derivatives capable of participating in
cyclotrimerization with an appropriate aryl enaminone (similar
to the hypothetical transformation illustrated in eq 1), and mono-
(benzocrown) TAB’s would be accessed from reaction of
enaminones such as 2 with an excess of an aryl ethynyl ketone.
Rather than approach the synthesis of mono- and bis(benzo-
crown)-substituted TAB’s separately via the two routes outlined
above, we reasoned that both types of compounds may be
constructed simultaneously and in serviceable yield via direct
condensation of two different enaminone reactants, either 2 or
3 and a second enaminone not derived from a benzo(crown
ether). This approach offers several practical advantages in that
the required enaminone starting materials are easily prepared
in one step from acetylated arenes (see Scheme 1) and
trimerization of enaminones in AcOH/pyridine affords TAB
products in high yield at the expense of unwanted oligomers.14
While co-trimerization of two enaminones can produce up to
four different triaroylbenzene products, we expect that the
product ratio will be subject to alteration by adjusting the relative
stoichiometry of the starting materials. The success of this
approach relies on the ability to effectively separate and purify
the TAB products; consequently an enaminone possessing a 12-
carbon alkoxy group at the para position was selected as a
condensation partner to imbue mono- and bis-crown adducts
with greater solubility while also attenuating the polarity of such
materials, thereby aiding chromatographic separation.
TB15C5 4 and the symmetrical TAB 7 (obtained from homo-
trimerization of enaminone 6) in an approximately 1:1 ratio.
Gratifyingly, the mixed triaroylbenzenes possessing two (8,
BB15C5) and one (9, MB15C5) benzo(15-C-5) group(s) proved
to be the major products. The observed ratio of TAB’s (1:1.2:
5.4:16.7 for 7:4:8:9, respectively) differs somewhat from the
theoretical product ratio of 1:8:6:12. Specifically, the amount
of tris(benzo-crown) 4 is significantly less than that predicted
based upon purely statistical considerations. In part, this may
reflect difficulties in isolating 4 via column chromatography
due to its affinity for silica gel. Alternatively, the various
cyclotrimerizations occurring during the reaction may proceed
at different rates that favor generation of heterotrimers. While
further studies are needed to clarify this issue, the ease and
rapidity with which differentially functionalized TAB’s 8 and
9 are obtained is noteworthy. Moreover, TAB’s 8 and 9, together
with symmetrical tris(crown ether)s 4 and 5, represent suitable
substrates for an initial assessment of the cation-binding ability
and selectivity of ionophores constructed around a triaroylben-
zene framework.
In the event (Scheme 2), enaminone 2 was combined with 6
in a 2:1 ratio and subjected to cyclotrimerization conditions.
As expected, four triaroylbenzene products were obtained in
combined 80% overall yield. Chromatographic purification of
the product mixture resulted in isolation of the symmetrical
The cation-binding abilities of tris(crown ether)s 4 and 5 were
first qualitatively examined in picrate extraction experiments.
(13) This method is predicated upon mechanistic studies of the cyclot-
rimerization reaction reported by Iwamura: Matsuda, K.; Nakamura, N.;
Takahashi, K.; Inoue, K.; Koga, N.; Iwamura, H. J. Am. Chem. Soc. 1995,
117, 5550.
(14) We have observed formation of intractable tars (presumably
polymeric in nature) along with desired TAB’s in the course of cross-
cyclotrimerizations involving enaminones and aryl ethynyl ketones (see refs
8-10).
2762 J. Org. Chem., Vol. 73, No. 7, 2008

Mono-, Bis-, and Tris(crown ether)s
TABLE 1. Picrate Extraction by Crown Ethers 4-5 and 10-13a,b
of the data obtained for 4 with that obtained for bis- and mono-
(crown ether)s 8 and 9 may then provide insight into the
relationship between the number of benzo(crown ether) units
and cation-binding selectivity. Such information should prove
useful in furthering our efforts aimed at designing heterotopic
receptors as outlined in eq 1. Additionally, such binding data
appear to be largely absent from reports describing the prepara-
tion of various other tris(crown ether)s.17 Consequently, binding
assays were performed using isothermal titration calorimetry
(ITC) so that all thermodynamic parameters associated with ion
binding, including metal ion stoichiometry, could be conve-
niently obtained simultaneously.18
percent extraction
crown
Li+
Na+
K+
Cs+
4 (TB15C5)c
5 (TB18C6)c
10 (B15C5)d
11 (B18C6)d
12 (AB15C5)d
13 (AB18C6)d
4.5
2.3
7.0
6.1
3.4
8.5
10
9.7
37
27
13
14
21
100
22
100
7.3
100
1.5
21
10
35
17
16
a Extraction conditions: aqueous phase [MOH] ) 0.1 M, [picric acid]
) 7.5 × 10-5 M, 3 mL; organic phase CHCl3, 3 mL. b Experimental %
extraction values represent an average of three trials. c [Crown] ) 1.2 ×
10-3 M. d [Crown] ) 3.6 × 10-3 M.
Excess of selected metal salts possessing weakly coordinating
lipophilic counterions (NaSCN, KSCN, CsBPh4) was dissolved
in acetonitrile and injected into solutions of the crown ethers,
and the results of these experiments are shown in Table 2. For
comparison, calorimetrically determined binding data for the
complexation of Na+ and K+ by B15C5 10 and B18C6 11 are
also included. Examination of binding stoichiometry for TB15C5
4 reveals a decreasing cation/4 ratio (N) as a function of
increasing cation ionic diameter. Two sodium ions are bound
by 4 as compared to 1.5 potassium ions and one cesium ion. A
single benzo(15-C-5) macrocycle is well-suited to host a single
Na+, so we attribute the incomplete metalation of 4 upon
treatment with NaSCN to negative cooperativity, perhaps arising
from unfavorable electrostatic interactions between solvated ions
and the dicationic Na24 adduct.2a,19 In contrast, benzo(15-C-5)
rings are known to interact with K+ ions via formation of bis-
(crown)-potassium chelates.15 The observed K+:4 ratio of 3:2,
then, may indicate assembly of potassium ion bridged as-
semblies. The exact structure of such assemblies is not known
with certainty; however, binding data obtained from bis- and
mono-benzo(15-C-5) analogues 8 and 9 seemingly provide some
insight into this issue (vide infra). Only a single Cs+ ion is
accommodated per molecule of 4, and the large ionic diameter
of this cation also mandates formation of sandwich-type
complexes. The favorable entropy term for Cs+ complexation
may reflect the ability of a single cesium ion to interact with
two benzo(crown ether) units from the same TAB receptor (i.e.,
intramolecular chelation), resulting in extensive desolvation of
both the cation and the receptor. Notably, entropic costs
associated with K+ ion binding by 4 are significantly greater,
perhaps indicating formation of a larger ternary supramolecular
host-guest assembly as discussed below.20,21 Differences in the
average binding constants (log K) between 4 and the three
cations examined are also apparent, with K+ ion binding
For comparison, the parent monotopic benzo(crown ether)s 10
(B15C5) and 11 (B18C6), and acetyl benzo(crown ether)s 12
(AB15C5) and 13 (AB18C6) were examined as well. The results
of these experiments are summarized in Table 1. Among the
benzo(15-crown-5) derivatives studied, simple B15C5 10 ex-
hibited the highest extraction ability toward sodium picrate,
while the tris(crown) derivative 4 was most active in the
extraction of potassium picrate. As it is well known that 15-
crown-5 ethers coordinate K+ ions in nonaqueous solvents via
formation of 2:1 crown:metal sandwich complexes,15 the greater
extractability of potassium picrate by 4 presumably reflects the
ability of two benzo(15-crown-5) units (either from the same
or from two different TAB’s) to chelate a single metal ion. The
slightly diminished overall extraction ability of 4 as compared
to 10 may reflect an attenuation of ion-binding caused by the
presence of electron-withdrawing carbonyl groups conjugated
to the benzo(crown) moieties. Indeed, the acetyl-substituted
analogue 12 also displays decreased extraction ability for all
ions when compared to 10.16 Nonetheless, the benefits of
polytopic crown ether receptors with respect to influencing
cation-binding selectivity are apparent in the liquid-liquid
extraction results obtained for the 15-C-5 series of substrates.
In contrast, extraction experiments proved to be ill-suited for
analysis of the 18-C-6 series of compounds as all crown ethers
(5, 11, and 13) exhibited 100% extraction of K+ ion under the
conditions employed.
(17) For other examples of tris(crown ether)s, see: (a) Huang, Z. B.;
Kim, S. H.; Chang, S. H. Bull. Korean Chem. Soc. 2006, 27, 893. (b) Huang,
Z. B.; Kang, T. J.; Chang, S. H. New J. Chem. 2005, 29, 1616. (c) Huang,
Z. B.; Chang, S. H. Synlett 2005, 1703. (d) Elwahy, A. H. M.; Abbas, A.
A. Tetrahedron Lett. 2006, 47, 1303. (e) Morey, J.; Orell, M.; Barcelo´, M.
AÄ .; Deya`, P. M.; Costa, A.; Ballester, P. Tetrahedron Lett. 2004, 45, 1261.
(f) Beer, P. D.; Hopkins, P. K.; McKinney, J. D. Chem. Commun. 1999,
1253. (g) Weber, E.; Skobridis, K.; Ouchi, M.; Hakushi, T.; Inoue, Y. Bull.
Chem. Soc. Jpn. 1990, 63, 3670. (h) To¨ke, L.; Bitter, I.; Agai, B.; Csonger,
E.; To´th, K.; Lindner, E.; Horva´th, M.; Harfouch, S.; Pungor, E. Liebigs
Ann. 1988, 349. (i) Le Berre, V.; Ange´ly, L.; Simonet-Gue´guen, N.; Simonet,
J. J. Chem. Soc., Chem. Commun. 1987, 984. (j) Weber, E. J. Org. Chem.
1982, 47, 3478. (k) Frensch, K.; Vo¨gtle, F. Liebigs Ann. 1979, 2121.
(18) Schneider, H.-J.; Yatsimirsky, A. Principles and Methods in
Supramolecular Chemistry; John Wiley & Sons: Chichester, 2000; pp 205-
208.
The extraction experiments described above confirm that
assembly of three crown ether units around a central triaroyl-
benzene core results in viable ionophores, at least toward alkali
metal cation guests. We next sought a more quantitative means
of assessing the strength of tris(crown)-cation interactions as
well as a method for determining the host-guest binding
stoichiometry between 4/5 and monovalent cations. Comparison
(15) (a) Mallinson, P. R.; Truter, M. R. J. Chem. Soc., Perkin Trans. 2
1972, 1818. (b) Izatt, R. M.; Terry, R. E.; Nelson, D. P.; Chan, Y.; Eatough,
D. J.; Bradshaw, J. S.; Hansen, L. D.; Christensen, J. J. J. Am. Chem. Soc.
1976, 98, 7626. (c) Inoue, Y.; Hakushi, T.; Liu, Y.; Tong, L.-H.; Hu, J.;
Zhao, G.-D.; Huang, S.; Tian, B.-Z. J. Phys. Chem. 1988, 92, 2371. (d)
Steed, J. W. Coord. Chem. ReV. 2001, 215, 171.
(19) (a) Janssen, P. G. A.; Jonkheijm, P.; Thordarson, P.; Gielen, J. C.;
Christianen, P. C. M.; van Dongen, J. L. J.; Meijer, E. W.; Schenning, A.
P. H. J. J. Mater. Chem. 2007, 17, 2654. (b) Bouquant, J.; Delville, A.;
Grandjean, J.; Laszlo, P. J. Am. Chem. Soc. 1982, 104, 686.
(16) Liu, Y.; Wang, H.; Zhang, Z.-H.; Tian, B.-Z.; Huang, S. J. Inclusion
Phenom. Macrocycl. Chem. 1999, 34, 187.
J. Org. Chem, Vol. 73, No. 7, 2008 2763

Pigge et al.
TABLE 2. Thermodynamic Parameters and Stoichiometry of Alkali Cation Binding by Tris(crown ether)s 4 and 5, Bis(crown ether) 8, and
Mono(crown ether) 9 in CH3CN As Determined by ITCa,b
∆H
T∆S
∆G
d
crown
cation
Nc
log K
(kcal mol-1
)
(kcal mol-1
)
(kcal mol-1
)
4 (TB15C5)
Na+
K+
1.89 ( 0.07
1.51 ( 0.01
1.12 ( 0.03
2.69 ( 0.01
2.79 ( 0.01
1.70 ( 0.01
1.88 ( 0.04
1.09 ( 0.05
1.05 ( 0.06
0.52 ( 0.07
1
3.32 ( 0.02
4.68 ( 0.02
3.88 ( 0.04
4.06 ( 0.01
4.26 ( 0.01
4.36 ( 0.01
3.37 ( 0.02
4.09 ( 0.03
3.54 ( 0.02
3.63 ( 0.02
4.47
-6.10 ( 0.31
-10.60 ( 0.13
-1.43 ( 0.06
-3.94 ( 0.02
-4.98 ( 0.02
-5.60 ( 0.05
-5.61 ( 0.14
-12.52 ( 0.99
-4.36 ( 0.31
-11.30 ( 1.42
-5.62
-1.57
-4.31
3.85
1.60
0.84
-4.53
-6.29
-5.28
-5.54
-5.82
-5.94
-4.60
-5.59
-4.83
-4.85
e
Cs+
Na+
K+
5 (TB18C6)
Cs+
Na+
K+
0.34
8 (BB15C5)
9 (MB15C5)
10 (B15C5)
11 (B18C6)
-1.01
-6.93
0.47
-6.45
0.45
-8.97
2.28
1.14
Na+
K+
Na+
K+
0.5
1
1
4.74
4.71
4.75
-15.42
f
g
g
Na+
K+
-4.11
-5.31
a Experiments performed using single injection method. Values for N, log K, ∆H, and ∆S are averages of three separate trials. b T ) 298 K. c N )
number of cations bound/TAB. d Calculated from average ∆H and ∆S values. e Reference 23c. f Reference 15c - data obtained in MeOH:H2O (8:2) solution.
g Reference 22.
exhibiting approximately an order of magnitude higher log K
as compared to Na+ binding (a result that mirrors the cation
selectivity displayed in extraction experiments).22
5 in acetonitrile may likewise account for the favorable entropy
term apparent in the formation of cation:5 guest:host adducts.
Smaller crown macrocycles (such as 15-crown-5 derivatives)
are not expected to exhibit similar solvation phenomena in
acetonitrile.24,25
Binding parameters for cations and TB18C6 analogue 5 differ
in several respects from those observed for 4. First, cation:5
binding stoichiometries approach 3:1 for both Na+ and K+ and
2:1 for Cs+. Thus, unlike the situation encountered with the
combination of Na+ and 4, metalation of all three benzo(crown)
units does not appear to be precluded in this system. The
magnitudes of the average association constants for 5 and all
three cations are similar, and each interaction is favored on
both enthalpic and entropic grounds (in contrast to the thermo-
dynamic binding profile of 4). While crown ether-cation
interactions in organic solvents are typically enthalpically driven,
positive entropy changes have been noted in the binding of
various cations with 18-crown-6 itself (14) in acetonitrile. This
effect has been ascribed to the unique ability of acetonitrile
(relative to other aprotic solvents) to solvate the 18-C-6
macroring. Disruption of the solvation shell upon cation binding
then contributes to positive ∆S values.23 Extensive solution
phase solvation of 14 in acetonitrile is supported by results
obtained from computational and spectroscopic experiments,24,25
and indirectly by solid-state structural characterization of a 2:1
CH3CN:14 complex.26 In addition, a number of benzo(18-C-6)
derivatives have also been shown to form solid-state complexes
with multiple acetonitrile molecules.27 Extensive solvation of
The tris(crown ether) 4 displays an intriguing cation affinity/
selectivity profile. To further probe possible cooperative effects
operative in this system and to gain insight into the nature of
chelated and/or bridged ion/ionophore assemblies, we have also
examined the interactions of structurally related bis- and mono-
benzo(15-C-5) TAB derivatives 8 and 9 with Na+ and K+ ions
(Table 2). Triaroylbenzene 9 possessing only a single benzo-
(15-C-5) ring accommodates one Na+ ion and exhibits an
association constant comparable to the average log K of the
tris(crown) 4-sodium system. The overall free energy of sodium
binding between these two receptors (∆G) is also similar,
although the respective enthalpic and entropic thermodynamic
contributions differ slightly with sodium binding to 4 being more
enthalpically driven than sodium binding to the mono-crown
9. Sodium ion complexation by the bis(crown ether) 8 exhibits
a thermodynamic profile very similar to that of 4. Each receptor
displays nearly identical affinities for the binding of two Na+
ions while also possessing comparable ∆H, T∆S, and calculated
∆G terms. While the average binding constant for sodium does
diminish in the series 9 > 8 > 4, the maximum difference in
log K values is only a factor of 1.6, and all binding data compare
favorably with similar sodium ion binding measurements
obtained on B15C5 (10) itself.15b,23c Our conclusion, then, is
(20) Solid-state structural data may prove helpful in elucidating the exact
nature of the crown-alkali cation complexes discussed; however, attempts
to obtain X-ray quality crystals of 4, 5, 8, and 9 along with their metalated
derivatives have thus far been unsuccessful.
(21) NMR experiments aimed at characterizing crown-alkali cation
interactions were inconclusive. Significant complexation-induced shifts in
the 1H NMR spectra of TAB derivatives obtained before and after addition
of an excess of metal salt were absent.
(22) Stepwise association constants were not determined. Instead, the
log K values shown in Table 2 reflect an average of all binding events.
Values obtained for tris(crown)s 4 and 5 are similar to association constants
reported for simpler benzo(crown ether)s and alkali cations. For a
compilation of binding data, see: Izatt, R. M.; Pawlak, K.; Bradshaw, J.
S.; Bruening, R. L. Chem. ReV. 1991, 91, 1721.
(23) (a) Ohtsu, K.; Ozutsumi, K. J. Inclusion Phenom. Macrocycl. Chem.
2003, 45, 217. (b) Ohtsu, K.; Kawashima, T.; Ozutsumi, K. J. Chem. Soc.,
Faraday Trans. 1995, 91, 4375. (c) Buschmann, H.-J. J. Solution Chem.
1988, 17, 277.
(26) (a) Rogers, R. D.; Richards, P. D.; Voss, E. J. J. Inclusion Phenom.
1988, 6, 65. (b) Garrell, R. L.; Smyth, J. C.; Fronczek, F. R.; Gandour, R.
D. J. Inclusion Phenom. 1988, 6, 73.
(27) (a) Bryan, J. C.; Engle, N. L.; Sachleben, R. A.; Hay, B. P. Acta
Crystallogr. 2001, C57, 1359. (b) Rogers, R. D.; Henry, R. F.; Rollins, A.
N. J. Inclusion Phenom. Mol. Recognit. Chem. 1992, 13, 219. (c) Allwood,
B. L.; Fuller, S. E.; Ning, P. C. Y. K.; Slawin, A. M. Z.; Stoddart, J. F.;
Williams, D. J. J. Chem. Soc., Chem. Commun. 1984, 1356.
(24) Troxler, L.; Wipff, G. J. Am. Chem. Soc. 1994, 116, 1468.
(25) Xu, M.; Petrucci, S.; Eyring, E. M. J. Inclusion Phenom. Mol.
Recognit. Chem. 1992, 12, 237.
2764 J. Org. Chem., Vol. 73, No. 7, 2008

Mono-, Bis-, and Tris(crown ether)s
uents on the same TAB to chelate a single metal ion. Examina-
tion of molecular models (CPK) reveals that attainment of a
face-to-face geometry (an ideal orientation for coordination of
a single cation) is unlikely, however, due to the semirigid nature
of the triaroylbenzene framework. Inoue and co-workers
encountered a similar situation in their studies of potassium ion
binding by bis-benzo(15-C-5) ethers connected through linkers
possessing varying degrees of flexibility.15c It was observed that
the 1:1 complex between K+ and a bis-benzo(crown ether)
possessing a single methylene linker exhibited a more negative
entropic term than that found for the parent intermolecular 2:1
benzo(15-C-5):K+ sandwich. These workers attributed this effect
to a partially solvated “open-clam” binding arrangement caused
by the inability of the two crown rings to attain a face-to-face
orientation. Longer and more flexible tethers led to 1:1
complexes in which intramolecular cation chelation was char-
acterized by higher binding constants and decreased entropic
costs. While we also observe a similar trend as a function of
increasing numbers of benzo(15-C-5) substituents (i.e., higher
log K values and decreased entropic costs), the relative ability
(or inability) of 4 and 8 to engage in intramolecular K+ chela-
tion does not change. Hence, we speculate that the calori-
metrically determined potassium ion binding parameters are a
consequence of ternary supramolecular assemblies along the
lines of 15-16. Further evidence in support of this assertion
can be found in the results of picrate extraction experiments
(Table 1). Specifically, Kikukawa and co-workers have noted
a “bis-crown” effect in picrate extractions involving linked
benzo(crown ether)s capable of chelating alkali metals too large
for the individual crown ether components. These bis(crown
ether)s were found to be much more effective extraction agents
than their monomeric counterparts.7b Similar “bis-crown” effects
have been observed in other systems as well.6,29 If a polytopic
crown ether such as 4 were capable of intramolecular potassium
chelation, then one would expect to observe significantly
enhanced K+ picrate extraction as compared to simpler mono-
topic analogues 10 and 12. The potassium picrate % extraction
values of 21, 22, and 7.3 for 4, 10, and 12, respectively,
however, do not appear indicative of such a “polycrown”
effect.30
Ionophores possessing multiple crown ether groups often
display cation-binding selectivities that differ from those
exhibited by monotopic analogues. In most instances, this altered
selectivity arises from intramolecular interactions between crown
components and cation substrates.6,7 Notably, despite the
apparent absence of this metal binding motif in 4 and 8,
enhanced K+/Na+ selectivity is nonetheless observed. The ratio
of K+/Na+ average binding constants (Ka’s) is observed to
increase with increasing numbers of benzo(15-C-5) substituents.
Thus, the mono-crown conjugate 9 displays the lowest K+/Na+
selectivity (1.2), which increases to 5.4 for BB15C5 8 and to
23 for TB15C5 4. Although the modest potassium ion selectivity
observed in this study is not in a range necessary for practical
separation applications, systematic modification of the basic
TAB framework designed to enhance not just cation binding
ability but also cation selectivity should be possible (e.g.,
through incorporation of an anion binding moiety as outlined
in eq 1). Work along these lines is underway.
FIGURE 1. Schematic representation of K+-bridged TAB dimers
formed from bis-crown 8 (complex 15 - TAB:K+ ) 1:1) and 4
(complex 16 - TAB:K+ ) 2:3).
that while the stoichiometry of Na+ ion binding differs as a
function of the number of benzo(15-C-5) substituents, the three
TAB derivatives examined function as more or less equivalent
sodium ion receptors. Negative cooperativity in the binding of
Na+ by 4, however, seemingly limits the extent of metalation,
and one benzo(crown ether) ring remains vacant. Finally, it
appears that the presence of dodecyloxy chains in the unsym-
metrical TAB’s 8 and 9 does not affect ion binding ability.
In contrast to the results obtained with Na+, the affinity of
these receptors toward potassium ions is observed to signifi-
cantly increase with an increase in the number of benzo(15-C-
5) groups. Thus, the average binding constant for 4/K+ is ∼11
times greater than the binding of K+ to 9, while bis-crown ether
8 exhibits an approximately 3-fold greater Ka relative to the
monotopic congener. The binding is enthalpically driven, and
the ∆H values are more negative than those encountered in
sodium binding. These favorable enthalpy terms are partially
offset, however, by considerably more negative entropic con-
tributions. The binding stoichiometry between mono-benzo(15-
C-5) TAB and K+ is consistent with a 2:1 (9:K+) complex.
Formation of such a supramolecular aggregate is expected to
be entropically costly, providing the major contribution to the
large negative T∆S term observed in the calorimetric binding
profile. Indeed, a similarly large and unfavorable entropy term
has been recorded for the 2:1 complex between simple benzo-
(15-C-5) and KSCN (although this titration was performed in
MeOH/H2O rather than acetonitrile).15c Significantly, potassium
binding to 8 and 4 also exhibits stoichiometries and entropic
costs that can be rationalized by invoking formation of TAB
dimers bridged by two (15) and three (16) K+ ions, respectively
(Figure 1). In these cases, we speculate that formation of the
first dibenzocrown-K+ assembly is entropically the most costly,
but formation of additional K+ ion chelates benefits from a
certain degree of pre-organization. A marked decrease in
unfavorable entropy is observed for 4, which may reflect greater
desolvation inherent in a triply bridged structure such as 16.
Thus, enhanced K+ ion binding in 4 is a manifestation of
positive cooperativity resulting from the presence of three benzo-
(15-C-5) rings.28
An alternative to the binding arrangement described above
exists in that it may be possible for two benzo(crown) substit-
(28) Related stacked poly(crown ether) assemblies mediated by multiple
bridging metal cations have been observed in other systems: (a) Thanabal,
V.; Krishnan, V. J. Am. Chem. Soc. 1982, 104, 3643. (b) Sielcken, O. E.;
van Tilborg, M. M.; Roks, M. F. M.; Hendriks, R.; Drenth, W.; Nolte, R.
J. M. J. Am. Chem. Soc. 1987, 109, 4261. (c) Shinmori, H.; Furuta, H.;
Osuka, A. Tetrahedron Lett. 2002, 43, 4881. (d) Chitta, R.; Rogers, L. M.;
Wanklyn, A.; Karr, P. A.; Kahol, P. K.; Zandler, M. E.; D’Souza, F. Inorg.
Chem. 2004, 43, 6969.
(29) Bartsch, R. A.; Eley, M. D.; Marchand, A. P.; Shukla, R.; Kumar,
K. A.; Reddy, G. M. Tetrahedron 1996, 52, 8979.
(30) Similarly, the % extraction of Cs+ by the benzo(18-C-6) series of
compounds (5, 11, 13) does not show any enhancement as a function of
multiple crown ether substituents.
J. Org. Chem, Vol. 73, No. 7, 2008 2765

Pigge et al.
Enaminone 3. The procedure described above was applied to
4-acetylbenzo(18-C-6)34 (1.70 g, 4.80 mmol) and 5.0 mL of N,N-
dimethylformamide dimethyl acetal. No solid formed directly from
the reaction mixture upon cooling, so the contents of the reaction
flask were concentrated in vacuo to afford 3 as a yellow oil that
solidified on standing (1.30 g, 66%). Mp 54-56 °C. 1H NMR (300
MHz, CDCl3) δ 7.76 (d, J ) 12.3 Hz, 1H), 7.58 (t, J ) 14.1 Hz,
2H), 6.86 (d, J ) 8.3 Hz, 1H), 5.69 (d, J ) 12.3 Hz, 1H), 4.23-
4.18 (m, 4H), 3.94-3.90 (m, 4H), 3.77-3.07 (m, 12H), 3.07-
2.80 (br s, 6H). 13C NMR (75 MHz, CDCl3) δ 187.2, 153.8, 151.5,
148.4, 133.4, 121.4, 113.3, 112.3, 97.6, 70.9, 70.7, 69.4, 69.0. IR
(neat) ν (cm-1) 1640. HRMS (ESI) calcd for C21H32NO7 [M +
H]+, 410.2179; found, 410.2179.
Conclusions
We have developed concise synthetic routes to mono-, bis-,
and trisbenzo(crown ether)s assembled around 1,3,5-triaroyl-
benzene (TAB) scaffolds. These materials are conveniently
prepared from readily available starting materials via enaminone
cyclotrimerization. While benzo(15-C-5) and benzo(18-C-6)
building blocks were utilized in this study, we expect other
benzo(crown ether) derivatives to display similar reactivity.
Thus, the procedures outlined here should represent general and
widely applicable methods for construction of polytopic iono-
phores. The cation binding abilities of tris-benzo(15-C-5) 4 and
tris-benzo(18-C-6) 5 were examined using picrate extraction
experiments and isothermal titration calorimetry. Additionally,
the affinities of bis- and mono-benzo(15-C-5) analogues 8 and
9 toward Na+ and K+ ions were also evaluated via ITC. Taken
together, the binding studies appear to indicate that these
polytopic crown ethers do not form intramolecular crown ether-
metal chelates when exposed to cations too large to be
accommodated by individual crown macrorings. Instead, binding
occurs through formation of cation-bridged aggregates such as
dimeric TAB assemblies 15 and 16. Positive cooperativity was
observed in the binding of K+ ions to 4 in addition to a modest
level of K+/Na+ selectivity. We are currently examining the
feasibility of using structurally related TAB frameworks to
organize heterotopic receptors for simultaneous binding of
cations and anions. Incorporation of anion-binding functionality
(such as urea groups31) into the hydrocarbon chains in con-
structs resembling 15 may lead to self-assembly of three-
dimensional receptors capable of encapsulating polyvalent salts
(e.g., K2HPO4). In addition, we envision that triaroylbenzene-
based crown ether derivatives may serve as useful supra-
molecular building blocks in the construction of a variety of
other functional materials.32
Tris-benzo(15-C-5) TAB 4. Using the trimerization conditions
of Elghamry,12 enaminone 2 (1.00 g, 2.74 mmol) was dissolved in
10 mL of 4:1 AcOH:pyridine and heated in a 120 °C oil bath for
12 h. The solvent was then removed in vacuo to afford a brown
residue. Water was added, and the mixture was vigorously stirred
for several hours. The desired triaroylbenzene 4 was obtained as a
colorless solid collected after filtration and drying under vacuum
1
(0.64 g, 73%). Mp 142-144 °C. H NMR (300 MHz, CDCl3) δ
8.25 (s, 3H), 7.49 (s, 3H), 7.37 (d, J ) 8.4 Hz, 3H), 6.86 (d, J )
8.5 Hz, 3H), 4.21-4.19 (m, 12H), 3.93-3.91 (m, 12H), 3.76 (s,
24H). 13C NMR (75 MHz, CDCl3) δ 193.0, 153.2, 148.3, 138.0,
132.7, 128.7, 125.5, 113.7, 112.0, 71.2, 70.5, 69.6, 68.4. IR (neat)
ν (cm-1) 1658. HRMS (ESI) calcd for C51H61O18 [M + H]+,
961.3859; found, 961.3858. Anal. Calcd for C51H60O18: C, 63.74;
H, 6.29. Found: C, 63.29; H, 6.46.
Tris-benzo(18-C-6) TAB 5. Using the procedure given for
the preparation of 4, enaminone 3 (1.30 g, 3.17 mmol) yielded 5
1
(1.00 g, 86%) as a pale yellow solid. Mp 165-167 °C. H NMR
(300 MHz, CDCl3) δ 8.25 (s, 3H), 7.49 (s, 3H), 7.32 (d, J ) 10.3
Hz, 3H), 6.88 (d, J ) 8.4 Hz, 3H), 4.23-4.21 (m, 12H), 3.97-
3.92 (m, 12H), 3.78-3.69 (m, 36H). 13C NMR (75 MHz, CDCl3)
δ 193.8, 153.6, 148.9, 138.7, 133.0, 129.3, 125.9, 114.1, 111.6,
70.0, 70.6, 69.3, 69.0, 68.9. IR (neat) ν (cm-1) 1658. HRMS (FAB,
NBA) calcd for C57H73O21 [M + H]+, 1093.4645; found, 1093.4662.
Anal. Calcd for C57H72O21: C, 62.63; H, 6.63. Found: C, 62.41;
H, 6.75.
Experimental Section33
Enaminone 6. 4-Hydroxyacetophenone (0.70 g, 5.14 mmol) and
1-iodododecane (1.38 g, 4.66 mmol) were combined in 15 mL of
DMF. Potassium carbonate (0.64 g, 4.70 mmol) was added, and
the reaction was heated in a 150 °C oil bath for 12 h. The DMF
was evaporated, and the residue was partitioned between H2O and
ether. The layers were separated, and the organic phase was washed
sequentially with 5% aq NaOH solution, H2O, and brine. The ether
solution was dried over anhydrous MgSO4, filtered, and concen-
trated to afford an oily residue, which was purified by flash column
chromatography (3:1 hexanes:EtOAc) to afford 4-dodecyloxy-
Enaminone 2. 4-Acetylbenzo(15-C-5)34 (0.95 g, 3.06 mmol) and
N,N-dimethyl formamide dimethyl acetal (3.0 mL) were combined
and heated in a 120 °C oil bath for 12 h. The oil bath was then
removed, and the mixture was allowed to cool to room temperature
to produce a yellow solid. The solid was broken up in hexanes,
collected by vacuum filtration, and dried to afford 2 (1.01 g, 90%).
Mp 114-116 °C. 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J ) 12.3
Hz, 1H), 7.50 (t, J ) 8.7 Hz, 2H), 6.84 (d, J ) 8.3 Hz, 1H), 5.69
(d, J ) 12.4 Hz, 1H), 4.23-4.16 (m, 4H), 3.93-3.89 (m, 4H),
3.76 (s, 8H), 3.02-2.88 (br s, 6H). 13C NMR (75 MHz, CDCl3) δ
188.5, 154.8, 152.7, 149.6, 134.6, 122.2, 114.0, 113.0, 92.3, 71.7,
70.9, 70.1, 69.5, 69.3. IR (neat) ν (cm-1) 1640. HRMS (EI) calcd
for C19H27NO6 [M]+, 365.1839; found, 365.1841.
1
acetophenone (0.76 g, 49%). H NMR (300 MHz, CDCl3) δ 7.92
(d, J ) 9.0 Hz, 2H), 6.93 (d, J ) 9.0 Hz, 2H), 4.01 (t, J ) 6.4 Hz,
2H), 2.54 (s, 3H), 1.80 (m, 2H), 1.45-1.26 (m, 18H), 0.87 (br s,
3H). Without further characterization, this material (0.66 g, 2.17
mmol) was combined with 2.0 mL of N,N-dimethyl formamide
dimethyl acetal and heated in a 120 °C oil bath for 12 h. Volatile
liquid was removed in vacuo to afford 6 as a yellow oil that
solidified on standing (0.76 g, 97%). Mp 74-76 °C. 1H NMR (300
MHz, CDCl3) δ 7.89 (d, J ) 7.0 Hz, 2H), 7.78 (d, J ) 12.3 Hz,
1H), 6.9 (d, J ) 7.0 Hz, 2H), 5.71 (d, J ) 12.3 Hz, 1H), 3.99 (t,
J ) 6.6 Hz, 2H), 3.02 (br d, 6H), 1.81-1.74 (m, 2H), 1.45-1.26
(m, 18H), 0.88 (t, J ) 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
187.4, 161.5, 153.7, 132.8, 129.4, 113.7, 91.7, 68.0, 31.9, 29.5,
29.0, 26.0, 22.6, 14.1. IR (neat) ν (cm-1) 1640. HRMS (ESI) calcd
for C23H38NO2 [M + H]+, 360.2903; found, 360.2905.
(31) Snellink-Rue¨l, B. H. M.; Antonisse, M. M. G.; Engbersen, J. F. J.;
Timmerman, P.; Reinhoudt, D. N. Eur. J. Org. Chem. 2000, 165 and
references cited.
(32) Selected examples of supramolecular materials fashioned from
substituted crown ethers: (a) Badjic´, J. D.; Ronconi, C. M.; Stoddart, J. F.;
Balzani, V.; Silvi, S.; Credi, A. J. Am. Chem. Soc. 2006, 128, 1489. (b)
Hennrich, G.; Rurack, K.; Spieles, M. Eur. J. Org. Chem. 2006, 516. (c)
Huang, F.; Nagvekar, D. S.; Slebodnick, C.; Gibson, H. W. J. Am. Chem.
Soc. 2005, 127, 484. (d) Steinke, N.; Frey, W.; Baro, A.; Laschat, S.; Drees,
C.; Nimtz, M.; Ha¨gele, C.; Giesselmann, F. Chem.-Eur. J. 2006, 12, 1026.
(e) Gokel, G. W.; Leevy, W. M.; Weber, M. E. Chem. ReV. 2004, 104,
2723. (f) Dykes, G. M.; Smith, D. K. Tetrahedron 2003, 59, 3999. (g)
Percec, V.; Cho, W.-D.; Ungar, G.; Yeardley, D. J. P. Chem.-Eur. J. 2002,
8, 2011.
Co-trimerization of Enaminones 2 and 6. Preparation of
TAB’s 4 and 7-9. A mixture of 2 (0.60 g, 1.64 mmol) and 6
(0.29 g, 0.82 mmol) in 7.5 mL of 4:1 AcOH:pyridine was heated
in a 120 °C oil bath for 24 h. The solvent was then evaporated,
and the residue was combined with H2O (20 mL) and extracted
(33) For general experimental details, see the Supporting Information.
(34) Stott, P. E.; Bradshaw, J. S.; Parish, W. W.; Copper, J. W. J. Org.
Chem. 1980, 45, 4716.
2766 J. Org. Chem., Vol. 73, No. 7, 2008

Mono-, Bis-, and Tris(crown ether)s
with EtOAc (2 × 20 mL). The combined organic layer was dried
over anhydrous MgSO4, filtered, and concentrated to afford 0.63 g
(80%) of crude material consisting of a mixture of the four possible
triaroylbenzene products. Separation and purification of the desired
TAB’s was achieved via flash column chromatography using
gradient elution (20% EtOAc in hexanes-100% MeOH). The
products eluted from the column in the order 7 (22 mg, 4.1%),
mono-crown 9 (120 mg, 22%), bis-crown 8 (370 mg, 69%), and
tris-crown 4 (27 mg, 5.0%) The combined isolated yield was 539
mg (69% overall, 86% of the crude product).
General Procedure for Picrate Extraction Experiments. A
CHCl3 solution of 4 or 5 (3.0 mL, 3.6 × 10-3 M) and an aqueous
solution (3.0 mL) consisting of alkali metal hydroxide (0.1 M) and
picric acid (7.5 × 10-5 M) were combined in a test tube and
vigorously agitated for 1.5 h. The layers were allowed to separate,
and a 2.5 mL aliquot of the aqueous phase was diluted to 5.0 mL.
The absorbance of the aqueous phase at 355 nm before and after
agitation with the crown solution was compared to determine the
% extraction. Extraction experiments involving 10-13 were
performed using 3.6 × 10-3 M solutions of crown ether (i.e., 3
times the concentration of 4 and 5). Data in Table 1 are averages
of three trials.
Isothermal Titration Calorimetry. Calorimetric measurements
were performed in acetonitrile at 298 K on a computer-controlled
VP-ITC microcalorimeter (Microcal, Inc.) against a reference
solution of 100% acetonitrile. Acetonitrile (HPLC grade) was
purified by passing through a column of activated molecular sieves
immediately prior to use. Concentrations of crown ether solutions
were 0.5 mM for each experiment. Sodium and potassium titrant
solutions were prepared from NaSCN and KSCN (50 mM in
MeCN). Cesium titrant solutions were prepared from CsBPh4 (10
mM). Binding isotherms for Na+ and K+ were obtained upon
continuous injection of 160 µL of titrant solution into 1.42 mL of
crown ether solution over 1600 s. Evaluation of Cs+ binding was
performed similarly except that 280 µL of titrant was injected over
2800 s. Binding curves were obtained from nonlinear least-squares
analysis of the isotherms using the Origin analysis package provided
by Microcal, Inc. Data in Table 2 represent averages of three
separate trials.
Characterization Data. 7. Waxy semisolid. 1H NMR (300 MHz,
CDCl3) δ 8.26 (s, 3H), 7.84 (d, J ) 8.8 Hz, 6H), 6.95 (d, J ) 8.8
Hz, 6H), 4.03 (t, J ) 6.4 Hz, 6H), 1.83-1.78 (m, 6H), 1.48-2.36
(m, 54H), 0.88 (t, J ) 6.8 Hz, 9H). 13C NMR (75 MHz, CDCl3) δ
193.9, 163.4, 138.7, 133.1, 132.6, 128.9, 114.3, 68.4, 31.9, 29.5,
29.3, 29.0, 22.6, 14.1. IR (neat) ν (cm-1) 1658. HRMS (ESI) calcd
for C63H91O6 [M + H]+, 943.6816; found, 943.6806.
8. Pale yellow solid. Mp 50-51 °C. 1H NMR (300 MHz, CDCl3)
δ 8.26 (s, 3H), 7.84 (d, J ) 8.8 Hz, 2H), 7.49 (s, 2H), 7.38 (d, J
) 8.3 Hz, 2H), 6.96 (d, J ) 8.8 Hz, 2H), 6.87 (d, J ) 8.4 Hz, 2H),
4.21-4.19 (m, 8H), 4.03 (t, J ) 6.4 Hz, 2H), 3.95-3.91 (m, 8H),
3.77 (br s, 16H), 1.9-1.85 (m, 2H), 1.32-1.26 (m, 18H), 0.87 (t,
J ) 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 193.9, 193.8, 163.4,
153.8, 149.1, 138.7, 133.1, 129.3, 126.0, 114.3, 111.6, 71.2, 70.4,
70.3, 69.3, 69.2, 69.0, 68.7, 68.4, 31.9, 29.7, 29.6, 29.5, 29.4, 22.7,
14.1. IR (neat) ν (cm-1) 1649. HRMS (ESI) calcd for C55H70O14‚
Na [M + Na]+, 977.4664; found, 977.4668.
1
9. Colorless oil. H NMR (300 MHz, CDCl3) δ 8.26 (s, 3H),
7.84 (d, J ) 7.0 Hz, 4H), 7.48 (s, 1H), 7.38 (m, 1H), 6.96 (d, J )
7.0 Hz, 4H), 6.86 (d, J ) 8.4 Hz, 1H), 4.21-4.19 (m, 4H), 4.03 (t,
J ) 6.6 Hz, 4H), 3.95 (m, 4H), 3.76 (br s, 8H), 1.83-1.76 (m,
4H), 1.48-1.26 (m, 36H), 0.87 (t, J ) 6.7 Hz, 6H). 13C NMR (75
MHz, CDCl3) δ 194.1, 163.7, 154.0, 149.3, 139.0, 133.3, 132.9,
129.6, 129.1, 126.2, 114.6, 111.9, 71.4, 70.6, 70.5, 69.2, 68.6, 32.1,
Acknowledgment. We thank the Department of Chemistry
and the Department of Microbiology, University of Iowa.
Supporting Information Available: Copies of 1H and 13C NMR
spectra, calorimetric data. This material is available free of charge
via the Internet at http://pubs.acs.org.
29.9, 29.8, 29.8, 29.7, 29.6, 29.3, 26.2, 22.9, 14.3. IR (neat) ν (cm-1
)
1659. HRMS (ESI) calcd for C59H81O10 [M + H]+, 949.5830;
found, 949.5823.
JO7026867
J. Org. Chem, Vol. 73, No. 7, 2008 2767