51 research outputs found
A Zinc-Mediated Deprotective Annulation Approach to New Polycyclic Heterocycles
A straightforward approach to new polycyclic heterocycles, 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-ones, is presented. It is based on the ZnCl2-promoted deprotective 6-endo-dig heterocyclization of N-Boc-2-alkynylbenzimidazoles under mild conditions (CH2Cl2, 40 °C for 3 h). The zinc center plays a dual role, as it promotes Boc deprotection (with formation of the tert-butyl carbocation, which can be trapped by substrates bearing a nucleophilic group) and activates the triple bond toward intramolecular nucleophilic attack by the carbamate group. The structure of representative products has been confirmed by X-ray diffraction analysis
Computational mechanistic study of thionation of carbonyl compounds with Lawesson's reagent
The thionation reaction of carbonyl compounds with Lawesson's reagent (LR) has been studied using density functional theory methods and topological analyses. After dissociation of LR, the reaction takes place through a two-step mechanism involving (i) a concerted cycloaddition between one monomer and the carbonyl compound to form a four-membered intermediate and (ii) a cycloreversion leading to the thiocarbonyl derivative and phenyl(thioxo)phosphine oxide. Topological analyses confirmed the concertedness and asynchronicity of the process. The second step is the rate-limiting one, and the whole process resembles the currently accepted mechanism for the lithium salt-free Wittig reaction. No zwitterionic intermediates are formed during the reaction, although stabilizing electrostatic interactions are present in initial stages. Phenyl(thioxo)phosphine oxide formed in the thionation reaction is capable of performing a second thionation, although with energy barriers higher than the first one. The driving force of the thionation reactions is the formation of trimers from the resulting monomers. In agreement with experimental observations, the amides are the most reactive when compared with esters, aldehydes, and ketones and the reaction is slightly influenced by the polarity of the solvent. Whereas for amides and esters substituents have little effect, aldehydes and ketones are influenced by both steric and electronic effects.This work was supported by the Spanish Ministerio de Economia y Competitividad (MINECO) (Project CTQ2013-44367-C2-1-P), by the Fondos Europeos para el Desarrollo Regional (FEDER), and by the Gobierno de Aragon (Zaragoza, Spain, Bioorganic Chemistry Group, E-10). M.A.C. thanks the University of Catania for partial financial support.Peer Reviewe
Quantum Mechanics Study on Hydrophilic and Hydrophobic Interactions in the Trivaline–Water System
With
the aim to elucidate hydrophobic effects in the unfolded state
of peptides, DFT-M062X computations on the Val<sub>3</sub>H<sup>+</sup>·<i>n</i>H<sub>2</sub>O (<i>n</i> up to
22) clusters have been accomplished. As far as the main chain is concerned,
four conformers with β-strand and/or polyproline type II conformations,
PPII (indicated as β–β, β–PPII, PPII−β,
and PPII–PPII), have been found by changing the ϕ and
ψ angles. For bare peptide, the side chain (isopropyl) of each
residue can independently take on three different orientations with
negligible effects on energetics. The great isopropyl spatial separations
in β–β and β–PPII conformers allow
for the construction of synergic and extensive water–water
and water–peptide H-bonding in the minimal hydration Val<sub>3</sub>H<sup>+</sup>·22H<sub>2</sub>O models without significant
steric encumbrance. Conversely, due to the proximity of the isopropyl
of the central residue with the other two, some restrictions in the
water shell construction around the peptide become evident for the
PPII–PPII conformer and the number of energetically accessible
structures decreases. This is indicative of correlated motion involving
isopropyls and backbone mediated by water molecules, the origin of
the nearest neighbor effects. Comparing the thermodynamic data of
Ala<sub>3</sub>H<sup>+</sup>·22H<sub>2</sub>O and Val<sub>3</sub>H<sup>+</sup>·22H<sub>2</sub>O, what emerges is that both hydration
enthalpy and entropy drive the β-strand stability of the latter
Effects of Hydration on the Zwitterion Trialanine Conformation by Electronic Structure Theory
Exploration
of interfacial hydration networks of zwitterion and
nonionized trialanine has been performed using DFT-M062X quantum chemical
computations explicitly considering up to 41 water molecules. The
step-by-step water molecules peptide surrounding, carried out for
unfolded extended (β), polyproline II (PPII) conformations reveals
the crucial importance of explicit solvent effects in stabilizing
the zwitterion form and the left-handed PPII-helix ubiquitously found
at room temperature for short polyalanines. Hydration effects are
much greater for the ionized form of the peptide; thus, the zwitterion
is about 10 kcal mol<sup>–1</sup> more stable than the nonionized
form. For the β → PPII transformation, the two components
of free Gibbs energy act in the opposite direction; thus, it is favored
by enthalpy but not by entropy. These findings agree with experimental
data that report an equilibrium between these conformers modulated
by temperature. Thermodynamic functions of the four conformers (β–β,
β–PPII, PPII−β, and PPII–PPII) for
zwitterion trialanine are similar to those derived for the protonated
one (Ala<sub>3</sub>H<sup>+</sup>); therefore, the peptidic conformation
is independent of the pH of the solution. Rather, it reflects the
high propensity of alanine toward PPII helix. The enthalpic preference
of the PPII has electrostatic origin and it is owing to a more favorable
interaction of dipole of each peptidic residue with water dipole of
H-bonded molecules
BET & ELF Quantum Topological Analysis of Neutral 2-Aza-Cope Rearrangement of γ-Alkenyl Nitrones
The 2-Aza-Cope rearrangement of γ-alkenyl nitrones is a rare example of the neutral thermal 2-aza-Cope process that usually takes place with cationic species. During the rearrangement, a redistribution of bonds and electronic density occurs in one kinetic step. However, the introduction of substituents with different steric requirements and electronic features might alter the activation energies and the synchronicity of the reaction. The electron localization function (ELF) analysis and its application to Bonding Evolution Theory (BET) analysis within the context of Molecular Electron Density Theory (MEDT) is an excellent tool to monitor the electron density along the reaction coordinate and thus investigate in detail bond breaking and formation and the corresponding energy barriers. By analyzing topological ELF calculations of seventeen 2-aza-Cope nitrone rearrangements with selected substituents, the main factors influencing the synchronicity of the process were investigated. This MEDT study results revealed that the rearrangement is a non-polar process mostly influenced by steric factors rather than by electronic ones, and confirms the pseudoradical character of the process rather than any pericyclic electron-reorganization
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