A macrobicyclic receptor with versatile recognition properties: Simultaneous binding of an ion pair and selective complexation of dimethylsulfoxide

Article abstract of DOI:10.1021/ja994487r

A bicyclic receptor was synthesized and evaluated for its ability to bind alkali halide salts and polar neutral molecules in organic solvents. The receptor design is relatively straightforward in the sense that it is a combination of a dibenzo-18-crown-6

Full text of DOI:10.1021/ja994487r

J. Am. Chem. Soc. 2000, 122, 6201-6207
6201
A Macrobicyclic Receptor with Versatile Recognition Properties:
Simultaneous Binding of an Ion Pair and Selective Complexation of
Dimethylsulfoxide
Martin J. Deetz, Maoyu Shang, and Bradley D. Smith*
Contribution from the Department of Chemistry and Biochemistry, UniVersity of Notre Dame,
Notre Dame, Indiana 46556-5670
ReceiVed December 23, 1999
Abstract: A bicyclic receptor was synthesized and evaluated for its ability to bind alkali halide salts and polar
neutral molecules in organic solvents. The receptor design is relatively straightforward in the sense that it is
a combination of a dibenzo-18-crown-6 and a bridging 1,3-phenyldicarboxamide. In the presence of 1 mol
equiv of metal cation, chloride affinities are enhanced in the order: K+ (9-fold enhancement) > Na+ (8-fold
enhancement) . Cs+ (no enhancement). An X-ray crystal structure shows that the receptor binds sodium
chloride as a solvent-shared ion pair. The receptor has very weak affinity for acetonitrile, nitromethane, or
acetone in chloroform solvent, whereas the association constant for dimethylsulfoxide is 160 M-1 at 295 K.
An X-ray crystal structure shows that the dimethylsulfoxide is bound deeply in the receptor cavity and forms
hydrogens bonds to the receptor via a bridging water molecule. There is also evidence for CH-O interactions.
Solid-liquid extraction studies show that the receptor can dissolve and associate with urea, primary amides,
and primary sulfonamides in CDCl3 but does not dissolve amino acids.
Introduction
An ongoing enterprise in supramolecular chemistry is the
design, synthesis, and study of low-molecular weight receptor
compounds with convergent functionality.1 Such receptors
exhibit a range of interesting and potentially useful molecular
recognition properties. Most of the earliest examples were
homoditopic receptors that contained two identical binding sites
connected by a linker.2 These compounds can chelate a
structurally symmetric guest or alternatively bind two very
similar guests simultaneously. More recently, attention has
turned to heteroditopic receptors that contain two quite different
binding sites, for example a Lewis acidic site and Lewis basic
site.1-3 These compounds are able to bind a single heteroditopic
guest or simultaneously bind two non-identical guests. The
invention of convergent heteroditopic hosts is a challenging
problem in molecular design because the binding sites have to
be incorporated into a suitably preorganized scaffold that holds
them in close proximity, but not so close that the sites interact.
In this contribution we describe the design and synthesis of
bicyclic receptor 1 (Figure 1), as well as an evaluation of its
molecular recognition properties. The design of receptor 1 is
relatively straightforward in the sense that it is a combination
of two well-studied binding systems; a dibenzo-18-crown-6 (B2-
Figure 1. Macrobicyclic receptor 1 and control mixture 7/B218-C-6
with hydrogen numbering scheme.
18-C-6),4 and a bridging 1,3-phenyldicarboxamide.5 The key
structural feature that allows these binding sites to be easily
incorporated into a highly preorganized bicycle is the known
preference of N-methylanilides to adopt a syn conformation.6
Although this conformational effect has been recognized for
some time, it is rarely exploited by synthetic chemists as a way
of producing convergent or juxtaposed binding sites.7
We find that bicycle 1 is a versatile receptor for a range of
salt and neutral molecule guests. Analysis of the supramolecular
complexes using solution-state NMR and X-ray crystallography
shows the basis for the molecular recognition and suggests how
next-generation receptors may be developed as useful molecular
devices.
* Corresponding author. Telephone: 219-631-8632. Fax: 219-631-6652.
E-mail: smith.115@nd.edu.
(1) (a) Schneider, H. J.; Yatsimirski, A. Principles and Methods in
Supramolecular Chemistry; Wiley: Somerset, 2000. (b) Lehn, J. M.
Supramolecular Chemistry; VCH: Weinheim, 1995.
(2) For reviews of ditopic receptors for cations, see: Sutherland, I. O.
In AdVances in Supramolecular Chemistry; Gokel, G. W., Ed.; JAI Press:
Greenwich, 1990; Vol. 1, 65-108. For anions, see: Sessler, J. L.; Sabsom,
P. I.; Andrievsky, A.; Kra´l, V. In The Supramolecular Chemistry of Anions;
Bianci, A., Bowman-James, K., Carcia-Espana, E., Eds.; VCH: Weinheim,
1997; 355-420. For neutral molecules, see: Webb, T. H.; Wilcox, C. S.
Chem. Soc. ReV. 1993, 22, 383-395.
(3) Reetz, M. T. In ComprehensiVe Supramolecular Chemistry; Atwood,
J. L., Davies, J. E. D., MacNicol, D. D., Vo¨gtle, F., Lehn, J.-M., Gokel, G.
W., Eds.; Pergamon: Oxford, 1996; Vol. 2, 553-562.
(4) Cation Binding by Macrocycles; Inoue, Y., Gokel, G. W., Eds.;
Marcel Dekker: New York, 1990.
(5) (a) Kavallieratos, K.; Bertao, C. M.; Crabtree, R. H. J. Org. Chem.
1999, 64, 1675-1683. (b) Hu¨bner, G. M.; Gla¨ser, J.; Seel, C.; Vo¨gtle, F.
Angew. Chem., Int. Ed. 1999, 38, 383-386. (c) Hughes, M. P.; Smith, B.
D. J. Org. Chem. 1997, 62, 4492-4501. (d) Fan, E.; Van Arman, S. A.;
Kincaid, S.; Hamilton, A. D. J. Am. Chem. Soc. 1993, 115, 369-370.
(6) Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.; Shudo, K. J. Am.
Chem. Soc. 1992, 114, 10649-10650.
(7) Krebs, F.; Larsen, M.; Jørgensen, M.; Jensen, P. R.; Bielecki, M.;
Schaumburg, K. J. Org. Chem. 1998, 63, 9872-9879.
10.1021/ja994487r CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

6202 J. Am. Chem. Soc., Vol. 122, No. 26, 2000
Deetz et al.
Scheme 1a
a (a) H2 (30psi), Pd-C, DMF, 98%, (b) 4-nitrobenzoyl chloride, Et3N, CH2Cl2, 99%, (c) NaH, CH3I, DMF, 99%, (d) Fe (powder), HCl, 81%,
(e) corresponding isophthaloyl dichloride, Et3N, CH2Cl2, 55-75 %.
1
Table 1. Change in Receptor H NMR Chemical Shifts (∆δ) upon Guest Extraction
∆δ (ppm)a
receptor
guest
solvent
1
2
3
4
5
6
7
8
9
1a
KCl
DMSO-d6 -0.035 -0.085
0.020
0.238
1.028 0.353 0.008
0.280 0.105 0.011
0.038
0.065
0.040 -0.038
0.066
0.079
0.149
0.035
0.035
0.006
0.015
7 + B218-C-6 KCl
DMSO-d6
toluenesulfonamide CDCl3
toluamide
urea
L-alanine
L-phenylalanine
0.016
0.002
1b
1b
1b
1b
1b
-
-
-
-
-
-0.011 -0.387 -0.206 0.066 0.072
CDCl3
CDCl3
CDCl3
CDCl3
0.064 -0.395
0.130 0.139 0.059 -0.051 -0.094
0.498 0.126 0.000 -0.080 -0.072
0.000 0.037 0.019 -0.003
0.029 0.013 0.017 0.007
0.032
0.014
0.016
0.177
0.028
0.015
0.005 -0.010
0.004 0.006
a See Figure 1 for hydrogen numbering scheme.
Results and Discussion
solution of 1a and extracted KCl was also analyzed by mass
spectrometry. A positive ion FAB mass spectrum showed a peak
at m/z 825 corresponding to the [1a‚K]+ complex, while a
negative ion FAB spectrum exhibited peaks at m/z 785 [1a-
H]-, 821 [1a‚Cl]-, and 859 [1a‚KCl-H]-. No higher binding
stoichiometries were observed. The solid-liquid extraction
experiment was repeated using a control mixture of diamide
75a and B218-C-6 (Figure 1). The smaller changes in receptor
chemical shifts (Table 1) reflect a lower extent of receptor
complexation.13 Thus, the covalently connected heteroditopic
receptor 1a is the superior salt extractant.
Synthesis. The syntheses of receptor analogues 1a and 1b
are described in Scheme 1. The synthetic pathway is notable
because it is short, high yielding, amenable to scale-up, and
highly flexible in terms of structural modification. The pathway
begins with a double nitration of dibenzo-18-crown-6. The
product is an almost equal mixture of cis and trans isomers
which can be readily separated by fractional crystallization.8
For this intitial study the cis isomer, 2, was chosen to continue
the synthesis, however, it is anticipated that the trans isomer
will eventually be utilized as a diastereomeric analogue.
Catalytic hydrogenation of the nitro groups affords the corre-
sponding diamine, 3, which is subsequently coupled with
4-nitrobenzoyl chloride. N-Methylation is achieved in DMF
using sodium hydride and iodomethane to produce 5 in excellent
yield. Catalytic hydrogenation of 5 is not a clean reaction, while
reduction with iron powder in HCl produces 6 in very good
yield. Finally, ring closure to produce 1a or 1b is achieved in
55-75% yield by reaction of 6 with the appropriate isophthaloyl
dichloride under dilute conditions. The success of the ring
closure reaction is attributed to the highly preorganized con-
(10) Earlier examples of salt-binding receptors: (a) Tsukube, H.
Tetrahedron Lett. 1981, 22, 3981-3985. (b) Tsukube, H. J. Chem. Soc.,
Perkin Trans. 1 1982, 2359-2364. (c) Zinic, M.; Frkanec, L.; Skaric, V.;
Trafton, J.; Gokel, G. W. J. Chem. Soc. Chem. Commun. 1990, 1726-
1728. (d) Olsher, U.; Frolow, F.; Dalley, N. K.; Weiming, J.; Yu, Z. Y.;
Knoleoch, J. M.; Bartsch, R. A. J. Am. Chem. Soc. 1991, 113, 6570-6574.
(e) Reetz, M. T.; Niemeyer, C. M.; Harms, K. Angew. Chem., Int. Ed. Engl.
1991, 30, 1474-1476. (f) Arafa, E. A.; Kinnear, K. I.; Lockhart, J. C. J.
Chem. Soc. Chem. Commun. 1992, 61-64. (g) Petit, W.; Iwai, Y.;
Barfknecht, C. F.; Swenson, D. C. J. Heterocycl. Chem. 1992, 29, 877-
881. (h) Flack, S. S.; Chaumette, J.-L.; Kilburn, J. D.; Langley, G. J.;
Webster, M. J. Chem. Soc. Chem. Commun. 1993, 399-400. (i) Badouche,
S.; Jaquet, L.; Lobo-Recio, M. A.; Marzin, C.; Tarrago, G. J. Inclusion
Phenom. 1993, 138, 16, 81-89. (j) Kinnear, K. I.; Mousley, D. P.; Arafa,
E.; Lockhart, J. C. J. Chem. Soc., Dalton Trans. 1994, 3637-3643. (k)
Rudkevich, D. M.; Brzozka, Z.; Palys, M.; Visser, H. C.; Verboom, W.;
Reinhoudt, D. N. Angew. Chem., Int. Ed. Engl. 1994, 33, 467-469. (l)
Savage, P. B.; Holmgren, S. K.; Gellman, S. H. J. Am. Chem. Soc. 1994,
116, 4069-4070. (m) Nagasaki, T. Fujishima, H.; Takeuchi, M.; Shinkai,
S. J. Chem. Soc., Perkin Trans. 1 1995, 1883-1888. (n) Rudkevich, D.
M.; Merca-Chalmers, J. D.; Verboom, W.; Ungaro, R.; de Jong, F.;
Reinhoudt, D. N. J. Am. Chem. Soc. 1995, 117, 6124-6124. (o) Kim, Y.
H.; Calabrese, J. McEwen, C. J. Am. Chem. Soc. 1996, 118, 1545-1546.
(p) Voyer, N.; Gue´rin, B. J. Chem. Soc., Chem Commun. 1997, 2329-
2330. (q) Nabeshima, T.; Hasiguchi, A.; Yazawa, S.; Haruyama, T.; Yano,
Y. J. Org. Chem. 1998, 63, 2788-2789. (r) Beer, P. D.; Dent, S. W. J.
Chem. Soc., Chem. Commun. 1998, 825-826. (s) Cooper, J. B.; Beer, P.
D. J. Chem. Soc., Chem. Commun. 1998, 129-130. (t) Pelizzi, N.; Casnati,
A.; Friggeri, A.; Ungaro, R. J. Chem. Soc., Perkin Trans. 2 1998, 1307-
1311. (u) Redman, J. E.; Beer, P. D.; Dent, S. W.; Drew, M. G. D. J. Chem.
Soc., Chem. Commun. 1998, 231-232. (v) Bryan, J. C.; Sachlebon, R. A.;
Lavis, J. M.; Davis, M. C.; Burns, J. H.; Hay, B. P. Inorg. Chem. 1998, 37,
2749-2755.
formation adopted by the precursor 6.
9-11
Salt Binding.
Receptor 1a was initially examined by
1H NMR for its ability to extract solid KCl into DMSO solution.
The changes in receptor chemical shifts (Table 1) are consistent
with formation of a rapidly exchanging receptor-salt complex.
The largest change is a downfield movement of 1.03 ppm for
the receptor NH protons which is indicative of hydrogen bonding
with a guest chloride ion.12 Comparison of the NH ∆δ with the
solution-state values in Table 2 indicates that receptor 1a extracts
an almost stoichiometric amount of KCl into DMSO. The
(8) Feigenbaum, W. M.; Michel, R. H. J. Polym. Sci., Part A: Polym.
Chem. 1971, 817-820.
(9) Reviews that discuss salt-binding receptors: (a) Antonisse, M. M.
G.; Reinhoudt, D. N. J. Chem. Soc., Chem. Commun. 1998, 443-448. (b)
Kimura, E.; Koike, T. J. Chem. Soc., Chem. Commun. 1998, 1495-1500.
(c) Stibor, I.; Hafeed, D. S. M.; Lhotak, P.; Hodacova, J.; Koca, J.; Cajan,
M. Gazz. Chim. Ital. 1997, 127, 673-685. (d) Reference 3.

Design and Synthesis of Bicyclic Receptor
J. Am. Chem. Soc., Vol. 122, No. 26, 2000 6203
Table 2. Anion Association Constants (M-1) and ΝΗ ∆δMax
(ppm)a
anionb
1a
1a + Na+c
1a + K+c
1a + Cs+c
Cl-
Br-
I-
50 (0.93)
9 (0.18)
,1 (<0.01)
410 (1.16)
470 (1.28)
27 (0.38)
11 (0.03)
60 (0.95)
a T ) 295 K, [1a] ) 10 mM in DMSO-d6/CD3CN (3:1) in the
presence or absence of 1 mol equiv of metal cation. Association
constants are the average of all receptor protons which exhibited
significant complexation-induced shifts; uncertainty (15%. The ∆δmax
values are in parentheses and represent the change in NH chemical
shift after 10 equiv of added anion. b As tetrabutylammonium salt. c As
tetraphenylborate salt.
Figure 2. Change in NH chemical shift (NH ∆δ) for receptor 1a (10
mM) in DMSO-d6/CD3CN (3:1) at 295 K as a function of increasing
amounts of tetrabutylammonium chloride: (0) absence of potassium
tetraphenylborate; (O) presence of 10 mM potassium tetraphenylborate.
A solution-phase complexation study was undertaken to
determine if receptor 1a exhibits binding cooperativity. Experi-
mentally, this was achieved by measuring the effect of alkali
cations on the receptor binding affinities for halide anions. Anion
1
binding constants were determined using standard H NMR
titration curves generated upon addition of tetrabutylammonium
chloride to solutions of 1a in the presence and absence of
potassium tetraphenylborate are shown in Figure 2.
titration methods.14 First, solutions of 1a in DMSO-d6/CD3CN
(3:1) were titrated with the tetrabutylammonium salts of Cl-,
Br-, and I-. The tetrabutylammonium cation is a highly diffuse
cation and does not bind to crown ethers.4 Thus, the binding
constants observed with the tetrabutylammonium salts are
reflective of receptor/anion affinity. As expected, the receptor
amide NH signal underwent large downfield changes in chemi-
cal shift upon anion complexation. Other receptor protons also
exhibited significant complexation-induced shifts. The resulting
titration isotherms fitted nicely to a 1:1 binding model using
established iterative curve-fitting methods.5c,14,15 As described
in Table 2, the order of anion binding constants for host 1a is
Cl- > Br- . I-, a trend that is consistent with that observed
by previous workers using simpler 1,3-phenyldicarboxamide
hosts.5,12 The titrations were repeated in the presence of 1 mol
equiv of either Na+, K+, or Cs+ tetraphenylborate. The NH
In the presence of 1 mol equiv of metal cation, the chloride
affinities were enhanced in the following order: K+ (9-fold
enhancement) > Na+ (8-fold enhancement) . Cs+ (no en-
hancement) (Table 2). The enhancement in Cl- binding constant
induced by the presence of K+ is almost the same as that induced
by Na+ which reflects the fact that in polar aprotic solvents
such as DMSO and acetonitrile, dibenzo-18-crown-6 derivatives
have about the same affinity for these two metal cations.16,17
The largest cooperative effect occurs when K+ is present during
the titration with I- (Table 2). This agrees with a trend that
cation-induced cooperative effects increase as the anion becomes
less basic.10t,11a,18 A rationalization of this correlation will be
provided elsewhere.18
Additional information concerning the receptor binding
behavior is gained from the solid-state structure of a 1a‚NaCl
complex (Figure 3). Single crystals were obtained from a
solution of 1a, tetrabutylammonium chloride, and sodium
tetraphenylborate in chloroform/methanol/water solvent. X-ray
analysis shows that a Na+ is complexed within the dibenzo-
18-crown-6 with average Na-O distances of 2.67 Å. The Na+
is also coordinated by an axial water molecule. A Cl- is
hydrogen-bonded to the two receptor NH residues (Cl-N
distances are 3.34 and 3.31 Å; N-H-Cl angles are 152° and
177°) on the exo face of the bridging 1,3-phenyldicarboxamide
such that the distance between the complexed Na+ and Cl- ions
is 7.31 Å. The central cavity of the macrocycle contains either
a chloroform molecule (62% relative occupancy), or two water
molecules (38% relative occupancy) that are not shown. The
molecular dipole of the chloroform is aligned with the dipole
generated by the 1a‚NaCl complex. Thus, in the solid-state,
receptor 1a prefers to bind NaCl as a solvent-shared ion pair.19
It is worth noting that Moyer and co-workers recently described
a tetrabenzo-24-crown-8 host that binds cesium nitrate as a
solvent-separated ion pair.11m It is possible that many salt-
binding systems work this way, and it may be useful to consider
this feature in future receptor designs.
(11) Recent examples of salt-binding receptors: (a) Beer, P. D.; Hopkins,
P. K.; McKinney, J. D. J. Chem. Soc., Chem. Commun. 1999, 1253-1254.
(b) Kubik, S. J. Am. Chem. Soc. 1999, 121, 5846-5855. (c) Barboiu, M.
D.; Hovnanian, N. D.; Luca, C.; Cot, L. Tetrahedron 1999, 55, 9221-
9232. (d) Chrisstoffels, L. A. J.; De Jong, F.; Reinhoudt, D. N.; Sivelli, S.;
Gazzola, L.; Casnati, A.; Ungaro, R. J. Am. Chem. Soc. 1999, 121, 10142-
10151. (e) White, D. J.; Laing, N.; Miller, H.; Parsons, S.; Coles, S.; Tasker,
P. A. J. Chem. Soc., Chem. Commun. 1999, 2077-2078. (f) Lutzen, A.;
Rebslo, A. R.; Schalley, C. A.; O’Leary, B. M.; Rebek, J. J. Am. Chem.
Soc. 1999, 121, 7455-7456. (g) Kubik, S.; Goddard, R. J. Org. Chem.
1999, 64, 9475-9486. (h) De Wall, S.; Barbour, L. J.; Gokel, G. W.; J.
Am. Chem. Soc. 1999, 121, 8405-8406. (i) Meadows, E. S.; De Wall, S.
L.; Barbour, L. J.; Gokel, G. W. J. Chem. Soc., Chem. Commun. 1999,
1557-1558. (j) Bartoli, S.; Roelens, S. J. Am. Chem. Soc. 1999, 121,
11908-11909. (k) Teramae, N.; Shigemori, K.; Nishizawa, S. Chem. Lett.
1999, 1185-1186. (l) Andrisano, V.; Gottarelli, G.; Masiero, S.; Heijne,
E. H.; Pieraccini, S.; Spada, G. P. Angew. Chem., Int. Ed. 1999, 38, 2386-
2388. (m) Levitskaia, T. G.; Bryan, J. C.; Saclebon, R. A.; Lamb, J. D.;
Moyer, B. A. J. Am. Chem. Soc. 2000, 122, 554-562. (n) Kavallieratos,
K.; Sachleben, R. A.; Van Berkel, G. J.; Moyer, B. A. J. Chem. Soc., Chem.
Commun. 2000, 187-188.
(12) The fact that 1b is a selective receptor for DMSO explains a couple
of curious observations concerning its anion binding ability. First the anion
association constants determined for 1a in DMSO (Table 2) are unusually
low.5 This is because the DMSO is more than just a polar solvent, it directly
competes for the receptor binding site. This also explains why the NH ∆δ
values upon anion binding are also relatively small;5a the binding of anion
to 1a in DMSO involves displacement of a hydrogen-bonded DMSO
molecule, and thus the receptor NH chemical shift is not greatly changed.
(13) A control titration of 7 with N(Bu)4Cl in DMSO shows that the
NH signal for 7 moves about 0.7 ppm downfield when it is saturated with
Cl-. Thus, the NH ∆δ of 0.28 ppm observed upon treatment of a DMSO
solution of 7/B218-crown-6 with excess solid KCl (Table 1) indicates that
the 7/B218-crown-6 mixture extracts about 0.4 mol equiv of KCl.
(14) Kelly, T. R.; Kim, M. H. J. Am. Chem. Soc. 1994, 116, 7072-
7080.
Neutral Molecule Binding. During the above NMR titration
studies, we noticed that receptor 1a appeared to associate
(16) De Jong, F.; Reinhoudt, D. N. In AdVances in Physical Organic
Chemistry; Gold, V., Bethell, D., Eds.; Academic Press: London, 1980; p
307.
(17) Hofmanova, A.; Koryta, J.; Brezina, M.; Mittal, M. L. Inorg. Chim.
Acta 1978, 28, 73-80.
(18) Shukla, R.; Kida, T.; Smith, B. D. Unpublished results.
(19) Muller, P. Pure Appl. Chem. 1994, 66, 1077-1184.
(15) Wilcox, C. S. In Frontiers in Supramolecular Organic Chemistry
and Photochemistry; Schneider, H.-J., Du¨rr, H., Eds.; VCH: Weinham,
1991; 123-143.

6204 J. Am. Chem. Soc., Vol. 122, No. 26, 2000
Deetz et al.
Figure 4. Change in NH chemical shift (NH ∆δ) for receptor 1b (10
mM) in CDCl3 at 295 K as a function of increasing amounts of: (O)
DMSO; (0) acetone; (4) methylphenylsulfoxide.
Table 3. Association Constants, Ka, and ΝΗ ∆δmax
a
receptor/guest
Ka (M-1
)
∆δmax (ppm)b
1b/DMSO (1.3 mM H2O)
1b/DMSO (5 mM H2O)
1b/DMSO (15 mM H2O)
1b/methylphenyl sulfoxide
1b/dimethyl sulfone
1b/acetonitrile
1b/nitromethane
1b/acetone
1b/malononitrile
160
160
150
30
9
0.38
0.38
0.38
0.48
-0.29
-0.17
<-0.1
<0.01
c
2
<1
,1
c
10/DMSO
70
0.23
a Ιn CDCl3, T ) 295 K, [receptor] ) 10 mM. Association constants
are the average of all receptor protons which exhibited significant
complexation-induced shifts; uncertainty (20%. b The change in
chemical shift of the NH protons after 20 equiv of added guest.
c Precipitate formed.
Figure 3. Front and side views of the X-ray crystal structure of
[1a‚Na+‚CHCl3‚Cl-] showing 50% probability ellipsoids. Absent are
disordered solvent molecules found in the lattice voids away from the
macrocyclic cavity.
Scheme 2a
strongly with the DMSO cosolvent.12 Although the literature
contains a number of crystal structures of compounds complexed
with DMSO,20 to the best of our knowledge there is no example
of a receptor that selectively binds DMSO in organic solution.21
Therefore, the chloroform-soluble analogue 1b was prepared
and examined by 1H NMR for its ability to associate with polar
aprotic guests. Titration isotherms were generated and fitted to
a 1:1 binding model using iterative curve fitting methods.5c,14,15
As reflected by Figure 4, receptor 1b is unusually selective for
DMSO in CDCl3 solution. Crown ethers typically have a higher
affinity for acetonitrile and nitromethane than for DMSO,22 but
in this case the trend is strongly reversed (Table 3). The com-
plexation-induced shifts indicate deep inclusion of the DMSO
into the receptor cavity. For example, the NH signal for 1b
moves 0.38 ppm downfield upon saturation with DMSO guest,
and conversely, the DMSO methyl signal is 0.21 ppm upfield
a (a) H2 (30psi), Pd-C, THF, 100%, (b) 5-tert-butylisophthaloyl
dichloride, Et3N, THF, 59%.
when it is saturated with receptor. Further evidence in favor of
a heteroditopic interaction is the observation that control macro-
cycle 10 (Scheme 2) binds DMSO with less than half of the
affinity of 1b (Table 3). In this case, the DMSO methyl signal
is essentially unchanged when it is saturated with receptor 10.
Additional binding information was gained from an X-ray
crystal structure of the 1a‚DMSO complex (Figure 5). The
structure shows that the DMSO is located at a definite position
inside the receptor cavity, but the sulfur atom is disordered
between two sites on either side of the triangle formed by the
oxygen and the two carbon atoms. The DMSO oxygen is
hydrogen-bonded to a water molecule (O-O distance of 2.64
Å) that in turn is hydrogen-bonded to the host NH residues
(O-N distances are 3.08 and 2.98 Å; N-H-O angles are both
177°). One of the DMSO methyl groups is bonded to the crown
ether through a set of C-H-O interactions (average C-O
distances of 3.41 Å)20a and resides in the shielding cone of the
crown benzo groups, while the other methyl points away from
the host cavity.
(20) (a) Wijaya, K.; Moers, O.; Blaschette, A.; Jones, P. G. Acta
Crystallogr., 1998, C54, 1707-1710. (b) Bhattacharyya, P.; Slawin, A. M.
Z.; Smith, M. B.; Williams, D. J.; Woollins, J. D. J. Chem. Soc., Dalton
Trans. 1996, 3647-3651. (c) Helgeson, R. C.; Paek, K.; Knobler, C. B.;
Maverick, E. F.; Cram, D. J. J. Am. Chem. Soc. 1996, 118, 5590-5604.
(d) Daitch, C. E.; Hampton, P. D.; Duesler, E. N. Inorg. Chem. 1995, 34,
5641-5645. (e) Reichwein, A. M.; Verboom, W.; Harkema, S.; Spek, A.
L.; Reinhoudt, D. N. J. Chem. Soc., Perkin Trans. 2 1994, 1167-1172. (f)
Furphy, B. M.; Harrowfield, H. J. M.; Ogden, M. I.; Skelton, B. W.; White,
A. H.; Wilner, F. R. J. Chem. Soc., Dalton Trans. 1989, 2217-2221. (g)
Harata, K. Bull. Chem. Soc. Jpn. 1978, 51, 1644-1648.
(21) Binding of DMSO in aqueous solvent has been reported: Fujimoto,
T.; Yanagihara, R.; Kobayashi, K.; Aoyama, Y. Bull. Chem. Soc. Jpn. 1995,
68, 2113-2124.
(22) (a) Izatt, R. M.; Bradshaw, J. S.; Pawlak, K.; Bruening, R. L.; Tarbet,
B. J. Chem. ReV. 1992, 92, 1261-1354. (b) Izatt, R. M.; Pawlak, K.;
Bradshaw, J. S.; Bruening, R. L. Chem. ReV. 1995, 95, 2529-2586.

Design and Synthesis of Bicyclic Receptor
J. Am. Chem. Soc., Vol. 122, No. 26, 2000 6205
liquid extraction studies (Table 1) show that 1b can dissolve
and strongly bind urea, primary amides, and primary sulfon-
amides in CDCl3, but not dissolve amino acids. The changes in
host 1H NMR chemical shifts indicate that the extracted guests
are deeply included in the host cavity, although it appears that
the host-guest orientations vary (e.g., compare toluenesulfona-
mide to toluamide in Table 1).
Future Studies. The syntheses of analogues 1a and 1b from
precursor 2 demonstrate how easily the receptor bridging unit
can be modified to produce receptors for a range of neutral and
salt guests. In addition, a number of chiral dibenzocrown ethers
are known,26 and thus there appears to be a variety of ways of
modifying the scaffold and building enantioselective receptors.
For example, efforts are underway to produce an enantioselective
methyl sulfoxide receptor which can be used as a resolving
agent. Examination of the X-ray crystal structures in Figures 3
and 5 suggests that it should be possible to use bicycle 1 as a
“wheel” to generate novel rotaxanes. An attractive approach is
the trapping method using anionic templates, described recently
by Seel and Vo¨gtle.27,28 As salt-binding receptors, bicycle 1 and
its later-generation derivatives should be useful in a range of
applications such as selective extraction, membrane transport,
chemosensing, homogeneous catalysis, and phase-transfer ca-
talysis.1
Experimental Section
Materials. All salts and NMR solvents were purchased from Aldrich
and, after being checked for purity, were used as supplied. K(BPh)4
was synthesized according to a literature procedure.29
cis-Di(nitrobenzo)-18-crown-6, 2.8 Dibenzo-18-crown-6 (5.19 g,
14.4 mmol) was dissolved in CHCl3 (104 mL). Acetic acid (78 mL)
was added to the solution over 10 min, which was then stirred at room
temperature for an additional 5 min. A solution of HNO3 (3.6 mL) in
acetic acid (10.4 mL) was added via dropping funnel over 15-20 min.
The solution was stirred at room temperature for 1 h and then heated
to reflux for 3 h whereupon a precipitate formed. The solution was
cooled, and the precipitate (predominantly the trans isomer) was filtered
(2.85 g, 6.33 mmol, 44%, mp 237-242 °C, lit.8 247-252 °C). Upon
sitting for a further 48 h, the cis isomer precipitated from the mother
liquor (2.56 g, 5.69 mmol, 40%, mp 203-205 °C, lit.8 206-232 °C).
Each compound was isolated as a pale yellow solid. The combined
yield was 84%. Residual acetic acid was removed by dissolving the
sample in DMF followed by addition of water to precipitate pure 2. 1H
NMR (300 MHz, DMSO-d6) δ 3.85 (m, 8H), 4.21(m, 8H), 7.15 (d,
2H, J ) 9 Hz), 7.72 (d, 2H, J ) 2.7 Hz), 7.89 (dd, 2H, J ) 9, 2.7 Hz).
13C NMR (75 MHz, DMSO-d6) δ 153.8, 147.7, 140.6, 117.6, 111.3,
106.6, 68.4, 68.0. IR (KBr) (ν, cm-1) 3638.7, 3435.2, 3093.1, 2954.9,
2886.6, 1591.2, 1502.0, 1336.2, 1230.9, 1129.5, 1055.9, 807.6, 744.8.
MS (FAB+) exact mass calcd for C20H22N2O10 [M + H]+ 451.1353,
found 451.1333.
Figure 5. Front and side views of the X-ray crystal structure of [1a‚
DMSO‚H2O] showing 50% probability ellipsoids. The front view shows
how the included DMSO is disordered.
Although a bridging water molecule is observed in the solid-
state it does not appear to be present or necessary for solution-
phase complexation for two reasons. (i) Receptor 1b has a weak
affinity for water in CDCl3. For example, addition of 15 mM
of water induces essentially no change in the receptor NH
chemical shift. (ii) The observed DMSO/1b association constant
in CDCl3 is unchanged when the water/1b ratio is systematically
changed from 0.13 to 1.5 (Table 3).23 The solid-state structure
in Figure 5 indicates that if receptor 1b maintains the same
conformation in solution then, in the absence of water, an
included DMSO molecule would be unable to simultaneously
contact the NH resides at the top of the 1b cavity and the crown
ether oxygens at the bottom.24 This suggests that in chloroform
solution, the bound DMSO is disordered within the 1b cavity.
The titration isotherms for the different receptor protons are
within experimental error; thus, there is no evidence that the
DMSO prefers to associate with one part of the receptor cavity
over another.25 A corollary of this solution-state binding model
is that bicycle 1b may be a good receptor for slightly larger
heteroditopic guests. Thus, 1b was examined for its ability to
associate with other types of neutral polar compounds. Solid-
cis-Di(aminobenzo)-18-crown-6, 3. cis-Di(nitrobenzo)-18-crown-
6, 2, (0.78 g, 1.73 mmol) was dissolved in hot DMF (70 mL). The
solution was degassed using argon, then 10% Pd/C (0.156 g) was added
and the flask placed in a pressurized hydrogenation apparatus. The
chamber was charged with H2 (30 psi) and shaken for 1 h and 45 min.
The mixture was filtered through a silica gel/Celite plug and the solvent
removed in vacuo. Compound 6 was isolated as a tan solid (0.640 g,
1
1.64 mmol, 98%, mp 178-182 °C, lit.8 180-184 °C). H NMR (300
MHz, DMSO-d6) δ 3.73-3.82 (m, 8H), 3.89-3.98 (m, 8H), 4.65 (bs,
4H), 6.05 (dd, 2H, J ) 8.4, 2.4 Hz), 6.23 (d, 2H, J ) 2.3 Hz), 6.62 (d,
(23) For a discussion of the effects of water on hydrogen-bonding systems
in chloroform, see: Adrian, J. C., Jr.; Wilcox, C. S. J. Am. Chem. Soc.
1991, 113, 678-680.
(26) Zhang, X. X.; Bradshaw, J. S.; Izatt Chem. ReV. 1997, 97, 331-
3361.
(24) It is possible that the solid-state structure is not maintained in
solution. An attractive alternative is a host/guest complex that has the DMSO
oxygen in contact with the receptor NH residues and both DMSO methyl
groups involved in CH-π interactions with the aromatic rings lining the
receptor cavity. This binding model is supported by the upfield complexation
induced shift of 0.21 ppm for the DMSO methyl groups.
(25) For a recent example of a disordered host/guest system studied by
NMR see ref 11 g.
(27) Seel, C.; Vo¨gtle, F. Chem. Eur. J. 2000, 6, 21-24.
(28) In the period since manuscript submission, we have successfully
prepared a rotaxane using bicycle 1b as the “wheel”. Mass spectrometry
experiments indicate that the rotaxane can bind metal cations but it is unable
to bind anions. Shukla, R.; Deetz, M. J.; Smith, B. D. Unpublished results.
(29) Honda, H.; Ono, K.; Murakami, K. Macromolecules 1990, 23, 515-
520.

6206 J. Am. Chem. Soc., Vol. 122, No. 26, 2000
Deetz et al.
2H, J ) 8.5 Hz). 13C NMR (75 MHz, DMSO-d6) δ 149.1, 143.4, 139.2,
115.6, 105.4, 100.8, 69.2, 69.2, 69.0, 67.6. MS (FAB+) exact mass
calcd for C20H26N2O10 [M + H]+ 390.1791, found 390.1778.
J ) 8.2 Hz), 4.10 (bs, 4H), 3.85 (bs, 8H), 3.72 (bs, 4H), 3.30 (s, 6H)
ppm. 13C NMR (75 MHz, DMSO-d6) δ 169.7, 164.2, 147.8, 146.5,
139.0, 137.5, 134.0, 132.2, 131.4, 128.5, 125.7, 120.7, 120.1, 119.1,
111.9, 111.0, 68.8, 67.6, 67.1, 37.5 ppm. MS (FAB+) exact mass calcd
for C44H43N4O10 [M + H]+ 787.2979, found 787.2947.
cis-Di((4-nitrophenylcarboxamido)benzo)-18-crown-6, 4. Di(ami-
nobenzo)-18-crown-6, 3, (0.50 g, 1.29 mmol) was dissolved in CH2-
Cl2 (50 mL) along with triethylamine (376 µL, 2.7 mmol, 2.1 equiv),
and the solution stirred for 5 min at room temperature under an
atmosphere of argon. 4-Nitrobenzoyl chloride (0.5 g, 2.7 mmol, 2.1
equiv, recently recrystallized from hexanes) was added as a solution
in CH2Cl2 via dropping funnel over 10 min. A bright yellow precipitate
formed immediately. The solution was stirred for 3 h, filtered, and rinsed
with CH2Cl2, and 4 was isolated as a yellow-brown solid (0.82 g, 99%,
tert-Butyl Macrobicycle 1b. To a solution of compound 6 (0.063
g, 0.096 mmol), and triethylamine (29 µL, 0.21 mmol) dissolved in
anhydrous CH2Cl2 (50 mL) was added a solution of 5-tert-butylisoph-
thaloyl dichloride (0.025 g, 0.096 mmol) dissolved in anhydrous CH2-
Cl2 (50 mL) via dropping funnel over 2 h at room temperature. The
mixture was heated overnight under an atmosphere of argon. The
solvent was removed leaving a white solid. Chromatography on silica
(90:9:1 CHCl3/MeOH/H2O, Rf ) 0.17) yielded 1b as a glass (0.060 g,
1
mp > 260 °C). H NMR (300 MHz, DMSO-d6) δ 3.84 (m, 8H), 4.06
1
0.071 mmol, 75%). H NMR (300 MHz, DMSO-d6) δ 9.94 (s, 2H),
(m, 8H), 6.94 (d, 2H, J ) 9 Hz), 7.32 (dd, 2H, J ) 9, 2 Hz), 7.44 (d,
2H, J ) 2 Hz), 8.16 (d, 4H, J ) 9 Hz), 8.35 (d, 4H, J ) 9 Hz), 10.41
(s, 2H). 13C NMR (75 MHz, DMSO-d6) δ 163.4, 149.1, 147.6, 144.7,
140.7, 132.1, 129.1, 123.5, 112.5, 112.2, 68.9, 68.9, 67.8, 67.6. MS
(FAB+) exact mass calcd for C34H32N4O12 [M + H]+ 689.2095, found
689.2123.
8.40 (s, 1H), 8.06 (s, 2H), 7.56 (d, 4H, J ) 8.5 Hz), 7.28 (d, 4H, J )
8.7 Hz), 7.06 (d, 2H, J ) 2.1 Hz), 6.64 (d, 2H, J ) 8.6 Hz), 6.41 (d,
2H, J ) 8.5 Hz, 2.1 Hz), 4.09 (bs, 4H), 3.85 (bs, 8H), 3.71 (bs, 4H),
3.29 (s, 6H), 1.34 (s, 9H) ppm. 13C NMR (75 MHz, DMSO-d6) δ 169.6,
164.3, 151.9, 147.8, 146.5, 138.9, 138.8, 137.4, 133.9, 132.1, 128.5,
127.9, 123.1, 120.1, 119.0, 118.9, 111.9, 111.1, 68.8, 67.6, 67.1, 37.4,
34.6, 30.8 ppm. MS (FAB+) exact mass calcd for C44H42N5O12 [M +
H]+ 832.2830, found 832.2828.
cis-Di((N-methyl-4-nitrophenylcarboxamido)benzo)-18-crown-
6, 5. Compound 4 (0.50 g, 0.73 mmol) was dissolved in warm,
anhydrous DMF (100 mL). Sodium hydride (0.33 g, 8.3 mmol, ∼12
equiv, 60% dispersion in mineral oil) was added to the solution all at
once. The yellow-brown solution turned a deep red color. The solution
was stirred at room temperature for 10 min under an atmosphere of
argon. Methyl iodide (230 µL, 3.6 mmol, ∼5 equiv) was added over 5
min. The solution was stirred for 30 min, and a color change from
deep red to a pale brown color was observed. The solution was
quenched with saturated NH4Cl (aqueous) and poured into a separatory
funnel containing water (100 mL) and EtOAc (100 mL). The aqueous
layer was extracted twice with EtOAc. The combined organic layers
were dried over MgSO4, and the solvent was removed in vacuo. The
mineral oil was removed by washing with hexanes. The residual brown
oil was chromatographed (90:9:1 CHCl3/MeOH/H2O, Rf ) 0.33),
yielding 5 as a yellow syrup (0.54 g, 0.73 mmol, 99%, mp 86-90 °C).
1H NMR (300 MHz, CDCl3) δ 3.46 (s, 6H), 3.94-3.88 (m, 12H), 4.07-
4.04 (m, 4H), 6.54 (m, 4H), 6.63 (d, 2H, J ) 8 Hz), 7.43 (d, 4H, J )
8.6 Hz), 8.03 (d, 4H, J ) 8.6 Hz). 13C NMR (75 MHz, CDCl3) δ 168.3,
148.8, 147.8, 147.7, 142.3, 136.7, 129.2, 123.0, 119.6, 112.4, 69.5,
69.4, 69.4, 68.5, 68.4, 68.3, 68.2, 38.4. MS (FAB+) exact mass calcd
for C36H36N4O12 [M + H]+ 717.2408, found 717.2453.
Triethyleneglycol Di(3-nitrobenzoyl) Ester, 8. 3-Nitrobenzoyl
chloride (0.21 g, 1.1 mmol) and triethylamine (0.34 mL, 2.5 mmol)
were dissolved in CH2Cl2 (10 mL). Triethylene glycol (0.07 mL, 0.5
mmol) was added via dropping funnel as a solution in CH2Cl2 (5 mL)
over 5 min. The mixture was heated to reflux under an atmosphere of
argon for 30 min, cooled, washed twice with 0.5 M HCl (aqueous),
then saturated NaCO3 (aqueous), and finally with water. The organic
phase was dried over MgSO4. Removal of the solvent gave a yellow
oil which was chromatographed on silica (1:1 EtOAc/hexanes, Rf )
1
0.23) yielding 8 as a clear oil (0.11 g, 0.25 mmol, 50%). H NMR
(300 MHz, CDCl3) δ 8.85 (s, 2H), 8.40 (d, 2H, J ) 8.0 Hz), 8.38 (d,
2H, J ) 8.0 Hz), 7.65 (t, 2H, J ) 7.5 Hz), 4.53 (t, 2H, J ) 4.0 Hz),
3.87 (t, 2H, J ) 4.2 Hz), 3.72 (s, 4H) ppm. 13C NMR (75 MHz, CDCl3)
δ 164.2, 148.1, 135.2, 131.7, 129.5, 127.3, 124.4, 70.6, 68.9, 64.7 ppm.
MS (FAB+) mass calcd for C20H20N2O10 [M + H]+ 449, found 449.
Triethyleneglycol Di(3-aminobenzoyl) Ester, 9. Compound 8 (0.44
g, 1 mmol) was dissolved in THF (15 mL). Pd-C (0.1 g) was added,
and the flask was charged with H2 (∼1 atm) after 3.25h the reaction
was filtered through a Celite/silica gel plug and the solvent removed
1
in vacuo leaving 9, (0.39 g, 1 mmol) as a clear oil. H NMR (300
cis-Di((N-methyl-4-aminophenylcarboxamido)benzo)-18-crown-
6, 6. Compound 5 (0.31 g, 0.43 mmol) was dissolved in concentrated
HCl (10 mL). Iron powder (∼0.3 g) was added to the solution and the
flask swirled. The flask was placed in a oil bath at 80 °C with occasional
swirling until the bubbling subsided and the liquid became transparent.
The residual iron was removed by extraction with a magnetic stir bar.
The mixture was poured into a separatory funnel with ice and
concentrated NaOH (aqueous) was added until a gray precipitate
persisted. The aqueous layer was extracted six times with EtOAc. The
combined organic layers were dried over MgSO4, and removal of the
solvent yielded 6 as a white solid (0.23 g, 0.35 mmol, 81%, dec 117
MHz, CDCl3) δ 7.42 (ddd, 2H, J ) 1.0, 1.5, 8.0 Hz), 7.34 (dd, 2H, J
) 1.9, 2.2 Hz), 7.18 (t, 2H, J ) 7.6 Hz), 6.83 (ddd, 2H, J ) 1.0, 2.5,
8.0 Hz), 4.41-4.44 (m, 4H), 3.90 (bs, 4H), 3.79-3.82 (m, 4H), 3.70
(s, 4H) ppm. 13C NMR (75 MHz, CDCl3) δ 166.7, 146.5, 131.0, 129.2,
119.7, 119.4, 115.8, 70.7, 69.2, 64.0 ppm. MS (FAB+) mass calcd for
C20H24N2O6 [M + H]+ 389, found 389.
Control Macrocycle 10. A three-necked flask was equipped with
two dropping funnels and charged with THF (40 mL). The addition
funnels were charged with solutions of compound 9 (0.12 g, 0.32 mmol)
and Et3N (0.1 mL, 0.7 mmol) in THF (50 mL) and 5-tert-butylisoph-
thaloyl dichloride (0.08 g, 0.32 mmol) in THF (50 mL), with the
contents emptied concurrently over a period of 1 h. The mixture was
stirred overnight under an atmosphere of argon. The solution was
filtered to remove some Et3N‚HCl and the solvent removed in vacuo.
Chromatography on silica (1:1 EtOAc/hexanes f 100% EtOAc) yielded
10 (0.1 g, 0.19 mmol, 59%, mp >260 °C) as a white solid. Rf (1:1
EtOAc/hexanes) ) 0.16. 1H NMR (300 MHz, CDCl3) δ 9.44 (bs, 2H),
8.93 (d, 2H, J ) 7.5 Hz), 7.95 (t, 2H, J ) 8.0 Hz), 7.85 (bs, 2H), 7.81
(d, 2H, J ) 7.9 Hz), 7.69 (bs, 1H), 7.62 (bs, 2H), 4.52 (m, 4H), 3.98
(bs, 4H), 3.87 (s, 4H), 1.01 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3)
δ 166.7, 166.2, 151.8, 138.5, 133.8, 130.7, 130.5, 127.9, 125.7, 123.1,
121.6, 119.7, 70.9, 70.4, 65.3, 34.4, 30.5 ppm. MS (FAB+) exact mass
calcd for C32H34N2O8 [M + H]+ 575.2393, found 575.2417.
1
°C). H NMR (300 MHz, CDCl3) δ 3.26 (s, 6H), 3.71 (m, 4H), 3.77
(m, 4H), 3.91 (m, 4H), 3.98 (m, 4H), 5.32 (bs, 4H), 6.31 (d, 4H, J )
8.6 Hz), 6.54 (dd, 2H, J ) 8.5, 2.3 Hz), 6.72 (d, 2H, J ) 2.4 Hz), 6.77
(d, 2H, J ) 8.6 Hz), 6.96 (d, 4H, J ) 8.7 Hz). 13C NMR (75 MHz,
CDCl3) δ 170.5, 148.4, 146.7, 139.2, 130.8, 124.6, 119.2, 113.4, 112.4,
111.9, 69.5, 69.4, 68.3, 68.2, 38.8. MS (FAB+) mass calcd for
C36H41N4O8 [M + H]+ 657, found 657.
Macrobicycle 1a. To a solution of compound 6 (0.097 g, 0.15
mmol), and triethylamine (45µL, 0.33 mmol) dissolved in anhydrous
CH2Cl2 (150 mL), was added a solution of isophthaloyl dichloride
(0.031 g, 0.15 mmol) dissolved in anhydrous CH2Cl2 (75 mL) via
dropping funnel over 3 h at room temperature. The mixture was heated
overnight under an atmosphere of argon. The solvent was removed
leaving a white solid. Chromatography on silica (190:9:1 f 90:9:1
CHCl3/MeOH/H2O) yielded 1 as a white solid (0.064 g, 0.081 mmol,
Extraction Studies. Solutions of receptors in appropriate deuterated
1
solvents were prepared (∼1 mM) in 5 mm NMR tubes. An initial H
1
55%, mp >260 °C). Rf (90:9:1 CHCl3/MeOH/H2O) ) 0.17. H NMR
NMR spectrum was acquired for each tube. Insoluble guests were added
in excess as powders, and the NMR tubes were shaken for 5 min and
then incubated for 15 h at room temperature. The NMR spectra were
acquired and the change in receptor chemical shifts extracted from the
(300 MHz, DMSO-d6) δ 10.00 (s, 2H), 8.57 (s, 1H), 8.05 (d, 2H, J )
7.7 Hz), 7.65 (t, 1H, J ) 7.8 Hz), 7.57 (d, 4H, J ) 8.6 Hz), 7.29 (d,
4H, J ) 8.5 Hz), 7.06 (s, 2H), 6.64 (d, 2H, J ) 8.5 Hz), 6.40 (d, 2H,

Design and Synthesis of Bicyclic Receptor
J. Am. Chem. Soc., Vol. 122, No. 26, 2000 6207
following formula: ∆δ ) δfinal - δinitial. In the case of KCl extraction,
the % of receptor that was bound to KCl was determined from the NH
∆δ values.13
ylborate in chloroform/methanol/water solvent. Crystallographic sum-
mary: [1a‚NaCl‚2.62CHCl3‚2.14H2O‚0.31C6H14], Mr ) 1223.29, mon-
oclinic, P21/n, Z ) 4 in a cell of dimensions a ) 14.075(2) Å, b )
17.906(7) Å, c ) 23.885(3) Å, â ) 106.455(17)°, V ) 5773(3) Å3,
Fcalc ) 1.407 mg M-3, F(000) ) 2523. The structure was refined on
F2 to a Rw ) 0.2408, with a conventional R ) 0.0925 (5166 reflections
with I > 2σ(I)), and a goodness of fit ) 1.06 for 724 refined parameters.
Hydrogen atoms were restrained using riding models or by bond length
restraints.
X-ray Structure of 1a‚DMSO. Single crystals were obtained from
slow cooling of 1a in DMSO. Crystallographic summary: monoclinic,
[1a‚1.5DMSO‚2H2O], Mr ) 940.04, C2/c, Z ) 8 in a cell of dimensions
a ) 38.531(3) Å, b ) 14.1236(10) Å, c ) 17.5199(17) Å, â ) 102.880-
(3)°, V ) 9294.4(13) Å3, Fcalc ) 1.344 mg M-3, F(000) ) 3976. The
structure was refined on F2 to a Rw ) 0.2165, with a conventional R )
0.0856 (5419 reflections with I > 2σ(I)), and a goodness of fit ) 0.989
for 631 refined parameters. All non-amide hydrogens were restrained
using riding models, while the amide hydrogens restrained by bond
length.
1H NMR Titrations. Salt-Binding. Receptor 1a was titrated with
tetrabutylammonium halide in the presence and absence of alkali
tetraphenylborate. In each case, a 10 mM solution of 1a in DMSO-
d6/CD3CN (3:1) was prepared in a 5 mm NMR tube (solution volume
750 µL). Where applicable the solution also contained 1 mol equiv of
alkali tetraphenylborate. Small aliquots of tetrabutylammonium halide
stock solution (0.75 M) were added, and a spectrum was acquired after
each addition. Care was taken to avoid water absorption from the
atmosphere. The concentrations and equivalents were adjusted to give
the optimum change in Weber p values (0.2-0.8).15 The total volume
of added guest solution was 100 µL or 10 mol equiv. Titration isotherms
for all receptor protons that exhibited significant complexation-induced
shifts (usually the signals corresponding to H3, H4, and H5; see Figure
1) were fitted to a 1:1 binding model using an iterative curve-fitting
method that has been previously described.5c For each system the
extracted association constants for the different isotherms were always
within 15% of the average value.
Neutral Molecule-Binding. Receptor 1b (10mM) was titrated with
neutral guest in CDCl3 (750 µL). Aliquots of guest stock solution (0.75
M) were added, and a spectrum was acquired after each addition. The
total volume of added guest was 200 µL or 20 mol equiv. Titration
isotherms for all receptor protons that exhibited significant complex-
ation-induced shifts (generally the signals corresponding to H3, H4,
and H5; see Figure 1) were fitted to a 1:1 binding model using an
iterative curve-fitting method that has been previously described.5c
X-ray Structure of 1a‚NaCl. Single crystals were obtained from a
solution of 1a, tetrabutylammonium chloride, and sodium tetraphen-
Acknowledgment. This work was supported by the National
Science Foundation and the University of Notre Dame (George
M. Wolf and Reilly fellowships for M.J.D.).
Supporting Information Available: NMR spectra of recep-
tors (PDF). X-ray crystal data in CIF format, This material is
available free of charge via the Internet at http://www.pubs.acs.org.
JA994487R