No / The separation of racemates into pure enantiomers through crystallization is an important industrial process. This study provides further validation of a novel, predictive approach for spontaneous resolution in which crystal structure prediction simulations are used to explore the relative stabilities of racemic solids versus enantiopure solids. 2-(4-Hydroxyphenyl)-2,5,5-trimethylpyrrolidine-1-oxy (compound 1) has previously been shown to be a racemic conglomerate, while a similar compound, 2-(3-hydroxyphenyl)-2,5,5-trimethylpyrrolidine-1-oxy (compound 2), was not. A conformational search using the Dreiding force field revealed 10 conformational minima for compound 1, and 20 for compound 2. Atomic charges were calculated using unrestricted DFT B3LYP 6-311G** optimized structures, and a crystal structure prediction was performed using the Dreiding force field, considering all low-energy gas-phase conformations and all relevant space groups. Analysis of the predicted crystal structures suggests that compound 1 is a racemic conglomerate, but compound 2 is not. This is in agreement with the experimental evidence.

No / The triazoylketone discussed in this paper crystallises from racemic solutions as a conglomerate. Here, we report the ternary phase diagram confirming the conglomerate behaviour of this molecule. Through computation we also explore the underlying reasons for the absence of a racemic compound in this system and the evident epitaxial crystallisation leading to crystals of almost racemic compositions but which retain the crystal structure of the pure enantiomer. / EU-project ‘IntEnant’, Integrated Synthesis and Purification of Enantiomers

The reaction of [BrRe(CO)₄]₂ with 2-(diphenylphosphino)pyridine (PN) and 6-(diphenylphosphino)-2-formylpyridine (PON) was investigated. The reactions were regiospecific and exclusively produced the phosphorus-coordinated products, BrRe(CO)₄(κᵖ-PN) and BrRe(CO)₄(κᴾ-PON). The kinetics for the chelate ring closure (κᴾ→ κᴾᴺ) in BrRe(CO)₄(κᴾ-PN) were confirmed to occur by dissociative CO loss. The reaction of [BrRe(CO)₄]₂ with 2-(diphenylphosphino)pyridine (PN) was modeled computationally by DFT calculations. The preferred reaction pathway for the substitution reaction was determined to occur by direct attack of the pnictogen donor on the dimer and formation of the κᴺ isomer as the kinetic substitution product occurs. The κᴺ kinetic product then rapidly isomerizes to the κᴾ thermodynamic product by way of a reversible ligand dissociation. Treatment of the tetrahedral cluster H₂Ru₃(CO)₃(μ₃-S) (1) with 2-(diphenylphosphino)thioanisole (PS) furnishes the cluster H₂Ru₃(CO)₇(κ²-PS)(μ₃-S) (2). Cluster 2, which exhibits a chelated thiophosphine ligand (κ²-PS), exists as a pair of diastereomers with Keq = 1.55 at 298 K that differ in their disposition of ligands at the Ru(CO)(κ²-PS) center. The PS ligand occupies the equatorial sites (Peq, Seq) in the kinetic isomer and axial and equatorial sites (Pax, Seq) in the thermodynamically favored species. The reversible first-order kinetics to equilibrium have been measured experimentally by NMR spectroscopy and HPLC over the temperature range 293-323 K. The substitution reaction involving 1 and the isomerization of the PS ligand in 2 were investigated by DFT calculations. The computational results support a phosphine-induced expansion of the cluster polyhedron that is triggered by the associative addition of the PS donor to 1. The observed isomerization of the PS ligand in 2 is best explained by a tripodal rotation of the CO and PS groups at the Ru(CO)(κ²-PS) center that is preceded by a regiospecific migration of one of the edge-bridging hydrides to the non-hydride-bridged Ru-Ru bond in 2. The chiral clusters 1,2-Ru₃(μ-H)₂(μ₃-S)(CO)₇(μ-1p1,2p2-POP) (A) and 1,2-Ru₃(μ-H)₂(μ₃-S)(CO)₇(μ-1p2,2p1-POP) (B) were formed were formed from reaction of Ru₃(μ-H)₂(μ₃-S)(CO)₉ with 1-diphenylphosphino-2-[2-(diphenylphosphino)ethoxy]benzene (POP). Chiral clusters A and B were fully characterized by IR and NMR spectroscopy. Additionally, the molecular structure of A was solved by X-ray crystallography. Chiral cluster A was resolved into its enantiomers by preparative HPLC with a chiral column. The enantiomers were characterized by electronic circular dichroism (ECD) spectroscopy and their absolute stereochemical configuration was determined by X-ray crystallography.

Yes / Mandelic acids are prototypic chiral molecules where the sensitivity of crystallized forms (enantiopure/racemic compound/polymorphs) to both conditions and substituents provides a new insight into the factors that may allow chiral separation by crystallization. The determination of a significant number of single crystal structures allows the analysis of 13 enantiopure and 30 racemic crystal structures of 21 (F/Cl/Br/CH3/CH3O) substituted mandelic acid derivatives. There are some common phenyl packing motifs between some groups of racemic and enantiopure structures, although they show very different hydrogen-bonding motifs. The computed crystal energy landscape of 3-chloromandelic acid, which has at least two enantiopure and three racemic crystal polymorphs, reveals that there are many more possible structures, some of which are predicted to be thermodynamically more favorable as well as slightly denser than the known forms. Simulations of mandelic acid dimers in isolation, water, and toluene do not differentiate between racemic and enantiopure dimers and also suggest that the phenyl ring interactions play a major role in the crystallization mechanism. The observed crystallization behavior of mandelic acids does not correspond to any simple “crystal engineering rules” as there is a range of thermodynamically feasible structures with no distinction between the enantiopure and racemic forms. Nucleation and crystallization appear to be determined by the kinetics of crystal growth with a statistical bias, but the diversity of the mandelic acid crystallization behavior demonstrates that the factors that influence the kinetics of crystal nucleation and growth are not yet adequately understood. / EPSRC, Max Planck Society for the Advancement of Sciences, UCL-MPS Impact Ph.D. Fellowship, EU COST Action

This research was focused on the study of the polymer dormant radical systems, species containing free radical structures that have longer lifetimes and greater stability than radicals in general. In order to understand the nature and reactivity of the dormant radicals, polymeric systems capable of producing dormant free radicals were synthesised. In addition, the use of these novel polymeric materials in a range of applications were studied. Those applications exploited the nature of the dormant radical groups and included controlled modifications in the polymeric structure, heterogeneous catalysis and chromatographic separations.

Owing to the growing demand for enantiopurity in biological and chemical processes, tremendous efforts have been devoted to the synthesis of homochiral metal-organic materials (MOMs) because of their potential applications in chiral separation and asymmetric catalysis. In this dissertation, the synthetic strategies for homochiral MOMs are discussed keeping the focus on their applications. Two distinct approaches have been taken to synthesize chiral structures with different topologies and accessible cavities. The chiral MOMs have been utilized in enantioselective separation of racemates. Chiral variants of the prototypal metal-organic framework MOF-5, δ-CMOF-5 and [lambda]-CMOF-5, have been synthesized by preparing MOF-5 in the presence of L-proline or D-proline, respectively. CMOF-5 crystallizes in chiral space group P213 instead of Fm-3m as exhibited by MOF-5. The phase purity of CMOF-5 was validated by single crystal and powder X-ray diffraction, IR spectroscopy, TGA, N2 adsorption, microanalysis and solid-state CD. CMOF-5 undergoes a reversible single crystal to single crystal phase change to MOF-5 when immersed in a variety of organic solvents although N-methyl-2-pyrolidone, NMP, does not induce loss of chirality. Indeed, MOF-5 undergoes chiral induction when immersed in NMP, affording racemic CMOF-5. A pair of homochiral network materials (CNMs), [Co2(S-man)2(bpy)3](NO3)2·guests (1S) and [Co2(R-man)2(bpy)3](NO3)2·guests (1R) based upon S-mendelic acid and R-mendelic acid were synthesized and characterized, respectively. The cationic networks contain 1D homochiral channels with the cross section of 8.0 Å × 8.0 Å. The chiral amphiphilic channel surfaces lined with hydrophilic nitrate anions and hydrophobic phenyl groups are capable for multiple interactions with guest species. Chiral resolution of 1-phenyl-1-propanol (PP) enantiomers was performed utilizing the homochiral porosity of 1S and 1R through different time period at different temperatures with/without additives. The mechanism for enantioselective separation of PP was fully investigated through single crystal structural analysis of guest exchanged 1S and 1R. Chiral resolution of PP revealed enhanced performance with additive, which can significantly improve the ee value from 32% to 60%.

The work described in this thesis involves the study of weak interactions by NMR spectroscopy and using them to develop novel applications. The two different applications chosen are i) using molecular interactions for chiral discrimination and ii) understanding the nature of the interaction between peptide and nanoparticles to develop potent antibacterial agents. The thesis, which is divided into five chapters starts with a general introduction of NMR spectroscopy for the study of molecular interactions in conjunction with other techniques. The remaining four chapters focus on four different areas/projects that I have worked on. Chapter 1: Introduction This chapter reviews different kinds of molecular interactions along with the introduction to NMR spectroscopy and other techniques used for all the studies. Starting with the application of chiral discrimination the chapter proceeds to the general introduction of antimicrobial peptides, silver nanoparticles and the strategy for peptide resonance assignment. Chapter 2: Chiral discrimination for versatile functionalities There are many chiral agents available for discriminating enantiomers which mainly target specific functional groups. In this study, we have explored a strategy involving ternary complexation to investigate chiral discrimination of different kind of functional groups by NMR spectroscopy. The proposed protocol was employed for the enantiodiscrimination of molecules containing functional groups, such as amino alcohols, secondary alcohols, cyanohydrins, oxazolidones, diols, thiones and epoxides, using a phosphorous based three component mixture. The simple mixing and shaking of enantiopure 1,1’-binaphthyl-2,2’-diyl hydrogenphosphate (BNPA), 4-(dimethylamino)pyridine (DMAP) and a chiral analyte in the solvent CDCl3 served as a chiral solvating agent and resulted in well-dispersed peaks for each enantiomer in the 1H NMR spectrum. Discrimination was achieved not only for the proton at the chiral center but also for multiple proton sites. The J-resolved technique was used for alleviating the spectral complexity pattern to accurately measure the chemical shift difference. The devised approach also permitted the precise measurement of the enantiomeric excess (ee). Chapter 3: Simultaneous discrimination of secondary alcohols and carboxylic acids In this chapter, I describe two novel ternary ion-pair complexes, which serve as chiral solvating agents (CSA), for enantio discrimination of secondary alcohols and carboxylic acids. The superiority of CSA over other auxiliaries arises due to the formation of diastereomeric complexes through non-covalent interactions with the analyte. By exploiting the acid-base interaction strategy and employing DMAP, which further enhanced the hydrogen bonding efficiency the discrimination for both carboxylic acids and secondary alcohols were achieved. The protocol for discrimination of secondary alcohols is designed by using one equivalent mixture each of enantiopure mandelic acid, 4-dimethylaminopyridine (DMAP) and a chiral alcohol. For discrimination of carboxylic acids, the ternary complex is obtained by one equivalent mixture each of enantiopure chiral alcohol, DMAP, and a carboxylic acid. Furthermore, the formation of the complex was supported by calculating the energy-minimized structure of the proposed complex by density functional theory (DFT). The designed protocols also permit accurate measurement of the enantiomeric composition. Chapter 4: Enhanced potency of nanoparticle-antimicrobial peptide conjugates Antibiotic resistance is emerging as the new global health problem. Due to the blatant misuse and overuse of these drugs has resulted in the bacteria becoming resistant to a wide range of antibiotics. Researchers have found an alternative of current antibiotics which are a group of peptides known as antimicrobial peptides (AMP). But using these molecules as drug is rather costly due to high synthesis cost. Further the antibacterial activity of silver nanoparticle is well established. However, due to its toxic nature after, it cannot be used in high concentration. The conjugation of nanoparticles with antimicrobial peptides is emerging as a promising route to achieve superior anti-microbial activity. However, the nature of peptide-nanoparticle interactions in these systems remains unclear. This study describes the interactions of antimicrobial peptide with silver nanoparticles by NMR spectroscopy in conjunction with other biophysical techniques to completely understand the underlying mechanism of interaction between nanoparticles and peptide. It reveals that the conjugation process involves dynamic interaction between the nanoparticle and the peptide. This study also confirms the enhanced antibacterial efficiency of the nano-conjugate towards bacterial killing compared to the nanoparticle or the peptide alone. Chapter 5: Mechanistic insights into the action of nano-conjugates It is well established that antimicrobial peptides act as pore-formers to rupture the bacterial cells. This chapter is focused on studying the mechanism of action of the nano-conjugate with bacterial membrane mimic models. This study for the first time reveals the details of nanoconjugate membrane interaction at an atomic level. The pore formation mechanism and the enhanced efficiency of the nanoconjugate were explored using fluorescence spectroscopy, CD spectroscopy, and NMR spectroscopy. Structural changes of the peptide and the nanoparticle bound peptide have been captured which infers the propensity of the peptide to form a helical structure upon interacting with the membrane. The calculated structure of the peptide and nanoparticle bound peptide remains almost identical in presence of the membrane mimic environment. In the case of the nanoconjugate, the increase in local positive charge concentration makes the system to penetrate the bacterial membrane faster which further allows the nanoparticle to access the intercellular organelles easily. This dual mode of mechanism thus makes this nano-conjugate a promising antibacterial agent towards multi drug resistant bacteria. In summary, the thesis has focused on the studies of weak intermolecular interactions in different chemical and biological systems using NMR spectroscopy. It is demonstrated that in certain chemical systems, such interactions can be exploited to discriminate enantiomers and determine the enantiopurity of compounds by NMR. In the case of biomolecules, such weak interactions exist when protein or peptides interact with nanoparticles. Using silver nanoparticles, it is shown that such interactions result in a stable conjugate system. NMR spectroscopy provides valuable insights into the structure and dynamics of the system. Further, by using anti-microbial peptides conjugated with silver nanoparticles, new superior antibacterial agents can be developed.

Cette thèse s’articule autour de trois projets principaux indépendants les uns des autres. En premier lieu, nous avons développé une méthode de résolution chirale innovante reposant sur l’écoulement de Taylor-Couette et ne nécessitant donc pas l’utilisation d’une phase stationnaire. Les résultats de cette étude sont présentés dans le chapitre 2. En parallèle, nous nous sommes également investis en chimie supramoléculaire et avons notamment commencé à explorer l’effet d’un faible champ magnétique (< 2 T) sur le processus d’auto-assemblage de motifs moléculaires paramagnétiques. Nos efforts expérimentaux sont consignés dans le chapitre 3, chapitre à la fin duquel nous discutons de l’intérêt des états hors-équilibre dissipatifs, en particulier en chimie supramoléculaire. Ces derniers sont d’ailleurs (encore aujourd’hui) une branche énigmatique de la thermodynamique dans la mesure où de tels systèmes ne sont encore décrits par aucun principe thermodynamique (à l’inverse des systèmes à l’équilibre, parfaitement décrits par la thermodynamique classique) rendant leur prédiction compliquée. Dans le chapitre 4, nous exposons notre tentative de description d’un système dissipatif (un oscillateur de pH tout organique) au moyen de mesures calorimétriques à flux continu. Ces trois projets, bien que très différents, s’articulent néanmoins tous autour d’une philosophie commune : l’auto-assemblage loin de l’équilibre. / This thesis deals with three main projects, which are loosely related to one another. Chapter one introduces the progress made in the field of mechanical chiral resolution. The second chapter of this thesis shows the development of a resolution method based on Taylor-Couette flow, and how nonequilibrium self-assembly amplifies the resolution process. The third chapter describes our efforts to control non-equilibrium self-assembly by using weak magnetic fields (<2T). Finally, in chapter four, we show our attempts to describe non-equilibrium dissipative states using continuous-flow calorimetry. All chapters contain elements of non-equilibrium self-assembly or non-equilibrium systems, hence the title: “Non-equilibrium self-assembly: from shear flows to magnetic fields”

L’acide γ-aminobutyrique ou GABA est le principal neurotransmetteur inhibiteur présent dans le système nerveux central (CNS). Afin d’obtenir un nouveau dérivé cyclobutanique du GABA, le cis-3,4CB-GABA, sous forme énantiomériquement pure, deux stratégies de synthèses efficaces et reproductibles ont été mises au point. Ces deux voies de synthèse impliquent toutes les deux une étape-clé de photocycloaddition [2+2] qui permet de créer le cycle à 4 chaînons. La première consiste en une homologation de l’acide cis-2-aminocyclobutanique (cis-ACBC), et la deuxième est une synthèse multi-étape qui utilise le caprolactame comme composé de départ.D’autre part, grâce à une synthèse stéréosélective du (1R,2S)-cis-2,3CB-GABA, quelques oligomères C- et N-protégés – di, tri, et tétra-peptides – de cet aminoacide ont été préparés. Ceux-ci ont été caractérisés par les techniques de RMN 1D et 2D, IR, RX. Les analyses ont montré qu’il n’existe pas d’interactions non-covalentes (liaisons hydrogène) inter-résidu au sein de ces structures moléculaires. En revanche, la propriété de gélification de ces oligomères dans différents solvants organiques a été mise en évidence. Des solutions et des gels formés à partir de ces peptides ont été analysés par microscope électronique à balayage et des clichés ont été obtenus montrant une organisation du dipeptide et du tetrapeptide en fibrilles. Le tripeptide lui n’a présenté aucun assemblage intermoléculaire régulier. / The γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). In order to obtain new enantiomerically pure cyclobutanic derivative of GABA, the cis-3,4CB-GABA, two efficient synthetic strategies have been established. Both synthetic routes employed a photocycloaddition [2 +2] protocol, which provided the cyclobutanic ring. The first route involved the homolgation of the cis-2-aminocyclobutanecarboxylic acid (cis-ACBC), whereas the second route is a multi-step synthesis using caprolactam as starting material.On the other hand, the (1R,2S)-cis-GABA-2,3CB was synthetized, and a series of N- and C-protected oligomers of di, tri, and tetrapeptides of this amino acid were prepared. These oligomers were characterized by NMR (1D and 2D) techniques, IR, and X-ray. The analyses have shown that there are no non-covalent interactions (hydrogen bonds) between the residues of each oligomers. However, the gelation property of these oligomers in various organic solvents was demonstrated. Solutions and gels formed from these peptides were analyzed by scanning electron microscopy, and the obtained images showed a fibrous organization of the di- and tetrapeptide, while the tripeptide showed no regular intermolecular assembly.

Dans un premier chapitre, nous avons présenté un historique succinct de la chimiothérapie antivirale et l'utilisation d'analogues nucléos(t)idiques. Nous nous sommes focalisés en particulier sur les nucléosides phosphonates acycliques (ANP) en tant qu'antiviraux potentiels. Dans un second chapitre, nous avons décrit la synthèse de β-céto, β-hydroxylamino et β-O-(benzyl)hydroxylamino ANP dérivés de l'adénine et de la cytosine. Les isomèrs (R) et (S)-β-hydroxy-ANP ont été préparés par dédoublement du racémique correspondant avec le (S)-MPA et l'attribution des configurations absolues a été effectuée par RMN et calculs de modélisation moléculaire. Nous avons aussi développé une méthodologie de synthèse de β-azido-ANP, ces derniers étant utilisés pour la préparation de β-amino-ANP par hydrogénation catalytique. Dans un troisième chapitre, nous avons présenté la synthèse des 2H-azirine et cis-aziridne-ANP et examiné lʹ ouverture de cycle comme voie d'accès à des ANP α,β-fonctionnalisés. Les propriétés biologiques de ces nouveaux ANP ont été évaluées en culture cellulaire sur un certain nombre de virus à ADN et ARN. / In the first chapter, we presented a brief history of antiviral chemotherapy and use of nucleos(t)ide analogues, especially acyclic nucleoside phosphonates as potential antiviral agents. In the chapter-II we have successfully synthesized ¦Â-keto, ¦Â-hydroxylamino and ¦Â-O-(benzyl)hydroxylamino ANPs of adenine and cytosine derivatives. Then (R) and (S)-¦Â-hydroxy-ANPs were prepared via chiral resolution of racemic ¦Â-hydroxy-ANPs with (S)-MPA and assignment of absolute configuration was achieved using NMR and molecular modeling studies. We also developed a methodology for the synthesis of ¦Â-azido-ANPs and those were used for the preparation of ¦Â-amino-ANPs by catalytic hydrogenation. In third chapter, we synthesized 2H-azirine and cis-aziridine-ANPs and explored their ring opening to functionalized ¦Á,¦Â-ANPs. The novel ANPs obtained during this study were evaluated for their inhibitory effect on a number of DNA and RNA viruses in cell culture experiments.