Tautomeric Equilibria Studies by Mass Spectrometry

Tautomerism in organic chemistry has been extensively studied in condensed phase by spectrometric methods, mainly by IR and NMR techniques. Mass spectrometry studies start 40 years ago but just recently it has been recognized the importance of the mass spectral data for the study of tautomerism in the gas phase.
Mass spectrometry can provide valuable information in regard to tautomeric equilibria when studying mass spectra among the members of different families of organic compounds.
The relevance of the mass spectral data resides on several facts but there are two that are of key importance:
1-	Mass spectral fragmentation assignments should be tautomer specific since the corresponding abundances ratios are supposed to be correlated to the keto/enol contents.
2-	Ionization in the ion source is supposed to have no effect on the position of the equilibrium so that the results reflect the tautomers content in the gas phase previous to ionization.
Some of the carbonylic compounds do not exhibit noticeable tautomerism so the fragment abundances assigned to the enol form is very low or not measurable. Since enolization is more noticeable in the case of thio-derivatives (which correlates adequately with the oxygenated analogues), the study of their mass spectra is an interesting choice to reach some degree of generalization. 
In addition, experimental findings are supported by semiempirical theoretical calculations, which probed to be adequate not only for supporting tendency correlations among the members of a compound family but also to calculate heats of tautomerization in gas phase.
Reports using mass spectrometry for tautomerism are becoming less common. One of the reasons is that now it would appear that the interpretation of MS results is not as straightforward as it was once believed, even though in a recent review it was written that: “Mass spectrometry is the most informative and practical method for studying and identifying tautomers in the gas phase” [1]. 
In fact, mass spectrometry seems to be very informative for studying and identifying tautomers, because in this case external factors like solvents, intermolecular interactions, etc., can be excluded by transferring the tautomeric system into gas phase, where the process becomes truly unimolecular [1].
This review covers the study of Tautomerism by Mass Spectrometry in the last four decades. 
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Use of Structure-And Ligand-Based Drug Design Tools for the Discovery of Small Molecule Inhibitors of Cysteine Proteases for the Treatment of Malaria and Sars Infection

A wide array of molecular modeling tools were utilized to design and develop inhibitors against cysteine protease of P. Falciparum Malaria and Severe Acute Respiratory Syndrome (SARS). A number of potent inhibitors were developed against cysteine protease and hemoglobinase of P. falciparum , referred as Falcipains (FPs), by the structure-based virtual screening of the focused libraries enriched in soft-electrophiles containing compounds. Twenty one diverse, non-peptidic, low micromolar hits were identified. A combined data mining and combinatorial library synthesis approach was performed to discover analogs of virtual screening hits and establish the structure-activity relationships (SAR). However, the resulting SAR of the identified hits was unusually steep in some cases and could not be explained by a traditional analysis of the interactions (electrostatics, van der Waals or H-bond). To gain insights, a statistical thermodynamic analysis of explicit solvent in the ligand binding domain of FP-2 and FP-3 was performed that explained some of the complex trends in the SAR. Furthermore, the moderate potency of a subset of FP-2 hits was elucidated using quantum mechanics calculations that shoreduced reactivity of the electrophilic center of these hits. In addition, solvent thermodynamics and reactivity analysis also helped to elucidate the complex trends in SAR of peptidomimetic inhibitors of FP-2 and FP-3 synthesized in our laboratory. Multi nanosecond explicit solvent molecular dynamics simulations were carried out using the docking poses of the known inhibitors in the binding site of SARS-3CLpro, a cysteine protease important for replication of SARS virus, to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Analysis of the simulation studies led to the identification of certain protein-ligand interaction patterns which would be useful in further structure based design efforts against cysteine protease (3CLpro) of SARS

Synthetic and computational investigations into reaction pathways towards complex heterocyclic ring systems

Tetrazocines are eight-membered rings possessing four nitrogen atoms. The development of new synthetic routes to novel heterocyclic systems has remained a critical branch of synthetic organic chemistry due to potential applications in biomimetics and pharmaceuticals, such as dyes and explosives. 1,2,3,5-tetrazocines were originally proposed as an intermediate in the formation of 1,3a,6,6atetrahydroimidazo[4,5-c]pyrazole (a promising anti-fungal agent) from the irradiation of 2,3a,4,6a-tetraphenyl-3,3a,4,5,6,6a hexahydropyrrolo-[2,3-d]-1,2,3-triazole. One of our main aims was to synthesise novel 1,2,3,5-tetrazocines that possessed three phenyl and one methyl group(s) attached to the eight-membered ring, as previously synthesised 1,2,3,5-tetrazocines are of the tetra-phenyl variety. Adopting the established synthetic route in the pursuit of novel 1,2,3,5-tetrazocines proved difficult however, as the asymmetric nature of the 1,2,3,5-tetrazocine precursors (dihydrazones) resulted in altered reactivity as compared with their symmetric equivalents, this finding was rationalised using distributed multipole analysis. Ab initio calculations (B3LYP/6-31G(d)) indicate that for an underivatised 1,2,3,5- tetrazocine, the planar (aromatic) structure is the most stable, though this is not observed experimentally, presumably due to steric repulsions between the large aromatic substituents often used to stabilise these molecules. Excluding the planar geometry, we found that there is a significant thermodynamic stabilisation of 1,2,3,5- tetrazocine over the 1,3a,6,6a-tetrahydroimidazo[4,5-c]pyrazole, providing a novel route to heterocyclic systems

Computational studies on complex reaction mechanics

Molecular modeling with density functional and higher level methods was used to study mechanisms for the reactions of carbonyl compounds with ozone, the Doering-Moore-Skattebol Rearrangement, bis-lactam cyclizations, and thermal rearrangements of ortho-ethynyltoluene. Ozonation of both formaldehyde and acetone can proceed by one of two slow pathways: stepwise addition across the carbonyl group or hydrogen atom abstraction. The Doering-Moore-Skattebol Rearrangement proceeds as a triangular lithium-halogen carbenoid, opening stereospecifically to an allene, with lithium-halogen dissociation occurring after the transition state. Bis-lactam cyclization is rapid, reversible, and thermodynamically controlled. The experimentally observed major product is confirmed by computations as thermodynamically most stable. Thermal rearrangements of o-ethynyltoluene proceed through competitive [1,2] and [1,5] H-shifts. Chrysene is formed as a minor product by dimerization of a novel intermediate, orthoxylallene

Thermochemistry and kinetics: hydrogen atom addition reactions with alkenes, oxidation of cyclopentadienone, trifluoroethene and transport properties

Thermochemical and transport properties and reaction kinetic parameters are important to understand and to model atmospheric chemistry, combustion and other thermal systems. These processes are all important to the environment. Thermochemical properties kinetic parameters and models for several atmospheric and combustion related chemical systems are determined using computational chemistry coupled with fundamentals of thermodynamics and statistical mechanics. Transport properties of hydrocarbon and oxygenated hydrocarbons which are important to the calculation of fluid dynamics of gas phase flow reactions and mixing needed for evaluation in the combustion and thermal (flow) fluid dynamic modeling. Transport properties of radicals cannot be measured so computational chemistry is method of choice. The dissertation determine dipole moment, polarizability and molecular diameters of hydrocarbon and oxygenated hydrocarbons needed for calculation of multicomponent viscosities, thermal conductivities, and thermal diffusion coefficients. Cyclopentadienone with cyclic five-member ring aromatic structure is an important intermediate in combustion systems. Thermochemical and kinetic parameters for the initial reactions of cyclopentadienone radicals with O2 and the thermochemical properties for cyclopentadienone - hydroperoxides, alcohols, alkenyl , alkoxy and peroxy radicals are determined by use of computational chemistry via Density Functional Theory (DFT) and the composite, Complete Basis Set (CBS) methods. Enthalpies of formation (ΔfH°298) with the isodesmic reaction schemes with several work reactions for each species are used for standard enthalpies. Entropy and heat capacity, S° (T) and CP° (T) (50 K ≤ T ≤ 5000 K) are also determined. Chemical activation kinetics using quantum RRK analysis for k(E) and master equation for fall-off are used for kinetic parameters and to show significance of chain branching as a function of temperature and pressure. The cyclopentadienone vinylic carbon radicals of with molecular oxygen appear to undergo chain branching via reaction with O2, to a higher extent to that of vinyl and phenyl radicals. Reaction kinetics of hydrogen atom addition to primary (P), secondary (S), tertiary (T) vinylic (olefin) carbons to form an alkyl radical is investigated using Density Functional Theory (DFT) and ab initio composite level methods. Results from calculations at different levels are compared with the experimental literature data for hydrogen atom addition to Ethylene, Propene, 1-Butene, E-2-Butene, Z-2-Butene, and Isobutene. Activation energy and rate constants for forward and reverse paths are investigated and compared with available experimental data. One goal of the study is to determine accurate calculation method for use on large molecules. Chlorofluorocarbons are widely present in the environment. Thermochemical and kinetic properties work will aid in the understanding the chlorofluorocarbons reactions in combustion and atmospheric environments. Trifluoroethene (CF2=CHF) reaction in atmospheric and combustion environment initiated via OH radical system is investigated. The HF generated channel is currently not reported in any kinetic study. It is important as the toxic gas that can cause severe respiratory damage in humans

Enols and Allylic Alcohols as Building Blocks in Synthetic Organic Chemistry. Experimental and Theoretical Studies.

144 p.The presen thesis describes computational and experimental studies used to drive the reactivity o allylic and enol subtrates towards new transformations. These synthetic methods give access to a number of organic molecules that may serve as important moieties in synthetic organic chemistry. Additionally, this thesis describes the synthesis of Metal-Organic Frameworks (MOFs) and their use in catalytic organic reactions. The introductory chapter gives an overview of the concept of catalysis emphasizing those that have been used in the thesis. Moreover, synthetic procedures for the formation of MOFs and their use in catalysis. The importance and reactivity of allylic substrates are also presented. A short introduction to hypervalent iodine and their reactivity. Finally, a brief description of computational studies. Chapter 2, an umpolung protocol for the cross-nucleophile coupling of silyl enol ethers with heteronucleophiles mediated by a benzodioxole. The mechanistic study of the reaction has been carried out employing DFT calculations and kinetic investigations. Paper ITotgether with deuterium labelling studies and kinetic simulations, DFT calculations have been used in Chapter 3 for the examination of the base-catalyzed [1.n]-proton shift in conjugated polyenyl ethers. Paper IIChapter 4, describes the synthesis of the family MIL-101(Cr) and MIL-101-NH2(Cr) employing microwave-assisted methods. The method has been compared to the common solvothermal synthetic pathways using common characterization techniques for heterogeneous materials. Paper IIIFinally, Chapter 5 of this thesis describes the synthesis of a UiO-67 MOF containing a iminophosphorane superbase to study the effect of spatial confinement within a MOF on the stereospecific isomerization of allylic systems. Paper IV, Supporting Information

Biological Systems Workbook: Data modelling and simulations at molecular level

Nowadays, there are huge quantities of data surrounding the different fields of biology derived from experiments and theoretical simulations, where results are often stored in biological databases that are growing at a vertiginous rate every year. Therefore, there is an increasing research interest in the application of mathematical and physical models able to produce reliable predictions and explanations to understand and rationalize that information. All these investigations are helping to overcome biological questions pushing forward in the solution of problems faced by our society. In this Biological Systems Workbook, we aim to introduce the basic pieces allowing life to take place, from the 3D structural point of view. We will start learning how to look at the 3D structure of molecules from studying small organic molecules used as drugs. Meanwhile, we will learn some methods that help us to generate models of these structures. Then we will move to more complex natural organic molecules as lipid or carbohydrates, learning how to estimate and reproduce their dynamics. Later, we will revise the structure of more complex macromolecules as proteins or DNA. Along this process, we will refer to different computational tools and databases that will help us to search, analyze and model the different molecular systems studied in this course

Regio- and stereo-specific propylene-carbon monoxide alternating copolymers :: synthesis, characterization, and application/

Compounds of palladium with many different chelated bisphosphine ligands were investigated for their catalysis of alternating copolymerization of propylene (P) with carbon monoxide (CO). The bisphosphine structure and chelate ring size influence strongly the activity, regio- and stereo-selectivity of the catalysts. Molecular mechanics calculations on $\pi$-olefin complex showed that the non-bonded interaction between propylene and the ligands on Pd is both regio- and stereo-selective. Electronic factor and presence of chiral center were crucial for the regio- and stereo-regularity control of the catalyst, respectively. Primary insertion is more probable than secondary insertion, and the enantioselective catalysts favor the meso enchainment of propylene. The crystalline copolymer has the hexagonal unit cell structure with a = b = 15.5 A, and c = 8.97 A. The single crystalline copolymer chain is a 3\sb1 fold helix. GC-MS of oligomers showed that most chains are initiated by Pd-H species; and $\beta$-hydrogen elimination is the dominant chain termination process. The anaerobic photodegradation behaviors of bulk alternating copolymers of P-CO and E-CO have been studied by irradiation with 2537 A light. Photolysis of the former resulted in weight loss, molecular weight depression, cross-linking, and the formation of hydroxyl and terminal vinyl groups. The room temperature quantum yields of chain scission and Norrish type II reactions were found to be 0.015 $\pm$ 0.002 and 0.011 $\pm$ 0.002. P-CO alternating copolymer was blended with poly(methyl methacrylate) (PMMA) by solution precipitation. Various aspects of blends behavior were studied by DSC, DMTA, DETA, FTIR, and CP-MAS solid state NMR. The blends exhibited single T\rm\sb{g}\u27s at all compositions, which is an indication of the miscible blends. $\beta$-relaxation of P-CO copolymer was detected by DETA at -65\sp\circC for the first time. The measurement of rotating frame NMR relaxation time, \rm T\sb{1\rho}\sp{H}, showed that the average distance between P-CO and PMMA is less than 30 A

Thermochemistry of fluorinated aldehydes and corresponding radicals;thermochemistry and kinetics of diethyl ether and ethyl oxirane relative to reactions under atmospheric and combustion conditions

Fundamental thermochemical properties including enthalpies (ΔH°f 298), entropies (S°(T)), heat capacities (Cp(T)), and bond dissociation energies (BDEs) for several common and complex hydrocarbon fuel species are determined using computational chemical methods. ΔH°f 298 values are calculated using isodesmic reactions with the CBS-APNO, CBS-4M, CBS-QB3, G2, G3, G4, Weizmann-1 (W1U) and M06-2X, ωB97X, B3-LYP with basis set 6-31G+ (d,p) and 6-31G++(d,p) calculation methods. Structures, moments of inertia, vibrational frequencies, and internal rotor potentials are calculated for contributions to entropies and heat capacities. Kinetic rate parameters are calculated for hydrogen abstraction and chemical activation reactions. The recommended ideal gas phase ΔH°f298 (kcal mole-1) values calculated for several normal hydrocarbons and fluorinated species including corresponding radicals from loss of hydrogen atoms show strong comparison to available literature values. Ethers C—H BDEs in the primary position in comparison to the secondary position increase by 3-8 kcal mole-1 for aliphatic chains. Cyclic ethers posses Entropies (S*298 in cal/mole K) are estimated using B3-LYP methodology with basis sets 6-31+G(d,p) and 6-31++G(d,p) computed frequencies and geometries. Rotational barriers are determined and hindered internal rotational contributions for S*298K and Cp(T) are calculated using the rigid rotor harmonic oscillator approximation, with direct integration over energy levels of intramolecular rotation potential energy curve. Thermochemical properties for the fluorinated carbon groups CO/C/F, C/CO/F3, C/CO/F/H2, C/C/CO/F/H, C/C/CO/F2, and C/C/CO/F/H are investigated. Previously published enthalpies for fluoroacetaldehyde, fluoroacetaldehyde fluoride, difluoroacetaldehyde, difluoroacetaldehyde fluoride, trifluoroacetaldehyde and trifluoroacetaldehyde fluoride that were previously determined via isodesmic reactions schemes are revised using updated reference species values