Hydrogen bonding in anion recognition: A family of versatile, nonpreorganized neutral and acyclic receptors

Article abstract of DOI:10.1021/jo982382l

The diamides and disulfonamides m-C₆H₄(CONHAr)₂ (Ar = Ph, 1; p-n-BuC₆H₄, 2, 2,4,6-Me₃C₆H₂, 3), m-C₆H₄(SO₂NHPh)₂, 4, and 2,6

Full text of DOI:10.1021/jo982382l

J . Org. Chem. 1999, 64, 1675-1683
1675
Hyd r ogen Bon d in g in An ion Recogn ition : A F a m ily of Ver sa tile,
Non p r eor ga n ized Neu tr a l a n d Acyclic Recep tor s
Konstantinos Kavallieratos,† Christina M. Bertao, and Robert H. Crabtree*
Chemistry Department, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107
Received December 4, 1998
The diamides and disulfonamides m-C6H4(CONHAr)2 (Ar ) Ph, 1; p-n-BuC6H4, 2, 2,4,6-Me3C6H2,
3), m-C6H4(SO2NHPh)2, 4, and 2,6-C6H3N(CONHPh)2, 5, readily synthesized on a multigram scale,
bind strongly to halides and acetate in organic solvents with Ka’s as high as 6.1 × 104 (NMR
spectroscopy). The binding stoichiometry is 1:1 in solution for all cases except for the 4‚F- and
4‚OAc- complexes, where both 1:1 and 1:2 binding stoichiometries were found. The association
constants in CD2Cl2 (1H NMR) follow the trend Cl- > Br- > I- for all the receptors. F- and OAc-
binding may be stronger or weaker than Cl- depending on the nature of the receptor. The presence
of the pyridine nitrogen in 5 and of the more rigid amide in 1-3 and 5 vs the less rigid sulfonamide
structure in 4 increases selectivity for smaller anions. The enthalpy and entropy of formation for
2‚Cl- were ∆H ) -31 kJ /mol; ∆S ) -23 J /(mol‚K) (VT-NMR). The X-ray structure of [PPh4]2[1‚
Br][Br]‚CH2Cl2, shows 1:1 complexation of Br- via two N-H‚‚‚Br- hydrogen bonds and a syn-syn
nonplanar binding conformation for 1. Solution hydrogen bonding was confirmed by FT-IR and
NMR spectroscopy. The receptor conformation changes on complexation. Trends in structure/binding
relationships show receptor flexibility is an important factor in anion recognition.
Molecular recognition of cations1 is long established,
but anion binding has only more recently attracted
interest2 for its biomedical3 and environmental4 signifi-
cance. Anion receptors may be useful for phase-transfer
catalysis, separations,5 and anion-selective electrodes,
and several recent reviews6 have appeared. Many such
receptors bind anions tightly and selectively, but they
often have elaborate structures that require multistep
synthesis, and none are commercially available. Many
are poorly soluble in nonpolar organic media, but very
few are also easily synthesized on a large scale and
therefore available for widespread use. Acyclic synthetic
anion receptors are either positively charged7 or contain
Lewis acid centers.8 In the former class, selectivity is
modest owing to the dominance of nondirectional elec-
trostatic interactions.9
† Present address: Oak Ridge National Lab, Bldg. 4500S/MS-6119,
P.O. Box 2008, Oak Ridge, TN 37831-6119.
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10.1021/jo982382l CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/13/1999

1676 J . Org. Chem., Vol. 64, No. 5, 1999
Kavallieratos et al.
Neutral hosts that bind guests exclusively through
hydrogen bonding by pyrrole,10 urea,9b,11 or amide groups12
have recently been developed. Hamilton13-15 and Still16
have reported isophthalamide or urea derivatives as
receptors for nucleotide bases,13 barbiturates,14 dicar-
boxylic acids and dicarboxylates,15 and peptides;16 Davis17
reported triamide and trisulfonamide halide receptors.
No halide binding properties for simple isophthalamides
were reported previously.
using modified versions of reported20 procedures. They
were purified by recrystallization from benzyl alcohol (1),
methanol (2, 4, 5), or ethanol (3). The new compounds 2
and 3 as well as 421 were characterized by FT-IR, and
1H NMR, and elemental analysis or high-resolution mass
spectra. The known compounds 120 and 522 gave spectro-
scopic data identical to those reported.21b
Preorganization generally increases selectivity but
limits synthetic accessibility. Here we look at a minimally
preorganized system available in one step to test if two
properly located amide or sulfonamide groups can give
selective anion binding. We now report anion receptors
that are not only efficient and selective but also easily
available and soluble in organic solvents and therefore
widely applicable.
As part of our studies on hydrogen bonding,18 we
recently reported the halide receptors 1 and 2 in a
communication19 and now report in full on these and on
the related receptors 3-5, also extending our studies to
fluoride and acetate. All the receptors have a meta
arrangement of two hydrogen-bonding groups, but they
differ in the nature of the groups, in the rigidity of
the skeleton, and in being alicyclic or heterocyclic. The
study of anion binding properties of receptors having
slightly different structures with five different anions
allows us to demonstrate the importance of hydrogen
bonding for anion recognition in these systems as well
as to interpret the relationship between certain receptor
structural features and the strength and selectivity of
anion binding.
Resu lts a n d Discu ssion
Syn th esis of Recep tor s 1-5. Compounds 1-5 are
available in good yields from the commercially available
acid dichlorides and the corresponding anilines in DMF
P r elim in a r y 1H NMR a n d 19F NMR Stu d ies. The
less soluble compounds 1, 2, and 5 in a CH2Cl2 suspension
are solubilized by addition of solid Ph4PX salts (X ) Cl-,
Br-, I-, OAc-).23 The 1H NMR spectra of 1-5 also showed
dramatic chemical shift changes upon anion addition. In
particular the N-H protons involved in hydrogen bond-
ing and the 2-C-H protons located close to the anion both
give large downfield shifts (Figure 1). For the other
central ring protons the shifts are smaller. For the aniline
CH’s the chemical shifts are also significant, particularly
for the ortho 2-C-H, which gives a downfield shift.
The sharp 19F NMR resonance for (n-Bu)4NF in CD2-
Cl2 at -117.0 ppm (upfield from CFCl3) broadens into
the baseline on addition of receptors 1-5 in slight excess,
indicating interaction with fluoride.
(10) (a) Sessler, J . L.; Cyr, M.; Furuta, H.; Kral, V.; Mody, T.;
Morishima, T.; Mitsuhiko, S.; Weghorn, S. Pure Appl. Chem. 1993, 65,
393. (b) Sessler, J . L.; Cyr, M.; Lynch, V.; McGhee, E.; Ibers, J . A. J .
Am. Chem. Soc. 1990, 112, 2810. (c) Gale, P. A.; Sessler, J . L.; Kral,
V.; Lynch, V. J . Am. Chem. Soc. 1996, 118, 5140.
(11) (a) Scheerder, J .; Fochi, M.; Engbersen, J . F. J .; Reinhoudt, D.
N. J . Org. Chem. 1994, 59, 7815. (b) Scheerder, J .; van Duynhoven, J .
P. M.; Engbersen, J . F. J .; Reinhoudt, D. N. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1090.
(12) (a) Goswami, S.; Hamilton, A. D.; Van Engen, D. J . Am. Chem.
Soc. 1989, 111, 3425. (b) Hunter, C. A. J . Chem. Soc., Chem. Commun.
1991, 749. (c) Pascal, R. A.; Spergel, J .; Van Engen, D. Tetrahedron
Lett. 1986, 27, 4099.
(13) Hamilton, A. D.; Van Engen, D. J . Am. Chem. Soc. 1987, 109,
5035.
(14) (a) Chang, S. K.; Hamilton, A. D. J . Am. Chem. Soc. 1988, 110,
1318. (b) Chang, S. K.; Van Engen, D.; Fan, E.; Hamilton, A. D. J .
Am. Chem. Soc. 1991, 113, 7640.
(15) (a) Garcia-Tellado, F.; Goswami, S.; Chang, S. K.; Geib, S. J .;
Hamilton, A. D. J . Am. Chem. Soc. 1990, 112, 7393. (b) Fan, E.; van
Arman, S. A.; Hamilton, A. D. J . Am. Chem. Soc. 1993, 115, 369.
(16) (a) Wennemers, H.; Yoon, S. S.; Still, W. C. J . Org. Chem. 1995,
60, 1108. (b) Shao Y.; Still, W. C. J . Org. Chem. 1996, 61, 6086. (c)
Still, W. C. Acc. Chem. Res. 1996, 29, 155.
F T-IR Stu d y. The 1:1 bromide adduct 1‚Br was
crystallized and fully characterized by X-ray diffraction
(see below), and so we were interested in comparing the
solution data with the solid-state material of known
structure, best achieved by FT-IR spectroscopy, a tech-
(17) Davis, A. P.; Perry, J . J .; Williams, R. P. J . Am. Chem. Soc.
1997, 119, 1793.
(18) (a) Lee, J . C., J r.; Peris, E.; Rheingold, A. L.; Crabtree, R. H. J .
Am. Chem. Soc. 1994, 116, 11014. (b) Peris, E.; Lee, J . C., J r.; Rambo,
J . R.; Eisenstein, O.; Crabtree, R. H. J . Am. Chem. Soc. 1995, 117,
3485. (c) Wessel, J .; Lee, J . C., J r.; Peris, E.; Yap, G. P. A.; Fortin, J .
B.; Ricci, J . S.; Sini, G.; Albinati, A.; Koetzle, T. F.; Eisenstein, O.;
Rheingold, A. L.; Crabtree, R. H. Angew. Chem., Int. Ed. Engl. 1995,
34, 2507. (d) Richardson, T. B.; de Gala, S.; Crabtree, R. H. J . Am.
Chem. Soc. 1995, 117, 12875.
(20) Khanna, Y. P.; Pearce, E. M.; Forman, B. D.; Bini, D. A. J .
Polym. Sci. Polym. Chem. Ed. 1981, 19, 2799.
(21) (a) Autenrieth, W.; Hennings, R. Ber. 1902, 1388. (b) Spectro-
scopic characterization for 4 has not been reported previously and is
given in the Experimental Section.
(22) Horino, H.; Sakaba, H.; Arai, M. Synthesis 1989, 715.
(23) For guest effects on host self-assembly see: Meissner, R. S.;
Rebek, J ., J r.; de Mendoza, J . Science 1995, 270, 1485.
(19) Kavallieratos, K.; de Gala, S. R.; Austin, D. J .; Crabtree, R. H.
J . Am. Chem. Soc. 1997, 119, 2325.

Hydrogen Bonding in Anion Recognition
J . Org. Chem., Vol. 64, No. 5, 1999 1677
F igu r e 1. 1H NMR spectra of 3 before (top) and after (bottom) Bu4NF addition (10 equiv).
hydrogen bonded νN-H band at 3430 cm-1 in dilute
nique that has seen limited application in molecular
recognition.24 The solution FT-IR spectral changes of 1
and 2 in CH2Cl2 on Br- addition indicate binding. In
dilute (2, 5 × 10-4 M) CH2Cl2 solution 2 shows a band at
3430 cm-1, assigned to νNH for the free amide, which, on
addition of 1 equiv of Ph4PBr, is replaced by bands at
3228 and 3175 cm-1, consistent with the presence of
coupled hydrogen-bonded N-H groups (Figure 2). FT-
IR spectra (Table 1) for 1, 2, 1‚Br- and 2‚Br- were
measured both in dilute CH2Cl2 solutions and in thin
films, formed by evaporation of a CH2Cl2 solution. The
film data proved to be a useful proxy for solid state
because the IR spectra of the 1‚Br- and 2‚Br- adducts
in thin film and dilute solution proved to be identical and
very similar, respectively, to that of the crystalline form
for 1‚Br- of known structure. The ca. 230 cm-1 low energy
shift in νN-H on going from dilute receptor solution to the
adduct in thin film is consistent with N-H‚‚‚Br hydrogen
bonding.24,25 Unlike the case for the adducts 1‚Br- and
2‚Br-, the FT-IR spectra for pure 1 and 2 both change
on moving from solution to thin film, showing only a non
solution, but only a hydrogen bonded νN-H band at 3305
cm-1 in thin film, characteristic of a self-associated
amide.
These data indicate that (a) the receptors 1 and 2 are
self-associated in the solid state but not in dilute CH2-
Cl2 solutions, probably via N-H‚‚‚OdC hydrogen bonds;
(b) Br- binding occurs for 1 and 2 via N-H‚‚‚Br hydrogen
bonding, both in the solid-state and in solution; and (c)
N-H‚‚‚OdC bonding is not observed in the presence of
Br-, either in solution or in the thin film.
X-r a y Str u ctu r e of 1‚Br -. The 1‚Br- adduct was
successfully crystallized as [PPh4]2[1‚Br][Br]‚CH2Cl2, and
the structure was determined26 by X-ray diffraction
(Table 2). The results, discussed in the communication19
(Figure 3, Table 3,26c and Supporting Information) show
the presence of a 1:1 complex of [1‚Br], of an extra
(24) McQuade, D. T.; McKay, S. L.; Powell, O. R.; Gellman, S. H. J .
Am. Chem. Soc. 1997, 119, 8528.
(25) J effrey, G. A.; Saenger, W. Hydrogen Bonding in Biological
Structures; Springer: Berlin, 1994.

1678 J . Org. Chem., Vol. 64, No. 5, 1999
Kavallieratos et al.
F igu r e 2. Solution FT-IR spectra of 2 after (top) and before (bottom) Br- addition.
Ta ble 1. N-H Str etch in g F r equ en cies for F r ee 1 a n d 2
Ta ble 2. Su m m a r y of Cr ysta l Da ta for th e
[P P h 4]2[1‚Br ][Br ]‚CH2Cl2 Str u ctu r e26
a n d Th eir Br - Ad d u cts
compound
νN-H (solution) (cm-1
)
νN-H (thin film) (cm-1
)
empirical formula C69H58N2O2P2Br2Cl2
fw (g/mol)
cryst dimens (mm)
space group
a (Å)
b (Å)
c (Å)
1239.89
1
3430
3302
0.14 × 0.18 × 0.23
triclinic P1h (No. 2)
9.379(5)
12.823(5)
25.412(8)
100.63(3)
94.43(4)
101.09(4)
2927(5)
2
1.406
1272
15.62
52.6
12619
11865 (Rint ) 0.074)
6020
2
3430
3281
1‚Br-
2‚Br-
3231 and 3184
3229 and 3175
3228 and 3180
3232 and 3171
formula unit of [PPh4]Br, and of a molecule of CH2Cl2.
The receptor adopts an unusual twisted syn-syn confor-
mation that allows it to form two N-H‚‚‚Br hydrogen
bonds with one Br- ion lying out of the plane of the
central arene ring. As a result, the two amide bonds are
also significantly out of the central arene plane (dihe-
drals: 25.79° for N1-C7-O1 and 34.88° for N2-C14-O2).
The bromide ion is not coordinated to any other remote
groups. Electron density found in reasonable positions
was tentatively assigned to the two N-H hydrogens,
which were not refined. After the usual normalization
R (deg)
â (deg)
γ (deg)
U (Å3)
Z value
Dcalc (g cm-3
F(000)
)
µ (Mo KR) (cm-1
max 2θ (deg)
)
no. of reflns collected
no. of ind reflns
obs reflns (I > 3σI)
refinement method
function mimimized
variables
full-matrix least-squares
∑w(|Fo| - |Fc|)2
712
0.049, 0.057
2.04
(26) (a) Full crystal data parameters are given in the Supplementary
Information. (b) Instrumental details and experimental procedures are
given in the Experimental Section. (c) Our previous communication19
reported distance and angle values that were erroneously said to be
normalized but were not. The values that appear here are correctly
normalized.
R, Rw
goodness of fit parameter
max. and min. peaks in the
final difference map (e Å-3
2.12 (max), -0.56 (min)
)

Hydrogen Bonding in Anion Recognition
J . Org. Chem., Vol. 64, No. 5, 1999 1679
All the distances involving aromatic hydrogens were
determined on the basis of positioning of these atoms at
calculated positions (dC-H ) 0.95 Å).
Ca m b r id ge St r u ct u r a l Da t a b a se a n d R ecep t or
Con for m a tion . The Cambridge Structural Database27
(CSD) gave few examples of structurally characterized
N-H‚‚‚Br- interactions (dH‚‚‚Br < 2.8 Å),25 between a
bromide ion and a neutral organic compound.28 In
contrast, many examples were found where the organic
species is positively charged and the Br- acts as a
counterion. Chloride cocrystallization with a neutral
organic compound showing N-H‚‚‚Cl- close contacts was
more common than for bromide, but still rare.
The CSD also allowed comparison of the receptor
conformation.29 In the absence of a guest, isophthala-
mides show syn-anti or anti-anti conformations rather
than the syn-syn conformation seen here. The formation
of two hydrogen bonds to the same ion forces the receptor
to adopt the observed conformation. A similar syn-syn
conformational preference is seen for isophthalamide
bound to urea30 but not for free or self-associated isoph-
thalamides.
The free receptor conformations for analogues of 1 and
5 have been extensively investigated by Hunter et al.,31a
who found that the syn-anti conformation of 1 lies 22
kJ /mol lower in energy than our syn-syn conformation.
If the formation of the two N-H‚‚‚Br bonds induces the
conformational change, the necessary energy must be
supplied by hydrogen bond formation. In contrast, pyri-
dine 5 has a syn-syn and almost planar31b conformation
in the free state that is more stable than the syn-anti
one by 25 kJ /mol31a and is therefore preorganized for
binding. For the sulfonamide receptor 4 (for which we
find both syn-syn 1:1 and anti-anti 1:2 complexation
1
F igu r e 3. Two ORTEP views of the crystal structure showing
the [1‚Br-] unit (50% probability ellipsoids). Some of the
hydrogen atoms are omitted for clarity.
behavior with fluoride and acetate, see below), H NMR
monitoring of the 2-C-H and the aniline moiety aromatic
resonances suggests that the unbound sulfonamide has
the anti-anti conformation, since its spectrum shows
similarities in pattern to that of the anti-anti 1:2
complex but is distinctly different from that of the syn-
syn 1:1 complex formed initially. A plot (Figure 4) of the
2-C-H chemical shift versus fluoride concentration shows
a maximum downfield shift for the mole ratio [F-]/[4] )
0.9. The aniline aromatic resonances in the free sulfona-
mide and in the 1:2 complex show a well-resolved t-t-d
pattern with integration 2:1:2 for the o-, m-, and p-C-H
arene protons. On progressive addition of F- up to a
[F-]/[4] ratio of 0.9, this pattern collapses to an unre-
solved multiplet. Beyond a [F-]/[4] ratio of 1.2, the
Ta ble 3. Selected In ter m olecu la r Dista n ces a n d An gles
atoms
distance (Å)
Br1-H2
Br1-H1
Br1-H11
Br1-H3
Br1-H12
Br1-N2
Br1-N1
Br1-C13
2.41
2.63
3.01
3.34
3.08
3.44
3.64
3.58
atoms
angle (deg)
Br1-H2-N2
Br1-H1-N1
Br1-H11-C13
173
165
119
(27) Source: Cambridge Crystallographic Database, Version 5.12.
Cambridge Crystallographic Data Center, 12 Union Road, Cambridge,
CB2 1EZ, U.K.
planes
dih. angle (deg)
(28) (a) Lebioda, L.; Stadnicka, K. Acta Crystallogr., Sect B 1977,
33, 2905. (b) De Lucas L.; Einspahr, H., Bugg, C. E. Acta Crystallogr.,
Sect B 1979, 35, 2724. (c) Meulemans, R.; Piret, P.; Van Meersche, M.
Acta Crystallogr., Sect B 1971, 27, 1187. (d) Truter, M. R.; Vickery, B.
L. Acta Crystallogr., Sect B 1972, 28, 387. (e) Mak, T. C. W. J . Inclusion
Phenomena 1990, 8, 199. (f) Knoch, F.; Appel, R.; Lange, J . Z.
Kristallogr. 1994, 209, 914. (g) Elding-Ponten, M. Acta Crystallogr.,
Sect C 1977, 33, 2905.
(29) (a) Yang, J .; Fan, E.; Geib, S. G.; Hamilton, A. D. J . Am. Chem.
Soc. 1993, 115, 5314. (b) Foresti, E.; Riva di Sanseverino, L.; Sabatino,
P. Acta Crystallogr., Sect. C. 1986, 42, 220.
(30) Geib, S. G.; Vincent, C.; Fan, E.; Hamilton, A. D. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 119.
C1-6, N1-C7-O1
29.6
28.3
25.8
34.9
C15-20, N2-C14-O2
C8-C13, N1-C7-O1
C8-C13, N2-C14-O2
to dN-H )1.03 Å, Br‚‚‚H distances of 2.63 and 2.41 Å and
N-H‚‚‚Br angles of 165° and 173° were found, consistent
with hydrogen bonding.25,26c The much larger distance of
3.01 Å from the 2-C-H hydrogen to the Br ion as well as
the 119° C-H‚‚‚Br angle indicate that there is no
significant C-H‚‚‚Br- hydrogen bonding interaction de-
(31) (a) Hunter, C. A.; Purvis D. A. Angew. Chem., Int. Ed. Engl.
1992, 31, 792. (b) Hamuro, Y.; Geib, S. J .; Hamilton, A. D. J . Am. Chem.
Soc. 1996, 118, 7529.
1
spite the large downfield H NMR shift for this hydrogen.

1680 J . Org. Chem., Vol. 64, No. 5, 1999
Kavallieratos et al.
F igu r e 4. Titration curve for sulfonamide 4 and Bu4NF in
CD2Cl2 (2-C-H proton resonance), showing the maximum
downfield shift for [F-]/[4] ) 0.9.
F igu r e 5. 2-C-H titration plot for receptor 2 and Ph4PCl in
CD2Cl2.
spectrum gradually reverts to a pattern similar to that
of the unbound receptor as the anti-anti 1:2 complex is
formed.
F igu r e 6. N-H titration plots for 2 + X- (X- ) Cl-, Br-, I-,
F-, OAc-).
(X ) Cl-, Br-, I-) gave 1:1 binding isotherms for both
the N-H and the 2-C-H resonances (Figure 6). The
2-C-H resonance was generally sharper and therefore
allowed more accurate determination of ∆δ. The N-H
and C-H titration curves for each of the receptors 2 and
3 were very similar, and the analysis gave the same Ka’s
within experimental error. Receptor 1 was not studied
because of its limited solubility. An accurate number
could not be obtained for 5 + I- because of the low Ka
and limited solubility of Ph4PI in sufficiently high
concentrations. Figure 6 shows all five different titration
N-H curves obtained for 2 with Cl-, Br-, I-, F-, and
OAc-.
Deter m in a tion of Bin d in g Stoich iom etr y by J ob
P lots.33 The complexation stoichiometries indicated by
the titration curves were also confirmed by the continu-
ous variation method (J ob plots) (Figure 7). [RX-] is the
supramolecular complex concentration as determined by
the ratio of chemical shift change ∆δ/∆δmax for the corre-
sponding N-H and C-H protons. For all the 1:1 cases,
bell-shaped J ob plots were obtained with maxima for
mole ratio [R]t/[R]t + [X-]t of 0.5 or [R]t/[X-]t of 1. One
exception was the 5 + OAc- case, which gave a maximum
at [5]t/[5]t + [X-]t of 0.55, probably suggesting a small
contribution from 2:1 complexation. Figure 7 shows
comparable J ob plots for 2 with different anions but from
the same stock receptor solution, giving a qualitative
picture of the observed selectivity for each receptor.
.
.
.
.
.
.
1H NMR Titr a tion s.32 To determine the association
constants, Ka, for the anion receptor interaction of 1-5
with Cl-, Br-, I-, F-, and OAc- in CD2Cl2 solution, we
used the standard NMR titration method32 with monitor-
ing of ∆δ N-H and ∆δ 2-C-H, in a dilute receptor CD2-
Cl2 solution in the concentration range (0.5-1) × 10-3
M, with the addition of 1.0 × 10-2 to 1.0 × 10-1 M CD2-
Cl2 solutions of the corresponding anion salt in the same
receptor concentration, followed by analysis with a
nonlinear regression method. A typical binding curve is
shown in Figure 5.
A 1:1 stoichiometry was found in all cases except for
the sulfonamide 4, with fluoride and acetate, in which
both 1:1 and 1:2 binding stoichiometries were found
(Figure 4). Receptors 2-5 with Ph4PX (X ) Cl-, Br-, I-)
or (n-Bu)4NX (X ) F-, OAc-) and receptor 4 with Ph4PX
Da ta An a lysis: Associa tion Con sta n ts.32 A 1:1
binding isotherm gave a satisfactory fit in all cases except
(32) Connors, K. A. Binding Constants, 1st ed.; J ohn Wiley & Sons:
New York, 1987; pp 189-215.

Hydrogen Bonding in Anion Recognition
J . Org. Chem., Vol. 64, No. 5, 1999 1681
Ta ble 4. Ma xim u m Ch em ica l Sh ift Ch a n ges a n d
a
Associa tion Con sta n ts Ka a t 19.2 °C in CD2Cl2
2 +
∆δ max
∆δ max
∆G
(kJ /mol)
anion (N-H) (ppm) (C-H) (ppm)
Ka (M-1
)
F-
4.65
3.20
2.80
2.57
3.73
1.55
0.95
0.74
0.59
0.98
30000 (10%)
61000 (12%)
7100 (3%)
460 (7%)
-25.1
-26.8
-21.6
-14.9
-24.1
Cl-
Br-
I-
OAc-
19800 (5%)
3 +
∆δ max
∆δ max
Ka
anion (N-H) (ppm) (C-H) (ppm)
(M-1
)
∆G (kJ /mol)
F-
4.03
3.16
2.76
2.33
3.60
1.05
1.28
1.11
0.91
1.02
7500 (10%)
5300 (5%)
1400 (8%)
220 (10%)
2800 (15%)
-21.7
-20.9
-17.6
-13.1
-19.3
Cl-
Br-
I-
F igu r e 7. J ob plots for 2 (using a 3.5 × 10-4 M stock solution)
and Ph4PX (X ) Cl-, Br- , I-).
OAc-
5 with I-, as discussed above. The expression used for
4 +
∆δ max
stoichiometry
anion (C-H) (ppm) of binding
∆G
(kJ /mol)
the 1:1 nonlinear regression is shown in eq 5.32,34
Ka (M-1
)
F-
1.20
1:1 + 1:2
K11 ) 55000 (25%) -26.6
∆δ ) ([R]t + [X-]t + Ka - ((([R]t + [X-]t +
-1
K12 ) 1000 (10%)
20000 (6%)
-16.8
-24.1
-20.5
-17.3
Cl-
Br-
I-
1.50
1.40
1.16
1.74
1:1
1:1
1:1
1:1 + 1:2
Ka-1)2 - 4[X-]t[R]t)1/2))∆δmax/(2[R]t) (5)
4600 (4%)
1200 (15%)
OAc-
K11 ) 21000 (25%) -24.2
K12 ) 300 (12%) -13.9
In eq 5, [R]t is the total receptor concentration, Ka is the
association constant, and [X-]t is the total anion concen-
tration. ∆δ and ∆δmax are the observed and maximum
chemical shift changes for the monitored resonances. For
the F- + 4 and OAc- + 4 cases in which both 1:1 and 1:2
binding were observed, the expression of eq 6 was used
for analysis of the 2-C-H titration curve:
5 +
∆δ max
∆G
(kJ /mol)
anion
(N-H) (ppm)
Ka (M-1
)
F-
4.68
1.54
1.85
0.99
2.30
24000 (18%)
1500 (30%)
57 (6%)
<20
525 (6%)
-24.5
-17.8
-9.8
>-7.3
-15.2
Cl-
Br-
I-
∆δ ) ([R]t + [X-]t + K11 - ((([R]t + [X-]t +
-1
Ac-
a
K11-1)2 - 4[X-]t[R]t)1/2)) × ∆δmax/(2[R]t) - ([R]t +
Errors calculated from the deviation of three independent
measurements.
-1
[X-]t + K12 - ((([R]t + [X-]t + K12-1)2 -
are present and the host skeleton is flexible, allowing
adjustment of conformation according to guest size. No
repulsive lone pairs are present for receptors 1-4, and
this appears to be an important factor for strong binding,
particularly for the bulkier anions. Receptor flexibility
seems to be a favorable factor that has been largely
ignored in the past36 and appears to be more important
for bulkier and softer anions (at least in these systems).
Moreover the receptors are readily available in multi-
gram quantities from inexpensive and commercially
available starting materials, via a synthesis that allows
easy variation of substituents.
4[X-]t[R]t)1/2))∆δmax/(2[R]t) (6)
In eq 6, K11 and K12 are the association constants for the
formation of the 1:1 and 1:2 complexes, respectively.
Equation 6 assumes that K11 . K12 and also that the
2-C-H shifts of the uncomplexed receptor and the 1:2
complexed ones are identical, so that the two consecutive
steps can be treated independently in an additive way.
The correctness of both assumptions were verified by the
results, since we obtained fits with very high R values,
with K11 . K12 and more importantly with an [R]t value
(which we left as a free parameter rather than defining
it arbitrarily) essentially the same as the one we used in
the experiment. The association constants and the cor-
responding ∆G’s are shown in Table 4.
Table 4 shows that the Ka’s are unusually high for
acyclic and nonpreorganized receptors, especially for the
smaller and harder anions, but are also high even for
the larger and softer anions, for which selective receptors
are generally difficult to design. The less rigid disulfona-
mide 4 binds iodide with a quite impressive Ka value for
such a simple receptor.35 This we ascribe to a disposition
of the two hydrogen bonds that allows formation of two
almost linear hydrogen bonds. No rigid or bulky groups
The acidity of the N-H hydrogen has a significant
influence. The less acidic hexamethyl receptor 3 shows
a sharp decrease in binding constant for Cl- as compared
to 2; steric factors could also play a role, however.
Sulfonamides (pKa ≈ 9-10) are about 5 pKa units more
acidic than amides, (pKa ≈ 14-15),37 a factor that would
be expected to increase their H-bond donor ability and
their binding constants dramatically. We find this is not
generally the case, except for the F- and OAc- cases,
where a mixed 1:1 and 1:2 stoichiometry may play an
additional role. The cavity size of the receptors, their
flexibility, and the need for the two donor groups to
converge on one acceptor atom, to form the two linear
hydrogen bondsseasier for 4 because of the freer rotation
about the HN-C(arene) bondsare the most important
(33) Connors, K. A. Binding Constants, 1st ed.; J ohn Wiley & Sons:
New York, 1987; pp 24-28.
(34) Kavallieratos, K., Ph.D. Thesis, Yale University, 1998.
(35) For examples of I- complexation, see: (a) Beer, P. D.; Cooper,
J . B. J . Chem. Soc., Chem. Commun. 1998, 129. (b) Rohrbach, R. P.;
Rodriguez, L. J .; Eyring, E. M.; Wojcik, J . F. J . Phys. Chem. 1977, 81,
944. (c) Worm, K.; Schmidtchen, F. P. Angew. Chem., Int. Ed. Engl.
1995, 34, 65.
(36) Eblinger, F.; Schneider; H.-J . Angew. Chem., Int. Ed. Engl.
1998, 37, 726.
(37) Andersen, K. K. In Comprehensive Organic Chemistry; Barton,
D. H. R., Ed.; Pergamon Press: Oxford, 1979; Vol. 4, p 345.

1682 J . Org. Chem., Vol. 64, No. 5, 1999
Kavallieratos et al.
determine the Ka at different temperatures for the 2 +
Cl- case. A van’t Hoff plot (Supporting Information) gives
a ∆H of -31 kJ /mol and a ∆S of -23 J /(mol‚K), as
expected for a 1:1 interaction of two molecules in an
organic solvent.40
Con clu sion
Strong and selective anion binding can be achieved
with simple nonpreorganized m-diamides or disulfona-
mides, which are synthetically obtainable on a multigram
scale. The importance of hydrogen bonding for anion
recognition in these systems was demonstrated by a
crystal structure of 1‚Br that shows a syn-syn nonplanar
binding conformation. The study of anion binding proper-
ties of receptors having slightly different structures with
five different anions allowed us to demonstrate the
importance of hydrogen bonding for anion recognition in
these systems as well as to interpret the relationship
between certain receptor structural features and the
strength and selectivity of anion binding.
F igu r e 8. Plot of ∆G vs ionic radius. Experimental hydration
free enthalpies (scaled) and ionic radii are taken from ref 39.
factors, particularly in the series Cl-, Br-, I-. For
instance, the bulky iodide is preferred for the more
flexible disulfonamide group versus the less flexible
amide one. For chloride, in contrast, the Ka is unusually
high for the rigid amide 2 presumably because of size
compatibility. We were not able to obtain a crystal of the
chloride adduct to confirm this assumption. However for
similar metal-containing macrocyclic systems recently
reported by Beer et al.,2p a much more planar structure
was obtained for chloride versus bromide. For the hard
and small fluoride and acetate ions, the higher acidity
may be the predominant factor giving sulfonamide its
very high Ka’s. From the results for 2-4 and 5 with Cl-,
Br-, and I-, we see that increased receptor rigidity (in
the order 4 < 3 < 2 < 5) leads to enhanced binding of
the smaller halides. Table 4 shows that 5, with its
nitrogen lone pair close to the anion binding site, prefers
binding the smaller halides. Such a lone pair is known
to be sterically more bulky than an aromatic C-H bond,38
and electrostatic repulsion between the negatively charged
anions and the lone pair is expected to decrease the
binding strength. This effect is more pronounced for the
larger I- and Br- and much smaller for F-, giving
receptor 5 the highest selectivity for smaller anions.
Figure 8 summarizes the results of Table 4 in a form
that makes the observed relative trends more obvious.
The inclusion of scaled (10-1) free enthalpies of hydra-
tion39 in the graph provides a comparison and confirms
that smaller, harder anions are better H-bond acceptors
than larger and softer ones. The right-hand part of the
graph includes the larger anions Cl-, Br-, and I- and
shows nearly straight lines for the different receptors,
and the different slopes show the various size selectivities
of the receptors. The less rigid sulfonamide 4 has the
smallest slope, only marginally different from the trend
in hydration enthalpy, suggesting that the receptor
prefers Cl- over I- mainly because the NH‚‚‚Cl- H-bonds
are stronger. This does not appear to be the case for the
more rigid receptor 2, however, because the slope is three
times larger. The presence of an N lone pair instead of a
C-H in the pyridine receptor 5 results in an even larger
increase in the slope and therefore in the selectivity.
∆H a n d ∆S of In ter a ction : VT NMR Da ta . A
variable-temperature NMR titration study allowed us to
Trends in structure/binding relationships show recep-
tor flexibility is an important factor in anion recognition.
Applications of these and other flexible receptors with
simple structure to various areas of interest can be
anticipated.
Exp er im en ta l Section
Gen er a l Com m en ts. All solvents were of analytical grade
and were used without further purification. Isophthaloyl
dichloride, aniline, p-n-butylaniline, and 2,4,6-trimethylaniline
1
(Aldrich) were used as received. H NMR spectra (GE-Omega
300 MHz) were referenced to residual solvent resonances. FT-
IR spectra were recorded on a MIDAC M1200 FT-IR spectro-
photometer. Elemental analyses were performed by Atlantic
Microlab Inc. Norcross, GA, or Robertson Microlit Laboratories
Inc., Madison, NJ . Fast atom bombardment (FAB) high-
resolution mass spectra were obtained at the laboratories of
Dr. Stephen Mullen at the University of Illinois at Urbanas
Champaign.
1,3-Ben zen edicar boxam ide-N,N′-bis(4-bu tylph en yl) (2).
The compound was synthesized by a modification of the
previously published method for 1.20 To dimethylformamide
(DMF, ca. 75 mL) in a 250 mL flask was added p-n-butylaniline
(9.25 g, 0.062 mol) with magnetic stirring. Isophthaloyl dichlo-
ride (6.33 g, 0.031 mol) was added gradually, and the reaction
mixture was stirred at room temperature for ca. 30 min and
then poured into water (300 mL). The product was precipitated
as a white powder, which was washed three times with water.
The diamide was air-dried and subsequently recrystallized
from ethanol/benzyl alcohol. The colorless crystals were washed
with methanol and dried in vacuo at 90 °C for 4 h. Yield: 10.62
1
g (80%). H NMR (CD2Cl2, 19.2 °C): δ (ppm) 8.38 (s br, 1H),
8.05 (dd, 2H, J ) 7.8 Hz, 1.9 Hz), 7.98 (s, br, 2H), 7.64 (t, 1H,
J ) 7.8 Hz), 7.56 (d, 4H, J ) 8.2 Hz), 7.21 (d, 4H, J ) 8.2 Hz),
2.61 (t, 4H, J ) 7.7 Hz), 1.60 (m, 4H), 1.36 (m 4H), 0.94 (t,
6H, J ) 7.2 Hz). FT-IR (CH2Cl2, thin film - cm-1): 3281 (br
ν
N-H), 1650, 1523, 1410, 1324, 1104, 927, 824, 714, 703. FT-
IR (dil. solution, cm-1): νN-H 3430. Elemental anal. Calcd for
28H32N2O2: C, 78.5; H, 7.53; N, 6.54. Found: C, 77.37; H,
C
7.26; N, 6.25. High-resolution mass spectrometry (FAB): Calcd
for (MH+) 429.254 204, found 429.254 000.
1,3-Ben zen edicar boxam ide-N,N′-bis(2,4,6-tr im eth ylph e-
n yl) (3). Isophthaloyl dichloride (2.11 g, 10.3 mmol) was added
gradually to a solution of 2,4,6-trimethylaniline (2.81 g, 20.8
mmol) in DMF (25 mL) and was allowed to react for 15 min.
The solution was added to excess water (200 mL), resulting
(38) Huheey, J . E.; Keiter, E. A.; Keiter, R. L. Inorganic Chemistry;
Harper-Collins: New York, 1993.
(39) Marcus, Y. J . Chem. Soc., Faraday Trans. 1 1991, 87, 2995.
(40) Lewis, G. N.; Randall, M. Thermodynamics; McGraw-Hill: New
York, 1961.

Hydrogen Bonding in Anion Recognition
J . Org. Chem., Vol. 64, No. 5, 1999 1683
in the formation of a thick, white precipitate, which was
filtered through a coarse-fritted glass funnel, washed multiple
times with water, and air-dried. Recrystallization from ethanol
gave the pure product that was dried at 80 °C in vacuo. Yield:
1.77 g (43%). 1H NMR (CD2Cl2, 19.2 °C): δ (ppm) 8.51 (s, 1H),
8.12 (dd, 2H, J ) 7.8 Hz, 1.9 Hz), 7.73 (t, 1H, J ) 7.7 Hz),
7.61 (br s, 2H), 7.02 (s, 4H), 2.41 (s, 6H), 2.18. (s, 12H). FT-IR:
(film) (cm-1) 3234 (νN-H), 1635, 1516, 1429, 1304, 1256, 844,
735. Elemental anal. Calcd for C26H30N2O2: C, 77.6; H, 7.51;
N, 6.96. Found: C, 77.80; H, 7.14; N, 6.74.
N-H protons and the aromatic 2-C-H protons were monitored
as a function of the anion concentration up to the point where
the chemical shift change reached saturation. The association
constant Ka was calculated from the obtained curves (∆δ N-H
vs [X-] and ∆δ C-H vs [X-]) via nonlinear regression analysis
carried out with the Kaleidagraph program43 and using the
curve fit for simple 1:1 binding (eq 5).32 In the cases where
both a 1:1 and 1:2 stoichiometry occurred (4 + F- or OAc-),
the analysis was carried out using the more complex eq 6. All
the runs were carried out for three independent samples, and
the values obtained for Ka agreed within <5%. The concentra-
tion of the receptor solution was set as a free parameter for
fitting, and the value obtained was found to agree within 10%
with the concentration value actually used. The values ob-
tained for the Ka from the aromatic 2-C-H and the N-H
protons were found within the same range. In all cases more
than 10 equiv of anion was added before the titration was
terminated. All measurements were carried out in triplicate
using independent samples.
Con tin u ou s Va r ia tion Meth od (J ob p lots). Stock solu-
tions of the receptor (3.5 × 10-4 M for 2, 1.0 × 10-3 M for 3-5)
and the corresponding anion salt (3.5 × 10-4 or 1.0 × 10-3 M,
respectively) in CD2Cl2 were prepared. Ten NMR tubes were
filled with 500 mL solutions of the host and guest in the
following volume ratios (in mL): 50:450, 100:400, 150:350, 200:
300, 250:250, 300:200, 350:150, 400:100, 450:50, 500:0. 1H
NMR spectra were recorded, and the concentration of the
complex was calculated as follows: [complex] ) ([R]t) × (δobs
- δo)/(δc - δo) (3), where [R]t is the total concentration of the
receptor in the solution, δobs is the observed chemical shift for
the N-H or any 2-C-H protons, δo is the chemical shift for
the free host, and δc is the chemical shift of the N-H or the
2-C-H protons in the complex. J ob plot curve maxima at mol
fraction of 0.5 were observed for host:guest molar ratios of 1:1
and were confirmed for both N-H and 2-C-H resonances
when applicable.
1,3-Ben zen ed isu lfon a m id e-N,N′-bis(d ip h en yl) (4). The
compound was synthesized by a modification of the previously
published method for 1.21a 1,3-Benzenesulfonyl chloride (4.27
g, 15.5 mmol) was added gradually to a solution of aniline (2.89
g, 31 mmol) in DMF (40 mL) and was allowed to react for 30
min. The solution was added to excess water (150 mL), and a
crystalline white solid was precipitated, filtered through a
coarse fritted glass funnel, washed many times with water,
and air-dried. Recrystallization from methanol/water gave the
pure product, which was dried in vacuo for 8 h at 60 °C.
1
Yield: 2.51 g (42%). H NMR (CD2Cl2, 19.2 °C): δ (ppm) 8.33
(t br, 1H, J ) 1.7 Hz), 7.82 (dd, 2H, J ) 7.9 Hz, 1.9 Hz), 7.48
(t, 1H, J ) 8.0 Hz), 7.25 (td, 4H, J ) 7.9 Hz, 1.6 Hz), 7.16 (tt,
2H, J ) 7.5 Hz), 7.02 (dt, 4H, J ) 8.1 Hz, 1.5 Hz), 6.92 (s, br,
2H). FT-IR (CH2Cl2, thin film, cm-1): 3264 (br νN-H), 3072,
1598, 1495, 1415, 1343, 1177, 1154, 924. Elemental anal. Calcd
for C18H16N2S2O4: C, 55.7; H, 4.15; N, 7.21; S, 16.5. Found:
C, 55.72; H, 4.24; N, 7.20; S, 16.44.
Cr ysta llogr a p h y. Crystal data and data collection param-
eters are summarized in Table 2.2.26a A colorless prismatic
crystal (0.14 × 0.18 × 0.23 mm) of C69H58N2O2P2Br2Cl2 was
mounted on a glass fiber. All measurements were carried out
on an Enraf-Nonius CAD-4 diffractometer with graphite-
monochromated Mo KR radiation. The data were collected at
a temperature of -90 ( 1 °C using the ω-2θ scan technique
to a maximum 2θ value of 52.6°. The structure was solved by
the Patterson method.41 The non-hydrogen atoms were refined
anisotropically. The hydrogen atoms, except for the N-H
hydrogen atoms, were included in calculated positions. The
N-H hydrogen atoms were located in the difference map, but
not refined.
Solu tion a n d Th in F ilm F T-IR. Solutions of the receptors
and PPh4 halide salts of similar concentrations were prepared
in CH2Cl2. The two solutions were mixed in equal amounts,
and the spectrum of the new solution was obtained in a NaCl,
FT-IR cell. Right after the collection the same solution was
layered on a NaCl plate in order to form a thin film (via slow
evaporation), and the spectrum was obtained. The same
procedure was applied for the solutions of the free receptors.
All calculations were performed using the TEXSAN42 crys-
tallographic software package of the Molecular Structure
Corporation.
1H NMR Titr a tion s. Solutions of receptor R in CD2Cl2
(dried under activated 4 Å molecular sieves) were prepared
in the concentration range 2.0 × 10-4 to 1.0 × 10-3 M. One
milliliter of these solutions was titrated in NMR tubes with
1.0 × 10-2 to 1.0 × 10-1 M solutions of Ph4PX salts (for Cl-,
Br-, and I-) or Bu4NX salts (for OAc- or F-), which also
contained receptor in the same concentration as the titrated
solutions. A 1 M solution in THF was used as tetrabutylam-
monium fluoride source. Solution transfers were performed by
syringe and septa techniques. The resonances assigned to the
Ack n ow led gm en t. We thank the NSF for support,
Susan de Gala for solving the crystal structure, the Yale
STARS program for a grant to C.M.B., and Professors
David J . Austin and J ohn P. Caradonna for valuable
discussions and suggestions.
Su p p or tin g In for m a tion Ava ila ble: Tables of crystal-
lographic data for the adduct of 1 with PPh4Br are available,
as well as J ob and van’t Hoff plots for the receptors. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(41) Sheldrick, G. M.; Egert, E. SHELXSL-93, General Direct
Methods and Automatic Patterson; University of Go¨ttingen: Go¨ttingen,
Germany, 1993.
(42) TEXSAN-TEXSRAY Structure Analysis Package; Molecular
Structure Corporation: 1989.
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(43) KaleidaGraph, Version 3.0.2; Synergy Software (PCS Inc.):
Reading, PA 19606. Developed by Abelbeck Software Inc.