The first identfied 2-oxoglutarate (2OG) dependent oxygenase was a collagen modifying enzyme in the work by Hutton et al. in 1967. Subsequent work has revealed that 2OG dependent oxygenases are a large family with diverse biological roles. With small molecule substrates, these enzymes catalyse a wide range of oxidative reactions, including those that form part of antibiotic biosynthetic pathways. The currently accepted consensus mechanism for catalysis by 2OG-dependent oxygenases is based on crystallographic data, kinetics and on quantum chemical calculations. The consensus mechanism involves oxidative decarboxylation of 2OG by reaction with an oxygen molecule producing CO₂, succinate and a reactive oxidising species that reacts with the 'prime' substrate. Deacetoxycephalosporin C synthase (DAOCS) is a 2OG-dependent oxygenase involved in cephalosporin biosynthesis. The mechanism of DAOCS is of particular interest because it has recently been proposed to be different from the consensus mechanism. The new mechanism proposal from Valeg ard et al. is primarily based on high-resolution crystallographic data with support from steady-state kinetic experiments and quantum-chemical calculations. The work in discussed in this thesis aimed to test the proposal of Valegård et al. by using a combination of spectroscopic and spectrometric methods analysing enzyme-substrate interactions. Substrate binding was investigated using both protein-observe (Chapter 3) and ligand-observe (Chapter 4.1 and 4.2) methods. Preliminary UV-visible data on enzyme-substrates complex formation was also obtained. The strength of substrate and cosubstrate binding was characterised through dissociation constant measurement. An activity assay (Chapter 2) that allows for direct and simultaneous monitoring of 2OG decarboxylation and penicillin ring expansion was optimised. Both the ligand-observe and protein-observe binding experiments as well as the preliminary UV-visible data indicate that the formation of a ternary complex between DAOCS, 2OG and the penicillin substrate is viable. The activity assay conclusively showed that in the presence of unnatural substrates, such as penicillin G, 2OG oxidation is significantly uncoupled from penicillin oxidation. Uncoupled turnover does not occur in the presence of the natural substrate, penicillin N, which is an aspect that should be considered in the analysis of the steady-state kinetic data. Overall, the results provide evidence that, the consensus mechanism for 2OG-dependent oxygenases is viable for DAOCS, at least in the presence of the natural substrate, penicillin N. It is possible that in the presence of an unnatural substrate, the catalytic process undergoes a more complex mechanism, possibly with the direct involvement of reducing agents in the system.

Iminosugars, carbohydrate analogues in which nitrogen replaces the endocyclic oxygen, have attracted much interest due to their biological activity. Iminosugars inhibit carbohydrate-processing enzymes, thereby affecting many biological processes. Several iminosugars are licensed drugs, with many more compounds undergoing clinical trials. The main subject of this thesis is the synthesis and evaluation of novel iminosugars, particularly the effects of structural modifications on the biological activity of these compounds. Chapter 1 describes the role of carbohydrate-processing enzymes in the body, and explores the therapeutic applications of iminosugars that arise from their activity against these enzymes. Examples of substituted iminosugars are reviewed, and the effects of substituents on enzyme inhibition are described. Chapter 2 concerns methyl-branched swainsonine derivatives. Swainsonine has shown potential as a cancer treatment through its inhibition of α-mannosidase. The synthesis of (6R)- and (6S)-C-methyl D-swainsonine is described; both compounds were potent and selective α-mannosidase inhibitors (IC₅₀ 3.8 μM, 14 μM). Although less active than the parent compound, their selectivity for Golgi mannosidase over lysosomal mannosidase may be more important than the absolute value against the model enzyme. Chapter 3 describes the synthesis of a 2-C-methyl L-fucose derivative. A diastereoselective Kiliani reaction allowed the formation of a single lactone bearing a new quaternary centre. The utility of this intermediate in accessing di-branched iminosugars was explored; however, attempts to introduce nitrogen to the lactone lacked the necessary stereoselectivity. Chapter 4 relates to the synthesis of pyrrolidine iminosugars, specifically methyl amides. Two enantiomeric dihydroxyproline amides were synthesised; the D-proline derivative was a potent β-N-acetylhexosaminidase inhibitor (IC₅₀ values of up to 3.6 μM), but the L-enantiomer was completely inactive. Inhibition of N-acetylhexosaminidases is relevant to the treatment of cancer and lysosomal storage diseases, and this work contributed to a wider project investigating the effects of altered stereochemistry on the biological activity of pyrrolidine amides.

The human α-lactalbumin (α-LA) molten globule formed at low pH is a model for the study of protein folding intermediates. The molten globule lacks native-like side-chain interactions, resulting in a fluctuating ensemble of tertiary structures, characterisation of which has been precluded by severe line-broadening in NMR spectra and a lack of long-range NOEs. Paramagnetic relaxation enhancements (PREs) have been measured in a variant of α-LA in which all native cysteines have been mutated to alanine (all-Ala α-LA). Cysteine residues have been mutated into regions of interest and spin labelled with MTSL. These measurements have confirmed that all-Ala α-LA forms a compact molten globule. Transient, long-range interactions that are stabilising the compact fold have also been identified using PREs measured in urea-denatured states. This has identified several interactions formed by hydrophobic residues from both the α- and β-domain, which could be important for initiating and driving folding. The molten globule’s 3D topology has been probed by measuring long-range distances between MTSL pairs using Double Electron-Electron Resonance (DEER). Broad distance distributions have been identified between elements of secondary structure, indicative of a fluctuating but compact fold. By contrast, a narrower distance distribution has been measured within one of the major helices, indicative of native-like secondary structure. The surface accessibility of all-Ala α-LA and that of two other variants ([28-111] α-LA and 4SS α-LA) has been probed using solvent PREs obtained using TEMPOL, a paramagnetic co-solute. This has revealed differences in the solvent-exposure of hydrophobic residues due to the removal of disulphide bonds. This method has also identified buried hydrophobic residues that contribute to forming the molten globule’s stable, native-like core.

This thesis describes the combination of two sources of cold atomic or molecular species which can be used to study a wide range of ion-molecule reactions. The challenges in forming these species and in determining the fate of reactive events are explored throughout. Reactions occur in a volume within a radio-frequency ion trap, in which ions have previously been cooled to sub-Kelvin temperatures. Ions are laser-cooled, with migration of ions slowed sufficiently to form a quasi-crystalline spheroidal structure, deemed a Coulomb crystal. Fluorescence emitted as a consequence of laser-cooling is detected; the subsequent fluorescence profiles are used to determine the number of ions in the crystal and, in combination with complementary simulations, the temperature of these ions. Motion imparted by trapping fields can be substantial and simulations are required to accurately determine collision energies. A beam of decelerated molecules is aimed at this stationary ion target. An ammonia seeded molecular beam enters a Stark decelerator, based on the original design of Meijer and co-workers. The decelerator uses time-varying electric fields to remove kinetic energy from the molecules, which exit at speeds down to 35 m/s. A fast-opening shutter and focussing elements are subsequently used to maximise the decelerated flux in the reaction volume while minimising undecelerated molecule transmission. Substantial fluxes of decelerated ammonia are obtained with narrow velocity distributions to provide a suitable source of reactant molecules. Combination of these two techniques permits studies of reactions between atomic ions and decelerated molecules that can be entirely state-specific. Changes in the Coulomb crystal fluorescence profile denote changes in the ion identities, the rate of these changes can be used to obtain rate constants. Determination of rate constants is even possible despite the fact that neither reactant nor product ions are directly observed. This work has studied reactions between sympathetically cooled Xe⁺ ions and guided ND3 and has obtained data consistent with prior studies. Determination of reactive events is complicated if ion identities can change without affecting the fluorescence profile, or if multiple reaction channels are possible. A range of spectroscopic techniques are discussed and considered in regards to determining rate constants and product identities. Pulsed axial excitation of trapped ions can follow rapid changes in average ion weights and subtle changes for small crystals. Time-of-flight mass spectrometry is also demonstrated using the trapping electrodes and is suitable for discrimination of ions formed within the trap.

This thesis expands the scope for using the permethylpentalene ligand and its precursors in the synthesis of organometallic complexes. <strong>Chapter one</strong> begins with a brief review of linked metallocenes, with which multimetallic compounds bridged by pentalene ligands have often been compared, followed by a comprehensive review of the routes used to make pentalenes and substituted pentalenes. Organometallic compounds of pentalenes are introduced, with a focus on bimetallic systems. <strong>Chapter two</strong> explores the diversification of substituents added to the permethylpentalene (Pn*) precursor WeissH₄, to include ethyl and isopropyl groups. Low-symmetry mono-, di-, tri- and tetraalkylated products are formed, eight such organic molecules have been identified by NMR spectroscopy, and two characterised crystallographically. It has been demonstrated that subsequent hydrolysis and decarboxylation of two of these products produces low-symmetry alkylpentalene precursors. The chapter concludes with discussions on the selectivity exhibited in these reactions, and the assignment of stereochemistry. <strong>Chapter three</strong> describes the synthesis of the first homoleptic double metallocene complex of iron. Fe₂Pn*₂ has been characterised by X ray diffraction, and cyclic voltammetry studies demonstrate four accessible oxidation states (-1, 0, +1, +2). Magnetic measurements in the solid and solution state reveal an unusual triplet configuration, and DFT calculations indicate the origin of a high magnetic moment likely resides in unquenched orbital angular momentum contributions from SOMOs which have metal d character. Fe₂Pn*₂ is EPR silent at 5, 40, and 300 K both in solution and the solid state, suggesting a large zero-field splitting parameter. The reaction of the di-iron complex with carbon monoxide, ethylene and H2 is reported; the bimetallic CO adduct, Fe₂(&mu; &eta;⁵,&eta;³ Pn*)(&mu; &eta;⁵,&eta;¹ Pn*)(CO)₂, has been crystallographically characterised, and contains a highly distorted allylic bonding motif, which to the author’s knowledge is believed to be unique among iron complexes. <strong>Chapter four</strong> discusses the interaction of the bidentate Pn* ligand in anti bimetallic fused metallocenes. A new ligand exchange route has been developed to access the complexes (MCp)₂Pn* (M = Co, Ni), and the isostructural complexes (MCp*)₂Pn* have been made for M = Fe, Co, Ni by salt metathesis reactions. All five complexes have been characterised by single crystal X-ray crystallography, and have diamagnetic ground states in solution in common with their Pn bridged analogues. Variable temperature NMR studies reveal a spin-equilibrium between S = 0 and S = 1 in the dinickel complexes. DFT calculations reproduce the spin states found, and suggest the distortion towards &eta;³ coordination observed on crossing from Fe, to Co, to Ni, results from population of orbitals with M―bridgehead antibonding character. The electronic structures show it is important to draw comparisons between isoelectronic linked metallocenes. Electrochemical studies on the diiron, dicobalt, and (NiCp)₂Pn* complexes reveal at least three redox events for each. <strong>Chapter five</strong> documents the successful synthesis and characterisation of monometallic complexes of iron and manganese with Pn*H ligands. The isostructural complexes Fe(Pn*H)₂ and Mn(Pn*H)₂ can have been characterised crystallographically, and are potential precursors for accessing heterometallic, and multimetallic complexes. Mn(Pn*H)₂ is a rare example of a manganese sandwich compound and magnetic studies on a single isomer in the solution and solid states suggest it adopts intermediate spin states of S = 2 in solution, and S = 3/2 in the solid state. <strong>Chapter six</strong> gives experimental details for all syntheses and studies described in the preceding chapters. <strong>Chapter seven</strong> provides characterising data for all new compounds. Fitting data for VT NMR and SQUID studies are provided in the <strong>appendix</strong> at the end of this thesis. Crystallographic data in the form of .cif files, DFT output files, and raw SQUID data, can be found in the <strong>electronic appendix</strong>.

Analogues of Antibacterial Natural Products Elizabeth Anne Heaviside, St Catherine’s College, University of Oxford DPhil Thesis, Trinity Term 2012 This thesis is concerned with the synthesis and biological evaluation of structural mimics for the natural products 16-methyloxazolomycin and lemonomycin which display potent biological activity including antibacterial and antitumour activity. Chapter 1 explores methods and approaches to the discovery of new antibacterial drugs and the challenges faced in this respect. It also gives an overview of the properties of the natural products investigated in the following chapters and summarises previous synthetic approaches to these molecules published in the scientific literature. Chapter 2 describes the work carried out towards the synthesis of the diazabicyclo[3.2.1]octane unit of the tetrahydroisoquinoline antitumour antibiotic lemonomycin. The intended retrosynthesis of the natural product led to a 2,5-disubstituted pyrrolidine bearing a 1ʹ-amino functional group; a series of routes were explored for the synthesis of this unit. Using (S)-pyroglutamic acid, strategies using Eschenmoser and thiolactim ether coupling reactions were investigated. A sequence based on the formation of a pyrrolidine ring from the cyclisation of an appropriately substituted oxime ether derived from L-phenylalanine was then implemented but a competing Beckmann rearrangement/Grob fragmentation prevented access to the desired heterocycle. Preliminary investigations were also carried out on the modification of cyclic imines derived from oxime ethers which did not undergo Beckmann rearrangement. Chapter 3 describes the synthesis of a library of densely functionalised tetramic acid and pyroglutamate mimics for the right-hand fragment of 16-methyloxazolomycin, and their coupling with a gem-dimethylamide unit mimicking the middle fragment of the natural product. Tetramates were accessed through the Dieckmann cyclisation of N-acyloxazolidines and were derivatised with various alkyl halides. The pyroglutamates were accessed via the highly diastereoselective aldol cyclisation of N-acyloxazolidines formed by the amide coupling of a threonine derived oxazolidine and β-keto-acids. A series of β-keto-acids were synthesised through the acylation and subsequent ring-opening/decarboxylation reaction of Meldrum’s acid. The formation of right-hand/middle fragment adducts was explored using cycloaddition, alkylation and Sonogashira chemistry before a Wittig protocol led to the formation of adducts (E)- and (Z)- 402 and 403. Biological evaluation of the compounds synthesised in this chapter was carried out using both broth and hole-plate bioassays and active compounds were identified. Of particular note was that the Wittig adducts displayed a higher level of activity against Gram-negative E. coli than either the pyroglutamate or amide motifs alone.

La present tesi doctoral s'emmarca dins el camp de la química teòrica icomputacional. El primer objectiu, que va ser el de partida, consistia a veure si els índexosbielectrònics derivats de la teoria AIM podien ser útils per estudiar la reorganitzacióelectrònica al llarg d'una reacció. De forma paral·lela es va plantejar un objectiumetodològic, el càlcul dels índexos mencionats a altres nivells de teoria, com podia serDFT o CI. CI. Aquests dos objectius varen portar a molts d'altres, tot i que els principals són:Objectiu 1. Estudi de la reorganització de parells d'electrons al llarg d'unareacció.Objectiu 2. Efecte de la solvatació sobre l'estructura de parells d'electrons d'unamolècula.Objectiu 3. Càlcul dels índexos de localització i deslocalització als nivells de teoriadel funcional de la densitat i post-Hartree-Fock.Objectiu 4. Caracterització de l'enllaç per pont d'hidrogen per mitjà del'estructura dels parells d'electrons.Objectiu 5. L'índex de deslocalització: nou criteri electrònic d'aromaticitat.

The knowledge of geometry of molecular complexes formed via molecular association in solution through weak interactions is always important to understand the origin of stability and function of an array of molecules, supramolecular assemblies, and macromolecular networks. Simple 1:1 molecular complexes are very useful in this regard as they provide a model to understand both the nature of these interactions and their structural implications. Several weak noncovalent forces from long range (van der Waal’s, electrostatic, induction, dispersion) to short range (charge transfer) govern the geometry, that is, relative orientation of the two molecules in such a complex. On one hand, we find 1:1 electron donor acceptor (EDA) complexes such as naphthalene-tetracyanobenzene, hexamethylbenzene-chloranil etc. which stack parallel or in slipped parallel geometry in their crystals. On the other, benzene dimer has been found to stabilize in T shaped geometry in all its three physical states. In this thesis, I focus on 1:1 EDA complexes in solution. A good volume of literature is available which deals with the optical studies on the formation of such complexes. It has been suggested that the nature of the intermolecular interactions stabilizing these complexes in the gas phase or in their crystals is modified by the presence of solvent-solute interactions in solution thus bringing in difference in the solution geometry. However, the existing experimental techniques, both optical and magnetic, are unable to determine the exact geometries of 1:1 EDA complexes in solution. This opens an opportunity to probe their geometry in solution. The quadratic nonlinearity or first hyperpolarizability (β) of a molecule is a measure of the change in dipole moment (or polarization) in the second order of the applied electrical field and thus has a purely electronic origin. It is a tensorial property and can be resolved in components along the three dimensions. The number of β components and the nonlinear optical anisotropies in a typical donor-acceptor type dipolar molecule, defined as (equation) (where1, 2, 3 axes define the molecular frame, 1 being the direction along the principal axis of symmetry and pointing from the acceptor toward the donor), are determined by the symmetry /structure of the molecule. It has been shown theoretically that the 1:1 EDA complexes possess large hyperpolarizabilities. In the case of pNA dimers calculation revealed that the geometry of the dimer and its symmetry is important for obtaining the correct estimate of β from its tensorial components. Therefore, it should be possible to use the values of tensorial β components to construct the unknown geometry of such complexes. Experimentally macroscopic depolarization ratios (D and D′) in the laboratory fixed frame (XYZ, X being the direction of polarization and Z the direction of propagation of the incident light), are measured from the polarization resolved intensities of second harmonic scattering from molecules in solution using the hyper-Rayleigh scattering technique. The depolarization ratios are correlated to the anisotropy parameters, u and v through a co-ordinate transformation. In this thesis I, have first, characterized the quadratic nonlinear optical property of a variety of 1:1 electron donor acceptor complexes and used the values of u and v obtained from depolarized hyper-Rayleigh scattering to deduce their geometry in solution. Chapter 1 provides an introduction to the 1:1 electron donor acceptor complexes, their relevance to chemistry and biology. It also contains an introduction to nonlinear optical processes in molecules. The objective of the present work and scope of the investigation carried out in this thesis is presented in this chapter. Chapter 2 describes the details of the experimental polarization resolved HRS technique. The geometrical model adopted for the analysis of the HRS data has also been introduced and the method of analysis has been described in detail in this chapter. Chapter 3 presents the measurement of β values of two series of 1:1 EDA complexes of variously substituted methylbenzenes donors with tetrachloro-p-benzoquinone (CHL) and dicyanodichloro-p-benzoquinone (DDQ) acceptors at 1064 nm. In agreement with recent theoretical results we find large first hyperpolarizabilities for these complexes. The β values are greater than that of the typical push-pull molecule p-nitroaniline (pNA). We also find that in general β decreases with decrease in the donor strength. Chapter 4 presents the β values for the two series of EDA complexes of CHL and DDQ acceptors at 1907 nm. The values of β are less in magnitude at 1907 nm than that at 1064 nm which is due to the dispersion effect in β. In Chapter 5 and 6, it is described how depolarized hyper-Rayleigh scattering can be utilized to probe geometries of 1:1 complexes in solution. Chapter 5 concentrates mainly on 1:1 EDA complexes of CHL and DDQ and TCNB (tetracyanobenzene), while chapter 6 contains examples of other 1:1 molecular complexes where the noncovalent interactions are much weaker, such as in benzene-naphthalene, benzene-methoxybenzene, benzene-hexafluorobenzene and benzene-chlorobenzene pairs. We find the geometry of 1:1 EDA complexes in solution in terms of tilt angle (θ) and twist angle (ϕ) between the donor and acceptor pairs. The angle θ varies from 29°-47° for different pairs of EDA complexes, while ϕ varies within 34° and 38°. We find that the geometry of 1:1 EDA complexes in solution is different (twisted and tilted cofacial and twisted ‘V’) from those in the crystalline or gaseous states (cofacial), if known. We find that both benzene-naphthalene and benzene-chlorobenzene pairs assume twisted ‘T’ shape geometry with θ = 82° and 85°, respectively, and φ = 38°, while benzene-hexafluorobenzene assumes a twisted ‘V’ shape. A strong solvent effect is seen in the geometry of the benzene- methoxybenzene complex. The tilt angle is 55° when chloroform is used as a solvent and it is 82° without chloroform. Chapter 7 is the concluding chapter where the main work done in this thesis is summarized and future directions are presented.

Thesis (Ph.D.); Submitted to the University of California, Berkeley, CA (US); 21 Dec 2004. / Published through the Information Bridge: DOE Scientific and Technical Information. "LBNL--56768" Urban, Jeffry Todd. USDOE Director. Office of Science. Office of Basic Energy Sciences (US) 12/21/2004. Report is also available in paper and microfiche from NTIS.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / This work describes the molecular and supramolecular structure of fourteen pyrazolo[1,5-a]pyrimidines from bond lengths, torsion angles, angles between planes and interatomic distances. The data discussed were originated from xray and theoretical calculations. Torsion angle N1-N8-C3a-N4, algles between planes of pyrazole and pyrimidine rings and the pyrazolo[1,5-a]pyrimidine RMS value showed that the fused rings are plane. The heterocyclic ring bond lengths demonstrated that the p-electrons are delocalized by resonance and the peripheral electronic distribution of this p-electrons is similar to the naphthalene. The bond length obtained from theoretical calculations (AM1, PM3, RM1 e ab initio) have a correlation with experimental for pyrazolo[1,5-a]pyrimidine ring bonds and for bonds of their substituents.The supramolecular assembly of pyrazolo[1,5-a]pyrimidine reveals that interactions type halogen···Lewis base (Cl···N, F···F, Cl···Cl, Cl···Br), halogen···p (F···p, Cl···p e Br···p) and p-p interactions (pyrazole, pyrimidine and aryl) were the main interactions observed by self-assembly of the pyrazolo[1,5-a]pyrimidines. The atoms in supramolecular synthons were invariable with modifications of substituent at C5. However, was sensitive to variations of substituents at C3. This composes a notable example of substituent effect in the synthon robustness. The halogenated functions at C7(CCl3, CF3), C3 (Br) and in remote positions at C5 (4-Br-Ph) present the competition between chlorine and bromine atoms in the formation of supramolecular synthons. These observations are in accordance with recent s-hole theory and are some of few experimental example of theory. Finally, the aromaticity of pyrazolo[1,5-a]pyrimidines was determined by geometric index HOMA (Harmonic Oscillator Model of Aromaticity) from theoretical (AM1, PM3, RM1 e ab initio) and x-ray bond length. In this work, was also proposing new parameters to heterocyclic HOMA calculations. The results show HOMA values higher than 0.900 that is in accordance with aromaticity properties of these systems. / Este trabalho apresenta o estudo da estrutura molecular e supramolecular de uma série de 14 pirazolo[1,5-a]pirimidinas a partir de dados de comprimentos e ângulos de ligação, ângulos diedros, ângulos entre planos, distâncias interatômica de interações intermoleculares. Os dados apresentados foram obtidos por difratometria de raios-X e cálculos teóricos de orbitais moleculares. Os dados do ângulo diedro N1-N8-C3a-N4, ângulo entre os planos do pirazol e da pirimidina, e a média da raiz quadrada dos átomos do anel pirazol[1,5- a]pirimidina demonstraram que os anéis pirazol e pirimidina formadores do anel fundido estão no mesmo plano. Os comprimentos de ligação entre os átomos do núcleo heterocíclico demonstraram que os elétrons-p estão deslocalizados caracterizando um sistema em ressonância e que a distribuição eletrônica se assemelha a do naftaleno, com os elétrons distribuídos pela periferia do sistema heterocíclico. Os comprimentos de ligação obtidos por cálculos teóricos (Austin Method 1, Parametrized Method 3, Recife Method 1 e ab initio) apresentaram boa correlação com dados experimentais tanto para o núcleo pirazolo[1,5-a]pirimidina quanto para os substituintes. Ainda foram realizados estudos da organização supramolecular das pirazolo[1,5-a]pirimidina. As principais interações intermoleculares observadas nas pirazolo[1,5- a]pirimidinas foram do tipo halogênio···base de Lewis (Cl···N, F···F, Cl···Cl, Cl···Br), halogênio···p (F···p, Cl···p e Br···p) e interações do tipo p-p (entre anéis pirazol, pirimidina e arila). Os átomos envolvidos na interação foram persistentes com a variação do susbtituinte no C5 do anel. Entretanto as interações foram modificadas pela mudança de substituintes no C3 do anel, constituindo um exemplo notável do efeito do substituinte no empacotamento cristalino. A presença de funções halogenadas nas posições C7(CCl3, CF3), C3 (Br) e em posições remotas de substituintes em C5 (4-Br-Ph) mostraram a competição entre átomos de cloro e de bromo na organização supramolecular destes compostos. Estas observações estão de acordo com a recente teoria sobre a existência de uma superfície com potencial positivo na ligação Chalogênio (s-hole) e constituem um dos poucos exemplos experimentais para esta teoria. Por fim, foi determinada a aromaticidade de pirazolo[1,5-a]pirimidinas usando o índice geométrico HOMA (Harmonic Oscilator Model of Aromaticity) a partir dos dados de comprimentos de ligações obtidos por difratometria de raios-X e obtidos por cálculos teóricos (AM1, PM3, RM1 e ab initio). Neste trabalho também foram propostos novos parâmetros para a adequação do cálculo de aromaticidade para heterociclos. Os resultados mostraram valores de HOMA maiores que 0,900, que são condizentes com as características de aromaticidade descritas para estes compostos.