Self-assembly thermodynamic reversibility

Kubo and Nishiyabu describe the use of reversible boronate esterification to build well-ordered microparticles through supramolecular polymerisation of benzene-l,4-diboronic acid with tetraols. When pentaerythritol is used as the tetraol component for self-assembly, thermodynamically stable flower-like microparticles are produced. Surface functionalisation enables formation of nanometal-deposited heterogeneous catalysts and white-light-emissive chemosensors. 

Tethering may be a reversible or an irreversible process. Irreversible grafting is typically accomplished by chemical bonding. The number of grafted chains is controlled by the number of grafting sites and their functionality, and then ultimately by the extent of the chemical reaction. The reaction kinetics may reflect the potential barrier confronting reactive chains which try to penetrate the tethered layer. Reversible grafting is accomplished via the self-assembly of polymeric surfactants and end-functionalized polymers [59]. In this case, the surface density and all other characteristic dimensions of the structure are controlled by thermodynamic equilibrium, albeit with possible kinetic effects. In this instance, the equilibrium condition involves the penalties due to the deformation of tethered chains. 

Many opportunities conversely are supported by reversible reactions of QM despite the noted complications. One example includes the synthesis and chiral resolution of binaphthol derivatives by two cycles of QM formation and alkylation.77 The reversibility of QM reaction may also be integrated in future design of self-assembling systems to provide covalent strength to the ultimate thermodynamic product. To date, QMs have already demonstrated great success in supporting the opposite process, spontaneous disassembly of dendrimers (Chapter 5). 

In terms of thermodynamics, two situations may arise in biocatalytic self-assembly (1) the enzyme reaction and self-assembly process are both favoured in isolation, or (2) the enzyme reaction itself is thermodynamically unfavoured but involves a small change in free energy that can be overcome by the overall free energy change from the stabilisation of the self-assembled structure. The latter gives rise to a fully reversible system that operates under thermodynamic control (Fig. 4). 

Fig. 4 Free energy diagram for the two possible situations in enzyme-triggered formation of supramolecular assembly. Left. The enzyme-catalysed reaction and self-assembly process are both favoured independently and therefore uncoupled. Right. Enzyme-triggered self-assembly under thermodynamic control formation of the building blocks is thermodynamically unfavoured in isolation and occurs in reversible fashion when coupled to a sufficiently stable self-assembled structure formation...

The weak physical forces that hold together self-assembled nanoparticles are, of course, susceptible to disruption under the influence of thermodynamic and/or mechanical stresses. Hence some workers have investigated ways to reinforce nanoscale structures via covalent bonding. For instance, improved stability of protein nanoparticles, in particular, casein micelles, can be achieved by enzymatic cross-linking with the enzyme transglutaminase, which forms bonds between protein-bound glutamine and lysine residues. By this means native casein micelles can be converted from semi-reversible association colloids into permanent nanogel particles (Huppertz and de Kruif, 2008). 

In a strict self-assembly process, the final product is produced entirely spontaneously when the components are mixed together in the correct ratios under a given set of conditions of temperature, pH, concentration etc. The product formation must be completely reversible and represent the thermodynamic minimum for the system. In essence, all the information necessary for the assembly to occur is coded into the constituent parts. The concept of strict self-assembly is rooted in the Thermodynamic Hypothesis of Afinison who suggested that under physiological conditions the native structure of a protein is... 

The clean, precise, and reversible modification of surfaces represents an important opportunity to expand the application range of self-assembly. In particular, the thermodynamic control and reversibility of CSA can be exploited for the error-free generation of three-dimensional architectures directly on surfaces. 

Many other examples of outwardly complex molecular structures, whose salient architectural features appear to self-assemble from their constituent building blocks, have been documented [16]. The formation of the DNA double helix from its constituent chains is perhaps the quintessential example, whilst the perfect reconstitution of the intact tobacco mosaic virus from its constituent RNA and protein monomers also exhibits all the hallmarks of a cooperative self-assembly process [17]. The same is true of ribonuclease. Reconstitution of this enzyme in the presence of mercaptoethanol, to allow reversible exchange of the four disulfide bridges, proceeds smoothly to generate eventually only the active conformation from many possible isomeric states [18], In each of these cases, the thermodynamic stability of the product is vital in directing its synthesis. These syntheses could therefore be termed product-directed. 

Scheme 1 The elegant 18-component self-assembly of molecular Borromean rings under thermodynamic control [156], which utilizes reversible imine bonds to incite self-correction of the iconic interlocked structure at equilibrium...

Template-directed synthesis has also been exploited for combinatorial purposes in which a reversible reaction and the use of thermodynamic templates have been used. Two different processes have been envisaged and validated, both of which consider the dynamic optimization of a receptor-ligand interaction where one of the partners is the template that drives the self-assembly of a reversible library of other partners from which the best binder for the template is selected (Fig. 8.53). If the receptor is a template, a library made using a reversible reaction is incubated with the receptor and... 

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