Search

Noble element time projection chambers are a leading technology for rare event detection in physics, such as for dark matter and neutrinoless double beta decay searches. Time projection chambers typically assign event position in the drift direction using the relative timing of prompt scintillation and delayed charge collection signals, allowing for reconstruction of an absolute position in the drift direction. In this paper, alternate methods for assigning event drift distance via quantification of electron diffusion in a pure high pressure xenon gas time projection chamber are explored. Data from the NEXT-White detector demonstrate the ability to achieve good position assignment accuracy for both high- and low-energy events. Using point-like energy deposits from 83mKr calibration electron captures (E∼45 keV), the position of origin of low-energy events is determined to 2 cm precision with bias

Polytetrafluoroethylene (PTFE) is an excellent diffuse reflector widely used in light collection systems for particle physics experiments. In noble element systems, it is often coated with tetraphenyl butadiene (TPB) to allow detection of vacuum ultraviolet scintillation light. In this work this dependence is investigated for PTFE coated with TPB in air for light of wavelengths of 200 nm, 260 nm, and 450 nm. The results show that TPB-coated PTFE has a reflectance of approximately 92% for thicknesses ranging from 5 mm to 10 mm at 450 nm, with negligible variation as a function of thickness within this range. A cross-check of these results using an argon chamber supports the conclusion that the change in thickness from 5 mm to 10 mm does not affect significantly the light response at 128 nm. Our results indicate that pieces of TPB-coated PTFE thinner than the typical 10 mm can be used in particle physics detectors without compromising the light signal.

If neutrinos are their own antiparticles the otherwise-forbidden nuclear reaction known as neutrinoless double beta decay can occur. The very long lifetime expected for these exceptional events makes its detection a daunting task. In order to conduct an almost background-free experiment, the NEXT collaboration is investigating novel synthetic molecular sensors that may capture the Ba dication produced in the decay of certain Xe isotopes in a high-pressure gas experiment. The use of such molecular detectors immobilized on surfaces must be explored in the ultra-dry environment of a xenon gas chamber. Here, using a combination of highly sensitive surface science techniques in ultra-high vacuum, we demonstrate the possibility of employing the so-called Fluorescent Bicolor Indicator as the molecular component of the sensor. We unravel the ion capture process for these molecular indicators immobilized on a surface and explain the origin of the emission fluorescence shift associated to the ion trapping.

Radio-frequency (RF) carpets with ultra-fine pitches are examined for ion transport in gases at atmospheric pressures and above. We develop new analytic and computational methods for modeling RF ion transport at densities where dynamics are strongly influenced by buffer gas collisions. An analytic description of levitating and sweeping forces from phased arrays is obtained, then thermodynamic and kinetic principles are used to calculate ion loss rates in the presence of collisions. This methodology is validated against detailed microscopic SIMION simulations. We then explore a parameter space of special interest for neutrinoless double beta decay experiments: transport of barium ions in xenon at pressures from 1 to 10 bar. Our computations account for molecular ion formation and pressure dependent mobility as well as finite temperature effects. We discuss the challenges associated with achieving suitable operating conditions, which lie beyond the capabilities of existing devices, using presently available or near-future manufacturing techniques.

We report a measurement of the half-life of the Xe136 two-neutrino double-β decay performed with a novel direct-background-subtraction technique. The analysis relies on the data collected with the NEXT-White detector operated with Xe136-enriched and Xe136-depleted xenon, as well as on the topology of double-electron tracks. With a fiducial mass of only 3.5 kg of Xe, a half-life of 2.34-0.46+0.80(stat)-0.17+0.30(sys)×1021yr is derived from the background-subtracted energy spectrum. The presented technique demonstrates the feasibility of unique background-model-independent neutrinoless double-β-decay searches.

Next-generation neutrinoless double beta decay experiments aim for half-life sensitivities of ∼ 1027 yr, requiring suppressing backgrounds to < 1 count/tonne/yr. For this, any extra background rejection handle, beyond excellent energy resolution and the use of extremely radiopure materials, is of utmost importance. The NEXT experiment exploits differences in the spatial ionization patterns of double beta decay and single-electron events to discriminate signal from background. While the former display two Bragg peak dense ionization regions at the opposite ends of the track, the latter typically have only one such feature. Thus, comparing the energies at the track extremes provides an additional rejection tool. The unique combination of the topology-based background discrimination and excellent energy resolution (1% FWHM at the Q-value of the decay) is the distinguishing feature of NEXT. Previous studies demonstrated a topological background rejection factor of ∼ 5 when reconstructing electron-positron pairs in the 208Tl 1.6 MeV double escape peak (with Compton events as background), recorded in the NEXT-White demonstrator at the Laboratorio Subterráneo de Canfranc, with 72% signal efficiency. This was recently improved through the use of a deep convolutional neural network to yield a background rejection factor of ∼ 10 with 65% signal efficiency. Here, we present a new reconstruction method, based on the Richardson-Lucy deconvolution algorithm, which allows reversing the blurring induced by electron diffusion and electroluminescence light production in the NEXT TPC. The new method yields highly refined 3D images of reconstructed events, and, as a result, significantly improves the topological background discrimination. When applied to real-data 1.6 MeV e−e+ pairs, it leads to a background rejection factor of 27 at 57% signal efficiency. [Figure not available: see fulltext.].

Translation of photophysical properties of fluorescent sensors from solution to solid-gas environments via functionalized surfaces constitutes a challenge in chemistry. In this work, we report on the chemical synthesis, barium capture ability and photophysical properties of two families of monocolor and bicolor fluorescent sensors. These sensors were prepared to capture barium cations that can be produced in neutrinoless double beta decay of Xe-136. These sensors incorporate crown ether units, two different fluorophores, aliphatic spacers of different lengths, and a silatrane linker that forms covalent bonds with indium tin oxide (ITO) surfaces. Both species shared excellent Ba 2+ binding abilities. Fluorescent monocolor indicators (FMIs), based on naphthyl fluorophores, showed an off-on character in solution controlled by photoinduced electron transfer. Fluorescent bicolor indicators (FBIs), based on benzo[ a ]imidazo[5,1,2- cd ] fluorophores, exhibited a significant change in their emission spectra on going from the free to the barium-bound state. Both FMIs and FBIs showed similar photophysics in solution and on ITO. However, their performance on ITO was found to be attenuated, but not fully extinguished, with respect to the values obtained in solution, both in terms of intensity and selectivity between the free and Ba 2+ -bound states. Despite this issue, improved performance of the FBIs based on confocal microscopy of the directly attached molecules was observed. These selective FMI and FBI chemosensors installed on tailor-made functionalized surfaces are promising tools to capture the barium cations produced in the double beta decay of Xe-136. The identification of this capture would boost the sensitivity of the experiments searching for the Xe-136-based neutrinoless double beta decay, as backgrounds would be almost totally suppressed., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A pair of enantiopure [6]-azairidahelicenes incorporating chirality at the metal center and on the helicenic ligand were synthesized by dynamic kinetic resolution (dkr) of a configurationally labile [4]-helicenic ligand (4-(2-pyridyl)-benzo[g]phenanthrene, L1H) using bis-cyclometalated chiral-at-metal only iridium(III) precursors as chiral inductors. The origin of the observed dkr is attributed to the different conformation and stability of diastereomeric reaction intermediates formed during the cyclometalation process. The isolated enantiomers exhibited circularly polarized phosphorescence (CPP), with |g phos | values of 1.8×10 -3 ., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Dehydration of alcohols in the presence of copper(II) sulfate has been analyzed computationally. Density functional theory (DFT) calculations on selected alcohols indicate that this reaction can take place via two possible mechanisms: (a) concerted - although asynchronous - type II dyotropic reactions, or (b) stepwise E1-like processes, in which cleavage of the C-O bond occurs in the first step, followed by syn proton elimination. Our calculations show the relationship between the initial alcohol structure and the preferred mechanism, which is a type II dyotropic reaction for primary alcohols, whereas a stepwise process is the favored one when stable carbocation intermediates are energetically accessible. The dehydration of dehydrolinalool (2,7-dimethyl-6-en-1-yn-3-ol, DHL) to yield different alkenes of interest in the fragrance industry is discussed as a case study of its regiochemistry.

In general, electrocyclizations follow the Woodward-Hoffmann's rules of conservation of orbital symmetry. These rules have been extensively verified in low-order processes, both in thermal and photochemical reactions, up to eight π-electrons. However, when the number of π-electrons in the system increases, some deviations of that general rules can be found. This focused review highlights the main features of reported higher-order electrocyclizations involving 10, 12, 14, 16 and 18 π-electrons. Some of these examples constitute useful intermediates in the synthesis of biologically active compounds. When computational studies were not included in the reported examples, DFT calculations have been performed to be included in this review. Analysis of the respective pericyclic topologies shows the importance of computational tools for understanding the selectivity observed experimentally., (© 2023 The Authors. ChemPlusChem published by Wiley-VCH GmbH.)

Computational studies on the electrophilic cyclization between alkynes and transient carbocations or Lewis-acid-activated epoxides show that the regiochemistry of the reaction depends on the terminal or internal position of the triple bond. Reactants possessing terminal alkynyl groups lead to six-membered rings, whereas internal alkynes yield five-membered rings through 6-endo-dig and 5-exo-dig electrophilic cyclizations, respectively. The regiochemistry of the reaction is not determined by two-electron interactions, but by the minimization of Pauli repulsion. This scenario is preserved in related biomimetic reactions leading to steroid scaffolds. In this latter case, the stereochemistry of the cyclization reaction is oriented towards the formation of equatorial C-C bonds connecting the new six-six- and six-five-membered fused rings., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Aromaticity is one of the most deeply rooted concepts in chemistry. But why, if two-thirds of existing compounds can be classified as aromatic, is there no consensus on what aromaticity is? σ-, π-, δ-, spherical, Möbius, or all-metal aromaticity… why are so many attributes needed to specify a property? Is aromaticity a dubious concept? This perspective aims to reflect where the aromaticity community is and where it is going., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

If neutrinos are their own antiparticles the otherwise-forbidden nuclear reaction known as neutrinoless double beta decay can occur. The very long lifetime expected for these exceptional events makes its detection a daunting task. In order to conduct an almost background-free experiment, the NEXT collaboration is investigating novel synthetic molecular sensors that may capture the Ba dication produced in the decay of certain Xe isotopes in a high-pressure gas experiment. The use of such molecular detectors immobilized on surfaces must be explored in the ultra-dry environment of a xenon gas chamber. Here, using a combination of highly sensitive surface science techniques in ultra-high vacuum, we demonstrate the possibility of employing the so-called Fluorescent Bicolor Indicator as the molecular component of the sensor. We unravel the ion capture process for these molecular indicators immobilized on a surface and explain the origin of the emission fluorescence shift associated to the ion trapping., (© 2022. The Author(s).)

The asymmetric synthesis of bicyclic highly substituted tetrahydropyrans is described. The reaction is catalyzed by unnatural γ-dipeptides based on densely substituted l- and d-proline derivatives. This organocatalytic one-pot reaction takes place among a ketone, a nitroalkene, and an aldehyde to yield an octahydro-2 H -chromene scaffold. Monomeric species, from which the corresponding γ-dipeptides are synthesized, cannot catalyze the reaction, thus confirming the emergent nature of the catalytic behavior of these dimeric species.

The synthesis and isolation of one of the few examples of a π-extended diamagnetic phenazine dication have been achieved by oxidizing a phenanthrene-based dihydrophenazine precursor. The resulting dication was isolated and fully characterized, highlighting an aromatic distorted structure, generated by the conformational change upon the oxidation of the dihydrophenazine precursor, which is also correlated with a marked electrochromic change in the UV-vis spectrum. The aromaticity of the dication has also been investigated theoretically, proving that the species is aromatic based on all major criteria (structural, magnetic, and energetic). Moreover, the material presents an intriguing dual reactivity, resulting in ring contraction to a π-extended triarylimidazolinium and reduction to the dihydrophenazine precursor, depending on the nature of the nucleophile involved. This result helps shed light on the yet largely unexplored reactivity and properties of extended dicationic polycyclic aromatic hydrocarbons (PAHs). In particular, the fact that the molecule can undergo a reversible change in conformation upon oxidation and reduction opens potential applications for this class of derivatives as molecular switches and actuators.

Computational-experimental analysis has allowed determining that the stereochemistry of the Staudinger reaction between ketenes and imines is strongly associated with the nature of the imine, which affects the two steps of the reaction. The first step, namely the nucleophilic attack of the sp 2 -hybridized nitrogen atom of the imine on the sp-hybridized carbon atom of the ketene, is affected by the energetically accessible in situ isomerization patterns of the imine. The second step consists of a conrotatory electrocyclization of the zwitterionic intermediate formed in the previous step. This latter pericyclic step depends on the inward/outward torquoelectronic effects generated by the substituents of the imine. The impact of these factors on the stereochemistry of this reaction has been analyzed kinetically by numerical methods. The results of these simulations are compatible with the experimental results and support these conclusions., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Different densely substituted L- and D-proline esters were prepared by asymmetric (3+2) cycloaddition reactions catalyzed by conveniently selected EhuPhos chiral ligands. The γ-nitro-2-alkoxycarbonyl pyrrolidines thus obtained in either their endo or exo forms were functionalized and coupled to yield the corresponding γ-dipeptides. The catalytic properties of these latter dimers were examined using aldol and conjugate additions as case studies. When aldol reactions were analyzed, an additive behavior in terms of stereocontrol was observed on going from the monomers to the dimers. In contrast, in the case of the conjugate additions between ketones and nitroalkenes, the monomers did not catalyze this reaction, whereas the different γ-dipeptides promoted the formation of the corresponding Michael adducts. Therefore, in this latter case emergent catalytic properties were observed for these novel γ-dipeptides based on unnatural proline derivatives. Under certain conditions stoichiometric amounts of ketone, acid and nitroalkene), formation of N-acyloxy-2-oxooctahydro-1H-indoles was observed., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Molecular entities whose fluorescence spectra are different when they bind metal cations are termed bicolour fluorescent molecular sensors. The basic design criteria of this kind of compound are presented and the different fluorescent responses are discussed in terms of their chemical behaviour and electronic features. These latter elements include intramolecular charge transfer (ICT), formation of intramolecular and intermolecular excimer/exciplex complexes and Förster resonance energy transfer (FRET). Changes in the electronic properties of the fluorophore based on the decoupling between its constitutive units upon metal binding are also discussed. The possibility of generating fluorescent bicolour indicators that can capture metal cations in the gas phase and at solid-gas interfaces is also discussed.

Photodynamic therapy has been used to treat a variety of diseases, however, there is continuing search for new biocompatible photosensitizers. Herein, we demonstrate for the first time that imidazo[1,2-a]pyrimidine compounds are able to generate singlet oxygen species and can act as photosensitizers in the intracellular environment. Our results show that this class of compounds absorb and emit in the 400-500 nm region, present low cytotoxicity in the dark, are efficiently uptaken by cells, are fluorescent in intracellular medium, and generate singlet oxygen upon irradiation, killing cancer cells within 2 h at low concentration (2.0 μm). The imidazo[1,2-a]pyrimidine compounds are a potential new tool for phototheranostics, because they can be simultaneously used for fluorescence imaging and photodynamic therapy., (© 2020 Wiley-VCH GmbH.)

Background and Aims: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits., Approach and Results: Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters., Conclusions: These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs., (© 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

A plethora of preclinical evidences suggests that pharmacological targeting of epigenetic dysregulation is a potent strategy to combat human diseases. Nevertheless, the implementation of epidrugs in clinical practice is very scarce and mainly limited to haematological malignancies. In this review, we discuss cutting-edge strategies to foster the chemical design, the biological rationale and the clinical trial development of epidrugs. Specifically, we focus on the development of dual hybrids to exploit multitargeting of key epigenetic molecules deregulated in cancer; the study of epigenetic-synthetic lethality interactions as a mechanism to address loss-of-function mutations, and the combination of epidrugs with other therapies such as immunotherapy to avoid acquired chemoresistance and increase therapy sensitivity. By exploring these challenges, among others, the field of epigenetic chemical biology will increase its potential for clinical benefit, and more effective strategies targeting the aberrant epigenome in cancer are likely to be developed both in haematological and solid tumours., Competing Interests: Conflict of interest statement M.B. discloses no conflicts of interest. F.P.C. and M.E. are consultants of Quimatryx., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Observation of the neutrinoless double β decay is the only practical way to establish that neutrinos are their own antiparticles 1 . Because of the small masses of neutrinos, the lifetime of neutrinoless double β decay is expected to be at least ten orders of magnitude greater than the typical lifetimes of natural radioactive chains, which can mimic the experimental signature of neutrinoless double β decay 2 . The most robust identification of neutrinoless double β decay requires the definition of a signature signal-such as the observation of the daughter atom in the decay-that cannot be generated by radioactive backgrounds, as well as excellent energy resolution. In particular, the neutrinoless double β decay of 136 Xe could be established by detecting the daughter atom, 136 Ba 2+ , in its doubly ionized state 3-8 . Here we demonstrate an important step towards a 'barium-tagging' experiment, which identifies double β decay through the detection of a single Ba 2+ ion. We propose a fluorescent bicolour indicator as the core of a sensor that can detect single Ba 2+ ions in a high-pressure xenon gas detector. In a sensor made of a monolayer of such indicators, the Ba 2+ dication would be captured by one of the molecules and generate a Ba 2+ -coordinated species with distinct photophysical properties. The presence of such a single Ba 2+ -coordinated indicator would be revealed by its response to repeated interrogation with a laser system, enabling the development of a sensor able to detect single Ba 2+ ions in high-pressure xenon gas detectors for barium-tagging experiments.

A mild, metal-free bromination method of arenes has been developed using the combination of bis(trifluoroacetoxy)iodobencene and trimethylsilyl bromide. In situ-formed dibromo(phenyl)-λ3-iodane (PhIBr 2 ) is proposed as the reactive intermediate. This methodology using PIFA/TMSBr has been applied with success to a great number of substrates (25 examples). The treatment of mono-substituted activated arenes led to para-brominated products ( 2u-z ) in excellent 83-96% yields. Density functional theory calculations indicate a stepwise mechanism involving a double bromine addition followed by a type II dyotropic reaction with concomitant re-aromatization of the six-membered ring.

An efficient and simple synthesis of novel trisubstituted 1H-pyrroles 4a-qvia 1,3-dipolar cycloaddition of Δ3-trifluoromethyloxazolones 2a-d with both chromium and tungsten alkynyl Fischer carbene complexes (1a-h) is described. An unexpected and unreported -CF3 group elimination process was observed in the pyrrole structure. Our experimental and theoretical data suggested that the metal fragment may be responsible for this phenomenon. The dipolar cycloaddition proceeded efficiently to produce a single regioisomer, which was unambiguously established through NMR and single-crystal X-ray diffraction studies. Nevertheless, the reaction of alkynyl carbenes bearing an α,β,γ,δ-unsaturated moiety with excess oxazolone 2a produced a polycyclic compound 6 speculatively formed through a cascade reaction involving 1,6-, 1,4- and 1,2-nucleophilic addition steps.

Designed repeat proteins catalyze the 1,3-dipolar reaction between an imine and a π-deficient dipolarophile in THF solution to form unnatural nitroproline esters, a reaction that no enzyme can catalyze. NMR studies and mutation experiments show that both acidic and basic residues can catalyze the reaction. The diastereocontrol of the reaction depends on the flexibility of the protein and on the number and location of the active lysine and glutamate residues, which can participate independently or forming dyads that promote the formation of unusual diastereomeric cycloadducts. QM/MM calculations permit one to rationalize the origins of this Huisgenase activity and of its diastereocontrol.

Chlorosulfate derivatives are interesting reagents that have been traditionally used to get other sulfur-containing compounds by formal nucleophilic substitution of the chlorine atom. This work describes a different mode of reactivity of alkyne-containing chlorosulfates to get sultones, the sulfur analogues of lactones. The complex skeletal rearrangement observed in this transformation is comparable to those intricate processes promoted or catalyzed by organometallic compounds. However, the reaction here described does not require any reagent or additive, being just a thermal process. Computational calculations support a mechanism based on a series of cascade reactions where almost every step is counterintuitive. Some of these steps include original processes related to classical reactions, thus adding complementary views to traditional organic chemistry., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Catalytic enantioselective 1,3-dipolar cycloaddition between imino esters and electrophilic alkenes, employing chiral metal complexes derived from copper(I) and silver(I) salts and ( S )-DM- or ( S )-DTBM-Segphos as ligands produces diastereodivergently exo- or endo-cycloadducts, respectively. The effect of the functional group of the dipolarophile and the fine tuning of the catalyst plays an important role in promoting reverse diastereoselectivities. The origins of experimentally observed enantioselectivity and diastereoselectivity data, as well as the origin of the observed switched endo/exo ratios, are also explained by means of density functional theory calculations.

The so-called Securinega alkaloids constitute a class of tetracyclic biologically active specialised metabolites isolated principally from subtropical plants belonging to the Phyllanthaceae family. Following a strategy based on alternative hypotheses for their biosynthesis, an easy and time-efficient divergent synthesis enabled access to twelve of those alkaloids featuring (neo)(nor)securinane skeletons. Moreover, this work permitted to reassign the absolute configurations of (+)-virosine B and (-)-episecurinol A., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A highly enantioselective catalytic method for the synthesis of quaternary α-trifluoromethyl derivatives of 3-oxo esters is described. The reaction uses lanthanum(III) triflate and chiral PyBOX-type C 2 -symmetric ligands to generate intermediate La III complexes that incorporate an enolate moiety of the starting 3-oxo ester and the trifluoromethylation transfer reagent. The enantioselectivity of the reaction stems from the efficient blockage of one of the prochiral faces of the La III enolate by one unit of the C 2 -symmetric ligand., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The organocatalytic properties of unnatural α-amino acids are reviewed. Post-translational derivatives of natural α-amino acids include 4-hydroxy-l-proline and 4-amino-l-proline scaffolds, and also proline homologues. The activity of synthetic unnatural α-amino acid-based organocatalysts, such as β-alkyl alanines, alanine-based phosphines, and tert-leucine derivatives, are reviewed herein. The organocatalytic properties of unnatural monocyclic, bicyclic, and tricyclic proline derivatives are also reviewed. Several families of these organocatalysts permit the efficient and stereoselective synthesis of complex natural products. Most of the reviewed organocatalysts accelerate the reported reactions through covalent interactions that raise the HOMO (enamine intermediates) or lower the LUMO (iminium intermediates)., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

All possible demethylation reactions of a diverse family of quaternary alkaloids by means of DFT calculations are here described. We aim to develop a rational model that allows the explanation of the high selectivity observed experimentally and predicts the occurrence of new alkaloid derivatives. To this end, we have performed a detailed analysis of the initial reagents and products. In addition, as a proof of concept, an experimentally unknown demethylation reaction of coralyne has been carried out, thus verifying the reliability of the theoretical model presented here.

An unexpected 1,3-dioxa-[3,3]-sigmatropic rearrangement during the treatment of aryl- and alkenyl-substituted allylic alcohols with activated isocyanates is reported. The reorganization of bonds is highly dependent on the electron density of the aromatic ring and the nature of isocyanate used. This metal-free tandem reaction from branched allyl alcohols initiated by a carbamoylation reaction and followed by a sigmatropic rearrangement thus offers a new access to ( E)-cinnamyl and conjugated ( E, E)-diene carbamates, such as N-acyl and N-sulfonyl derivatives. A computational study was conducted in order to rationalize this phenomenon, and a rearrangement progress kinetic analysis was performed.

NMR-based techniques are supposed to be incapable of distinguishing pure crystalline chemical enantiomers. However, through systematic studies of cross-polarization magic angle spinning (CP-MAS) NMR in a series of amino acids, we have found a rather unexpected behavior in the intensity pattern of optical isomers in hydrogen/nitrogen nuclear polarization transfer that would allow the use of CP NMR as a nondestructive enantioselective detection technique. In all molecules considered, the d isomer yields higher intensity than the l form, while the chemical shift for all nuclei involved remains unchanged. We attribute this striking result to the onset of electron spin polarization, accompanying bond charge polarization through a chiral center, a secondary mechanism for polarization transfer that is triggered only in the CP experimental setup. Electron spin polarization is due to the chiral-induced spin selectivity effect (CISS), which creates an enantioselective response, analogous to the one involved in molecular recognition and enantiospecific separation with achiral magnetic substrates. This polarization influences the molecular magnetic environment, modifying the longitudinal relaxation time T 1 of 1 H, and ultimately provoking the observed asymmetry in the enantiomeric response.

The (3+2) cycloaddition between azomethine ylides and alkenes is an efficient, convergent and stereocontrolled method for the synthesis of unnatural pyrrolidine and proline scaffolds. In this review, the application of this reaction to the synthesis of enantiopure organometallic ligands for asymmetric catalysis is presented first. These new EhuPhos ligands can participate in a second generation of 1,3-dipolar reactions that generate an offspring of unnatural proline derivatives that behave as efficient organocatalysts. These densely substituted unnatural l-proline derivatives exhibit distinct features, different to those described for natural l-proline and its derivatives. Finally, several examples of biologically active proline derivatives obtained by means of (3+2) cycloadditions involving azomethine ylides are presented. These applications show the character of privileged structures of these polysubstituted pyrrolidine rings.

1,3-Dipolar cycloadditions (1,3-DC) between imino esters (as precursors of N-metallated azomethine ylides) and π-deficient alkenes are promoted by cooperative asymmetric Lewis acid/Brønsted base catalysis. The components of these catalytic pairs are silver salts derived from enantiopure commercially available BINOL-based phosphoric acids and Cinchona alkaloids. Chiral phosphoric silver(I) salts promote HOMO raising of in situ formed 1,3-dipoles, whereas protonated cinchona alkaloids generate a LUMO lowering for the dipolarophiles resulting in a global acceleration of the 1,3-DC. The best results were obtained with BINOL-derived silver phosphate and hydrocinchonine. Matching between both cooperative metallo- and organocatalyst results in an enhanced enantiomeric excess, superior to that reached by both separate components. NOESY experiments and DFT calculations are compatible with a non-covalent interaction (hydrogen bond) between both catalysts, which results in close contacts and mutually coupled chiral environments., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An efficient and alternative synthesis of exo-imidazolidin-2-one dienes is described. A condensation reaction was carried out with bis-imino derivatives, diacetyl, and triphosgene, affording symmetrically N, N-disubstituted dienes. The use of alkyl methyl α-diketones led to the formation of nonsymmetrical dienes, which underwent isomerization to provide more stable inner-outer-ring dienes under Lewis acid conditions. Evaluation was made of the reactivity as well as regio- and stereoselectivity of these dienes in Diels-Alder reactions. They proved to be highly reactive and selective. DFT calculations of the transition states accounted for their behavior.

Herein, we present a fast, efficient and general one-pot method for the synthesis of 11C-labelled compounds via the Negishi cross-coupling reaction. Our approach, based on the in situ formation of [11C]CH3ZnI and subsequent reaction with aryl halides or triflates, has proven efficient to synthesize [11C]thymidine, a biologically relevant compound with potential applications as a proliferation marker. Theoretical calculations have shown irreversible formation of a tetracoordinated nucleophilic 11C-Zn(ii) reagent and electronic requirements for an efficient Negishi coupling.

In this work, we studied computationally the N-demethylation reaction of methylamine, dimethylamine, and trimethylamine as archetypal examples of primary, secondary, and tertiary amines catalyzed by high-field low-spin Fe-containing enzymes such as cytochromes P450. Using DFT calculations, we found that the expected C-H hydroxylation process was achieved for trimethylamine. When dimethylamine and methylamine were studied, two different reaction mechanisms (C-H hydroxylation and a double hydrogen atom transfer) were computed to be energetically accessible and both are equally preferred. Both processes led to the formation of formaldehyde and the N-demethylated substrate. Finally, as an illustrative example, the relative contribution of the three primary oxidation routes of tamoxifen was rationalized through energetic barriers obtained from density functional calculations and docking experiments involving CYP3A4 and CYP2D6 isoforms. We found that the N-demethylation process was the intrinsically favored one, whereas other oxidation reactions required most likely preorganization imposed by the residues close to the active sites.

A new diastereo- and enantioselective three-component cyclization reaction is described. The reaction takes place between a ketone, a carboxylic acid, and a nitroalkene to yield a bicyclic octahydro-2H-indol-2-one scaffold possessing three chiral centers. This reaction involves a rearrangement of the nitro group under simple thermal conditions. A plausible mechanism is proposed for this new reaction based on DFT calculations and isotope-labeling experiments. A new concise enantioselective synthesis of the alkaloid (+)-pancracine is presented as an example of the potential of this novel organocatalytic cyclization reaction in the synthesis of natural products., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Meso-aryl expanded porphyrins present a structural versatility that allows them to achieve different topologies with distinct aromaticities. Several studies appeared in the literature studying these topological switches from an experimental and theoretical point of view. Most of these publications include density functional theory calculations, being the B3LYP the most used methodology. In this work, we show that the selection of the functional has a critical role on the geometric, energetic, and magnetic results of these expanded porphyrins, and that the use of an inadequate methodology can even generate spurious stationary points on the potential energy surface. To illustrate these aspects, in this article we have studied different molecular distortions of two expanded porphyrins, [32]-heptaphyrin and [26]-hexaphyrin using 11 DFT functionals and performing single point energy calculations at the local pair natural orbital coupled cluster DLPNO-CCSD(T) method, which have been carried out for benchmarking purposes. For some selected functionals, the dispersion effects have also been evaluated using the D3-Grimme's dispersion correction with Becke-Johnson damping. Our results let us to conclude that the CAM-B3LYP, M05-2X, and M06-2X functionals are the methodologies that provide a more consistent description of these topological switches, while other methods, such as B3LYP, BPE, and BP86, show a biased description. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

The reactivity of nitrogen mustard mechlorethamine (mec) with purine bases towards formation of mono- (G-mec and A-mec) and dialkylated (AA-mec, GG-mec and AG-mec) adducts has been studied using density functional theory (DFT). To gain a complete overview of DNA-alkylation processes, direct chloride substitution and formation through activated aziridinium species were considered as possible reaction paths for adduct formation. Our results confirm that DNA alkylation by mec occurs via aziridine intermediates instead of direct substitution. Consideration of explicit water molecules in conjunction with polarizable continuum model (PCM) was shown as an adequate computational method for a proper representation of the system. Moreover, Runge-Kutta numerical kinetic simulations including the possible bisadducts have been performed. These simulations predicted a product ratio of 83:17 of GG-mec and AG-mec diadducts, respectively., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel catalytic system based on covalently modified DNA is described. This catalyst promotes 1,3-dipolar reactions between azomethine ylides and maleimides. The catalytic system is based on the distortion of the double helix of DNA by means of the formation of Pt(ii) adducts with guanine units. This distortion, similar to that generated in the interaction of DNA with platinum chemotherapeutic drugs, generates active sites that can accommodate N -metallated azomethine ylides. The proposed reaction mechanism, based on QM(DFT)/MM calculations, is compatible with thermally allowed concerted (but asynchronous) [π4s + π2s] mechanisms leading to the exclusive formation of racemic endo -cycloadducts.

The reaction of chiral N-tert-butanesulfinyl aldimines with β-keto acids under basic conditions at room temperature proceeds with high levels of diastereocontrol, leading to β-amino ketones in high yields. Based on DFT calculations, an eight-membered cyclic transition state involving coordination of the lithium atom to the oxygens of carboxylate and sulfinyl units was proposed, being in agreement with the observed experimental diastereomeric ratios. The synthesis of the piperidine alkaloid (-)-pelletierine was successfully undertaken in order to demonstrate the utility of this methodology.

Organocatalysis is becoming an important tool in polymer science because of its versatility and specificity. To date a limited number of organic catalysts have demonstrated the ability to promote stereocontrolled polymerizations. In this work we report one of the first examples of chirality transfer from a catalyst to a polymer in the organocatalyzed ring-opening polymerization (ROP) of rac-lactide (rac-LA). We have polymerized rac-LA using the diastereomeric densely substituted amino acids (2S,3R,4S,5S)-1-methyl-4-nitro-3,5-diphenylpyrrolidine-2-carboxylic acid (endo-6) and (2S,3S,4R,5S)-1-methyl-4-nitro-3,5-diphenylpyrrolidine-2-carboxylic acid (exo-6), combined with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a cocatalyst. Both diastereoisomers not only showed the ability to synthesize enriched isotactic polylactide with a P m higher than 0.90 at room temperature but also were able to preferentially promote the polymerization of one of the isomers (l or d) with respect to the other. Thus, exo-6 preferentially polymerized l-lactide, whereas endo-6 preferred d-lactide as the substrate. Density functional theory calculations were conducted to investigate the origins of this unique stereocontrol in the polymerization, providing mechanistic insight and explaining why the chirality of the catalyst is able to define the stereochemistry of the monomer insertion.

The N-demethylation reactions of N,N,N-trimethylpropan-1-ammonium and N,N-dimethyl- and N-methylpropan-1-aminium cations in the presence of [(AcO) 2 (imidazole) 2 (H 2 O)Fe=O] complex have been studied by density functional theory. These transformations are suitable models for the N-demethylation of tri-, di-, and monomethylated lysine residues of histones in the presence of Jumonji-C containing histone demethylases. It has been found that the N-demethylation reaction is stepwise and occurs on triplet and quintet potential energy hypersurfaces. Both spin states are nearly degenerated and the quantum jump from one state to another has a transition probability close to one. The preferred intrinsic mechanism depends upon the methylation degree. For trimethylated residues the mechanism consists of a proton abstraction from a methyl group followed by a formation of a hydroxymethylaminium intermediate. This mechanism also occurs when dimethylated residues are able to orientate one methyl group towards the Fe=O group of the catalytic site. In contrast, when a N-H group of the substrate is close enough to the Fe=O group, the intrinsically preferred N-demethylation reaction leads to the formation of an iminium intermediate that can be hydrolyzed to form the corresponding N-demethylated product., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The use of alkenyl arenes as dipolarophiles in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides is reported. Under appropriate reaction conditions with a Cu I or Ag I catalyst either the exo or the endo adduct was obtained with high stereoselectivity. This process provides efficient access to highly enantiomerically enriched 4-aryl proline derivatives. The observed results are compatible with the blockage of one prochiral face of the 1,3-dipole, as well as with the efficient transmission of electrophilicity towards the terminal carbon atom of the dipolarophile. This polarization results in a change from a concerted to a stepwise mechanism., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The reactivity of cisplatin towards different nucleophiles has been studied by using density functional theory (DFT). Water was considered first to analyze the factors that govern the transformation of cisplatin into more electrophilic aquated species by using an activation-strain model. It was found that the selectivity and reactivity of cisplatin is a delicate trade-off between strain and interaction energies and that the second chloride is a worse leaving group than the first. When similar studies were carried out with imidazole, guanine (G), and adenine (A), it was found that in general the second nucleophilic substitution reactions have lower activation barriers than the first ones. Finally, simulations of the structural restrictions imposed by the DNA scaffold in intra- and interstrand processes showed that the geometries of the reaction products are nonoptimal with respect to the unrestrained A and G nucleophiles, although the energetic cost is not considerable under physiological conditions, which thus permits nucleophilic substitution reactions that lead to highly distorted DNA., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A donor-stabilized 1,3-disila-2,4-diazacyclobutadiene presents an exceptionally short nonbonded Si⋅⋅⋅Si distance (2.23 Å), which is as short as that of Si=Si bonds (2.15-2.23 Å). Theoretical investigations indicate that there is no bond between the two silicon atoms, and that the unusual geometry can be related to a significant coulomb repulsion between the two ring nitrogen atoms. This chemical pressure phenomenon could provide an alternative and superior way of squeezing out van der Waals space in highly strained structures, as compared to the classical physical methods., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)