Control of regioselectivity by the lone substituent through steric and electronic effects in the nitrosoarene ene reaction of deuterium-labeled trisubstituted alkenes

For the ene reaction of 4-nitronitrosobenzene (ArNO) with a variety of primary and secondary lone alkyl-substituted substrates, the twix/twin regioselectivity is constant at about 85:15. In contrast, for the lone tert-butyl group and for lone aryl substituents, the twix regioisomer is obtained exclusively. These regioselectivities have been rationalized in terms of steric interactions and coordination between the enophile and the substrates in the transition states of the first reaction step.     

Interpretation of anomeric effect in the N-C-N unit with the quantum theory of atoms in molecules

The conformational preferences of six model compounds for the N-C-N anomeric unit (methanediamine, 2,2-propanediamine, N,N,N',N'-tetramethyl-methanediamine, 1,3-dizacyclohexane, 1,3,5-triazacyclohexane, and 2-aminopiperidine) were analyzed within the framework of the Quantum Theory of Atoms in Molecules. The relative stabilization of the conformers is related to two factors: (i) the reduction of the electron population experienced by the hydrogens of the central methylene when they display more gauche arrangements to lone pairs (lp) and (ii) the reduction of the electron population of aminic hydrogens when the corresponding N-H bond is in a parallel arrangement to the lone pair of another N. The former depletion takes place in lp-N-C-N antiperiplanar dispositions, whereas the latter is shown in lp-N-C-N gauche arrangements. Therefore, we can say that the electron density removed from the central hydrogens is moved to an aminic one on going from an antiperiplanar to a gauche disposition of a lp-N-C-N unit. The relative energies of aminic and central hydrogens in the conformer series is the main factor determining the conformational preference. In contrast to what happens in O-C-O containing compounds (where both N(H) depletions take place in the O-C-O-H gauche dispositions), the stabilization gained by N and C atoms plays a secondary role. This is in line with a general trend exhibited by hydrogens as the most available (less energy cost) atomic basins for receiving or providing electron density along a chemical change. It also explains why the anomeric conformational stabilization due to the N-C-N units is significantly less than that of the O-C-O- units. Moreover, the variations of electron population due to conformational changes are not in keeping with the stereoelectronic model of the anomeric effect, as was previously found for diverse molecules containing the O-C-O anomeric unit.     

Nuclear magnetic resonance analysis of pharmaceuticals : Part XV. Determination of sulfamethoxazole and trimethoprim in combination in tablets

The determination of sulfamethoxazole and trimethoprim as a mixture in tablets by n.m.r. spectrometry is reported. Formamide containing 8% formic acid is the solvent system with t-butanol as the internal standard. The resonances for the hydrogens on all three methyl groups of the methoxyl functions together with hydrogens of the lone methylene group are integrated as a measure of trimethoprim, whereas the hydrogens of the methyl group of the oxazole heterocycle are integrated to determine sulfamethoxazole. A mixture of two standards and representative commercial tablets were analyzed by the procedure; the results are satisfactory.     

Atoms in molecules interpretation of the anomeric effect in the O--C--O unit

The conformational preferences of two model compounds for the O--CH2--O anomeric unit: methanediol and dimethoxymethane analyzed within the framework of the QTAIM theory provide a new interpretation of the anomeric effect. The characteristic stabilization of the gauche conformers of these compounds is accompanied by a progressive reduction of the electron population of the hydrogens of the central methylene as the number of their gauche interactions to lone pairs rises. The electron population removed from these atoms during the conformational change is gained in the gauche conformers by atoms of larger atomic number, which results in a more negative molecular energy. Also, the variations displayed by atomic populations and the QTAIM delocalization indexes are not keeping in line with the hyperconjugative model of the anomeric effect.     

Thionin-sensitized intrazeolite photooxygenation of trisubstituted alkenes: substituent effects on the regioselectivity as probed through isotopic labeling

The regioselectivity for the intrazeolite photooxygenation of several trisubstituted alkenes with geminal dimethyl groups was examined. The length of the alkyl chain at the lone position was varied, and as end groups, the phenyl or the cyclohexyl functionalities were chosen. The general trend for all alkenes is a significant increase of the reactivity at the twin position compared to the photooxygenation in solution. For the cyclohexyl-substituted alkenes, it was found that the regioselectivity is nearly independent of the alkyl chain length. However, for the phenyl-substituted alkenes, the ene reactivity of the allylic methylene hydrogen atoms at the lone position and the twix/twin regioselectivity depend significantly on the distance of the phenyl group from the double bond. These trends are discussed in terms of cation-pi interactions and conformational effects. Intramolecular and intermolecular isotope effects in the intrazeolite photooxygenation of deuterium-labeled alkenes suggest that a perepoxide-type intermediate is formed in the rate-determining step. Type I photooxygenation that involves reaction of the radical cations of the alkenes with superoxide ion are unlikely.     

Stereoelectronic Aspects of the Anomeric Effect in Fluoromethylamine

High-level ab initio calculations have been made for fluoromethylamine to study structural and energetic effects of the relative orientation of the N lone pair to the C? F bond. The anti-conformer (N lone pair anti-planar to the C? F bond) corresponds to the global energy minimum. It has the longest C? F distance, the shortest C? N distance, and is 7.5 kcal·mol^?1 more stable than the related perpendicular conformation (lone pair perpendicular to the C? F bond). The syn-conformation also shows hallmarks of the anomeric effect: long C? F bond, short C? N bond, and energetic stability when allowance is made for the two pairs of eclipsed hydrogens. The transition state for N inversion is close to the syn-structure; rotation about the C? N bond is strongly coupled with this inversion process. Small bond distance changes of ca. 0.02 Å between parallel and perpendicular conformations are associated with dissociation energy differences of ca. 30 kcal·mol^?1. Various criteria for assessing the strength of the anomeric effect are discussed.     

The theoretical design of neutral planar tetracoordinate carbon molecules with C(C)(4) substructures

Using a new charge-compensation strategy, we designed neutral molecules with perfectly planar C(C)(4)-type tetracoordinate carbon arrangements (ptC) employing DFT computations. These designs, based on the planar preference of methane dications, replace two remote carbons in spiroalkaplanes by borons or two remote hydrogens by BH(3) groups; the two formally anionic boron units which result compensate the formal double positive charge on the central ptC's. The LUMOs correspond to the "wasted" lone pair HOMOs of the alkaplanes. As compared to the latter, pi occupancies on the central carbon are much smaller (less than 0.7e), and the IPs are much larger. The newly predicted compounds utilize all of the electrons more effectively. There are no lone pairs, and the ptC-C bond lengths are ca. 1.50 A. The Wiberg bond index sums of the ptC's are near 3.2, and the boron sums are close to 4.     

Molecular recognition of ammonium ion by tetrahomodioxacalix[4]biscrown

The first theoretical study on the conformational features and the complexation behaviors upon ammonium ion binding of tetrahomodioxacalix[4]biscrown-4 has been performed using molecular dynamic simulations and density functional theory. The conformational analyses show that the relative stability and the geometry of the ammonium ion complexes are directly contributed by the number of putative hydrogen bonds between oxygen lone pairs and ammonium hydrogens.     

Steric and conformational control of the regioselectivities in the ene reaction with trisubstituted cycloalkenes: comparison of the enophiles singlet oxygen, triazolinedione, and nitrosoarene

The nitrosoarene ene reaction with the cycloalkenes 1-3 and E-4 proceeds in high twix regioselectivity to afford the hydroxylamine ene products 1a-4a (twix) and 1b-4b (twin, except far E-4 twix). Steric interactions in the enophile attack are responsible for the skew trajectory of the nitrosoarene enophile. For Z-1-methylcyclooctene (Z-4), twin abstraction dominates, caused by conformational constraints (transannular interactions) in the hydrgogen-atom abstraction. The balance between these steric and conformational factors dictates the regioselectivity in the ene reaction     

An experimental and computational study on the reactivity and regioselectivity for the nitrosoarene ene reaction: comparison with triazolinedione and singlet oxygen

The regioselectivities and the reactivities (relative rates) for the ene reaction of the enophile 4-nitronitrosobenzene (ArNO) with an extensive set of regiochemically defined acyclic and cyclic olefins have been determined. These experimental data establish that the ArNO enophile attacks the olefinic substrate along the novel skew trajectory, with preferred hydrogen abstraction at the corner (twix regioselectivity). This is in contrast to the isoelectronic species singlet oxygen ((1)O(2)), which abstracts at the higher substituted side of the double-bond (cis effect), and triazolindione (TAD), which undergoes the ene reaction at the more crowded end (gem effect). Ab initio computations (B3LYP/6-31+g) for the ene reaction of the ArNO with 2-methyl-2-butene reveal that the steric effects between the aryl group of the enophile and the substituents of the olefin dictate the skew trajectory. These computations identify the aziridine N-oxide (AI) as a bona fide intermediate in this ene reaction, whose formation is usually rate-determining and, thus, irreversible along the skew trajectory (twix selectivity). The reversible generation of the AI becomes feasible when conformational constraints outweigh steric effects, as manifested by enhanced twin regioselectivity.     

Beta-deuterium isotope effects on amine basicity, "inductive" and stereochemical

Secondary beta deuterium isotope effects on acidity constants of ammonium ions are measured using a remarkably precise NMR titration method. Deuteration is found to increase the basicity of methylamine, dimethylamine, benzylamine, and N,N-dimethylaniline. The effect is attributed to a lowered zero-point energy of a CH bond adjacent to an amine nitrogen. The method permits a determination of the stereochemical dependence of the isotope effect in a locked piperidine, and it is found that deuteration is more effective when antiperiplanar to a lone pair. The values are consistent with a cos(2) dependence on dihedral angle, with no detectable angle-independent inductive effect.     

Markovnikov‐Selective Radical Addition of S‐Nucleophiles to Terminal Alkynes through a Photoredox Process

Direct radical additions to terminal alkynes have been widely employed in organic synthesis, providing credible access to the anti‐Markovnikov products. Because of the Kharasch effect, regioselective control for the formation of Markovnikov products still remains a great challenge. Herein, we develop a transition‐metal‐free, visible light‐mediated radical addition of S‐nucleophiles to terminal alkynes, furnishing a wide array of α‐substituted vinyl sulfones with exclusive Markovnikov regioselectivity. Mechanistic investigations demonstrated that radical/radical cross‐coupling might be the key step in this transformation. This radical Markovnikov addition protocol also provides an opportunity to facilitate the synthesis of other valuable α‐substituted vinyl compounds.     

Ene reaction of singlet oxygen,triazolinedione, and nitrosoarene with chiral deuterium-labeled allylic alcohols: the interdependence of diastereoselectivity and regioselectivity discloses mechanistic insights into the hydroxy-group directivity

The ene reaction of singlet oxygen ((1)O(2)), triazolinedione (TAD), and nitrosoarene, specifically 4-nitronitrosobenzene (ArNO), with the tetrasubstituted 1,3-allylically strained, chiral allylic alcohol 3,4-dimethylpent-3-en-2-ol (2) leads to the threo-configured ene products in high diastereoselectivity, a consequence of the hydroxy-group directivity. Hydrogen bonding favors formation of the threo-configured encounter complex threo-EC in the early stage of ene reaction. For the analogous twix deuterium-labeled allylic alcohol Z-2-d(3), a hitherto unrecognized dichotomy between (1)O(2) and the ArNO and TAD enophiles is disclosed in the regioselectivity of the tetrasubstituted alcohol: Whereas for ArNO and TAD, hydrogen bonding with the allylic hydroxy group dictates the regioselectivity (twix selectivity), for (1)O(2), the cis effect dominates (twin/trix selectivity). From the interdependence between the twix/twin regioselectivity and the threo/erythro diastereoselectivity, it has been recognized that the enophile also attacks the allylic alcohol from the erythro pi face without assistance by hydrogen bonding with the allylic hydroxy functionality.     

CH...O and CH...F links form the cage structure of dioxane-trifluoromethane

The molecular beam Fourier transform microwave spectrum of 1,4-dioxane-trifluoromethane has been assigned and measured. The two subunits form a cage stabilized by one C-H...O and two C-H...F weak hydrogen bonds. The C-H...O link involves the axial lone pair of one of the two equivalent ring oxygens, while the two C-H...F bridges connect trifluoromethane to the two axial hydrogens in positions 3 and 5. The dissociation energy has been estimated from the D(J) centrifugal distortion parameter to be approximately 6.8 kJ/mol.     

The AZARYPHOS Family of Ligands for Ambifunctional Catalysis: Syntheses and Use in Ruthenium‐Catalyzed anti‐Markovnikov Hydration of Terminal Alkynes

The family of AZARYPHOS (aza–aryl–phosphane) phosphane ligands, containing a phosphine unit and sterically shielded nitrogen lone pairs in the ligand periphery, is introduced as a tool for developing ambifunctional catalysis by the metal center and nitrogen lone pairs in the ligand sphere. General synthetic strategies have been developed to synthesize over 25 examples of structurally diverse (6‐aryl‐2‐pyridyl)phosphanes (ARPYPHOS), (6‐alkyl‐2‐pyridyl)phosphanes (ALPYPHOS), 4,6‐disubsituted 1,3‐diazin‐2‐ylphosphanes or 1,3,5‐triazin‐2‐ylphosphanes, quinazolinylphosphanes, quinolinylphosphanes, and others. The scalable syntheses proceed in a few steps. The incorporation of AZARYPHOS ligands ( L ) into complexes [RuCp( L )₂(MeCN)][PF₆] (Cp=cyclopentadienyl) gives catalysts for the anti‐Markovnikov hydration of terminal alkynes of the highest known activities. Electronic and steric ligand effects modulate the reaction kinetics over a range of two orders of magnitude. These results highlight the importance of using structurally diverse ligand families in the process of developing cooperative ambifunctional catalysis by a metal and its ligand.     

Rearrangements in methanolysis of bis(2-bromoalkyl)selenides

Addition of selenium dibromide to 1-hexene, 1-octene, and allylic ethers occurs through the formation of intermediate kinetic anti-Markovnikov adducts that further transform into more thermodynamically stable Markovnikov adducts presumably via seleniranium intermediates. The methanolysis of both Markovnikov and anti-Markovnikov adducts leads to the formation of the same products in approximately the same ratio thus showing that the reaction proceeds through seleniranium intermediates.     

Solid-phase supported nitrosocarbonyl intermediates: Old scope and new limitations in the organic synthesis

Nitrosocarbonyl intermediates on solid polystyrenic support are generated at room temperature by the mild oxidation of resin-bound stable nitrile oxides. They undergo one-pot ene reactions with tetramethyl- and trimethyl-ethylene and other highly substituted olefins. Less substituted ethylenes as well as cyclohexene and cyclopentene are heavily disfavoured and nitrosocarbonyls on solid phase undergo fast dimerization and/or decomposition pathways. These outcome strongly limit the SP applications in organic synthesis, although applicable to structurally specific N-alkenyl hydroxamic acids.     

Competitive binding of methanol and propane for water via matrix-isolation spectroscopy: implications for inhibition of clathrate nucleation

Methanol is a well-known thermodynamic inhibitor of clathrate hydrate formation. The interactions responsible for the inhibition, however, are not well-identified. Propane is a relatively simple hydrocarbon that forms a clathrate hydrate under mild conditions. This paper reports data about the interaction of methanol with water-propane complex. Methanol, water, and propane are isolated in carbon tetrachloride, and the interaction is probed with infrared spectroscopy. Water is known to interact with propane via the oxygen lone pairs and the propane methylene hydrogens. Experimental evidence indicates that methanol hydrogen bonds to water via donation of the hydroxyl hydrogen (K = 4.4 × 10(2)). Methanol does not have a direct interaction with propane. These results are consistent with an inhibitory mechanism in which methanol competes with propane for the oxygen atom of water.     

The nitrosocarbonyl hetero-Diels-Alder reaction as a useful tool for organic syntheses

Organic transformations that result in the formation of multiple covalent bonds within the same reaction are some of the most powerful tools in synthetic organic chemistry. Nitrosocarbonyl hetero-Diels-Alder (HDA) reactions allow for the simultaneous stereospecific introduction of carbon-nitrogen and carbon-oxygen bonds in one synthetic step, and provide direct access to 3,6-dihydro-1,2-oxazines. This Review describes the development of the nitrosocarbonyl HDA reaction and the utility of the resulting oxazine ring in the synthesis of a variety of important, biologically active molecules.     

Renner-Teller/Jahn-Teller intersections along the collinear axes of polyatomic molecules: C2H2 + as a case study

Recently we discussed the Renner-Teller effect in triatomic molecules [J. Chem. Phys. 125, 094102 (2006)]. In that article the main message is that the Renner-Teller phenomenon, just like the Jahn-Teller phenomenon, is a topological effect. Now we extend this study to a tetra-atomic system, namely, the C(2)H(2) (+) ion, for which topological effects are revealed when one atom surrounds the triatom axis or when two atoms surround (at a time) the two-atom axis. The present study not only supports the findings of the previous study, in particular, the crucial role played by the topological D matrix for diabatization, but it also reveals new features which are expected to be more and more pronounced the larger the original collinear molecule. As already implied, shifting away two atoms from the collinear molecular axis does not necessarily abolish the ability of the remaining two atoms to form topological effects. Moreover, the study indicates that when the two hydrogens are shifted away, the CC axis produces two kinds of topological effects: (1) a Renner-Teller effect (characterized by a topological phase of 2pi) which is revealed when the two hydrogens surround, rigidly, this axis (as mentioned above), and (2) a Jahn-Teller effect (characterized by a topological phase of pi) which is revealed when one of the hydrogens surrounds this axis while the other hydrogen is clamped to its position.