Anti Isomers Research Articles

PP-Rotation, P-Inversion and Metathesis in Diphosphines Studied by DFT Calculations: Comments on Some Literature Conflicts

The potential energy surface for internal rotation about the phosphorus–phosphorus bond was calculated at the PCMDCM/B3LYP/6-311++G(d,p) computational level for a set of eight symmetrical, unsymmetrical and P-stereogenic diphosphines; H4P2, Me4P2, (CF3)4P2, Ph4P2, Me2P–P(CF3)2, Me2P–PPh2, and the meso- and dl-isomers of Me(CF3)P–PMe(CF3) and MePhP–PMePh. Certain trends in the data were elucidated and compared with conflicting data from the literature regarding the relative population of anti and gauche rotational isomers. The pyramidal inversion barriers (stereomutation barriers in P-stereogenic cases) for the same set of diphosphines was estimated through the inversion transition states and also compared to literature values. Finally, the Me4P2 + (CF3)4P2 → 2Me2(CF3)2P2 metathesis reaction was also explored to evaluate its feasibility versus inversion. The finding of larger barriers in the metathesis than in the inversion rules in favour of an inversion mechanism for the stereomutation of P-stereogenic diphosphines.

Synthesis and spectroscopic studies of highly fluorescent, solvatochromic diastereomers with differentially stacked bithiophene-substituted quinoxaline rings

Diastereomeric C-shaped molecules containing closely stacked bithiophene-substituted quinoxaline rings were synthesized and characterized by NMR, UV–vis absorption, and fluorescence spectroscopy. The unique geometry of each diastereomer resulted in different degrees of π-overlap between the bithiophene-substituted quinoxaline ring chromophores, modulating their spectroscopic properties. The donor-acceptor nature of this chromophore gave rise to its positive solvatochromism. 1H NMR and UV–vis absorption spectroscopy confirmed the existence of π-π interactions in the ground state between the quinoxaline rings in both molecules but between the bithiophene rings only in the syn isomer. They exhibited significant emission maxima bathochromic shifts, a strong, positive solvatochromism, increased band broadening, and larger Stokes shifts when compared to a compound with an unstacked chromophore. Additionally, the syn isomer consistently showed λmax,em value red-shifts and larger band broadening and Stokes shifts compared to the anti isomer due to the greater π-overlap in the syn isomer.

A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus.

The stereochemical course of the cyclisation reaction catalysed by the bacterial 1,8-cineol synthase from Streptomyces clavuligerus was investigated using stereospecifically deuterated substrates. In contrast to the well investigated plant enzyme from Salvia officinalis, the reaction proceeds via (S)-linalyl diphosphate and the (S)-terpinyl cation, while the final cyclisation reaction is in both cases a syn addition, as could be shown by incubation of (2-13C)geranyl diphosphate in deuterium oxide.

Jean F. Normant (1936–2016)

Jean F. Normant, professor emeritus at the Université Pierre et Marie Curie, Paris, died on June 9, 2016 at the age of 80. He was internationally recognized in the field of organometallic chemistry applied to organic synthesis, including copper, manganese, and zinc derivatives. Professor Jean F. Normant died on June 9, 2016 at the age of 80. He was professor emeritus at the Université Pierre et Marie Curie, Paris, and was internationally recognized in the field of organometallic chemistry applied to organic synthesis. Normant's many important contributions to synthetic methodology include his report from 1971 on a highly regio- and stereoselective syn addition of organocopper reagents to alkynes leading to alkenylcopper species that are key intermediates for the stereoselective preparation of a broad range of trisubstituted olefins. This carbocupration of alkynes led to many synthetic applications, including the total synthesis of insect pheromones. Furthermore, he developed a range of important copper(I)-catalyzed reactions that allow the diastereo- and enantioselective synthesis of complex organic molecules. Normant made key contributions in various other important fields such as organomanganese chemistry, where he showed the exceptional ability of organomanganese(II) reagents (RMnX) to undergo high-yielding acylation reactions with acid chlorides. He thoroughly investigated the chemistry of geminated bis-organometallic species of zinc and magnesium, as well as the reactivity of various lithium carbenoids. Normant contributed significantly to the field of organofluorine chemistry by preparing a range of new lithiated or zincated unsaturated fluorinated reagents, and noticed the exceptional thermal stability of zinc fluorinated carbenoids. He also carried out fundamental work on the configurational stability of benzylic and allenic zinc carbenoids, and developed novel elegant carbocyclization and enantioselective carbolithiation reactions. Normant was born on January 29, 1936, in Angers (Maine-et-Loire, France). He studied chemistry at the École Nationale Supérieure de Chimie de Paris, an elite chemistry school, and obtained his PhD at the Faculté des Sciences de Paris (Sorbonne) under the supervision of Charles Prévost in 1963. During his PhD, he studied the reactivity of Grignard reagents with organic halides in polar aprotic solvents. He was successively maître de conférences (lecturer) at the Université de Reims (1965–1969) and at the Université de Paris-Sorbonne (1969–1973). In 1973, he was made professor at the Université Pierre et Marie-Curie (UPMC; Paris VI), where he remained for the rest of his career and was made professor emeritus after his retirement in 2000. Normant's outstanding career was recognized by a range of international prizes, including awards from the Van ’t Hoff Foundation (1967), the Japanese Chemical Society (1977 and 1991), the UK Royal Society of Chemistry (2000), as well as French prizes such as the Prix Adrien (1963) and the Prix Lebel (1990) from the Société Chimique de France (SCF). He received two prizes from the French Académie des Sciences, namely the Prix Jungfleisch (1967) and Prix de l'Etat (1987), and also the silver medal of the CNRS (1979). He followed in the footsteps of his father Henri Normant by being made a member of the Académie des Sciences in 1993. Normant published more than 360 articles including important reviews, book chapters, and a text book on organic chemistry written in French together with his father (2nd edition 1968). His scientific work received more than 10 000 citations and has profoundly influenced organometallic chemistry. He supervised around 50 PhD students and created a school of organometallic chemistry at the UPMC, and many former co-workers progressed to academic positions at universities worldwide. Jean Normant was an exceptionally enthusiastic scientist, and a wonderfully inspirational and highly creative chemist with an exceptional knowledge of the chemical literature. He also had a unique approach to chemical reactivity in anticipating the behavior of new organometallic reagents. He shaped the field of organocopper chemistry for organic synthesis, and organocopper species derived from Grignard reagents are referred to as “Normant cuprates” in several standard textbooks. Normant was a passionate chemist and his enthusiasm for the subject was infectious. The daily coffee-break chemistry discussion with students and co-workers at 4 pm was an institution of Normant's laboratory and the highlight of the day. Many creative ideas originated in these discussions. Normant was a brilliant supervisor and colleague, who was profoundly human and showed great modesty and kindness. Although he was only moderately attracted to administrative responsibilities, he acted as a dedicated President of the Organic Chemistry Division of the SCF for some years. Jean Normant was married and had three children, and the death of his beloved wife Catherine a few years ago strongly affected him. He will be sadly missed by both the French and international scientific communities.

Stereospecific Synthesis of Alkenes by Eliminative Cross-Coupling of Enantioenriched sp(3) -Hybridized Carbenoids.

1-Aryl-1,2-dialkylethenes were generated by a sequence of electrophilic substitution, 1,2-metalate rearrangement, and β-elimination initiated by the addition of enantioenriched α-(carbamoyloxy)alkylboronates to enantioenriched lithiated carbamates. The carbenoid stereochemical pairing [i.e., "like"=(S)+(S) or "unlike"=(S)+(R)] and the elimination mechanism (syn or anti), not substituent effects, determined the configuration of the trisubstituted alkene target. For example, (Z)-2,5-diphenyl-2-pentene was produced in 70 % yield with E/Z=5:95 by a like combination of Li and B carbenoids and syn (thermal) elimination whereas the E isomer was obtained in the same yield with E/Z>98:2 by an otherwise identical process involving an unlike stereochemical pairing. The concept elaborated overcomes an intrinsic limitation of traditional strategies for direct connective alkene synthesis, which cannot realize meaningful stereochemical bias unless the alkene substituents are strongly differentiated.

Stereospecific Synthesis of Alkenes by Eliminative Cross‐Coupling of Enantioenriched sp3‐Hybridized Carbenoids

Abstract1‐Aryl‐1,2‐dialkylethenes were generated by a sequence of electrophilic substitution, 1,2‐metalate rearrangement, and β‐elimination initiated by the addition of enantioenriched α‐(carbamoyloxy)alkylboronates to enantioenriched lithiated carbamates. The carbenoid stereochemical pairing [i.e., “like”=(S)+(S) or “unlike”=(S)+(R)] and the elimination mechanism (syn or anti), not substituent effects, determined the configuration of the trisubstituted alkene target. For example, (Z)‐2,5‐diphenyl‐2‐pentene was produced in 70 % yield with E/Z=5:95 by a like combination of Li and B carbenoids and syn (thermal) elimination whereas the E isomer was obtained in the same yield with E/Z>98:2 by an otherwise identical process involving an unlike stereochemical pairing. The concept elaborated overcomes an intrinsic limitation of traditional strategies for direct connective alkene synthesis, which cannot realize meaningful stereochemical bias unless the alkene substituents are strongly differentiated.

Direct Organocatalysed Double Michael Addition of α‐Angelica Lactone to Enones

The direct vinylogous Michael addition of unactivated α‐Angelica lactone to enones under iminium activation using 9‐amino‐9‐deoxy‐epi‐quinine as catalyst along with 2‐hydroxy‐1‐naphthoic acid as co‐catalyst has led to the formation of γ,γ‐disubstituted butenolides in high yields, moderate‐to‐good diastereoselectivities and excellent enantioselectivities. The readily available catalytic system over‐rides the steric hindrance, which would otherwise lead to the preferential formation of the syn isomer, to afford the anti isomer instead. Under enamine activation, the anti isomer selectively undergoes cyclisation to the hexahydrobenzofuran‐2(3H)‐one, which is readily separated from the left‐over syn isomer. Mechanistic details, including the fate of the pro‐nucleophile and the origin of the diastereoselectivity, are also discussed.

ChemInform Abstract: Gold‐Catalyzed Cyclizations of Alkynyl Silyl Enol Ethers: An Easy Access to Bicyclo[3.2.1]octanone Derivatives.

The efficient gold-catalyzed cyclization reactions of alkynyl silyl enol ethers were successfully applied to the preparation of bicyclo[3.2.1]octanone derivatives. Accordingly, after optimization of the gold catalytic system, several bicyclic α,β-unsaturated keto adducts were synthesized in good to excellent yields. The process followed a major 5-exo cyclization via an anti addition of the silyl enol ether to the π-activated intermediate, which was demonstrated by a deuterium incorporation experiment. A 6-endo cyclization process was observed for a silyl enol ether bearing an electron-donating aromatic group.

New Catalytic Method for the Synthesis of β‐Hydroxy Selenides

In the presence of NH4I as catalyst and m‐chloroperbenzoic acid as oxidant, the Se–Se bond cleavage of diselenides undergoes smoothly. The in situ generated reactive electrophilic Se species reacts with alkenes quickly, and a series of β‐hydroxy selenides are prepared in good yields. This new catalytic method for synthesis of β‐hydroxy selenides is a stereospecific anti addition, which occurs with a Markovnikov orientation.

Conformational Transformations in Aromatic Nitroso Oxides.

A systematic theoretical study on conformational transformations of monosubstituted (ortho- and para-) aromatic nitroso oxides R-C6H4NOO was performed. The existence of two rotation axes enables two types of conformational transitions in substituted arylnitroso oxides: trans/cis (rotation around the N-O bond) and syn/anti (rotation around the C-N bond, which is important in ortho isomers). The complete set of conformers was localized for R-C6H4NOO using four selected density functional (M06-L, mPWPW91, OLYP, and HCTH) and augmented polarization basis set of triple splitting. It was found that the activation enthalpy of the trans-cis conformational transition is nearly insensitive to the nature of R and ranges within 58-60 kJ/mol for para isomers. The ortho substituent has an insignificant effect on ΔH(≠)trans→cis: it increases this value by ∼5 kJ/mol in syn isomers and decreases it by ∼3 kJ/mol in anti isomers. On the contrary, the syn-anti conformational barrier is considerably affected by the substituent R; an increase in the electron-withdrawing properties of R decreases ΔH(≠)syn→anti. The activation enthalpies grow with increasing polarity of the solvent, as it was found using IEFPCM calculation. The values of relaxation time for all conformational equilibria were calculated and compared with known lifetimes of aromatic nitroso oxides. Our results suggest that syn/anti transitions occur fast enough in the scale of the experimental lifetime. However, trans/cis transformations proceed more slowly. And under certain conditions discussed in the paper, the rate of this conformational transition limits that of irreversible decay of nitroso oxide.

An acyl-Claisen/Paal-Knorr approach to fully substituted pyrroles

The synthesis of fully substituted pyrroles using the Paal-Knorr reaction on acyl-Claisen derived 2,3-syn-disubstituted-1,4-diketones is reported. The use of the acyl-Claisen rearrangement allows the synthesis of wide variety of syn-substituted 1,4-diketones which are shown to be better substrates for pyrrole condensation than their corresponding anti isomers. When the reaction was performed open to air the use of nucleophilic amines in the pyrrole forming step leads to auto-oxidation of the 5-methyl group giving exclusively 5-formyl pyrroles.

ChemInform Abstract: Fluorination of α,β‐Unsaturated Carbonyl Compounds Using Elemental Fluorine.

AbstractIn contrast to other halogens, the addition of fluorine to alkenes occurs as a syn addition.

Pyrene-Bridged Boron Subphthalocyanine Dimers: Combination of Planar and Bowl-Shaped π-Conjugated Systems for Creating Uniquely Curved π-Conjugated Systems.

Pyrene-bridged boron subphthalocyanine dimers were synthesized from a mixed-condensation reaction of 2,7-di-tert-butyl-4,5,9,10-tetracyanopyrene and tetrafluorophthalonitrile, and their syn and anti isomers arising from the result of connecting two bowl-shaped boron subphthalocyanine molecules were successfully separated. Expansion of the conjugated system of boron subphthalocyanine through a pyrene bridge caused a redshift of the Q band absorption relative to the parent pyrene-fused monomer, whereas combining the curved π-conjugation of boron subphthalocyanine with the planar π-conjugation of pyrene enabled facile embracement of C60 molecules, owing to the enhanced concave-convex π-π stacking interactions.

Gold‐Catalyzed Cyclizations of Alkynyl Silyl Enol Ethers: An Easy Access to Bicyclo[3.2.1]octanone Derivatives

AbstractThe efficient gold‐catalyzed cyclization reactions of alkynyl silyl enol ethers were successfully applied to the preparation of bicyclo[3.2.1]octanone derivatives. Accordingly, after optimization of the gold catalytic system, several bicyclic α,β‐unsaturated keto adducts were synthesized in good to excellent yields. The process followed a major 5‐exo cyclization via an anti addition of the silyl enol ether to the π‐activated intermediate, which was demonstrated by a deuterium incorporation experiment. A 6‐endo cyclization process was observed for a silyl enol ether bearing an electron‐donating aromatic group.magnified image

Modeling of the Reaction Mechanism of Enzymatic Radical C-C Coupling by Benzylsuccinate Synthase.

Molecular modeling techniques and density functional theory calculations were performed to study the mechanism of enzymatic radical C–C coupling catalyzed by benzylsuccinate synthase (BSS). BSS has been identified as a glycyl radical enzyme that catalyzes the enantiospecific fumarate addition to toluene initiating its anaerobic metabolism in the denitrifying bacterium Thauera aromatica, and this reaction represents the general mechanism of toluene degradation in all known anaerobic degraders. In this work docking calculations, classical molecular dynamics (MD) simulations, and DFT+D2 cluster modeling was employed to address the following questions: (i) What mechanistic details of the BSS reaction yield the most probable molecular model? (ii) What is the molecular basis of enantiospecificity of BSS? (iii) Is the proposed mechanism consistent with experimental observations, such as an inversion of the stereochemistry of the benzylic protons, syn addition of toluene to fumarate, exclusive production of (R)-benzylsuccinate as a product and a kinetic isotope effect (KIE) ranging between 2 and 4? The quantum mechanics (QM) modeling confirms that the previously proposed hypothetical mechanism is the most probable among several variants considered, although C–H activation and not C–C coupling turns out to be the rate limiting step. The enantiospecificity of the enzyme seems to be enforced by a thermodynamic preference for binding of fumarate in the pro(R) orientation and reverse preference of benzyl radical attack on fumarate in pro(S) pathway which results with prohibitively high energy barrier of the radical quenching. Finally, the proposed mechanism agrees with most of the experimental observations, although the calculated intrinsic KIE from the model (6.5) is still higher than the experimentally observed values (4.0) which suggests that both C–H activation and radical quenching may jointly be involved in the kinetic control of the reaction.

Cyanotriflation gives versatile acrylonitriles

Chemists in Germany have added a new dimension to preparing acrylonitriles with the first method for adding both a cyano group and a triflate group to an alkyne (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b00869). Xi Wang and Armido Studer of the University of Münster took advantage of a known aryl(cyano)iodonium triflate reagent that other groups have used to transfer the cyano group or the triflate group. But until now, no one had devised a reaction system to add both groups to another molecule at once, in this case a range of alkynes and diynes. The Münster team’s syn addition proceeds with regio- and stereochemical control at up to gram scale via a radical mechanism mediated by an iron phenanthroline catalyst, leading to a host of triflate-modified acrylonitriles. The researchers found that the triflate provides a handle for further functionalizing the acrylonitriles via palladium-catalyzed cross-coupling reactions (example shown) to make

Undeniable Confirmation of the syn-Addition Mechanism for Metal-Free Diboration by Using the Crystalline Sponge Method.

The stereochemical outcome of the recently developed metal-free 1,2-diboration of aliphatic alkenes has, until now, only been elucidated by indirect means (e.g. derivatization). This is because classical conformational analysis of the resulting 1,2-diboranes is not viable; in the (1)H NMR spectrum the relevant (1)H resonances are broadened by (11)B, and the occurrence of the products as oily compounds precludes X-ray crystallographic analysis. Herein, the crystalline sponge method is used to display the crystal structures of the diboronic esters formed from internal E and Z olefins, evidencing the stereospecific syn addition mechanism of the reaction, which is fully consistent with the prediction from DFT calculations.

Understanding anionic Chugaev elimination in pericyclic tetracene formation

The reaction pathway for the formation of tetracenes from the diols 1,2-C6H4(CHOHCCAr)2, LiHDMS, CS2 and MeI has been modelled by computational methods at the CBS-QB3 level of theory. Comparison of PhCHOC(=S)YCCPh (Y=S− or SMe) indicates a slight kinetic advantage for the anionic system towards [3,3]-sigmatropic rearrangement [Eact(calcd) 19.7 vs 21.8 kcal mol−1]. Using anthracene-based models, 10-{SC(=O)Y}-4a,10-dihydroanthracene (Y=S− or SMe), allows direct comparison of both syn and anti-manifolds in the neutral versus anionic Chugaev elimination. syn-Elimination of [HSC(=O)S]- is distinctly favoured [Eact(calcd) 11.4 kcal mol−1] versus syn elimination of neutral methylated HSC(=O)SMe [Eact(calcd) 27.5 kcal mol−1]. The smaller barrier to syn elimination of the anionic leaving group is in accord with the low temperature conditions required for this Chugaev reaction (60 °C) and suggests a general advantage in carrying out Chugaev eliminations in anionic manifolds.

Mechanism of the Platinum(II)-Catalyzed Hydroamination of 4-Pentenylamines

The mechanism of the platinum(II)-catalyzed intramolecular hydroamination of benzyl 4-pentenylamines has been evaluated under stoichiometric and catalytic conditions. Reaction of a benzyl 2,2-disubstituted 4-pentenylamine with [(PPh3)Pt(μ-Cl)Cl]2 forms a thermally sensitive platinum amine complex that undergoes irreversible, intramolecular ligand exchange with the pendant C═C bond to form a reactive platinum π-alkene complex. The π-alkene complex undergoes rapid, outer-sphere C–N bond formation, evidenced by the anti addition of Pt and N across the complexed C═C bond, to form a thermally stable zwitterionic platinamethylpyrrolidinium complex. The zwitterionic complex is rapidly and exergonically deprotonated by free amine to form a neutral, bicyclic azaplatinacyclobutane complex that likely exists as a discrete 1:1 adduct with ammonium salt in the nonpolar reaction medium and that represents the resting state of the catalytic cycle. Turnover-limiting intramolecular protodemetalation of the azaplatinacyclobutane–ammonium adduct followed by ligand exchange releases the 2-methylpyrrolidine product.

Formation of the syn isomer of [Fe(IV)(Oanti)(TMC)(NCMe)](2+) in the reaction of Lewis acids with the side-on bound peroxo ligand in [Fe(III)(η(2)-O2)(TMC)](.).

We demonstrate that the reactions of [Fe(III)(η(2)-O2)(TMC)](+) (TMC = tetramethylcyclam) with Lewis acids (H(+) and NO(+)) afford the recently described syn isomer of [Fe(IV)(O)(TMC)(NCMe)](2+) (and not the anti isomer as had been tacitly assumed). This outcome is a logical consequence of the fact that the side-on peroxo ligand is bound to the syn face of the Fe(TMC) unit in the precursor.