Vicinal Substituents Research Articles

3-sulfonyloxyaryl(mesityl)iodonium triflates as 1,2-benzdiyne precursors with activation via ortho-deprotonative elimination strategy

Benzyne has long captivated the attention of chemists and has gained numerous synthetic achievements. Among typical benzyne generation methods, removal of two vicinal substituents from 1,2-difunctionalized benzenes, i.e., Kobayashi’s protocol, are prevailing, while ortho-deprotonative elimination from mono-substituted benzene lags far behind. Despite the advantages of atom economy and ready achievability of precursors, a bottle neck for ortho-deprotonative elimination strategy resides in the weak acidity of the ortho-hydrogen, which normally demands strong bases as the activating reagents. Here, an efficient aryne generation protocol is developed, where ortho-deprotonative elimination on 3-sulfonyloxyaryl(mesityl)iodonium triflates occurs under mild conditions and the generated 3-sulfonyloxyarynes can serve as efficient 1,2-benzdiyne synthons. This array of 1,2-benzdiyne precursors can be conveniently prepared with high functional group tolerance, and densely substituted scaffolds can be accessed as well. Carbonate and fluoride salts are found to serve as efficient activating reagents, which are the weakest bases used in ortho-deprotonative elimination strategies. Particularly, this scaffold has predictable chemoselective generation of the designated aryne intermediates. The success of this ortho-deprotonative elimination protocol sets up a unique platform with a broad spectrum of synthetic applications.

Contrasting roles of bond orbital interactions contributing to conformational stabilities of flavan-3-ol structures

It is not easy to explain the conformational stability of flavan-3-ols. Factors governing it were investigated based on bond orbital interactions. The interactions between the substituent groups on the C2 and C3 positions play a critical role in the conformational stabilities. In the benzoyloxy types, the destabilization effects due to the interaction between the bonding orbital of the aromatic ring on C2 and the lone pair orbital of the oxygen atom on C3 are responsible for the relative stability of the conformations. In contrast, the conformational stabilities of the hydroxy types are determined by the stabilization effects arising from the electron delocalization from the bonding orbital to the vacant orbitals of the atoms. These results show that the stabilization effects due to the electron delocalization between the vicinal substituent groups is an important factor in the conformational stability of molecules in addition to the destabilization effects due to steric repulsion.

The effect of vicinal di-halo substituents on the organogelling properties of aromatic supramolecular gelators and their application as soft templates

Vicinal di-halo substituents have a determinant effect on the supramolecular self-assembly and properties of aromatic physical gelators with application as soft templates.

The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors.

Colchicine site ligands suffer from low aqueous solubility due to the highly hydrophobic nature of the binding site. A new strategy for increasing molecular polarity without exposing polar groups—termed masked polar group incorporation (MPGI)—was devised and applied to nitrogenated combretastatin analogues. Bulky ortho substituents to the pyridine nitrogen hinder it from the hydrophobic pocket while increasing molecular polarity. The resulting analogues show improved aqueous solubilities and highly potent antiproliferative activity against several cancer cell lines of different origin. The more potent compounds showed moderate tubulin polymerization inhibitory activity, arrested the cell cycle of treated cells at the G2/M phase, and subsequently caused apoptotic cell death represented by the cells gathered at the subG0/G1 population after 48 h of treatment. Annexin V/Propidium Iodide (PI) double-positive cells observed after 72 h confirmed the induction of apoptosis. Docking studies suggest binding at the colchicine site of tubulin in a similar way as combretastatin A4, with the polar groups masked by the vicinal substituents. These results validate the proposed strategy for the design of colchicine site ligands and open a new road to increasing the aqueous solubility of ligands binding in apolar environments.

Chameleon-Like Activating Nature of the Spirooxindole Group in Donor-Acceptor Cyclopropanes.

The concept of a chameleon activating group is considered in the context of donor-acceptor cyclopropane chemistry. When spiro-conjugated with cyclopropane, oxindole can act as an acceptor or a donor depending on the electronic nature of vicinal substituents. This dichotomy is reflected in the alteration of chemoselectivity of spiro[oxindole-1,3'-cyclopropane] ring opening with nucleophiles.

Structure of Silicon-Substituted Polytricyclononene Films: Small-Angle Neutron Scattering Data

Polytricyclononenes are new polymers having high permeability values not only for atmospheric gases, but also gaseous hydrocarbons. Thin films (≤100 μm) used in gas-separation membrane technologies are necessary to be studied to improve the gas transport properties of these polymers. The structure of polytricyclononene films with two vicinal side substituents Si(CH3)3 in a monomer unit synthesized via additive polymerization scheme is studied in this work by a small-angle neutron scattering method. As a whole, the amorphous film has a local orientation order due to chain fragments with spiral conformation. The size of the ordered regions is comparable to the length of units correlations in the polymer chain (Kuhn segment) and is 8–9 nm. Free volume and type of voids (pores) formed in the polymer film due to inhomogeneous packing are also found.

Understanding the effects of vicinal carbon substituents and configuration on organofluorine hydrogen-bonding interaction.

An investigation of C–F⋯H–O hydrogen bonds in the complexes CHnXCHnF⋯H2O (n = 0, 1, 2; X = H, F, Cl, Br) was performed at the MP2/aug-cc-pVTZ level. We found that the electron-withdrawing halogen substituents on the vicinal carbon cause the fluorine atom, participating in the hydrogen bond formation, to be less negatively charged. Thus, the halogen groups weaken the strength of organofluorine hydrogen bond by inductive effect. The position of the substituents on the vicinal carbon affects the strength of the C–F⋯H–O interaction. Compared with that in other isomers, the electron withdrawing substituent in 1-fluoro-ethane with stagger conformation as well as in 1-fluoro-ethene with trans configuration much weakens the interaction of C–F⋯H–O due to the hyperconjugative interaction between σ(C–F) and . By analogy, the electron-donating ones could largely strengthen it. We found that there is a good linear relationship between electron density at the BCP of F⋯H and Wiberg bond indexes (WBI) as well as between natural bond-bond polarizability (NBBP) and WBI, which indicates that the magnitude of NBBP and WBI could be a good indicator of the hydrogen bond strength.

“Naked” Iridium(IV) Oxide Nanoparticles as Expedient and Robust Catalysts for Hydrogenation of Nitrogen Heterocycles: Remarkable Vicinal Substitution Effect and Recyclability

AbstractIridium(IV) oxide nanoparticles were facilely prepared from iridium trichloride hydrate and sodium hydroxide by a ball‐milling reaction at room temperature. The “naked” iridium nanocatalyst showed high stability and activity for the hydrogenation of a series of nitrogen heterocycles, for the first time, under a hydrogen balloon at room temperature with a selectivity of higher than 99%. Besides, an unprecedented substitution‐dependent effect was discovered, where substrates with vicinal substituents on 2‐, 3‐, or 8‐positions exhibited distinctly higher reaction rates than unsubstituted or remote substituted ones. Extraordinary recyclability was discovered in the hydrogenation of 2‐methylquinoline for 30 runs without loss of activity.magnified image

2-Pyridone-based fluorophores: Synthesis and fluorescent properties of pyrrolo[3,4-c]pyridine derivatives

Several novel pyrrolo[3,4-c]pyridine derivatives were synthesized in good yields via hydrolysis and intramolecular heterocyclization of vicinal substituents in compounds of pyrid-2-one series. Both synthesized pyrrolo[3,4-c]pyridine-1,3,4-triones and 1-iminopyrrolo[3,4-c]pyridine-3,4-diones are fluorescent in various solvents with emission maxima in the blue-green region of the spectrum.

ChemInform Abstract: Mechanistic, Crystallographic, and Computational Studies on the Catalytic, Enantioselective Sulfenofunctionalization of Alkenes.

The stereocontrolled introduction of vicinal heteroatomic substituents into organic molecules is one of the most powerful ways of adding value and function. Although many methods exist for the introduction of oxygen- and nitrogen-containing substituents, the number of stereocontrolled methods for the introduction of sulfur-containing substituents pales by comparison. Previous reports from our laboratories have described sulfenofunctionalizations of alkenes that construct carbon-sulfur bonds vicinal to carbon-oxygen, carbon-nitrogen or carbon-carbon bonds with high levels of diastereospecificity and enantioselectivity. This process is enabled by the concept of Lewis-base activation of Lewis acids, which provides activation of Group 16 electrophiles. To provide a foundation for the expansion of substrate scope and improved selectivities, we have undertaken a comprehensive study of the catalytically active species. Insights gleaned from kinetic, crystallographic and computational methods have led to the introduction of a new family of sulfenylating agents that provide significantly enhanced selectivities.

Asymmetric synthesis of a functionalized tricyclo[6.2.0.02,6]decane ring system present in kelsoene and poduran

Synthesis of a functionalized tricyclo[6.2.0.02,6]decane derivative in enantiomerically pure form, the core structure present in the natural products kelsoene and poduran, is described. The key steps involve a stereocontrolled copper (I)-catalyzed intramolecular [2 + 2] photocycloaddition of a 1, 6-diene prepared from D-mannitol to form a substituted bicyclo[3.2.0]heptane derivative and a ring closing olefin metathesis involving the vicinal substituents on the five-membered ring of the bicyclo[3.2.0]heptane derivative. An asymmetric synthesis of a functionalized tricyclo[6.2.0.02,6]decane derivative has been described. The key step involves an intramolecular Cu (I)-catalyzed [2 + 2] photocycloaddition of a 1,6-diene derived from D-mannitol to provide a bicyclo[3.2.0]heptane derivative. Annulation of a five-membered ring on to the five-membered ring of this derivative using RCM provided the title compound.

Regio-controlled synthesis of unsymmetrical pyrazine-fused sinomenine derivatives and discriminate substitution effects on TNF-α inhibitory activity

A unified regio-controlled synthetic protocol combined with the use of Suzuki couplings, in a diverse fashion, has been developed and successfully applied to the synthesis of various pairs of unsymmetrical pyrazine-fused derivatives of sinomenine, a natural immunemodulating alkaloid. Introduction of two vicinal aromatic substituents to the pyrazine functionality resulted in significant improvement of TNF-α inhibitory activity, and a number of new derivatives exhibited even higher inhibition rate than that of positive control SB202190. In addition, discriminate but complicated substitution effects of these sinomenine–pyrazine hybrids have been observed on tumor necrosis factor-α (TNF-α) inhibitory activity.

Asymmetric Organocatalytic Michael/Henry Domino Reactions through Hydrogen‐Bond Activation: Kinetic Access to Indane Scaffolds Bearing cis‐Vicinal Substituents

Catalyst directs towards­ cis! A bifunctional hydrogen-bond-catalyzed Michael/Henry domino reaction allows preferential asymmetric access to the kinetic cis-nitroindanol products with excellent enantioselectivity through a postulated matched transition state (see scheme; H-Bo = hydrogen bond activation). This high yielding protocol opens up a new strategy to access highly useful enantio-enriched cis-aminoindanol-containing ligands and catalysts.

The preferred all-gauche conformations in 3-fluoro-1,2-propanediol

A competition between the terminal fluorine and hydroxyl groups by the central hydroxyl group as hydrogen bond donor in 3-fluoro-1,2-propanediol would be expected to dictate the conformational isomerism of this compound, but also the repulsion between the electronegative and bulky vicinal substituents. Indeed, an intramolecular hydrogen bond has been verified only for a local minimum using QTAIM calculations, while the most stable conformer exhibits an all-gauche conformation with a small stabilizing contribution from the nF→σ interaction. The preferred orientation of the OH and F substituents was confirmed from the chemical shifts and coupling constants of the diastereotopic hydrogens. This conformational preference, which is calculated to exist both in the gas phase and solution (using implicit CHCl3 and CH3CN solvents), is better described by predominant hyperconjugative interactions over Lewis-type interactions. The strong contribution from antiperiplanar interactions involving σCH and σCC as electron donors and σ and σ as electron acceptors dictates the gauche effect in 3-fluoro-1,2-propanediol rather than a hydrogen bond. The absence of JF,H(O) and JH(O),H(O) coupling constants confirms that any influence from a hydrogen bond to the conformational isomerism of 3-fluoro-1,2-propanediol is secondary.

On the way to understand antioxidants: chromanol and dimethoxyphenols gas‐phase acidities

Some antioxidant mechanisms displayed by several phenolic compounds relate with OH bond dissociation energy. One way for its determination, in the gas-phase, relies on acidity measurements. Gas-phase acidities were determined experimentally, applying the kinetic method, for chromanol and four dimethoxyphenols, and theoretically through quantum chemical DFT calculations for chromanol, six dimethoxyphenols and 3,4,5-trimethoxyphenol. The experimental acidity order, 2,3-dimethoxyphenol > 3,5-dimethoxyphenol > 2,6-dimethoxyphenol > 3,4-dimethoxyphenol ≈ phenol > chromanol shows good agreement with the theoretical acidity order, 2,5-dimethoxyphenol > 2,3-dimethoxyphenol > 3,4,5-trimethoxyphenol > 3,5-dimethoxyphenol ≈ 2,4-dimethoxyphenol > 2,6-dimethoxyphenol > 3,4-dimethoxyphenol > phenol > chromanol. These acidity trends were rationalized in terms of the substituent effects on the thermodynamic stabilities both of the parent phenols and the corresponding phenoxide ions. DFT calculations also evidenced the occurrence of intramolecular C-H···O hydrogen bonds whenever there are vicinal substituents (either OH, O(-) or OCH(3)) which induce further stabilization of the geometries.

An asymmetric route to total synthesis of the furano lignan (+)-veraguensin

Total synthesis of the furano lignan (+)-veraguensin is described. The key steps involve a diastereoselective aldol-type condensation of an ester enolate having an α-chiral center with an aromatic aldehyde and a novel isomerization of the syn vicinal substituents on the furan ring via a ring opening–ring closing protocol.

Chiral Discrimination of α-Chiral Ammonium Ions by Sterically Geared Chiral Tripodal Oxazolines

” conformation (“1,3,5-up/2,4,6-down” conformation) to avoid otherwise increased steric repulsion between the vicinal substituents of the benzene frame. Use of such sterically bulky subunits within a molecule to enable it to adopt a thermodynamically favored conformation with mini-mum steric interactions has been dubbed as “steric gearing.”

Carbon‐13 NMR of fluorocyclopropanes

Carbon-13 and hydrogen NMR data are presented for several cyclopropanes with one to four fluorine atoms attached to the ring. Substituents directly attached to a ring carbon are found to unshield that carbon to an extent increasing with their electronegativity, but remote substituents may have an opposite effect. Relative orientation of the substituent groups, especially if they are bulky, also has a strong influence on the ring-carbon shifts. Chemical shifts of carbons in methyl groups attached to the ring change to an extent which is additive in the effects of gem and cis substituents. One-bond coupling of ring carbons with fluorines is affected both by geminal and vicinal substituents, in a way generally related to their electronegativity. It is tentatively concluded that two-bond coupling between ring carbons and ring-attached fluorines depends in magnitude primarily on what groups are cis to the fluorine. Two-bond coupling between a carbon atom in a ring-attached methyl and the hydrogen gem to the methyl appears to be vanishingly small, but there is appreciable three-bond coupling of the methyl carbons to vicinal hydrogens.

Structural Chemistry of Aldols

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

アルドール化合物の構造化学

Structural investigation of organic compounds gives not only fundamental knowledge in chemistry but also guideline for design of functional materials and its synthetic strategies. The structure of aldols was systematically investigated. Intrinsic conformational preference was elucidated by DFT calculation of the simplest aldol, 3-hydroxypropanal. The “eclipsed” conformation with intramolecular hydrogen bond is the most stable. Cyclohexanone-derived aldols, which can fix at “eclipsed” conformation, were selected as standard compounds for systematic analysis of solutionphase behavior and crystal structure. The combination of molecular-weight measurement, NMR and IR studies in solution elucidated the detailed geometry of these typical aldols. The equilibrium distribution between conformers is controlled by the intramolecular and intermolecular hydrogen bond, gauche interactions between the vicinal substituents, and sometimes CH/π attraction. Since the conformational preference is not always fitted with the assumption in the empirical method for determining the relative configuration (Stiles-House method), this method must be used with the greatest care. The preferred structure in solution often differs greatly from the crystalline-state geometry. Generally the racemic C (3) -unsubstituted cyclohexanone-based aldols crystallize as a monomer or a heterochiral dimer with the stable “eclipsed” conformation. The enantiomerically pure aldols, however, tend to form intermolecular hydrogen bonds generating a helical chain. Introduction of a C (3) substituent completely destroys the stable conformation yielding an unusual C (2) -C (3) trans-diaxial conformation. This enables the formation of a hydrogen-bonded polymer along screw axis or glide plane.