Recognition properties of carboxylic acid bioisosteres: Anion binding by tetrazoles, aryl sulfonamides, and acyl sulfonamides on a calix[4]arene scaffold

Article abstract of DOI:10.1021/jo200031u

Tetrazoles and acyl sulfonamides are functional groups that are common in medicinal chemistry but virtually unexplored as recognition elements in supramolecular chemistry. We report here on the anion binding properties of these highly acidic N-H functiona

Full text of DOI:10.1021/jo200031u

ARTICLE
pubs.acs.org/joc
Recognition Properties of Carboxylic Acid Bioisosteres: Anion Binding
by Tetrazoles, Aryl Sulfonamides, and Acyl Sulfonamides on a
Calix[4]arene Scaffold
Thomas Pinter, Subrata Jana, Rebecca J. M. Courtemanche, and Fraser Hof*
Department of Chemistry, University of Victoria, Victoria, Canada V8W 3V6
S Supporting Information
b
ABSTRACT: Tetrazoles and acyl sulfonamides are functional
groups that are common in medicinal chemistry but virtually
unexplored as recognition elements in supramolecular chem-
istry. We report here on the anion binding properties of these
highly acidic NꢀH functional groups. We have prepared two
new calixarene-based tetrazole-containing hosts, as well as new
acetyl sulfonamide and benzoyl sulfonamide hosts. We also
report on analogous hosts bearing the better-known aryl sulfonamide functional group as a point of comparison. We find that these
hosts are competent anion binders and that the recognition of anions by these groups is highly dependent on their conformational
preferences. We also report in detail on the preferred molecular shape of each acid bioisostere as determined by calculations and
structural database surveys, and discuss how these shapes impact binding in the context of the reported hosts.
’ INTRODUCTION
recognition elements, the recognition properties of the more
highly acidic acetyl and benzoyl sulfonamides have, to our
knowledge, completely escaped the attention of supramolecular
chemists.
Tetrazoles, aryl sulfonamides, and acyl sulfonamides (Figure 1)
are commonly used as carboxylic acid mimics in modern drug
development, where they are valued for the acidity of their NꢀH
functional groups. Relative to their carboxylic acid counterparts,
compounds containing these groups often show improved oral
availability, metabolic stability, and potency.1ꢀ3 Not surprisingly, a
vast number of small molecule therapeutic targets containing
tetrazole,4 aryl sulfonamide,5,6 and acyl sulfonamide7ꢀ9 functionality
have been successfully developed. Losartan is one of the six
approved tetrazole-containing angiotensin II type 1 receptor
(AT1) antagonists used for the treatment of hypertension.10
Sulfanitran has been shown to stimulate transport properties of
human multidrug resistance protein 2 (MRP2)11 and is also an
active ingredient in Novastat, a coccidiostat used in the poultry
industry.12 Navitoclax is a potent inhibitor of the antiapoptotic
protein Bcl-xL, overexpression of which is linked to several types
of cancer.13
These classes of functional groups have two possible modes of
encoding molecular recognition: when protonated, the acidic
hydrogen atoms should be excellent hydrogen bond donors
useful for binding anions and other hydrogen bond acceptors;
when deprotonated, the resulting anionic conjugate bases of
these functional groups are potential cation binders. Our group
and others have investigated the recognition properties of
deprotonated tetrazoles toward various cations.14ꢀ20 Recently,
we reported that a simple tris(tetrazole) host in its neutral,
protonated form is among the most potent neutral binders of
anions yet reported.21 This spurred us to explore further the
anion binding properties of tetrazoles and other acid bioisosteres.
While aryl sulfonamides have been previously employed as anion
’ RESULTS
To study these groups within the context of a well-understood
scaffold, we carried out syntheses to affix each of them to
calix[4]arene. We explored the binding of the resulting hosts
with several biologically important halides and oxyanions and
determined the roles of functional group conformational pre-
ferences on guest binding. We report that although the NꢀH
proton acidities of the three classes of compounds are similar,
tetrazoles proved to be superior anionic binders relative to their
acyl and aryl sulfonamide analogues in this context.
The advanced bromocalixarene intermediates 4 and 5
were further converted to their cyano counterparts 6 and 7
(Scheme 1).22 The copper-mediated cyanation of 4 to produce 623
was hampered by solubility problems, low yields, and harsh condi-
tions. Accordingly, we pursued a milder, palladium-catalyzed pro-
cess for the synthesis of 7 that improved yields and reaction times.
The tetrazole-containing hosts 8 and 9 were produced in good yield
by treatment of each cyanated calixarene with ZnBr2 and NaN3
using a variation on the method of Demko and Sharpless.24
The known chlorosulfonyl calix[4]arene25 10 was the starting
point for the synthesis of all reported aryl and acyl sulfonamide
hosts. We found that stirring 10 with the appropriate p-substituted
aniline in hot pyridine provided the best route to the aryl
Received: January 5, 2011
Published: April 04, 2011
r
2011 American Chemical Society
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Figure 1. Representative drugs Losartan, Sulfanitran, and Navitoclax containing tetrazole, aryl sulfonamide, and acyl sulfonamide functionality,
respectively.
Scheme 1. Synthesis of Tetrazole-Containing Hosts 8 and 9
Scheme 2. Synthesis of Aryl and Acyl Sulfonamide Hosts
sulfonamide hosts appended with a variety of anilines bearing
electron-donating and -withdrawing substituents. While the more
conventional conditions for sulfonamide synthesis (Et2i-PrN (
DMAP) failed to provide fully tetra-substituted products, the
method in neat pyridine consistently provided clean products and
yields between 49% and 83%.
An extensive body of literature on the preparation of acyl
sulfonamide exists,26ꢀ31 but we found almost all literature methods
incapable of providing the clean reactions and high conversions
required in order to isolate significant quantities of the 4-fold-
symmetric acyl sulfonamide products 14 and 15. Synthesis of acyl
sulfonamide hosts was first attempted using chlorosulfonyl 10 as
starting material. Reaction of 10, a primary amide (benzamide), and
pyridine/DMAP even at reflux failed to produce the desired acyl
sulfonamide product 15. Use of Et3NorEt2i-PrN in various solvents
at elevated temperatures led to complex mixtures and/or extremely
slow reaction rates. We then turned our attention to N-acylation
approaches that start instead with a primary sulfonamide. We created
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Figure 2. Exemplary binding data for each functional group studied. Left: Experimental data fit to a 1:1 binding isotherm arising from titrations of
Bu4Nþ Clꢀ into (a) tetrazole host 9 at 1 mM, (b) aryl sulfonamide host 11 at 1 mM, and (c) acyl sulfonamide host 15 at 1 mM. Insets: Job plots for each
host plus (() Bu4NþClꢀ . Data for (9) Bu4NþTsOꢀ also included for host 15. Total concentrations for all Job plots = 5 mM. Right: Stacked plots of
partial 1H NMR spectra arising from the same titrations. Equivalents of Bu4NþClꢀ added are indicated at far right.
the known primary sulfonamide 1325 in one step by treating
10 with NH3 and reacted it with benzoyl chloride in pyridine/
DMAP; again, conversions were extremely low, and 15 could not be
isolated from the complex mixture. We attempted to couple 13 with
benzoic acid32 using 1-ethyl-3-(3-dimethylaminopropyl)carbodi-
imide (EDC) in the presence of tertiary amine bases but observed
instead rapid formation of benzoic anhydride from self-coupling of
benzoic acid prior to slow reaction of the resulting anhydride to give
some acyl sulfonamide-containing products. Finally, we found that
solvent- and base-free conditions,32 in which the primary sulfon-
amide 13 is treated with neat benzoyl chloride or acetyl chloride at
high temperatures, proved to be a superb method that produced 14
and 15 in 98% and 67% yields, respectively.
Binding constants were determined by duplicate or triplicate
1H NMR titrations. Host solutions (1 mM) in CD3CN were first
prepared, and portions of each were used to make up guest
solutions (30ꢀ80 mM) in order to ensure that the host con-
centrations were kept constant throughout the titration. Repre-
sentative binding curves and Job plots for each functional group,
along with stacked plots following the downfield shifts of NꢀH
signals for 11, 12, 14, and 15 and aryl CꢀH signals for 8 and 9
from which these curves were generated, are shown in Figure 2.
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Table 1. Anion Affinities in CD3CN of Tetrazole Functionalized Hosts 8 and 9, Aryl Sulfonamide Functionalized Hosts 11 and 12,
and Acyl Sulfonamide Functionalized Hosts 14 and 15
a
Kassoc (Mꢀ1
)
ꢀ
ꢀ
host
Bu4NþClꢀ
Bu4NþBrꢀ
Bu4NþIꢀ
Bu4NþTsOꢀ
Bu4NþNO3
Bu4NþHSO4
8
8450 ( 983
3560 ( 1395
616 ( 78
716 ( 72
804 ( 57
116 ( 16
322 ( 4
94 ( 5
62 ( 16
70 ( 9
29 ( 12
41 ( 2
24 ( 7
<10b
1407 ( 300
515 ( 44
59 ( 1
5796 ( 1481
328 ( 13
39 ( 15
98 ( 3
656 ( 338
336 ( 12
49 ( 1
9
11
12
14
15
1026 ( 52
389 ( 23
246 ( 11
124 ( 2
183 ( 12
105 ( 4
72 ( 11
55 ( 1
112 ( 57
28 ( 4
116 ( 112
75 ( 4
a Values reported are the averages resulting from tracking multiple host signals during 2ꢀ3 titrations for each host/guest pair. Errors reported are
standard deviations. b Insignificant chemical shifts observed during titrations.
Association constants are reported in Table 1. The effect of
remote substitution on the lower rim was tested by comparing
propyl-substituted 8 and glycol-substituted 9. The propyl-sub-
stituted host 8 showed increased binding potency (>2-fold for
chloride and tosylate, >10-fold for nitrate) relative to the glycol
lower-rim substitution (9), indicating binding affinity and selec-
tivity depends somewhat on the conformational control provided
by lower-rim functionality.33 All other sulfonamide and acyl
sulfonamide hosts were prepared with the glycol feet, however,
which improved their solubility in CD3CN and also provided a
common basis for comparison.
calixarene conformations that allow only 3 NꢀH donors to
engage the anion (see Supporting Information). Despite the
gross differences in scaffold conformations, we noted similarities
in the functional groups’ own dihedral angles between both
families of complexes. Our NMR data did not reveal which of the
two types of calixarene conformation were operative in solution
(it is probably a mixture of both), so we probed instead the role of
each functional groups’ conformational preferences in hostꢀ
guest complex formation.
We examined the inherent conformational preferences of each
of these acid bioisosteres, isolated and detached from the
calixarene, using HF dihedral driving calculations about each
rotatable bond in each of the functional groups. These calcula-
tions were put on a solid footing of experimental data by mining
the CSD for all existing crystal structures containing relevant
fragments and determining the relative occurrences of different
dihedral angles. The combined computational and data-mining
analyses for the key dihedral angles that define the inherent shapes
of these bioisosteres are presented in Figures 4 (tetrazoles) and 5
(aryl and acyl sulfonamides).
Affinities ranged up to 8.5 ꢁ 103 Mꢀ1, with each host
showing the highest affinities for chloride among all anions
tested (Table 1). Ingeneral, tetrazole-functionalized hosts 8 and 9
bound most anions almost an order of magnitude more tightly
than their aryl and acyl sulfonamide analogues11ꢀ12 and 14ꢀ15.
Among the aryl sulfonamides the binding of nitro-substituted host
12 to various guests was tighter than the corresponding methyl-
substituted host 11, as expected on the basis of the increased
acidity and corresponding increase in hydrogen bond donation
ability for 12. This trend was not observed when the comparison
was extended to include acyl sulfonamides 14 and 15. Although
acetyl and benzoyl sulfonamides like 14 and 15 are several orders
of magnitude more acidic than aryl sulfonamides like 11 and 12,
the binding of anions by acyl sulfonamides was found to be
significantly weaker than binding by aryl sulfonamides for all cases
tested.
Computational analysis of phenyl-(5-tetrazole)’s relative en-
ergy as the dihedral angle about the biaryl bond is driven from
0 to 180° shows a barrier of 13 kJ/mol on the potential energy
surface at an angle of 90°, when conjugation with the benzene
ring is broken (Figure 4b). Unlike related systems such as
biphenyl, the potential energy surface remains completely flat
until the phenyl-tetrazole bond is twisted g30° out of co-
planarity. Surveying the CSD for similar fragments (Figure 5a)
revealed a generally similar trend, with the large majority of
structures having a dihedral angle (50° from co-planar and a
paucity of structures with dihedral values near 90°. In this case
the CSD data is biased away from co-planarity of tetrazole and
arene by the preponderance of crowded ortho-substituted 2-(5-
tetrazolyl)-biphenyls, as in Losartan (Figure 1), in the CSD.
Superimposing this simple angular preference onto the more
complex structures of hosts 8 and 9 reveals why they are less
potent than our earlier tris(tetrazole) host despite the inherent
’ DISCUSSION
These functional groups are known first and foremost for their
acidity. Representative NꢀH pKa values are 4.6, 8.5, and 5.2 for
exemplary tetrazole,34 aryl sulfonamide,35 and acyl sulfonamide8
moieties, respectively. The large discrepancies between the anion
binding strength of the aforementioned hosts were unexpected
and do not follow a simple pKa trend between the different
classes of acid bioisoteres. We hypothesized that their varying
conformations, largely ignored in their simple classification as
interchangeable replacements for carboxylic acids, might play a
large role in determining their anion-binding affinities. Molecular
modeling studies were carried out to investigate the structures of
the hostꢀguest complexes. We were able to find a local minimum
for each host in which the calixarene is in a perfect “cone”
conformation and all four H-bond donor groups engage a central
anion symmetrically (Figure 3), as well as a collection of local
minima for each host involving puckered “pinched cone”
strength of the tetrazole NH Xꢀ hydrogen bond; The com-
3 3 3
plex of a simplified analogue of host 8 with Clꢀ (Figure 3a)
demands that this dihedral is at the disfavored 90° angle (costing
∼13 kJ/mol per tetrazole) in order for all four tetrazole moieties
to engage the guest simultaneously.
The shapes of the aryl and acyl sulfonamides are defined by three
important dihedral angles. The conformations of the rotatable
carbonꢀsulfur bonds for aryl sulfone type functionalities
(θ1, Figure 5a) have been reported in detail elsewhere and are
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Figure 3. Local minima that involve the maximum four hostꢀguest hydrogen bonds for representative hostꢀguest complexes (HF/6-31þG*). Lower-
rim substituents have been omitted. (a) Tetrazole functionalized host 8/9 complexed with Clꢀ. Calculated average phenyl-tetrazole biaryl dihedral angle
86.6 ( 0.1°. (b) Aryl sulfonamide functionalized host 11 complexed with Clꢀ. Calculated average θ2 and θ3 dihedral angles 167.9 ( 0.5° and 50.5 (
1.0°, respectively. (c) Acyl sulfonamide functionalized host 15 complexed with Clꢀ. Calculated average θ2 and θ3 dihedral angles 162.8 ( 3.8° and
28.1 ( 8.4°, respectively. (d) Acyl sulfonamide host 15 complexed with TsOꢀ. Calculated average θ2 and θ3 dihedral angles 160.5 ( 3.4° and
11.9 ( 3.0°, respectively.
although the depths of the energy wells are different. Data from the
CSD (histograms in Figure 5c and d) show perfect agreement with
the calculated angular preferences. In contrast, we find a strong
divergence in the shape preferences of acyl and aryl sulfonamides
about the NꢀC dihedral θ3. In acyl sulfonamides, a strong pre-
ference for the planar trans (θ3 = 180°) or cis (θ3 = 0°) amide
conformations is revealed by both the crystallographic data
(Figure 5f) and the strong preference for these angles observed in
the DFT-calculated potential energy surface (Figure 5h). In contrast,
the calculations and CSD data show that the rotation of the
Figure 4. (a) Histogram generated by a survey of the Cambridge
Structural Database (CSD) showing frequencies of biaryl dihedral angles
reported in the literature for a simplified phenyl-(5-tetrazole) model. (b)
Energy diagram calculated at the HF/6-31þG* level of theory when
driving the biaryl dihedral angle from 0 to 180° in phenyl-(5-tetrazole).
equivalent bond in the aryl sulfonamides, in this case an aniline
NꢀC type functional group, is essentially a flat potential energy
surface with no preferences or barriers to rotation (Figure 5h). Again,
the CSD data agree, in this case showing that aryl sulfonamides can
adopt almost any value for θ3 with no discrimination between
conformations (Figure 5g). These data help us to evaluate the shapes
of the hostꢀguest complexes shown in Figure 3 and in the
Supporting Information. Regardless of the calixarenes’ conforma-
tions, the acyl and aryl sulfonamides must adopt a conformation
wherein θ2 = 160ꢀ170° (calculated values: aryl sulfonamides
∼168°, acyl sulfonamides ∼160°, see Figure 3) in order to direct
their NꢀH bonds toward the guest. This is disfavored in both types
of sulfonamide, and the larger penalty paid for the acyl sulfonamide
(∼40 kJ/mol per functional group) must be at least in part
similar (at θ1 = ∼90°) for both classes of compounds.36,37 We
analyzed the sulfonamide dihedral for rotation about the SꢀN bond
(θ2, Figure 5a) and the amide/aniline dihedrals that define rotation
about the neighboring NꢀC bonds (θ3, Figure 5a) in an attempt to
help us understand the experimental anion binding data that we
reported above. Calculated energy profiles show that both acyl
sulfonamides and aryl sulfonamides share the same preference for
conformation about their SꢀN bonds (θ2 = ∼60°, Figure 5e),
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Figure 5. (a) Labeling of key dihedral angles θ2 and θ3 in acyl and aryl sulfonamides. (b) Two views of the global minimum energy conformation of a
representative acyl sulfonamide fragment, N-acetyl benzenesulfonamide. (c, d) Histograms showing the frequencies of reported θ2 dihedral angles for
(c) acyl sulfonamide fragments and (d) aryl sulfonamide fragments from among all structures in the Cambridge Structural Database (CSD). (e) Energy
profiles calculated for the same fragments while driving θ2 from 0 to 180° in the acyl sulfonamide (b) and aryl sulfonamide (9) fragments. (f, g)
Histograms showing the frequencies of reported θ3 dihedral angles for (f) acyl sulfonamide fragments and (g) aryl sulfonamide fragments from among all
structures in the CSD. h) Energy profiles calculated for the same fragments while driving θ3 from 0 to 180° in the acyl sulfonamide (b) and aryl
sulfonamide (9) fragments. All energies calculated at the HF/6-31þG* level of theory.
responsible for the binding constants we observe for hosts 14 and 15
being so much lower than would be predicted by their high acidity.
the dihedral preferences). We are continuing in our efforts to
expand the supramolecular toolbox using new and readily accessible
functional groups.
’ CONCLUSION
’ EXPERIMENTAL SECTION
Our experimental binding data show that all three of these
carboxylic acid bioisosteres are capable of forming well-ordered
complexes with anions using their acidic NꢀH hydrogen bond
donors. Tetrazoles have demonstrated their high inherent affinity
for anions, and their ability to outperform carboxylic acids in a
prior study21 and sulfonamides in this study suggests that they
should find expanded use as potent binders of anions that operate
in a variety of structural contexts. Whereas aryl sulfonamides
have been repeatedly explored as anion binders,38 acetyl and
benzoyl sulfonamides have not. Although the calixarene scaffold
employed here does not effectively present the NH groups in a
convergent manner, we feel that acyl sulfonamides have unique
properties that hold promise for their further development. They are
much more acidic than their normal sulfonamide counterparts.
More importantly, we’ve shown that their shapes are rigidly defined
by strong conformational preferences at all three rotatable dihedral
bonds (see Figure 5b for the globally “perfect”shape that meets all of
Proton (1H) NMR spectra were recorded on 500, 360, or 300 MHz
spectrometers, as indicated in each case. Carbon (13C) NMR spectra
were recorded 125, 90, or 75 MHz as indicated in each case. Masses were
acquired using high-resolution electrospray ionization mass spectra
(HR-ESI-MS). Infrared spectra were recorded on KBr pellets as neat
films, using thin films on KBr plates. All reactions were carried out under
nitrogen unless otherwise indicated. Procedures for the preparation of
4,23 6,23 10,25 and 1325 have been previously reported.
25,26,27,28-Tetrakis(propoxy)-5,11,17,23-tetrakis-
(tetrazole)calix[4]arene (8). 25,26,27,28-Tetrakis(propoxy)-5,11,
17,23-tetrakis(cyano)calix[4]arene 6 (275 mg, 0.36 mmol), zinc bro-
mide (656 mg, 2.9 mmol), and sodium azide (190 mg, 2.9 mmol) were
added to a pressure tube containing MeOH (5 mL) and H2O (5 mL).
The tube was sealed, and the mixture was heated to 140 °C for 24 h with
vigorous stirring. The reaction was allowed to cool to ambient tempera-
ture, and 1 M HCl (10 mL) and ethyl acetate (10 mL) were added. The
mixture was stirred until all solid had dissolved, and the aqueous layer
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was extracted with ethyl acetate (3 ꢁ 15 mL). The combined organic
layers were evaporated, 0.5 M NaOH (30 mL) was added, and the
mixture was stirred at ambient temperature for 2 h. The resulting zinc
hydroxide precipitate was filtered, and with vigorous stirring the filtrate
was acidified with 1 M HCl to pH 1. The crude brown solid was filtered,
allowed to air-dry, and purified by flash chromatography (SiO2, 10ꢀ20%
MeOH in CH2Cl2 gradient) to afford 180 mg (95%) of a brown solid.
Mp: 175 °C (dec). IR (KBr, thin film): 2962w, 2922w, 2872w, 1617w,
1559 m, 1458 m, 1358s, 1213 m, 1043w, 1005w, 962 m, 896 m, 752w,
563w. 1H NMR (CD3OD, 500 MHz): δ 1.09 (t, J = 7.4 Hz, 12 H), 2.02
(6, J = 7.5 Hz, 8 H), 3.45 (d, J = 1.7 Hz, 4 H), 4.03 (t, J = 7.3 Hz, 8 H),
4.64 (d, J = 13.7 Hz, 4 H), 7.42 (s, 4 H). 13C NMR (CD3OD, 125 MHz):
δ 10.9, 24.7, 32.04, 78.7, 119.4, 128.8, 137.6, 156.7, 160.9. LR-MALDI-
MS: 887.5 (MNaþ, C44H48N16O4Naþ; calcd 887.4). HR-ESI-MS:
865.4175 (MHþ, C44H48N16O4Hþ; calcd 865.4123).
MHz): δ 3.43 (s, 12 H), 3.46 (d, J = 13.6 Hz, 4 H), 3.92 (t, J = 4.7 Hz,
8 H), 4.32 (t, J = 4.7 Hz, 8 H), 4.78 (d, J = 13.6 Hz, 4 H), 7.53 (s, 8 H).
13C NMR (CD3OD, 75 MHz): δ 31.8, 59.0, 73.2, 75.1, 119.3, 128.6,
137.5,156.5, 160.7. HR-ESI-MS: 951.3735 (MNaþ, C44H48N16O8Naþ;
calcd 951.3739).
General Procedure for the Preparation of Aryl Sulfonam-
ide Substituted Calix[4]arenes 11 and 12. A flask containing
chlorosulfonyl calix[4]arene 10 (50 mg, 0.048 mmol), the appropriate p-
substituted aniline (0.77 mmol), and pyridine (4 mL) was heated to
70 °C with stirring. The reaction was left to stir for an additional 8 h at
which point it was quenched with 1 M HCl (10 mL) and diluted with
CH2Cl2 (15 mL). The organic layer was washed with 1 M HCl (3 ꢁ
10 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude
products were purified by flash chromatography (SiO2, 10% MeOH in
CH2Cl2).
25,26,27,28-Tetrakis(ethoxymethoxy)-5,11,17,23-tetrakis
(bromo)calix[4]arene (5). Adapted from a previously reported
procedure.23 25,26,27,28-Tetrakis(ethoxymethoxy)calix[4]arene (410
mg, 0.7 mmol) and NBS (623 mg, 3.5 mmol) were stirred in anhydrous
DMF (10 mL) for 24 h at room temperature. The reaction was
quenched by the dropwise addition of 1 M HCl (6 mL). The precipitate
was filtered and recrystallized in MeOH, yielding 420 mg (66%) of a
white solid. The crude product was purified by flash chromatography
(SiO2, 3% EtOAc in hexanes) yielding 420 mg (66%) of a white solid.
Mp: 180ꢀ182 °C. IR (KBr, thin film): 2924s, 1572w, 1456s, 1197s,
1127s. 1H NMR (CDCl3, 360 MHz): δ 3.06 (d, J = 13.6 Hz, 4 H), 3.35
(s, 12 H), 3.72 (t, J = 5.0 Hz, 8 H), 4.05 (t, J = 5.3 Hz, 4 H), 4.41 (d, J =
13.5 Hz, 4 H), 6.79 (s, 8 H). 13C NMR (CDCl3, 90 MHz): δ 30.5, 58.6,
71.7, 73.3, 115.5, 131.1, 136.4, 155.3. HR-ESI-MS: 994.9643 (MNaþ,
C40H44O8NaþBr4; calcd 994.9633).
25,26,27,28-Tetrakis(ethoxymethoxy)-5,11,17,23-tetrakis
(p-toluenesulfamoyl)calix[4]arene (11). Brown solid. Yield = 53
mg, 83%. Mp: 140ꢀ144 °C. IR (KBr, thin film): 3251 m, 2923 m, 1511s,
1
1463 m, 1451 M, 1332 m, 1301 M, 1264 m, 1149s, 1105m. H NMR
(CDCl3, 300 MHz): δ 2.28 (s, 12 H), 3.08 (d, 4 H, J = 13.7 Hz), 3.25 (s,
12 H), 3.64 (t, 8 H, J = 4.4 Hz), 4.08 (s, 8 H), 4.46 (d, 8 H, J = 13.7 Hz),
6.90ꢀ7.23 (m, 24 H). 13C NMR (CD3CN, 75 MHz): δ 20.9, 31.5, 58.6,
72.5, 74.8, 123.9, 128.2, 130.7, 135.2, 135.5, 136.3, 136.4, 161.0. HR-ESI-
MS: 1355.3998 (MNaþ, C68H76N4O16S4Na, calcd 1355.4037).
25,26,27,28-Tetrakis(ethoxymethoxy)-5,11,17,23-tetrakis
(4-Nitrobenzenesulfamoyl)calix[4]arene (12). Yellow solid.
Yield: 49%. Mp: 140ꢀ144 °C. IR (KBr, thin film): 2926w, 1595s,
1520s, 1495 m, 1464 m, 1343s, 1264w, 1150s, 1106m. 1H NMR
(CD3CN, 300 MHz): δ 3.15 (s, 12 H), 3.31 (d, 4 H, J = 13.7 Hz),
3.65 (t, 8 H, J = 4.6 Hz), 4.13 (t, 8 H, J = 4.6 Hz), 4.50 (d, 4 H, J = 13.5
Hz), 7.22 (m, 16 H), 8.14 (m AA0XX0, 8 H), 8.38 (s, 4 H). 13C NMR
(CD3CN, 75 MHz): δ 31.4, 58.6, 72.5, 75.0, 119.7, 126.3, 128.1,
134.4, 136.8, 144.8, 144.8, 161.6. HR-ESI-MS: 1479.2854 (MNaþ,
C64H64N8O24S4Na, calcd 1479.2814)
25,26,27,28-Tetrakis(ethoxymethoxy)-5,11,17,23-tetrakis
(acetylsulfonamido)calix[4]arene (14). A flask containing com-
pound 13 (80 mg, 0.082 mmol) and acetyl chloride (3 mL) was brought
to reflux with stirring. The mixture was stirred for an additional 24 h, and
the acetyl chloride was removed in vacuo yielding 92 mg (98%) of a white
solid that was used without further purification. Mp: 150ꢀ154 °C (dec).
IR (KBr, thin film): 3220w, 2921w, 1686s, 1449s, 1419 m, 1343 m,
1266 m, 1151s, 1108s, 1044 m. 1H NMR (acetone-d6, 300 MHz): δ 3.39
(s, 12 H), 3.52 (d, 4 H, J = 13.5 Hz), 3.88 (t, 8 H, J = 4.8 Hz), 4.33 (t, 8 H,
J = 4.8 Hz), 4.72 (d, 4 H, J = 13.5 Hz), 7.50 (s, 8 H), 10.28 (s, 4 H). 13C
NMR (CD3CN, 75 MHz): δ 24.0, 31.2, 58.9, 72.6, 75.3, 128.7, 134.8,
136.6, 161.6, 170.3. HR-ESI-MS: 1163.2567 (MNaþ, C48H60N4O20S4-
Na, calcd 1163.2581).
25,26,27,28-Tetrakis(ethoxymethoxy)-5,11,17,23-tetrakis
(cyano)calix[4]arene (7). Compound 5 (450 mg, 0.46 mmol),
Zn(CN)2 (950 mg, 8.2 mmol), Pd2(dba)3 [tris(dibenzylideneace-
tone)dipalladium(0)] (92 mg, 0.1 mmol), and dppf (128 mg, 0.23
mmol) were added to an oven-dried Schlenk flask that was then purged
with nitrogen and evacuated three times. Anhydrous DMF (5.0 mL) was
added, and the flask was sealed and heated at 140 °C for 96 h. The
reaction was then allowed to cool to ambient temperature and trans-
ferred to a round-bottom flask, and the DMF removed in vacuo. The
crude black product was purified by flash chromatography (SiO2, 20%
CH2Cl2 in EtOAc) yielding 228 mg (67%) of a brown solid. Mp: 212 °C.
IR (KBr, thin film): 2927w, 2881w, 2819w, 2225s, 1471s, 1125s, 1036s,
1
895 m, 735 m. H NMR (CDCl3, 360 MHz): δ 3.21 (d, J = 13.9 Hz,
4 H), 3.34 (s, 12 H), 3.71 (t, J = 4.43 Hz, 8 H), 4.15 (t, J = 4.8 Hz, 8 H),
4.54 (d, J = 13.8 Hz, 4 H), 6.99 (s, 8 H). 13C NMR (CDCl3, 90 MHz): δ
30.5, 58.9, 71.8, 74.2, 107.3, 118.4, 132.7, 136.0, 160.0. HR-ESI-MS:
779.3054 (MNaþ, C44H44N4O8Naþ; calcd 779.3057).
25,26,27,28-Tetrakis(ethoxymethoxy)-5,11,17,23-tetrakis
(tetrazole)calix[4]arene (9). Compound 7 (275 mg, 0.36 mmol),
zinc bromide (656 mg, 2.9 mmol), and sodium azide (190 mg, 2.9
mmol) were added to a pressure tube containing MeOH (5 mL) and
H2O (5 mL). The tube was sealed, and the mixture was heated to 140 °C
for 24 h with vigorous stirring. The reaction was allowed to cool to
ambient temperature, and 1 M HCl (10 mL) and ethyl acetate (10 mL)
were added. The mixture was stirred until all solid had dissolved, and the
aqueous layer was extract with ethyl acetate (3 ꢁ 15 mL). The combined
organic layers were evaporated, 0.5 M NaOH (30 mL) was added, and
the mixture was stirred at ambient temperature for 2 h. The resulting zinc
hydroxide precipitate was filtered, and with vigorous stirring the filtrate
was acidified with 1 M HCl to pH 1. The crude brown solid was filtered,
allowed to air-dry, and purified by flash chromatography (SiO2, 10ꢀ20%
MeOH in CH2Cl2 gradient) yielding 220 mg (65%) of a yellow solid.
Mp: 230ꢀ232 °C (dec). IR (KBr, thin film): 2923 m, 1616w, 1559 m,
25,26,27,28-Tetrakis(ethoxymethoxy)-5,11,17,23-tetrakis
(benzoylsulfonamido)calix[4]arene (15). A flask containing
compound 13 (45 mg, 0.046 mmol) and benzoyl chloride (5 mL) was
heated to 140 °C with stirring. The mixture was stirred for an additional
72 h and was then concentrated to near dryness in vacuo. Et2O (5 mL)
was added, and the resulting precipitate was filtered and air-dried.
The white solid (43 mg, 67%) was collected and used without further
purification. Mp: 260ꢀ265 °C (dec). IR (KBr, thin film): 2922w, 1699s,
1454s, 1435s, 1347 m, 1262 m, 1155s, 1108w. 1H NMR (CD3CN, 500
MHz): δ 3.28 (s, 12 H), 3.48 (d, 4 H, J = 13.7 Hz), 3.77 (t, 8 H, J = 4.6
Hz), 4.24(t, 8 H, J =4.3 Hz), 4.63 (d, 4 H, J = 13.5 Hz), 7.48 (t, 8 H, J = 7.7
Hz), 7.53 (s, 8 H), 7.62 (m AA0XX0, 8 H), 7.80 (m AA0XX0, 8 H), 9.77
(s, 4 H). 13C NMR (CD3CN, 125 MHz): δ 31.5, 58.8, 72.6, 75.2, 129.3,
129.3, 129.7, 133.7, 134.2, 134.5, 136.4, 161.9, 166.3. HR-ESI-MS:
1411.3231 (MNaþ, C68H68N4O20S4Na, calcd 1411.3207).
Binding Studies. NMR binding studies were performed 500 and
360 MHz spectrometers for the sulfonamide- and tetrazole-containing
1
1460s, 1456s, 1220w, 1123 m, 1040 m. H NMR (acetone-d6, 300
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The Journal of Organic Chemistry
ARTICLE
compounds, respectively. Deuterated acetonitrile was used as purchased
from Cambridge Isotope Laboratories. Spectra were referenced to
residual solvent. Binding constants were determined by duplicate or
triplicate 1H NMR titrations. Host solutions (1 mM) in CD3CN were
first prepared, and portions of each were used to make up guest solutions
(30ꢀ80 mM) in order to ensure that the host concentrations were kept
constant throughout the titration. Guest solutions were injected into
host solutions incrementally, beginning with 10 μL injections and
gradually raising the injection volume to 200 μL until the NMR tube
was filled to capacity, resulting in final guest concentrations ranging from
5 to 52 equiv for strong- and weak-binding guests, respectively. Binding
constants were determined by monitoring the downfield shifts of NꢀH
protons for sulfonamide-functionalized hosts and CꢀH protons for
tetrazole-functionalized host. Chemical shift data was fit to the 1:1
binding isotherm using a program developed by Dr. J.M. Sanderson,
Centre for Bioactive Chemistry, Department of Chemistry, Durham
University, Durham, U.K. that is available at http://dur.ac.uk/j.m.
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’ ACKNOWLEDGMENT
We thank Christine Greenwood for expert NMR assistance.
This research was supported by NSERC. We also thank Dr. J. M.
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that was used to fit NMR data to a 1:1 binding isotherm. F.H. is a
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