Prototropic Shift Research Articles

A series of ruthenium(II) organometallic complexes incorporating pyridine-2-carboxylato ligand: Detailed spectroscopic and computional studies

The reaction of Ru(κ2C,O-RL)(PPh3)2(CO)Cl, 1 with excess sodium salt of pyridine-2-carboxylic acid (Napic) furnishes the complexes of the type Ru(κ1C-RL)(PPh3)2(CO) (pic), 2(R) with excellent yield (κ2C,O-RL is C6H2O-2-CHNHC6H4R(p)-3-Me-5, κ1C-RL is C6H2OH-2-CHNC6H4R(p)-3-Me-5 and R is Me, OMe, Cl). The chelation of pic is attended with the cleavage of Ru–O and Ru–Cl bonds and iminium–phenolato→imine–phenol prototropic shift. The 1 ​→ ​2 conversion is irreversible and the type 2 species are thermodynamically more stable than the acetate, nitrite and nitrate complexes of 1. The spectral (UV–vis, IR, 1H NMR) and electrochemical data of the complexes are reported. In dichloromethane solution the complexes display one quasi–reversible RuIII/RuII cyclic voltammetric response with E1/2 in the range 0.72–0.80 ​V vs. Ag/AgCl. The crystal and molecular structure of Ru(κ1C-MeOL)(PPh3)2(CO)(pic)∙CH3CN is reported which revealed distorted octahedral RuC2P2NO coordination sphere. The pairs (P, P), (C, O) and (C, N) define the three trans directions. The electronic structures of the complexes are also scrutinized by density functional theory (DFT) and time–dependent density functional theory (TD–DFT) calculations.

Visible-Light-Mediated Heterocycle Functionalization via Geometrically Interrupted [2+2] Cycloaddition.

The [2+2] photocycloaddition is the most valuable and intensively investigated photochemical process. Here we demonstrate that irradiation of N‐acryloyl heterocycles with blue LED light (440 nm) in the presence of an IrIII complex leads to efficient and high yielding fused γ‐lactam formation across a range of substituted heterocycles. Quantum calculations show that the reaction proceeds via cyclization in the triplet excited state to yield a 1,4‐diradical; intersystem crossing leads preferentially to the closed shell singlet zwitterion. This is geometrically restricted from undergoing recombination to yield a cyclobutane by the planarity of the amide substituent. A prototropic shift leads to the observed bicyclic products in what can be viewed as an interrupted [2+2] cycloaddition.

Visible‐Light‐Mediated Heterocycle Functionalization via Geometrically Interrupted [2+2] Cycloaddition

AbstractThe [2+2] photocycloaddition is the most valuable and intensively investigated photochemical process. Here we demonstrate that irradiation of N‐acryloyl heterocycles with blue LED light (440 nm) in the presence of an IrIII complex leads to efficient and high yielding fused γ‐lactam formation across a range of substituted heterocycles. Quantum calculations show that the reaction proceeds via cyclization in the triplet excited state to yield a 1,4‐diradical; intersystem crossing leads preferentially to the closed shell singlet zwitterion. This is geometrically restricted from undergoing recombination to yield a cyclobutane by the planarity of the amide substituent. A prototropic shift leads to the observed bicyclic products in what can be viewed as an interrupted [2+2] cycloaddition.

Spirocyclic Tetramates by Sequential Knoevenagel and [1,5]-Prototropic Shift.

Highly functionalized spirocyclic tetramates were prepared via a sequential Knoevenagel reaction and [1,5]-prototropic shift (T-reaction) of bicyclic tetramates. While these compounds isomerize in solution, stable analogues can be prepared via an appropriate choice of substituents. Further modification of these compounds allows for the introduction of aromatic groups, making them suitable as skeletons for application in medicinal chemistry.

Spectroscopic, structural, electrochemical, and cytotoxicity studies on dithiocarbamato-chelated ruthenium organometallics incorporating imine-phenol function

The heterogeneous phase reaction of [Ru(η2-RL)(PPh3)2(CO)Cl] (1) with the sodium salts of dimethyl dithiocarbamate (MeDTC), diethyl dithiocarbamate (EtDTC), and pyrrolidine dithiocarbamate (PyrDTC) ligands led to the isolation of bright-yellow crystalline solids of type [Ru(η1-RL)(PPh3)2(CO)(R′DTC)] (2(R)(R′DTC)) where η2-RL is C6H2O-2-CHNHC6H4R(p)-3-Me-5, η1-RL is C6H2OH-2-CHNC6H4R(p)-3-Me-5, R is Me, OMe, Cl, and R′ = Me, Et, Pyr. The binding of dithiocarbamate ligand is accompanied by the dissociation of Ru-O and Ru-Cl bonds along with concomitant prototropic shift from iminium–phenolato to imine–phenol motif. The reaction also involves a sterically controlled change in rotational conformation in going to the products. The X-ray crystal structure of [Ru(η1-ClL)(PPh3)2(CO)(EtDTC)] (2(Cl)(EtDTC)) has been described here. An account of different spectral (UV–Vis, IR, NMR) and electrochemical data of the complexes are also asserted. Density functional theory (DFT) and time-dependent density functional theory (TD-DFT) analyses were performed to scrutinize the electronic structure and the absorption spectra of the complexes. One of the dithiocarbamato complexes has also been found to have in vitro antiproliferative properties against MDA-MB-231 breast cancer cell line which was determined by MTT assay. Cell death occurs mainly through apoptosis and flow cytometric analysis indicates that the complex induces cell cycle arrest in the sub G0/G1 phase.

Pyridine-2-olato chelated ruthenium(II) organometallics incorporating imine-phenol function: spectroscopic, structural, electrochemical, and theoretical studies

The heterogeneous phase reaction of excess sodium salt of 2-hydroxypyridine (OHpy) with [Ru(κ2C,O-RL)(PPh3)2(CO)Cl] (1) afforded complexes of the type [Ru(κ1C-RL)(PPh3)2(CO)(Opy)] (2) in excellent yield [κ2C,O-RL is 4-methyl-6-((N-R-arylimino)methyl)phenolato-C2,O), κ1C-RL is 4-methyl-6-((N-R-arylimino)methyl)phenol-C2) and R is H, Me, OMe, Cl]. The chelation of Opy is attended with the cleavage of Ru-O and Ru-Cl bonds and iminium-phenolato → imine-phenol prototropic shift. The 1→2 conversion is irreversible and the type 2 species are thermodynamically more stable than the acetate, nitrite, and nitrate complexes of 1. The spectral (UV-vis, IR, NMR) and electrochemical data of the complexes are reported. In dichloromethane solution the complexes display one quasi-reversible RuIII/RuII cyclic voltammetric response with E1/2 in the range 0.65–0.69 V versus Ag/AgCl. The crystal and molecular structures of [Ru(κ1C-HL)(PPh3)2(CO)(Opy)]·2C6H6·0.5H2O, 2(H)·2C6H6·0.5H2O and [Ru(κ1C-ClL)(PPh3)2(CO)(Opy)]·2C6H6·0.25H2O, 2(Cl)·2C6H6·0.25H2O are reported, which revealed a distorted octahedral RuC2P2NO coordination sphere. The pairs (P,P), (C,O), and (C,N) define the three trans directions. The electronic structures of the complexes are also scrutinized by density functional theory.

Designing Reactions with Post-Transition-State Bifurcations: Asynchronous Nitrene Insertions into C–C σ Bonds

Summary Discoveries of chemical reactions with potential energy surfaces with post-transition-state bifurcations are increasing in frequency. Although such potential energy surface features are often discovered accidentally, we demonstrate here that they can be designed rationally. We describe a process for designing such reactions and apply it to the design of a nitrene addition/alkyl-shift reaction with a post-transition state bifurcation. We examine substituent effects on this reaction and propose a dynamics-based model for selectivity control.

The Hydrazine–O2 Redox Couple as a Platform for Organocatalytic Oxidation: Benzo[c]cinnoline‐Catalyzed Oxidation of Alkyl Halides to Aldehydes

AbstractAn organocatalytic oxidation platform that capitalizes on the capacity of hydrazines to undergo rapid autoxidation to diazenes is described. Commercially available benzo[c]cinnoline is shown to catalyze the oxidation of alkyl halides to aldehydes in a novel mechanistic paradigm involving nucleophilic attack, prototropic shift, and hydrolysis. The hydrolysis and reoxidation events occur readily with only adventitious oxygen and water. A survey of the scope of viable substrates is shown along with mechanistic and computational studies that give insight into this mode of catalysis.

The Hydrazine-O2 Redox Couple as a Platform for Organocatalytic Oxidation: Benzo[c]cinnoline-Catalyzed Oxidation of Alkyl Halides to Aldehydes.

An organocatalytic oxidation platform that capitalizes on the capacity of hydrazines to undergo rapid autoxidation to diazenes is described. Commercially available benzo[c]cinnoline is shown to catalyze the oxidation of alkyl halides to aldehydes in a novel mechanistic paradigm involving nucleophilic attack, prototropic shift, and hydrolysis. The hydrolysis and reoxidation events occur readily with only adventitious oxygen and water. A survey of the scope of viable substrates is shown along with mechanistic and computational studies that give insight into this mode of catalysis.

Empirical Valence Bond Simulations Suggest a Direct Hydride Transfer Mechanism for Human Diamine Oxidase.

Diamine oxidase (DAO) is an enzyme involved in the regulation of cell proliferation and the immune response. This enzyme performs oxidative deamination in the catabolism of biogenic amines, including, among others, histamine, putrescine, spermidine, and spermine. The mechanistic details underlying the reductive half-reaction of the DAO-catalyzed oxidative deamination which leads to the reduced enzyme cofactor and the aldehyde product are, however, still under debate. The catalytic mechanism was proposed to involve a prototropic shift from the substrate–Schiff base to the product–Schiff base, which includes the rate-limiting cleavage of the Cα–H bond by the conserved catalytic aspartate. Our detailed mechanistic study, performed using a combined quantum chemical cluster approach with empirical valence bond simulations, suggests that the rate-limiting cleavage of the Cα–H bond involves direct hydride transfer to the topaquinone cofactor—a mechanism that does not involve the formation of a Schiff base. Additional investigation of the D373E and D373N variants supported the hypothesis that the conserved catalytic aspartate is indeed essential for the reaction; however, it does not appear to serve as the catalytic base, as previously suggested. Rather, the electrostatic contributions of the most significant residues (including D373), together with the proximity of the Cu2+ cation to the reaction site, lower the activation barrier to drive the chemical reaction.

<i>Ab initio</i> and DFT Study of Prototropic and Metallotropic 1,5-Shifts of Isolobal Cyclopentadienyl Derivatives

The structures, energies and sigmatropic behaviour of η 1 -cyclopenta-2,4-dienylborane (1) and η 1 -cyclopentadiene-three carbonyl cobalt (I) (2) were examined using DFT-B3LYP/6-311+G ** level of theory. Both BH 2 and Co(CO) 3 fragments in these compounds are isolobal. Results indicate that -BH2 and -Co(CO)3 in sigmatropic shifts had similar behaviour. Furthermore, in compounds 1 and 2, prototropic shifts have similar mechanisms. In compounds 1 and 2, metallotrotropic shift acts faster than prototropic shift. Migration of proton and Co(CO) 3 took place through suprafacial [1,5]-sigmatropic mechanism, but -BH 2 shift took place through antrafacial [1,3]-rearrangement. The barrier energies of prototropic shift in compounds 1 and 2 are 15.94 kcal mol -1 and 33.13 kcal mol -1 respectively. These energies are lower than those of brotropic shifts in compound 1 (0.16 kcal mol -1 ) or migration of CO(CO) 3 in compound 2 (3.76 kcal mol -1 ).

α-Amination and the 5-exo-trig cyclization reaction of sulfur-containing Schiff bases with N-phenyltriazolinedione and their anti-lipid peroxidation activity

Triazolinedione quenches efficiently the 1,2-dipoles from Schiff bases of glycine esters which are formed via a [1,2-H]-prototropic shift of their α-hydrogens, and affords the respective α-aminated products in good yields. Competition experiments show a stabilization of the 1,2-dipole from the sulfide substituent. 5-exo-trig cyclization of N-PhTAD with Schiff bases of other amino acids gave triazolines. The antioxidative and lipoxygenase inhibitory activities of the novel synthesized compounds were studied.

Easy construction of furo[2,3-f]isoindole core by the IMDAV reaction between 3-(furyl)allylamines and α,β-unsaturated acid anhydrides

The vinylogues of furfurylamines, easily available in two steps from furylacroleins (3-(furyl)allylamines), were studied in a tandem N-acylation/intramolecular [4+2] cycloaddition with maleic, pyrocinchonic, and citraconic anhydrides, as well as furylacryloyl and cinnamoyl chlorides. By using a domino reaction of 3-(furyl)allylamines and α,β-unsaturated acid anhydrides under mild conditions, various hexahydro-4H-furo[2,3-f]isoindoles and their carboxyl derivatives were synthesized efficiently. The domino sequence includes three steps: acylation of the nitrogen atom in 3-(furyl)allylamines, intramolecular Diels–Alder cycloaddition in the resulting N-acyl vinylfurans (IMDAV reaction), and prototropic shift of the adducts followed by recovery of aromaticity of the furan nucleus. The key step, IMDAV reaction, leads to the target products, furo[2,3-f]isoindoles, diastereoselectively and with relatively high yields.

Acetylacetonato chelated ruthenium organometallics incorporating imine–phenol function: Spectroscopic, structural, electrochemical and cytotoxicity studies

The heterogeneous phase reaction of Ru(η2-RL)(PPh3)2(CO)Cl, 1 with lithium acetylacetonate (Liacac) afforded the complexes of the type Ru(η1-RL)(PPh3)2(CO)(acac), 2 in excellent yield where η2-RL is C6H2O-2-CHNHC6H4R(p)-3-Me-5 and η1-RL is C6H2OH-2-CHNC6H4R(p)-3-Me-5 and R is H, Me, Cl. The chelation of acac is attended with the cleavage of Ru–O and Ru–Cl bonds and iminium–phenolato→imine–phenol prototropic shift. A sterically controlled change in rotational conformation is involved in the 1→2 conversion. The conversion is irreversible and the type 2 species are thermodynamically more stable than the carboxylate, nitrite and nitrate complexes of 1. The crystal structures of Ru(η1-MeL)(PPh3)2(CO)(acac), 2(Me) and Ru(η1-ClL)(PPh3)2(CO)(acac), 2(Cl) are reported. Spectral (UV–Vis, IR, 1H NMR) and electrochemical data of the complexes are also reported. The electronic structure and the absorption spectra of the complexes are scrutinized by the density functional theory (DFT) and time-dependent density functional theory (TD-DFT) analyses. The complexes were also screened in vitro for their antiproliferative properties against the MCF-7 breast cancer cell lines by using the MTT assay. Flow cytometric analysis showed that the complexes arrested the cell cycle in the sub G0 phase.

Pseudopericyclic 1,5- versus Pericyclic 1,4- and 1,6-Electrocyclization in Electron-Poor 4-Aryl-2-azabuta-1,3-dienes: Indole Synthesis from 2H-Azirines and Diazo Compounds.

Transformations of 2-azabuta-1,3-dienes, formed in Rh2(OAc)4-catalyzed reactions of diazo carbonyl compounds with 2H-azirines, dramatically depend on the nature of substituents. 4,4-Diphenyl-2-azabuta-1,3-dienes with two electron-acceptor substituents at C(1) undergo thermal 1,5-cyclization to give indoles in good yields. The increase in electron-withdrawing ability of C(1)-substituents facilitates the reaction that proceeds via pseudopericyclic 1,5-electrocyclization of 2-azabutadiene into 7aH-indolium ylide followed by prototropic shift. 3,4-Diphenyl-2-azabuta-1,3-dienes, resulting from reaction of 2,3-diphenyl-2H-azirine and diazo compounds, do not produce indoles via 1,5-cyclization due to the trans-configuration of the 4-Ph-group and the nitrogen, but undergo 1,4-cyclization to 2,3-dihydroazetes. 1,6-Cyclization into 2H-1,4-oxazines with participation of the oxygen of ester or amide group at C(1) of corresponding 2-azabuta-1,3-dienes does not take place due to kinetic and thermodynamic reasons. Instead of this, 1,6-electrocyclization with participation of phenyl substituent at C(4) of the 2-azabuta-1,3-dienes, providing isoquinoline derivatives, can occur at elevated temperatures. The DFT-calculations (mPWB1K/6-31+G(d,p)) confirm the dependence of 2-azabuta-1,3-diene transformation type on the nature of substituents.

A quantum chemical study of the mechanism of the regioselective domino-reaction of O-vinyl-2-tetralone oxime

Quantum chemical (DFT) methods are used to study the mechanisms of intramolecular rearrangements (domino-transformations) in O-vinyl-2-tetralone oxime, which potentially can produce both conjugated and non-conjugated dihydrobenzindoles. Transition states of elementary reaction steps are localized. The 1,3-prototropic shift promoted by a mediator molecule (H2O) is the limiting step. An activation barrier of the formation of conjugated indole is 4.14 kcal/mol lower than the formation channel on the non-conjugated analog. Activation barriers of syn-(Z)/anti-(E)-isomerization in O-vinyl-2-tetralone oxime are analyzed. It is shown that with regard to barriers of the promoted prototropic shift, Z/E-isomerization is a rapid process.

CuSO4–Glucose for in Situ Generation of Controlled Cu(I)–Cu(II) Bicatalysts: Multicomponent Reaction of Heterocyclic Azine and Aldehyde with Alkyne, and Cycloisomerization toward Synthesis of N-Fused Imidazoles

The catalytic efficiency of mixed Cu(I)-Cu(II) system in situ generated by partial reduction of CuSO(4) with glucose in ethanol (nonanhydrous) under open air has been explored. With this catalysis, the multicomponent cascade reaction of A(3)-coupling of heterocyclic amidine with aldehyde and alkyne, 5-exo-dig cycloisomerization, and prototropic shift has afforded an efficient and eco-friendly synthesis of therapeutically important versatile N-fused imidazoles. Diverse heterocyclic amidines, several of which are known to be poorly reactive, and aldehydes are compatible in this catalytic process.

Regioselective Rhodium(II)‐Catalyzed Hydroaminations of Propargylguanidines

Regioselective Rhodium(II)‐Catalyzed Hydroaminations of Propargylguanidines

Flash vacuum thermolysis generation and a UV-photoelectron spectroscopy study of the N-substituted iminoacetonitriles

Flash vacuum thermolysis of cis and trans 1-benzyl and 1-allyl-2-cyano-3-phenylzetidines ( 1a and 1b) at 470 °C resulted in the formation of E and Z isomers of N-benzyl and N-allyl iminoacetonitriles 2a and 2b, respectively, beside small amounts of products 3a and 3b of their [1,3] prototropic shifts. It was found that the thermal fragmentation of the azetidine ring occurred fully regioselectively with a cleavage of the C2–C3 and C4–N bonds, but not the N–C2 and C3–C4 bonds. The UV-photoelectron spectrum of compound 2b was measured and analyzed with the aid of quantum chemical calculations of ionization energies. The strong modification of the electronic structure of the simplest carbon–nitrogen double bond upon the α,β substitution is due to the combined electron-withdrawing effect of the nitrile group and the donor effect of the allyl group.

Prototropic and metallotropic migration of isolobal fragments on indol rings. Theoretical study and NBO analysis

Molecular structures, energies, NBO analysis and sigmatropic behaviour of 1-Indenyl(dihydro)borane (1) and 1-Indenyl-threecarbonylcobalt(I) (2) were investigated using DFT and ab initio molecular orbital methods. In these compounds BH2 and Co(CO)3 fragments areisolobal. The Results of calculations using B3LYP, HF and MP2methods [Basis set 6-311+G**] showed that -BH2 and -Co(CO)3 had similar behaviour in sigmatropic shifts. Prototropic shifts in compounds 1 and 2 have similar mechanisms too. Results showed that metallotrotropic shift is faster than Prototrpic shift in compounds 1 and 2. The activation energies (Ea) of Prototropic shift in compounds 1 and 2 are 18.83 and 17.38 kcal.mol-1. These energies are higher than -BH2 shifts in compound 1 (10.11 kcal.mol-1) or migration of -Co(CO)3 fragment in compound 2 (12.39 kcal.mol-1). Lower amount of activation energy in borotropic shift and cobalt`s fragment shift show that rotation of boron and cobalt on the indol ring can happen in the ambient temperature. Calculation results revealed that migration of proton and Co(CO)3 was carried out via suprafacial[1,2]-sigmatropic mechanism while -BH2 shift took place via antrafacial [1,3]-rearangment.