Neste trabalho é apresentada a síntese e a caracterização de compostos do tipo 2-(2’- hidroxifenil)benzazóis derivados da 1,3,5-triazina, fluorescentes devido a um mecanismo de transferência protônica intramolecular no estado excitado (TPIEE). Foram preparados quatro novos corantes diclorotriazinil-(hidroxifenil)benzazólicos, que apresentam emissão de fluorescência na região azul-verde do espectro visível e deslocamentos de Stokes compatíveis com substâncias que sofrem o fenômeno da TPIEE. Estas substâncias foram caracterizadas por diversas técnicas espectroscópicas (IR, RMN e HR-MS), enquanto que as análises fotofísicas (absorção no ultravioleta-visível e emissão de fluorescência) foram realizadas em solução e no estado sólido. Os ensaios preliminares realizados indicam a possibilidade de emprego desses corantes como sondas fluorescentes de material celulósico. / The synthesis and characterization of new 2-(2’-hydroxyphenyl)benzazoles derivatives from 1,3,5-triazine, fluorescent due to an excited state intramolecular proton transfer (ESIPT) mechanism, were presented in this work. The four new dichlorotriazinylbenzazole derivatives synthesized present fluorescence emission in the blue-green region of the spectra and Stokes shift compatible with ESIPT compounds. The characterization of the new fluorescent reactive dyes by means of spectroscopic (IR, RMN, UV-Vis and fluorescence) and spectrometric (HRMS) techniques, and the study of the possibilities to dye cellulose fibers were carried out. Fluorescent cellulose fibers were prepared using the dyes and a methodology used in the industry and show no color change when observed in the visible light (white cellulose) and a blue-green fluorescence when irradiated with UV light.

Neste trabalho é apresentado a síntese, caracterização e estudo fotofísico de novos derivados triazinil-benzazólicos fluorescentes por transferência protônica intramolecular no estado excitado (ESIPT). Trata-se da síntese do cloreto cianúrico com diferentes 2-(2'-hidroxifenil)benzazóis, dois grupos bastante atrativos do ponto de vista sintético e tecnológico. O cloreto cianúrico devido a sua versatilidade sintética e os 2-(2'- hidroxifenil)benzazóis por apresentarem propriedades fotofísicas muito interessantes, como uma intensa emissão de fluorescência com um grande deslocamento de Stokes. Estes novos derivados foram caracterizados por RMN-¹H, IV, TGA, ponto de fusão, análise elementar e HR-MS. / The synthesis, characterization and photophysic analysis of new fluorescent triazinbenzazolic derivatives by excited state of intramolecular protonic transference (ESIPT) is presented in this study. It deals with the synthesis of the cyanuric chloride with different 2-(2'-hidroxyfenyl)benzazoles. Two very attractive groups from the synthetic and technological point of view. The cyanuric chloride due to its synthetic versatility and the 2-(2'-hydroxyphenyl)benzazoles because they present very interesting photophysical properties, such as an intense fluorescence emission with a great Stoke shift. These new derivatives were characterized by RMN-¹H, IV, TGA, fusion point, elementary analysis and HR-MS.

Neste trabalho é apresentado a síntese, caracterização e estudo fotofísico de novos derivados triazinil-benzazólicos fluorescentes por transferência protônica intramolecular no estado excitado (ESIPT). Trata-se da síntese do cloreto cianúrico com diferentes 2-(2'-hidroxifenil)benzazóis, dois grupos bastante atrativos do ponto de vista sintético e tecnológico. O cloreto cianúrico devido a sua versatilidade sintética e os 2-(2'- hidroxifenil)benzazóis por apresentarem propriedades fotofísicas muito interessantes, como uma intensa emissão de fluorescência com um grande deslocamento de Stokes. Estes novos derivados foram caracterizados por RMN-¹H, IV, TGA, ponto de fusão, análise elementar e HR-MS. / The synthesis, characterization and photophysic analysis of new fluorescent triazinbenzazolic derivatives by excited state of intramolecular protonic transference (ESIPT) is presented in this study. It deals with the synthesis of the cyanuric chloride with different 2-(2'-hidroxyfenyl)benzazoles. Two very attractive groups from the synthetic and technological point of view. The cyanuric chloride due to its synthetic versatility and the 2-(2'-hydroxyphenyl)benzazoles because they present very interesting photophysical properties, such as an intense fluorescence emission with a great Stoke shift. These new derivatives were characterized by RMN-¹H, IV, TGA, fusion point, elementary analysis and HR-MS.

Neste trabalho de Mestrado, foram feitos estudos do comportamento fotofísico da fisetina em diversos solventes através de medidas de absorção de luz UV-Visível, fluorescência estática e resolvida no tempo e da interação entre fisetina (3,3\',4\',7-tetrahidroxiflavona) e 7-hidroxiflavona com ciclodextrinas ( beta e gama) (CDs) através de experimentos de absorção de luz UV-Visível, sinal induzido de dicroísmo circular, fluorescência estática e resolvida no tempo, anisotropia de estado estacionário e RMN de 1H, focando a dependência destas medidas em função da temperatura e do pH. Os resultados experimentais foram comparados com estudos mecânico-quânticos baseados no modelo semi-empírico SAM1 (AMPAC), e nos funcionais B3LYP e MPW1PW91, da Teoria do Funcional de Densidade, empregando os conjuntos de funções de base 6-311G* e 3-21G**. Os estudos da fisetina em diferentes solventes próticos e apróticos mostraram que a fluorescência da sonda é fortemente dependente do solvente. Resultados experimentais indicam a formação de complexos de inclusão entre as CDs e os flavonóides acima. A fisetina com ?-CD forma complexo de estequiometria 1:1 nos meios neutro/ácido e básico, cujos valores de constante de complexação são 900 +- 100 +_ 240 +_ 90 (L/mol), respectivamente. Os dados teóricos evidenciaram que a inclusão da fisetina na beta-CD ocorre preferencialmente pelo anel fenila. O complexo com a gama-CD apresenta estequiometria de 1:1 em meio ácido/neutro e de 1:2 em meio básico, com constantes de complexação de 94 +- 30 e 130 +- 10 (L/mol), respectivamente. Os estudos com a 7-hidroxiflavona revelaram que somente ocorre a formação de complexos com a beta-CD de estequiometria 1:1 e não há dependência do pH. As constantes de complexação obtidas nos meios ácido/neutro e básico são similares, 1430 +-- 510 e 1220 +- 165 L/mol, respectivamente. / In this work, the photophysics of fisetin (3,3\',4\',7-tetrahydroxyflavone) in several solvents was studied through UV-vis absorption spectra, steady-state and time-resolved fluorescence measurements. The interaction between fisetin and 7-hydroxyflavone and cyclodextrins (b- e g-) (CDs) was also investigated by UV-vis absorption spectra, induced signal of circular dichroism, steady-state and time-resolved fluorescence, steady-state anisotropy, and 1H NMR, with dependence on pH and temperature. Some experimental data were compared with quantum-mechanics studies based on the SAM1 (AMPAC) semi-empirical model, as well as with the B3LYP and MPW1PW91 functional models from the Density Functional Theory using the 6-311G* and 3-21G* basis sets. The study of the photophysics of fisetin in protic and aprotic solvents showed a complex behavior and a strong dependence on the solvent. The occurrence of many equilibria between the possible structures of fisetin, e.g. the normal, a few deprotonated ones, and the tautomer due to the excited state intramolecular proton transfer can be responsible for the complex analyses of these experimental data. The spectroscopic measurements show that, at pH 4.0 and 6.5, the complex fisetin - b-CD is formed in a Fis:b-CD 1:1 stoichiometry and an equilibrium constant (K) of 900 ± 100 L/mol. In basic medium (pH 11.5), K decreases to 240 ± 90 L/mol. Molecular modeling points out that the inclusion complex is formed preferentially via entry of the fisetin phenyl group into b-CD. On the other hand, the fisetin - g-CD has a stoichiometry of 1:1 in acid/neutral solutions and of 1:2 in basic conditions. The K values are 94 ± 30 e 130 ± 10 (L/mol), respectively. The 7-hydroxyflavone can only form inclusion complexes with b-CD. The stoichiometry is 1:1 and there is no dependence on pH. Both equilibrium constants determined either in acid or basic medium is very similar to each other, 1430 ± 510, and 1220 ± 165 L/mol, respectively. For this reason, we suppose that the inclusion of this compound into b-CD is also through the phenyl ring of the flavonoid.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-05-13T18:09:13Z No. of bitstreams: 1 fabiodesouzafernandes.pdf: 24065820 bytes, checksum: da2a7ed64d78294c49d6e226495eda40 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-06-27T21:20:25Z (GMT) No. of bitstreams: 1 fabiodesouzafernandes.pdf: 24065820 bytes, checksum: da2a7ed64d78294c49d6e226495eda40 (MD5) / Made available in DSpace on 2016-06-27T21:20:25Z (GMT). No. of bitstreams: 1 fabiodesouzafernandes.pdf: 24065820 bytes, checksum: da2a7ed64d78294c49d6e226495eda40 (MD5) Previous issue date: 2016-02-29 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Na Química Medicinal, dentre as várias técnicas de planejamento racional para a síntese de novas moléculas bioativas, a hibridação é umas das mais usadas. A união de dois ou mais compostos biologicamente ativos, no intuito de se criar um novo fármaco que conserve as propriedades biológicas das moléculas base e/ou crie uma nova atividade biológica para o composto híbrido, faz desta técnica um caminho rápido, eficaz e oportuno no descobrimento de novos candidatos a fármacos. Sinteticamente, dentre os vários métodos de junção de duas ou mais moléculas a Reação de Mannich está entre as metodologias aplicadas para isto. Este primeiro capítulo trata da síntese N-bases de Mannich derivadas da pirazinamida, que resultou na obtenção de dezenove compostos inéditos. Em um primeiro momento, foi realizada a tentativa de síntese de N-bases de Mannich derivadas da pirazinamida, utilizando três diferentes aminoálcoois Nalquilados. O desenvolvimento da metodologia mostrou que a reação era dependente do pH, tendo este que ser básico. No entanto, a baixa conversão da reação, juntamente com a difícil purificação do produto, uma vez que o mesmo apresentava o mesmo fator de retenção da pirazinamida e alta instabilidade impedindo qualquer funcionalização in situ inviabilizou qualquer possibilidade de continuação desta síntese. Desta forma, foi feita a substituição dos aminoálcoois N-aquilados por piperazinas N-substituídas, contendo cadeias lipofílicas, uma porção D-galactose, amidas lipofílicas, aminoalcoóis aromáticos e heteroaromáticos, sendo sintetizados 5 derivados inéditos da piperazina. A partir da reação de Mannich das piperazinas Nsubstituídas com a pirazinamida foram obtidas quatorze N-Bases de Mannich inéditas. Tanto as piperazinas N-substituídas como as N-bases de Mannich sintetizadas, foram submetidas à avaliação de suas atividades antibacterianas, antibiofilme e antituberculose, sendo que os resultados para atividade antibiofilme apresentaram bastante promissores. As lactamas são amidas cíclicas presentes em vários produtos naturais e em compostos sintéticos com atividade biológica. Devido a esta importância dentro da química medicinal, várias são as estratégias desenvolvidas para a síntese destes anéis heterocíclicos, com o objetivo de se conseguir uma síntese rápida, eficiente, estereoseletiva e utilizando a química verde para destes compostos. Dentre as várias metodologias sintéticas que permitem a obtenção estereoseletiva de Lactamas está à reação de Mannich-Acilação, inicialmente desenvolvida por Castagnoli em 1969 e aperfeiçoada recentemente pelo grupo de pesquisa do Professor Dr. Jared Shaw. Sendo assim, o segundo capítulo aborda desenvolvimento de uma metodologia a paritr da reação de Mannich-Acilação para a síntese de δ-lactamas como suporte para um estudo computacional sobre o mecanismo e estereoseletividade da reação. Para isso, a síntese do anidrido altamente reativo α-ciano glutárico, bem como, dos anidridos α- ciano glutárico substituídos com grupos metila ou fenila nas posições β ou γ foram realizadas. O escopo e as limitações da reação imina-anidrido com uma ampla variedade de iminas também foi investigada. As reações contendo aminas substituídas por grupos alquil volumosos e aromáticos foram mais diastereoseletivas. Já as reações envolvendo o uso dos anidridos α-ciano glutáricos não substituídos e contendo os grupos metila e fenila na posição β mostraram-se altamente diastereoseletivas, enquanto que para as reações envolvendo o anidrido α-ciano glutárico substituídos na posição γ houve uma perda da seletividade. Os estudos computacionais mostraram que a origem do estereocontrole da reação se dá na etapa de acilação, onde efeitos estéreos e trans anulares para o estado de transição na forma eclipsada justificam a formação do produto majoritário tendo uma relação syn entre os grupos carboxilato e fenil. Neste capítulo também foram exploradas algumas aplicações, no que diz respeito à utilização das δ-lactamas como possíveis inibidores da proteína FtsZ, em um estudo onde as δ-lactamas serviram como substratos na reação clássica de descarboxilação alilativa e na síntese dos produtos naturais Gelsidilam e Gelgamina B tendo a reação de Mannich-Acilação desenvolvida neste capítulo como uma das etapas chave. / In the Medicinal Chemistry, there are many techniques for development of new bioactive molecules. One way to do a rational planning of new drugs is using the molecular hybridization technique. In the molecular hybridization, the combination of two or more biologically active compounds in order to create a new pro-drug that preserves the biological properties or improve efficacy when compared to the parent drugs, makes this technique a quick way, effective and timely in the discovery of new drug candidates. Mannich reaction can be applicable to combine two or more fragments of drugs with biological activity. The first chapter will show the synthesis of new N-Mannich bases derived from pyrazinamide, which resulted in the synthesis of nineteen novel compounds. First of all, we tried to make the synthesis of new N-Mannich bases from of reaction between pyrazinamide, formaldehyde and N-alkylated amino alcohols. The development of this methodology showed that the reaction was pH dependent and it had to be basic. So we tried to control the pH of reaction using some bases, but the lower conversion of reaction together with the difficult purification of the product and the high instability led to an unsuccessful planning to get the products desired. Because of this, was made replacing of N-alkylated amino alcohols by N-substituted piperazines having lipophilic chain, D-galactose moiety, lipophilic amides, aromatic and heteroaromatic amino alcohols. With these new components we ran the Mannich reactions and was possible to synthesize fourteen novel N-Mannich bases. The N-substituted piperazines and N-Mannich bases synthesized were evaluated by antibacterial, antibiofilm and antituberculosis activities. The results of antibiofilm and antibacterial activity for some hybrids were very promising. In the second chapter, was developed a methodology to the synthesis of δ- lactams from cycloaddition between imines and cyano glutaric anhydrides like a support to mechanism and diastereoselectivity study of reaction. For this was made the synthesis of β, γ-substituted and unsubstituted cyano anhydrides. The scope of reaction was studied using differents amines and aldehydes. The reactions that were ran with bulky alkyl-substituted amines or aromatic amines were more selective than methylamine. The reactions involving the use of α-cyano-glutaric anhydrides unsubstituted or containing methyl groups and phenyl in the β position showed high diastereoselectivity. Reactions using the γ substituted anhydrides had a poor diastereoselectivity. Computational studies showed that acylation step is a determinant factor to diastereoselectivity, where the eclipsed transition state to anti product has steric and trans anular effects. Some applications of -lactams were made in other studies involving Tethering technique, decarboxylative allylation and total synthesis of Gelsedilam and Gelegamine B.

Quantum optimal control theory is applied to find optimal pulses for controlling the motion of an ion and a molecule for two different applications. Those optimal pulses enable the control of the dynamics of the system by driving the atom or the molecule from an initial state to desired states.The evolution equations obtained by means of the quantum optimal control theory are resolved iteratively using a monotonic convergent algorithm. A number of simulation parameters are varied in order to get the optimal pulses including the duration of the pulses, the time step of the time grid, a penalty factor that limits the maximal intensity of the fields, and a guess pulse which is used to start the optimal control.The optimal pulses obtained for each application are analyzed by Fourier transform, and also by looking at the time evolution of the populations that they generate in the system.The first application is the preparation of specific vibrational states of acetylene that are usually not reachable from the ground state, and that would remain unpopulated by usual spectroscopy. Relevant state energies and transition dipole moments are extracted from the experimental literature and especially from the global acetylene Hamiltonian conferring an uncommon precision to the control simulation. The control starts from the ground state. The target states belongs to the polyad Ns=1, Nr=5 of acetylene which includes two vibrational dark states and one vibrational bright state. First, the simulation is performed with the Schrödinger equation and in a second step, with the Liouville--von Neumann equation, as mixed states are prepared. Indeed, the control starts from a Boltzmann distribution of population in the rotational levels of the vibrational ground state chosen in order to simulate an experimental condition. But the distribution is truncated to limit the computational effort. One of the dark states appears to be a potential target for a realistic experimental investigation because the average population of the Rabi oscillation remains high and decoherence is expected to be weak. The optimal pulses obtained have a high fidelity, have a spectrum with well-resolved peak frequencies, and their experimental feasibility seems achievable within the current abilities of experimental laboratories.The second application is to propose an experimental realization of a microscopic physical device able to simulate quantum dynamics. The idea is to use the motional states of a Cd^+ ion trapped in an anharmonic potential to realize a quantum dynamics simulator of a single-particle Schrödinger equation. In this way, the motional states store the information and the optimal pulse manipulates this information to realize operations. In the present case, the simulated dynamics was the propagation of a wave packet in a harmonic potential. Starting from an initial quantum state, the pulse acts on the system to modify the motional states of the ion in such a way that the final superposition of motional states corresponds to the results of the dynamics. This simulation is performed with the Liouville--von Neumann equation and also with the Lindblad equation as dissipation is included to test the robustness of the pulse against perturbations of the potential. The optimal pulses that are obtained have a high fidelity which shows that the ion trap system has correctly realized the quantum dynamics simulation. The optimal pulses are valid for any initial condition if the potential of the simulation or the mass of the propagated wave packet is unchanged. / La théorie du contrôle optimal quantique est utilisée pour trouver des impulsions optimales permettant de contrôler la dynamique d'un atome et d'une molécule les menant d'un état initial à un état final. Les équations d'évolution obtenues grâce au contrôle optimal limitent l'intensité maximale de l'impulsion et sont résolues itérativement grâce à l'algorithme de Zhu--Rabitz. Le contrôle optimal est utilisé pour réaliser deux objectifs. Le premier est la préparation d'états vibrationnels de l'acétylène qui sont généralement inaccessibles par transition au départ de l'état vibrationnel fondamental. Ces états, appelés états sombres, sont les états cibles de la simulation. Ils appartiennent à la polyade Ns=1, Nr=5 de l'acétylène qui en contient deux ainsi qu'un état, dit brillant, qui lui est accessible depuis l'état fondamental. Les énergies des états du système et les moments de transitions dipolaires sont déterminés à partir d'un Hamiltonien très précis qui confère une précision inhabituelle à la simulation. Un des états sombres apparaît être un candidat potentiel pour une réalisation expérimentale car la population moyenne de cet état reste élevée après l'application de l'impulsion.Les niveaux rotationnels des états vibrationnels sont également pris en compte.Les impulsions optimales obtenues ont une fidélité élevée et leur spectre en fréquence présente des pics résolus.Le deuxième objectif est de proposer la réalisation expérimentale d'un dispositif microscopique capable de simuler une dynamique quantique. Ce travail montre qu'on peut utiliser les états de mouvement d'un ion de Cd^+ piégé dans un potentiel anharmonique pour réaliser la propagation d'un paquet d'onde dans un potentiel harmonique. Ce dispositif stocke l'information de la dynamique simulée grâce aux états de mouvements et l'impulsion optimale manipule l'information pour réaliser les propagations. En effet, démarrant d'un état quantique initial, l'impulsion agit sur le système en modifiant les états de mouvements de l'ion de telle sorte que la superposition finale des états de mouvements corresponde aux résultats de la dynamique. De la dissipation est incluse pour tester la robustesse de l'impulsion face à des perturbations du potentiel anharmonique. Les impulsions optimales obtenues ont une fidélité élevée ce qui montre que le système a correctement réalisé la simulation de dynamique quantique. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

The research work reported in this thesis is focused on the chiral analysis, quantification of enantiomeric composition, assignment of absolute configuration of molecules with chosen functional groups. The weak intra-molecular hydrogen bonding interactions are detected by exploiting several multinuclear and multi-dimensional techniques. Pulse sequences have been designed to manipulate the spin dynamics to derive specific information from the complex NMR spectra encountered in diverse situations. Broadly, the thesis can be classified in to three sections. The section I containing two chapters reports the introduction of new chiral auxiliaries and protocols developed for enantiomeric discrimination, measurement of enantiomeric contents, assignment of absolute configuration for molecules possessing specific functional groups using chiral solvating and derivatizing agents. The section II, reports NMR experimental evidence for the observation of the rare type of intramolecular hydrogen bonds involving organic fluorine in biologically important organic molecules, that are corroborated by extensive DFT based theoretical calculations. The section II also discusses the H/D exchange mechanism as a tool for quantification of HB strengths in organic building blocks. The section III reports the two different novel NMR methodologies designed for deriving information on the scalar interaction strengths in an orchestrated manner. The designed sequences are able to completely eradicate the axial peaks, prevents the evolution of unwanted couplings and also yields ultrahigh resolution in the direct dimension, permitting the accurate measurement of scalar couplings for a particular spin. The brief summary about each chapter is given below. Chapter 1 provides a general introduction to one and two dimensional NMR spectroscopy. The pedagogical approach has been followed to discuss the conceptual understanding of spin physics and the NMR spectral parameters. The basic introduction to chirality, existing approaches in the literature for discrimination of enantiomers and the assignment of absolute configuration of molecules with chosen functional groups and their limitations are briefly discussed. The brief introduction to hydrogen bond, experimental methods to obtain the qualitative information about the strengths of hydrogen bonds, and the theoretical approaches employed in the thesis to corroborate the NMR experimental findings have been provided. The mechanism of H/D exchange, the utilization of exchange rates to derive strengths of intra-molecular hydrogen bond in small molecules have also been discussed. This chapter builds the bridge for the rest of the chapters. Each of these topics are discussed at length in the corresponding chapters. Part I: NMR Chiral Analysis: Novel Protocols Chapter 2 discusses a simple mix and shake method for testing the enantiopurity of primary, secondary and tertiary chiral amines and their derivatives, amino alcohols. The protocol involves the in-situ formation of chiral ammonium borate salt from a mixture of C2 symmetric chiral BINOL, trialkoxyborane and chiral amines. The proposed concept has been convincingly demonstrated for the visualization of enantiomers of a large number of chiral and pro-chiral amines and amino alcohols. The protocol also permits the precise measurement of enantiomeric composition. The significant advantage of the protocol is that it can be performed directly in the NMR tube, without any physical purification. The structure of the borate complex responsible for the enantiodifferentiation of amines has also been established by employing multinuclear NMR techniques and DFT calculations. From DOSY and 11B NMR experiments it has been ascertained that there are only two possible complexes or entities which are responsible for differentiating enantiomers. From the combined utility of DFT calculations and the 11B NMR chemical shifts, the structure of the borate complex has been determined to be an amine-coordinated complex with the N atom of the amine. Chapter 3 discusses a simple chiral derivatizing protocol involving the coupling of 2-formylphenylboronic acid and an optically pure [1,1-binaphthalene]-2,2-diamine for the rapid and accurate determination of the enantiopurity of hydroxy acids and their derivatives, possessing one or two optically active centers. It is established that this protocol is not only rapid method for discrimination of enantiomers but also highly effective for assigning the absolute configuration of various chiral hydroxy acids and their derivatives. The developed protocol involves the coupling of 2-formylphenylboronic acid with (R)-[1,1-binaphthalene]-2,2-diamine, and 2-formylphenylboronic acid with (S)-[1,1-binaphthalene]-2,2-diamine as chiral derivatizing agents. The absence of aliphatic peaks from the derivatizing agent, large chemical shift separation between the discriminated peaks of diastereomers, and the systematic change in the direction of displacement of peaks for an enantiomer in a particular diastereomeric complex, permitted the unambiguous assignment of absolute configuration. Part II : Rare Type of Intramolecular Hydrogen Bonding In chapter 4 The rare occurrence of intramolecular hydrogen bonds of the type N–H˖˖˖F–C, in the derivatives of imides and hydrazides in a low polarity solvent, is convincingly established by employing multi-dimensional and multinuclear solution state NMR experiments. The observation of 1hJFH, 2hJFN, and 2hJFF of significant strengths, where the spin polarization is transmitted through space among the interacting NMR active nuclei, provided strong and conclusive evidence for the existence of intra-molecular hydrogen bonds. Solvent induced perturbations and the variable temperature NMR experiments unambiguously supported the presence of intramolecular hydrogen bond. The two dimensional HOESY and 15N–1H HSQC experiments reveals the existence of multiple conformers in some of the investigated molecules. The 1H DOSY experimental results discarded any possibility of self or cross-dimerization of the molecules. The results of DFT based calculations, viz., Quantum Theory of Atoms In Molecules (QTAIM) and Non Covalent Interaction (NCI), are in close agreement with the NMR experimental findings. In chapter 5 the rates of hydrogen/deuterium (H/D) exchange determined by 1H NMR spectra have been utilized to derive the strength of hydrogen bonds and to monitor the electronic effects in the site-specific halogen substituted benzamides and anilines. The theoretical fitting of the time dependent variation in the integral areas of 1H NMR resonances to the first order decay function permitted the determination of H/D exchange rate constants (k) and their precise half-lives (t1/2) with high degree of reproducibility. The comparative study also permitted the determination of relative strengths of hydrogen bonds and the contribution from electronic effects on the H/D exchange rates. Part III: Novel NMR Methodologies for the Precise Measurement of 1H-1H Couplings Chapter 6 describes two novel NMR methodologies developed for the precise measurement of 1H-1H couplings. Poor chemical shift dispersion and the pairwise interaction among the entire coupled network of protons results in the severely complex and overcrowded one dimensional 1H NMR spectra, hampering both the resonance assignments and the accurate determination of nJHH. The available two-dimensional selective refocusing (SERF) based experiments suffer from the evolution of magnetization from uncoupled protons as intense uninformative axial peaks. This creates ambiguity in the identification of peaks belonging to the coupled partners of a selectively excited proton, hindering the extraction of their interaction strengths. This challenge has been circumvented by designing two novel experimental technique, cited as “Clean-G-SERF” and “PS-Clean-G-SERF”. The Clean-G-SERF technique completely eradicates the axial peaks and suppresses the evolution of unwanted couplings while retaining only the couplings to the selectively excited proton. The method permits the accurate determination of spin-spin couplings even from a complex proton NMR spectrum in an orchestrated manner. The PS-Clean-G-SERF technique has been designed for the complete elimination of axial peaks and undesired couplings, with a blend of ultra-high resolution achieved by real time broad band homonuclear decoupling has been discussed in this chapter. The spin dynamics involved in both these pulse sequences have been discussed. The diverse applications of both these novel experiments have been demonstrated.

Le diabète de type 2 est aujourd’hui une maladie de plus en plus répandu. En ce sens il est nécessaire de mettre au point de nouveau composé permettant d’inhiber la gluconéogenèse. C’est pourquoi nous nous sommes intéressé à la synthèse du FR225654 1, décaline présentant une activité hypoglycémiante in vivo après administration par voie orale et inhibiteur de la néoglucogenèse in vitro (IC50 = 1,1.10-7 M). Ce composé, isolé en 2005 du champignon Phoma sp N°00144 et jamais encore synthétisé à ce jour, possède un mécanisme d’action inconnu. La nécessité d’une synthèse par voie chimique convergente et flexible, permettant l’accès à des analogues, est donc évidente. La stratégie consistait à préparer une trans-décaline par le biais d’une réaction de Diels-Alder intramoléculaire à partir d’un triène précurseur. La combinaison de ces travaux a constitué une avancée importante dans le cadre de la synthèse du FR225654, un hypoglycémiant potentiel. La mise au point d’une synthèse convergente du précurseur de la réaction de Diels-Alder permettra notamment d’effectuer par la suite des modifications aisées en vue de la préparation d’une vaste gamme d’analogues simplifiés. A ce jour, le produit de cyclo-addition a été isolé et caractérisé, validant ainsi l’étape clé de la stratégie de synthèse. Ainsi, l’accès rapide au FR225654 est rendu possible et la synthèse d’analogues est maintenant envisageable. Les produits synthétisés feront l’objet d’une évaluation biologique, l’objectif ultime étant d’accéder à de nouveaux médicaments pour le traitement du diabète de type 2. / Type 2 diabetes mellitus (T2DM) is a growing worldwide health concern that is expected to afflict over 366 million people by 2030. FR225654 is a novel gluconeogenesis (GNG) inhibitor recently isolated from the culture broth of Phoma sp.. This compound selectively inhibits GNG of primary rat hepatocytes and shows highly hypoglycemic effects in several in vivo mouse models (80% decrease of glycemia). However, to date, the mechanism of action and molecular target remain unknown. From a structural point of view, FR225654 exhibits a highly oxygenated trans-decalin ring substituted by a β-keto-enol moiety and a side-chain bearing a conjugated carboxylic acid and a trisubstituted olefin. Project specific objectives were to design an efficient total synthesis which could also permit a straightforward access to diverse analogues. This feature would constitute a crucial step for the further understanding of Structure Activity Relationship of FR225654. The work consists in synthesizing separately a side chain and a trans-decalin core by means of an intramolecular Diels-Alder reaction from a precursor. To date, synthesis of the precursor has been achieved in 13 steps as well as the side chain. The Intramolecular Diels-Alder reaction has also been validated in order to accomplish the first total synthesis of FR225654.

(FOR FIGURES REFER THE MAIN PDF FILE) Supramoleculr chemistry, aptly termed by Lehn as the study of molecular sociology, is the chemistry of the intermolecular bond, focusing on the structures and functions of “supermolecules” –chemical system formed by the association between two or more molecular components. While interrelated, this discipline forges beyond the domain of traditional molecular chemistry, which seeks to master the manipulation of the covalent bond between atoms and uncover the principle that governs the structures and properties of molecular species. Supramolecular chemistry assayas to blend the comprehensive resources of molecular chemistry with designed control of the intermolecular interactions to engineers supramolecular with features as well defined as those of the constituent molecular themselves. Not surprisingly, it has been stated that supramoleculars are to molecules and the intermolecular bond what molecules are to atoms and the covalent bond. In the realm of molecular crystals, the focus of supramolecular chemistry and indeed, the scope of the present thesis coverings with that of a rather recent, but rapidly emerging scientific discipline, namely crystal engineering. Coined nearly four decades ago in connection with photodimerization reaction in crystalline cinnamic acids, the term” crystal engineering” has since then broadened its expanse considerably and is, at present, most appropriately defined as“the understanding of intermolecular interactions in the context of crystal packing and the utilization of such understanding in the design of new solids with desired physical and chemical properties”. It would be befitting to remark that it is very pursuit (and more often than not, the elusive target) of being able to make functional solids by design that has allowed crystal engineering to evolve from an object of mere Scientific curiosity to a subject of tremendous utilization value. No proof for this assertion might be greater than that which lies in the fervent efforts put forth by pharmaceutical companies in understanding and controlling drug polymorphism, especially in the wake of the contemporary legal implications attendant with observing such a phenomenon. Polymorphism in molecular crystals results from the possibility of at least two different arrangements of the molecular of a given compound in the solid state and has therefore often been regarded as the” dark side” of crystal engineering. On one hand, polymorphism presents itself as an important probe in the study of structure-property relationship and allows elucidation of the varied macroscopic properties of the same molecule self-assembled in different crystalline environments. On the other hand, the phenomenon poses an implicit complication when predicating the product of a crystallization process forms the goal of a crystal engineering project. This is particularly true in case of crystal structure prediction (CSP) from the molecular structure of a given compound, where the experimentally obtained polymorphic modification may be a kinetic form and therefore, need not correspond to the one ranked lowest in energy from the computational studies. Indeed, this dichotomy between a thermodynamically and a kinetically controlled crystallization process reflects the underlying uncertainty associated with judging the outcome of a crystallization event. In this concept of a supramolecular synthon has been postulated to assimilate both thermodynamic and kinetic alternative, and therefore provide a working model for heuristic crystal design. By analogy with corey’s definition of a molecular synthon, a supramolecular synhon has been described” a structural unit within a supramolecule which can be formed and/or assembled by known or conceivable synthetic operations involving intermolecular interactions”. Being entirely probabilistic in nature, the robutness and thus, the transferability of a particular synthon to a designed crystal is assessed from a systermatic evolution of its recurrence in crystal structures of representative molecules. The Cambridge Structural Database (CSD), which announced the inclusion of the 500000th crystal structures in its archives last year, provides an invaluable cache of experimentally determined structures and the foundation for crystal design in this regard. The practically of the supramolecular synthon approach, now almost synthymous with crystal engineering, has been demonstrated not only in the successful design of a number of functional solids, but also in its possible application in CSP as a knowledge-based alternative. Irrespective of the approach, a basic paradigm can however be constructed from any crystal engineering strategy, viz. construct the molecular building blocks and assemble these, with a prior knowledge of the possible non-covalent interactions, in a manner that leads to the desired crystal structure. This premise will form the central theme of the present thesis, entitled “From molecular to supramolecular: Probing solid state self –assemblies of conformatonally locked polycyclitos and structural siblings”. The dissertation will deal with the nuances of the self-assemblies of four classes of structurally related crystalline polycyclie compounds, all fashioned from a prototypical rigid trans-decalin backbone derived from commonly available aromatic precursors like naphthalene and anthracene. The thesis will be presented in four chapters, each based on one of the four functional make-ups present in the molecular under study. • Chapter 1.Relating intramolecular O-H…Ohydrogen bondigs to conformational locking: Design and self-assemblies of crystalline polyclitols. • Chapter 2.Preferences of supramolecular assemblies towards competing inter- and intramolecular O-H…O hydrogen bonds: A case study in crystalline acyldervaeives of conformarionally locked polyclitols. •Chapter 3.Synthesis of novel polyhydroxylated flustrates: Probing fluorine interactions in a conformatonally constructed environment. • Chapter 4. Strength vs.accessiblity: Universe the patterns of self-recognition in designer conformationally locked aminoacohols. A brief overview of each chapter is presented below. The first chapter of the thesis investigates the supramolecular chemistry of an O-H…O Hydrogen Bond formed between hydroxyl groups that have been constrained to occupy spatiality invariant position in the crystal structure of a polycyclitol (a portmanteau word derived from polycyclic cyclitol). Having been constructed on a grid trans-decalin carbocyclic backbone, the polycyclitols under study 1-6 are conformatonally locked and destined to exhibit an axial rich disposition of the hydroxyl groups, so that the OH functionalities in 1,3-relationship are automatically brought into a favorable geometry for the formation of intramolecular O-H…O hydrogen bonds. Working within this paradigm, which was formulated both logically and on the basis of the observed H-bonding patterns in the crystal structures of several conformationally locked polyols, we were able to demonstrate that intramolecular H-bonding between 1,3-syndisxial OH groups can be used as a tool to preordain the position of the intermolecular O-H…O-bond donors and accepts in the specially crafted polycyclitols 1-3. this observation not only simplified a qualitative visualization of the various packing patterns in 1-3, but also allowed us to propose, based on previously reported CSD analysis, the packing motifs mostlikely to converge with the experimental results. Despite its qualitative nature, the O-H…O hydrogen bonding patters, proposed for 1-3 were found to conform well with those observed experimentally for the tetrols 1 and 3, and even for the two polymorphic modifications of the hexol 2[Figure 1] The determination role played by intramolecular O-H…O bonding in the supramolecular assembly of 2, a novel bicycle C2h symmetric hexol having an all axial disposition of the six hydroxyl functionalities, prompted us to study the crystal packing of the three diastereomeric perhydro-2,3,4q,6,6,8a-naphthalenehexols 4-6. the end-to-end co-operative intramolecular O-H…O-H hydrogen bonding chain on both faces of the molecule, as observed in case of 2, through an axial-equatorial. Figure 1. (left) one of the packing modes proposed for the hexol 2. Note that the H-bonding pattern involves all donor/acceptor oxygen and incorporates infinite chains of O-H…O bonds of O-H….O bonds; (right) Molecular packing observed experimentally in the polymorph of the hexol 2 Transposition of one or more of the peripheral yhdroyl groups. With increased freedom now allowed to the OH groups in the choice of their H-bonding partners, as a compared to 2 crystal packing in the polycyclitols 4-6 evolved from the simplistic model of hydrogen bonding proposed and observed for 2,to ivoke more complex patterns of self assembly mediated through O-H…O-bonds In the second chapter, the crystal structures of four conformationally locked esters, namely tetraaccetate 7/tetrabenzoate 8 of hexol 2 and the diacetate9/dibenzoate 10 of tetrol1,have been analyzed in order to examine the preference of their supramolecular assemblies towards competing inter and intramolecular O-H…O hydrogen bonds. To this end, all the four esters under study were specially crafted on a trans-decalin backbone with the objective of relegating the O-H…O H-bond donors( in form of the 30 OH groups) to the molecular interior and having the peripheral H-bond accepters (in form of the 20 acyl groups) in 1,3-syndiaxial relationship. It was anticipated that this common design element would allow the supramolecular assembly of the easters to evolve along two possible pathway, namely one which employs intermoleculars O-H…O H-bonds (pathway 1) and the other that sacrifises those for intramolecular O-H…O H-bonds and settles for a crystal packing dictated by weak intermolecular interactions alone (pathway 2) A pure sample of 7 crystallized along pathway 1 in two enantiotropic modifications, one obtained at room temperature (form) and the other at 20 C0 (form) [Figure 2]. Behaving much like a temperature guided molecular switch, the tetraacetate 7 could be shifted reversibly between the forms response to changes in the ambient temperature. Thus, the form converted at -4 OC to the denser form, which displayed an unusual kinetic stability till 67 OC and transformed back to the form beyond this temperature. Subsequently, the close similarity between the self-assemble of the two dimonrphs of 7 and the diastereomer 11 was exploited in order to stimulated 7 to fallow the pathway 2 through preferential inhibition of pathway 1[Figure 3]. Interstingly, the nucleation inhibition 11 was obtained serendipitously a route 7 via an apparent breakdownof furst-platter rule. Unlike the tetraceatate 7, crystal packing in the tetrabenzoate 8 preferred to fallow exclusively pathway 2. The individualistic nature of the self-assemblies of 7 and 8 found to be in contrast commonalities noted in the mode of molecular assembly in 9 and 10 both of which conformed to a combination of pathway 1 and 2. A rationale for the preferred crystallization pathway of the four estes 7-10 as well as probable mechanism for the observed reversible transformation between the forms the tetracetate 7 will be put forth in this chapter. Figure 2. (Model for pathway 1) Molecular packing in the forms of the tetraacetate 7. The non-interacting hydrogen atoms have been omitted for clarity. Figure 3. (Model for pathway 2) The nucleation inhibitor 11 and form of the tetraacetate 7. The non-interacting hydrogen atoms have been omitted in the molecular packing diagram for clarity. In light of the wide ranging application of organofluorine compounds and the ambiguity that resides over the disposition of fluorine as a H-bond accepter, the third chapter utilizes three specially designed fluorinated polycyclitols 12-14 investigate the role of covalently bonded flurine in crystal structures of lesser studied aliphatic fluorous substracts and probe its capacity to engage itself in C(sp3)-F…H-X(sp3)(X=O and/or C) H-bounding, in presence of its isostere, the hydrozyl group. Conformatonality locked with well defined spatial disposition of functional groups, all the fluorinated polycyclitols 12-14 bear a fluorohydrin moiety, embedded in a rigid trans-decalin framework. In 12 and 14, it was conceived that the presence of a hydroxyl donor in a favorable 1, 3-syndiaxial relationship to a fluoro group on one side and a hydroxyl group on the other would allow an unambiguous comparison between the two isoteric functionalities (C-OH and C-F) to serve as acceptors for intramolecular hydrogen bonds (O-H…O and purported O-H…F respectively) The difluorodiol 13 was sought to serve as a control to assess the change in the C-F…H-X interactions (if any) which might be observed upon incorporating the peripheral secondary hydroxyl groups in 14. The result presented in this chapter will revel, in particular, that C(sp3) –F…H-C(sp3) hydrogen bonds, though weak and lesser investigated, can indeed be observed and supramolecular recognition motifs, involving such interactions, can be conserved even in crystal structures laden with stronger O-H…O hydrogen bonds [Figure 4}. Figure 4. (Left) Molecular packing in the difluorodiol 13, showing how four intermolecular C-H…F hydrogen bonds forms a part of a R22 H-bonding motif (encircled). This centrosymmentic supramolecular recognition unit is observed even in the molecular packing in the difluorohexol 14 (right). Non-interacting H atoms have been omitted in both diagrams for the sake of clarity. The forth chapter details an in-depth study carried out on the self-assembly of a conformationally locked aminoalchohol 15, in which the amino protons serve as mere spectators, the molecular packing in the crystal being realized through the co-operativity between O-H…N H-bonds and weak π-π stacking interaction (Figure 5b). The crystal structure of 15 was quite intriguing on three sailent grounds (a) previous studies on the supramolecular assemblies in the aminols have shown that both amino and hydroxyl protons participate in H-bonding in the crystal structures of such compounds; (b) the fact that the hydrogen atoms of the NH2 group Figure 5. (Left) Laplacian distribution map in the planes defined by (a) the double bonds, (c) O-H…N-H-bond, and (d) π-π stacking interactions in the aminoalclhol 15. Contours havse been drawn at logarithmic intervals in ▼2 ρb, eÅ-5. Solid lines indicate positive contours and dotted lines negative contours. (b) Molecular packing in 15. Non-interacting H atoms have been omitted for the sake of clarity.remain as mere bystanders in anomalous if one were to abide by the Etter’s rule; (c) the rather well-difined π-π stacking interactions in crystal structure of the aminoalcohol occurs between isolated olefinic bonds-a rarely encountered form of non-covalent interaction. Charge destiny analysis was carried out on the aminoalcoholf 15 not only to catheterize the non-covalent interactions existing in the supramolecular assembly in terms of topological features of electrol destiny at their bond critical points, but also to confirm the non-involvement of the amino H-atoms in any form of either intra- or intermoalecular hydrogen bonds beyond the criteria of mere geometry (Figure a,c,d). The maverick nature of the self-assembly of 15 was elucidated as resulting from the preference of the molecules to assemble with O-H…N H-bonds. This automatically relegated the hydrogen atoms of the tertiary amine to the interior of the conformationally locked cabocycclic scaffold, thereby making them far less accessible than the peripheral C=C bonds.

Chemical biology encompasses the study and manipulation of biological system using chemistry, often by virtue of small molecules or unnatural amino acids. Much insight has been gained into the mechanisms of biological processes with regards to protein structure and function, metabolic processes and changes between healthy and diseased states. As an ever expanding field, developing new tools to interact with and impact biological systems is an extremely valuable goal. Herein, work is described towards the synthesis of a small library of heterocyclic-containing small molecules and the mechanistic details regarding the interesting and unexpected chemical compounds that arose; an alternative set of non-toxic copper catalyzed azide-alkyne click conditions for in vivo metabolic labelling; and the synthesis of an unnatural amino acid for further chemical modification via [3+2] cycloadditions with nitrones upon incorporation into a peptide of interest. Altogether, these projects strive to supplement pre-existing methodology for the synthesis of small molecule libraries and tools for metabolic labelling, and thus provide further small molecules for understanding biological systems.