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3 Combining a Hydrophobic Cavity and A Tren-Based Unit: Design of Tunable, Versatile, but Highly Selective Receptors

3 Combining a Hydrophobic Cavity and A Tren-Based Unit: Design of Tunable, Versatile, but Highly Selective Receptors

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378



12.3.2



BIOMIMETIC CAVITIES AND BIOINSPIRED RECEPTORS



Versatility of a Polyamine Site45



12.3.2.1 Highly Resistant Funnel Complexes With Zn2+ , Cu2+ , and

Cd2+ , the calix[6]tren ligand leads to funnel complexes with the metal ion

coordinated by the tren cap and an exchangeable neutral molecule bound to the

metal in the calixarene pocket, as depicted in Figure 12.10.46 The XRD structure

of a Zn2+ complex displays a 5-coordinate metal ion bound to a guest EtOH ligand

and to the tren cap in an asymmetrical environment (right inset, Figure 12.10).

Due to both a strong chelate effect and a full cavity-controlled access to the metal

center, the Zn complexes appeared remarkably resistant and better hosts than

their parent tris(imidazolyl) calix[6]-based complexes. They are resistant to bases,

acids, and even electrophiles (e.g., NBu4 OH, AcOH, and MeI). Most interestingly,

they proved not only capable of hosting a variety of small guest ligands such as

alcohols, nitriles, amides, or primary amines, but also allowed the binding of large

guests such as imidazole, benzylamine, and dodecyldiamine under experimental

conditions for which the parent systems (Figure 12.5) underwent decoordination

of Zn.

12.3.2.2 Complexation of Ammonium Ions In the absence of metal ion,

this calix-cryptand is insensitive to neutral species such as alcohols, amides, and

amines in chloroform solutions at millimolar (mM) concentrations. However,



Figure 12.10 Versatility of the calix[6]tren receptor as a tetracation, a monocation, or a

Zn(II) complex.45



COMBINING A HYDROPHOBIC CAVITY AND A TREN-BASED UNIT



379



the presence of primary or secondary ammonium ions leads to the competitive

monoprotonation of the tren cap and formation of endo complexes with the

ammonium ion accommodated into the cavity. The competitive protonation of

the host is overpassed by the addition of an excess of the corresponding free

amine (Figure 12.10). The endo complexation of ammonium ions is selective

as the picrate salts of EtNH3 + , nPrNH3 + , nBuNH3 + , or Me2 NH2 + are readily

bound with 1/3/0.1/0.05 relative affinities, respectively, whereas inclusion of

Me4 N+ Pic− is not detected under the same experimental conditions. By analogy

with related calix[6]arene-based receptors,47 the recognition is rationalized by

H-bonding interactions between the guest ammonium ion and phenoxyl units of

the calixarene core together with CH–π interactions within the cavity.

12.3.2.3 A Polarized Receptor for Polar Neutral Molecules In strong

contrast to the neutral calix[6]tren, the tetracationic derivative, obtained through

protonation with an excess of a strong acid (e.g., >4 equiv of trifluoroacetic acid,

TFA), can recognize polar neutral molecules (G). Hence, intracavity complexation

of alcohols, nitriles, amides, ureas, and even acetaldehydes was observed upon

the addition of only a few molar equivalents of these guests G in chloroform

(Figure 12.10). The driving force of the recognition event consists of a combination

of electrostatic charge–dipole and H-bonding interactions between the protonated

cap and the guest, as shown by the following sequence of relative affinity (rel.

aff.): Imi (imidazolidin-2-one, a cyclic urea, see Figure 12.10, left inset, μ = 3.9

D; rel. aff. = 500)

DMF (3.9 D; 1) > AcNH2 (3.7 D; 0.6) > EtOH (1.7 D;

0.14). Indeed, apolar molecules such as alkanes are not complexed. As shown on

the XRD structure of a related system (vide infra),48 the selectivity for Imi stems

from a four H-bonding array leading to remarkable host–guest complementarities.

12.3.2.4 A Versatile Biomimetic Receptor that Needs to Be Polarized

In conclusion, in the absence of a hydrophobic effect that requires water as the

solvent, nonpolar interactions (van der Waals, CH–π ) are not strong enough to

allow the efficient binding of neutral guests by the neutral calix[6]tren receptor.

However, the tren cap is highly basic and thus can be used to polarize the structure

by protonation. In addition, the tren unit offers a strong chelate binding site for a

metal ion. Each form of polarized receptor is capable of complexing neutral species

into the hydrophobic cavity with high but different selectivities. For instance, the

perprotonated calixtren strongly binds a urea, whereas the coordination of this

guest was not observed with the Zn complex. All these results are reminiscent of

molecular recognition processes encountered in natural systems. Indeed, enzymes

are highly selective catalysts that bind their substrate in well-defined geometries

and, in many cases, recognition involves cationic NH3 + groups belonging to Lys or

Arg residues. All in all, these results validate the biomimetic approach that consists

of associating in close proximity a cationic subunit and a hydrophobic cavity to

build up efficient receptors for neutral species.



380



BIOMIMETIC CAVITIES AND BIOINSPIRED RECEPTORS



12.3.3 Polyamido and Polyureido Sites for Synergistic Binding

of Dipolar Molecules and Anions

12.3.3.1 The Trisamido Site: A Unique Recognition Tool with Combined Dipolar and H-Bonding Interactions NMR spectroscopy studies in

chloroform showed that the calix[6]trenamide host strongly binds polar neutral

guests (G) displaying (1) an acceptor H-bonding group that interacts with the convergent NH groups of the trisamido cap, and (2) donor H-bonding group(s) that

interact with the phenoxy groups of the calix core (Figure 12.11). Indeed, the inclusion of ureas and amides was detected, again, with high selectivities (see the rel.

aff. displayed in Figure 12.11). The host–guest complex with Imi is even stable

in a protic environment [CD3 OD/CDCl3 (3:2), Ka = 430 M−1 ]. In strong contrast with the calix[6]tren receptor, the protonated trenamido host is insensitive to

polar neutral molecules. This reluctance is rationalized by the competing formation of a stable five-membered intramolecular H-bonded ring between NH+ and

an introverted C O (Figure 12.11). Here, the NH+ proton induced a conformational reorganization of the trisamido recognition site into an insensitive form of

the receptor.

12.3.3.2 The Trisureido Site: A Remarkable Neutral Anion Binding

Site49 In CD3 CN, the trenurea host strongly binds anions at the level of the

crypturea cap thanks to (1) a conformational flip of the aromatic units, (2) the

highly favorable cavity filling by the OMe groups, and (3) the spreading of the

ureido arms (see structures displayed in Figure 12.12). The anion recognition

proceeds through H-bonding interactions as shown by the substantial 1 H NMR

downfield shift of the ureido protons (Figure 12.12). The association constants Ka

displayed in Table 12.1 indicate that the binding discrimination is mostly based

on the size of the anions. Very interestingly, the binding of Cl− is efficient in

a protic solvent (Ka = 20 ± 2 M−1 at 298 K in CD3 OD). This remarkable result

highlights the fact that neutral receptors can bind anions in protic solvents provided

that they possess a highly preorganized H-bonding recognition site isolated from

the solvent.



Figure 12.11 Host–guest properties of calix[6]trenamide toward neutral guests. Inset:

Energy minimized structure of the inclusion complex calix[6]trenamide ⊃ Imi. Selected

˚ N(host)–O(Imi): 2.84 and 2.86; N(Imi)–O(host): 2.80 and 2.82.43

distances (A):



COMBINING A HYDROPHOBIC CAVITY AND A TREN-BASED UNIT



ArH ArH



NH



CH2O OMe



381



tBu

W



S



(a)



ArH ArH

(b)

7.0



8.0



6.0



5.0



4.0

ppm



3.0



2.0



1.0



0.0



Figure 12.12 1 H NMR spectra (CD3 CN, 300 MHz, 298 K) of (a) calix[6]trenurea;

(b) after addition of 1 equiv of TBA+ Cl− . : TBA+ ; w: water; s: residual solvent.49



TABLE 12.1 Association Constants Ka of Calix[6]trenurea Toward

Anions X− in CD3 CN (Ref. 49)

AnionaX−



Geometry of X−



Ka (M−1 )b



Cl−

Br−

I−

CN−

N3 −

AcO−

NO3 −



Spherical

Spherical

Spherical

Linear

Linear

V-shaped

Trigonal



48300

1930

ndc

640

215d

160

98



a TBA+



salts.

determined at 243 K and defined as Ka = [host ⊃ X− ]/([host] [X− ]). Errors estimated ±10%.

c

Not detected.

d

Determined at 298 K.

bK



a



12.3.3.3 Heteroditopic Receptors for Organic Contact Ion Pairs The

ability of calix[6]trenamide and calix[6]trenurea to recognize an ammonium ion

simultaneously to an anion was investigated by NMR spectroscopy in chloroform.

In both cases, the complexation of the ammonium ion only proceeds when an

anion is co-bound in the trisureido cap (Figure 12.13). This positive cooperativity is due to the close proximity between the two complexed ions and thus

to their strong electrostatic interaction. These heteroditopic receptors stress the

importance of binding the two ions as a contact ion pair in order to avoid their



382



BIOMIMETIC CAVITIES AND BIOINSPIRED RECEPTORS



Figure 12.13 Host–guest properties of calix[6]trenamide and calix[6]trenurea toward

anions and organic contact ion pairs. Top inset: Energy minimized structure of the inclu˚ N(host)–F− : 2.78,

sion complex calix[6]trenamide ⊃ PrNH3 + F− . Selected distances (A):

+

+



43, 49

2.80, and 2.99; N (guest)–O(host): 2.96; N (guest)–F : 2.08.



highly energetically unfavorable dissociation. In the case of the trenureido receptor, ternary complexes with various anions X− (X− = F− , Cl− , or Br− ) and linear

ammonium ions of various length (e.g., propyl-, hexyl-, or dodecylammonium) are

obtained (Figure 12.14a). High cumulative binding constants (e.g., β2 > 1.6 × 109

M−2 for PrNH3 + Cl− ) were obtained. Calix[6]trenurea also presents a strong affinity for bulkier quaternary ammonium salts and biologically relevant ammonium

salts such as the neurotransmitter acetylcholine chloride or a dopamine hydrochloride derivative (β2 > 2.3 × 106 M−2 in the case of TMA+ Cl− ) (Figure 12.14b).

Very interestingly, most of the ternary host–guest complexes are stable in a protic



s



(a)



OMe

NH

w

OMe



(b) NH

8.0



7.0



4.0



ppm



3.0



2.0



1.0



0.0



−1.0



−2.0



Figure 12.14 1 H NMR spectra (CDCl3 , 300 MHz, 298 K) of (a) calix[6]trenurea ⊃

dodecylammonium chloride and (b) calix[6]trenurea ⊃ acetylcholine chloride. : included

ammonium ion; ∇: free ammonium ion; w: water; s: residual solvent.49



SELF-ASSEMBLED CAVITIES



383



environment; for instance, the complex with acetylcholine chloride was still visible in a mixture of CD3 OD/CDCl3 (4:1). In the case of the trenamido host, the

binding of contact ion pairs exclusively proceeded with F− as the anionic partner (i.e., no cation complexation was apparent with Cl− , AcO− , MeSO3 − , NO3 − ,

or SO4 2− ) (Figure 12.13). This remarkable selectivity is due to the smallness of

the binding site provided by the convergent NH groups of the cryptamide cap.

Interestingly, 1 H and 19 F NMR experiments revealed significant scalar couplings

between the fluoride anion of the ternary complexes and the NH amido protons as

well as the NH3 + of the included propylammonium ion (i.e., 1h J scalar couplings

across N–H... F− hydrogen bonds). The energy-minimized structure of the ternary

PrNH3 + F− complex is depicted in Figure 12.13. The very short distance between

˚

the fluoride and the charged nitrogen of the ammonium ion (dN+...F − = 2.08 A)

shows the presence of a strong electrostatic interaction at the level of the ion pair.

As in other complexes, the ammonium ion is further stabilized by the calixarene

host through a combination of CH–π interactions with the aromatic walls and Hbonding interaction with a phenoxy oxygen. Besides its interaction with the cation,

the anion is strongly bound to the convergent hydrogen-bond donor NH groups.

Finally, in the case of both receptors (i.e., calix[6]trenamide and calix[6]trenurea),

the protonation of the cap of the ternary complexes triggers the release of the anion

and, as a consequence, of the ammonium ion.

12.3.4



Acid–Base Controllable Receptors



Another interesting feature of these tren derivatives lies in the presence of proton

sensitive site(s) at the level of the polar aza cap. As shown above, the protonation of

the basic cap of the hosts led to positively charged cavities whose host properties

toward dipolar guests are governed by strong charge–dipole interactions. In the

case of the calix[6]tren receptor, a drastic increase in binding strength was observed

with the protonation of the receptor. In contrast, guest release can be triggered by

addition of an acid to the trenamido receptor. This negative cooperativity is due to

the conformational reorganization of the more rigid trenamide binding site that turns

off the amido binding properties of the cap. These controllable binding properties

make possible the reversible interconversion of different modes of recognition. For

instance, a three-way supramolecular switch was obtained with the calix[6]trenurea

host–guest system (Figure 12.15). The protonation of the apical nitrogen of the cap

acts as an effector that allows the switch from one mode of recognition to another

and a remarkable guest selection from a complex mixture. In other words, these

receptors nicely illustrate how the host properties of a hydrophobic cavity can

be tuned by the environment, which is reminiscent of natural systems and their

propensity to pH control.

12.4



SELF-ASSEMBLED CAVITIES



Self-assembly is ubiquitous in biological systems. It allows reversible and programmable assembly of subcomponents into functional complex structures. Data



384



BIOMIMETIC CAVITIES AND BIOINSPIRED RECEPTORS



Calix[6]trenurea⊃PrNH3+Cl− ( )



DBU



DBU

PicH



PicH

or Pic−

Cl



a)

b)

c)

d)

e)

0.8



0.0



−0.8



−1.6



ppm

Calix[6]trenurea⊃lmi ( )



Calix[6]trenurea⊃TMA+Cl− ( )



Figure 12.15 Three-way supramolecular switch triggered by the addition of acid or

base to calix[6]trenurea. 1 H NMR spectra (400 MHz, 298 K, high-field region) in

CDCl3 /CD3 OD (98:2) of (a) mixture of calix[6]trenurea, PicH (1 equiv), TMA+ Cl− (2.5

equiv), PrNH3 + Cl− (15 equiv), and Imi (2.5 equiv); (b) after addition of DBU (2 equiv);

(c) after addition of DBU (25 equiv); (d) after addition of PicH (12 equiv); and (e) after

addition of PicH (22 equiv). •: included Imi; : included PrNH3 + ; ♦: included TMA+ .49



storage, regulation and replication phenomena, catalytic transformations, membrane

transport, and many other tasks essential to living systems lie on self-assembled

materials. In addition to the two above described strategies (supramolecular capping via metal coordination and covalent capping), a third approach based on

ionic interactions was exploited to obtain calix[6]arene-based receptors. In biological receptors, ammonium and carboxylate residues of a protein scaffold are often

involved in substrate recognition. It is also a major tool for protein folding into an

active state. Having this in mind, calix[6]trisamine and calix[6]trisacid (depicted

in Figure 12.16) have been used for obtaining positively and negatively polarized

cavities.

12.4.1 Receptors Decorated with a Triscationic or a

Trisanionic Binding Site

The free base calix[6]trisamine undergoes a fast cone–cone inversion at RT and

is not suitable for hosting neutral molecules. In contrast, its trifluoroacetic acid



SELF-ASSEMBLED CAVITIES



385



Figure 12.16 Small rim 1,3,5-trisfunctionalized calix[6]arenes with amine and carboxylic acid groups.



protonated form is locked in the cone conformation, and NMR studies in CDCl3

have revealed that polar neutral molecules, such as alcohols, ureas, amides, or

sulfoxydes, are efficiently endo-complexed.50 X-ray structure of the endo complex

with DMF shows that the ammonium arms are self-assembled through a network of

H-bonding interactions with the trifluoroacetate counteranions (Figure 12.17). This

assembly of the arms thus forms an ion paired cap that (1) freezes the cavity in

the cone conformation and (2) polarizes the hydrophobic cavity with a tricationic

protic site. In general, the guests orient their dipole moment along the C3 axis of

the cavity and are bound via a combination of H-bonding interactions with the

ammonium arms and the phenoxyl units, CH–π interactions with the aromatic

walls, and dipole–charge interactions. In adequacy with this finding, the endobinding of neutral molecules with low polarity (ketones, ethers, halogeno-alcanes)

has never been observed. Hence, guest selection based on size, shape, and electronic

structure occurs in this simple system. For instance, a cyclic urea (imidazolidin2-one) is very well recognized and, to date, behaves as the best “key” for the

calix[6]trisammonium host.

The reverse situation is observed with calix[6]trisacid derivatives

(Figure 12.17).51 Upon acid–base reaction with an excess of amine, the

triscarboxylate structure is frozen in the cone conformation and is able to

endo-complex one of the ammonium counterion, even in pure methanol solution.

NMR studies evidenced that the exo complexation of at least one ammonium

ion is required for the quantitative endo-binding process to occur. The X-ray

structure with EtNH3 + revealed that the two exo-bound ammonium ions are

involved in ion pairing interactions with adjacent carboxylate arms, thus forming

a supramolecular cap in a way similar to that observed for the protonated form of

calix[6]trisamine. The third (endo) ammonium ion is stabilized via a combination

of weak interactions (charge–dipole, H-bonding, and CH–π ), and displays a

remarkable C3 complementarity with the triscarboxylate binding site of the host.

Again, the calixarene cavity acts as a funnel and provides size and shape selection,

primary ammonium ions being best recognized. Such a size selection can be used

to tune the supramolecular cap. For instance, the bulky terbutylammonium ion is

exclusively recognized in exo position, which allows the quantitative inclusion



386



Figure 12.17 Opposite strategies for the supramolecular capping via ion pairing of the

calix[6]arene core. X-ray structures of (left) calix[6]trisammonium ⊃ DMF and of (right)

calix[6]triscarboxylate ⊃ EtNH3 + (dashed lines indicate H bonds).50, 51



SELF-ASSEMBLED CAVITIES



387



of a primary ammonium ion of interest upon addition of strictly one equivalent.

Inclusion of large biorelevant ammonium guests (e.g., spermine, spermidine, and

organosoluble derivatives of dopamine and 6-hydroxytryptamine) has also been

observed with calix[6]triacids deprived of three of the tBu groups at the large rim.

12.4.2



Receptors Capped Through Assembly with a Tripodal Subunit



The self-assembly strategy not only provides a simple means to obtain efficient

receptors, but can be extended to the construction of more sophisticated multitopic

receptors through the coupling of two cavities. Indeed, a tripodal triscarboxylic

acid can advantageously replace the excess of strong acid used for the capping

of calix[6]trisamine (Figure 12.18).52 However, in these softer acids, presence of

a guest molecule was mandatory for obtaining discrete self-assembled structures,

which now are ternary. In other words, the self-assembly process between the

calix[6]trisamine and the triscarboxylic cap is directed by the guest molecule. Its

inclusion contributes to the shaping of the cavity through an induced-fit process,

which optimizes the directionality of the intersubunit interactions. The stability of

the [1+1+1] complexes depends on the preorganization of the cap: with a rigid

tripod they are stable in pure methanol solution (Figure 12.18). Also interestingly,

when the rigid triscarboxylic platform is concave as exemplified by the bowl-shape

cyclotriveratrylene scaffold, [1+1+2] self-assembled ditopic receptors are obtained

(Figure 12.18). One molecule of Imi is included in each cavity, but with different

recognition processes, and thus different affinities. In this system, one equivalent

of guest is required to shape the calixarene receptor, whereas the second equivalent

may or may not be present in the rigid bowl-shape cap.



Figure 12.18 Supramolecular capping of a calix[6]trisamine with tripodal triscarboxylic

acid subunits (guest molecules: Imi).52



388



BIOMIMETIC CAVITIES AND BIOINSPIRED RECEPTORS



12.4.3 Heteroditopic Self-Assembled Receptors with

Allosteric Response

The possibility of coupling two cavities is of great interest as it may open the way to

receptors with allosteric response. This is indeed what was obtained when the rigid

triscarboxylic cap of the cyclotriveratrylene unit was substituted for the flexible

calix[6]trisacid (Figure 12.19).48 Mixing equimolar amounts of such partners led

only to nondiscrete species. This is obviously ascribed to the high flexibility of the

calix[6]arene skeletons. However, the selective formation of a discrete species can

be triggered by the addition of the respective guest molecules, that is, a polar neutral

molecule and an ammonium ion. The obtained supramolecular heteroditopic receptors correspond to a rare case of [1+1+1+1] quaternary self-assembly in which the

calixarenes are connected in a tail-to-tail manner (diabolo-like topology). The X-ray

structure with Imi and propylammonium as guests (Figure 12.19) revealed a high

degree of complementarities between the four partners (size, shape, and electronic

structure): triple ion pairing and up to 15 H bonds stabilize the supramolecular

structure. This allows an extremely selective self-assembly process with no error

and good stability as these quaternary complexes tolerate the presence of a large

amount of a protic solvent at millimolar (mM) concentration.



Figure 12.19 Self-assembled ditopic receptors with allosteric response. Bottom left:

X-ray structure with PrNH3 + and Imi as guests. Dashed lines indicate H bonds.48



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