Revealing the art and science of self-replicating rotaxanes

Abstract

This thesis reveals the strategies for the construction and replication of mechanically interlocked molecules, particularly rotaxanes, which consist of a macrocyclic ring that encircles a linear component terminated with bulky groups. The work highlights our recent research activities in exploring the recognition-mediated synthesis of this class of interlocked molecule and its amplification by replication. Our starting point is the minimal model of self-replication. The introductory chapters (Chapter 1 and 2) provide some background and significance to the study, which presents comprehensive review of the published work carried out in the area of self-replication with existing examples from biomimetic and discrete synthetic assemblies. In Chapter 1, we mainly discuss the do and the donʼts in designing successful self-replicating systems based on our own experience in previous work. Our chief concerns in Chapter 2 are the understanding of the chemistry of the mechanical bond and the synthesis of rotaxanes by three means of approaches (clipping, threading and stoppering, and slippage). Attractive and useful examples are illustrated for each mechanism. Moreover, the definition and the roles of templated-synthesis of interlocked molecules are described. Recent advances in the understanding of the nature of the mechanical bond have also been introduced into molecular electronic devices. Emphasis is placed in Chapter 3 upon the essential requirements for the design of self-replicating rotaxanes, namely a recognition site, a reactive site and a binding site. These aspects are explained in the designed minimal model chosen in the past (Replication model 1) and the alternate proposed models (Replication model 2 and Replication model 3). The importance of high association constant to provide substantial amount of pseudorotaxane [L•M] precursors is exemplified in the simple kinetic model of rotaxane formation. The advantages and disadvantages of each independent minimal replication model are also summarized. In the self-replicating rotaxane frameworks, the principal strategy involves a selection of an efficient macrocycle to accommodate the guest unit. Thus, Chapter 4 exclusively describes the design, synthesis and binding properties of a series of macrocycle incorporating the hydrogen bond donors and/or hydrogen bond acceptors motif. In particular, the guests were designed and synthesised based on the mutual interactions with the macrocycle framework and the binding experiments is described in details. An account is provided of the problems faced in the synthetic attempts towards the formation of these macrocycles. The novel macrocycle MEU demonstrated a deficient binding performance with amide and urea compounds, and thus abandoned in later stages. The developed macrocycle MDG and MP have been selected as our workhorse macrocycles, which successfully increase the binding strength in the pseudorotaxanes formation. We have learnt that the association constant, Kₐ can be manipulated by the changing the binding site of the guest or redesign the framework of the macrocycle itself. An exhaustive investigation of the performance of self-replicating rotaxanes focuses on Replication model 1 is demonstrated in Chapter 5. It was evident now that as a consequence of low Kₐ, a substantial amount of thread is present over rotaxane. The implementation of the simple kinetic model of rotaxane formation is prevailed through out this chapter. The position of the central reversible equilibrium in this model effectively resulted in a different reactivity of thread and rotaxane. Therefore, it is concluded that the ratio of rotaxane and thread is sensitive to both the association constant for the [L•M] complex and to the ratio of k[subscript(rotaxane)]/k[subscript(thread)]. The key marker for the efficiency of the rotaxane-forming protocol is the ratio of rotaxane, R to thread, T. In previous chapter, the Kₐ for the [L•M] complex was around 100 M⁻¹ and k[subscript(T)] = 3 k[subscript(R)], which led to an unacceptably small [R]/[T] ratio. We demonstrated for the first time in Chapter 6, that it is possible to manipulate the Kₐ for the [L•M] complex by means of a change in temperature. Yields of a rotaxane can be improved by employing a two-step capture protocol. Cooling a solution of the linear and macrocyclic components required for the rotaxane increases the population of the target pseudorotaxane, which is then captured by a rapid capping reaction between an azide and PPh₃. The resulting iminophosphorane rotaxane can then be manipulated synthetically at elevated temperatures. Following this, these imines could be reduced readily to afford the stable amine rotaxane. Replication model 2 is subsequently proposed as alternate replication framework in Chapter 7, which realised significant advantages over the first model. A number of designs of a potential self-replicating rotaxane have been fabricated in order to integrate self-replication with the formation of rotaxanes. An account is provided of the problems faced with the unanticipated larger cavity of the newly prepared acid recognition macrocycles, and hence, force us to search for a new scaffold of the nitrone structures. Pleasingly, a substantial amount of rotaxane was present, mostly as trans diastereoisomer. It is concluded that the resulting rotaxane structures may be self-replicating through the recognition-mediated pathways from the preliminary kinetic experiments. Nonetheless, the remainder of the full kinetic analysis are prevented given a small quantity of the necessary building block. Chapter 8 reveals our recent efforts to demonstrate the notions behind the final replication scheme, Replication model 3. We have become aware that the reactive site must be placed sufficiently far away from the binding site to inhibit the remote steric effect through the proximity of the macrocyclic component. The design of novel nitrone structures is described in details. We bring together conclusions that can be drawn from three designated replication models in Chapter 9. Experimental and synthetic procedures of the target compounds and appropriate spectroscopic analysis of the products are elaborated in Chapter 10.