Tải bản đầy đủ - 0 (trang)
2 Molecular Clefts, Capsules, and Cages

2 Molecular Clefts, Capsules, and Cages

Tải bản đầy đủ - 0trang

20



BIOINSPIRED SELF-ASSEMBLY I: SELF-ASSEMBLED STRUCTURES













Selective guest uptake (sometimes associated with chiral recognition)

Induced high catalytic activity

Concentration and guest storage of particular guests (including toxic species)

Molecular/ionic guest transport processes



The guest can range from a single molecule (or ion) to considerably larger

entities. In many cases, where guest uptake occurs, this involves transfer from the

bulk surroundings into the microenvironment in the host’s cavity. Such enclosure

typically has a marked effect on the guest, with inclusion generally resulting in a

range of altered properties. In a good many instances this has been demonstrated

to include a marked alteration of guest reactivity (even when the cavities lack

specifically tailored functional groups of the type present at the active sites of

enzymes).6, 8, 13, 16–20 To give just one example, a carboxylate group is unable to

hydrolyze a polysaccharide in water but can do so when enclosed at the active site

of lysozyme since in the latter case the “protecting” solvating water shell has been

effectively stripped in the hydrophobic pocket of the enzyme, effectively enhancing

the nucleophilicity of the carboxylate group.

The spontaneous and often selective inclusion of numerous neutral and charged

(both cationic and anionic) guests in the cavities of a wide range of cage-like

synthetic hosts (often referred to as “container” molecules or assemblies)9, 11 – 14

has now, of course, been the subject of a vast number of studies, with many

systems of this type showing parallels in their behavior and properties to those

observed in Nature’s encapsulating systems.15 For example, like particular natural cage and cage-like systems, the reaction of molecules held in the restricted

cage environments of particular synthetic hosts has been documented to differ significantly from their reaction in bulk solution.6, 8, 13, 16 – 20 Encapsulations giving

rise to novel stereo- and regioselective reactions are well documented; for example,

Diels–Alder reactions displaying unusual regioselectivities have been demonstrated

under such conditions.16 Once again, factors such as the degree of complementarity

present between host and guest together with solvation/desolvation differences, the

restriction of possible guest conformations in the cavity, and the forced presence

of reagent proximity may all contribute to such a reactivity difference.

Over the past two decades there has been increased effort to devise syntheses for larger cage-like molecules and assemblies, a number of which exhibit

polyhedral shapes corresponding to those of Platonic or Archimedean solids.21

While the majority of these larger structures fall within the realm of metallosupramolecular chemistry,22 – 27 a range of such larger metal-free structures has

now also been reported.8, 14, 28–32 A number of the larger polyhedral structures28, 33

mirror the shapes of particular naturally occurring systems such as the virus capsids and the protein enzyme lumazine synthase. The capsids represent a welldefined group of biostructures34 that serve as the protein shells of viruses and

consist of oligomeric structural subunits that enclose the genetic material of the

virus. Collectively, they are assembled from common protein building blocks

whose shapes and connection points give rise to their shell-like structures. The

faces of these unusual cages are composed of one or more proteins and are held



MOLECULAR CLEFTS, CAPSULES, AND CAGES



21



together by weak noncovalent interactions. Overall, capsids prototypically display

icosahedral (12 vertices and 20 equilateral triangular faces) structures—although

a number of other closed polyhedral shapes, including dodecahedra, truncatedicosahedra, and pentakis-dodecahedra, also occur.35 Similarly, lumazine synthase,

an enzyme that catalyzes the penultimate step in the conversion of a precursor to

riboflavin,36 has a shape composed of protein subunits in the form of a large icosahedral assembly (60 subunits ≡ 12 pentamer). Examples of larger synthetic cages

whose shapes resemble these unusual natural systems are presented later in this

chapter.

2.2.1



Organic Cage Systems



As intimated earlier, the range of purely organic cage and cage-like structures now

synthesized is quite large. Individual systems of great structural diversity have

been investigated across both the fully covalent and self-assembled categories.

For example, cage-like systems that range from simple self-assembling micelles

that can act as primitive hosts, to large container systems capable of including

a nanoscale guest or multiple smaller guests have now been reported.37 Indeed,

numerous organic cages and clefts of varying size have been synthesized over

the past 40 years or so. These include the well-known cryptand and fullerene

categories of closed cages as well as a range of fully organic “closed” and “open”

cages based on preformed macrocyclic scaffolds such as the natural cyclodextrins or

synthetic cyclic derivatives based on calixarene, resorcinarene, and curcurbit[n]uril

rings.29, 38, 39 Cram’s spherands, cavitands, and related derivatives also fall into

this category.40, 41

Fully covalent larger organic cages and cage-like systems not derived from the

preformed ring systems just mentioned have also been synthesized via conventional

direct organic synthesis starting from a range of precursors.42 – 44 However, in part

as a consequence of the nonreversibility of the majority of most classical organic

reaction types, such cavity-containing products have tended to be obtained in quite

low overall yield.42 For example, the interesting cage trinacrene 1 (Scheme 2.1),

which was proposed as a suitable host for a range of organic, organometallic, and

O



O

O



O



O



O



O



O

O

1



Scheme 2.1



22



BIOINSPIRED SELF-ASSEMBLY I: SELF-ASSEMBLED STRUCTURES



inorganic guests,45 was prepared in a conventional four-step synthesis starting from

furan and hexabromobenzene in an overall yield of less than 0.01%!42, 46

In view of the above propensity for conventional synthetic procedures to result

in low overall yields, the use of a template strategy provides a potential means for

assisting the formation of a particular cavity-containing product in higher yield.

With regard to this, it is noted that templation is a common process employed

by Nature for directing the formation of covalent bonds—as exemplified by the

building of protein chains on messenger RNA via catalysis involving the ribosome. Indeed, the use of templation to direct the formation of self-assembled cages

and capsules has been a moderately common procedure over many years.47 For

example, in a recent study, it was demonstrated that the water soluble cavitand 2

(Scheme 2.2) spontaneously forms a self-assembled dimeric capsule in the presence

of different hydrophobic templating guests that include highly complementary rigid

steroids as well as, perhaps surprisingly, flexible straight-chain hydrocarbons.48

The templating action in the latter case is presumably driven by weak C-H-π

interactions of the hydrocarbon guests with 2 as well as through the operation of

the hydrophobic effect.

In contrast to the above self-assembled (supramolecular) systems, the use of

templates has been less frequently exploited for the preparation of fully covalent cage and capsule products,41 especially for synthesizing larger (nanoscale)

cages.

Although in principle more restricted in scope, the rise of dynamic covalent

chemistry49, 50 over recent years has provided a successful approach for the synthesis of a number of larger all-covalent organic cages. The use of dynamic covalent chemistry mimics the reversible behavior associated with many biosynthetic



H

O



O



O



O



O



O



O



O

HO



O



HO



O



H



H

O



O



H



H



O



O



O



O



H



HO



O



H

O



HO



OH



OH



O



H



H



O



O

2



Scheme 2.2



O



O



OH



O



OH



23



MOLECULAR CLEFTS, CAPSULES, AND CAGES



processes in that it relies on reversible covalent bond formation and hence promotes

the formation of the target cage in higher yield through the provision of “error correction” (provided the cage corresponds to the most stable thermodynamic product

under the conditions employed).50, 51

For the majority of studies of the above type, the synthetic procedure has been

centered on the use of reversible imine (Schiff base) bond formation.42, 52 Imine

linkages are one of the few organic groups that can exist in solution in equilibrium

with their precursors—namely, the corresponding carbonyl (aldehyde or ketone)

and amine derivatives—where the equilibrium corresponds to the reversible hydrolysis or solvolysis of the imine linkage. In an increasing number of instances such

an approach has allowed the generation of cages in fewer steps and in higher

yield than occurs on employing a more traditional synthetic approach such as that

exemplified by the synthesis of 1 (Scheme 2.1).

The power of dynamic covalent synthesis is convincingly demonstrated by

its use in a one-pot synthesis to yield imine-linked, fully covalent nanocubes of

type 3 (Scheme 2.3). Both cubes were obtained in approximately 90% yield.

In these products the tritopic C3 -triformylcyclobenzylene unit 4 (Scheme 2.3)

was employed to form each corner of the cube, with the corners being linked via

linear diamines to yield the sides. Overall, this involved the formation of 24 imine

bonds. The tri-aldehyde 4 was chosen as a suitable precursor for the corners since

the linked aryl units holding the aldehydes are essentially orientated mutually

orthogonally. The mixing of 4 with the required diamine (1,4-phenylenediamine

or benzidine), in an 8:12 ratio in chloroform containing trifluoroacetic acid

as catalyst, led in each case to the formation of the corresponding cube of

type 3.



OR

X

OR



RO



RO

RO



X

OR

RO



X

X



OR



OR



X



X



X



CHO



OR

CHO



X

RO

OR



RO



RO

4



RO



OR



OR

RO



RO



X



OR



RO



OHC



RO

RO



OR

Where X =



N



or



N



N



X



X

OR



and R = hexadecyl



3



Scheme 2.3



N



24



2.2.2



BIOINSPIRED SELF-ASSEMBLY I: SELF-ASSEMBLED STRUCTURES



Metallosupramolecular Cage Systems



There are now a very considerable number of metallosupramolecular cage and

capsule systems formed by self-assembly processes in which metal ions are incorporated in the framework of the cage structures and which show inclusion behavior

that resembles that exhibited by biological systems. As some of these systems have

recently been reviewed,6, 16, 22, 26, 27, 53 only a selected few examples will be mentioned here. In the first of these, Fe(II) was demonstrated to interact in acetonitrile

with the quaterpyridine-derived ligand 5 (Scheme 2.4), leading to the assembly of

an 8+ charged tetrahedral shaped cation of type [Fe4 L6 ]8+ which was found to

spontaneously encapsulate the polyatomic anions BF4 − , PF6 − , and [FeCl4 ]− from

solution.25, 54

There is evidence that the smaller BF4 − anion undergoes fast exchange in and

out of the cavity while the larger PF6 − anion is slow to enter the cavity and, once

inside, showed no tendency for exchange under ambient conditions. The structure

of the [FeCl4 ]− inclusion complex is depicted in Figure 2.2.24 In this case the cage

H3C



CH3

N



N



N



N



5



Scheme 2.4



Figure 2.2 X-ray structure of the cationic metallosupramolecular cage [Fe4 L6 (FeCl4 )]5+

in which an [FeCl4 ]− anion occupies the center of the tetrahedron.



MOLECULAR CLEFTS, CAPSULES, AND CAGES



25



OH



HO

O



O

6



Scheme 2.5



was shown to be selective for the singularly charged Fe(III) species, [FeCl4 ]− , over

its doubly charged Fe(II) analog, [FeCl4 ]2− .

In contrast to the above cationic cage, the extended neutral tetrahedral cage

assembled from the doubly deprotonated form of 6 (Scheme 2.5) (incorporating

4,4 -biphenylene rather than 1,4-phenylene spacers) and Fe(III) in tetrahydrofuran (THF) was shown by X-ray diffraction to have the structure illustrated by

Figure 2.3.

˚ 3 and was found to

This metallocage has an enlarged internal volume of 844 A

encapsulate four tetrahydrofuran solvent molecules in the solid state,55 contrasting



Figure 2.3 X-ray structure of the neutral metallosupramolecular cage [Fe4 L6 (THF)4 ]5+

in which four tetrahydrofuran molecules occupy the cavity of the tetrahedron.



26



BIOINSPIRED SELF-ASSEMBLY I: SELF-ASSEMBLED STRUCTURES



˚ 3 volume observed for the smaller phenylene-spaced analog which

with the 174 A

included a single tetrahydrofuran molecule.

As mentioned already, many examples of larger self-assembled metallocages

displaying other polyhedral shapes have also been reported by various groups. The

design and successful synthesis of new “box-like” (cubic) cages based on the subcomponent Schiff base assembly reaction shown in Figure 2.4 has been reported.56

In this, the reaction of the Ni(II) or Zn(II) tetrakis(4-aminophenyl)porphyrin complexes of type 7 (or the corresponding diprotonated free ligand–not shown in

Figure 2.4) with 2-formylpyridine and Fe(II) trifluoromethanesulfonate (triflate,

OTf− ) in dimethylformamide (DMF) yielded the corresponding tetra-Schiff base

derivative intermediates of type 8 (ML, where M = Ni or Zn). Reaction of these

with Fe(II) resulted in metal-directed assembly to form the corresponding cubic

assembly.



Figure 2.4



Synthesis and structure of metallo-cubes of type 9.



MOLECULAR CLEFTS, CAPSULES, AND CAGES



27



The X-ray structure of the guest-free [Fe8 (M-L)6 ]16+ (M = Ni) cage incorporating Ni(II) in the respective porphyrin rings of each L is given as 9 in Figure 2.4.

Each face of the cube is formed by a porphyrin moiety with each corner occupied

by a low-spin Fe(II) metal center that has an octahedral N6 -donor coordination

shell derived from three pyridylimine fragments from three different M-L ligands.

Single cubes display homochirality with respect to their Fe(II) centers, while their

single crystals are racemic with equal numbers of each chiral form present. The

˚ 3 in this case. An integral part of the design

internal volume of the cage is 1340 A

of this cage type was the incorporation of large areas of π -electron density in the

walls of the cavity since it was a goal of this investigation to produce a receptor

cage that would include large unsaturated organic species such as (flat) coronene

(C18 H12 ) as well as individual spherical fullerene molecules.

Accordingly, the [Fe8 (M-L)6 ]16+ (M = Ni) cage was found to uptake three

coronene molecules while both C60 and C70 were demonstrated to form 1:1 inclusion complexes, with the latter fullerene showing higher binding affinity, perhaps

reflecting the less symmetrical nature of this guest, allowing greater π –π interaction with the cavity walls. NMR evidence suggested that the three coronene

molecules adopt a triple-sandwich π -stacked arrangement. Because the pore sizes

in the walls of the fully formed cage type are quite small (with a spherical guest

˚ to enter the cage without distorting the

requiring a radius of no greater than ∼1 A

pore), it was postulated that guest exchange requires decomplexation of at least one

of the pyridylmethyl imine arms from a Fe(II) center. Thus, a “gate mechanism,”

which in principle can be controlled chemically, for example, by pH variation,

appears to be a feature of (large) guest binding by this cage type.

Over recent years a series of M12 L24 spherical assemblies have been generated

using self-assembly procedures, with such species typically having diameters of

several nanometers. An early example of such a self-assembled metallocage was

reported in 2001.57 The self-assembly of isophthalic acid (1,3-benzenedicarboxylic

acid) with Cu2+ yielded such a product composed of 12 dinuclear copper paddlewheel cluster units and 24 bridging dicarboxylate ligands in the shape of a discrete

˚ 3.

polyhedron with an internal spherical cavity estimated to be close to 1600 A

At about the same time a similar structure was found to self-assemble from the

interaction of 5-hydroxy-isophthalic acid with Cu2+ .58 The kinetics of formation

of this functionalized derivative has since been reported59 and its incorporation

into polymers investigated.60 The cage displays cuboctahedral symmetry and is

remarkably stable.61 The large internal cavity of this polyhedron is maintained by

the rigid metal–organic scaffold.

A further example of such a highly symmetric assembly from the Fujita group

is shown in Figure 2.5.62 This structure also self-assembles from a total of 36

components (12 Pd(II) and 24 L) and once again displays cuboctahedral symmetry

(diameter of 2.6 nm). Unlike the formation of infinite metal–organic framework

structures by linear rod-like ligand systems, the slight bend in the present ligand

(see Figure 2.5) results in a constant radius of curvature as the structure assembles,

ultimately leading to the observed finite spherical network whose impressive capsidlike structure was confirmed by an X-ray diffraction study.



28



BIOINSPIRED SELF-ASSEMBLY I: SELF-ASSEMBLED STRUCTURES



Figure 2.5 The X-ray crystal structure of the nanocage of composition [Pd12 L24 ]24+ ;

counterions and solvent molecules are not shown.



Most recently, these structures have been extended to M24 L48 spherical assemblies with a mass of >20,000 Da. Not surprisingly, such species have a substantially

larger diameter, approaching 4.0 nm.23

2.3 ENZYME MIMICS AND MODELS:

THE EXAMPLE OF CARBONIC ANHYDRASE

As already mentioned, the ubiquitous enzymes are, of course, especially characterized by the selective uptake of a guest substrate into an encapsulating cavity or

pocket, coupled with high induced catalytic reactivity. As for “simple” cage and

cage-like systems of the type just discussed, the characteristic substrate selectivity

shown by the enzymes is clearly again strongly associated with the nature of the

cavity; including its dimensions, lipophilicity, and the presence or absence of complementary functional groups. The presence of a portal and/or sufficient flexibility

of the host cage to permit ingress and egress of a substrate is also an important

feature.63

In general, two goals have predominated in the investigation of synthetic enzyme

mimics: first, as an aid for defining the active site of a natural system as well

as for probing its potential mode of action; and second, to probe the possibility



ENZYME MIMICS AND MODELS: THE EXAMPLE OF CARBONIC ANHYDRASE



29



of producing a functioning catalyst system for application in the “real world.”

However, in general, the catalytic activity of most synthetic systems tends to be

low to moderate in comparison to that of the native enzymes—in part, likely due

to the common absence of some form of polyfunctional activation in the former,

relative to the situation known to occur in most natural enzymes. The following

discussion focuses on the well-studied zinc enzyme carbonic anhydrase.

Carbonic anhydrase II is an enzyme that reversibly converts carbon dioxide into

the bicarbonate ion. The active site incorporates a zinc ion bound to three histidines

and a water molecule, such that a distorted tetrahedral coordination geometry is

present. A feature of the system is that the zinc-bound water molecule has a pKa

of near 7 and hence is readily deprotonated under physiological conditions (see

Figure 2.6). Deprotonation is promoted by the Lewis acidity of the zinc center but

also appears to be assisted by the bound water being part of a hydrogen bonded

network within the cavity (not shown).

There have been many studies employed to model the active site of carbonic

anhydrase, with most of these involving the assembly of simple zinc complexes

using a selection of ligand types that were perceived to be suitable for modeling the

nature of the histidines in the natural system. Most of the studies have focused on

the role of the Zn(II)–OH− group for the hydration of CO2 (as well as on the reverse

process, the dehydration of HCO3 − ).64 For example, in a series of early studies, tripodal (substituted) tris(pyrazolyl)borate ligand derivatives were employed to

form complexes of type [ZnL(OH)]+ as mimics of the active site of carbonic anhydrase. The resulting complex assemblies showed similarities to the natural system.65

First, the coordinated zinc is tetrahedrally coordinated. Second, the low pKa of the

zinc-bound water was demonstrated (∼ 6.5 in one instance) and, third, it was also

shown that the bound hydroxide ion reacts rapidly and reversibly with CO2 .

In other, related biomimetic studies, Kimura and co-workers have investigated

the zinc complex, [ZnL(H2 O]2+ , where L is the triaza-macrocycle,1,5,9triazacyclododecane 10 (Scheme 2.6). The pKa of the zinc-bound water molecule

measured by potentiometric means was 7.3—again close to that of the natural

system.64, 66 This zinc complex system was demonstrated to induce catalytic



H

O

Zn2+



N



N



NH



N

N

H



Figure 2.6



NH



Part of the active site of carbonic anhydrase II.



Tài liệu bạn tìm kiếm đã sẵn sàng tải về

2 Molecular Clefts, Capsules, and Cages

Tải bản đầy đủ ngay(0 tr)

×