Simple Nitriles Research Articles

Regio- and Enantioselective Intermolecular Aminofluorination of Alkenes via Iodine(I)/Iodine(III) Catalysis.

The regio‐ and enantio‐selective, intermolecular vicinal fluoroamination of α‐trifluoromethyl styrenes has been achieved by enantioselective II/IIII catalysis. Leveraging C 2‐symmetric resorcinol‐based aryl iodide catalysts, it has been possible to intercept the transient iodonium intermediate using simple nitriles, which function as both the solvent and nucleophile. In situ Ritter reaction provides direct access to the corresponding amides (up to 89 % yield, e.r. 93 : 7). This main group catalysis paradigm inverts the intrinsic regioselectivity of the uncatalyzed process, thereby providing facile access to tertiary, benzylic stereocenters bearing both CF3 and F groups. Privileged phenethylamine pharmacophores can be generated in which there is complete local partial charge inversion (CF3 δ−/F δ− versus CH3 δ+/H δ+). Crystallographic analyses of representative β‐fluoroamide products reveal highly pre‐organized conformations that manifest the stereoelectronic gauche effect.

Tandem Synthesis of Tetrasubstituted NH Pyrroles from Simple Nitriles.

An efficient tandem route to obtain tetrasubstituted NH pyrroles in a one-pot manner has been developed, staring from simple nitriles, ethyl bromoacetates, and zinc. This reaction involves oxidative dimerization of the zinc bromide complex of β-enaminoesters using cerium ammonium nitrate (CAN) as an oxidant, affording 2,3,4,5-tetrasubstituted pyrroles in yields up to 91%.

Modeling transmission windows in Titan’s lower troposphere: Implications for infrared spectrometers aboard future aerial and surface missions

From orbit, the visibility of Titan’s surface is limited to a handful of narrow spectral windows in the near-infrared (near-IR), primarily from the absorption of methane gas. This has limited the ability to identify specific compounds on the surface—to date Titan’s bulk surface composition remains unknown. Further, understanding of the surface composition would provide insight into geologic processes, photochemical production and evolution, and the biological potential of Titan’s surface. One approach to obtain wider spectral coverage with which to study Titan’s surface is by decreasing the integrated column of absorbers (primarily methane) and scatterers between the observer and the surface. This is only possible if future missions operate at lower altitudes in Titan’s atmosphere. Herein, we use a radiative transfer model to measure in detail the absorption through Titan’s atmosphere from different mission altitudes, and consider the impacts this would have for interpreting reflectance measurements of Titan’s surface. Over our modeled spectral range of 0.4–10 μm, we find that increases in the width of the transmission windows as large as 317% can be obtained for missions performing remote observations at the surface. However, any appreciable widening of the windows requires onboard illumination. Further, we make note of possible surface compounds that are not currently observable from orbit, but could be identified using the wider windows at low altitudes. These range from simple nitriles such as cyanoacetylene, to building blocks of amino acids such as urea. Finally, we discuss the implications that the identifications of these compounds would have for Titan science.

π‐Conjugated Triazenes and Nitriles: Simple Photoinduced Synthesis of Anilides Using Mild and Metal‐Free Conditions

AbstractA simple, clean, direct, photochemical, and metal‐free approach to produce structurally diverse anilides in good to excellent yields (up to 99%), by utilizing π‐conjugated triazene reactivity and simple nitriles is presented. Interestingly, natural sunlight is also shown to provide effective delivery of amides, with yields up to 99%.

Chemical bonding in cuprous complexes with simple nitriles: octet rule and resonance concepts versus quantitative charge-redistribution analysis.

Chemical bonding in a set of six cuprous complexes with simple nitriles (CN-, HNC, HCN, CH3NC, and CH3CN) is investigated by means of a recently devised analysis scheme framed in density-functional theory and quantitatively singling out concurrent charge flows such as σ donation and π backdonation. The results of our analysis are comparatively assessed against qualitative models for charge redistribution based on the popular concepts of octet rule and resonance structures, and the relative importance of different charge-flow channels relating to σ donation, π back-donation, polarization, and hyperconjugation is discussed on a quantitative basis.

Organic thiocyanates - glucosinolate enzymatic degradation products or artefacts of the isolation procedure?

Glucosinolates are abundant in plants of the order Brassicales, and they are degraded by myrosinases into various organic breakdown products: isothiocyanates, thiocyanates, nitriles, etc., depending on their structure, conditions of hydrolysis, the presence of certain protein cofactors. Their most common hydrolysis products are isothiocyanates, while simple nitriles, epithionitriles, and thiocyanates are produced occasionally. Organic thiocyanates are described from a very limited number of Brassicales taxa. Up to now benzyl, (4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl, 4- methylthiobutyl, and allyl thiocyanates were reported as products of glucosinolates autolysis. The present review summarizes the knowledge on the mechanism of organic thiocyanate formation from the corresponding thioglucosides. The enzymatic formation of organic thiocyanates is believed to be enabled by thiocyanate-forming protein (TFP), but they could be formed via metabolic routes that do not involve TFP. All of the reported thiocyanates are produced from stable (carbo)cationic species that allow an isomerization of an isothiocyanate to thiocyanate, and vice versa. Although the possibility that thiocyanates can be biosynthesized in plats under certain conditions cannot be dismissed, allyl thiocyanate can be a thermal isomerization artefact of the original isothiocyanate that is formed in the heated zones of the gas chromatograph, while other thiocyanates could form in an aqueous medium via heterolytic dissociation to ambident nucleophilic SCN- and its recapture. One should always be aware of this analytical shortcoming when concluding on the presence and quantity of these specific (iso)thiocyanantes in the analyzed sample.

Free Radical Addition of Nitrile, Ketone, and Ester to Alkyne and the Selectivity Discussion.

A general and practical atom transfer radical addition (ATRA) of simple nitriles, ketones, and esters to alkynes was developed. It can allow an efficient access to a wide range of β,γ-unsaturated nitriles, ketones, and esters. The unique chemoselectivity in this system is also discussed.

Iron is a centrally bound cofactor of specifier proteins involved in glucosinolate breakdown.

Glucosinolates, a group of sulfur-rich thioglucosides found in plants of the order Brassicales, have attracted a lot of interest as chemical defenses of plants and health promoting substances in human diet. They are accumulated separately from their hydrolyzing enzymes, myrosinases, within the intact plant, but undergo myrosinase-catalyzed hydrolysis upon tissue disruption. This results in various biologically active products, e.g. isothiocyanates, simple nitriles, epithionitriles, and organic thiocyanates. While formation of isothiocyanates proceeds by a spontaneous rearrangement of the glucosinolate aglucone, aglucone conversion to the other products involves specifier proteins under physiological conditions. Specifier proteins appear to act with high specificity, but their exact roles and the structural bases of their specificity are presently unknown. Previous research identified the motif EXXXDXXXH as potential iron binding site required for activity, but crystal structures of recombinant specifier proteins lacked the iron cofactor. Here, we provide experimental evidence for the presence of iron (most likely Fe2+) in purified recombinant thiocyanate-forming protein from Thlaspi arvense (TaTFP) using a Ferene S-based photometric assay as well as Inductively Coupled Plasma-Mass Spectrometry. Iron binding and activity depend on E266, D270, and H274 suggesting a direct interaction of Fe2+ with these residues. Furthermore, we demonstrate presence of iron in epithiospecifier protein and nitrile-specifier protein 3 from Arabidopsis thaliana (AtESP and AtNSP3). We also present a homology model of AtNSP3. In agreement with this model, iron binding and activity of AtNSP3 depend on E386, D390, and H394. The homology model further suggests that the active site of AtNSP3 imposes fewer restrictions to the glucosinolate aglucone conformation than that of TaTFP and AtESP due to its larger size. This may explain why AtNSP3 does not support epithionitrile or thiocyanate formation, which likely requires exact positioning of the aglucone thiolate relative to the side chain.

Mineral Grains, Dimples, and Hot Volcanic Organic Streams: Dynamic Geological Backstage of Macromolecular Evolution

The hypothesis of hot volcanic organic stream as the most probable and geologically plausible environment for abiogenic polycondensation is proposed. The primary synthesis of organic compounds is considered as result of an explosive volcanic (perhaps, meteorite-induced) eruption. The eruption was accompanied by a shock wave propagating in the primeval atmosphere and resulting in the formation of hot cloud of simple organic compounds-aldehydes, alcohols, amines, amino alcohols, nitriles, and amino acids-products, which are usually obtained under the artificial conditions in the spark-discharge experiments. The subsequent cooling of the organic cloud resulted in a gradual condensation and a serial precipitation of organic compounds (in order of decreasing boiling point values) into the liquid phase forming a hot, viscous and muddy organic stream (named "lithorheos"). That stream-even if the time of its existence was short-is considered here as a geologically plausible environment for abiogenic polycondensation. The substances successively prevailing in such a stream were cyanamide, acetamide, formamide, glycolonitrile, acetonitrile. An important role was played by mineral (especially, phosphate-containing) grains (named "lithosomes"), whose surface was modified with heterocyclic nitrogen compounds synthesized in the course of eruption. When such grains got into hot organic streams, their surface catalytic centers (named "lithozymes") played a decisive role in the emergence, facilitation and maintenance of prebiotic reactions and key processes characteristic of living systems. Owing to its cascade structure, the stream was a factor underlying the formation of mineral-polymeric aggregates (named "lithocytes") in the small natural streambed cavities (dimples)-as well as a factor of their further spread within larger geological locations which played a role of chemo-ecological niches. All three main stages of prebiotic evolution (primary organic synthesis, polycondensation, and formation of proto-cellular structures) are combined within a common dynamic geological process. We suppose macromolecular evolution had an extremely fast, "flash" start: the period from volcanic eruption to formation of lithocyte "populations" took not million years but just several tens of minutes. The scenario proposed can be verified experimentally with a three-module setup working with principles of dynamic (flow) chemistry in its core element.

Initiation of ER Body Formation and Indole Glucosinolate Metabolism by the Plastidial Retrograde Signaling Metabolite, MEcPP

Plants have evolved tightly regulated signaling networks to respond and adapt to environmental perturbations, but the nature of the signaling hub(s) involved have remained an enigma. We have previously established that methylerythritol cyclodiphosphate (MEcPP), a precursor of plastidial isoprenoids and a stress-specific retrograde signaling metabolite, enables cellular readjustments for high-order adaptive functions. Here, we specifically show that MEcPP promotes two Brassicaceae-specific traits, namely endoplasmic reticulum (ER) body formation and induction of indole glucosinolate (IGs) metabolism selectively, via transcriptional regulation of key regulators NAI1 for ER body formation and MYB51/122 for IGs biosynthesis). The specificity of MEcPP is further confirmed by the lack of induction of wound-inducible ER body genes as well as IGs by other altered methylerythritol phosphate pathway enzymes. Genetic analyses revealed MEcPP-mediated COI1-dependent induction of these traits. Moreover, MEcPP signaling integrates the biosynthesis and hydrolysis of IGs through induction of nitrile-specifier protein1 and reduction of the suppressor, ESM1, and production of simple nitriles as the bioactive end product. The findings position the plastidial metabolite, MEcPP, as the initiation hub, transducing signals to adjust the activity of hard-wired gene circuitry to expand phytochemical diversity and alter the associated subcellular structure required for functionality of the secondary metabolites, thereby tailoring plant stress responses.

NSP-Dependent Simple Nitrile Formation Dominates upon Breakdown of Major Aliphatic Glucosinolates in Roots, Seeds, and Seedlings of Arabidopsis thaliana Columbia-0.

One of the best-studied plant defense systems, the glucosinolate-myrosinase system of the Brassicales, is composed of thioglucosides known as glucosinolates and their hydrolytic enzymes, the myrosinases. Tissue disruption brings these components together, and bioactive products are formed as a consequence of myrosinase-catalyzed glucosinolate hydrolysis. Among these products, isothiocyanates have attracted most interest as chemical plant defenses against herbivores and pathogens and health-promoting compounds in the human diet. Previous research has identified specifier proteins whose presence results in the formation of alternative product types, e.g., nitriles, at the expense of isothiocyanates. The biological roles of specifier proteins and alternative breakdown products are poorly understood. Here, we assessed glucosinolate breakdown product profiles obtained upon maceration of roots, seedlings and seeds of Arabidopsis thaliana Columbia-0. We identified simple nitriles as the predominant breakdown products of the major endogenous aliphatic glucosinolates in root, seed, and seedling homogenates. In agreement with this finding, genes encoding nitrile-specifier proteins (NSPs) are expressed in roots, seeds, and seedlings. Analysis of glucosinolate breakdown in mutants with T-DNA insertions in any of the five NSP genes demonstrated, that simple nitrile formation upon tissue disruption depended almost entirely on NSP2 in seeds and mainly on NSP1 in seedlings. In roots, about 70–80% of the nitrile-forming activity was due to NSP1 and NSP3. Thus, glucosinolate breakdown product profiles are organ-specifically regulated in A. thaliana Col-0, and high proportions of simple nitriles are formed in some parts of the plant. This should be considered in future studies on biological roles of the glucosinolate-myrosinase system.

Crystal structure of the Epithiospecifier Protein, ESP from Arabidopsis thaliana provides insights into its product specificity

Specifier proteins are important components of the glucosinolate-myrosinase system, which mediate plant defense against herbivory and pathogen attacks. Upon tissue disruption, glucosinolates are hydrolyzed to instable aglucones by myrosinases, and then aglucones will rearrange to form defensive isothiocyanates. Specifier proteins can redirect this reaction to form other products, such as simple nitriles, epithionitriles and organic thiocyanates instead of isothiocyanates based on the side chain structure of glucosinolate and the type of the specifier proteins. Nevertheless, the molecular mechanism underlying the different product spectrums of various specifier proteins was not fully understood. Here in this study, we solved the crystal structure of the Epithiospecifier Protein, ESP from Arabidopsis thaliana (AtESP) at 2.3 Å resolution. Structural comparisons with the previously solved structure of thiocyanate forming protein, TFP from Thlaspi arvense (TaTFP) reveal that AtESP shows a dimerization pattern different from TaTFP. Moreover, AtESP harbors a slightly larger active site pocket than TaTFP and several residues around the active site are different between the two proteins, which might account for the different product spectrums of the two proteins. Together, our structural study provides important insights into the molecular mechanisms of specifier proteins and shed light on the basis of their different product spectrums.

Radical-promoted site-specific cross dehydrogenative coupling of heterocycles with nitriles.

A first free-radical triggered site-specific cross dehydrogenative coupling reaction of heterocycles with simple nitriles is developed. It allows efficient and facile access to various C-2 cyanoalkylated furans, thiophenes, indoles, and pyrroles. The extremely high selectivities in this case indicate that functionalization of an inert C-H bond could be well-controlled by radical initiation.

Tandem Synthesis of Polysubstituted Pyridines via the Indium(III)‐Triflate‐Catalyzed Cycloaddition/Oxidative Aromatization of Blaise Reaction Intermediates with α,β‐Unsaturated Ketones

AbstractA tandem one‐pot method for the construction of polysubstituted pyridines with complete control of the substitution pattern has been developed. The zinc bromide β‐enamino ester intermediates of the Blaise reaction of simple nitriles with a Reformatsky reagent undergo Michael addition with conjugated ketones in the presence of a catalytic amount of In(OTf)3. Final intramolecular cyclization and oxidative aromatization yields polysubstituted pyridines in this tandem one‐pot cascade.

Molecular models and mutational analyses of plant specifier proteins suggest active site residues and reaction mechanism

As components of the glucosinolate-myrosinase system, specifier proteins contribute to the diversity of chemical defenses that have evolved in plants of the Brassicales order as a protection against herbivores and pathogens. Glucosinolates are thioglucosides that are stored separately from their hydrolytic enzymes, myrosinases, in plant tissue. Upon tissue disruption, glucosinolates are hydrolyzed by myrosinases yielding instable aglucones that rearrange to form defensive isothiocyanates. In the presence of specifier proteins, other products, namely simple nitriles, epithionitriles and organic thiocyanates, can be formed instead of isothiocyanates depending on the glucosinolate side chain structure and the type of specifier protein. The biochemical role of specifier proteins is largely unresolved. We have used two thiocyanate-forming proteins and one epithiospecifier protein with different substrate/product specificities to develop molecular models that, in conjunction with mutational analyses, allow us to propose an active site and docking arrangements with glucosinolate aglucones that may explain some of the differences in specifier protein specificities. Furthermore, quantum-mechanical calculations support a reaction mechanism for benzylthiocyanate formation including a catalytic role of the TFP involved. These results may serve as a basis for further theoretical and experimental investigations of the mechanisms of glucosinolate breakdown that will also help to better understand the evolution of specifier proteins from ancestral proteins with functions outside glucosinolate metabolism.

ChemInform Abstract: One‐Pot Nitrile Aldolization/Hydration Operation Giving β‐Hydroxy Carboxamides.

AbstractA variety of aromatic and aliphatic β‐hydroxy carboxamides is smoothly prepared by aldol reaction of aldehydes with simple nitriles and subsequent hydration of the nitrile functionality.

A thiocyanate-forming protein generates multiple products upon allylglucosinolate breakdown in Thlaspi arvense

Glucosinolates, amino acid-derived thioglycosides found in plants of the Brassicales order, are one of the best studied classes of plant secondary metabolites. Together with myrosinases and supplementary proteins known as specifier proteins, they form the glucosinolate–myrosinase system that upon tissue damage gives rise to a number of biologically active glucosinolate breakdown products such as isothiocyanates, epithionitriles and organic thiocyanates involved in plant defense. While isothiocyanates are products of the spontaneous rearrangement of the glucosinolate aglycones released by myrosinase, the formation of epithionitriles and organic thiocyanates depends on both myrosinases and specifier proteins. Hydrolysis product profiles of many glucosinolate-containing plant species indicate the presence of specifier proteins, but only few have been identified and characterized biochemically. Here, we report on cDNA cloning, heterologous expression and characterization of TaTFP, a thiocyanate-forming protein (TFP) from Thlaspi arvense L. (Brassicaceae), that is expressed in all plant organs and can be purified in active form after heterologous expression in Escherichia coli. As a special feature, this protein promotes the formation of allylthiocyanate as well as the corresponding epithionitrile upon myrosinase-catalyzed hydrolysis of allylglucosinolate, the major glucosinolate of T. arvense. All other glucosinolates tested are converted to their simple nitriles when hydrolyzed in the presence of TaTFP. Despite its ability to promote allylthiocyanate formation, TaTFP has a higher amino acid sequence similarity to known epithiospecifier proteins (ESPs) than to Lepidium sativum TFP. However, unlike Arabidopsis thaliana ESP, its activity in vitro is not strictly dependent on Fe 2+ addition to the assay mixtures. The availability of TaTFP in purified form enables future studies to be aimed at elucidating the structural bases of specifier protein specificities and mechanisms. Furthermore, identification of TaTFP shows that product specificities of specifier proteins can not be predicted based on amino acid sequence similarity and raises interesting questions about specifier protein evolution.

One‐Pot Nitrile Aldolization/Hydration Operation Giving β‐Hydroxy Carboxamides

A variety of aromatic and aliphatic β-hydroxy carboxamides is smoothly prepared by aldol reaction of aldehydes with simple nitriles and subsequent hydration of the nitrile functionality.

ChemInform Abstract: Synthesis of Aryl Ketones by Palladium(II)‐Catalyzed Decarboxylative Addition of Benzoic Acids to Nitriles.

AbstractA new rapid synthesis of (het)aryl ketones (III) and (V) is achieved by reaction of ortho‐substituted (het)arylcarboxylic acids with simple nitriles in the presence of a Pd(II)—methylbipyridine catalyst system.

Key Role of Fe2+ in Epithiospecifier Protein Activity

The chemical nature of the hydrolysis products from the glucosinolate-myrosinase system depends on the presence or absence of supplementary proteins such as epithiospecifier proteins (ESPs). ESPs promote the formation of epithionitriles from terminal alkenyl glucosinolates and, as recent evidence suggests, simple nitriles at the expense of isothiocyanates. From a human health perspective isothiocyanates are the most important because they are major inducers of carcinogen-detoxifying enzymes. Fe(2+) is an essential factor in ESP activity, although several recent studies have highlighted discrepancies in the understanding of the ESP-iron interaction. To investigate further the role iron species play in regulating ESP activity, four ESP-containing seedpowders were analyzed for ESP and myrosinase activities, endogenous iron content, and glucosinolate degradation products after the addition of iron species, specific chelators, and reducing agents. For the first time this paper shows the effect of these additions on the hydrolysis of individual glucosinolates that constitute the total pool. Aged seeds and 3-day seedlings were also tested to investigate the effects of seed storage and early plant development on iron levels and ESP activity. The four ESP-containing plant systems tested gave two distinctive responses, thus providing strong evidence that ESPs vary markedly in their Fe(2+) requirement for activity. The results also indicated that reduction of ferric to ferrous iron drives variations in ESP activity during early plant development. The reverse oxidation reaction provided a convincing explanation for the loss of ESP activity during seed storage. Aged seeds produced seedlings with substantially lower ESP activity, and there was a concomitant loss in germination rate. It was concluded that manipulation of endogenous iron levels of ESP-containing plants could increase the conversion of glucosinolates to isothiocyanates and enhance potential health benefits.