A highly efficient, preorganized macrobicyclic receptor for halides based on CH... and NH...anion interactions

Article abstract of DOI:10.1021/ja047070g

The preorganized, macrobicyclic azaphane (1) exhibits remarkable strong, selective fluoride binding comparable to the most effective bis(tren) cryptands despite binding anions via only three NH groups coupled with three CH hydrogen bond donors. The lower intrinsic affinity of CH donors is compensated by the high degree of preorganization exhibited by azacyclophane 1. Compound 1 is prepared via a tripod-tripod cyclization reaction between 1,3,5-tris- bromomethyl-benzene and an aliphatic tripodal hexatosylated polyamine, followed by the reduction of the resulting bicyclic tosylamine. The crystal structures of the bicyclic tosylamine 2 and four macrobicyclic polyammonium halide salts of 1 are reported. X-ray studies revealed the formation of inclusive 1:1 complexes of 1 with fluoride, chloride, bromide, and iodide. Potentiometric titrations showed very high binding constants for fluoride and chloride with a F ^-/Cl^- selectivity of more than five logarithmic units. The final geometry of the anion cryptates is largely determined by optimization of NH and CH...anion interactions coupled with unfavorable anion-π repulsion for the larger anions.

Full text of DOI:10.1021/ja047070g

Published on Web 09/11/2004
A Highly Efficient, Preorganized Macrobicyclic Receptor for
Halides Based on CH‚‚‚ and NH‚‚‚Anion Interactions
Christos A. Ilioudis,† Derek A. Tocher,‡ and Jonathan W. Steed*,§
Contribution from the Department of Chemistry, King’s College London, Strand,
London, WC2R 2LS, U.K., Department of Chemistry, UniVersity College London,
20 Gordon Street, London WC1H 0AJ, and Department of Chemistry,
UniVersity of Durham, UniVersity Science Laboratories,
South Road, Durham, DH1 3LE, U.K.
Received May 19, 2004; E-mail: jon.steed@durham.ac.uk
Abstract: The preorganized, macrobicyclic azaphane (1) exhibits remarkable strong, selective fluoride
binding comparable to the most effective bis(tren) cryptands despite binding anions via only three NH
groups coupled with three CH hydrogen bond donors. The lower intrinsic affinity of CH donors is
compensated by the high degree of preorganization exhibited by azacyclophane 1. Compound 1 is prepared
via a tripod-tripod cyclization reaction between 1,3,5-tris-bromomethyl-benzene and an aliphatic tripodal
hexatosylated polyamine, followed by the reduction of the resulting bicyclic tosylamine. The crystal structures
of the bicyclic tosylamine 2 and four macrobicyclic polyammonium halide salts of 1 are reported. X-ray
studies revealed the formation of inclusive 1:1 complexes of 1 with fluoride, chloride, bromide, and iodide.
Potentiometric titrations showed very high binding constants for fluoride and chloride with a F-/Cl- selectivity
of more than five logarithmic units. The final geometry of the anion cryptates is largely determined by
optimization of NH and CH‚‚‚anion interactions coupled with unfavorable anion-π repulsion for the larger
anions.
Introduction
Polyammonium macrobicycles constitute one of the most
successful and widely used classes of molecules for anion
binding.15,16 Hosts such as the octaazacryptand (OAC) and bis-
(tren) (BT, Figure 1) have been reported by Dietrich et al. to
show very high binding constants for halide species. In the
hexaprotonated form, the small cryptand OAC has a very large
log Ks value of 10.55 for fluoride17 (or 11.218) whereas BT has
log Ks values of 4.10 and 3.00 for fluoride and chloride,
respectively.19 It was proposed that the preorganized array of
six NH+ donors in protonated OAC is highly complementary
to F-. It is remarkable, however, that the ligand BT also
potentially presents six NH groups in a preorganized array and
yet is so much less effective at binding fluoride, despite the
Anion coordination chemistry1 is one of the most topical and
challenging areas of current research within supramolecular
chemistry.2,3 The field includes exciting current work in the
binding and transport of nucleotides4,5 and amino acids,6,7 along
with applications in catalysis,8 analytical chemistry,9,10 and
anion-templated reactions.11-13
Various types of receptors have been synthesized and used
as complexones for anionic species in the past 35 years.14
† King’s College London.
‡ University College London.
§ University of Durham.
(1) Bianchi, A.; Bowman-James, K.; Garcia-Espana, E. Supramolecular
Chemistry of Anions; Wiley-VCH: New York, 1997.
(2) Lehn, J.-M. Supramolecular Chemistry, 1st ed.; VCH: Weinheim, Germany,
1995; p 271.
comparable affinity for chloride. The larger cryptands have an
2- 20,21
affinity for larger anions such as CrO4
.
(3) Steed, J. W.; Atwood, J. L. Supramolecular Chemistry; Wiley: Chichester,
U.K., 2000.
(4) Adams, R. L. P.; Knowler, J. T.; Leader, D. P. The Biochemistry of the
Nucleic Acids; Chapman and Hall: New York, 1986.
(5) Wirth, W.; Blotevogel-Baltronat, J.; Kleinkes, U.; Sheldrick, W. S. Inorg.
Chim. Acta 2002, 339, 14-26.
In our previous crystallographic studies of aliphatic polyam-
monium halide salts,22 we noted a preference for halide species
toward the adoption of trigonal coordination environments in
(6) Kyne, G. M.; Light, M. E.; Hursthouse, M. B.; de Mendoza, J.; Kilburn, J.
D. J. Chem. Soc., Perkin Trans. 1 2001, 1258-1263.
(7) Wehner, M.; Schrader, T. Angew. Chem., Int. Ed. 2002, 41, 1751-1754.
(8) Lehn, J.-M. Supramolecular Reactivity and Catalysis of Phosphoryl Transfer.
In Bioorganic Chemistry in Healthcare and Technology; Pandit, U. K.,
Alderweireldt, F. C., Eds.; Plenum Press: New York, 1991.
(9) Snyder, L. R.; Glajch, J. L.; Kirkland, J. J. Practical HPLC Method
DeVelopment; Wiley & Sons: New York, 1988.
(14) Schmidtchen, F. P.; Berger, M. Chem. ReV. 1997, 97, 1609-1646.
(15) Ilioudis, C. A.; Steed, J. W. J. Supramol. Chem. 2001, 1, 165-187.
(16) Llinares, J. M.; Powell, D.; Bowman-James, K. Coord. Chem. ReV. 2003,
240, 57-75.
(17) Dietrich, B.; Dilworth, B.; Lehn, J.-M.; Souchez, J.-P.; Cesario, M.;
Guilhem, J.; Pascard, C. HelV. Chim. Acta 1996, 79, 569-587.
(18) Reilly, S. D.; Khalsa, G. R. K.; Ford, D. K.; Brainard, J. R.; Hay, B. P.;
Smith, P. H. Inorg. Chem. 1995, 34, 569-575.
(10) Schmidtchen, F. P. Nachr. Chem. Tech. Lab. 1988, 36, 8-12.
(11) Yang, X.; Knobler, C. B.; Hawthorne, M. F. Angew. Chem., Int. Ed. Engl.
1991, 30, 1507-1508.
(19) Dietrich, B.; Guilhem, J.; Lehn, J.-M.; Pascard, C.; Sonveaux, E. HelV.
Chim. Acta 1984, 67, 91-104.
(20) Maubert, B. M.; Nelson, J.; McKee, V.; Town, R. M.; Pa`l, I. J. Chem.
Soc., Dalton Trans. 2001, 1395-1397.
(12) Zeng, Z.; Yang, X.; Knobler, C. B.; Hawthorne, M. F. J. Am. Chem. Soc.
1993, 115, 5320-5321.
(21) McKee, V.; Nelson, J.; Town, R. M. Chem. Soc. ReV. 2003, 32, 309-325.
(22) Ilioudis, C. A.; Hancock, K. S. B.; Georganopoulou, D. G.; Steed, J. W.
New J. Chem. 2000, 24, 787-798.
(13) Zeng, Z.; Knobler, C. B.; Hawthorne, M. F. J. Am. Chem. Soc. 1995, 117,
5105-5113.
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J. AM. CHEM. SOC. 2004, 126, 12395-12402
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A R T I C L E S
Ilioudis et al.
the availability of NH donors (the more NH donors there are,
the fewer CH‚‚‚anion interactions are formed). Given these
results, a new ligand (1) based on the tren unit has been
designed. Compound 1 retains the six secondary NH groups
seen in the species shown in Figure 1 and hence might be
expected to bind anions in hexaprotonated form, with secondary
amine groups separated by a propylenic chain to minimize
electrostatic repulsions in the protonated form. However, the
insertion of an arene unit provides a more rigid cavity such as
to prevent the three proximal (benzylic) NH groups converging
upon included anions, while simultaneously restricting the
conformational freedom of the remainder of the cryptand. It
was also anticipated that hydrohalide complexes of 1 might give
insight into the tolerance of such systems toward unfavorable
halide-π interactions. Compound 1 represents a contracted
version of the original cone-shaped ether derivative reported
by Heyer and Lehn in 198623 and is an expanded version of a
tiny proton-binding cryptand recently synthesized by us.24 We
now report the synthesis, detailed X-ray studies of four halide
salts, and solution stability constants for halide binding of the
newly synthesized macrobicyclic azaphane 1.
Results and Discussion
Figure 1. Bis(tren) based macrobicycles.
Synthesis. The synthesis of macrobicycle 1 was based upon
the tripod coupling process described by Dietrich et al.25 The
reaction sequence followed is given in Scheme 1. The key
synthetic step involves the condensation of the tris-terminal
tosylamine tripodal compound 8 with the tripodal 1,3,5-
tribromo-trimethylbenzene (4) in a large excess of Cs2CO3 under
high dilution conditions.26,27 All reactions leading up to the
the presence free triprotonated tren (2,2′,2′′-triaminoethylamine).
For example, in the case of chloride in triprotonated 2,2′,2′′-
triaminoethylamine trichloride, the halide is positioned at the
apex of a trigonal pyramid of NH+ donors. The exposed opposite
face of the chloride anion interacts with a range of CH2 groups,
forming a range of CH‚‚‚anion hydrogen bonds, depending on
Scheme 1. Synthesis of the Macrobicyclic Azaphane 1
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A Preorganized Macrobicyclic Receptor for Halides
A R T I C L E S
iodide, the macrobicycle crystallized in its hexaprotonated form,
whereas the bromide salt 1‚7HBr‚3H2O involved a heptapro-
tonated cryptand. Importantly, in all four cases, a halide anion
is located inside the cavity of the macrobicycle. Key structural
parameters are given in Table 1. Crystallographic parameters
for the new macrobicyclic systems are given in Table 2.
The most striking feature of the structures of protonated 1
is the significant lengthening of the host cavity (as exem-
plified by the Napical‚‚‚centroid distance, Table 1) compared
to the precursor 2, along with a corresponding decrease in
the helical twist angle. Thus the main conformational change
on protonation and anion complexation comprises a facile
lengthening and concomitant untwisting of the macrobi-
cycle. Surprisingly, this effect is most marked for the small-
est anion, F- which exhibits the longest Napical‚‚‚cen-
troid distance of 7.52 Å. The structural similarity between
the fluoride complex of 1‚6H+ and the hexaprotonated OAC
is marked (Figure 4), with CH2 groups from both the end of
the propylenic chains (C8 and C20) and even the middle
(C15) all interacting29 with the included fluoride anion in
a fashion similar to the NH moieties in the OAC cryp-
tate (Figure 3). OAC displays the largest binding con-
stants known for fluoride.17 The average N‚‚‚F- distance
for the complexed fluoride in the case of OAC is 2.835
Å, whereas the corresponding distance for cryptand 1 is
2.648(3) Å, suggesting a very good match between the cavity
of the newly synthesized cryptand and fluoride anion and
displacement of the anion toward the NH donors and away
from the weaker hydrogen bonding CH sites (hydrogen
bond distances: N(4)‚‚‚F(1): 2.679(3) Å, N(5)‚‚‚F(1): 2.619-
(3) Å, N(6)‚‚‚F(1): 2.646(3) Å, C(8)‚‚‚F(1): 3.414(3) Å,
C(15)‚‚‚F(1): 3.356(3) Å, C(20)‚‚‚F(1): 3.297(3) Å). The lower
Figure 2. X-ray crystal structure of 2. All atoms belonging to the tosyl
moieties have been removed for the sake of clarity with the exception of
sulfur atoms.
synthesis of compound 8 proceeded under satisfactory yields,
but the macrobicyclization afforded only 19% of the tosylamine
2. Detosylation of 2 afforded the target compound in good yield.
All new compounds were characterized by the usual analyti-
cal and spectroscopic techniques (see Experimental Section).
The structure of the hexatosylate 2 was determined by X-ray
crystallography to provide information about the degree of
preorganization of the receptor in the absence of protonation
or anionic guest species. Suitable crystals for X-ray diffraction
for 2 were grown by slow diffusion of pentane in a concentrated
solution of the product in dichloromethane. The aliphatic portion
of the tosylated macrobicycle is clearly preorganized for the
intracavity binding of a halide anion (Figure 2), exhibiting an
in28 conformation of the apical nitrogen atom. The distance from
the apical N atom to the aromatic ring centroid is relatively
short in comparison to the analogous halide complexes (vide
infra, N‚‚‚centroid distance 5.872(19) Å), consistent with
minimization of free cavity volume. This contraction has the
effect of splaying out the lower (benzylic) amine nitrogen atoms
(N‚‚‚N distances 6.408 Å, C3 symmetric) in a fashion unsuitable
for convergent guest binding. The methylenic chains are,
however, appropriately positioned to interact with a potential
guest species. It would be anticipated that upon protonation the
cavity would enlarge as a consequence of repulsions between
the protonated amine nitrogen atoms, resulting in an increase
of the Napical‚‚‚centroid distance and a decrease of the helical
twist angle (taken as the N(1)-N(2)-N(3)-C(2) torsion angle,
59.1° in 2) of the C3 chiral, propeller-like conformation.
Hydrohalide Salts of Compound 1. It has proved possible
to crystallize compound 1 in the presence of fluoride, chloride,
bromide, and iodide from an aqueous solution of the corre-
sponding haloacid by slow evaporation. A mixed fluoride/silicon
hexafluoride hydrate salt (1‚2HF‚2H2SiF6‚7H2O) resulted from
crystallization with hydrofluoric acid, presumably as a result
of glass corrosion. The chloride complex also crystallized as a
hydrate 1‚6HCl‚4H2O. The polyiodide salt 1‚2HI‚4HI3 was
obtained from hydroiodic acid, with the I3- arising from partial
aerobic iodide oxidation. In the case of fluoride, chloride, and
+
NH2 groups hydrogen bond with anions outside the cavity.
The other halide anions Cl- to I- are all held in a similar fashion,
with three NH‚‚‚X- and three CH‚‚‚X- hydrogen bonds
completing a pseudo-octahedral coordination about each halide
guest (Figure 4). Hydrogen bond distances increase approxi-
mately in proportion to the anion ionic radii. As in the fluoride
case, the overall Cl- binding environment, distorted octahedral,
is once more very similar to the one observed for the corre-
sponding hexaprotonated octaazacryptand OAC‚6HCl‚2.75H2O.30
In the case of 1‚6HCl‚4.5H2O, and despite less competition for
chloride binding from a second set of NH groups, the average
N‚‚‚Cl- distance for the newly synthesized complex is 3.164-
(8) Å, slightly larger than that observed in OAC‚6HCl‚2.75H2O
(3.085 Å), probably indicative of a better match between the
cavity of OAC and chloride than between the cavity of 1 and
chloride, at least in the solid state. In the bromide case, there
are two conformationally very different independent molecules
(Figure 4b and c). Both exhibit a short NHapical‚‚‚Br- interaction
because the cryptand is heptaprotonated, but the resulting strain
is apparently sufficient to destabilize the convergent geometry
of the three tren secondary ammonium groups and allow the
+
formation of a conformer with an NH2 group pointing out of
the cavity. Thus, one intracavity bromide ion exhibits a
CH‚‚‚Br- interaction instead of an NH+‚‚‚Br- hydrogen bond
(Figure 4c). The other conformer exhibits the more conventional
(23) Heyer, D.; Lehn, J. M. Tetrahedron Lett. 1986, 27, 5869-5872.
(24) Ilioudis, C. A.; Bearpark, M. J.; Steed, J. W. Unpublished work, 2004.
(25) Dietrich, B.; Hosseini, M. W.; Lehn, J.-M.; Sessions, R. B. HelV. Chim.
Acta 1985, 68, 289-299.
(26) Dietrich, B.; Lehn, J.-M.; Sauvage, J. P.; Blanzat, J. Tetrahedron 1973,
29, 1629-1645.
(29) Desiraju, G. R.; Steiner, T. The Weak Hydrogen Bond in Structural
Chemistry and Biology; Oxford University Press: Oxford, 1999; p 480.
(30) Hossain, M. A.; Linares, J. M.; Miller, C. A.; Seib, L.; Bowman-James,
K. Chem. Commun. 2000, 2269-2270.
(27) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95-102.
(28) Park, C. H.; Simmons, H. E. J. Am. Chem. Soc. 1968, 90, 2431-2433.
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A R T I C L E S
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Table 1. Structural Data for the Cryptates Reported in the Present Worka
compound
7HBr
1‚
2HF
‚
2H2SiF6
‚
7H2O
1
‚
6HCl
‚
4H2O
1
‚
‚3H2O
1
‚
2HI
‚
4HI3
2
Napex‚‚‚X- (Å)
3.066(3)
4.506(3)
7.520(4)
3.445(7)
3.528(7)
3.652(8)
3.743(9)
7.169(11)
7.185(11)
10.6-29.4
6.3-13.9
3.169(12)
3.187(14)
3.653(14)
3.675(14)
6.804(19)
6.849(18)
9.0-36.0
1.9-63.2c
3.786(13)
3.692(13)
7.468(18)
9.0-28.7
-
-
cntr‚‚‚X- (Å)
Napex‚‚‚cntr (Å)
5.872(19)
59.1
helical twist angle (deg)b
20.5-31.8
a Data for the tosylated precursor 2 are included for comparison. Napex refers to the apical nitrogen atom of the ligand, X- refers to the corresponding
halide anion inside the cavity of the cryptand, and “cntr” (centroid) refers to the point that corresponds to the center of the aromatic ring of the cryptand.
b The helical twist angle is defined as the Napical-NH2-NH2-Caryl torsion angle. The values for two crystallographically unique cryptates for the chloride
and the bromide salts are given. c Disordered.
Table 2. Crystallographic Parameters for New Macrobicyclic Systems
2
1
‚
2HF
‚
2H2SiF6
‚
7H2O
1
‚
6HCl
‚
4.5H2O
1
‚
7HBr
‚
3H2O
1‚2HI‚4HI3
formula
M
system
space group
a/Å
b/Å
c/Å
C69H87Cl6N7O12S6
1611.61
rhombohedral
R3
C24H65F14N7O7Si2
885.97
monoclinic
P21/n
14.0345(9)
15.9137(10)
17.6318(11)
C24H60Cl6N7O4.5
731.51
triclinic
C24H58Br7N7O3
1052.10
triclinic
P1h
11.2538(4)
18.0137(8)
20.9088(8)
74.548(3)
82.221(2)
73.058(3)
3900.5(14)
2
C24H51I14N7
2214.32
triclinic
P1h
11.4033(12)
11.5662(12)
21.966(2)
85.670(2)
83.181(2)
61.557(2)
2528.8(5)
2
P1h
16.3404(23)
11.2494(8)
16.2958(12)
21.1945(19)
78.3122(27)
85.1281(32)
82.6143(40)
3719.3(13)
2
28.0178(27)
R/deg
â/deg
96.2392(45)
γ/deg
V/Å3
6479.0(18)
3
3914.6(14)
6
Z
No. msd. rflns
No. un. rflns
R1 (on F, I > 2σ(I))
wR2 (on F2, all data)
10 189
5656
0.2118
0.3388
13 422
7845
0.0550
0.1405
43 774
13 301
0.1420
0.3553
24 842
15 500
0.1135
0.2951
20 906
11 340
0.0756
0.1956
Figure 3. Encapsulation of a fluoride anion (a) in the crystal structure of 1‚2HF‚2H2SiF6‚7H2O and (b) in the crystal structure of OAC‚3HF‚HCl‚2SiF6‚
5H2O. The similarities between the ligand conformations and the coordination geometries of the included anions are evident.
three NH‚‚‚Br- and three CH‚‚‚Br- short contacts in addition
to the apical interaction with C‚‚‚Br- distances between 3.644-
(17) and 3.936(14) Å, typical for this kind of interaction. It is
useful to make a comparison between this structure and other
structures of protonated tren units with bromide anions.22 In
the case of the monoprotonated tren monobromide, a clear
chelate effect was observed for the tren unit, with unprotonated
secondary amine units as well as the ammonium group
interacting with the anion. In contrast, the tetraprotonated tren
tetrabromide displays no chelate effect at all, probably because
of the mutual repulsion among the ammonium moieties. Moving
to the iodide case, N‚‚‚I- distances for the ammonium moieties
of the tren unit are 3.427(13), 3.441(13), and 3.479(13) Å.
Again, three C-H‚‚‚I- weak interactions complete the coordi-
nation sphere of the complexed iodide (Figure 4d) with C‚‚‚I-
distances at 3.620(15), 3.728(13), and 3.740(15) Å.
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A Preorganized Macrobicyclic Receptor for Halides
A R T I C L E S
Figure 4. Encapsulation of (a) a chloride anion in the crystal structure of 1‚6HCl‚4.5H2O and (b, c) bromide in 1‚7HBr‚3H2O, two conformationally
different independent molecules. An additional NH+‚‚‚Br- hydrogen bond in each case is formed because the cryptand is heptaprotonated with Napical‚‚‚Br-
distances of 3.169(12) Å and 3.187(14) Å. Disordered H atoms on C46 not shown. (d) Iodide anion in the crystal structure of 1‚2HI‚4HI3. Smaller “bite”
angles are observed as a result of the positioning of the encapsulated iodide further away from the apical nitrogen atom.
Interestingly, the fluoride salt exhibits a rather long
anion‚‚‚centroid separation of 4.506 Å, a parameter that remains
remarkably constant at ca. 3.6 Å for all of the other anions
(Table 1), including both symmetry-independent molecules in
the case of the Cl- and Br- analogues. The fact that this rather
short distance does not increase with increasing halide size
suggests that the halide anions are in repulsive contact with the
aromatic ring and hence suggests that the binding of all halides
except F- should consequently be destabilized. This observation
is borne out by potentiometric titration data (vide infra). The
flexibility of the aliphatic end of the molecule is exemplified
in the consistent increase in the Napical‚‚‚X- distance from 3.06
Å in the fluoride case to 3.78 Å in the iodide case. The exception
to this rule is the bromide salt, which would be expected to
exhibit a short Napical‚‚‚Br- distance because the apical nitrogen
atom is protonated, in contrast to all of the other structures,
and hence an additional NHapical‚‚‚Br- hydrogen bond is formed.
The effects of the proximity of the aromatic ring on the overall
length of the cryptand (Napical‚‚‚centroid distances, Table 1)
contrast with the relatively minor changes observed in related
systems. For example, in the case of OAC the apical N‚‚‚N
distance is 6.60 Å for the chloride complex24 and 6.65 Å for
the fluoride complex.17 The cavity dimensions for the “Bis-
Tren” fluoride, chloride, and bromide complexes are 7.66 and
8.02 Å (two crystallographically unique ligands), 7.40, and 7.50
Å, respectively.19
The locations of the extracavity anions are shown for the
2-
-
SiF6 and I3 species in Figure 5. The anions approach each
one of the sides of the approximately C3 symmetric cryptate,
+
interacting with the tren NH2 units via bifurcated NH‚‚‚F
9
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A R T I C L E S
Ilioudis et al.
The pH titration data are consistent with crystal structures
for the fluoride and chloride complexes. In fact, remarkably
high binding constants, consistent with the formation of a 1:1
inclusion complex, are observed in the presence of excess of
fluoride anion (Table 4). Significantly lower binding constants
were observed for chloride, comparable to those obtained for
the small octaazacryptand (Figure 1), and 1‚6H+ exhibits a
marked F-/Cl- selectivity (>105), again paralleling OAC.17,18
The high fluoride affinity and F-/Cl- selectivity observed for
1 are remarkable in that, as shown crystallographically, F-
complexation occurs via only three NH moieties, reinforced by
interactions with three CH2 groups. The clear implication is that
the preorganization of the host system is a significantly more
important factor than the nature of the binding groups.
Figure 5. Packing of extracavity anions in the crystal structure of (a) 1‚
2HF‚2H2SiF6‚7H2O and (b) 1‚2HI‚4HI3.
Although potentiometric and X-ray diffraction studies are in
agreement and consistent with the formation of intracavity
complexes in the case of F- and Cl-, no binding is observed
for Br- or NO3- anions. The weak binding of Br- in particular
is surprising given that this anion (and I-) is included in the
cavity in the solid state; however, it is likely that inclusion of
larger halides introduces significant strain and hence destabilizes
solution binding, particularly involving unfavorable anion‚‚‚π
interactions. The fact that intracavity inclusion of the larger
halide anions is observed crystallographically can be traced to
the conditions under which compound 1 was crystallized in the
presence of hydrobromic or hydroiodic acid. Concentrated acidic
solutions were used for crystallization experiments resulting,
in the case of the bromide complex, in a heptaprotonated host
and in both cases very high effective concentrations of halide
anions. This phenomenon was also investigated in the case of
OAC.30 An inclusive complex with chloride was obtained by
treatment with concentrated hydrochloric acid despite the fact
that earlier work suggested an enormous F-/Cl- selectivity of
more than eight logarithmic units for this cryptand. The workers
investigated the affinity patterns of this cryptand by NMR
techniques and concluded that it displays a dramatic enhance-
ment of its affinity for chloride below pH 2.5. It is likely that
compound 1 is subjected to the same effect at low pH, forming
cryptate complexes with both bromide and iodide. The origins
in this shift in selectivity may well be explicable in terms of
protonation of the apical tertiary amine nitrogen atom, introduc-
ing an additional NH+‚‚‚X- hydrogen bond as observed in the
crystal structure of 1‚7HBr‚3H2O. This behavior cannot be
studied by pH titrations because conventional potentiometric
techniques employed are only generally considered to be
accurate over a pH range of 2.5-11.
-
hydrogen bonds in the case of SiF6 (N‚‚‚F distances 2.726-
(3)-3.101(3) Å) and NH‚‚‚I interactions for I3-. Similar packing
is observed for the chloride and bromide analogues, and in all
cases additional CH‚‚‚X- weaker interactions are also formed
between the cryptand and the extracavity anions.
Solution Studies. The protonation constants for 1 were
determined potentiometrically and are shown in Table 3. These
values are not very different from protonation constants
measured for other azaphane cryptands such as m-BTC and
p-BTC (Figure 1), as well as a series of related cryptands.31 It
seems that the existence of propylene units balances a greater
loss of basicity expected because of mutual Coulombic repulsion
and the existence of the aromatic unit. The first three protonation
constants presumably represent the pKa values of the amine
moieties of the tren unit, and indeed they are close to the
corresponding values for tren itself. The benzylic NH groups
are more difficult to protonate because of the delocalization of
the amine lone pair into the aryl ring.32 The last protonation
constant presumably corresponds to the apical nitrogen, which
remains unprotonated in most of the systems studied in this
work, and is similar to that found for tren itself under the same
experimental conditions.
The protonation behavior of this ligand was also studied in
the presence of 0.01 M TsOH/0.1 M TsONa. The tosylate anion
was chosen because it is unlikely to bind with the macrocyclic
cavity of 1. With the exception of the first basicity constant, all
other basicity constants were found to be smaller than those
observed in the presence of 0.01 M HNO3/0.1 M NaNO3, and
the last protonation constant was not apparently accessible under
the experimental conditions. The NO3- anion (and other smaller
hydrogen bond acceptor anions by implication) apparently has
a significant role is stabilizing higher protonated species.
The anion binding stability constants of ligand 1 were
investigated in the presence of 0.01 M TsOH and 0.1 M TsONa
as supporting electrolyte. pH titrations were conducted in the
presence of excess of NaF, NaCl, NaBr, and NaNO3. Essentially
no change of the titration curve was observed in the titration of
1 in the presence of NaBr or NaNO3 compared to the reference
measurement, suggesting very low binding constants. First
stability constants for F- and Cl- are shown in Table 4 for
various protonated species.
Experimental Section
Materials. The starting materials were obtained in the highest purity
available and used without further purification.
NMR Spectra. 1H and 13C NMR spectra at room temperature were
measured with a Bruker Avance NMR spectrometer, operating at 360
and 90 MHz, respectively, and the chemical shifts are reported in parts
per million relative to tetramethylsilane.
Mass Spectra. Fast atom bombardment (low resolution) mass spectra
were obtained with a Kratos MS 890 mass spectometer. High-resolution
mass spectra were obtained with a Bruker Apex III mass spectrometer
by electrospray ionization.
(31) Arnaud-Neu, F.; Fuangswasdi, S.; Maubert, B.; Nelson, J.; McKee, V. Inorg.
Chem. 2000, 39, 573-579.
(32) Bencini, A.; Bianchi, A.; Garcia-Espana, E.; Micheloni, M.; Ramirez, J.
A. Coord. Chem. ReV. 1999, 188, 97-156.
Elemental Analysis. Elemental analysis for carbon, hydrogen, and
nitrogen was carried out by the Elemental Analysis Service at the
London Metropolitan University.
9
12400 J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004

A Preorganized Macrobicyclic Receptor for Halides
A R T I C L E S
Table 3. Logarithms of the Stepwise Protonation Constants for meta-Cyclophane 1a
log K1
log K2
log K3
log K4
log K5
log K6
log K7
log Ki
1b
9.50(16)
9.58(19)
9.99
9.82(7)
9.50(11)
9.02
8.47(7)
7.90(12)
7.98
7.61(10)
6.85(11)
7.20
7.18(10)
4.99(9)
6.40
6.75(6)
3.19(10)
5.67
2.37(10)
51.70(66)
42.01(72)
46.26
1c
-
-
-
BTd
OACe
11.2
9.4
7.6
5.78
4.4
-
38.38
a Values for BT and OAC (Figure 1) are included for comparison. b 0.001 M ligand 1, 0.01 M HCl, 0.1 M NaNO3. c 0.001 M ligand 1, 0.01 M TsOH,
0.1 M TsONa. d 0.1 M NaClO4 taken from ref 32. e 0.1 M KNO3 log K5 is a two-proton step, taken from ref 32.
Table 4. First Anion Binding Constants Observed for Ligand 1 at
In the crystal structure of 1‚7HBr‚3H2O, bromide atoms Br(4), Br-
(5), Br(7), Br(8), Br(9), Br(10), Br(17), and Br(18) were disordered
and given half occupancy each.
Different States of Protonationa
log K1
The relatively poor precision of the structures of 1‚6HCl‚4.5H2O,
1‚7HBr‚3H2O, and 2 arises principally from sample quality issues.
Crystals of these large unit cells, solvated systems proved in general
to be small, to be of high mosaicity, and to exhibit a marked tendency
toward formation of multiple, fused crystallites. In each case, a number
of samples were examined with an emphasis on obtaining a crystal as
nearly single as possible. In the case of 1‚6HCl‚4.5H2O and 1‚7HBr‚
3H2O, the problems are increased by disorder and absorption issues.
However, the overall atom positions are clear and unambiguous,
particularly the location of the intracavity anion.
The crystal structure of 1‚2HI‚4HI3 was obtained using a Bruker
SMART APEX CCD diffractometer using graphite-monochromated Mo
KR radiation (λ ) 0.71073 Å) at 298 ( 2 K. Data reduction and
integration were carried out with SAINT+, and absorption corrections
were applied using the program SADABS. Structures were solved by
direct methods and developed using alternating cycles of least-squares
refinement and difference Fourier synthesis. All non-hydrogen atoms
were refined anisotropically. Hydrogen atoms were placed in calculated
positions, and their thermal parameters were linked to those of the atoms
to which they were attached (riding model). For structure solution and
refinement, we used the SHELXTL PLUS V6.10 program package.
Synthesis. Trimethyl-1,3,5-Benzenetricarboxylate (3). Benzene-
tricarboxylic acid (10.0 g, 47.5 mmol), methanol (200 mL), and
concentrated sulfuric acid (2.5 mL) were mixed and then refluxed for
24 h. The solvent was evaporated, and the residue was dissolved in
chloroform (200 mL) and then washed with a saturated solution of
potassium carbonate (250 mL). The solvent was removed under reduced
pressure to afford 3 as a white powder (10.91 g, 92%).
-
species
F-
Cl-
Br-
NO3
1‚H6X
1‚H5X
1‚H4X
1‚H3X
9.54(12)
7.84(8)
5.65(12)
4.86(9)
4.19(13)
3.88(9)
2.06(26)
-
-
-
-
-
-
-
-
-
a The acid dissociation constant (log K ) 3.25) for HF was included in
the calculations. Values for bromide and nitrate were apparently too small
to measure.
Potentiometric Titrations. All potentiometric titrations were per-
formed at room temperature, using carbonate-free NaOH with a Titrino
model 736 GP along with a Metrohm combined glass electrode. The
protonation constants were determined from titrations of an ap-
proximately 10-3 M ligand solution containing an excess of HNO3 or
TsOH (typically 0.01 M) in the presence of NaNO3 or TsONa to
maintain ionic strength at 0.1 M. Anion binding constants for anionic
species X- were determined from titrations of an approximately 10-3
M ligand solution containing excess of TsOH (0.01 M or more) in the
presence of approximately 0.01 M of the corresponding salt NaX, and
TsONa (0.1 M) to maintain ionic strength at 0.1 M. The range of
accurate pH measurements was considered to be 2.5-11. Stability
constants were calculated with the program HYPERQUAD.33
X-ray Crystallography. Crystal data and data collection parameters
are summarized in Table 1. Crystals were mounted using silicon grease
on a thin glass fiber. All crystallographic measurements (except in the
case of 1‚2HI‚4HI3) were carried out with a Nonius Kappa CCD
diffractometer equipped with graphite monochromated Mo KR radiation
using wide φ- and ω-scans. Data collection temperature was 120 K,
maintained by using an Oxford Cryosystem low-temperature device.
Integration was carried out by the Denzo-SMN package.34 Data sets
were corrected for Lorentz and polarization effects and for the effects
of absorption (Scalepack)34 and crystal decay where appropriate.
Structures were solved using the direct methods option of SHELXS-
9735 and developed using conventional alternating cycles of least-
squares refinement (SHELXL-97)36 and difference Fourier synthesis
with the aid of the program XSeed.37 In all cases, non-hydrogen atoms
were refined anisotropically except for some disordered atoms, while
C-H hydrogen atoms were fixed in idealized positions and allowed to
ride on the atom to which they were attached. Hydrogen atom thermal
parameters were tied to those of the atom to which they were attached.
Where possible, acidic hydrogen atoms were located experimentally,
and their positional and isotropic displacement parameters were refined.
All calculations were carried out on an IBM-PC compatible personal
computer.
1H NMR (CDCl3): 8.88 (s, 3H), 4.00 (s, 9H); 13C NMR (CDCl3):
165.82, 135.00, 131.59, 53.03; MS m/z (FAB) 253 ([M + H]+); Anal.
Calcd for C12H12O6: C, 57.14%; H, 4.80%. Found: C, 57.18%; H,
4.82%.
1,3,5-Tribromo-trimethylbenzene (4). A quantity of 6.00 g (222
mmol) of lithium aluminum hydride was added to 600 mL of dry THF.
Then, 15 g (59.5 mmol) of 4 in 600 mL of dry THF was added dropwise
at room temperature under vigorous stirring and an atmosphere of N2.
After dropwise addition was completed, the mixture was heated to reflux
for 24h. The excess of reducing agent was destroyed by slow addition
of water, and the solvent was evaporated. Then, 450 mL of a 48%
HBr solution and 750 mL of toluene were added and heated to reflux
for 24 h. The organic layer was separated, and the aqueous portion
was extracted several times with diethyl ether. The organic layers were
combined and removed under reduced pressure. The crude material
was purified through a short column of silica with a 1/1 mixture of
n-hexane/toluene. The solvents were evaporated under high vacuum
In the crystal structure of 1‚6HCl‚4.5H2O, chloride atoms Cl(7), Cl-
(9), Cl(10), and Cl(13) were disordered and given half occupancy each.
1
to afford 19.12 g (53.6 mmol, 90% yield) of 4. H NMR (CDCl3):
7.36 (s, 3H), 4.46 (s, 6H); 13C NMR (CDCl3): 139.45, 129.99, 32.62;
MS m/z (FAB) 357 ([M + H]+); Anal. Calcd for C9H9Br3: C, 30.54%;
H, 2.54%. Found: C, 30.12%; H, 2.55%.
(33) Gans, P.; Sabatini, A.; Vacca, A. Talanta 1996, 43, 1739-1753.
(34) Otwinowski, Z.; Minor, W. Methods in Enzymology. In Methods in
Enzymology; Carter, C. W., Sweet, R. M., Eds.; Academic Press: London,
1997; Vol. 276, pp 307-326.
Tris-[2-(tosyl)-ethyl]-amine (5). Tris(2-aminoethyl)amine (4.83 g,
33.0 mmol) was dissolved in 70 mL of water containing 4.23 g (106
mmol) of NaOH. To this solution, p-toluenesulfonyl chloride (19.17
g, 100 mmol) in 60 mL of ether was added dropwise with vigorous
stirring at room temperature. After the addition was complete, stirring
(35) Sheldrick, G. M. SHELXS-97, University of Go¨ttingen: Go¨ttingen,
Germany, 1997.
(36) Sheldrick, G. M. SHELXL-97, University of Go¨ttingen: Go¨ttingen,
Germany, 1997.
(37) Barbour, L. J. J. Supramol. Chem. 2001, 1, 189-191.
9
J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12401

A R T I C L E S
Ilioudis et al.
was continued for 2 h, and the reaction mixture was allowed to stand
for 12 h. The white solid that precipitated was filtered, washed with
copious amounts of water, and dried under high vacuum to afford 5 as
mmol, 19% yield). The same reaction performed with K2CO3 afforded
only 11% yield. H NMR (CDCl3): 7.68 (d, J ) 8.2, 6H), 7.62 (d, J
1
) 8.2, 6H), 7.57 (s, 3H), 7.25 (m, 12H), 4.12 (s, 6H), 3.15 (b, 6H),
3.06 (b, 6H), 2.84 (b, 6H), 2.44 (b, 6H), 2.36 (s, 9H), 2.33 (s, 9H),
1.62 (b, 6H); 13C NMR (CDCl3): 144.02, 143.74, 135.35, 134.78,
130.24, 130.14, 128.80, 128.38, 127.98, 127.60, 56.12, 55.41, 49.30,
48.96, 45.20, 27.73, 21.91; MS m/z (FAB) 1315 ([M + H]+); Anal.
Calcd for C66H81S6O12N7: C, 59.03%; H, 6.08%; N, 6.26%. Found:
C, 59.20%; H, 6.19%; N, 6.39%.
1
a white powder (16.28 g, 26.7 mmol, 81% yield). H NMR (CDCl3):
7.78 (d, J ) 8.3, 6H), 7.27 (d, J ) 8.3, 6H), 5.96 (b, 3H), 2.90 (b,
6H), 2.48 (b, 6H), 2.40 (s, 9H); 13C NMR (CDCl3): 143.70, 137.15,
130.18, 127.59, 54.55, 41.16, 21.92; MS m/z (FAB) 609 ([M + H]+);
Anal. Calcd for C27H36S3O6N4: C, 53.27%; H, 5.96%; N, 9.20%.
Found: C, 53.31%; H, 5.89%; N, 9.15%.
5,9,12,15,19,24,28-Heptaaza-tricyclo[10.10.8.13,21]hentriaconta-
1(22),2,21(31)-triene (1). A mixture of 2 (0.5 g, 0.38 mmol), phenol
(2.0 g, 21.25 mmol), and 30 mL of 48% aqueous HBr was stirred and
heated to reflux for 72 h. After cooling to room temperature, the mixture
was repeatedly washed with chloroform. The aqueous phase was cooled
to 0 °C, and sodium hydroxide was added slowly until the pH of the
solution became at least 12. The product was extracted in chloroform,
which was removed under high vacuum to afford the free amine as a
3,3′,3′′-Tritosyl-6,6′,6′-nitrilotri(3-azahexanenitrile) (6). A mixture
of 5 (15.0 g, 24.6 mmol), acrylonitrile (5.3 mL, 81.3 mmol), K2CO3
(11.2 g, 81.3 mmol), and 200 mL of CH3CN were heated at 70 °C and
stirred for 3 days. Upon cooling, H2O (1 L) and CHCl3 (650 mL) were
added, and the aqueous phase was washed with CHCl3 (3 × 200 mL).
The combined organic layers were dried under high vacuum, and the
residue was recrystallized from MeOH/CHCl3 to afford the product as
1
white solid (16.6 g, 22.9 mmol, 93% yield). H NMR (CDCl3): 7.67
1
(d, J ) 8.3, 6H), 7.28 (d, J ) 8.3, 6H), 3.33 (t, J ) 6.8, 6H), 3.20 (t,
J ) 6.8, 6H), 2.80 (t, J ) 7.5, 6H), 2.63 (t, J ) 6.7, 6H), 2.37 (s, 9H);
13C NMR (CDCl3): 149.23, 140.94, 135.57, 132.68, 124.33, 58.52,
52.21, 50.51, 26.58, 23.72; MS m/z (FAB) 727 ([M + H]+); Anal.
Calcd for C36H45S3O6N7: C, 56.30%; H, 5.91%; N, 12.77%. Found:
C, 56.22%; H, 5.85%; N, 12.70%.
3,3′,3′′-Tritosyl-6,6′,6′-nitrilotri(3-azahexylamine) (7). 6 (7.27 g,
10 mmol) was dissolved in a solution of B2H6 in THF (200 mL, 1.0
M) and heated to reflux for 12 h under N2. After cooling to room
temperature, MeOH (30 mL) was added slowly to destroy excess B2H6,
and the solvents were evaporated. The residue was dissolved in 2.5 M
HCl/MeOH (300 mL) and refluxed for 3 h. The solvents were
evaporated, the residue was partitioned between CHCl3 (250 mL) and
1 M NaOH (150 mL), and the aqueous layer was extracted with CHCl3
(2 × 150 mL). The organic layers were combined and dried under
high vacuum to afford the crude amine as a viscous oil, which was
used directly to the next step.
N,N′,N′′-3,3′,3′′-Hexatosyl-6,6′,6′-nitrilotri(3-azahexylamine) (8).
Compound 7 afforded directly from the prevous step was dissolved in
THF (150 mL)/CH2Cl2 (15 mL). To this mixture, Et3N (15.6 mL, 112
mmol) and TsCl (6.23 g, 32 mmol) in 20 mL THF were added over 10
min, and the mixture was stirred for 12 h at room temperature. The
solvents were evaporated, and the residue was partitioned between
CHCl3 and H2O. The aqueous layer was extracted with CHCl3 (2 ×
150 mL), and the organic layers were combined and dried under under
high vacuum. The residue was purified by column chromatography on
silica (CH2Cl2) to afford 8 as a powder (4.86 g, 4.5 mmol, 45% yield).
1H NMR (CDCl3): 7.77 (d, J ) 8.3, 6H), 7.70 (d, J ) 8.3, 6H), 7.39
(d, J ) 8.3, 6H), 7.33 (d, J ) 8.3, 6H), 2.99 (b, 6H), 2.91 (b, 6H),
2.75 (b, 6H), 2.48 (s, 9H), 2.46 (s, 9H), 0.87 (b, 12H); 13C NMR
(CDCl3): 144.04, 143.65, 137.12, 136.00, 130.32, 130.08, 127.58,
127.39, 54.33, 47.90, 47.49, 40.61, 29.35, 21.91, 21.89; MS m/z (FAB)
1228 ([M + H]+); Anal. Calcd for C57H75S6O12N7: C, 55.72%; H,
6.15%; N, 6.84%. Found: C, 55.74%; H, 6.00%; N, 7.34%.
5,9,15,19,24,28-Hexakis-(toluene-4-sulfonyl)-5,9,12,15,19,24,28-
heptaaza-tricyclo[10.10.8.13,21]hentriaconta-1(22),2,21(31)-triene (2).
8 (5.50 g, 4.48 mmol) and Cs2CO3 (80 g, 245.5 mmol) were suspended
in refluxing CH3CN (700 mL). To this mixture, a solution of 4 (1.60
g, 4.48 mmol) in CH3CN (700 mL) was added dropwise. After the
addition was complete, the suspension was refluxed and stirred for 36
h and then filtered. The solvent was removed, and the crude product
was purified by column chromatography on silica (toluene/AcOEt, 85/
15). The product was obtained as a white crystalline solid (1.13 g, 0.49
waxy solid (80 mg, 0.19 mmol, 50% yield). H NMR (CDCl3): 7.20
(s, 3H), 3.84 (s, 6H), 2.63 (b, 12H), 2.57 (b, 12H), 2.40 (b, 6H), 1.53
(b, 6H); 13C NMR (CDCl3): 141.78, 126.71, 54.23, 53.44, 49.04, 47.79,
47.41, 31.74; HRMS calcd for C2313C1H45N7Na [M + H]+, 455.3662;
found, 455.3650.
Conclusion
Overall, it is concluded that complexation of a halide anion
by the protonated cryptand 1 in the solid state follows the same
pattern of distorted octahedral geometry, irrespective of the
complexed halide and irrespectiVe of the nature of the donor
groups. The structural unit N(CH2CH2NH2+CH2CH2CH2)3-
plays a very important role in the binding of the halides in the
newly synthesized cryptates.
Solution studies showed that basicity constants of 1 are in
good agreement with those observed for related macrobicyclic
azaphane species despite the unusual constraints placed on the
geometry and donor atom set of 1. Compound 1 in its
hexaprotonated form displays high selectivity for fluoride over
chloride (log KF-/log KCl- > 5), whereas no binding in aqueous
solution was found to take place for bromide and nitrate. An
explanation for the existence of cryptate inclusion complexes
of compound 1 in the solid state with bromide and iodide is
probably its dramatic enhancement of affinity for halides (at
least for bromide and iodide) at very low pH and concentration
effects.
Acknowledgment. We thank King’s College London and the
EPSRC for funding for the diffractometer system, the Depart-
ment of Chemistry at King’s College London for a studentship
(to C.A.I.), and the Nuffield Foundation for the provision of
computing equipment. We also thank Professor Peter Gans
(University of Leeds) for his advice on the usage of the program
HYPERQUAD.33
Supporting Information Available: X-ray structural data and
plots of pH titration curves for the basicity determination of 1
and its binding of F- and Cl- (PDF, CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA047070G
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12402 J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004