Learning from Proteins and Drugs: Receptors That Mimic Biomedically Important Binding Motifs - Designing Receptors for the Next Generation of Biosensors - page 38

Fig. 6 Amide and sulfonamide functionalized anion receptors exhibit different selectivities

Table 1 Anion affinities of aryl sulfonamide functionalized hosts 8 and 9, acyl sulfonamide
functionalized hosts 10 and 11, and tetrazole functionalized hosts 12 and 13
K assoc (M 1 )inCD 3 CN
Host Bu 4 N + Cl Bu 4 N + NBr Bu 4 N + OTs Bu 4 N + NO 3 Bu 4 N + HSO 4

10 600(10) 110(10) 60(5) 40(40) 50(5)

11 1,030(5) 320(5) 250(5) 100(5) 180(10)

12 100(50) 20(10) 100(100) 80(5) 70(20)

13 390(10) 90(5) 120(5) 60(5) 100(5)

14 8,450(10) 720(10) 1,400(20) 5,800(30) 660(50)

15 3,560(40) 800(10) 520(10) 330(5) 340(5)

Errors in brackets are standard deviations of 2-3 replicate titrations

interesting to note that the original report of isophthalamides as anion binders by
Crabtree also reports aryl sulfonamide analogs that have varying affinities and
selectivities relative to amides (Fig. 6 )[ 48 ]. Compound 6 exhibits threefold more
potent binding for chloride relative to 7 while 7 binds fluoride approximately twice
as strongly as 6.
We recently explored anion binding by all three bioisosteres—aryl sulfonamides,
acyl sulfonamides, and tetrazoles—affixed to a common calixarene scaffold. Hosts
8-13 were prepared and their binding with several biologically important halides
and oxyanions was determined. The results are summarized in Table 1 . These
studies revealed that although the N-H proton acidities of these three classes of
compounds are similar (representative N-H p K a values are 4.6, 8.5, and 5.2 for
tetrazole [ 49 ], aryl sulfonamide [ 50 ], and acyl sulfonamide [ 36 ] moieties, respec-
tively), tetrazoles proved to be superior anion-binding elements relative to their
sulfonamide analogs within this structural context. The expected trends based on
N-H proton acidities were in fact observed with aryl sulfonamides, as 8 bound all
anions studied less strongly than did electron poor 9. Notably, acyl sulfonamide
functionalized hosts 10 and 11, although known to be more acidic than simple aryl
sulfonamides were less competent hosts. These findings implied that there were
more forces at work in these systems than simply hydrogen bond donation (Fig. 7 ).
We hypothesized that their varying conformational preferences, largely ignored
in their simple classification as interchangeable replacements for carboxylic acids,
might play a role in determining their anion-binding affinities. Molecular modeling
studies were carried out to investigate the host-guest complexes. We identified
geometries for each host-guest complex in which the calix[4]arene is in a perfect
“cone” conformation and all four hydrogen bond donors are engaging the central