Nitrile Anions Research Articles

Chemoselective Synthesis of Cyanoformamides from Isocyanates and a Highly Reactive Nitrile Anion Reservoir

The direct addition of a nitrile anion to isocyanates is reported for a straightforward preparation of valuable cyanoformamides. Through the proper activation of an adequate silicon‐ate complex precursor (PhMe2SiCN) with a Lewis base (potassium tert‐amylate) under Barbier‐type conditions, the cyanide was instantaneously released, thus yielding the desired motif with full chemocontrol. No particular structural restriction was noticed for engaging in the transformation a wide series of commercially available isocyanates.

Transition‐Metal‐Free Alkylation of N‐Heterocycles with Nitriles via Heteroarylphosphonium Intermediates

AbstractHeteroarylphosphonium salts are easily accessible, versatile intermediates in functionalization of N‐heterocycles. Direct C−C bond formation by net substitution of the phosphine has so far required transition metal catalysts, the use of strongly basic reagents or redox catalysis. Here we describe a C−C bond formation in direct reactions of benzothiazol‐2‐yl‐phosphonium and pyridin‐4‐yl‐phosphonium salts and nitrile anions which, together with the direct synthesis of phosphonium salts from benzothiazoles and pyridines, constitutes an efficient and simple two‐step protocol for C−H functionalization of these heterocycles under mild conditions.

Multigram Synthesis of α‐ and γ‐((Hetera)cyclo)alkylpyridines through α‐Arylation of (Hetero)aliphatic Nitriles

AbstractA systematic study on the SnAr reaction of halogenated fluoropyridines and (hetero)aliphatic nitrile anions as an approach to the synthesis of functionalized pyridines bearing a (cyclo)alkyl or saturated heterocyclic substituent by is described. The scope of the method was demonstrated on a wide range of (hetero)aliphatic nitriles (including three‐ to six‐membered cycloalkane derivatives and N‐, O‐, S‐containing saturated heterocycles) and all isomeric halogenated 2‐and 4‐fluoropyridines. High chemo‐ and regioselectivity (i. e., exclusive substitution of the fluorine atom), as well as excellent scalability of the proposed reaction sequence were demonstrated (up to 450 g for the arylation step or up to 77 g of cycloalkylpyridine over two steps in a single run). The utility of the synthesized products was illustrated in the additional functional group transformations resulting in synthetically valuable pyridine‐containing building blocks.

Importance of non-covalent interactions in a nitrile anion metal-complex based on pyridine ligands: A theoretical and experimental approach

The solvothermal synthesis and crystal structure of [bis(thiocyanato-κN)bis(tris(pyridin-2-yl-κN)amine)iron(II)] (1) are described. The structure obtained was i subjected to theoretical analysis of interaction energies and intra- and intermolecular bonding. This comprehensive study illustrates the richness of non-covalent interactions that are exhibited by nitrile anionmetal complexes. The neutral complex lies on a crystallographic two-fold axis. The iron atom is octahedrally coordinated, with two thiocyanato ligands in cis positions, and the two trispyridine ligands coordinated via the nitrogen atoms of just two of the three pyridine rings. Energy analysis of five significant dimers, supplemented by a detailed analysis of the Hirshfeld surfaces, indicates attractive interaction energies of up to 101 kJ, with the strongest dimer stabilized by bifurcated CH⋯S hydrogen bonds and additional π⋯π interactions. Solid-state and molecular quantum mechanical calculations confirm the high-spin nature of the complex, which is also reflected in the FeN bond lengths, and highlights the relevance of intramolecular ligand-ligand interactions. From a combined analysis using the Quantum Theory of Atoms in Molecules and the Non-Covalent Interaction index it was possible to identify further specific intermolecular interactions contributing the stability of the crystal structure, such as the H⋯H bonds, as well as the presence of several delocalized van der Waals forces, which are mainly of dispersive origin.

α-C-H Bond Functionalization of Unprotected Alicyclic Amines: Lewis-Acid-Promoted Addition of Enolates to Transient Imines.

Enolizable cyclic imines, obtained in situ from their corresponding lithium amides by oxidation with simple ketone oxidants, are readily alkylated with a range of enolates to provide mono- and polycyclic β-aminoketones in a single operation, including the natural product (±)-myrtine. Nitrile anions also serve as competent nucleophiles in these transformations, which are promoted by BF3 etherate. β-Aminoesters derived from ester enolates can be converted to the corresponding β-lactams.

High-level ab initio quartic force fields and spectroscopic characterization of C2N.

While it is now well established that large carbon chain species and radiative electron attachment (REA) are key ingredients triggering interstellar anion chemistry, the role played by smaller molecular anions, for which REA appears to be an unlikely formation pathway, is as yet elusive. Advancing this research undoubtedly requires the knowledge (and modeling) of their astronomical abundances which, for the case of C2N-, is largely hindered by a lack of accurate spectroscopic signatures. In this work, we provide such data for both ground -CCN-(3Σ-) and low-lying c-CNC-(1A1) isomers and their singly-substituted isotopologues by means of state-of-the-art rovibrational quantum chemical techniques. Their quartic force fields are herein calibrated using a high-level composite energy scheme that accounts for extrapolations to both one-particle and (approximate) -particle basis set limits, in addition to relativistic effects, with the final forms being subsequently subject to nuclear motion calculations. Besides standard spectroscopic attributes, the full set of computed properties includes fine and hyperfine interaction constants and can be readily introduced as guesses in conventional experimental data reduction analyses through effective Hamiltonians. On the basis of benchmark calculations performed anew for a minimal test set of prototypical triatomics and limited (low-resolution) experimental data for -CCN-(3Σ-), the target accuracies are determined to be better than 0.1% of experiment for rotational constants and 0.3% for vibrational fundamentals. Apart from laboratory investigations, the results here presented are expected to also prompt future astronomical surveys on C2N-. To this end and using the theoretically-predicted spectroscopic constants, the rotational spectra of both -CCN-(3Σ-) and c-CNC-(1A1) are derived and their likely detectability in the interstellar medium is further explored in connection with working frequency ranges of powerful astronomical facilities. Our best theoretical estimate places c-CNC-(1A1) at about 15.3 kcal mol-1 above the ground-state -CCN-(3Σ-) species.

Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C-N bonds.

Bicyclic or tricyclic nitrogen-containing heterocyclic scaffolds were constructed rapidly by intramolecular nucleophilic aromatic substitution of metallated nitriles tethered by a urea linkage to a series of electronically unactivated heterocyclic precursors. The substitution reaction constitutes a ring expansion, enabled by the conformationally constrained tether between the nitrile and the heterocycle. Attack of the metallated urea leaving group on the nitrile generates a hydantoin that bridges the polycyclic products. X-ray crystallography reveals ring-dependant strain within the hydantoin.

Interstellar nitrile anions: Detection of C3N- and C5N- in TMC-1.

We report on the first detection of C3N- and C5N- towards the cold dark core TMC-1 in the Taurus region, using the Yebes 40 m telescope. The observed C3N/C3N- and C5N/C5N- abundance ratios are ~140 and ~2, respectively; that is similar to those found in the circumstellar envelope of the carbon-rich star IRC +10216. Although the formation mechanisms for the neutrals are different in interstellar (ion-neutral reactions) and circumstellar clouds (photodissociation and radical-neutral reactions), the similarity of the C3N/C3N- and C5N/C5N- abundance ratios strongly suggests a common chemical path for the formation of these anions in interstellar and circumstellar clouds. We discuss the role of radiative electronic attachment, reactions between N atoms and carbon chain anions C n -, and that of H- reactions with HC3N and HC5N as possible routes to form C n N-. The detection of C5N- in TMC-1 gives strong support for assigning to this anion the lines found in IRC +10216, as it excludes the possibility of a metal-bearing species, or a vibrationally excited state. New sets of rotational parameters have been derived from the observed frequencies in TMC-1 and IRC +10216 for C5N- and the neutral radical C5N.

Scalable Synthesis of Esp and Rhodium(II) Carboxylates from Acetylacetone and RhCl3·xH2O.

Rhodium(II) carboxylates are privileged catalysts for the most challenging carbene-, nitrene-, and oxo-transfer reactions. In this work, we address the strategic challenges of current organic and inorganic synthesis methods to access these rhodium(II) complexes through an oxidative rearrangement strategy and a reductive ligation reaction. These studies illustrate the multiple benefits of oxidative rearrangement in the process-scale synthesis of congested carboxylates over nitrile anion alkylation reactions, and the impressive effect of inorganic additives in the reductive ligation of rhodium(III) salts.

Ion interactions and dynamics in pseudohalide based ionic liquid electrolytes containing sodium solutes

Sodium batteries have been identified as a promising, inexpensive technology for future energy storage applications. However, while an optimum electrolyte is key to a high performance device, sodium electrolytes are still at an early stage of development. Recently we explored the cycling behavior of a series of electrolytes based on a readily available dicyanamide-based ionic liquid with various sodium salts added based on fluorinated anions in order to improve sodium electrochemistry. Herein we focus on the structure and ion dynamics in the bulk electrolyte. Electrolyte solutions of 1-methyl,1-propyl pyrrolidinium dicyanamide (C3mpyDCA) and 1-methyl,1-butyl pyrrolidinium tricyanomethanide (C4mpyTCM) with various sodium salts were studied in order to understand the effect of solute anion on physicochemical behavior, in particular phase behavior, ion dynamics and inter-ionic interactions. For the DCA systems strong Na+-DCA− interactions dominate. The expectation that switching to the TCM anion would see a weakening in the electrostatic interactions (due to a higher degree of charge delocalization and larger size ion) was not observed. Indeed the TCM systems led to less salt solubility, lower ionic conductivity and greater deviation from the Walden ideal KCl line. We use infrared and NMR spectroscopies to investigate ion-ion interactions and it appears that the nitrile anion dominates the Na coordination environment for both DCA and TCM ionic liquid systems.

Reductive C-C Coupling from α,β-Unsaturated Nitriles by Intercepting Keteniminates.

We present an atom-economic strategy to catalytically generate and intercept nitrile anion equivalents using hydrogen transfer catalysis. Addition of α,β-unsaturated nitriles to a pincer-based Ru-H complex affords structurally characterized κ-N-coordinated keteniminates by selective 1,4-hydride transfer. When generated in situ under catalytic hydrogenation conditions, electrophilic addition to the keteniminate was achieved using anhydrides to provide α-cyanoacetates in high yields. This work represents a new application of hydrogen transfer catalysis using α,β-unsaturated nitriles for reductive C-C coupling reactions.

Reductive C−C Coupling from α,β‐Unsaturated Nitriles by Intercepting Keteniminates

AbstractWe present an atom‐economic strategy to catalytically generate and intercept nitrile anion equivalents using hydrogen transfer catalysis. Addition of α,β‐unsaturated nitriles to a pincer‐based Ru−H complex affords structurally characterized κ‐N‐coordinated keteniminates by selective 1,4‐hydride transfer. When generated in situ under catalytic hydrogenation conditions, electrophilic addition to the keteniminate was achieved using anhydrides to provide α‐cyanoacetates in high yields. This work represents a new application of hydrogen transfer catalysis using α,β‐unsaturated nitriles for reductive C−C coupling reactions.

Synthetic modification and cytotoxic evaluation of 2-cyano-3,4-secotriterpenic methylketones

Triterpenic methylketones, known earlier and obtainable as a result of oxidative transformation of double bond(s) in 2-cyano-3,4-secoderivatives of the lupane and 18αH-oleanane types, can be regarded as promising intermediates for synthetic transformation. This study has demonstrated the acid-catalyzed α-bromination of methylketones as capable of providing a series of various bromine-substituted ketones with different degrees of halogenation, as well as the 3,23,24-trinor-3,4-seco-18αH-oleanane acid resulting from the tribromoketone by elimination of a bromoform fragment under the same conditions. The 3,4-seco-acid ester derivative was then transformed, via the base-catalyzed intramolecular nitrile anion cyclization, to a derivative with the ketonitrile fragment in the five-membered A cycle, dehydrogenation of which afforded a cyano enone derivative. With use of the base catalysis, the 3,4-secotriterpenic bromohydrins synthesized via stereoselective reduction of 18αH-oleanane mono- and dibromoketones were transformed to C(4) epimeric terminal 4,23-epoxides. According to cytotoxic screening of the synthesized compounds, the bromoketones showed the most pronounced cytotoxic effect, whereas their derivatives partially or completely lost their cytotoxicity against the tumor cell lines under MTT test. The IC50 values characterizing the proliferation inhibition of HCT116, MS, RD TE32, and PC3 cells for the most active 2-cyano-24,24-dibromo-19β,28-epoxy-3,4-seco-3,23-dinor-18αH-olean-4-one 7 spanned the range 2.06–7.51 μM.

Synthesis, cytotoxic evaluation, and molecular docking studies of the semi-synthetic “triterpenoid-steroid” hybrids

Synthetic transformations of steroids for drug discovery and improvement of drug effectiveness have been an important part of modern medicinal chemistry and pharmaceutical sciences. Pentacyclic triterpenoids, being represented in the nature by various structures and biogenetically related to steroids, can largely expand the spectrum of biologically active steroidal agents via synthesis of the so-called “triterpenoid-steroid” hybrids. In the presented work, the nitrile anion cyclizations of 3,4-secolupane and 3,4-seco-oleanane nitriles and follow-up synthetic transformations of the cyclized products with formation of the gemm-dimethyl-free A ring “triterpenoid-steroid” hybrids were studied. Furthermore, the resulting cyclic compounds were modified at C3, C4, and/or C5 positions of ring A, as well as at C20, C28, and C30 positions of the isopropylidene moiety in the case of lupane triterpenoids. The cytotoxic effect of the synthesized compounds against seven cancer cell lines HEp-2, HCT 116, MS, RD TE32, A549, MCF7, and PC3 was evaluated. The in silico identification of potential anticancer protein targets with regard to the compounds, which were active at micromolar concentrations against tested cell lines, was carried out. The molecular docking studies showed that compound 19, which demonstrated most pronounced cytotoxicity (IC50 0.64–3.17 μM) against all tested cell lines, fits well the active sites of CDK6 and HER2/neu.

Highly enantioselective metallation-substitution alpha to a chiral nitrile.

We report the deprotonation of a chiral nitrile and reaction of the resulting chiral organometallic species with a variety of electrophiles to give highly enantiomerically enriched 2-substituted nitrile products. The nitrile was treated with TMPMgCl and the resulting anion, an asymmetric alpha cyano Grignard species, was found to be configurationally stable at low temperature for a short time (half-life several minutes at -104 °C).

ChemInform Abstract: Enantioselective Rhodium‐Catalyzed Allylic Substitution with a Nitrile Anion: Construction of Acyclic Quaternary Carbon Stereogenic Centers.

AbstractThe scalable title reaction represents the first example of an asymmetric alkylation of α‐substituted benzylic nitrile anions with nitrile malonates for the preparation of acyclic quaternary carbon stereogenic centers.

Electron Localization of Anions Probed by Nitrile Vibrations.

Localization and delocalization of electrons is a key concept in chemistry, and is one of the important factors determining the efficiency of electron transport through organic conjugated molecules, which have potential to act as "molecular wires". This, in turn, substantially influences the efficiencies of organic solar cells and other molecular electronic devices. It is also necessary to understand the electronic energy landscape and the dynamics that govern electron transport capabilities in one-dimensional conjugated chains so that we can better define the design principles for conjugated molecules for their applications. We show that nitrile ν(C≡N) vibrations respond to the degree of electron localization in nitrile-substituted organic anions by utilizing time-resolved infrared detection combined with pulse radiolysis. Measurements of a series of aryl nitrile anions allow us to construct a semiempirical calibration curve between the changes in the ν(C≡N) infrared (IR) shifts and the changes in the electronic charges from the neutral to the anion states in the nitriles; more electron localization in the nitrile anion results in larger IR shifts. Furthermore, the IR line width in anions can report a structural change accompanying changes in the electronic density distribution. Probing the shift of the nitrile ν(C≡N) IR vibrational bands enables us to determine how the electron is localized in anions of nitrile-functionalized oligofluorenes, considered as organic mixed-valence compounds. We estimate the diabatic electron transfer distance, electronic coupling strengths, and energy barriers in these mixed-valence compounds. The analysis reveals a dynamic picture, showing that the electron is moving back and forth within the oligomers with a small activation energy of ≤kBT, likely controlled by the movement of dihedral angles between monomer units. Implications for the electron transport capability in molecular wires are discussed.

Enantioselective rhodium-catalyzed allylic substitution with a nitrile anion: construction of acyclic quaternary carbon stereogenic centers.

A direct and highly enantioselective rhodium-catalyzed allylic alkylation of allyl benzoate with α-substituted benzyl nitrile pronucleophiles is described. This simple protocol provides a new approach toward the synthesis of acyclic quaternary carbon stereogenic centers and provides the first example of the direct asymmetric alkylation of a nitrile anion. The synthetic utility of the nitrile products is amply demonstrated through conversion to various functional groups and the synthesis of a bioactive aryl piperazine in an expeditious four-step sequence.

Functionalization, cyclization and antiviral activity of A-secotriterpenoids

Triterpene derivatives with an α,β-alkenenitrile moiety in the five-membered ring A have been synthesized by nitrile anion cyclizations of 1-cyano-2,3-secotriterpenoids. Oxime-containing precursors, 2,3-secointermediates and five-membered ring A products of cyclizations were screened for in vitro antiviral activity against enveloped viruses – influenza A virus and human immunodeficiency virus type I (HIV-1). Lupane ketoxime and the 2,3-secolupane C-3 aldoxime which possess antiviral activities against both influenza A virus (EC50 12.9–18.2 μM) and HIV-1 (EC50 0.06 μM) were the most promising compounds.

Aryl nitrenium ions from N-alkyl-N-arylamino-diazonium precursors: synthesis and reactivity

A means of generating an N-alkyl-N-arylaminodiazonium ion, which then loses nitrogen to form a reactive aryl nitrenium intermediate, is described. In this sequence, a set of triazenyl acetonitriles was synthesized by nucleophilic addition of a nitrile anion to an aryl azide followed by temperature-dependent alkylation at either of two nucleophilic triazenyl nitrogen atoms. An α,α-disubstituted acetonitrile and N-arylaminodiazonium moiety (or aryl nitrenium ion upon loss of N2) are embedded in the resulting 1,3,3-trisubsituted triazene, which undergoes liberation and recombination of these two components under acidic conditions to yield an α-arylated acetonitrile containing an all-carbon-quaternary center. We propose that the N-alkyl-N-arylaminodiazonium ion loses nitrogen to generate an aryl nitrenium species, which then reacts with an α,α-disubstituted acetonitrile either at the para- or meta-position of the aromatic ring to afford p-alkylaminoaryl acetonitrile derivatives or 3,3-substituted 1-methylindolin-2-imines, depending on the substrates and conditions.