Enediolates and dienediolates of carboxylic acids in synthesis. Synthesis of β,γ-epoxyacids from α-chloroketones

1998

Abstract Lithium dienolates of saturated or α,β-unsaturated acids react with α-chloroketones provide a convenient method for preparation of highly sustituted β,γ-epoxyacids. These highly reactive compounds lead in most cases to variable ammounts of the corresponding β-lactones and allylic alcohols.

Addition of dianions of carboxylic acids to imines. Influence of the acid in the outcome of the reaction

2009

Gil Grau, Salvador, Salvador.Gil@uv.es, Parra Alvarez, Margarita, Margarita.Parra@uv.es, Rodriguez Abad, Pablo, roapa@alumni.uv.es

A Convenient Generation of Acetic Acid Dianion

2003

The lithium enediolate of acetic acid can be generated efficiently, as a 0.5 M solution in THF, using lithium amides prepared from n-butyllithium in THF and either diethylamine or 1,3,3-trimethyl-6-azabicyclo-(3.2.1)-octane (AZA). Its reaction with carbonyl compounds leads to the corresponding β-hydroxy acids in good to moderate yields. Better yields are usually obtained when these amines are added in sub-stoichiometric amounts. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Peptide-Capped Mesoporous Nanoparticles: Toward a more Efficient Internalization of Alendronate

2020

[EN] Osteoporosis is an illness which appears when the osteoblast/osteoclast activities are unbalanced taking place bone resorption (caused by osteoclasts) in higher extension than bone formation (induced by osteoblasts). Alendronate is one of the most used drugs for osteoporosis treatment despite its scarce bioavailability. Here we present the synthesis and characterization of mesoporous gated nanoparticles (two sets) for the controlled release of alendronate. The first set of nanoparticles (S1) were loaded with sulforhodamine B and capped with a peptide that could be selectively hydrolyzed by cathepsin K enzyme (overexpressed in osteoclasts). The second set (S2) was functionalized with am…

Chromogenic Detection of Nerve Agent Mimics by Mass Transport Control at the Surface of Bifunctionalized Silica Nanoparticles

2010

Chemical warfare (CW) agents are toxic chemicals that have been used in several terrorist attacks in recent years. Among CW species, nerve agents are probably the most dangerous; their high toxicity and facile synthesis underscores the need to detect these lethal compounds with quick, reliable procedures. Analytical methods based on enzymatic assays and physical measurements have generally been used to detect these hazards. However, these protocols usually have limitations such as low selectivity, poor portability, and a certain level of complexity. In recent years, several chromogenic and fluorogenic sensors, and reagents for the detection of nerve agents have been described. For instance,…

Nerve agent simulant detection by using chromogenic triaryl methane cation probes

2012

Two triaryl methane cations have been used as probes for colorimetric detection of nerve agent simulants. Buffered mixed aqueous solutions of 1 and 2 showed bathochromic shifts in the presence of DCNP (diethylcyanophosphonate) and DCP (diethylchlorophosphate). The colour modulation can be observed to the naked eye. Appropriate mechanisms for the recognition event are proposed. © 2012 Elsevier Ltd.

ChemInform Abstract: Enantioselective α-Alkylation of Unsaturated Carboxylic Acids Using a Chiral Lithium Amide.

2010

Abstract The regio- and stereochemistry of the alkylation of dienediolates from unsaturated carboxylic acids with benzylic halides, which often results in mixtures of isomers, can be controlled by means of changes in the lithium amide, allowing the α-regioisomer to be obtained as the major diastereoisomer. In addition, when chiral amines are used, moderate enantiomeric excesses can be attained.

ChemInform Abstract: Components of the Sex Pheromone of Chilo supressalis: Efficient Syntheses of (Z)-11-Hexadecenal and (Z)-13-Octadecenal.

2010

Abstract (Z)-11-Hexedecenal 1a and (Z)-13-octadecenenal 2a, components of the sex attractant pheromone of Chilo supressalis, have been synthesized as their ethylene acetals 1b and 2b from cyclododecanone 3, through intermediacy of the C12 ω functionalized acetals 8 and 12.

A new selective fluorogenic probe for trivalent cations.

2012

[EN] A new selective chromo-fluorogenic probe for Fe 3+, Cr 3+ and Al 3+ is reported. Detection limits are in the ¿M range and the fluorogenic sensing ability could be observed by the naked eye when illuminated with UV-light. No response is observed with divalent cations. © 2012 The Royal Society of Chemistry.

STUDIES ON BICYCLO[3.3.1]NONANES FOR SYNTHESIS OF CYCLOOCTENES

2002

This paper describes a full conformational and stereochemical study of bicylo[3.3.1]nonanes, obtained from the reaction between cinnamaldehyde and 1-morpholine 1-cyclohexene. NMR data and stereochemistry were unequivocally established and assigned by two-dimensional experiments and single-crystal X-ray analysis. The crystal structure of a minor compound, 4, is reported. Cyclooctenes, which are present in natural products with biological activities, were synthesized from the bicyclononanes via the Wharton fragmentation.

Chromogenic Chemodosimeter Based on Capped Silica Particles to Detect Spermine and Spermidine

2021

A new hybrid organic–inorganic material for sensing spermine (Spm) and spermidine (Spd) has been prepared and characterized. The material is based on MCM-41 particles functionalized with an N-hydroxysuccinimide derivative and loaded with Rhodamine 6G. The cargo is kept inside the porous material due to the formation of a double layer of organic matter. The inner layer is covalently bound to the silica particles, while the external layer is formed through hydrogen and hydrophobic interactions. The limits of detection determined by fluorimetric titration are 27 µM and 45 µM for Spm and Spd, respectively. The sensor remains silent in the presence of other biologically important amines and is a…

Highly selective and sensitive chromo-fluorogenic detection of the Tetryl explosive using functional silica nanoparticles

2011

Silica nanoparticles containing polyamines and thiol groups have been used as probes for the selective detection of Tetryl. © 2011 The Royal Society of Chemistry.

Alkylation of lithium dienediolates of butenoic acids. Regioselectivity effects of structure and leaving group of the alkylating agent

1998

Abstract Regioselectivity of alkylation of but-2-enoic acids 1 and 2 by alkyl halides strongly depends on the reactivity of the electrophile. High α selectivity results for saturated alkyl halides, whereas poor α-selectivity is obtained for highly reactive allyl and benzyl halides. For reactive alkylating halides selectivity is partly governed by the ion pairing aggregates of the dienediolates. Lithium bromide and the carboxylate generated in the ongoing reaction cause opposite effects on regioselectivity.

Hg2+ and Cu2+ selective detection using a dual channel receptor based on thiopyrylium scaffoldings

2009

2,4,6-Triphenylthiopyrylium functionalized with an aza-oxa-thia macrocycle is able to selectively recognize Hg2+ cation by a color change and Cu2+ cation by a remarkable significant emission enhancement.

Selective Recognition and Sensing of Succinate vs. Other Aliphatic Dicarboxylates by Thiourea-Functionalized Gold Nanoparticles

2016

Gold nanoparticles functionalized with thiourea moieties have been used as selective colorimetric sensors for the naked-eye detection of succinate versus other aliphatic dicarboxylates, all of them as their TBA salts. The detection process is based on the interparticle aggregation triggered by coordination of the end-carboxylates to the thiourea moieties of two different nanoparticles. This nanoparticle aggregation results in a batochromic shift of the plasmon resonance band and a visual color change from red to blue.

Towards the fluorogenic detection of peroxide explosives through host-guest chemistry

2018

[EN] Two dansyl-modified beta-cyclodextrin derivatives (1 and 2) have been synthesized as host-guest sensory systems for the direct fluorescent detection of the peroxide explosives diacetone diperoxide (DADP) and triacetone triperoxide (TATP) in aqueous media. The sensing is based on the displacement of the dansyl moiety from the cavity of the cyclodextrin by the peroxide guest resulting in a decrease of the intensity of the fluorescence of the dye. Both systems showed similar fluorescent responses and were more sensitive towards TATP than DADP.

A Chromogenic Probe for the Selective Recognition of Sarin and Soman Mimic DFP

2014

The synthesis, characterization and sensing features of a novel probe 1 for the selective chromogenic recognition of diisopropylfluorophosphate (DFP), a sarin and soman mimic, in 99:1 (v/ v) water/acetonitrile and in the gas phase is reported. Colour modulation is based on the combined reaction of phosphorylation of 1 and fluoride-induced hydrolysis of a silyl ether moiety. As fluoride is a specific reaction product of the reaction between DFP and the OH group, the probe shows a selective colour modulation in the presence of this chemical. Other nerve agent simulants, certain anions, oxidant species and other organophosphorous compounds were unable to induce colour changes in 1. This is one…

Colorimetric and fluorescent hydrazone-BODIPY probes for the detection of γ-hydroxybutyric acid (GHB) and cathinones

2022

Consumption and abuse of drugs is a general problem, which concerns our entire society. In some cases, drugs are used for recreational purposes; but in others, they are used to commit crimes such as Drug-Facilitated Sexual Assault (DFSA). In other cases, this consumption alters the consumer mood in such a way that risky situations can rise. In any case, detection of drugs in different environment is worthwhile. Here, two new chromogenic and fluorescent probes are reported. Detection of both cathinone derivatives and γ-hydroxybutyric acid (GHB) can be carried out with naked-eye with limits of detection of 0.4 μM and 0.3 μM for GHB and 2.0 μM for ephedrone. Selectivity in the presence of othe…

ChemInform Abstract: Trienediolates of Hexadienoic Acids in Synthesis. Synthesis of Retinoic and nor-Retinoic Acids.

2010

Abstract Double deprotonation of either (E,E)-3-methyl-2,4-hexadienoic acid 2, or 4,6-dimethyldihydro-2-pyrone 3 generates apparently the same lithium trienediolate, which affords ω-hydroxy acids 9 on reaction with ketones 7. Hydroxy acids 9 are easily dehydrated to octatrienoic acids 5, which are structurally related to retinoic acid. Similarly, sorbic acid 1 leads to nor-retinoic acid analogs 6.

Chromogenic detection of nerve agent mimics

2008

The current rise in international concern over criminal terrorist attacks via chemical warfare (CW) agents has resulted in an increasing interest in the detection of these lethal chemicals. Among CW species, nerve agents are extremely dangerous and their high toxicity and ease of production underscore the need to detect these deadly chemicals via quick and reliable procedures. A number of detection systems have been developed, most of them based on enzymatic and physical methodologies. However, these usually show limitations such as low selectivity, lack of portability and a certain complexity in their use. An alternative to these classical methods that has been gaining interest in recent y…

A simple synthesis of γ-aminoacids

2007

The addition of dianions of carboxylic acids to bromoacetonitrile, leads, in good yields, to the corresponding γ-cyanoacids that give γ-aminoacids on hydrogenation. This two-step methodology improves the results previously described.

Enantioselective sensing of dicarboxylates. Influence of the stoichiometry of the complexes on the sensing mechanism

2009

Two new cyclohexane-based thiourea chiral ligands have been synthesized in their enantiomerically pure forms. Both the ability of these ligands in the complexation of chiral dicarboxylates and their sensing properties have been studied. The influence of the stoichiometry of the formed complexes on the fluorescent properties of the systems has been established. The effect of additional substitution in the cyclohexyl moiety was considered by comparing the properties of the newly prepared ligands with those of similar compounds previously described.

Detection and discrimination of organophosphorus pesticides in water by using a colorimetric probe array

2014

[EN] Detection and discrimination of several organophosphorus pesticides in water using a colorimetric probe array containing twelve dyes has been achieved. A clear discrimination for malathion, leptophos, dichlorvos, dibrom and diazinon was observed. The array was used to determine the concentration of diazinon in orange leaves

Functional Magnetic Mesoporous Silica Microparticles Capped with an Azo-Derivative: A Promising Colon Drug Delivery Device

2018

[EN] Magnetic micro-sized mesoporous silica particles were used for the preparation of a gated material able to release an entrapped cargo in the presence of an azo-reducing agent and, to some extent, at acidic pH. The magnetic mesoporous microparticles were loaded with safranin O and the external surface was functionalized with an azo derivative 1 (bearing a carbamate linkage) yielding solid S1. Aqueous suspensions of S1 at pH 7.4 showed negligible safranin O release due to the presence of the bulky azo derivative attached onto the external surface of the inorganic scaffold. However, in the presence of sodium dithionite (azoreductive agent), a remarkable safranin O delivery was observed. A…

Surfactant-assisted chromogenic sensing of cyanide in water

2009

Chromogenic cyanide recognition in water was achieved by the use of a hydrophobic dye in micellar containers.

Mesoporous Silica Nanoparticles in Chemical Detection: From Small Species to Large Bio-Molecules

2021

A recompilation of applications of mesoporous silica nanoparticles in sensing from the last five years is presented. Its high potential, especially as hybrid materials combined with organic or bio-molecules, is shown. Adding to the multiplying effect of loading high amounts of the transducer into the pores, the selectivity attained by the interaction of the analyte with the layer decorating the material is described. Examples of the different methodologies are presented.

ChemInform Abstract: Optical Chemosensors and Reagents to Detect Explosives

2012

This critical review is focused on examples reported from 1947 to 2010 related to the design of chromo-fluorogenic chemosensors and reagents for explosives (141 references).

Unexplored nucleophilic ring opening of aziridines.

2010

The reactivity of dianions of carboxylic acids towards aziridines has been studied. Although, a similar reactivity to that of enolates from ketones, esters or amides has been observed, the method directly yields g-aminoacids in one step. The method is complementary of previous results of enenediolate reactivity with other electrophiles. A comparative study with the reactivity of this enediolates with epoxides is included.

ChemInform Abstract: Studies on Bicyclo[3.3.1]nonanes for Synthesis of Cyclooctenes.

2010

This paper describes a full conformational and stereochemical study of bicylo[3.3.1]nonanes, obtained from the reaction between cinnamaldehyde and 1-morpholine 1-cyclohexene. NMR data and stereochemistry were unequivocally established and assigned by two-dimensional experiments and single-crystal X-ray analysis. The crystal structure of a minor compound, 4, is reported. Cyclooctenes, which are present in natural products with biological activities, were synthesized from the bicyclononanes via the Wharton fragmentation.

Sex Pheromone of Chilo Suppressalis: Efficient Syntheses of (Z)-11-Hexadecenal, (Z)-13-Octadecenal And (Z)-9-Hexadecenal

1996

Abstract The constituents of the sex attractant pheromone of Chilo suppressalis: (Z)-11-Hexedecenal 1, (Z)-13-octadecenenal 2 and (Z)-9-Hexadecenal 3 have been synthesized as their ethylene acetals 19, 15 and 13, in six steps from easily available compounds. The synthetic methodology can be applied to preparative scale.

Iodine oxidative coupling of diene and triene-diolates of unsaturated carboxylic acids.

1991

Abstract Oxidative Coupling of the dianions of unsaturated carboxylic acids 1 , and 4 with iodine, which provides a convenient and facile preparation of γ,γ and e,e-dicarboxylic acids 2 and 5, apparently occurs through SET substitution of intermediate iodo-carboxylates.

A chalcone-based highly selective and sensitive chromofluorogenic probe for trivalent metal cations

2015

[EN] Anew chalcone-based probe for the chromofluorogenic sens-ing of trivalent (Al3 +,Fe3+,Cr3+,Ga3+,In3+and As3 +)overmono-and divalent cationsand anionsisreported. In the presence of trivalent metal cations,the probe was able to displayaremarkable color change from yellow to colorless that wasclearly visible to the naked eye. Also, the initial strongyellowemission was gradually quenched and substituted by aweaklyshifted band.

Functionalized Gold Nanoparticles as an Approach to the Direct Colorimetric Detection of DCNP Nerve Agent Simulant

2013

New functionalized gold nanoparticles have been synthesized and their ability to act as colorimetric molecular probes for the naked-eye detection of nerve agent simulant DCNP has been studied. The detection process is based on the com

Chromo-Fluorogenic Detection of Nerve-Agent Mimics Using Triggered Cyclization Reactions in Push-Pull Dyes

2010

A family of azo and stilbene derivatives (1-9) are synthesized, and their chromo-fluorogenic behavior in the presence of nerve-agent simulants, diethylchlorophosphate (DCP), diisopropylfluorophosphate (DFP), and diethylcyanophosphate (DCNP) in acetonitrile and mixed solution of water/acetonitrile (3:1 v/v) buffered at pH 5.6 with MES, is investigated. The prepared compounds contain 2-(2-N,N-dimethylaminophenyl)ethanol or 2-[(2-N,N-dimethylamino)phenoxy]ethanol reactive groups, which are part of the conjugated pi-system of the dyes and are able to give acylation reactions with phosphonate substrates followed by a rapid intramolecular N-alkylation. The nerve-agent mimic-triggered cyclization …

3-Formyl-BODIPY Phenylhydrazone as a Chromo-Fluorogenic Probe for Selective Detection of NO2 (g)

2016

Anew colorimetric and fluorogenic probe,based on a3-formyl boron dipyrromethene (BODIPY)phe-nylhydrazone, for the sensitive and selectivedetectionNO2(g) has been prepared. The probeinsolution experi-ences aremarkablehypsochromic shift of its absorptionand fluorescence emission bands in the presence gaseousNO2(g), leading to limits of detectio noffew ppb. Theprobe also works in the solid phase, adsorbed on filterpaper strips, or chemically immobilized on the surfaceofsilica nanop articles, with limitsofdetection to the nakedeye of about 0.5 ppm.

Efficient Addition of Acid Enediolates to Epoxides

2004

We report new conditions to facilitate the addition of dianions of carboxylic acids to epoxides as an alternative method to the use of aluminum enolates. These conditions require the use of a sub-stoichiometric (10%) amount of amine for dianion generation and the previous activation of the epoxide with LiCl. Other Lewis acids have been shown to be less effective. Yields are good but only low diastereoselectivity is attained, which has not been controlled despite attempts at optimization. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Polyenolates of unsaturated carboxylic acids in synthesis. A straightforward synthesis of retinoic acids.

1990

Abstract Retinoic acids are prepared in a two step procedure by addition of lithium trienediolates of sorbic acid and 3-methyl-sorbic acid to β-ionone.

Binding and Fluorescent Sensing of Dicarboxylates by a Bis(calix[4]pyrrole)-Substituted BODIPY Dye

2013

A bis(calix[4]pyrrole)-substituted BODIPY ditopic receptor 1 has been synthesised and characterised. The binding and sensing properties of 1 towards several aliphatic and aromatic dicarboxylates have been evaluated by using UV/Vis fluorescence and 1H NMR spectroscopy. The receptor strongly binds linear α,ω-dicarboxylates of appropriate lengths (C9 and C10) by acting as a cleft. For all dicarboxylates, the binding event is detected by a bathochromic shift in the UV/Vis spectra of the receptor and by strong quenching of its fluorescence.

Self-Immolative Linkers as Caps for the Design of Gated Silica Mesoporous Supports

2016

A new hybrid material based on sulforhodamine-B dye-loaded silica mesoporous nanoparticles capped with a self-immolative gate has been synthesized and characterized. The gated material's controlled release behavior is monitored under different pH conditions. Under acidic and neutral conditions, a low level of dye release is detected. However, at slightly basic pH, significant dye release occurs owing to deprotonation of the phenol moiety in the capping molecule, which results in its disassembly.

Multi-channel receptors based on thiopyrylium functionalised with macrocyclic receptors for the recognition of transition metal cations and anions.

2010

We report herein the synthesis and characterization of a family of ligands containing different cation binding sites covalently connected to a thiopyrylium signalling reporter. The receptors L1–L6 are able to signal the presence of certain metal cations via three different channels; i.e. electrochemically, fluorogenically and chromogenically. An acetonitrile solution of L1–L6 shows a bright blue colour due to a charge-transfer band in the 575–585 nm region. The colour variation in acetonitrile of L1–L6 in the presence of the metal cations Ag+, Cd2+, Cu2+, Fe3+, Hg2+, Ni2+, Pb2+ and Zn2+ has been studied. A selective hypsochromic shift of the blue band was found for the systems L4-Pb2+ and L…

A nitric oxide induced “click” reaction to trigger the aggregation induced emission (AIE) phenomena of a tetraphenyl ethylene derivative: A new fluor…

2020

Abstract An Aggregation Induced Emission (AIE) transduction mechanism has been used to detect nitric oxide (NO). A new tetraphenylethylene derivative functionalized with alkyne moieties has been prepared to work as a fluorescent probe. A “click” reaction was chosen because NO is able to generate the required catalytic species by reducing Cu(II) to Cu(I).

ChemInform Abstract: Synthesis of Dienedioic and Tetraenedioic Acids by Oxidative Coupling of Unsaturated Carboxylic Acid Dienediolates by 1,2-Diiodo…

2010

Abstract Acyclic and cyclic unsaturated carboxylic acids 1 to 4 are most easily converted to unsaturated dicarboxylic acids 5 to 8 by oxidative coupling of their diene- or triene-diolates by 1,2-diiodoethane. This procedure improves formerly reported oxidations by iodine or silver salts.

Lithium enediolates and dienediolates of carboxylic acids in synthesis: Alkylation with secondary halides

1998

Abstract High yields in the alkylation of dianions of α,β-unsaturated carboxylic acids with secondary halides can be obtained despite elimination reactions occurring. α-Regioselectivity for the alkylation of but-2-enoic acids ( 1–4 ) is seldom obtained. Although double bond stereoselectivity is higher than 99% for γ-alkylated products, stereoselectivity is rather poor for most of the α-alkylated products.

Experimental and theoretical investigations for the tandem alkylation–isomerization reactions between unsaturated carboxylic acids and allyl halides

2003

Abstract—Alkylation of dienediolates from unsaturated carboxylic acids with allylic halides when followed by solventless thermaltreatment at 150 to 2008C afford rearranged products on a trend highly dependent on the acarbon substitution. Thus, 2,2-bisallylated acidswith H atoms at C-2 lead to its 1,3-shift, whereas 2-methyl-2,2-bisallylated acids lead to the corresponding Cope rearrangement product. Inthe latter case, this tandem allylation-Cope reaction lead, in a highly regio and diastereoselective way, to products not accessible from directalkylation. B3LYP/6-31G p energies for the compounds involved at these isomerizations are in reasonable agreement with the experiments,allowing to exp…

Frontispiece: Self-Immolative Linkers as Caps for the Design of Gated Silica Mesoporous Supports

2016

Highly selective fluorescence detection of hydrogen sulfide by using an anthracene-functionalized cyclam-CuII complex

2013

An anthracene-functionalised cyclam-copper(II) complex for the detection of HS- in aqueous environments has been prepared. This probe displays poor fluorescence but can selectively and sensitively detect HS- anions in water over other anions, biothiols and common oxidants such as H2O2 through remarkably enhanced emission. This turn-on response in the presence of the HS- anion is ascribed to a demetallation reaction that inhibits emission quenching observed in the initial complex as a result of the presence of the paramagnetic Cu2+ centre. Moreover, real-time fluorescence imaging measurements confirm that probe [Cu(1)](2+) can be easily used to detect intracellular HS- at micromolar concentr…

ChemInform Abstract: Trienediolates of Hexadienoic Acids in Synthesis. Addition to Unsaturated Ketones. A Convergent Approach to the Synthesis of Ret…

2010

Abstract The regioselectivity of the addition of the lithium trienediolates generated from hexa-2,4dienoic acids 1 and 2 or the dihydropyran-2ones 4 and 5 to unsaturated ketones 6 is studied. Equilibration conditions favour reaction of the trienediolates through their ω carbon, and the ketones according to 1,2- and 1,4-additions. β-Ionone 6a and the aryl-butenone 6b lead to the 1,2-ω-adducts 8 , which undergo a facile acid catalyzed dehydration to retmoic acids 11 . On reaction with the unsaturated ketone 6b or with the aryl ketones 21 , the trimethyldihydropyran-2one S leads to γ-adducts derived from deprotonation of the chain methyl mbstituent along with the 1,4-ω-adducts.

Components of the Sex Pheromone of Chilo Supressalis: Efficient Syntheses of (Z)-11-Hexadecenal and (Z)-13-Octadecenal

1995

Abstract (Z)-11-Hexedecenal 1a and (Z)-13-octadecenenal 2a, components of the sex attractant pheromone of Chilo supressalis, have been synthesized as their ethylene acetals 1b and 2b from cyclododecanone 3, through intermediacy of the C12 ω functionalized acetals 8 and 12.

ChemInform Abstract: Alkylation of Lithium Dienediolates of Butenoic Acids. Regioselectivity Effects of Structure and Leaving Group of the Alkylating…

2010

Abstract Regioselectivity of alkylation of but-2-enoic acids 1 and 2 by alkyl halides strongly depends on the reactivity of the electrophile. High α selectivity results for saturated alkyl halides, whereas poor α-selectivity is obtained for highly reactive allyl and benzyl halides. For reactive alkylating halides selectivity is partly governed by the ion pairing aggregates of the dienediolates. Lithium bromide and the carboxylate generated in the ongoing reaction cause opposite effects on regioselectivity.

Trienediolates of hexadienoic acids in synthesis. synthesis of retinoic and nor-retinoic acids.

1993

Abstract Double deprotonation of either (E,E)-3-methyl-2,4-hexadienoic acid 2, or 4,6-dimethyldihydro-2-pyrone 3 generates apparently the same lithium trienediolate, which affords ω-hydroxy acids 9 on reaction with ketones 7. Hydroxy acids 9 are easily dehydrated to octatrienoic acids 5, which are structurally related to retinoic acid. Similarly, sorbic acid 1 leads to nor-retinoic acid analogs 6.

Selective and Sensitive Chromogenic Detection of Cyanide and HCN in Solution and in Gas Phase

2013

Two triphenylmethane based chemodosimeters for selective and chromogenic sensing of cyanide anions in aqueous environments and of hydrogen cyanide in gas phase were prepared and studied.

ChemInform Abstract: Iodine Oxidative Coupling of Diene- and Triene-Diolates of Unsaturated Carboxylic Acids.

2010

Abstract Oxidative Coupling of the dianions of unsaturated carboxylic acids 1 , and 4 with iodine, which provides a convenient and facile preparation of γ,γ and e,e-dicarboxylic acids 2 and 5, apparently occurs through SET substitution of intermediate iodo-carboxylates.

ChemInform Abstract: Enediolates and Dienediolates of Carboxylic Acids in Synthesis. Synthesis of β,γ-Epoxyacids from α-Chloroketones.

2010

Abstract Lithium dienolates of saturated or α,β-unsaturated acids react with α-chloroketones provide a convenient method for preparation of highly sustituted β,γ-epoxyacids. These highly reactive compounds lead in most cases to variable ammounts of the corresponding β-lactones and allylic alcohols.

3,3′-Disubstitued 2,2′-Bipyridines as Carboxylate Receptors: Conformational Regulation of the Bipyridine Moiety

2008

Two bipyridine derivatives were synthesized and characterized, and their ability to act as sensors for carboxylates was evaluated by UV/Vis and fluorescence studies. The influence of the substituents of the thiourea groups on the stoichiometry of the resulting dicarboxylate complexes was established. Conformational changes in the bipyridine moiety under different conditions were evaluated.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Efficacy of budesonide-loaded mesoporous silica microparticles capped with a bulky azo derivative in rats with TNBS-induced colitis.

2019

Abstract A colon targeted drug delivery system for inflammatory bowel diseases (IBD), consisting in budesonide loaded mesoporous silica microparticles functionalized with a selective azo-molecular gate (M-Bud), has been evaluated for in vivo efficacy. Experimental colitis in male Wistar rats was induced by rectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS). M-Bud was orally administered to the rats as a suspension in water. Colon/body weight ratio, clinical activity score, and histological evaluation were used as inflammatory indices to measure the performance of the microparticles. The formulation was compared with a suspension prepared from the commercial drug Entocord®. Sta…

A new fluorescent "turn-on" chemodosimeter for the detection of hydrogen sulfide in water and living cells

2013

[EN] A new fluorescent turn-on probe for the selective detection of hydrogen sulfide in water and living cells based on a 8-hydroxyquinoline fluorophore functionalized with a 2,6-dinitrophenyl ether moiety has been developed.

Trienediolates of hexadienoic acids in synthesis. Addition to unsaturated ketones. A convergent approach to the synthesis of retinoic acids

1995

Abstract The regioselectivity of the addition of the lithium trienediolates generated from hexa-2,4dienoic acids 1 and 2 or the dihydropyran-2ones 4 and 5 to unsaturated ketones 6 is studied. Equilibration conditions favour reaction of the trienediolates through their ω carbon, and the ketones according to 1,2- and 1,4-additions. β-Ionone 6a and the aryl-butenone 6b lead to the 1,2-ω-adducts 8 , which undergo a facile acid catalyzed dehydration to retmoic acids 11 . On reaction with the unsaturated ketone 6b or with the aryl ketones 21 , the trimethyldihydropyran-2one S leads to γ-adducts derived from deprotonation of the chain methyl mbstituent along with the 1,4-ω-adducts.

A Chemosensor Bearing Sulfonyl Azide Moieties for Selective Chromo-Fluorogenic Hydrogen Sulfide Recognition in Aqueous Media and in Living Cells

2014

A simple chemodosimeter based on a sulfonyl azide dye (1-Az), which displayed a highly selective response toward hydrogen sulfide anion in mixed aqueous media, was synthesised and characterised. Addition of hydrogen sulfide to acetonitrile/HEPES 1:1 solutions of 1-Az induced a clear colour change from red-orange to yellow, which was easily detected by the naked eye, and by an enhancement in the emission intensity. Other common anions, thiol-containing biomolecules and oxidants did not induce any noticeable colour or fluorescence modulation in the probe. The chemodosimeter also showed a good sensitivity, with limits of detection of 11.91 and 0.63 μM by using UV/Vis or fluorescence measuremen…

An Efficient Synthesis of γ-Aminoacids and Attempts to Drive Its Enantioselectivity

2008

Addition of carboxylic acid dianions to bromoacetonitrile lead, in good yields,to the corresponding gamma-cyanoacids, which on hydrogenation yielded gamma-amino acids. This two step methodology improves upon previously described results. Poor e.e's resultedfrom our attempts to drive the enantioselectivity of this transformation by chiral amide induction.

Amidase-responsive controlled release of antitumoral drug into intracellular media using gluconamide-capped mesoporous silica nanoparticles

2012

MCM-41 silica nanoparticles were used as inorganic scaffolding to prepare a nanoscopic-capped hybrid material S1, which was able to release an entrapped cargo in the presence of certain enzymes, whereas in the absence of enzymes, a zero release system was obtained. S1 was prepared by loading nanoparticles with Safranine O dye and was then capped with a gluconamide derivative. In the absence of enzymes, the release of the dye from the aqueous suspensions of S1 was inhibited as a result of the steric hindrance imposed by the bulky gluconamide derivative, the polymerized gluconamide layer and the formation of a dense hydrogen-bonded network around the pore outlets. Upon the addition of amidase…

Selective chromo-fluorogenic detection of trivalent cations in aqueous environments using a dehydration reaction

2016

[EN] Trivalent cations (Al3+, Fe3+, Cr3+, As3+, In3+ and Ga3+) induced a dehydration reaction of a chemodosimeter in water that is coupled with colour and emission changes.

Inside Cover: A Boron Dipyrromethene (BODIPY)-Based CuII-Bipyridine Complex for Highly Selective NO Detection (Chem. Eur. J. 44/2015)

2015

Unusual Regioselectivity in the Opening of Epoxides by Carboxylic Acid Enediolates

2008

Addition of carboxylic acid dianions appears to be a potential alternative to the use of aluminium enolates for nucleophilic ring opening of epoxides. These conditions require the use of a sub-stoichiometric amount of amine (10% mol) for dianion generation and the previous activation of the epoxide with LiCl. Yields are good, with high regioselectivity, but the use of styrene oxide led, unexpectedly, to a mixture resulting from the attack on both the primary and secondary carbon atoms. Generally, a low diastereoselectivity is seen on attack at the primary center, however only one diastereoisomer was obtained from attack to the secondary carbon of the styrene oxide.

Aryl carbinols as nerve agent probes. Influence of the conjugation on the sensing properties

2012

Two new aryl carbinols (1 and 3) have been synthesised and characterised and their ability as OFF-ON probes for the chromogenic detection of the nerve agent simulant in acetonitrile has been tested. In addition compound 2 has been also studied. The carbinols suffered a phosphorylation reaction followed by an elimination process giving rise to the corresponding carbocations. This transformation of the carbinol into the carbocation is responsible for a significant color change. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2012.

An Au(iii)–amino alcohol complex for degradation of organophosphorus pesticides

2015

An Au(III)–amino alcohol complex has been used to cleave organophosphorous pesticides of the dithiophosphate family. P–S bond breaking was readily demonstrated by 1H NMR, 31P NMR and MS. Thiol fragment release was also demonstrated using 2,4-dinitrobenzenesulfonyl fluorescein ethyl ester as a fluorescent sensor.

Selective opening of nanoscopic capped mesoporous inorganic materials with nerve agent simulants; an application to design chromo-fluorogenic probes.

2011

A hybrid nanoscopic capped mesoporous material, that is selectively opened in the presence of nerve agent simulants, has been prepared and used as a probe for the chromo-fluorogenic detection of these chemicals. © 2011 The Royal Society of Chemistry.

Boolean operations mediated by an ion-pair receptor of a multi-readout molecular logic gate

2013

A heteroditopic BODIPY dye that performs all basic Boolean operations with a cation (K+) and an anion (F-) as inputs and absorption, transmission and fluorescence as outputs is described. The molecular logic gate can also act as a digital comparator between the inputs.

Design of enzyme-mediated controlled release systems based on silica mesoporous supports capped with ester-glycol groups

2012

[EN] An ethylene glycol-capped hybrid material for the controlled release of molecules in the presence of esterase enzyme has been prepared. The final organic-inorganic hybrid solid S1 was synthesized by a two-step procedure. In the first step, the pores of an inorganic MCM-41 support (in the form of nanoparticles) were loaded with [Ru(bipy) 3]Cl 2 complex, and then, in the second step, the pore outlets were functionalized with ester glycol moieties that acted as molecular caps. In the absence of an enzyme, release of the complex from aqueous suspensions of S1 at pH 8.0 is inhibited due to the steric hindrance imposed by the bulky ester glycol moieties. Upon addition of esterase enzyme, del…

Mesoporous silica microparticles gated with a bulky azo derivative for the controlled release of dyes/drugs in colon.

2018

[EN] Mesoporous silica microparticles were prepared, loaded with the dye safranin O (M-Saf) or with the drug budesonide (M-Bud) and capped by the grafting of a bulky azo derivative. Cargo release from M-Saf at different pH values (mimicking those found in the gastrointestinal tract) in the absence or presence of sodium dithionite (a reducing agent mimicking azoreductase enzyme present in the colon) was tested. Negligible safranin O release was observed at pH 6.8 and 4.5, whereas a moderate delivery at pH 1.2 was noted and attributed to the hydrolysis of the urea bond that linked the azo derivative onto the external surface of the inorganic scaffold. Moreover, a marked release was observed w…

A Boron Dipyrromethene (BODIPY)-Based Cu(II) -Bipyridine Complex for Highly Selective NO Detection.

2015

[EN] A BODIPY-containing Cu-II-bipyridine complex for the simple selective fluorogenic detection of NO in air and in live cells is reported. The detection mechanism is based on NO-promoted Cu-II to Cu-I reduction, followed by demetallation of the complex, which results in the clearly enhanced emission of the boron dipyrromethene (BODIPY) unit.

Reaction of lithium enediolates with perfluoroketene dithioacetals. Synthesis of α-trifluoromethyl γ-dicarboxylic acid derivatives

2004

The reaction of perfluoroketene dithioacetals with dianions of carboxylic acids proceeds through the substitution of the vinylic fluoride. The preparative value of this reaction depends strongly on the reaction and work-up conditions, the optimisation of which led to use LDA as a base and multiple extraction techniques. The overall process may be considered as a formal synthesis of α-trifluoromethyl γ-dicarboxylic acid derivatives.

Fluorogenic detection of Tetryl and TNT explosives using nanoscopic-capped mesoporous hybrid materials

2013

[EN] A hybrid capped mesoporous material, which was selectively opened in the presence of Tetryl and TNT, has been synthesised and used for the fluorogenic recognition of these nitroaromatic explosives.

A new strategy for the synthesis of highly functionalised fluorinated compounds by reaction of lithium dianions of carboxylic acids with perfluoroket…

2005

The reaction of perfluoroketene dithioacetal with lithium dienediolates of carboxylic acids proceeds at the ω position probably through an addition to the π system followed by elimination of the vinylic fluoride. The preparative value of this reaction depends strongly on the reaction and work-up conditions. The overall process lead to highly functionalised synthons containing a trifluoromethyl group.

Chromogenic and fluorogenic reagents for chemical warfare nerve agents' detection

2008

The ease of production, the extreme toxicity of organophosphorus-containing nerve agents, and their facile use in terrorism attacks underscores the need to develop accurate systems to detect these chemicals. Among different technologies we review here recent advances in the design of chromo-fluorogenic methods for the specific detection of nerve agents. Optical sensing (especially colorimetric detection) requires usually low-cost and widely used instrumentation and offers the possibility of so-called “naked eye detection”. Recent reported examples suggest that the application of chromo-fluorogenic supramolecular concepts for the chromogenic or fluorogenic sensing of nerve agents might be an…

Biphenyl derivatives containing trimethylsilyl benzyl ether or oxime groups as probes for NO2 detection

2016

[EN] Four probes based in the use of a biphenyl moiety and functionalized with trimethylsilyl benzyl ether (P1 and P3) and oxime (P2 and P4) groups have been prepared and tested as optical probes for the detection of NO2. Reaction of NO2 with acetonitrile solutions of P2-P4 resulted in the formation of aldehydes 7 and 8 with a concomitant redshift of the absorption bands. Probe P2 displayed a bathochromic shift of 45 nm upon reaction with NO2 and was able to detect this poisonous gas at concentrations as low as 0.02 ppm. P2 was highly selective against NO2 and other gases (i.e. NO, CO2, H2S, SO2) and vapours of organic solvents (i.e. acetone, hexane, chloroform, acetonitrile or toluene) had…

ChemInform Abstract: New Conditions for the Generation of Dianions of Carboxylic Acids.

2010

Abstract Lithium carboxylic acid enediolates are generated efficiently using lithium amides prepared from thienyllithium or butyllithium and either diethylamine, piperazine, N,N′-dibenzylethylenediamine, N-benzylpiperazine or 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane, even in catalytic amounts.

5,5′-Bis-vanillin derivatives as discriminating sensors for trivalent cations

2015

[EN] Several bis-vanillin derivatives containing semicarbazone moieties have been prepared and used in discriminating trivalent cations. The prepared probes are readily obtained and they are usually highly crystalline. Depending on the ligand and the studied cations, quenching, enhancement or no changes in the fluorescence spectrum were observed. Using a series of the prepared ligands allows distinguishing between Fe3+, Cr3+ and Al3+. Detection limits and selectivity in front of divalent cations have been evaluated. (C) 2015 Elsevier Ltd. All rights reserved.

Discrimination of nerve gases mimics and other organophosphorous derivatives in gas phase using a colorimetric probe array.

2012

A colorimetric array for the chromogenic discrimination of organophosphorous derivatives in gas phase has been developed. The array allows us to classify the nerve agent simulants DFP, DCP and DCNP.

New conditions for the generation of dianions of carboxylic acids

1998

Abstract Lithium carboxylic acid enediolates are generated efficiently using lithium amides prepared from thienyllithium or butyllithium and either diethylamine, piperazine, N,N′-dibenzylethylenediamine, N-benzylpiperazine or 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane, even in catalytic amounts.

Polyenolates of Unsaturated Carboxylic Acids in Synthesis. Synthesis of Unsaturated α-Amino Acids and β-Hydrazing Acids

1991

Abstract Regioselective reaction of lithium diene-and triene-diolates 1 and 2 with O-diphenylphosphinyl hydroxylamine affords unsaturated α-amino acids 3 and 4. Addition to DEAD leads selectively to γ-hydrazino unsaturated acids 5 and 6.

Enantioselective α-alkylation of unsaturated carboxylic acids using a chiral lithium amide

2001

Abstract The regio- and stereochemistry of the alkylation of dienediolates from unsaturated carboxylic acids with benzylic halides, which often results in mixtures of isomers, can be controlled by means of changes in the lithium amide, allowing the α-regioisomer to be obtained as the major diastereoisomer. In addition, when chiral amines are used, moderate enantiomeric excesses can be attained.

NO2-controlled cargo delivery from gated silica mesoporous nanoparticles

2017

[EN] Cargo delivery from mesoporous silica nanoparticles loaded with sulforhodamine B and capped with a difluoroboron-dipyrromethene (BODIPY) derivative was triggered by a NO2-induced oxidative process.

ChemInform Abstract: Lithium Enediolates and Dienediolates of Carboxylic Acids in Synthesis: Alkylation with Secondary Halides.

2010

Abstract High yields in the alkylation of dianions of α,β-unsaturated carboxylic acids with secondary halides can be obtained despite elimination reactions occurring. α-Regioselectivity for the alkylation of but-2-enoic acids ( 1–4 ) is seldom obtained. Although double bond stereoselectivity is higher than 99% for γ-alkylated products, stereoselectivity is rather poor for most of the α-alkylated products.

Synthesis of Dienedioic and Tetraenedioic Acids by Oxidative Coupling of Unsaturated Carboxylic Acid Dienediolates by 1,2-Diiodoethane

1993

Abstract Acyclic and cyclic unsaturated carboxylic acids 1 to 4 are most easily converted to unsaturated dicarboxylic acids 5 to 8 by oxidative coupling of their diene- or triene-diolates by 1,2-diiodoethane. This procedure improves formerly reported oxidations by iodine or silver salts.

New approach to condensed pyrid-2-ones

2002

We wish to report a simple procedure for the preparation of 5-substituted-thienopyridin-7-ones and 7-substituted-1,6-naphthyridin-5(6H)-ones, in good yields, from the dianions of 3-methylthiophene-2-carboxylic and 2-methylnicotinic acids on treatment with nitriles. Brun Sanchez, Eva Maria, Eva.M.Brun@uv.es ; Gil Grau, Salvador, Salvador.Gil@uv.es ; Parra Alvarez, Margarita, Margarita.Parra@uv.es

Optical chemosensors and reagents to detect explosives

2012

[EN] This critical review is focused on examples reported from 1947 to 2010 related to the design of chromo-fluorogenic chemosensors and reagents for explosives (141 references). © 2012 The Royal Society of Chemistry.

13C NMR studies of dianions of unsaturated carboxylic acids

1994

Abstract 13C NMR Spectra of the dianions Li2-n resulting from double deprotonation of unsaturated carboxylic acids 1 to 6 by lithium dialkylamides, are examined. Higher field resonance for C2 than for C4 atoms are observed, which reveal higher elctron density at C2 than at C4, in agreement with the kinetic α-regioselectivity exhibited by these dianions on reaction with electrophiles.

A new simple chromo-fluorogenic probe for NO2 detection in air.

2015

[EN] A new chromo-fluorogenic probe, consisting of a biphenyl derivative containing both a silylbenzyl ether and a N,N-dimethylamino group, for NO2 detection in the gas phase has been developed. A clear colour change from colourless to yellow together with an emission quenching was observed when the probe reacted with NO2. A limit of detection to the naked eye of about 0.1 ppm was determined and the system was successfully applied to the detection of NO2 in realistic atmospheric conditions.

Protection against chemical submission: naked-eye detection of γ-hydroxybutyric acid (GHB) in soft drinks and alcoholic beverages

2020

Two new oxazole derivatives, able to detect γ-hydroxybutyric acid (GHB) in soft drinks and alcoholic beverages, by color and fluorescence changes, are reported.

A Simple System Based on a Thiourea-Modified Fluorescein for ω-Amino Acid Discrimination

2015

A thiourea-modified fluorescein derivative was synthesized by reaction of fluorescein isothiocyanate with 2-(2-aminoethoxy)ethan-1-ol. UV/Vis absorption and fluorescence emission spectroscopy studies demonstrated that this heteroditopic receptor was able to discriminate among linear aliphatic ω-amino acids with different chain lengths.

Azide and sulfonylazide functionalized fluorophores for the selective and sensitive detection of hydrogen sulfide

2015

[EN] Three fluorescent probes (1–3) for the selective and sensitive detection of hydrogen sulfide have been synthesized and characterized. Probe 1 is a coumarin derivative functionalized with an azide moiety whereas 2 contain the azide reactive group into a naphthalene fluorophore backbone. Probe 3 is composed also by a naphthalene fluorophore but, in this case, functionalized with a sulfonylazide reactive moiety. Probes 1 and 3 are non-fluorescent whereas 2 is weakly emissive in HEPES (10 mM, pH 7.4)–DMSO 99:1 (v/v). The emission behavior of the three probes was tested against selected anions, bio-thiols and oxidant molecules. Of all the chemical species tested, only HS− is able to induce …

A new chromo-fluorogenic probe based on BODIPY for NO2 detection in air

2014

[EN] A novel colorimetric probe for the selective and sensitive detection of NO2 in solution and in air based on a BODIPY core containing an oxime group has been prepared.

Not always what closes best opens better: mesoporous nanoparticles capped with organic gates

2019

ABSTRACT Four types of calcined MCM-41 silica nanoparticles, loaded with dyes and capped with different gating ensembles are prepared and characterized. N1 and N2 nanoparticles are loaded with rhodamine 6G and capped with bulky poly(ethylene glycol) derivatives bearing ester groups (1 and 2). N3-N4 nanoparticles are loaded with sulforhodamine B and capped with self-immolative derivatives bearing ester moieties. In the absence of esterase enzyme negligible cargo release from N1, N3 and N4 nanoparticles is observed whereas a remarkable release for N2 is obtained most likely due to the formation of an irregular coating on the outer surface of the nanoparticles. In contrast, a marked delivery i…

Perfluoroketene dithioacetals and perfluorodithiocarboxylic acid derivatives: Versatile tools for organofluorine synthesis

2007

Perfluoroketene dithioacetals are simple and versatile compounds that can be transformed into a large variety of trifluoromethyl derivatives, in particular aza- and thiaheterocycles, perhalodithiocrotonic esters, and fluorinated dithiol thiones. These unsaturated perfluorodithioesters and analogs give interesting polar cycloaddition reactions whose mechanism is strongly influenced by the fluorine substitution. This substitution plays an important role in the reactivity of saturated perfluorodithiocarboxylic acids as well. Except for the carbophilic addition of allyl Grignard reagents to perfluorocarboxamides, a domino thiophilic addition-fluoride elimination was the main reaction process. I…

Nanosensor for Sensitive Detection of the New Psychedelic Drug 25I-NBOMe.

2020

[EN] This work reports the synthesis, characterization, and sensing behavior of a hybrid nanodevice for the detection of the potent abuse drug 25I-NBOMe. The system is based on mesoporous silica nanoparticles, loaded with a fluorescent dye, functionalized with a serotonin derivative and capped with the 5-HT2A receptor antibody. In the presence of 25I-NBOMe the capping antibody is displaced, leading to pore opening and rhodamine B release. This delivery was ascribed to 5-HT2A receptor antibody detachment from the surface due to its stronger coordination with 25I-NBOMe present in the solution. The prepared nanodevice allowed the sensitive (limit of detection of 0.6 mm) and selective recogniti…

Heteroditopic chemosensor to detect γ-hydroxybutyric acid (GHB) in soft drinks and alcoholic beverages.

2021

Drug-Facilitated Sexual Assault (DFSA) is a problem of considerable dimensions on a global scale. Among the different compounds used in DFSA assaults, 4-hydroxybutyric acid (GHB) is one of the most elusive due to its physical and biological characteristics. Therefore, the development of real-time detection methods to detect GHB not only in drinks but also in urine is very important for personal and social security. Here, we report two new heteroditopic chemosensors capable of recognizing and detecting GHB in soft drinks, alcoholic beverages and synthetic urine. The compounds have two moieties: a trifluoroacetyl group and a thiourea, which are able to interact respectively with the hydroxyl …

Supplementary Material from Towards the fluorogenic detection of peroxide explosives through host–guest chemistry

2018

Towards the fluorogenic detection of peroxide explosives through host-guest chemistry

Supplementary Material from Mesoporous silica microparticles gated with a bulky azo derivative for the controlled release of dyes/drugs in colon

2018

Mesoporous silica microparticles were prepared, loaded with the dye safranin O (M-Saf) or with the drug budesonide (M-Bud) and capped by the grafting of a bulky azo derivative. Cargo release from M-Saf at different pH values (mimicking those found in the gastrointestinal tract (GIT)) in the absence or presence of sodium dithionite (a reducing agent mimicking azoreductase enzyme present in the colon) was tested. Negligible safranin O release was observed at pH 6.8 and 4.5, whereas a moderate delivery at pH 1.2 was noted and attributed to the hydrolysis of the urea bond that linked the azo derivative onto the external surface of the inorganic scaffold. Moreover, a marked release was observed …