Norcaradiene-Cycloheptatriene Equilibrium: A Heavy-Atom Quantum Tunneling Case.

The equilibrium between norcaradiene and cycloheptatriene, which has captivated chemists for more than half a century, is revisited by state-of-the-art quantum chemical calculations. Our theoretical data significantly deviate from the experimental results (J. Am. Chem. Soc., 1981, 26, 7791-7792), especially at low temperatures, where isomerization is dominated by heavy-atom tunneling. This effect results in an extremely short half-life for norcaradiene, rendering it undetectable. This work sheds light on this equilibrium, updating the kinetic and thermodynamic data while also expanding the repertoire of organic reactions controlled by this exotic quantum effect.

A True Reverse Anomeric Effect Does Exist After All: A Hydrogen Bonding Stereocontrolling Effect in 2-Iminoaldoses.

The reverse anomeric effect is usually associated with the equatorial preference of nitrogen substituents at the anomeric center. Once postulated as another anomeric effect with explanations ranging from electrostatic interactions to delocalization effects, it is now firmly considered to be essentially steric in nature. Through an extensive research on aryl imines from 2-amino-2-deoxyaldoses, spanning nearly two decades, we realized that such substances often show an anomalous anomeric behavior that cannot easily be rationalized on the basis of purely steric grounds. The apparent preference, or stabilization, of the ß-anomer takes place to an extent that not only neutralizes but also overcomes the normal anomeric effect. Calculations indicate that there is no stereoelectronic effect opposing the anomeric effect, resulting from the repulsion between electron lone pairs on the imine nitrogen and the endocyclic oxygen. Such data and compelling structural evidence unravel why the exoanomeric effect is largely inhibited. We are now confident, as witnessed by 2-iminoaldoses, that elimination of the exo-anomeric effect in the α-anomer is due to the formation of an intramolecular hydrogen bond between the anomeric hydroxyl and the iminic nitrogen, thereby accounting for a true electronic effect. In addition, discrete solvation may help justify the observed preference for the ß-anomer.

Reinvigorating aza-Michael reactions under ionic liquid catalysis: a greener approach.

Cholinium α-amino carboxylates, which debuted in the ionic liquid arena over a decade ago, exhibit superior stability and suitable physical properties relative to other RTILs. Although synthetic pursuits in such media, leveraging their dual role as solvents and catalysts, have been scarce so far, we herein illustrate their catalytic advantage in aza-Michael reactions in terms of low loading, acceleration and improved yields with respect to conventional conditions and other imidazolium-based ILs. These highly structured salts most likely act through multiple and cooperative non-covalent interactions. These mechanistic features have also been investigated through high-level computational analyses as well.

Exploring and Re-Assessing Reverse Anomeric Effect in 2-Iminoaldoses Derived from Mono- and Polynuclear Aromatic Aldehydes.

A curious and noticeable structural feature in Schiff bases from 2-aminoaldoses is the fact that imino tautomers arranged equatorially in the most stable ring conformation exhibit a counterintuitive reverse anomeric effect (RAE) in the mutarotational equilibrium, i.e., the most stable and abundant anomer is the equatorial one (ß). As shown by our very recent research, this effect arises from the total or partial inhibition of the exo-anomeric effect due to the presence of an intramolecular hydrogen bond between the anomeric hydroxyl and the iminic nitrogen in the axial anomer (α). When the Schiff base adopts either an enamine structure or the imino group is protonated, the exo-anomeric effect is restored, and the axial α-anomer becomes the most stable species. Although the intramolecular H-bonding should appropriately be interpreted as a genuine stereoelectronic effect, the magnitude of the RAE could be affected by other structural parameters. Herein and through a comprehensive analysis of benzylidene, cinnamylidene, naphthalene, phenanthrene, and anthracene aldehydes, we show the robustness of the RAE effect, which is similar in extent to simple aldehydes screened so far, irrespective of the size and/or hydrophobicity of the substituent at the nitrogen atom.

From Potential Prebiotic Synthons to Useful Chiral Scaffolds: A Synthetic and Structural Reinvestigation of 2-Amino-Aldononitriles.

This paper explores and revisits in detail the formation and characterization of sugar-based aminonitriles, whose ultimate origin can be traced to the interaction of biomolecules with cyanide. Although the synthesis and spectroscopic data of 2-amino-aldononitriles were reported long ago, there are both contradictory and confusing results among the published data. We have now addressed this concern through an exhaustive structural elucidation of acylated 2-amino- and 2-alkyl(aryl)amino-2-deoxyaldonitriles using mass spectrometry and FT-IR, FT-Raman, and NMR spectroscopies. Several structures could be unambiguously determined through single-crystal X-ray diffraction, which allowed us to correct other misassignments. Moreover, this study unveils how steric and electronic effects influence the acylation outcome of the amino, (alkyl, aryl)amino, or acetamido group at C-2. The chirality at the latter, which was assigned tentatively through optical rotation correlation, and hence the preferential threo stereochemistry generated during the cyanohydrin synthesis of 2-amino-2-deoxy aldononitriles have now been established with confidence.

Mechanistic Insights into the Oxidative Degradation of Formic and Oxalic Acids with Ozone and OH Radical. A Computational Rationale.

Gas-phase and aqueous oxidations of formic and oxalic acids with ozone and OH radicals have been thoroughly examined by DFT methods. Such acids are not only important feedstocks for the iterative construction of other organic compounds but also final products generated by mineralization and advanced oxidation of higher organics. Our computational simulation unravels both common and distinctive reaction channels, albeit consistent with known H atom abstraction pathways and formation of hydropolyoxide derivatives. Notably, reactions with neutral ozone and OH radical proceed through low-energy concerted mechanisms involving asynchronous transition structures. For formic acid, carbonylic H-abstraction appears to be more favorable than the dissociative abstraction of the acid proton. Formation of long oxygen chains does not cause a significant energy penalty and highly oxygenated products are stable enough, even if subsequent decomposition releases environmentally benign side substances like O2 and H2O.

Schiff Bases and Stereocontrolled Formation of Fused 1,3-Oxazolidines from 1-Amino-2-Indanol: A Systematic Study on Structure and Mechanism.

This paper thoroughly explores the formation of Schiff bases derived from salicylaldehydes and a conformationally restricted amino alcohol (1-amino-2-indanol), as well as the generation of 1,3-oxazolidines, a key heterocyclic core present in numerous bioactive compounds. We provide enough evidences, both experimental-including crystallographic analyses and DFT-based calculations on imine/enamine tautomerism in the solid state and solution. In the course of imine formation, a pentacyclic oxazolidine-oxazine structure could be isolated with complete stereocontrol, whose configuration has been determined by merging theory and experiment. Mechanistic studies reveal that, although oxazolidines can be obtained under kinetic conditions, the prevalence of imines obeys to thermodynamic control as they are the most stable structures. The stereochemical outcome of imine cyclization under acylating conditions leads to formation of 2,4-trans-oxazolidines.

Switchable Cycloadditions of Mesoionic Dipoles: Refreshing up a Regioselective Approach to Two Distinctive Heterocycles.

Mesoionic rings are among the most versatile 1,3-dipoles, as witnessed recently by their incorporation into bio-orthogonal strategies, and capable of affording unconventional heterocycles beyond the expected scope of Huisgen cycloadditions. Herein, we revisit in detail the reactivity of thiazol-3-ium-4-olates with alkynes, leading to thiophene and/or pyrid-2-one derivatives. A structural variation at the parent mesoionic dipole alters sufficiently the steric outcome, thereby favoring the regioselective formation of a single transient cycloadduct, which undergoes chemoselective fragmentation to either five- or six-membered heterocycles. The synthetic protocol benefits largely from microwave (MW) activation, which enhances reaction rates. The mechanism has been interrogated with the aid of density functional theory (DFT) calculations, which sheds light into the origin of the regioselectivity and points to a predictive formulation of reactivity involving competing pathways of mesoionic cycloadditions.

A synthetically benign one-pot construction of enamino-xanthene dyes.

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.

Synthesis of CxNy-rich polycyclic oligomers from primeval monomers in aqueous media.

A multichannel, non-thermolytic and efficient pathway is described toward the formation of functionalized carbon nitride-like oligomers, starting from readily available cyanamide and glyoxal (in ratios >2), in aqueous media under mild conditions. Such oligomers can be isolated as stable solids that result from structures involving cyanamide self-additions along with structures formally derived from the condensation of cyanamide, dicyandiamide or melamine with glyoxal, leading occasionally to oxygen-containing units. The oligomeric aggregates have masses up to 500 u, as inferred from mass spectra analyses, and their formation can be rationalized in terms of polyadditions of cyanamide (up to 10-mer) and glyoxal. The latter is not only a willing reaction partner, but also promotes facile condensation by enhancing the reactivity of nitrile fragments and inducing a significant lowering of the energy barriers. This mechanistic surmise is also supported by DFT calculations of the early condensation steps. As a result, melamine/triazine-type structures are obtained in aquatic environments under much milder conditions than those usually required by other synthetic procedures. Moreover, our results also help unveil the abiotic processes affording complex organic matter on celestial bodies and early earth.

On the Origin of Sugar Handedness: Facts, Hypotheses and Missing Links-A Review.

By paraphrasing one of Kipling's most amazing short stories (How the Leopard Got His Spots), this article could be entitled "How Sugars Became Homochiral". Obviously, we have no answer to this still unsolved mystery, and this perspective simply brings recent models, experiments and hypotheses into the homochiral homogeneity of sugars on earth. We shall revisit the past and current understanding of sugar chirality in the context of prebiotic chemistry, with attention to recent developments and insights. Different scenarios and pathways will be discussed, from the widely known formose-type processes to less familiar ones, often viewed as unorthodox chemical routes. In particular, problems associated with the spontaneous generation of enantiomeric imbalances and the transfer of chirality will be tackled. As carbohydrates are essential components of all cellular systems, astrochemical and terrestrial observations suggest that saccharides originated from environmentally available feedstocks. Such substances would have been capable of sustaining autotrophic and heterotrophic mechanisms integrating nutrients, metabolism and the genome after compartmentalization. Recent findings likewise indicate that sugars' enantiomeric bias may have emerged by a transfer of chirality mechanisms, rather than by deracemization of sugar backbones, yet providing an evolutionary advantage that fueled the cellular machinery.

Comments on "Molecular Chirality in Classical Spacetime: Solving the Controversy about the Spinning Cone Model of Rotating Molecules".

A recent mathematical analysis by Michel Petijean aimed at solving the Barron/Mislow controversy concerning the chirality or otherwise of a non-translating spinning cone concluded that both are right: the controversy is a matter of an arbitrary choice of a conversion factor. This reassessment highlights the different physicochemical properties of a stationary spinning cone and a chiral molecule and concludes that Petitjean's analysis is misleading.

Organic Sonochemistry: A Chemist's Timely Perspective on Mechanisms and Reactivity.

Sonochemistry, the use of sound waves, usually within the ultrasonic range (>20 kHz), to boost or alter chemical properties and reactivity constitutes a long-standing and sustainable technique that has, however, received less attention than other activation protocols despite affordable setups. Even if unnecessary to underline the impact of ultrasound-based strategies in a broad range of chemical and biological applications, there is considerable misunderstanding and pitfalls regarding the interpretation of cavitational effects and the actual role played by the acoustic field. In this Perspective, with an eye on mechanisms in particular, we discuss the potentiality of sonochemistry in synthetic organic chemistry through selected examples of past and recent developments. Such examples illustrate specific controlling effects and working rules. Looking back at the past while looking forward to advancing the field, some essentials of sonochemical activation will be distilled.

Primo Levi: A frustrated stereochemist?-Insight in hindsight.

Primo Levi (1919-1987) has become an iconic figure at the intersection of chemistry and culture. Levi has long been praised for his autobiographical account as survivor in Auschwitz and by his literary masterpiece "The Periodic Table." Little is however known beyond such facts, especially his academic period and early research on stereochemistry at the University of Turin, which were abruptly truncated by the racial laws and WWII. Even if, later on, Primo Levi succeeded as industrial chemist, he had a vivid interest in molecular asymmetry that lasted through his entire life. This concise paper highlights a little known academic period in the midst of social and political upheaval. Levi left us his humanity in an otherwise tortuous life, and his literature took inspiration from chemistry; perhaps as a metaphor connecting the physical world and people's life.

Does Pressure Break Mirror-Image Symmetry? A Perspective and New Insights.

This paper is aimed at dissecting and discussing the effect of high pressure on chirogenesis, thus unveiling the role of this universal force in astrochemical and primeval Darwinian scenarios. The first part of this contribution revisits the current status and recent experiments, most dealing with crystalline racemates, for which generation of metastable conglomeratic phases would eventually afford spontaneous resolution and hence enantioenriched mixtures. We then provide an in-depth thermodynamic analysis, based on previous studies of non-electrolyte solutions and dense mixtures accounting for the existence of positive excess volume upon mixing, to simulate the mirror symmetry breaking, the evolution of entropy production and dissipation due to enantiomer conversion. Results clearly suggest that mirror symmetry breaking under high pressure may be a genuine phenomenon and that enantioenrichment from initial scalemic mixtures may also take place.

Imine or Enamine? Insights and Predictive Guidelines from the Electronic Effect of Substituents in H-Bonded Salicylimines.

Imine and enamine bonds decorate the skeleton of numerous reagents, catalysts, and organic materials. However, it is difficult to isolate at will a single tautomer, as dynamic equilibria occur easily, even in the solid state, and are sensitive to electronic and steric effect, including π-conjugation and H-bonding. Here, using as model Schiff bases generated from salicylaldehydes and TRIS in a set of linear free energy relationships (LFER), we disclose how the formation of either imines or enamines can be controlled and provide a comprehensive framework that captures the structural underpinning of this prediction. This work highlights the potentiality of tailor-made designs en route to compounds with desirable functionality.

A fully diastereoselective oxidation of a mesoionic dipole with triplet molecular oxygen.

Oxidations with molecular oxygen are ubiquitous processes in biological systems where cofactor-dependent enzymes activate either oxygen or hydrogen peroxide to induce multichannel pathways. In stark contrast, such slow atmospheric oxidations are seldom harnessed in chemical synthesis and analysis. The present study unveils an unusual aerobic oxidation of a mesoionic dipole leading easily to a more functionalized skeleton. Although the synthetic scope has not been explored, two key considerations emerge from this transformation, as it proceeds with complete diastereoselection and could be successfully extrapolated to structurally related mesoionic chirons without racemization. How this oxidation actually occurs proved to be puzzling from the onset and only high-level computation reveals a cascade transformation, whose results reconcile theory and experiment. Hopefully, the mechanistic insights should help us to understand better the autoxidative reactions of organic molecules.

Chasing Synthetic Life: A Tale of Forms, Chemical Fossils, and Biomorphs.

This Essay focuses briefly on early studies elaborated by natural and chemical philosophers, and the once-called synthetic biologists, who postulated the transition from inanimate to animate matter and even foresaw the possibility of creating artificial life on the basis of physical and chemical principles only. Such ideas and speculations, ranging from soundness to weirdness, paved however the way to current developments in areas like abiotic pattern formation, cell compartmentalization, biomineralization, or the origin of life itself. In particular, the generation of biomorphs and their relationship to microfossils represents an active research domain and seems to be the logical way to bring the historical work up to the future, as some scientists are trying to make artificial cells. The last sections of this essay will also highlight modern science aimed at understanding what life is and, whether or not, it can be redefined in chemical terms.

Tautomerism and stereodynamics in Schiff bases from gossypol and hemigossypol with N-aminoheterocycles.

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.

Electronic effects in tautomeric equilibria: the case of chiral imines from d-glucamine and 2-hydroxyacetophenones.

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 (KT) and the electronic effect of the substituents.