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

Electroanalytical sensors using lipophilic cyclodextrins

Lipophilic dialkylated-a-, β- and γ-cyclodextrin derivatives were used as selective ionophores for a series of clinically relevant ammonium ions, and as enantioselective ionophores for both a- and β-aryl ammonium ions. Sensitive and selective potentiometric detection of the local anaesthetics lidocaine and bupivacaine was achieved by using 2,3,6 trioctyl-β-cyclodextrin as the ionophore, leading to micromolar detection limits. Interference studies showed that the simulated clinical electrolyte background caused minimal interference whereas organic interferents of similar size and charge caused some perturbation of the electrode response at a concentration of 10 mmol dm(^-3). An electrode comprising a plasticized biocompatible membrane matrix, TECOFLEX, with 2,6 didodecyl-β-cyclodextrin was incorporated in a flow injection analysis system and the response to lidocaine studied in the presence of human serum. Human serum caused no adverse effects to the electrochemical response of the electrode. These electrodes are, therefore, very suitable for on-line detection of local anaesthetics. Potentiometric detection of tricyclic antidepressants using didodecyl-a-, β- and γ- cyclodextrins as the ionophore, gave micromolar detection limits. Interference from simulated clinical electiolyte background and selected organic interferents gave similar results to those discussed above. In order to lower the detection limit to sub-nanomolar levels modified amperometric electrodes were assembled by depositing a membrane comprising plasticised TECOFLEX, 2,3,6 triethyl-β-cyclodextrin and TKB on the working electrode of a screen printed electrode. Lipophilic 2,6 didodecyl-a- and β-cyclodextrins exhibited enantiomeric discrimination in the binding of propranolol, ephedrine, amphetamine and methamphetamine. These results were confirmed using potentiometric and NMR techniques

Supramolecular Luminescent Sensors

There is great need for stand-alone luminescence-based chemosensors that exemplify selectivity, sensitivity, and applicability and that overcome the challenges that arise from complex, real-world media. Discussed herein are recent developments toward these goals in the field of supramolecular luminescent chemosensors, including macrocycles, polymers, and nanomaterials. Specific focus is placed on the development of new macrocycle hosts since 2010, coupled with considerations of the underlying principles of supramolecular chemistry as well as analytes of interest and common luminophores. State-of-the-art developments in the fields of polymer and nanomaterial sensors are also examined, and some remaining unsolved challenges in the area of chemosensors are discussed

Supramolecular sensing at the solid-liquid interface with phosphonate cavitands

The base of supramolecular chemistry rests on molecular recognition, that is the selective recognition of substrate molecules (guest) by synthetic receptors (host). The present thesis deals with the selective recognition properties of tetraphosphonate cavitands towards N-methylpyridinium and N-alkylammonium salts. In the first part of the thesis an extensive study of the thermodynamics of the complexation properties of tetraphosphonate cavitands towards N-methylpyridinium salts in solution via Isothermal Titration Calorimetry (ITC) is reported. The information obtained by the ITC in the recognition process of the receptor towards N-methylpyridinium salts were then exploited for the design of a new type of non-covalently linked-cavitand-stopped rotaxane. In the second part of the work, the complexation properties of cavitands were assessed towards N-alkylammonium salts at the solid-liquid interface via microcantilevers reaching an unprecedented real-time label-free selectivity. ITC was used as an independent tool for confirmation and rationalization of the results obtained with microcantilevers-based sensor. This approach has been then benchmarked by differentiating biological important molecules like sarcosine and glycine in water, reaching unique performances. The results obtained for the N-alkylammonium salts series opened the route to use microcantilevers for the online monitoring and the label-free sensing of biologically active ammonium-based molecules like drugs. The first experiments performed to test the recognition properties of tetraphosphonate cavitands towards drugs at the solid-liquid interface are described.La base della chimica supramolecolare risiede nel riconoscimento molecolare, cioè nel selettivo riconoscimento delle molecola di substrato (guest) da parte del recettore sintetico (host). La presente tesi si occupa delle selettive proprietà di riconoscimento dei cavitandi tetrafosfonati verso i sali di N-metilpiridinio e di N-alchilammonio. Nella prima parte della tesi è riportato uno studio estensivo relativo alla termodinamica delle proprietà complessanti dei cavitandi tetrafosfonati verso i sali di N-metilpiridinio tramite Titolazione Calorimetrica Isoterma (ITC). Le informazioni ottenute tramite ITC riguardanti il processo di riconoscimento del recettore con i sali di N-metilpiridinio sono state successivamente sfruttate per il design di una nuova tipologia di rotaxano, utilizzando i cavitandi come stopper non covalentemente legati all'asse. Nella seconda parte del lavoro sono state studiate le proprietà complessanti dei cavitandi nei confronti dei sali di N-alchilammonio all'interfaccia solido-liquido via microcantilever, raggiungendo una selettività label-free in tempo reale senza precedenti. La calorimetria, in questo caso, è stata usata come strumento indipendente per la conferma e la razionalizzazione dei risultati ottenuti tramite microcantilever. Questo approccio è stato poi testato differenziando molecole biologiche chiave come sarcosina e glicina in acqua, raggiungendo performance uniche. I risultati ottenuti per la serie di sali di N-alchilammonio ha aperto la strada per l'utilizzo dei microcantilever nel monitoraggio on-line e nel sensing label-free di molecole contenenti il gruppo amminico biologicamente attive come le droghe. Nell'ultima parte del lavoro vengono descritti gli esperimenti preliminari eseguiti per testare le proprietà di riconoscimento dei cavitandi tetrafosfonati verso le droghe all'interfaccia solido-liquido

Computational approaches in supramolecular chemistry with a special focus on virtual screening

Within this thesis novel computational tools for the rational design of synthetic host-guest complexes (SHGC) were developed and applied that employ the concepts of efficient virtual screening (VS) approaches. The first part describes the development of a fast structure prediction tool for flexible SHGC. The tool was validated on a test dataset comprising crystallographically determined SHGC. In nine of ten cases near-native solutions were generated. The tool can be applied for VS. In the second part of the thesis computational techniques were applied for designing SHGC based on ß-cyclodextrins (ß-CD). We performed a structure-based inverse virtual screening for identifying modified ß-CDs as receptors for the anticancer drug camptothecin (CPT). Six of the proposed receptors exhibited binding affinities which were significantly higher than for any other CPT-receptor. Furthermore, we applied a combination of a similarity-based virtual screening technique with a regression model (RM) for identifying novel high affinity guest molecules of ß-CD. Ten of the proposed guest molecules exhibited a binding free energy of lower than -20 kJ/mol. The last chapter describes a comparison of regression methods regarding their ability to generate predictive RM for thermodynamical parameters (dG, dH and dS) of ß-CD-guest complexes. dG could be predicted in good agreement with experimental values, none of the methods led to comparably good predictive models for dH. dS appears almost unpredictable.Im Rahmen dieser Arbeit wurden rechnergestützte Verfahren (RGV) zum gezielten Entwurf von synthetischen Wirt-Gast Komplexen (SWGK) entwickelt und eingesetzt. Dabei wurde ein Fokus auf schnelle virtuelle Screening (VS) Verfahren gelegt. Der erste Teil beschreibt die Entwicklung eines Programms zur schnellen Strukturvorhersage von flexiblen SWGK. Das Programm wurde auf einem Testdatensatz an kristallographisch vermessenen SWGK validiert. Für neun von zehn SWGK wurden nativ-ähnliche Lösungen gefunden. Das Programm kann für VS eingesetzt werden. Der zweite Teil der Arbeit behandelt RGV zum gezielten Entwurf von ß-Cyclodextrin (ß-CD) Komplexen. Mit Hilfe eines strukturbasierten inversen VS wurden sechs modifizierte ß-CD-Rezeptoren für den Krebsarzneistoff Camptothecin (CPT) gefunden, die deutlich höhere Bindungsaffinitäten zu CPT aufwiesen als alle bislang bekannten CPT-Rezeptoren. Zur Identifizierung neuer hochaffiner Gäste von ß-CD wurde ein ähnlichkeitsbasiertes VS Verfahren in Kombination mit einem Regressionsmodell (RM) eingesetzt. Zehn der mit Hilfe dieses Verfahrens vorgeschlagenen Moleküle wiesen eine Bindungsenergie von unter -20 kJ/mol auf. Das letzte Kapitel beschreibt einen Vergleich von drei Regressionsverfahren. Es wurde die Fähigkeit untersucht, vorhersagekräftige RM für thermodynamische Parameter (dG, dH und dS) von ß-CD-Gast-Komplexen zu generieren. dG konnte mit allen Methoden sehr gut vorhergesagt werden, während dH nur begrenzt und dS unzureichend vorhersagbar war

Hierarchical Supramolecular Assemblies Based on Host-Guest Chemistry between Cucurbit[n]uril and Azobenzene Derivatives

Cucurbit[8]uril (CB[8]) has attracted great interest in the cucurbit[n]uril (CB[\textit{n}]) family on account of its capability to simultaneously accommodate two guests inside its cavity, to form strong yet dynamic ternary complexes.Owing to the photo-induced \textit{trans} to \textit{cis} isomerisation property, azobenzene (Azo) derivatives have been widely employed in several host-guest systems, leading to various light-responsive materials. This thesis focuses on CB[8]-based ternary complexes, especially those involving Azo derivatives. These systems can be exploited as a platform to hierarchically fabricate supramolecular constructs, including crystalline structures and composite materials. Specifically, novel morphology-controlled (1D needle-like, 2D sheet-like) crystals have been prepared by adjusting the assembly of Azo-CB[8] complexes, which can be further developed to oriented macroscopic free-standing crystalline pillars grown from a glass surface. Next, a composite micelle-nanoparticle complex has been prepared utilising Azo-CB[8] assemblies, which demonstrates $\sim$90$\%$ efficiency in surfactant recycling. Finally, an organic CB[8]-mediated hydrogel reinforced by inorganic nanowires has been prepared. This hybrid structure shows increased stiffness due to various supramolecular interactions. Chapter 1 gives a brief introduction to CB[\textit{n}] host-guest chemistry with emphasis on CB[\textit{n}]-based crystalline structures and CB[8] ternary complexes. Recent progress of Azo-based host-guest chemistry is then reviewed. In addition, shape-controlled crystals formed \textit{via} supramolecular interactions are discussed at the end of the chapter. Chapter 2 focuses on the crystalline structure of the 1:2 homoternary complex formed between CB[8] and a methyl orange (MO) guest, which is the fastest CB[8]-based crystallisation to date. As a commonly used pH indicator, MO possesses an azobenzene moiety with both an electronically positive amino group and an anionic sulfonate group. At low pH values, formation of the homoternary complex 2MO@CB[8] occurs, serving as a ‘tectonic’ building block, which rapidly stacks into a herringbone arrangement. The intermolecular and intercomplex interactions inside 2MO@CB[8] crystals are discussed, whereby the CB[8] macrocycle orients the electrostatic charges on MO guests resulting in the repulsive interactions being shielded; this in turn leads to fast electrostatically-driven crystal growth. The 2MO@CB[8] system provides a promising approach for designing ultrarapid crystallisation systems derived from CB[\textit{n}] host-guest complexes. Moreover, the host-guest chemistry between CB[8] and a variety of Azo derivatives with different functional groups is discussed, demonstrating the influence of guest structures on their crystalline behaviours. Chapter 3 further explores the mechanism of 2MO@CB[8] crystallisation through a series of experimental and computational methods. Control over the crystal shape, length and growth rate can be achieved in a facile manner whilst maintaining the same (internal) unit cell. Therefore, the properties of the macro-scale crystals can be tuned at the molecular level through adjusting the assembly of 2MO@CB[8] building blocks. For example, tuning the ionic strength of the solution enables a second growth dimension, yielding 2D crystals with sheet-like and more complex morphologies. Furthermore, our understanding of oriented electrostatics provided by the homoternary tecton can then be exploited to prepare oriented macroscopic free-standing crystalline pillars grown from a glass surface at room temperature. Next, CB[8] ternary complexes have been employed as ‘bridges’ to link (organic) soft and (inorganic) hard materials together, resulting in composite materials. In chapter 4, a micelle-nanoparticle complex (\textbf{MNC}) structure has been assembled \textit{via} host-guest interactions between Azo-functionalised, cargo-loaded micelles and magnetic SiO$_2$ nanoparticles (NPs) functionalised with CB[8] catenanes. Owing to the photo-responsive and magnetic properties, \textbf{MNCs} can be exploited to recycle detergents (micelles) from aqueous solution. This is followed by the controlled release of the encapsulated hydrophobic molecules inside the micelle cavity. In this process, both the micelles and NPs can be recycled efficiently. The novel \textbf{MNC} structure provides a promising approach to recycle versatile drug carriers through host-guest chemistry. Chapter 5 introduces a CB[8]-based hydrogel in which inorganic nanowires (NWs) are employed to enhance the gel stiffness. The supramolecular hydrogel is comprised of methylviologen-functionalised poly(vinyl alcohol) (PVA-MV), hydroxyethyl cellulose with naphthyl moieties (HEC-Np) and CB[8]. The gel structure is effectively enhanced by the framework supporting effects of CePO$_4$ NWs and additional hydrogen bonding interactions between NWs and PVA-MV/HEC-Np polymers. The high aspect ratio NWs serve as a ‘skeleton’ for the network, providing extra physical crosslinks. This results in a single continuous phase hybrid supramolecular network with improved strength, showcasing a general approach to reinforce soft materials. Finally, this thesis closes with a summary and perspective chapter, concluding the present work and highlighting an insight towards future work. Utilising CB[8] ternary complexes, various supramolecular constructs can be prepared through hierarchical self-assemblies, leading to a wide variety of composite systems and functional materials in the future.China Scholarship Council, Cambridge Commonwealth, European and International Trus

New approaches for the development of chromo-fluorogenic sensors for chemical species of biological, industrial and environmental interest

Tesis por compendioEl presente proyecto de investigación está enfocado al desarrollo de sensores químicos fluoro-cromogénicos, para la detección y determinación de especies químicas de interés biológico, industrial y medioambiental de forma selectiva y con alta sensibilidad. En forma general, se busca el diseñar nuevos sistemas sensores basados en compuestos (receptores) formados por dos unidades: una unidad coordinante que interacciona con el anión a determinar y una unidad generadora de señal que alerta del reconocimiento molecular efectuado. Durante este estudio se están preparando diversas moléculas receptoras funcionalizandas con grupos modificadores de estructura para evaluar su influencia sobre las capacidades de detección y selectividad como receptores de especies específicas en diferentes condiciones y medios. Las diferentes aproximaciones en prueba implican a su vez el diseño y síntesis molecular, así como el análisis de las diferentes señales ópticas producidas en el reconocimiento, con el fin de diseñar sistemas de alta eficacia y eficiencia, y con posibilidades reales de aplicación.Santos Figueroa, LE. (2014). New approaches for the development of chromo-fluorogenic sensors for chemical species of biological, industrial and environmental interest [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/43216TESISPremios Extraordinarios de tesis doctoralesCompendi

Chiral separation of ketoconazole and itraconazole anti-fungal drugs using experimental and computational approaches

Drugs with multiple chiral centers were observed as very effective for treating various diseases. However, the enantiomeric resolution of multiple chiral center racemates is not much developed compared to racemates having a single asymmetric center. This work aimed to develop a chiral separation method for antifungal drugs using electrokinetic chromatography (EKC) and to elucidate mechanism of enantioseparation using a computer-aided molecular modelling study. Two azole antifungal drugs were selected namely ketoconazole and itraconazole, which consists of two and three chiral centers, respectively. The separation for ketoconazole was achieved using heptakis (2,3,6-tri-O-methyl)-ß-cyclodextrin (TM-ß-CD), a commonly used chiral selector, as it is relatively inexpensive and has a low UV absorbance in addition to an anionic surfactant, sodium dodecyl sulfate. The optimum conditions for chiral separation of ketoconazole was achieved using 10 mM phosphate buffer at pH 2.50 containing 20 mM TM-ß-CD, 5 mM SDS, and 1.0% (v/v) methanol with an applied voltage of 25 kV at 25°C with a 5-s hydrodynamic injection time at 50 mbar. The four ketoconazole stereoisomers were successfully resolved within 17 min (total analysis time was 28 min including capillary conditioning). The migration time precision of this method was examined to give a repeatability and reproducibility with RSDs = 5.80% (n = 3) and RSDs = 8.88% (n = 9), respectively. A computational study, using quantum mechanics calculations with AutoDock and semi-empirical PM3 calculations, were used to predict the enantiodiscrimination of ketoconazole enantiomers. A Density Functional Theory (DFT) single-point calculation at the level of B3LYP/6-311G (d,p) was performed for the PM3-optimized complexes to obtain more accurate binding energy and also electronic structures of the complexes. Molecular docking and DFT were simulated to predict the enantioresolution of itraconazole with two types of cyclodextrins (CDs), TM-ß-CD and (2-hydroxylpropyl)-?-cyclodextrin (HP-?-CD). The difference in energies of the inclusion complexes between the enantiomers and CD is a measure of chiral discrimination, which results in the separation of the enantiomers in the experimental studies. The dual-CD and triple-CD methods were developed for chiral separation of itraconazole using EKC. Highly sulfated ß-cyclodextrin (S-ß-CD), (2-hydroxylpropyl)-ß-cyclodextrin (HP-ß-CD), TM-ß-CD and HP-?-CD were screened as possible chiral selectors for enantioseparation of itraconazole. The enantioseparation of itraconazole was achieved using 10 mM phosphate buffer solution at pH 3.62 containing a mixture of 10 mM of each HP-ß-CD, TM-ß-CD and HP-?-CD and an applied voltage of 25 kV at 25°C. Both computational and experimental investigations complement each other prior to chiral recognition mechanism. Combination of molecular modelling and capillary electrophoresis appears as a new emerging method for chiral analysis of pharmaceutical drugs

Towards Chiral Sensors

This research was based in the area of macrocycles and involved the synthesis, analysis and evaluation of novel chiral cyclophanes and crown ethers. The aim of this project was to use the knowledge from the disciplines of molecular recognition and molecular sensor technology to explore new directions in the developing field of molecular sensors for chiral molecules. The long term aim was to produce a general class of compounds that could be utilised as chiral sensors for a variety of guest molecules