Ortho effect in the Bergman cyclization: interception of p-benzyne intermediate by intramolecular hydrogen abstraction

Intramolecular hydrogen atom (H-atom) abstraction from the o-OCH3 group effectively intercepts the p-benzyne intermediate in the Bergman cycloaromatization of 2,3-diethynyl-1-methoxybenzene (1) before this intermediate undergoes either retro-Bergman ring opening or external H-atom abstraction. This process leads to the formation of a new diradical and renders the cyclization step essentially irreversible. Chemical and kinetic consequences of this phenomenon were investigated through the combination of computational and experimental studies.     

Stereochemical Prins cyclization: electronic versus steric effects on the synthesis of 2,4,6-trisubstituted tetrahydropyran rings

A convenient approach towards the synthesis of both syn- and anti-2,4,6-chlorotetrahydropyrans has been developed. The electronic and steric influences on the stereochemistry of the Prins cyclized products were investigated based on the substituents of the homoallylic alcohol.     

Intramolecular hydrogen abstraction promoted by amidyl radicals. Evidence for electronic factors in the nucleophilic cyclization of ambident amides to oxocarbenium ions

A tandem 1,5-hydrogen atom transfer/radical oxidation/nucleophilic cyclization mechanism is proposed for the intramolecular hydrogen abstraction reaction promoted for primary carboxamidyl radicals. The electron-withdrawing capacity of the C-5 substituent can switch the reaction to give exclusively bicyclic spirolactams (6-oxa-1-azaspiro[4.5]decan-2-one) when R(1) = H or spirolactones (1,6-dioxaspiro[4.5]decan-2-one) when R(1) = OAc. With a substituent of medium polarity (R(1) = OMe), a mixture of lactones and lactams is formed.     

Influence of electronic and steric effects and hydrogen bonding on1H and13C spectral parameters in azo compounds

V. I. Vernadskii Institute of Geochemistry and Analytical Chemistry, Russian Academy of Sciences; Turin University, Turin, Italy. Translated from Zhurnal Strukturnoi Khimii, Vol. 33, No. 6, pp. 91–101, November–December, 1992.     

P-H activation using alkynylgold substrates: steric and electronic effects

The susceptibility of a prototypical hydrogen phosphonate to undergo P-H activation upon treatment with alkynylgold complexes has been studied. Dynamic solution behavior was observed during reactions involving triphenylphosphine ligated substrates and was attributed to rapid phosphine exchange between the alkynylgold starting material and the gold phosphonate product. The use of bulky biaryldialkylphosphine ligands eliminated the fluxional behavior, but did not significantly slow the rate of P-H activation. Similarly, changing the supporting ligand to an N-heterocyclic carbene did not significantly slow the rate of the reaction. Despite a number of reports outlining the functionalization of propargyl alcohols using gold catalysts, incorporating these groups into the architecture of the alkynylgold substrates did not alter the product distributions. Although the chemistry tolerated a range of supporting ligands, incorporating electron donating groups into the alkyne increased the rate of the reaction while electron-withdrawing groups slowed the reaction. A possible mechanism for the process includes a transition state containing significant pi-contribution from the alkyne. Due to the high yields of gold phosphonates obtained in this chemistry as well as the mild conditions of the reactions, the interception of intermediates/catalysts by substrates or ligands containing labile P-H donors is an issue that must be circumvented when designing or developing a gold catalyzed reaction that proceeds through alkynylgold intermediates.     

DFT study of 1-, 4-, and 5-substituted 2-oxo-1,2,3,4-tetrahydropyrimidines: substituent steric and electronic effects,and ring flipping

Steric and the electronic effects caused by the substituents in the 1-, 4-, and 5-positions of substituted 2-oxo-1,2,3,4-tetrahydropyrimidines were investigated using density functional theory at the B3LYP/6-31++G(d,p) level. Results of this study show that the heterocyclic ring adopts a pseudo-boat conformation, in which the C₄ and N₁ atoms are deviated from ring planarity. The C₄-substituent occupies a pseudo-axial position and the space orientation of the substituent depends on the type and position of the additional substituent in this aryl group. The heights of the C₄ and N₁ atoms from the boat plane and the orientation of 5-CO moiety toward the heterocyclic ring depend on the electronic and steric effects of the substituents in the various positions. Ring flip calculations for 4-phenyl substituent explain the extreme steric effect caused by the substituent in the 1-position. These calculations indicate the more favored pseudo-axial orientation of the phenyl group over the equatorial orientation.     

Density functional study of the ring effect on the Myers-Saito cyclization and a comparison with the Bergman cyclization

Myers-Saito cyclizations of a series of enyne-allenes and enyne-butatrienes have been studied by density functional methods. The pure DFT method, BPW91, in conjunction with the 6-311 basis set is demonstrated to be suitable to study these systems. Geometry optimizations and harmonic frequency calculations were applied for every reactant, transition structure, as well as product. It has been shown that the cyclic structure of reactant lowers significantly the critical distance and reaction barrier. For the Myers-Saito product of (5Z)-1,2,3,5-cyclononatetraen-7-yne (10R), the confinement of ring leads to an essential change of the biradical character from sigma-pi type to sigma-sigma type. The through-bond coupling is therefore involved in this product as in the Bergman products. With the enlargement of the ring, the geometrical distortion weakens the through-bond coupling and raises the stability of the products. As a consequence, 1,5-didehydroindene (10P) presents a particularly long critical distance and lower thermodynamic stability. Detailed comparisons of the reactivities of 10R, (Z)-1-cyclononene-3,8-diyne (13R), and (Z)-1-cyclodecene-3,9-diyne (14R) that represent the core structure of a category of natural antitumor drugs have also been made. It reveals that the reactivity of these three systems is quite similar, despite the fact that the thermochemical properties of the prototypical Myers-Saito and Bergman cyclizations are significantly different from each other.     

Abstraction of iodine from aromatic iodides by alkyl radicals: steric and electronic effects

Abstraction of the iodine atom from aryl iodides by alkyl radicals takes place in some cases very efficiently despite the unfavorable difference in bond dissociation energies of C-I bonds in alkyl and aryl iodides. The abstraction is most efficient in iodobenzenes, ortho-substituted with bulky groups. The ease of abstraction can be explained by the release of steric strain during the elimination of the iodine atom. The rate of abstraction correlates fairly well with the strain energy, calculated by density functional theory (DFT) and Hartree-Fock (HF) methods as a difference in the total energy of ortho and para isomers. However, besides the steric bulk, the presence of some other functional groups in an ortho substituent also influences the rate. The stabilization of the transition state, resembling a 9-I-2 iodanyl radical, by electron-withdrawing groups seems to explain a positive sign of the Hammett rho value in the radical abstraction of halogen atoms.     

Phospha-Michael additions to activated internal alkenes: steric and electronic effects

The addition of P(O)-H bonds to internal alkenes has been accomplished under solvent-free conditions without the addition of a catalyst or radical initiator. Using a prototypical secondary phosphine oxide, a range of substrates including cinnamates, crotonates, coumarins, sulfones, and chalcones were successfully functionalized. Highly activated acceptors such as isopropylidenemalononitrile and ethyl 2-cyano-3-methyl-2-butenoate underwent the phospha-Michael reaction upon simple trituration of the reagents at room temperature, whereas less activated substrates such as ethyl cinnamate and methyl crotonate required heating (>150 °C) in a microwave reactor to achieve significant consumption of the starting alkenes. For the latter alkenes, a competing reaction involving disproportionation of the ditolylphosphine oxide into ditolylphosphinic acid and ditolylphosphine was observed at the high temperatures needed to promote the addition reaction.     

Structure modulated electronic contributions to metalloenediyne reactivity: synthesis and thermal Bergman cyclization of MLX2 compounds

The synthesis of novel metalloendiyne complexes MLRX(2) (where L = 1,4-dibenzyl/diethyl-1,4-diaza-cyclododec-8-ene-6,10-diyne, X = halogen) are reported with their X-ray crystal structures and thermal Bergman cyclization temperatures. Two distinct types of constructs are obtained; the Zn(II) compounds are tetrahedral, while the Cu(II) and the Pd(II) compounds are all distorted- or square-planar. Each possesses structurally similar enediyne conformations and critical distances (3.75-3.88 A). The tetragonal Cu(II) species all exhibit Bergman cyclization temperatures between 140 and 150 degrees C in the solid state, while the square-planar Pd(II) analogues possess similar critical distances but cyclize at significantly higher temperatures (205-220 degrees C). In contrast, the Zn(II) derivatives show a marked halogen dependence, with X = Cl having the highest Bergman cyclization temperature, which is comparable to the Pd(II) square-planar set, while the ZnLX(2) compound with X = I shows the lowest Bergman cyclization temperature (144 degrees C), similar to the Cu(II) derivatives. Moreover, for the planar constructs, the R group has little influence on the cyclization temperatures; however, for the tetrahedral ZnLX(2) compounds, the steric influence of the R group plays a more significant role in the cyclization reaction coordinate by influencing the stability of the precyclized intermediate. This complex set of results is best interpreted by a combination of steric contributions and electronic interactions between the halogen through space (in the case of Zn(II)) and through bonds (in the case of Pd(II)) and the pi orbitals of the endiyne fragment. In contrast, for Cu(II) systems, the distorted square-planar geometry permits neither direct through space nor symmetry-allowed through bond communication between the orbital partners, and thus little variation in Bergman cyclization reactivity is observed.     

Solvent effects in hydrogen abstraction from cholesterol by benzophenone triplet excited state

Hydrogen abstraction from the C-7 position of cholesterol (Ch) by triplet excited benzophenone (BZP) exhibits remarkable solvent-dependence in product studies. Kinetic measurements on the intramolecular version of the process in dyads containing covalently linked Ch and BZP units reveal important solvent effects and significant stereodifferentiation.     

Enzyme dynamics and tunneling enhanced by compression in the hydrogen abstraction catalyzed by soybean lipoxygenase-1

A fully microscopical simulation of the rate-limiting hydrogen abstraction catalyzed by soybean lipoxygenase-1 (SLO-1) has been carried out. This enzyme exhibits the largest, and weakly temperature dependent, experimental H/D kinetic isotope effect (KIE) reported for a biological system. The theoretical model used here includes the complete enzyme with a solvation shell of water molecules, the Fe(III)-OH- cofactor, and the linoleic acid substrate. We have used a hybrid QM(PM3/d-SRP)/MM method to describe the potential energy surface of the whole system, and the ensemble-averaged variational transition-state theory with multidimensional tunneling (EA-VTST/MT) to calculate the rate constant and the primary KIE. The computational results show that the compression of the wild-type active site enzyme results in the huge contribution of tunneling (99%) to the rate of the hydrogen abstraction. Importantly, the active site becomes more flexible in the Ile553Ala mutant reactant complex simulation (for which a markedly temperature dependent KIE has been experimentally determined), thus justifying the proposed key role of the gating promoting mode in the reaction catalyzed by SLO-1. Finally, the results indicate that the calculated KIE for the wild-type enzyme has an important dependence on the barrier width.     

Reactions of Et(3)ZnLi with ketones: electronic and steric effects(1)

Toluene solutions of composition Et(3)ZnLi react rapidly with aldehydes and ketones to form addition products. Et(3)ZnNa and Et(3)ZnK solutions react readily with the same substrates although metalation, as well as addition, is significant with substrates having alpha-hydrogens. The Et(3)ZnM solutions react with 2-cyclohexenone to give mainly the 1,4-addition product. Relative rates of addition of Et(3)ZnLi to substituted acetophenones give a Hammett rho of 2.78. Addition of Et(3)ZnLi to acetophenone is slowed significantly by alpha and ortho methyl substituents; relative rates of addition to acetophenone, o-methylacetophenone, and tert-butyl phenyl ketone are 1.00, 0.012, and 0.003.     

Investigation of steric and electronic effects in the copper-catalysed asymmetric oxidation of sulfides

Steric and electronic effects in the copper-catalysed asymmetric oxidation of aryl benzyl, aryl alkyl and alkyl benzyl sulfides have been investigated. The presence of an aryl group directly attached to the sulfur is essential to afford sulfoxides with high enantioselectivities, with up to 97% ee for 2-naphthyl benzyl sulfoxide, the highest enantioselectivity achieved to date for copper-catalysed asymmetric sulfoxidation. In contrast, the benzyl substituent can be replaced by sterically comparable groups with no effect on enantioselectivity. Copper-mediated oxidation of substituted aryl benzyl sulfides display modest steric and electronic effects resulting in comparable or lower enantioselectivities to those obtained with the unsubstituted benzyl phenyl sulfide.     

Tuning and dissecting electronic and steric effects in ammonium receptors: nonactin vs artificial receptors

Ion selective electrodes (ISE) based on three different tripodal receptors (5, 6, and 7) have been investigated for sensing ammonium ion. Each receptor is based on three pyrazole groups that can accept three H-bonds from the bound ammonium ion. The receptor based on 4-bromo-3,5-dimethylpyrazole (6) is the most sensitive with a detection limit for ammonium ion of 2.5 x 10(-5) M at pH 8. The detection limits for the receptors based on 2,3-dimethylpyrazole (5) and unsubstitued pyrazole (7) are 1.0 x 10(-4) and 2.0 x 10(-4) M, respectively. The selectivities of the receptors 5, 6, and 7 for sensing ammonium ion over potassium ion (logK(NH)4+(/K)+) are -2.8, -2.3, and -1.7, respectively. In contrast, the detection limit and the selectivity of a nonactin-based ISE are 2.2 x 10(-5) M and -1.3, respectively. Crystallographic studies reveal that 6 accepts three H-bonds from the bound ammonium and singly protonated receptor 5 forms three H-bonds with the bound water molecule.