Orientador: Claudio Francisco Tormena / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-12T10:26:30Z (GMT). No. of bitstreams: 1 Anizelli_PedroRenato_M.pdf: 2613817 bytes, checksum: 7e7b3b7a48d38a072cffc5d19dc686b2 (MD5) Previous issue date: 2008 / Resumo: A preferência conformacional para 2-fluormetilenocicloexano (1), 2-clorometilenocicloexano (2), 2-bromometilenocicloexano (3), 2-N,N-dimetilaminametilenocicloexano (4) e 2-metoximetilenocicloexano (5), foram determinados usando constante de acoplamento spin-spin, entre hidrogênios a três ligações (JH2H3), enquanto que interações estereoeletrônicas foram obtidas por cálculos teóricos e análise NBO. O equilíbrio conformacional dos compostos 1-5 pode ser representado pelos seus confôrmeros axial e equatorial, sendo que o confôrmero axial, para um cada dos compostos (1-5), é o mais estável em fase vapor, solventes polares e não polares. Essa preferência conformacional pode ser atribuída a interações hiperconjugativas entre os orbitais p(C1-C7)s*(C2-Xax), s(C3-Hax)s*(C2-Xax), (LP3Xax)p*(C1-C7) e interações estéreo-repulsivas entre s(C7-H)(LP3Xeq). / Abstract: Conformational preferences for 2-fluoro-methylenecyclohexane (1), 2-chloromethylenecyclohexane (2), 2-bromomethylenecyclohexane (3), 2-N,N-dimethylaminomethylenecyclohexane (4) and 2-methoxymethylenecyclohexane (5) were determined using JHH spin-spin coupling constants, while stereoelectronic interactions were obtained by means of theoretical calculations and NBO (natural bond orbital) analysis. The conformational equilibrium of compounds 1-5 can be represented by their axial and equatorial conformers. The axial conformers for 1-5 are stable in polar and non-polar solvents. These conformational preferences were attributed to the hyperconjugative interactions between the p(C1-C7)s*(C2-Xax), s(C3-Hax)s*(C2-Xax) and (LP3Xax)p*(C1-C7) orbitals, and the repulsive steric interaction observed between s(C7-H)(LP3Xeq). / Mestrado / Quimica Organica / Mestre em Química

Abstract Phospholipids are the main components of cell membranes, lipoproteins and other membrane structures in living organisms. Properties of lipid molecules are important to the overall behaviour and interactions of membranes. Furthermore, characteristics of the biological membranes act as important regulators of membrane functions. Molecular dynamics (MD) simulations were applied in this thesis to study properties of biological membranes. A certain degree of acyl chain polyunsaturation is essential for the proper functioning of membranes, but earlier MD simulations had not addressed the effects of polyunsaturation. Therefore a solvated all-atom bilayer model consisting of diunsaturated 1-palmitoyl-2-linoleoyl-3-phosphatidylcholine (PLPC) molecules was simulated. The analysis of the simulation data was focused on the effects of double bonds on a membrane structure. Self-organising neural networks were applied to the analysis of the conformational data from the 1-ns simulation of PLPC membrane. Mapping of 1.44 million molecular conformations to a two-dimensional array of neurons revealed, without human intervention or requirement of a priori knowledge, the main conformational features. This method provides a powerful tool for gaining insight into the main molecular conformations of any simulated molecular assembly. Furthermore, an application of MD simulations in the comparative analysis of the effects of lipid hydrolysis products on the membrane structure was introduced. The hydrolysis products of the phospholipase A2 (PLA2) enzyme are known to have a role in a variety of physiological processes and the membrane itself acts as an important regulator of this enzyme. The simulations revealed differences in the bilayer properties between the original and hydrolysed phospholipid membranes. This study provides further evidence that MD simulations on biomembranes are able to provide information on the properties of biologically and biochemically important lipid systems at the molecular level.

Complexes with pincer ligand moieties have garnered much attention in the past few decades. They have been shown to be highly active catalysts in several known transition metal-catalyzed organic reactions as well as some unprecedented organic transformations. At the same time, the use of computational organometallic chemistry to aid in the understanding of the mechanisms in organometallic catalysis for the development of improved catalysts is on the rise. While it was common in earlier studies to reduce computational cost by truncating donor group substituents on complexes such as tertbutyl or isopropyl groups to hydrogen or methyl groups, recent advancements in the processing capabilities of computer clusters and codes have streamlined the time required for calculations. As the full modeling of complexes become increasingly popular, a commonly overlooked aspect, especially in the case of complexes bearing isopropyl substituents, is the conformational analysis of complexes. Isopropyl groups generate a different conformer with each 120 ° rotation (rotamer), and it has been found that each rotamer typically resides in its own potential energy well in density functional theory studies. As a result, it can be challenging to select the most appropriate structure for a theoretical study, as the adjustment of isopropyl substituents from a higher-energy rotamer to the lowest-energy rotamer usually does not occur during structure optimization. In this report, the influence of the arrangement of isopropyl substituents in pincer complexes on calculated complex structure energies as well as a case study on the mechanism of the isomerization of an iPrPCP-Fe complex is covered. It was found that as many as 324 rotamers can be generated for a single complex, as in the case of an iPrPCP-Ni formato complex, with the energy difference between the global minimum and the highest local minimum being as large as 16.5 kcalmol-1. In the isomerization of a iPrPCP-Fe complex, it was found that the isopropyl substituents not only influence the calculated structure energies, but they dictate the mechanism of isomerization with the rotation of isopropyl substituents from the arrangement in the starting material complex to the arrangement in the product complex being the rate-determining step.

Abstract: Pincer compounds are organometallic complexes with intriguing tunable reactivities. In this work we explore their unique properties and reactivities through spectroscopic and computational investigations, with a focus on the PN3P pincer platform. First, we conducted a computational study on five pincer complexes with stereogenic phosphine arms that have multiple well-defined rotamers. Significant energy differences could be found between the lowest and highest energy rotamer in each set of pincer complexes. All rotamers for reactant, transition state, and product, were evaluated in a reaction energy profile of a CO2 reduction by a pincer nickel hydride, and we found that this reaction could be found either favorable or unfavorable, depending on the choice of rotamer. A software to generate rotamers has been developed and applied to the work presented in this part. The zwitterionic aromatic resonance form has a large contribution in the dearomatized PN3P* nickel pincer complexes, which is demonstrated by the imine arm's ability to act as an organic σ-donor, similar to NHC catalysts. Related to this property, as well as the pincer compound's ability to undergo metal-ligand cooperation catalysis, is the basicity (or acidity) of pincer ligand spacer arms. Therefore, we have determined the Brønsted basicity of the imine arm in three PN3P* nickel pincer complexes in THF. The relative basicity was found to be strongly influenced by the X ligand trans to the PN3P* ligand, and less by alkyl groups on phosphine donor arms. Finally, we explored the reactivity between a PN3P* rhodium carbonyl pincer complex and dioxygen at room temperature in solution, and at elevated temperature in the solid state. Intriguingly, the singlet PN3P* rhodium carbonyl complex reacts with the triplet dioxygen both in solution and in the solid state to afford oxidation on the ligand backbone. This is possible due to the ligands ability to do a single-electron transfer to dioxygen. The solid state reaction was studied with in situ rhodium K-edge X-ray absorption spectroscopy under dioxygen flow, where an isobestic point was observed, and simulation studies support formation of a Rh-O2 adduct. In situ FTIR studies in a static dioxygen environment revealed that the PN3P* rhodium carbonyl complex is able to facilitate the incorporation of O2 into CO and CO2.

The insertion of ω- amino acid residues as guests into host α-peptide sequences permits expansion of the range of polypeptide secondary structures. The term ω- amino acid is used to refer to the entire family of residues generated by homologation of the backbone of α - amino acid residues. This explores the consequences of insertion of substituted β-residues (β3) , unsubstituted β-residues , unsubstituted γ-residues (gamma aminobutyric acid) and unsubstituted δ-residues (delta aminovaleric acid) into host α -peptide sequences. Chapter 1 provides an introduction to the conformational properties of β-peptides and reviews current literature on the structural features of peptides containing ω-amino acid residues. The available crystallographic information is summarized. The conformational properties of β- residues may be described by three degrees of torsional freedom : φ (N – Cβ) , θ (Cβ -Cα) and ψ (Cα-CO). Similarly, the conformational properties of γ -residues is based on four torsional parameters ( φ , θ1 , θ2, ψ) and the conformational properties of δ - residues is based on five degrees of freedom ( φ , θ1 , θ2, θ3,ψ). The rational use of β -residues in peptide design requires an understanding of the nature of local conformations, which are readily accessible. The conformational space for β -residues can be represented in a three dimensional plot. The observed distribution of φ , θ and ψ values for β -residues in peptide crystal structures presented in this section permits a correlation - between the torsion angle θ and the secondary structure context. The gauche (g+ and g ) conformations induce helical folding and the trans conformation is generally observed in the strands of a hairpin. The most striking feature of hybrid sequences is the observation of novel hydrogen bonded rings in peptide structures. Chapter 2 describes the effects of insertion of β-residues into specific positions in the strand segments of designed peptide hairpins. Insertion of β -residues into the strands of a hairpin changes the orientation of peptide bonds, resulting in a “polar sheet” arrangement. The conformational analysis of three designed peptide hairpins composed of α/β - hybrid segments are described: Boc-Leu-βPhe-Val-DPro-Gly- Leu-βPhe-Val-OMe (BBH8) , Boc-βLeu- Phe-βVal-DPro-Gly-βLeu-Phe-βVal-OMe (BAB8) and CF3COO-H3N+-Leu-Val-Val-βPhe-DPro-Gly-βPhe-Leu-Val-Val-OMe (BHFF10). All the peptides have been characterized by 500 MHz 1H-NMR spectroscopy and several crucial long range NOEs confirm a predominant population of β-hairpin conformations in CD3OH. X-ray diffraction studies on single crystals of peptide BBH8 reveal a β-hairpin conformation, stabilized by three cross-strand hydrogen bonds and a Type II′β-turn at the DPro-Gly turn segment. Designed β-hairpin peptide scaffolds may be used to probe cross-strand sidechain interactions in β-sheet structures. A previously reported peptide β-hairpin, Boc-Leu-Phe-Val-DPro-Gly-Leu-Phe-Val-OMe exhibited an anomalous far UV CD spectrum, which was interpreted in terms of interactions between facing aromatic chromophores, Phe 2 and Phe 7 (Zhao, C.; Polavarapu, P.L.; Das,C. and Balaram, P. J. Am. Chem. Soc., 2000, 122, 8228-8231). In BBH8 and BHFF10 the two cross-strand βPhe residues are at non-hydrogen bonding positions, with the benzyl sidechains pointing on opposite faces of the β- sheet. BBH8 yields a “hairpin –like” CD spectrum, with a minimum at 224 nm. The CD spectrum of BAB8 reveals a negative band at 234 nm and a positive band at 221 nm suggestive of an exciton split doublet. BHFF10 yields a “hairpine-like” CD spectrum, with a negative band at 220 nm. Chapter 3 describes the synthesis and conformational characterization of three hybrid decapeptides : Boc-Leu-Val-βGly-Val-DPro-Gly- Leu-βGly -Val-Val-OMe (BHB10), Boc-Leu-Val-γAbu-Val-DPro-Gly- Leu-γAbu -Val-Val-OMe (BHC10) and Boc- Leu-Val-δAva-Val-DPro-Gly- Leu-δAva -Val-Val-OMe (BHD10). These peptides were designed to systematically investigate the effect of insertion of additional methylene groups into the strands of a hairpin. The incorporation of additional carbon atoms changes the local polarity of the strands. 500 MHz NMR studies establish that BHB10 and BHD10 adopt predominantly β- hairpin conformations in methanol, with interstrand registry established by observation of long range NOEs. The observation of both DPro 4 (CαH) ↔ Gly 5 (NH) and Gly 5 (NH) ↔ Leu 6 (NH) NOEs provides evidence for a Type II ′β - turn for all the hairpins. In BHC10, no long range NOEs were observed. However, X-ray diffraction studies in single crystals reveal a β- hairpin conformation, nucleated by a DPro-Gly Type II′β-turn. Chapter 4 describes an attempt to incorporate one or two ω amino acid residues in the turn region of a potential hairpin, in order to assess the effect of expansion of the nucleating turn. The DPro-LPro segment has been shown to stabilize β-hairpin conformations in both cyclic (Shankaramma,S.C.; Moehle, K. ; James, S.; Vrijbloed, J.W.; Obrecht,D and Robinson, J.A. Chem Commun. 2003,1842-1843) and acyclic sequences ( Raj Kishore Rai ; S.Raghothama and P. Balaram , unpublished results) . In the present study the following turn segments have been considered: βDPro -αLPro , βLPro -αLPro and βLPro -αDPro. The synthesis and conformational analysis of three octapeptide sequences -Boc-Leu-Phe-Val-βDPro-αLPro-Leu-Phe-Val-OMe (βDPαLP8), Boc-Leu-Phe-Val-βLPro-αLPro-Leu-Phe-Val-OMe (βLPαLP8)and Boc-Leu-Phe-Val-βLPro-αDPro-Leu-Phe-Val-OMe (βLPαDP8) are described. In the βDPro-αLPro peptide, NMR evidence clearly supports a β-hairpin conformation, with a nucleating hybrid βα turn stabilized by a C11 (4 →1) hydrogen bond. In the other two octapeptides, no evidence for folded structures was obtained. These results suggest that nucleating turn formation is facilitated only in the heterochiral βD-αL case. Further expansion of the turn segment in potential hairpins has been investigated by inserting two contiguous β-residues into the center of a host α-peptide sequence. The conformational studies on two synthetic hexapeptides, Boc-Leu-Phe-βDPhe-βLPro-Phe-Leu-OMe (βDFβLP6) and Boc-Leu-Phe-βLPhe-βLPro-Phe-Leu-OMe (βLFβLP6) suggest that the βDPhe-βLPro segment is capable of forming a C12 turn in methanol. Two octapeptide sequences, Boc-Leu-Val-Leu-βDPhe-βLPro-Leu-Phe-Val-OMe (βDFβLP8N) and Boc-Leu-Val-Val-βDPhe-βLPro-Leu-Val-Val-OMe (βDFβLP8V) have also been investigated to probe the possible formation of hairpin structures. In these cases, spectroscopic analysis is hampered by the presence of multiple conformations, because of the tendency of the βDPhe-βLPro bond to exist in both cis and trans conformations. NMR studies on the conformational properties of a hexapeptide Boc-Leu-Val-βDPro-βLPro-Leu-Phe-OMe (βDPβLP6) in CDCl3 reveal that in the major conformer the Val 2(NH) ↔ Leu 5 (NH) NOE is observed, suggesting the presence of a 12-membered hydrogen bonded turn. A ββ - segment can give rise to two types of hydrogen bonded rings , 10 – membered (C10) and 12- membered (C12). In an attempt to generate C10 turns, an N-methylamino acid has been inserted next to a ββ - segment, preventing the formation of the 12 – membered turn. In such a situation formation of a 10-membered turn, with reverse hydrogen bond directionality, may be facilitated. The conformational properties of Boc-Leu-Val-βDPhe-βLPro-(N-Me) Leu- Phe-OMe (βDFβLPNMeL6) has been studied by 500 MHz NMR spectroscopy. The data suggests the formation of a C11 turn at the βLPro- (N-Me) Leu segment in CDCl3-DMSO mixtures, instead of formation of a C10 turn at the βDPhe -βLPro segment. Studies on the peptide Boc-Leu-Phe-Val-βLPro-(N-Me) Leu-Leu-Phe-Val-OMe (βLPNMeL8) also suggest the absence of turn formation and folded structures. In hybrid sequences, an important question to be addressed is whether ω amino acids can be accommodated into helical structures. Two contiguous β- residues have been inserted into a helical sequence. The conformational properties of a 11- residue peptide, Boc-Val-Ala-Phe-Aib-βVal-βPhe-Aib-Val-Ala-Phe-Aib-OMe (ABA11) are described in Chapter 5. This sequence was based on the parent α- peptide Boc-Val-Ala-Phe-Aib-Val-Ala-Phe-Aib-Val-Ala-Phe-Aib-OMe, which adopted a complete helical conformation in crystals (Aravinda, S.; Shamala, N.; Das, C .; Sriranjini, A.; Karle, I.L. and Balaram, P. J. Am. Chem. Soc. 2003, 125, 5308-5315). 500 MHz 1H-NMR studies establish a continuous helix over the entire length of the peptide in CDCl3 solution , as evidenced by diagnostic nuclear Overhauser effects. The molecular conformation in crystals reveals a continuous helical fold, stabilized by seven intramolecular hydrogen bonds. The characterization of two synthetic octapeptides Boc-Val-Ala-βPhe-Aib-Val-Ala-βPhe-Aib-OMe (VAβFU8) (βPhe residues have been incorporated at (i /i+4 positions) and Boc-Val-Ala-βPhe-Aib-βPhe-Ala-Val-Aib-OMe (βFUβF8) (βPhe residues have been incorporated at (i /i+2 positions) is also presented. NMR data suggests the retention of helical conformation in both the peptides. In order to delineate the conformations of hybrid peptides with three contiguous β-residues, two peptides have been synthesized Boc-Phe-Aib-βGly-βLeu-βPhe-Aib-Val-Ala-Phe-Aib-OMe (ABA10) and Boc-Val-Ala-Phe-Aib-βGly-βLeu-βPhe-Aib-Val-Ala-Phe-Aib-OMe (ABA12). NMR studies in chloroform support continuous helical conformation in the decapeptide.

Thesis (MSc)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Please refer to full text for abstract / AFRIKAANSE OPSOMMING: Sien asb volteks vir opsomming

Chapter 1 gives an introduction on the physical and electronic properties of fluorine and the C-F bond. The application of fluorine in organic chemistry, which is mainly attributed to the electronic properties of fluorine is described. The role of fluorine in neuropsychiatric drug development and for influencing the conformational study of bioactive amines is also illustrated. Chapter 2 of the thesis describes the synthesis of the two fluorinated stereoisomers (2R, 3S) and (2S, 3S) 3-fluoro N-methyl–D-aspartate (NMDA). These were prepared as analogues to study the binding conformation of NMDA on the glutameric NMDA receptor. The (2S, 3S)-3-fluoro NMDA D-72 was successfully prepared from diethyl D-tartrate. The (2S,3R)- stereoisomer was prepared by separation of diastereoisomers generated by reaction of a meso- epoxide with an enantiomerically pure amine, followed by fluorination. Both the (2S,3R)- and (2R,3S)- enantiomers were prepared separately, however assignment of the absolute configuration to each enantiomer could not be unambiguously proven. The fluorinated 3F-NMDA stereoisomers were assessed by dose response analysis and TEVC analysis in the rat glutamate receptor. The biological results show that the (2S, 3S)-3F NMDA D-72 is a good agonist, whereas (2R, 3S)- and (2S, 3R)-3-fluoro NMDA are inactive stereoisomers. The result of this study indicates that (2S, 3S)-3F NMDA D-72 is the only relevant agonist that can access a conformation for binding to NMDA receptor. Chapter 3 describes the preparation of fluorinated analogues of the calcium receptor agonist Cinacalcet. The (2R,1’R)-123 and (2S,1’R)-124 fluoro Cinacalcet diastereoisomers were prepared from 3’-(trifluoromethyl)cinnamic acid and 3’’-SF₅-137 Cinacalcet was synthesized from pentafluorosulfanyl benzyl alcohol. The biological assessment in the calcium receptor (CaR) revealed that both (2R,1’R)-123 and (2S,1’R)-124 fluoro Cinacalcet is slightly lower in potency compared to the non-fluorinated Cinacalcet 117. This suggests that the Cinacalcet 117 adopts an extended conformation when bound to the receptor. The 3’’-SF₅-137 Cinacalcet possesses equipotent activity with Cinacalcet 117.

A primeira parte da discussão de resultados desta tese relata o estudo da isomeria conformacional e das interações eletrônicas dos compostos carbonílicos α-dietoxifosforilsubstituídos (EtO)2P(O)CH2C(O)X (X= Me, Ph, OEt, Net2 e SEt). Este estudo foi realizado através das espectroscopias no infravermelho, Ressonância Magnética Nuclear de 13C e 31P, apoiados por cálculos ab initio nas bases HF/ 3-21G*e HF/6-31G** e difração de raio-X. As freqüências de vCO da única banda no infravermelho dos β-carbonilfosfonatos [XC(O)CH2P(O)(OEt)2: X=Me 1, Ph 2, OEt 3, Net2 4 and SEt 5] (série I), se correlacionaram muito bem com as frequências de vCO do rotâmero gauche das correspondentes β-carbonil sulfonas [XC(O)CH2SO2Et : X=Me 6, Ph 7, OEt 8, Net2 9 and SEt 10] (série II) concordando com os cálculos ab initio 6-31G** de 1ª e 6ª (X=Me) que indicaram a existência de uma única conformação gauche (g1) para a série I em solução. Os deslocamentos negativos anormais de freqüência da carbonila (ΔvCO) para ambas as séries segue aproximadamente a afinidade eletrônica do orbital π*CO dos compostos de referência MeC(O)X 11-15. Estes dados sugerem que a conformação gauche das séries I e II deve possuir uma geometria semelhante. O menor deslocamento positivo de frequência de estiramento assimétrico do grupo sulfonila (ΔvSO2) em comparação com o do grupo fosforila (ΔvPO) e o maior deslocamento negativo da carbonila gauche das β-carbonil sulfonas 6-10 em relação aos valores dos β-carbonil fosfonatos 1-5 correspondentes estão de acordo com os deslocamentos químicos em campo mais alto para a série II em relação à séries I. Estas tendências estão de acordo com o encurtamento da distância O(SO2) .... C(CO) em relação a O(PO) ... C(CO) nos compostos 6ª e 1ª, respectivamente, e são discutidos em termos da interação de transferência de carga O1p→ π* CO o qual é mais forte para a série II que para I. Este comportamento inesperado indica que o átomo de oxigênio do grupo sulfonil do SO2R é melhor doador de elétrons que o oxigênio do grupo fosforila P(O)(OR)2. Contudo, parâmetros geométricos intrínsecos à molécula parecem ser os responsáveis por este comportamento .. De fato, dados de difração de raio-X e cálculos ab initio de metilsulfonilmetil fosfonato de dietila MeSO2CH2P(O)(OR)2 (R= Et, 18, Me 18a) apoiam esta análise. As análises espectroscópicas e cálculos ab initio dos compostos alquil(aril)tiometil-fosfonatos de etila (EtO)2P(O)CH2SOnR (R=Me e Ph) e suas formas mono- (n=1) e di- (n=2) oxigenadas mostraram que os mesmos encontram-se na conformação quasi-gauche. Este estudo mostrou que tanto o deslocamento químico de 31 quanto a freqüência de vPO se correlacionam muito bem com os parâmetros indutivos (σI) do substituinte em α não levando em consideração as interações eletrônicas variáveis que ocorrem entre os substituintes em α e o fósforo do grupo fosforila. Os dados de Ressonância Magnética Nuclear de 13C para os compostos da série I foram interpretados como sendo devido à ação simultânea do efeito -I do grupo dietoxifosforila e da transferência de carga do oxigênio do grupo fosforila ao carbono carbonílico que se encontram na relação espacial gauche. Os estudos de Ressonância Magnética Nuclear de 13C corroboraram os dados de Infravermelho indicando que a transferência de carga O(PO) → π*CO nos rotâmeros gauche da série I é mais fraca que a interação de transferência de carga O(SO2) → π* CO no mesmo rotâmero da série II. Os deslocamentos químicos de 31P mostraram-se praticamente constante ao longo da série estudada (série I). Os espectros ultravioleta dos compostos da série I indicaram que a introdução do grupo dietoxifosforila na posição α à carbonila origina um deslocamento batocrômico da transição n→π*CO em relação aos compostos carbonílicos de referência. Este comportamento pode ser atribuído à ocorrência da interação hiperconjugativa entre os orbitais σ* C-P e da π*CO que estabiliza o orbital π*CO em maior extensão que o efeito -I estabiliza o nível de energia nO(CO). Como decorrência da semelhança conformacional entre os &#946-cetosulfóxidos [MeC(O)CH2S(O)Ph-X (X=Cl, H, Me e OMe)] e &#946-cetosulfonas [MeC(O)CH2SO2Ph-X (X=NO2, H, Me e OMe) e X-Ph-C(O)CH2SO2Et (X=NO2, CN, H, OMe e NH2)] com os correspondentes &#946-fosforil-sulfóxidos [(EtO)2P(O)CH2S(O)R (R= Me ou Ph)] e β-fosforilsulfonas [(EtO)2P(O)CH2SO2R (R= Me ou Ph)] e considerando-se que a série dos β-ceto-sulfóxidos e β-ceto-sulfonas apresentam uma citotoxicidade moderada em relação às células de linhagens leucêmicas humanas K562 (eritroleucemia), tumores de Ehrlich e células de linhagens e U937 (leucemia linfóide), estes dois últimos somente para os β-cetosulfóxidos, achou-se de interesse estudar a atividade citotóxica dos α-metilsulfinil- α-metilsulfonil- metanofosfonatos de dietíla em relação aos mesmos tipos de células tumorais. Os dados da citotoxicidade do α-metilsulfinil- e α-fenil-sulfinil-metanofosfonato de dietila indicaram que os mesmos apresentam um efeito citotóxico bem menor do que aquele observado nos β-cetosulfóxidos. O α-metilsulfonilmetilfosfonato de dietila apresentou uma atividade citotóxica similar em relação às duas séries de β-cetosulfonas. Já o α-fenilsulfonilmetilfosfonato de dietila não apresentou nenhum efeito de citotoxicidade significativo em relação às células tumorais testadas. Finalmente, esta tese relata também, o estudo das reações dos compostos carbonílico α-halossubstituídos X-C(O)CH2-Hal X (X= Me, Ph, OEt, Net2 and SEt) com fosfito de trietila em benzeno anidro à temperatura de refluxo de benzeno. Nessas condições observou-se a formação dos compostos carbonílicos α-dietoxifosforil-substituídos (EtO)2P(O)CH2C(O)X 1-5 e dos enolatos correspondentes CH2=C(X) [P(O)(EtO)2] , havendo mudança na proporção dos isômeros obtidos à medida que se varia o grupo ligado à carbonila. Os substituintes doadores de elétrons levam à formação preferencial dos cetofosfonatos (reação de Michael-Arbuzov) enquanto que substituintes atraentes de elétrons levam à formação preferencial de enolfosfatos (reação de Perkow). Estes dados sugeriram que a adição nucleofílica à carbonila com a formação de enolfosfatos depende da afinidade eletrônica do orbital π* CO. / The first part of the discussion of this thesis reports the conformational and electronic interaction study of some α-diethoxyphosphoryl-substituted carbonyl compounds (EtO)2P(O)CH2-C(O)X (X= Me , Ph , OEt , Net2 and SEt ). This study was performed by means of infrared, 13C and 31P Nuclear Magnetic Resonance spectroscopies supported by 3-21G* and 6-31G** ab initio computations and X-ray diffraction. The IR frequencies of the single vCO band of the β-carbonylphosphonates [XC(O)CH2P(O)(OEt)2: X=Me l, Ph 2, OEt 3, Net2 4 and SEt 5] (series I), which correlate well with the vCO frequencies of the gauche rotamer of the corresponding β-carbonyl sulfones [XC(O)CH2SO2Et : X=Me 6, Ph 7, OEt 8, Net2 9 and SEt 10] (series II) along with the ab initio 6-31G** computations of 1a and 6a (X=Me) have indicated the existence of only a single gauche conformer (g1) for series I in solution. The abnormal negative carbonyl frequency shifts (ΔvCO) for both series follow approximately the electron affinities of the π*CO orbital of the parent carbonyl compounds MeC(O)X 11-15. These data have suggested that the gauche conformations of series I and II should have similar geometry. The less positive asymmetric stretching sulfonyl frequency shifts (ΔvSO2) in comparison with the phosphoryl frequencies shifts (ΔvPO) and the larger negative carbonyl gauche shifts of the β-carbonyl sulfones 6-10 in relation to the corresponding values of the β-carbonyl phosphonates 1-5 are in line with the upfield carbonyl carbon chemical shifts for series II in relation to series I. These trends are in agreement with the shorter O(SO2) ....C(CO) contact in relation to the O(PO) ... C(CO) one in compounds 6a and 1a, respectively, and are discussed in terms of the OIp → &#960*CO charge transfer which is stronger for series II than for I. This unexpected behaviour indicates that the sulfonyl oxygen atom of SO2R group is a better electron donor than the phosphoryl oxygen atom of P(O)(OR)2 group. However the intrinsic geometric parameters of O=S-CH2 and O=P-CH2 moieties seems to be responsible for this behaviour. In fact X-ray and ab initio calculations of dialkyl methylsulfonyl-methylphosphonate MeSO2CH2P(O)(OR)2 (R=Et, 18, Me 18a) gives support to this analysis. The spectroscopic analysis and ab initio computations of the diethyl alkyl(aryl)thiomethyl-phosphonates (EtO)2P(O)CH2SOnR (R=Me and Ph) and their mono- (n=l) and di- (n=2) oxigenated derivatives, showed that the phosphoryl compounds assumes a quasi-gauche conformation. This study showed that both 31P chemical shifts and the vPO frequencies correlate well with the inductive effect (σI) of the α-substituents, not taking into account any electronic interaction which could occur between the α-substituents and the phosphoryl phosphorus atom. The 13C NMR data has been interpreted by the simultaneous occurrence of the -I effect and the charge transfer between the oxygen atom of this group and the carbonyl carbon atom in the gauche rotamer of the title compounds. The 13C NMR studies corroborated the infrared data indicating that the charge transfer O(PO) → π*CO in the gauche rotamers of the serie I is poorer that the charge transfer O(SO2) → π*COfor the serie II. Furthermore, the 31P chemical shifts are almost constant along the série I. The ultraviolet spectra of compounds of the serie I showed that the introduction of the diethoxyphosphoryl group in the α position of the carbonyl compounds originate a bathochromic shift of the n→π*CO transition in relation to their parent carbonyl compounds. This behavior was ascribed to the occurrence of the hyperconjugative interaction between the σ*C-P and π*CO orbitals which stabilize the π*CO orbital in a greater extension than the -I effect of the diethoxyphosphoryl group stabilizes the nO(CO) energy level. Due to conformational similarity between the β-ketosulfoxides MeC(O)CH2S(O)Ph-X (X=Cl, H, Me and OMe) and β-ketosulfones MeC(O)CH2SO2Ph-X (X=NO2, H, Me and OMe) and X-Ph-C(O)CH2SO2Et (X=NO2, CN, H, OMe and NH2) with the β-phosphorylsulfoxides corresponding (EtO)2P(O)CH2S(O)R (R= Me ou Ph) and β-phosphorylsulfones (EtO)2P(O)CH2SO2R (R= Me ou Ph) and considering that the β-ketosulfoxides and β-ketosulfones present a moderate cytotoxicity on human mieloid leukemia K562, on Ehrlich tumor cells and human monocytic cell line (U937), excepting the case of the two latter neoplasic cells which are sensitive to the β-ketosulfoxides, it became also of interest to test the cytotoxicity of the diethyl α-methyl(phenyl)sulfinyl- and α-methyl(phenyl)sulfonylmetane-phosphonates with respect to the above mentioned tumor cells. The cytotoxicity data of the diethyl α-methylsulfinyl- and α-phenylsulfinyl- methanephosphonates indicated that the β-phosphorylsulfoxides exhibit a poorer cytotoxic effect in relation to the β-ketosulfoxides towards the tumor cells tried. The diethyl α-methylsulfonyl methanephosphonates exhibit in relation to the β-ketosulfones a similar cytotoxic effect, while the diethyl α-phenylsulfonyl-methanephosphonate did not show any apparent cytotoxic effect. Finally, this thesis deals with the reactions of the α-halo-substituted carbonyl compounds Hal-CH2C(O)X (X= Me, Ph, OEt, Net2 and SEt) with triethylphosphite in anhydrous benzene under reflux. These reactions gave variable proportions of α-diethoxyphosphoryl-substituted carbonyl compounds (EtO)2P(O)CH2 -C(O)X (X= Me, Ph, OEt, Net2 and SEt) and the corresponding enolphosphates [CH2=C(X)[P(O)(EtO)2] with the changing of the substituent directly bonded to the carbonyl group. The electron-donating substituents originate preferentially the β-ketophosphonates (Michael-Arbuzov product) while electron-withdrawing substituents gave mainly the enolphosphates (Perkow product). These trends strongly suggest that the rate-limiting step of the reactions between the α-halo-substituted carbonyl compounds and triethylphosphite is the nucleophilic addition of the phosphorus lone pair to the carbonyl carbon leading to the obtention of the enolphosphates which in its tum depends on the electron-affinity of the π*CO orbital.

A presente tese relata a síntese e a análise conformacional das: N-metóxi-N-metil- 2-feniltiopropanamidas 4\'-substituídas (I), N-metóxi-N-metil-2- fenilssulfinilpropanamidas 4\'-substituídas (II) e N-metóxi-N-metil-2- fenilssulfonilpropanamidas 4\'-substituídas (III), através da espectroscopia no Infravermelho na região da banda da carbonila (vco), apoiada por cálculos teóricos. A análise conformacional de (I) indicou, através de dados de DFT/cc-pVDZ a existência de um equilíbrio entre duas conformações gauche devido à ocorrência de uma forte interação orbitalar estabilizante π*co/σc-s nas mesmas. A série dos derivados sulfinilados (II) apresentou-se como um par de diastereoisômeros. A análise conformacional para o diast1 (par enantiomérico CRSS/CSSR), através do cálculo HF/6-31G** e IV, indicou a existência de um equilíbrio conformacional entre dois confôrmeros quasi-cis (q-c1 e q-c2) e outro gauche (g), sendo os confôrmeros quasi-cis (q-c1 e q-c2) mais estáveis devido à interação de transferência de carga Oσ-(CO)→Sσ+SO mais intensa do que a interação Oσ-(SO)→Cσ+CO presente no confôrmero gauche (g). A análise para o diast2 utilizando-se o cálculo HF/6-31G** indicou a presença dos confôrmeros quasi-gauche (q-g), e quasi-cis (q-c3) sendo o primeiro mais estável no estado gasoso por apresentar uma interação transferência de carga cruzada Oσ-(CO)→Sσ+SO e Oσ-(SO)→Cσ+CO. Os dados de cálculo HF/6-31G** para os derivados sulfonilados (III) indicaram um equilíbrio conformacional entre duas conformações gauche (g1 e g2) decorrente de uma interação Coulômbica e de transferência de carga cruzada Oδ-(SO2)→Cδ+CO e Oδ-(CO)→Sδ+SO2. A presente Tese também relata a obtenção de compostos ß-lactâmicos acilados no carbono C3 e C4. As N-metóxi-N-metil-2-feniltiopropanamidas-4\'-substituídas (I) agem como acilantes do anel ß-lactâmico (N-fenil-2-azetidinona) para obtenção dos derivados ß-lactâmico C3 acilados. A reação foi realizada com sucesso, contudo, a purificação dos compostos alvo não se mostrou eficaz obtendo-se apenas as 3-[2- (4\'-feniltio)propanoil]-N-fenil- e 3-[2-(4\'- clorofeniltio)propanoil]-N-fenil-2-azetidinonas através de um processo de cristalização. Para a obtenção dos derivados ß-lactâmicos C4 acilados utilizou-se a N-metóxi-N-metil-4-oxo-1-fenilazetidina-2- carboxamida como acilante dos carbânions derivados de 4\'-fenilmetilssulfóxidos [4\'-YPhS(O)CH3 Y= OMe, Me, H]. Esta reação forneceu as 1-fenil- (4-fenilssulfinilacetil- 3 4\'-substituídos)-2-azetidinonas correspondentes com bons rendimentos. A redução destas azetidinonas-sulfóxidos forneceu as azetidinonas-sulfetos correspondentes também com bons rendimentos / This thesis reports the synthesis and the conformational analysis of: N-methoxy-N- methyl-2-[(4\'-substituted)-phenylthio]-propanamides (I), N-methoxy-N-methyl-2-[(4\'- substituted)-phenylsulfinyl]-propanamides (II) and N-methoxy- N-methyl-2-[(4\'- substituted)-phenylsulfonyl]-propanamides (III) by Infrared spectroscopy through the analysis of the carbonyl stretching band supported by theoretical calculations. The conformational analysis of (I) through DFT computations have indicated the equilibrium of two gauche conformations due to a strong stabilizing π*co/σc-s orbital interaction. The group of sulfinyl derivatives (II) exist as a diastereomeric pair. The conformational analysis of diast1 (enantiomeric pair CRSS/CSSR) through IR and HF/6-31G** has shown the existence of an equilibrium between two quasi-cis (q-c1 and q-c2) and one gauche (g) conformers, being the quasi-cis conformers the more stable ones due to the Oσ-(CO)→Sσ+SO charge transfer interaction which in turn is stronger than the Oσ-(SO)→Cσ+CO orbital interaction which takes place in the gauche (g) conformer. As for diast2 the HF/6-31G** computations along IR data has indicated 2 the occurrence of the quasi-gauche (q-g) and quasi-cis (q-c ) conformers, being the former the more stable one in gaseous phase due to the Oσ-(CO)→Sσ+SO e Oσ-(SO)→Sσ+CO crossed charge transfer. The HF/6-31G** and vco data for the sulfonylated derivatives (III) have shown the existence of the equilibrium between two gauche (g1 and g2) conformations which are stabilized through Oδ-(SO2)→Cδ+CO and Oδ-(CO)→Sδ+SO2 electrostatic and charge transfer interactions. This Thesis also deals with the preparation of some C3 and C4 acylated ß-lactamic compounds. The N-methoxy- N-methyl-2-[(4\'-substituted)-phenylthio-propanamides (I) act as acylating agents of the ß-lactamic ring (N-phenyl-2-azetidinone) in order to obtain the C-3 acylated ß-lactamic derivatives. These reactions gave the target products contaminated with starting material in good yields except for the 3-[2- (4\'phenylthio)propanoyl]-N-phenyl- and 3-[2-(4\'-chlorophenylthio)propanoyl]-N- phenyl-2-azetidinones which were obtained in pure form after crystallization. As for the C-3 acylated ß-lactamic derivatives they were obtained from the reaction of N-methoxy-N-methyl-4-oxo-1-phenylazetidine-2-carboxamide and the appropriate carbanions of 4\'-substituted phenylmethylsulfoxides. This reaction gave the corresponding 1-phenyl- (4-substituted-phenylsulfinylacetyl)-2-azetidinones in good yields. The corresponding azetidinone-sulfides were obtained from the reduction of the azetidinone-sulfoxides.

A presente tese relata um estudo espectroscópico de algumas α-heteroacetofenonas-orto-substituídas o-X-PhC(O)CH2-Y, onde X = F, Cl, Br, Me, OMe e NO2; Y = H, Br ou SO(n)Et, onde n = 1 ou 2. Este estudo foi realizado através da espectroscopia no infravermelho pela análise das bandas de v(CO) de todos os compostos estudados e pela análise das bandas de v(CBr) para Y = Br. No ultravioleta foi analisada a transição nO → π*CO para os compostos com Y = H e Br. Na espectroscopia de RMN de 13C foi analisado os deslocamentos químicos dos carbonos carbonílico e α-metilênico. As bandas de vCO dos compostos da série das acetofenonas-orto-substituídas, deconvoluídas computacionalmente a partir dos espectros de IV, usando-se corno solvente n-hexano, demonstraram a sobreposição de duas bandas para os substituintes Cl, Br e NO2, e a existência de apenas uma única banda para os substituintes F, Me e OMe. Esses resultados demonstram boa concordância com os cálculos de mecânica molecular efetuados com colaboração do Prof. Y. Hase (IQ-UNICAMP) e com cálculos ab initio efetuados pelo Prof. G. Distefano (Universitá di Ferrara, Itália). A análise no IV das bandas de vCO dos referidos compostos, em solventes de polaridade crescente (n-hexano, tetracloreto de carbono, clorofórmio e acetonitrila), em conjunto com os resultados dos cálculos de mecânica molecular, permitiram a atribuição das geometrias e as população relativas dos confôrmeros s-cis e s-trans. Assim, no estado gasoso e em solventes de baixa polaridade, a conformação s-cis é predominante para os casos onde o substituinte em posição orto é a orto-metilacetofenona. A conformação s-trans é a mais estável para· os casos onde X= OMe, F e NO2. Para os casos onde o orto substituinte é o Cl ou o Br, existe uma distribuição populacional aproximadamente igual de ambas conformações. A análise conformacional dos compostos da série das α-bromo-acetofenonas-orto-substituídas, também foi efetuada. A partir dos espectros de IV, em solventes de polaridade crescente, em conjunto com os resultados de cálculos de mecânica molecular, atribuiu-se a provável conformação paras as bandas de vCO resolvidas analiticamente. Com exceção do o-flúor derivado, onde a banda de estiramento da carbonila no IV apresentou a ocorrência de 2 componentes, as bandas de vCO dos demais compostos apresentaram a ocorrência de 3 componentes. Cada componente corresponde a uma determinada conformação: cis(s-cis), cis(s-trans), gauche(s-cis) ou gauche(s-trans). A análise das bandas vC-Br mostrou-se concordante com a análise das bandas de estiramento de carbonila. Assim, no estado gasoso e em solventes de baixa polaridade, a conformação gauche(s-trans) é a mais estável para os casos em que o orto-substituinte é flúor, cloro, bromo, metóxi e nitro. Para os casos em que orto-substituinte é o metil, a conformação mais estável é o gauche(s-cis). Também foram analisados os deslocamentos de freqüência de estiramento da carbonila (&#916v), em n-hexano, das α-bromo-acetofenonas-orto-substituídas em relação com os correspondentes compostos de referência com a mesma conformação (s-cis ou s-trans). Deslocamentos positivos eram esperados devido ao efeito indutivo do bromo substituinte em posição α, bem como o efeito de campo repulsivo entre os dipolos C=O e C-Br. Por outro lado, nas conformações gauche, ocorreram deslocamentos negativos, o que evidencia a ocorrência de uma hiperconjugação entre os orbitais π*C=O/σC-Br. Dados do UV demonstram uma batocromia da banda n→π* das α-bromo-acetofenonas-orto-substituídas em relação com os correspondentes compostos de referência, o que indica a ocorrência da interação hiperconjugativa entre os orbitais antiligantes π*C=O/σ*C-Br. A análise conformacional das α-etilsulfinil-acetofenonas-orto-substituídas foi realizada a partir da análise conjunta dos dados obtidos a partir da deconvolução das bandas de vCO registradas no IV e dos resultados de cálculos ab-initio HF/6-31 G** efetuados pelo Prof. G. Distefano. Para todos os compostos da série estudada, observamos no infravermelho que cada banda de vCO possui 2 componentes. Para os compostos com X = F, Me e OMe, os resultados dos cálculos indicaram que a conformação mais estável é a cis, devido principalmente a uma forte interação intramolecular entre os dipolos C=O e S=O. Esta interação foi verificada através do encurtamento da distância O(CO)...S(SO) em relação a soma dos raios de van der Waals. De fato, para X= F, Me e OMe, os encurtamentos de distâncias calculados foram respectivamente 0,396 , 0,402 e 0,410 Å. Para X = F e OMe, os substituintes em orto estão na conformação s-trans em relação à carbonila. Assim ,esta disposição espacial intensifica a interação O(CO)... S(SO) devido a polarização da carbonila causada pela proximidade dos heteroátomos eletronegativos F e O com o carbono carbonílico. Já no caso onde X = Me, o substituinte em orto encontra-se na conformação s-cis em relação à carbonila. Nesta geometria, a polarização da da ligação C=O é intensificada pela ligação de hidrogênio entre o oxigênio carbonílico e os hidrogênios do grupo metílico. Uma conseqüência importante das interações acima citadas é o abaixamento do valor da constante de força da vibração de estiramento da carbonila, devido a uma maior polarização da ligação C=O. Esta polarização pode ser quantificada através dos valores de carga do oxigênio carbonílico obtidos a partir dos cálculos ab-initio. Assim, para as bandas deconvoluídas de vCO no infravermelho, o componente de mais baixa freqüência foi atribuído a conformação cis para os derivados com X= F, OMe e Me. O componente de maior freqüência foi atribuído à conformação gauche. Esta conformação é estabilizada principalmente pela interação O(SO)...C(O), demonstrada pelos resultados dos cálculos ab-initio, onde foi observado um encurtamento da distância O(SO)... C(O) com relação a soma dos raios de van der Waals. Para X = NO2, a conformação gauche é significativamente mais estável do que a conformação cis. Isso se deve ao fato do grupo o-NO2-fenacila estar praticamente perpendicular à carbonila. Esta geometria origina um forte efeito indutivo -I que diminui significativamente a carga negativa no oxigênio carbonílico. Como conseqüência , a conformação cis é bastante desestabilizada. Por outro lado, o efeito indutivo -I causado pelo gn1po NO2 aumenta a carga positiva do carbono carbonílico favorecendo assim a interação O(SO)...C(CO) e estabilizando a conformação gauche. Portanto, o componente de menor freqüência e de maior população relativa observado nas bandas de vCO no infravermelho do o-nitro derivado foi atribuído à conformação gauche e o componente de maior freqüência à conformação cis. Para X = Cl, o resultado dos cálculos ab-inito demonstraram que a conformação cis deste composto é a que apresenta a menor carga negativa no oxigênio carbonílico e um menor encurtamento da distância O(CO)... S(SO) com relação à soma dos raios de van der Waals na série estudada, exceptuando-se o nitro derivado. Analogamente ao nitro derivado, esta baixa estabilidade da conformação cis é atribuída ao efeito -I do cloro. Na conformação gauche, além da estabilização devida a interação O(SO)...C(CO), ocorre também uma interação Cl...C(CO) que é mais forte do que as interações que ocorrem na conformação cis. Devido a baixa polarização da carbonila no confôrmero gauche, constatada através da baixa carga negativa no oxigênio carbonílico, e devido ao fato do cloro adotar uma conformação s-cis em relação à carbonila, originando um efeito de campo repulsivo entre os dipolos C-Cl e C=O, ocorre um aumento da constante de força de vibração da carbonila. Assim, o componente de maior freqüência e de maior população relativa observado nas bandas de vCO no infravermelho foi atribuído à conformação gauche. Já no confôrmero cis, o cloro está na conformação s-trans em relação a carbonila, e o efeito de campo entre os dipolos C-Cl e C=O passa a ser portanto cooperativo originando uma maior polarização da carbonila e por conseguinte uma diminuição da ordem de ligação da carbonila em relação aquela do confôrmero gauche. Portanto, o componente de mais baixa freqüência foi atribuído à conformação cis. As atribuições acima efetuadas para os confôrmeros cis e gauche são corroboradas pela excelente correlação obtida entre as freqüências de vCO atribuídas ao confôrmero cis e as calculadas por intermédio do cálculo ab-inito HF/6-31 G**. No projeto original deste trabalho, um dos objetivos era obter a série das α-etilsufonil-acetofenonas-orto-substituídas, Y = SO2Et, a fim de medir as bandas de vCO no infravermelho e estudar as interações eletrônicas existentes nestes compostos, a exemplo do que foi realizado nas outras séries de compostos da presente tese. Entretanto, de forma inesperada, não foi possível preparar toda a série com Y = SO2Et a partir da oxidação dos ceto-sulfetos correspondentes com peróxido de hidrogênio e ácido acético. Na realidade foram purificados e estudados apenas a α-etilsulfonil-orto-flúoracetofenona e a α-etilsulfonil-orto-nitroacetofenona. Com exceção da α-etiltio-orto-nitroacetofenona, a oxidação de todos os ceto-sulfetos resulta além da ceto-sulfona esperada, um segundo composto, que são os α-etilsulfonil-acetatos de fenila orto-substituídos correspondentes. Esta conclusão foi obtida através da análise dos espectros registrados na região de absorção da carbonila, onde além das bandas de vCO na região de 1700 cm-1, características das ceto-sulfonas, foram observadas outras bandas de vCO de maior freqüência, ao redor de 1750 cm-1. A formação de ésteres fenílicos pode ser explicada através de um rearranjo oxidativo conhecido como Rearranjo de Bayer-Villiger. Entretanto, observamos que o rearranjo oxidativo não ocorre de forma homogênea para todos os substituintes. No caso no nitro substituinte na posição orto, não ocorre a formação do éster, conforme análise no infravermelho na região de 1750 cm-1. Porém, no caso dos demais substituintes, observamos também as bandas vCO características de éster. A relação de populção relativa estér/cetosulfona foi correlacionada linearmente com valores das constantes σR dos respectivos substituintes, de onde concluiu-se que grupos doadores de elétrons, através de efeito mesomérico facilitam a formação do produto rearranjado. Assim, quanto maior for este poder de doação, maior será a proporção de éster fenílico formado. A partir destes fatos, podemos concluir ainda que o estado de transição do rearranjo oxidativo possui uma carga positiva. Assim, grupos doadores de elétrons estabilizam este estado de transição com carga positiva incipiente enquanto que grupos atraentes de elétrons o desestabilizam. Com a finalidade de esclarecer em qual grau de oxidação do enxofre ocorre o rearranjo de Bayer-Villiger foram preparadas a α-etilsulfinil-orto-flúor e a α-etilsulfinil-orto-metóxi-acetofenonas e as suas respectivas ceto-sulfonas. Em seguida, fez-se reagir estes compostos com peróxido de hidrogênio é ácido acético nas mesmas condições utilizadas para a oxidação de ceto-sulfetos a ceto-sulfonas. No caso da oxidação dos cetosulfóxidos obteve-se a éster-sulfona rearranjada na mesma proporção\' daquela obtida quando da oxidação do ceto-sulfeto correspondente. Já no caso da oxidação da ceto-sulfona não ocorreu nenhum rearranjo. Visto que a reação de oxidação de ceto-sulfeto a ceto-sulfóxido é uma reação relativamente rápida, pode-se inferir que o provável intermediário desta reação seja o ceto-sulfóxido, sem excluir no entanto que o rearranjo oxidativo possa ocorrer também com o ceto-sulfeto. / This thesis reports the conformational and electronic interaction studies of some α-hetero-ortho-substituted acetophenones o-Y-PhC(O)CH2X [Y = F, Cl, Br, Me, OMe e NO2; X= H(I), Br(II) and SOnEt, for n = 1 (III) and 2(IV)] . This study was performed by means of infrared spectroscopy through the analysis of the vc0 region for the whole series (I-IV) and of the vC-Br region for the α-bromo derivatives (II). The analysis of the n→π*CO transition and the ultraviolet spectra for series (I) and (II) was also perfonned. The vCO analysis of the ortho-substituted acetophenones (I), in n-hexane, along with Molecular Mechanics Calculations have indicated that the s-cis conformer is practically the only present for the ortho-methyl derivative, and the predominant one for the ortho-nitro derivative. The s-trans conformer is the more stable relative to the s-cis one for the ortho-methoxy and the ortho-fluoro derivatives. As for the ortho-chloro and the ortho-bromo derivatives, both the s-cis and the s-trans conformers are present in almost the same concentration. The vCO and the vC-Br analysis along with the Molecular Mechanics Calculations performed on the α-bromo-ortho-substituted acetophenones (II) have indicated the existence of 2 conformers for the ortho-fluoro derivative, and of 3 conformers for the other ortho-substituted acetophenones. Thus, the gauche(s-trans) conformer is the most stable for the ortho-fluoro, ortho-chloro, ortho-bromo , ortho-methoxy and the orthonitro derivatives, being the gauche(s-cis) conformer the most stable for the ortho-methyl derivative. The negative carbonyl frequency shifts (ΔvCO) of the gauche rotamer for the ortho-substituted acetophenones (II) with respect to the corresponding parent ortho-substituted acetophenones (I) having the same (s-cis) or (s-trans) conformations strongly suggest the occurrence of the hyperconjugation interaction which stabilize the referred conformations. Moreover the ultraviolet spectra of the α-bromoacetophenones (II) showed a bathochromic shift of the n→π*CO transition in relation to their parent acetophenones (I). This behaviour was ascribed to the occurrence of the hyperconjugative interaction between the π*CO and the σ* C-Br orbitals which stabilizes the π*CO orbital in a greater extent than the -I effect of the α-bromine stabilizes the nO(CO) energy level. The preferred conformations of the α-ethylsulfinyl-ortho-substituted acetophenones (III) were detennined by vCO infrared and HF/6-31G** ab-initio computations. In gas phase two more stable conformers were f ound which correspond to the cis2 and gauche3 rotamers having the ortho-substituents either at the s-cis or s-trans geometries with respect to the carbonyl group depending on specific compound considered. For compounds with Y=F, Me and OMe at the ortho position, the larger stability of the cis2 conformer has been attributed to the strong Coulombic and charge transfer interaction between the Sδ+ =Oδ- and Cδ+ =Oδ- dipoles. These interactions are responsible for the short O(CO)... S(SO) interatomic distances which are closer than the sum of the van der Waals radii by 0.396, 0.402 and 0.410Å, for the ortho substituents Y=F, Me and OMe, respectively. For Y=F and OMe derivatives, these ortho substituents assume the s-trans geometry with respect to the carbonyl group, whose Cooperative Field Effect between the heteroatom and the carbonyl carbon induces a larger polarization of the carbonyl group which in tum intesifies the Oδ-(CO)... Sδ+(SO) interaction. On the other hand for Y=Me the ortho substituent assumes the s-cis conformation in relation to the carbonyl group. In this geometry the hydrogen bond between Hδ+(Me)..Oδ-(CO) intensifies the polarization of the carbonyl group leading to a strong Oδ- (CO)..Sδ+(SO) interaction. The above mentioned interaction decreases the carbonyl force constant which lead to a smaller vCO frequency values for the cis rotamers in relation to the gauche ones for the ortho-F , ortho-OMe and ortho-Me derivatives. As for the ortho-nitro derivative (Y=NO2), where the nitro group is almost perpendicular to the carbonyl group, the gauche conformation is significantly more stable than the cis one. In this geometry a strong -I effect of the nitro group operates originating a strong decrease of the carbonyl oxygen negative charge and the si.multaneous increase of the carbonyl carbon positive charge. This behaviour reduces drastically the Oδ-(CO)..Sδ+(SO) interaction in the cis rotamer and acts favoring the Oδ-(SO)..Cδ+(CO) interaction which stabilizes the gauche rotamer. Thus, the more intense lower frequency component of the vCO doublet should correspond to the gauche rotamer and the less intense higher frequency component should correspond to the cis rotamer. As for Y =Cl the ab-initio computations have indicated that its cis conformer bears the smaller carbonyl oxygen negative charge (excepting the case of the ortho-nitro derivative) leading to a larger O(CO)S(SO) short contact with respect to the sum of the van der Waals radii. Similarly to the nitro derivative, the smaller stabilization of the cis conformer was ascribed to the strong -I effect of the chlorine atom. On the other hand in the gauche conformation, where the chlorine atam is in the s-cis geometry, besides the Oδ-(SO)..Cδ+(CO) interaction this conformation is stabilized by the Clδ-.. Cδ+(CO) interaction, which is stronger than the same interaction which operates in the cis conformation. The low polarization of the carboriyl group in the gauche(s-cis) conformer due to the Repulsive Field Effect between the ortho-chlorine and the carbonyl oxygen atoms originates a smaller carbonyl oxygen charge, which leads to an increase of the carbonyl force constant and thus in its frequency. Therefore, the higher frequency carbonyl doublet component was ascribed to the more stable gauche(s-cis) conformer and the lower one to the less stable cis(s-anti) conformer. The above assignments for the cis and gauche rotamers of the whole α-ethylsulfinyl-ortho-substituted acetophenones series were supported by the good correlation obtained between the vCO cis experimental and vCO computed frequencies. Aiming to obtain the α-ethylsulfonyl-ortho-substituted acetophenones series (IV) from oxidation reaction of the α-ethythio-ortho-substituted acetophenones with a mixture of hydrogen peroxide and acetic acid, variable amounts of the keto sulfones and the ortho-phenyl substituded α-ethylsulfonyl acetates o-Y-PhOC(O)CH2SO2Et (V) (ester sulfones) were unexpectedly obtained. In fact when the ortho-substituent is the Y=NO2 only the keto sulfone was obtained, but the ratio ester sulfone/keto sulfone varies from 0.0 to 0.60 on going from ortho-nitro to ortho-methoxy substituents. The formation of ester sulfones can be explained by the Oxidative Bayer-Villiger Rearrangement. The good correlation obtained between the ratio ester sulfone/keto sulfone and the resonance parameter (σR constant) suggests strongly that the transition state of the oxidative rearrangement originates an incipient positive charge which is stabilized mesomerically by electron-donor substituents and is destabilized by electron-attractive substituents. The α-ethylsulfinyl-ortho-methoxy and ortho-fluor acetophenones under the same oxidative conditions of the α-ethylthio-ortho-methoxy and ortho-fluor acetophenones gave the same ratio of the ester sulfones /keto sulfones. Considering that the oxidative reaction of the keto sulfides to keto sulfoxides is a relative fast reaction, it seems reasonable to suggest that the probable intennediate for the appearance of the ester sulfone may be the keto sulfoxide, but not excluding that the oxidative rearrangement could also occur from the keto sulfide. IR vCO analysis of the α-ethylsulfonyl-ortho-fluoro and ortho-nitro acetophenones along with ab-initio calculations of the model molecule: methylsulfonylacetone indicated that both keto sulfones exist in solution in two gauche conformations (gauche1, less polar; gauche2, more polar). The preferred conformations in the solid state determined by X-Ray diffraction for the ortho-fluoro derivative is the more polar gauche2 conformation , while in the case of the ortho-nitro derivative is the less polar gauche1 conformation.