Anti Isomers Research Articles

ChemInform Abstract: Synthesis of Pyrazole‐Fused Polycyclic Systems via Intramolecular 1,3‐Dipolar Cycloaddition Reactions.

Synthesis of a variety of pyrazole-fused systems starting from 4-iodopyrazolecarbaldehydes is described. The general strategy involves Suzuki coupling of 2-formyl aryl boronic acid with the 4-iodopyrazole derivatives generated from either Morita–Baylis–Hillman, Horner–Wadsworth–Emmons or Knoevenagel reactions followed by 1,3-dipolar cycloaddition reaction either by azomethine ylide or nitrile oxide. Interestingly, the cycloaddition reaction in substrates generated through Morita–Baylis–Hillman and Knoevenagel chemistries were diastereoselective for syn isomer. In contrast, the substrates prepared from Horner–Wadsworth–Emmons chemistry upon cycloaddition reactions afforded a mixture of syn and anti isomers in varying ratios.

Multiple Reaction Pathways Operating in the Mechanism of Vinylogous Mannich-Type Reaction Activated by a Water Molecule

A systematic search for reaction pathways for the vinylogous Mannich-type reaction was performed by the artificial force induced reaction method. This reaction affords δ-amino-γ-butenolide in one pot by mixing 2-trimethylsiloxyfuran, imine, and water under solvent-free conditions. Surprisingly, the search identified as many as five working pathways. Among them, two concertedly produce anti and syn isomers of the product. Another two give an intermediate, which is a regioisomer of the main product. This intermediate can undergo a retro-Mannich reaction to give a pair of intermediates: an imine and 2-furanol. The remaining pathway directly generates this intermediate pair. The imine and 2-furanol easily react with each other to afford the product. Thus, all of these stepwise pathways finally converge to give the main product. The rate-determining step of all five (two concerted and three stepwise) pathways have a common mechanism: concerted Si-O bond formation through the nucleophilic attack of a water molecule on the silicon atom followed by proton transfer from the water molecule to the imine. Therefore, these five pathways have comparable barriers and compete with each other.

Dissecting the Stereocontrol Elements of a Catalytic Asymmetric Chlorolactonization: Syn Addition Obviates Bridging Chloronium

We report absolute and relative stereochemistry of addition in enantioselective chlorolactonizations of 4-phenyl-4-pentenoic acid and its related t-butyl ester, catalyzed by (DHQD)2PHAL. Predominant syn addition of the chlorenium and the nucleophile across the olefin is observed. As shown by isotopic labeling, NMR spectroscopy, and derivative studies, the two new stereocenters formed by addition across the double bond are set independently and influenced by different factors. These findings suggest a stepwise process via an intermediate capable of lactone closure with either stereochemistry, in contradistinction to the more familiar scenario in which anti addition is dictated by a bridging chloronium ion intermediate.

Ligand-Controlled Remarkable Regio- and Stereodivergence in Intermolecular Hydrosilylation of Internal Alkynes: Experimental and Theoretical Studies

The first highly efficient ligand-controlled regio- and stereodivergent intermolecular hydrosilylations of internal alkynes have been disclosed. Cationic ruthenium complexes [Cp*Ru(MeCN)3](+) and [CpRu(MeCN)3](+) have been demonstrated to catalyze intermolecular hydrosilylations of silyl alkynes to form a range of vinyldisilanes with excellent but opposite regio- and stereoselectivity, with the former being α anti addition and the latter β syn addition. The use of a silyl masking group not only provides sufficient steric bulk for high selectivity but also leads to versatile product derivatizations toward a variety of useful building blocks. DFT calculations suggest that the reactions proceed by a mechanism that involves oxidative hydrometalation, isomerization, and reductive silyl migration. The energetics of the transition states and intermediates varies dramatically with the catalyst ligand (Cp* and Cp). Theoretical studies combined with experimental evidence confirm that steric effect plays a critical role in governing the regio- and stereoselectivity, and the interplay between the substituent in the alkyne (e.g., silyl group) and the ligand ultimately determines the observed remarkable regio- and stereodivergence.

Synthesis of Trisubstituted Alkenylstannanes through Copper‐Catalyzed Three‐Component Coupling of Alkylboranes, Alkynoates, and Tributyltin Methoxide

A versatile route to trisubstituted alkenylstannanes is presented. The alkyl and Sn moieties were introduced at the β and α carbon atoms of alkynoates, respectively, in a formal syn addition mode with complete regioselectivity. A variety of functional groups were tolerated in the alkylboranes and alkynoates.

Addition of Sulfonic Acids to Terminal Alkynes Catalyzed by a Rhodium Complex: Ligand Concentration‐Controlled Reaction Selectivity

AbstractA Rh‐catalyzed process for the regioselective formation of vinyl sulfonate esters in moderate to high yields through the hydrosulfonation of alkynes with sulfonic acids has been developed. Our synthetic approach is capable of adding a variety of alkynes to a set of sulfonic acids and is amenable to different phosphorus ligands, solvents, and Rh precursors. We control the chemo‐ and regioselectivity of the reaction to the Markovnikov vinyl sulfonate ester by tuning the concentration of the exogenous ligand, PPh3, which forms the active RhP species in situ. At lower PPh3 concentrations, the reaction favors the formation of vinyl sulfonate esters, whereas at higher PPh3 concentrations, the reaction favors the formation of vinylphosphonium salts. We perform Hammett analyses and kinetic isotope effect experiments to determine the steps of the catalytic mechanism. Reaction data for substituted acetylenes indicates syn and anti addition occur across the triple bond. Experiments performed with the vinylphosphonium salt as the exogenous ligand determined that the formation of the salt was not a necessary step in the catalytic mechanism for the direct formation of the vinyl sulfonate esters.

Insights into the Glycyl Radical Enzyme Active Site of Benzylsuccinate Synthase: A Computational Study

The fumarate addition reaction, catalyzed by the enzyme benzylsuccinate synthase (BSS), is considered to be one of the most intriguing and energetically challenging reactions in biology. BSS belongs to the glycyl radical enzyme family and catalyzes the fumarate addition reaction, which enables microorganisms to utilize hydrocarbons as an energy source under anaerobic conditions. Unfortunately, the extreme sensitivity of the glycyl radical to oxygen has hampered the structural and kinetic characterization of BSS, thereby limiting our knowledge on this enzyme. To enhance our molecular-level understanding of BSS, a computational approach involving homology modeling, docking studies, and molecular dynamics (MD) simulations has been used to deduce the structure of BSS's catalytic subunit (BSSα) and illuminate the molecular basis for the fumarate addition reaction. We have identified two conserved and distinct binding pockets at the BSSα active site: a hydrophobic pocket for toluene binding and a polar pocket for fumaric acid binding. Subsequent dynamical and energetic evaluations have identified Glu509, Ser827, Leu390, and Phe384 as active site residues critical for substrate binding. The orientation of substrates at the active site observed in MD simulations is consistent with experimental observations of the syn addition of toluene to fumaric acid. It is also found that substrate binding tightens the active site and restricts the conformational flexibility of the thiyl radical, leading to hydrogen transfer distances conducive to the proposed reaction mechanism. The stability of substrates at the active site and the occurrence of feasible radical transfer distances between the thiyl radical, substrates, and the active site glycine indicate a substrate-assisted radical transfer pathway governing fumarate addition.

Si–H Bond Activation at the Boron Center of Pentaphenylborole

Si–H bond activation is usually considered a domain of transition-metal complexes, and only few metal-free systems have proven suitable for this task. We have now found that Et3SiH readily reacts with pentaphenylborole to afford 1-bora-3-cyclopentenes as the syn and anti addition products. Here, Si–H bond cleavage is accomplished at a single boron center, a reactivity that is facilitated by a combination of high electrophilicity and loss of antiaromaticity. The mechanism of this transformation most likely involves a sequence of adduct formation, σ-bond metathesis, and conrotatory ring closure, similar to that observed for H/D exchange between H2 and silanes mediated by HB(C6F5)2 and heterolytic H2 splitting by boroles, respectively.

ChemInform Abstract: Rhodium Phosphine—Phosphite Catalysts in the Hydrogenation of Challenging N‐(3,4‐Dihydronaphthalen‐2‐yl) Amide Derivatives.

The enantioselective catalytic hydrogenation of N-(3,4-dihydronaphthalen-2-yl) amides (1) with rhodium catalysts bearing phosphine–phosphite ligands 4 has been studied. A wide catalyst screening, facilitated by the modular structure of 4, has found a highly enantioselective catalyst for this reaction. This catalyst gives a 93% ee in the hydrogenation of 1a and also produces high enantioselectivities, ranging from 83 to 93% ee, in the hydrogenation of several OMe- and Br-substituted substrates. In contrast, the structurally related enol esters 2 are very reluctant to undergo hydrogenation. A coordination study of the representative enamide 1d has shown an unusual η6-arene coordination mode, over the typical O,C,C chelating mode for enamides, as the preferred one for this substrate in a Rh(I) complex. Deuteration reactions of 1c,d indicate a clean syn addition of deuterium to the double bond without an isotopic effect on the enantioselectivity.

Isolation and structure of the anti,anti isomer and a DFT study of it and the syn,anti isomer of bis(tricarbonylchromium)dibenzo-[a,e]cyclooctatetraene. Evidence for an attractive electrostatic interaction between carbonyl oxygen atoms and Cr(CO)3-coordinated arene carbon atoms

When dibenzo[a,e]cyclooctatetraene and hexacarbonylchromium are refluxed in di-n-butyl ether/THF for an extended period, both the syn,anti and anti,anti isomers of the bis-tricarbonylchromium complex are obtained. After separation by column chromatography, the syn,anti:anti,anti isomer ratio is approximately 12:1. The anti,anti arrangement of the Cr(CO)3 groups was verified by X-ray crystallographic structure determination. The orientations of the two tricarbonylchromium tripods relative to the 1,2-disubstituted arene rings differ. One is exo staggered while the other is eclipsed. Intermolecular C–H⋯O hydrogen bonding is prevalent in the crystal and is reminiscent of the syn,anti isomer. A dimeric motif in the solid resulting from C–H⋯π interactions is observed. DFT calculations on both isomers confirms that the syn,anti isomer is favored. The preferred orientation for the anti Cr(CO)3 groups in both cases is exo staggered. However, the barrier to rotation is low, allowing hydrogen bonding to readily overcome this barrier and control the orientation of the tripod. While thermodynamic consideration support the preference for the syn,anti isomer, kinetic factors may also be important as this isomer would be formed preferentially due to steric inhibition of the diene coordination site by the mononuclear anti isomer. The stabilization of the syn,anti isomer occurs by an electrostatic attraction of the syn carbonyl groups with the anti Cr(CO)3-coordinated arene carbon atoms. A reexamination of the structural parameters verifies nonbonded carbon–oxygen distances less than the sum of the van der Waals radii in the syn,anti isomer. A search of the Cambridge Structural Database results in a significant number of interactions of this nature for arenetricarbonylchromium complexes.

Electrophilic Addition of Propargylic Cations to Allenes: Formation of Crowded Chloro‐ and Azido‐Enynes by Trapping of the Resulting Allylic Cations with TMSX (X = Cl, N3): A Synthetic and Computational Study

AbstractPropargylic cations, generated by the ionization of propargyl alcohols with catalytic amounts of Bi(OTf)3, react with aryl‐substituted allenes to generate incipient allylic cations that are quenched in the presence of TMSCl to form a number of sterically crowded chloro‐enynes as a mixture of Z and E isomers with a strong preference for the Z alkenes. Several other metallic triflates, M(OTf)3 (M = Sc, Yb, La), as well as bismuth nitrate Bi(NO3)3·5H2O also promote this reaction with similar conversions and stereoselectivity. Although trapping with TMSBr and TMSI gave intractable mixtures, trapping with TMSN3 in a couple of cases led to the isolation of the corresponding isomeric azido‐enynes, albeit in lower isolated yields and lower stereoselectivity. Competitive formation of the Meyer–Schuster rearrangement products was also observed. Sterically crowded chloro‐allenes did not form adducts with propargyl alcohols, instead they underwent a skeletal rearrangement under the influence of Bi(OTf)3 to form 2‐chloro‐butadienes. The results of DFT calculations indicated that the relative anti/syn energies of the propargyl cation and the energy difference between the Z/E isomeric products are too small to explain the stereochemical preference observed for the enynes. A study of the transition state in the crucial C–C bond‐forming step by DFT indicated that rotation of the benzylic portion away from the propargyl cation may be a key factor in favoring the anti isomer of the allylic cation.

Quinazolin-4-yl-sulfanylacetyl-hydrazone derivatives; Synthesis, molecular structure and electronic properties

Four new acetylhydrazone derivatives of quinazoline have been synthesized and characterized. The molecular structures and relative stabilities of four possible isomers for each acetylhydrazone are calculated using DFT/B3LYP/6-31G(d,p) method. The calculations results predicted higher stability of the E-isomers compared to the Z-isomers in the gas phase. The syn-E isomer is the predominant form in gaseous phase for all the studied hydrazones except for the hydrazone derived from salicylaldehyde where the anti-E is the most stable isomer. The latter is stabilized by two strong intramolecular H-bonds instead of one in the others. The electronic and spectroscopic properties of the most stable isomers were also calculated using the same level of theory. The calculated atomic polar tensor (APT) charges indicated an increase of the positive charge density at the H-sites involved in the H-bonding interactions. The HOMO and LUMO energies are negative indicating that the compounds under investigation are stable. The electronic transition from the ground state to the excited state belongs to π–π* transition. The calculated vibrational spectra showed strong red shifts and increase in the vibrational intensity of the NH and OH stretching modes due to the intramolecular H-bonding interactions. In DMSO solution, the NMR spectra of the studied hydrazones revealed that such polar solvents stabilize the syn isomers for all the studied hydrazones except for the hydrazone derived from salicylaldehyde where the anti isomer is the major.

Haloboration of internal alkynes with boronium and borenium cations as a route to tetrasubstituted alkenes.

Hail boration! 2-Dimethylaminopyridine-ligated dihaloborocations [X2B(2-DMAP)](+) with a strained four-membered boracycle were used for the haloboration of terminal and dialkyl internal alkynes (see scheme). Esterification then provided vinyl boronate esters as useful precursors to tetrasubstituted alkenes. Following mechanistic studies, the scope of the haloboration was expanded simply by variation of the amine. Pin = 2,3-dimethyl-2,3-butanedioxy.

Physical Properties and Structural Characterization of Ionic Liquids and Solid Electrolytes Utilizing the Carbamoylcyano(nitroso)methanide Anion

Invited for this month’s cover is the collaboration between three different groups at Monash University, Deakin University and the ARC Centre of Excellence for Electromaterials Science. The cover picture shows a photograph of an organic ionic plastic crystal, and the structure of the anti and syn isomers of the ccnm anion. Read the full text of the article on page 486.

Physical Properties and Structural Characterization of Ionic Liquids and Solid Electrolytes Utilizing the Carbamoylcyano(nitroso)methanide Anion

AbstractThe carbamoylcyano(nitroso)methanide (ccnm) anion has been used for the synthesis of eight new salts, two of which are liquid at room temperature. The ionic liquid containing a large phosphonium cation displays the highest thermal stability, while the imidazolium salt is the most fluid and conductive. Analysis of the crystal structures of four of the new materials, containing pyrrolidinium and small phosphonium cations, reveals notably different anion stacking behaviour depending on the nature of the cation. The solid [ccnm] salts all display good ionic conductivities, above 1 mS cm−1 for the four different pyrrolidinium species. This, and their soft appearance, is hypothesized to be a result of the presence of both the syn and anti conformational isomers of the [ccnm] anion. Finally, solid‐state NMR linewidth analysis and second moment calculations have been used to gain further insight into the disorder within one of the pyrrolidinium plastic crystals, revealing significant, quantifiable translational motion of some fraction of the material at temperatures over 0 °C.

Molybdenum and Tungsten Monoalkoxide Pyrrolide (MAP) Alkylidene Complexes That Contain a 2,6-Dimesitylphenylimido Ligand

Molybdenum and tungsten bispyrrolide alkylidene complexes that contain a 2,6-dimesitylphenylimido (NAr*) ligand have been prepared, in which the pyrrolide is the parent pyrrolide or 2,5-dimethylpyrrolide. Monoalkoxide pyrrolide (MAP) complexes were prepared through addition of 1 equiv of an alcohol to the bispyrrolide complexes. MAP compounds that contain the parent pyrrolide (NC4H4–) are pyridine adducts, while those that contain 2,5-dimethylpyrrolide are pyridine free. Molybdenum and tungsten MAP 2,5-dimethylpyrrolide complexes that contain O-t-Bu, OCMe(CF3)2, or O-2,6-Me2C6H3 ligands were found to have approximately equal amounts of syn and anti alkylidene isomers, which allowed a study of the interconversion of the two employing 1H–1H EXSY methods. The Keq values ([syn]/[anti]) are all 2–3 orders of magnitude smaller than those observed for a large number of Mo bisalkoxide imido alkylidene complexes, as a consequence of the destabilization of the syn isomer by the sterically demanding NAr* ligand. The rates of interconversion of syn and anti isomers were found to be 1–2 orders of magnitude faster for W MAP complexes than for Mo MAP complexes.

Synthesis of pyrazole-fused polycyclic systems via intramolecular 1,3-dipolar cycloaddition reactions

Synthesis of a variety of pyrazole-fused systems starting from 4-iodopyrazolecarbaldehydes is described. The general strategy involves Suzuki coupling of 2-formyl aryl boronic acid with the 4-iodopyrazole derivatives generated from either Morita–Baylis–Hillman, Horner–Wadsworth–Emmons or Knoevenagel reactions followed by 1,3-dipolar cycloaddition reaction either by azomethine ylide or nitrile oxide. Interestingly, the cycloaddition reaction in substrates generated through Morita–Baylis–Hillman and Knoevenagel chemistries were diastereoselective for syn isomer. In contrast, the substrates prepared from Horner–Wadsworth–Emmons chemistry upon cycloaddition reactions afforded a mixture of syn and anti isomers in varying ratios.

Rhodium Phosphine–Phosphite Catalysts in the Hydrogenation of Challenging N-(3,4-dihydronaphthalen-2-yl) Amide Derivatives

The enantioselective catalytic hydrogenation of N-(3,4-dihydronaphthalen-2-yl) amides (1) with rhodium catalysts bearing phosphine-phosphite ligands 4 has been studied. A wide catalyst screening, facilitated by the modular structure of 4, has found a highly enantioselective catalyst for this reaction. This catalyst gives a 93% ee in the hydrogenation of 1a and also produces high enantioselectivities, ranging from 83 to 93% ee, in the hydrogenation of several OMe- and Br-substituted substrates. In contrast, the structurally related enol esters 2 are very reluctant to undergo hydrogenation. A coordination study of the representative enamide 1d has shown an unusual η(6)-arene coordination mode, over the typical O,C,C chelating mode for enamides, as the preferred one for this substrate in a Rh(I) complex. Deuteration reactions of 1c,d indicate a clean syn addition of deuterium to the double bond without an isotopic effect on the enantioselectivity.

Dipalladium Complexes with Bridging Monoalkyl or Monophenyl Silyl Ligands in the Solid State and in Solution

HexSiH3, PhSiH3, and PhSiClH2 reacted with [Pd(PCy3)2] to yield dipalladium complexes with bridging silyl ligands: [{Pd(PCy3)}2(μ-HSiXR)2] (1, R = Hex, X = H; 2, R = Ph, X = H; 3, R = Ph, X = Cl). The X-ray crystallographic results displayed a typical bis(silyl)-bridged dinuclear structure with an anti conformation of the substituents on the Si atom in the solid state. Temperature-dependent NMR spectroscopic analyses of 1 and 2 revealed a dynamic syn–anti isomerization of the complex via exchange of the bridging and nonbridging Si–H hydrogens in solution. Complex 3 with bridging chloro(phenyl)silyl ligands did not show such a dynamic behavior.

Theoretical characterization of gas-phase thermolysis products of ethane-1,2-diol, 2-chloroethanol and 2-fluoroethanol

The transition structures and the activation energies for the possible thermal elimination of H2O, HF and HCl from ethane-1,2-diol, 2-fluoroethanol and 2-chloroethanol respectively, were investigated. The relative stabilities and associated barrier heights of syn and anti vinyl alcohol isomers and their acetaldehyde tautomer were estimated. HF, DFT/B3LYP and MP2 methods at 3-21G, 6-31+G(d), 6-311++G(d,p) and aug-cc-pvdz basis sets were applied to identify the stationary points of the studied systems. The optimized geometries and electronic energies of reactants, transition states and products were analyzed. The dependence of these properties upon the theoretical level was discussed. A concerted proton release and a hydroxide or halide ion expulsion mechanism was proposed to account for the thermal rearrangement of reactants to products. A thorough understanding of syn vinyl alcohol preference is provided by performing natural bond orbital (NBO) analysis. The oxygen atom lone pair (LP) and periplanar hyperconjugative effects are responsible for this preference. It was suggested that the LP hyperconjugative interactions with the C=C σ and π antibonds were the most important origin of the structural differences between the two vinyl alcohol isomers.