Chiral Auxiliaries and Chirogenesis

This Reprint Book highlights and overviews the most important and novel aspects of chiral auxiliary and chirogenesis in different natural/physical sciences and in modern technologies. In particular, some newly emerging classes of molecules used for these purposes are described. This book consists of four review articles and one research paper and is of interest for general chemistry readership, including graduate and postgraduate students, and for researchers specializing in the fields of chirality and stereochemistr

Estimation of Enantiomeric Excess Based on Rapid Host–Guest Exchange

Chiral molecules possess enantiomers that have non-superimposable chemical structures but exhibit identical nuclear magnetic resonance (NMR) spectra. This feature prevents the use of NMR spectroscopic methods for the determination of enantiomeric excesses (ee) of chiral molecules, using simple mixtures of their enantiomers. Recently, however, it was reported that the addition of a symmetrical prochiral molecule (a reporter or host) into a solution of chiral analyte can lead to estimation of ee through interactions involving rapid exchange of the chiral analyte (guest) in the formed host–guest complex. This is due to the ee-dependent splitting of NMR resonances of the prochiral host molecule based on averaging the chemical shift non-equivalency caused by the presence of a chiral guest. The mechanism is not dependent on diastereomer formation, and 1:1 host–guest complexes can also show ee-dependent NMR peak splitting. Prochiral molecules capable of ee sensing using the NMR technique are now referred to as so-called prochiral solvating agents (pro-CSAs). pro-CSAs represent a family of reagents distinct from the commonly used NMR chiral derivatizing reagents (where chiral auxiliaries are used to derivatize enantiomers to diastereomers) or chiral solvating agents (where chiral auxiliaries interact in an asymmetric manner with analyte enantiomers). pro-CSA methods are unique since neither pro-CSA nor NMR contains chiral factors, making the technique neutral with respect to chirality. Here, we review our recent work on this matter involving several different nominally achiral receptor molecules whose unique guest binding properties and solution characteristics (especially with regard to NMR spectroscopy) allow for the estimation of ee in the corresponding chiral guests

ENANTIOSELECTIVE CATALYSIS INSIDE RESORCIN[4]ARENE HEXAMER AND ITS DERIVATIVES

Molecular capsules can serve as enzyme mimetics enabling catalytic conversion of substrates inside the enclosed cavity. Supramolecular host XII self assembles via hydrogen bonds from six resorcin[4]arene building blocks 9b, and has an internal volume of 1400 Å3. Due to its highly dynamic nature, XII can reversibly encapsulate guest molecules and facilitate numerous reactions. Some of the reactions involving cationic intermediates require HCl as a co catalyst to occur inside hexameric capsule XII. However, the effect of the acid additive has never been investigated for capsule induced iminium co catalyzed 1,4 reduction of α,β unsaturated aldehydes. In the course of this work, we examined the influence of HCl and other additives on the reaction and revised the reaction conditions. Of particular interest is the positive effect observed for alcohol additive, which proved to be beneficial for this transformation inside XII. The optimized reaction conditions allowed to reach enantioselectivity of up to 92% ee. Additionally, we investigated the possibility of the direct chirality transfer inside similar to XII molecular capsules. Two different ways of introducing chirality on the resorcin[4]arene were explored. All of the obtained derivatives proved to self assemble in solution into hexameric capsules. These potentially catalytically active systems were further tested in terpene cyclization reactions. In this work, we report the first examples of optically active hexameric resorcin[4]arene based capsules and their ability to asymmetrically catalyze tail to head terpene cyclization reactions delivering up to 62% ee

Chemical Symmetry Breaking

This book entitled “Chemical Symmetry Breaking” is a collective volume of state-of-the-art reports on unique nonlinear chemical and physical symmetry-breaking phenomena that were experimentally observed upon a thermally or photochemically induced phase transition in various organic condensed phases, such as metastable liquid crystals, crystals, amorphous solids, and colloidal polymer materials, only under nonequilibrium conditions. Each author summarizes the introductory section in simple terms but in detail for beginners in this field. We wish that many readers familiarize themselves with the general concepts and features of nonlinear and nonequilibrium (or out of equilibrium) complexity theory, which govern a variety of unique dynamic behaviors observed in chemistry, physics, life science and other fields, so that they may discover novel symmetry-breaking phenomena in their own research areas

Unprecedented Reactivity of Fluorocarbons and the Synthesis of New Inclusion Compounds

A new and unprecedented reactivity of saturated fluorocarbons has been discovered. Application of this reaction to perfluorodecalin at ambient temperature and above is used to synthesis members of the 'octa-host' series. The mechanism of the reaction and its extension to analogous reactions, including different substrates (unsaturated fluorocarbons or other saturated fluorocarbons, particularly those with a tertiary carbon centre) and different nucleophiles is investigated. A Single Electron Transfer (SET) pathway is favoured. The 'octa-host' series itself, an extension of the 'hexa-host' series, is further investigated and new host inclusion discovered. A new class of host materials, octakis(aryloxy)naphthalenes, is synthesised. Structural investigation of six octa-hosts by X-ray single-crystal diffraction is used to elucidate their inclusion properties; uniquely one of the octa-hosts, octakis(m-tolylthio)-naphthalene has a 'clathrate' open-packed structure as a non-solvate, with no stabilisation other than by van der Waals forces . Another, octakis(cyclohexylthio)naphthalene, contains an axial C-S cyclohexyl bond conformation. These two solid-structures are also investigated by magic angle spinning solid state n.m.r. Other 'octa-host'-like variants were investigated, including routes to 'deca-hosts', anthracene based systems, both through classical synthesis routes and using the newly discovered reactivity of saturated fluorocarbons. More structural tuning of the 'hexa-'host' concept was investigated by the synthesis and solid-state structure elucidation of hexakis -(p-hydroxyphenyloxy) benzene, a potential beta-Hydroquinone analogue. Chiral legs for 'hexa-' and 'octa-hosts' were briefly investigated. The role of symmetry in partnership with molecular conformation and shape is analysed for the 'octa-hosts', C2 equivalents of the C3 'hexa-hosts', and general principles discussed. Fluorocarbon chemistry is summarised and recent progress in the directed design of inclusion compounds reviewed

Photo- and Redox-Driven Artificial Molecular Motors

Directed motion at the nanoscale is a central attribute of life, and chemically driven motor proteins are nature's choice to accomplish it. Motivated and inspired by such bionanodevices, in the past few decades chemists have developed artificial prototypes of molecular motors, namely, multicomponent synthetic species that exhibit directionally controlled, stimuli-induced movements of their parts. In this context, photonic and redox stimuli represent highly appealing modes of activation, particularly from a technological viewpoint. Here we describe the evolution of the field of photo- and redox-driven artificial molecular motors, and we provide a comprehensive review of the work published in the past 5 years. After an analysis of the general principles that govern controlled and directed movement at the molecular scale, we describe the fundamental photochemical and redox processes that can enable its realization. The main classes of light- and redox-driven molecular motors are illustrated, with a particular focus on recent designs, and a thorough description of the functions performed by these kinds of devices according to literature reports is presented. Limitations, challenges, and future perspectives of the field are critically discussed

Pt (Ⅱ) complexes-based assays for small biomolecules detection in aqueous media

Supramolecular principles such as self-assembly, stimuli-responsiveness, and adaptiveness are widely utilized concepts for developing advanced functional materials. Particularly, they have also significantly impacted analytical science development. In the last two decades, countless supramolecular binders, molecular probes, and chemosensors combined with innovative assays have led to a revolution in molecular sensing and medical diagnostics. Nevertheless, most of these molecular sensing systems are still suffering from either low-binding affinity or low-selectivity or decomposition in complex media such as biofluids, which are the main obstacles limiting their further practical applications. Therefore, the development of new molecular sensing systems that can reach practical requirements is still one of the frontiers in supramolecular chemistry. So far, traditional chromatography-based techniques, e.g., HPLC-MS, are often used for molecular sensing, which are reliable but usually time- and cost-intensive, difficult to do parallel analysis, and require trained personnel. Spectroscopic method-based chemosensors and probes may thus become more suitable for practical applications because of cost-effectiveness, ease of handling, and high-throughput screening ability. Herein, the self-assembling probe (SAP)-based molecular sensing concept is described. By combining molecular reactions and supramolecular interactions, both the high-selective and the high-binding affinity are achieved for the identification and quantification of analytes by utilizing SAP. Beginning with fundamental photophysical knowledge in luminescence, a general introduction of this thesis is given in Chapter 1. As primary candidates for constructing the self-assembling probes (SAPs), transition metal complexes, particularly platinum(II) complexes, are briefly reviewed, including their basic photophysics and applications. In addition, current molecular sensing concepts are introduced and discussed, providing the essential background for the proposed sensing concept in the following text. Small-emitting water-soluble fluorophores are in demand in many application fields, such as fluorescent labels in in-vivo research, indicator dyes in molecular sensing systems, and test cases for theoretical computation studies. In this context, a size-record breaking green-emissive fluorophore 3-hydroxy-isonicotinic aldehyde (HINA, 128 g/mol, λex = 525 nm) is investigated in Chapter 2. Furthermore, HINA also serves as the model case for demonstrating problems that molecular probes face, and it functions as a suitable indicator moiety in the construction of the SAPs. In Chapter 3, the self-assembling probe (SAP)-based molecular sensing concept is described, where time- and spectra-resolved information is observed for the distinction and quantification of target analytes. Due to the combination of the supramolecular and molecular interactions, thirteen tested structural similar analytes can be distinguished by merely using one probe, which overcame the low-selectivity problem of other current molecular sensing concepts. In addition, the potential application of SAPs in human biofluids is explored. As an extension of Chapter 3, Chapter 4 explores the mechanism of the high-selective SAP systems, which is essentially the supramolecular self-assembling of the SAP-analyte conjugates driven by the non-covalent interactions between the adjacent molecules. Therefore, the SAP concept was also applied for chirality sensing as the chiral analyte created a chiral environment and enhanced the chiral signal of the SAP-analyte conjugate. Finally, the conclusion of this thesis is given in Chapter 5. Outlook and suggestions regarding the further investigation of the SAP concepts are included as well

Toward Macromolecular Shape And Size Control: Novel Enantioselective Nitrations And Iterative Exponential Growth Methods For Polymer Synthesis

Chirality is a key principle in organic chemistry. All chiral compounds are non-superimposable mirror images of each other and therefore lack an improper axis of rotation (Sn). These mirror images often have identical properties in an achiral environment, however when two chiral molecules interact, they produce different shapes and properties. Nature, to this extent takes advantage of this aspect through unique formation of shape defined biological macromolecules that are tailored to carry out various life processes. This level of shape control is only made possible because of natural chiral monomers such as amino acids or glycosides that make up such macromolecules. Under new methods such as Chirality Assisted Synthesis (CAS), shape and size-controlled polymers and macromolecules can be realized through the use of chiral monomers to make well defined macromolecules. Because chirality dictates shape, and shape defines function in reference to macromolecules, controlling the chirality of monomers, while concurrently dictating shape and size can lead to the potential of biomimetic methodologies and cage like structures. Accessing shape defined monomers can be difficult especially when in reference to chiral compounds. The unique structure of enantiopure tribenzotriquinacenes show promise in the formation of well-defined cage like structures through utilization of CAS methodology. Synthesis of functionalized tribenzotriquinacenes along with development of an enantioselective electrophilic aromatic nitration method was attempted. Further exploration into the effectiveness of through-space enantioselective nitrations found a dependence on solvent temperature, and the auxiliary that is used. Synthetic difficulties, results, modifications and processes toward a generalized method are presented herein. In addition, controlling the size of polymers has always been a difficult synthetic challenge. Overall selectivity toward one product over another is determined via a variety of chemical properties. However, the formation of sequence and size defined polymers are a prominent aspect of natural polymers. The size selective synthesis, of unique ABAB sequenced polymers was attempted using an iterative exponential growth method. The ability to scale up these processes and create monodisperse oligoethers is also presented and described herein

Design, Synthesis and Characterisation of π-Extended Viologen-Based Molecular and Supramolecular Complexes with Cucurbit[n]urils

Viologens, 4,4'-bipyridinium dications (V$^{2+}$), have attracted much attention as electron mediators in a variety of photochemical, electrochemical and chemical processes ranging from catalysis, electrochromic devices to solar energy conversion and storage systems. % The different applications of viologens are related primarily to their facile one electron reduction of dicationic species, V$^{2+}$, to radical monocations, V$^{+.}$. % Moreover, the dynamic interactions of V$^{2+}$ derivatives with cucurbit[n]uril (CB[n], for n=7 or 8) macrocycles, the dimerisation of V$^{+.}$ radical cations inside the CB[8] molecular cavity as well as redox controlled stoichiometry of V$^{2+}$ based inclusion complexes make these systems highly attractive for supramolecular chemistry and dynamic nanosystems, $\textit{i.e.}$ molecular machines. % This doctoral thesis focuses on design, synthesis and characterisation of $\pi$-extended viologen-based molecular and supramolecular systems. % Integral to the project was to study assembly processes that involve extended viologen derivatives and CB[n] macrocycles as well as characterisation of the physicochemical properties of resulting host-guest systems. % A brief overview of viologen and CB[n] chemistry as well as fundamentals regarding self-assembly processes and how can they influence the optoelectronic properties of materials are discussed in Chapter~1. % % Chapter 2 describes the synthesis and characterisation of extended methyl viologen (EV[X]MV) derivatives with an aromatic extension between the pyridinium rings (X= phenylene, naphthalene, pyrene, chrysene, thiophene and dithiophene), their interactions with CB[7] and CB[8] macrocycles as well as physicochemical properties of the resultant host-guest systems are studied. % Methyl viologen (MV$^{2+}$) is a well-known guest for both CB[7] and CB[8] macrocycles. % On account of the different binding modes with CB[n], the optical as well as redox properties of MV$^{2+}$ can be modulated. % Here, the effect of the aromatic extension ([X]) on EV[X]MVs before and upon complexation with CB[7] and CB[8] is investigated using nuclear magnetic resonance (NMR), steady-state UV-Vis and photoluminescence (PL) spectroscopies as well as isothermal titration calorimetry (ITC) and cyclic voltammetry (CV). % Interestingly, dimerisation of selected extended methyl viologens with CB[8] and the charge accumulative properties of the resultant complexes were observed. In Chapter 3, synthesis and characterisation of a family of extended viologens with aromatic substituents (EV[X]R, further denoted as extended aryl viologens), their interactions with CB[7] and CB[8] macrocycles as well as physiochemical properties of the resultant host-guest systems are studied. % The design and synthesis of these new class of $\pi$-conjugated viologen derivatives are elaborated involving different aromatic bridging units, as well as rigid aromatic peripheral functionalisation with electron donating and electron withdrawing groups on the pyridinium rings. % Upon mixing with CB[8], the extended aryl viologen derivatives functionalised with electron donating groups self-assemble into 2:2 complexes. % Moreover, the extended work on EV[X]R molecules functionalised with different aromatic substituents, which are simultaneously encapsulated within CB[8] to form heteroquarternery complexes is discussed. % The nature and dynamics of the resulting ${\mathrm{CB[8]_2}}\cdot{(\mathrm{EV[X]R})_2}$ homo- and hetero-complexes are studied both in the ground as well as exited states upon interaction with light utilising NMR, steady-state and time-resolved spectroscopies as well as ITC experiments. Finally, in Chapter 4 the synthetic approach towards asymmetric aryl viologen (AV) and extended aryl viologen (EV[X]RR', where [X]= naphthalene) is presented. % Firstly, synthetic pathways based on the Zinke reaction for asymmetric aryl substitution of AV and EV are discussed. % Secondly, the supramolecular binding of the obtained asymmetric EV[Np]RR' with CB[8] is investigated along with the effect of supramolecular dimer formation on the optical properties. % Finally, the application of asymmetric aryl viologens in the formation of a bio-inspired nanofibers is presented.The Marie Curie FP7 SASSYPOL ITN (607602) programm

Protein nanopores as a platform for transmembrane nanodevices

Nanopore sensing has seen vast development over the past four decades. The technique originally looked to use electrophysiological methods to study native protein channels. However, it is now possible to exploit these proteins for sensing applications. Herein, we explore methods for covalent and non-covalent modification of a biological nanopore to achieve new functionality. Chapter 1 summarises the history of nanopore technology; from its inception as a method for studying native channels, to its deployment in nanopore sensing. To achieve effective sensing, native proteins have undergone a broad range of chemical modification to achieve enhanced functionality. This chapter explores the amalgamation of biological and solid-state nanopores. Chapter 2 seeks to the monitor the binding and catalytic turnover of substrates within a single cucurbituril molecule captured within a protein nanopore. Previous work has shown that cucurbiturils and cyclodextrins can transiently interact with an α-hemolysin channel. Capture of a single cucurbituril within a protein nanopore was achieved, and the dwell time of the binding events was optimised. Following this, it was demonstrated that observations of the catalysed Diels-Alder could be made at the single-molecule level. However, further optimisation of the resolution would be required to elucidate mechanistic information. Chapter 3 presents methods for in situ chemical functionalisation of a biological nanopore. Here, the focus is upon the chemical modification of a wild-type protein thereby to circumventing the need for mutagenesis. Three target residues are discussed: lysine, methionine and tyrosine. Successful modification was achieved at both the lysine and methionine sites of α-hemolysin. While some provisional success was recorded with tyrosine, the modifications were not reproducible. Chapter 4 introduces preliminary work towards the development of transmembrane molecular machines. This utilises the lysine modification discussed in Chapter 2 to covalently attach established synthetic molecular machines to the channel. Molecular switches, motors and pumps were all explored. Some success was achieved attaching the molecular machines to a protein channel. However, issues with pore stability limited the progress and true machine-like behaviour was not observed