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Polyhydroxylated phenols are components of biomass and precursors of pigments in plants. This paper reports a novel entry to xanthene dyes, involving the reaction of 2,4,6-trihydroxybenzaldehyde with primary aliphatic amines. This catalyst-free synthesis exhibits a high atom economy and can be conducted under eco-friendly conditions and operational simplicity.

A one-pot procedure for preparing a series of chiral imines by direct condensation of d-glucamine with 2-hydroxyacetophenones is described. Under conventional acetylation an unexpected mixture of two different peracetylated molecules is obtained, one with an open enamine structure, and the other incorporating an N-acetyl-1,3-oxazolidine into the acyclic skeleton. Surprisingly, both molecules coexist within the crystal's unit cell, as inferred from single-crystal X-ray analysis of a 5-bromo-substituted aryl derivative. Moreover, the 1,3-oxazolidine ring exists as rotational conformers (E,Z) owing to the restricted rotation around the N-acetyl bond. The equilibrium involving imine and enamine structures has been assessed in detail, providing in addition linear free-energy relationships between the tautomerization constants (K T ) and the electronic effect of the substituents.

Tautomerism plays a pivotal role in structural stabilization and reactivity. Herein we investigate in detail, aided by DFT simulations, the case of gossypol, a naturally occurring atropisomeric dialdehyde showing promising properties as a male contraceptive and an antineoplasic agent. Its toxicity linked to reactive aldehydo groups can be reduced through amino conjugation. The occurrence of either imino or enamino structures is puzzling indeed and a clear-cut rationale is missing yet. N-enamine-N-enamine structures are prevalent or exclusive tautomers for Schiff bases from gossypol, while their corresponding hydrazones only possess N-imine-N-imine structures both in solution and the solid state. The modification of interactions between the lone pairs on the nitrogen atoms by altering the steric hindrance of the non-iminic nitrogen can favor enamine tautomers. This assumption has now been confirmed and, in the solid state, hydrazones from N-aminopiperidine and their cis-2,6-dimethylderivative present bis-imine and bis-enamine structures, respectively. In solution, these compounds exist in equilibrium between both structures. The tautomerization mechanism, analysis of axial chirality and aromaticity in such H-bonded pseudorings are discussed as well.

Mono- and diaza-derivatives of malondialdehydes, namely 3-alkyl(aryl)amino-2-arylacroleins and 1,5-dialkyl(aryl)-3-arylvinamidines are open-chain systems in which extended electron delocalization and pseudoaromaticity can be envisaged. A set of diversely functionalized compounds has been synthesized and characterized by spectroscopic data and X-ray diffractometry. Quantum-chemical calculations were performed for all possible neutral tautomers and conformers in the gas phase and compared to those in polar solvents (CHCl3, DMSO, and EtOH) at the M06-2X/6-311++G(d,p) level. Tautomeric equilibria and conformational preferences can be rationalized in terms of structural factors, which can be roughly estimated as summation or subtractions of intramolecular interactions. As expected, a key role is played by intramolecular hydrogen bonds whose strength varies from the gas phase to polar ethanol. This issue also delves into the concept of resonance-assisted H-bond, where the donor and acceptor atoms are connected by a π-conjugated system. The most stable conformers (structures a and c) possess a high degree of pseudoaromaticity as inferred from HOMA indexes and other delocalization parameters.

Schiff bases derived from hydroxyl naphthaldehydes and o-substituted anilines have been prepared and their tautomerism assessed by spectroscopic, crystallographic, and computational methods. Tautomeric equilibria have also been studied and reveal in most cases a slight preference of imine tautomers in solution; a fact supported by DFT calculations in the gas phase as well as incorporating solvent effects through the SMD model. To simulate the effect exerted by the crystal lattice on tautomer stability, we have developed a computational protocol in the case of 1-tert-butyl-2-(2-hydroxy-1-naphthylmethylene)aminobenzene whose data have been obtained experimentally at 120 K. Although a rapid imine-enamine interconversion may be occurring in the solid state, the imine tautomer becomes the most stable form and the energy difference should be related to the difference in the packing of the molecules.

The azide-alkyne cycloaddition assisted by a self-assembled molecular flask developed by Rebek and coworkers (Org. Lett., 2002, 4, 327) has been simulated by means of the ONIOM methodology, thereby evidencing the reliability of this theoretical approach to model such large encapsulated systems. Experimental evidences accounting for this transformation within the supramolecular assembly such as the significant rate enhancement, complete regioselectivity, and product inhibition as the reaction proceeds have been qualitatively disentangled through estimation of the energy barriers and the structural characteristics of the corresponding host-guest complexes.

The conformational population of Z and E isomers of the amide bond in N-acetyl oxazolidines is dictated by the electronic nature of the vicinal aryl ring. Experimental and theoretical data support a rationale based on a strong and stereodirecting charge-charge interaction that should be added to the arsenal of non-covalent interactions and whose influence can be more important than once thought.

The archetypal Cu(I)-catalyzed alkyne-azide click cycloaddition (CuAAC) has been explored thoroughly via density functional calculations, modeling copper nuclei with the LANL2DZ basis set and aqueous environments with CPCM solvation. All the mechanistic proposals, ranging from the intermediacy of copper acetylides to π-complexes and multinuclear clusters have been compared. The known features of the CuAAC reaction such as the observed second order kinetics for the Cu(I) species and the marked regioselectivity have been taken into account. The calculated energy barriers point to the intermediacy of copper(i) acetylides with two metal centers, in agreement with the observed kinetics, which exhibit barriers of 10.1 kcal mol(-1) and 13.7 kcal mol(-1) for the 1,4- and 1,5-regiochemistries, respectively, thus accounting for the marked regioselectivity of the copper catalyzed azide-alkyne cycloaddition. The copper acetylide versus π-complexes dilemma has also been experimentally addressed through the click reaction of benzyl azide and isotopically labeled phenylacetylene. The total proton/deuterium exchange in the afforded triazole demonstrates the formation of a copper acetylide intermediate during the transformation.

The transformation of münchnones (mesoionic rings featuring the 1,3-oxazolium-5-olate core) into their sulfur counterparts (1,3-thiazolium-5-thiolates) by reaction with CS(2), pioneered by Huisgen and his group in the early 1970s, has been re-investigated in detail by means of both experimental and theoretical methods. The synthetic strategy can be tuned to incorporate donor and acceptor groups in appropriate positions. Calculations of molecular hyperpolarizabilities together with orbital topologies evidence that these sulfur-containing heterocycles exhibit nonlinear optical responses, thereby pointing to potential applications of mesoionic structures in the NLO field. From a mechanistic viewpoint, modeling of the whole systems at the B3LYP/6-31G(d) level reveals that concerted and stepwise pathways are operative depending on the substitution pattern of the parent münchnone, which also account for the experimental results.

This paper describes a methodology that correlates experimental chemical shifts (at the alpha proton) of proteins with their geometrical data (both dihedral angles and distances) obtained from 13 representative proteins, which are taken from the Protein Data Bank (PDB) and the BioMagRes Data Bank (BMRB). To this end, the experimentally measured proton chemical shifts of simple amides have been correlated with DFT-based calculated structures, at the B3PW91/6-31G* level. This results in a series of mathematical relationships, which are extrapolated to the above-mentioned proteins giving rise to a modified equation for such skeleta. It is relevant to note that the equation is also supported by a clear comparison with NMR data of a protein beyond the chosen set, such as insulin, even with lower errors. The model also relates the dependence of chemical shifts on hydrophobic and anisotropic effects at the amino acid residues.