Showing papers on "Steric effects published in 1996"

Molecular Recognition and Molecular Mechanics of Micelles of Some Model Asphaltenes and Resins

Abstract: Molecular mechanical calculations of resins and a highly aromatic model asphaltene extracted from the spectroscopic data of a 510 °C residue of a Venezuelan crude showed that the driving interaction in the micelle formation is the attraction between their aromatic planes. The molecular recognition process is completed by the interactions produced by the alkyl and cycloalkyl groups present in these molecules. The complex three-dimensional shape of the alkyl parts of this model asphaltene limits the growth of its micelles through steric interference. The shape of these asphaltene molecules allows the aggregation of only those resins that fit its aromatic regions and show the lowest steric interference with its alkyl groups. This type of molecular recognition may explain why only some resins are able to solubilize specific types of asphaltenes through the formation of stable aggregates. It was found also that the steric interference of the alkyl groups may limit the number of available sites for H bonding an...

Bond Dissociation Energies of O−H Bonds in Substituted Phenols from Equilibration Studies

Abstract: Bond dissociation energies (BDE) of several phenolic compounds have been determined by studying the equilibration of couples of phenols and of the corresponding phenoxyl radicals by means of EPR spectroscopy. Measurements were carried out in highly concentrated solutions submitted to continuous photolysis in the presence of di-tert-butyl peroxide. Since under this experimental condition the decay of the phenoxyl radicals was slower than the hydrogen transfer reaction from phenols to phenoxyls, equilibrium concentrations of the two radicals were actually measured. Due to the fact that the radical species are continuously generated in solution, phenols giving short-lived phenoxyl radicals could also be investigated by this method. All of the examined phenols are characterized by O−H bonds weaker than that of the parent compound, PhOH, and their BDE values can be calculated to a good approximation by an additive rule using fixed contributions for the various substituents. Only in the case of the sterically c...

Structure of DNA-porphyrin complex.

Abstract: We report the 2.4 A resolution X-ray structure of a complex in which a small molecule flips a base out of a DNA helical stack. The small molecule is a metalloporphyrin, CuTMPyP4 [copper(II) meso-tetra(N-methyl-4-pyridyl)porphyrin], and the DNA is a hexamer duplex, [d(CGATCG)]2. The porphyrin system, with the copper atom near the helical axis, is located within the helical stack. The porphyrin binds by normal intercalation between the C and G of 5' TCG 3' and by extruding the C of 5' CGA 3'. The DNA forms a distorted right-handed helix with only four normal cross-strand Watson-Crick base pairs. Two pyridyl rings are located in each groove of the DNA. The complex appears to be extensively stabilized by electrostatic interactions between positively charged nitrogen atoms of the pyridyl rings and negatively charged phosphate oxygen atoms of the DNA. Favorable electrostatic interactions appear to draw the porphyrin into the duplex interior, offsetting unfavorable steric clashes between the pyridyl rings and the DNA backbone. These pyridyl-backbone clashes extend the DNA along its axis and preclude formation of van der Waals stacking contacts in the interior of the complex. Stacking contacts are the primary contributor to stability of DNA. The unusual lack of van der Waals stacking contacts in the porphyrin complex destabilizes the DNA duplex and decreases the energetic cost of local melting. Thus extrusion of a base appears to be facilitated by pyridyl-DNA steric clashes.

The Total Synthesis of Dynemicin A Leading to Development of a Fully Contained Bioreductively Activated Enediyne Prodrug

Abstract: The title compound has been synthesized as its racemate in 33 steps. An intramolecular Diels−Alder reaction (see Scheme 5, 24 → 25) was used to provide control over the eventual cis C4−C7 relationship. The installation of another cis related ethynyl group at C2 arose from transformation 40 → 42 (see Scheme 8) whose directionality is governed by a benzophenone ketal functioning as a temporary steric control unit. Closure of the enediyne unit was accomplished on a trimethylsilylethoxycarbonyl (TEOC) protected dihydroquinoline derivative. It involved use of a novel bis-iodoalkyne/distannylethylene interpolative coupling transformation (61 + 58 → 63, Scheme 12). In the terminal phase of the synthesis, a novel iminoquinone ketal 74 (Scheme 15) was condensed with homophthalic anhydride derivative 78 (Scheme 16) as indicated in Scheme 17. The final deprotection involved cleavage of a methoxymethyl ester and two methoxymethyl phenol ethers. From this work, there arose the concept and demonstration of p-quinone mo...

Ground State Conformations and Entropic and Enthalpic Factors in the Efficiency of Intramolecular and Enzymatic Reactions. 1. Cyclic Anhydride Formation by Substituted Glutarates, Succinate, and 3,6-Endoxo-Δ4-tetrahydrophthalate Monophenyl Esters

Abstract: Intramolecular and enzymatic reactions require conformations in which the orbitals of reactants are properly aligned and van der Waals surfaces are in a near-attack conformation (NAC). Much of the changes in steric and electrostatic energies that take place in moving from the favored ground state conformation (FGSC) to the transition state are accounted for when the NAC has been assumed. Upon assessing the steric, electrostatic, and zero point energies, one is in position to calculate the probability of NAC formation. Using a series of monoesters of dicarboxylic acids, we have (i) created, via stochastic search, 10 000−40 000 minimized conformations per ester; (ii) chosen only the unique local minima conformations for each ester; (iii) determined the energies of each minimum conformation using MM3(92); (iv) identified the geometry of the NACs where the van der Waals overlap has not begun for the approach of carboxyl anion and ester carbonyl; and (v) calculated the mole fraction (probability, P) of each es...

Steric Effects on the Amide Isomer Equilibrium of Prolyl Peptides. Synthesis and Conformational Analysis of N-Acetyl-5-tert-butylproline N‘-Methylamides

Abstract: The influence of a bulky 5-position substituent on the amide isomer equilibrium N-terminal to proline has been explored via the synthesis and analysis of N-(acetyl)proline N‘-methylamide (1) and its respective cis- and trans-5-tert-butylproline amide diastereomers 2 and 3. The relative populations of the amide cis- and trans-isomers as well as the energy barriers for amide isomerization of 1−3 in D2O were ascertained using NMR with coalescence and magnetization transfer experiments. The relative populations of free C-terminal amide and hydrogen-bonded amide in the γ-turn conformation were also estimated by integrating the N−H stretch absorbances in the FT-IR spectra of 1−3 in CHCl3 and CCl4. In the prolyl peptides, the 5-tert-butyl substituent was found to exhibit profound effects on the amide isomer equilibrium, on the energy barrier for amide isomerization, and on the stability of the γ-turn conformation. Steric interactions between the 5-position substituent and the N-acetyl group disfavor the amide tr...

Role of Electronic Asymmetry in the Design of New Ligands: The Asymmetric Hydrocyanation Reaction

Abstract: The concepts of C2 symmetry and catalyst-substrate steric interactions have played an important role in the design and understanding of asymmetric catalysts and stereoselective reagents.1,2 The C2 symmetry element often simplifies the synthesis of the reagents and serves to reduce the number of competing diastereomeric intermediates in reactions involving their use.3,4 Most often, the models5 which adequately predict the stereochemical outcome of these reactions are based on the spatial orientation of groups within the disymmetric environment of the auxiliary or catalyst. Such steric-based, heuristic models are used not only to rationalize results but also to design more effective catalysts.6 Even so, examples of the electronic tuning of asymmetric catalysts are appearing in the literature with increasing frequency.7-12 Furthermore, in several cases, good enantioselectivities were obtained using chiral ligands without C2 symmetry.7,10-12 The underlying reasons for the dependence of enantioselectivity on ligand electronics are only poorly understood. Nonetheless, the mechanistic and structural information that has become available in these cases suggests that a rationale based on steric effects alone does not adequately explain the stereochemical outcome. For reactions under the Curtin-Hammett regime, stereoelectronics may well play a determining role in the relative transition-state energies involved in the enantioselective step(s).13-15 Thus, a transition metal complex with a bidentate ligand in which the two ligating atoms are electronically different could impart stereoelectronic control in the formation of a specific product, resulting in enhanced selectivity.14 Indeed such effects may be responsible for the high enantioselectivity observed in a number of asymmetric reactions wherein different chelating atoms are used.11,12 Unfortunately, a clear delineation of the steric and electronic effects is not possible in many of these systems. Ligands specifically designed to probe pure electronic asymmetry gave only moderate improvements over the more symmetric analogs.19 To the best of our knowledge such ligands have not been tested in asymmetric carbon-carbon bond-forming reactions. Here we report on the use of an electronically unsymmetrical bis-3,4diarylphosphinite ligand derived from an R-D-fructofuranoside (3) to achieve the highest enantioselectivity (R/S: 97.5/2.5) ever recorded for the asymmetric hydrocyanation reaction. In addition, the concept is further illustrated with the use of one of the simplest C2-symmetric systems, viz., a bis-phosphinite derived from (S,S)-tartranil (6). Vinylarenes react with HCN in the presence of Ni(0) complexes of vicinal diarylphosphinites to give exclusively the branched nitriles, which are potential intermediates for the synthesis of arylpropionic acids (eq 1). The enantioselectivity depends on the phosphorus substituents, and we have previously shown that electron-withdrawing substituents on phosphorus in a D-glucose-derived phosphinite system gave high ee’s (∼91%) for this reaction,10a,c in which the major product is the S-

Energetics and site specificity of the homolytic c-h bond cleavage in benzenoid hydrocarbons : an ab initio electronic structure study

Abstract: Electronic structure calculations carried out at the BLYP/6-311G** level of theory accurately predict the dissociation energy of the C−H bond in benzene. The analogous energies of the homolytic C−H bond cleavage in the other nine polycyclic aromatic hydrocarbons (PAHs) are found to be governed almost entirely by steric factors, the hydrogens from congested regions of the PAHs being removed preferentially. The removal of hydrogens is accompanied by highly regular changes in the molecular geometries, namely a widening of the ipso bond angle by ca. 6.0° and a concomitant shortening of the adjacent C−C bonds by ca. 0.02 A. These observations suggest an almost complete localization of the unpaired σ electrons on single carbon atoms and the separation of the local σ and π effects in the aryl radicals under study. This localization is confirmed by the computed charges and spin populations of atoms in the phenyl, 1-naphthalenyl, and 2-naphthalenyl radicals. In contrast with their UHF counterparts, the UBLYP elect...

Photogeneration of Amines from α-Keto Carbamates: Photochemical Studies

Abstract: We investigate the design of new photoprecursors of organic bases and the steric and electronic factors that control their photocleavage to give free amines. The design strategy involves the protection of an amine with novel [(benzoinyl)oxy]carbonyl groups and substituted analogs. The resulting masked amines owe their photosensitivity to the rich photochemistry of the benzoinyl chromophore. The photochemistry of this chromophore allows for the clean photogeneration of free amine upon irradiation with UV light below 400 nm in both the solid state and in solution. The structure of the benzoinyl chromophore was varied to determine the optimal chromophore design. By varying the chromophore design, the influence of various steric and electronic effects on the photoliberation of free amines from α-keto carbamates could be gauged. Structural modification of the aryl rings was intended to probe the electronic factors of the photocyclization. Substitution at the 2 position was varied to investigate the steric fact...

Molecular dynamics simulations of peptides from BPTI : A closer look at amide-aromatic interactions

Abstract: Molecular dynamics (MD) simulations of short peptides in water were performed to establish whether it is possible to reproduced experimental data from chemical shift measurements by nuclear magnetic resonance spectroscopy. Three different tetrapeptides were studied. The first, YTAP (Tyr-Thr-Gly-Pro), shows an electrostatic interaction between the aromatic ring of Tyr and the backbone amide hydrogen atom of Gly. The second, YTAP (Tyr-Thr-Ala-Pro), cannot make such an interaction because of steric hindrance of the Ala side chain and hence does not show a well-defined conformation. The third, FTGP (Phe-Thr-Gly-Pro), is shown to alternate between two different conformations. It is demonstrated that small differences in chemical shift, corresponding to these slightly different conformations, can be quantitatively modeled in MD simulations when using the proper force-field parameters and water model. Explicit inclusion of hydrogen atoms on the aromatic rings is essential for a proper description of electrostatic interactions, but the choice of the water model is equally important. We found that a combination of the SPC/E water model and a revised GROMOS87 force field gives close agreement with experiment, while the same and other force fields in combination with SPC or TIP3P water did not reproduce the NMR data at all. Simulations of a longer peptide from bovine pancreatic trypsin inhibitor, containing the YTGP sequence, did show the interaction between the aromatic ring and the amide hydrogen, but not as pronounced as the simulations of shorter peptides.

Steric and Electronic Effects, Enantiospecificity, and Reactive Orientation in DNA Binding/Cleaving by Substituted Derivatives of [SalenMn(III)](+).

Abstract: Twenty-six derivatives of [SalenMnIII]+ (1) bearing halogen, nitro, amino, ether, alkyl, or aryl substituents on the aromatic rings and/or at the imine positions or containing 1,3-propylene-, 1,2-p...

Binuclear zirconocene cations with μ-CH3-bridges in homogeneous Ziegler-Natta catalyst systems

Abstract: Binuclear zirconocene cations are observed by I H-NMR in C6D6 solutions containing B(C6F5)3 and an excess of a zirconocene dimethyl complex. The CH3-bridged cation [«C5H5)2ZrCH3)ilL-CH3)]+' solvent-separated from the anion H 3 C-B(C 6 F 5 )3' is present in equilibrium with (C5H5)2Zr(CH3)2 and the mononuclear ion pair [(C5H5)2ZrCHj ... H 3 C-B(C 6 F 5 )3]; in more concentrated solutions, a binuclear ion pair [«C5H5)2ZrCH3)ilL-CH3)+ ... H3C­ B(C6F5)3] is the dominant species. Similar equilibria are observed in C6D6 solutions containing B(C 6F5)3 and (CH3)4CiC5H4)2Zr(CH3)2' (CH3)2Si(C5H4)2Zr(CH3)2 or rac-(CH 3)2 Si(indenyJ)2 Zr(CH 3)2' Complexes with sterically more demanding ligands, such as (C5(CH3)5)2Zr(CH3)2 or rac-(CH3)2Si(2-methyl-benz[e]indenyJ)2Zr(CH3)2 do not form any binuclear species under these conditions. In the catalyst system rac-(CH3)2Si(indenyJ)2Zr(CH3)2/Bu3NH+B(C6F5);' activities for the polymerization of propene increase with excess of the dimethyl zirconocene complex. This effect is due in part to a sacrifice of some dimethyl zirconocene for the removal of impurities from the catalyst system and in part to a stabilization of the catalyst in the form of the binuclear cation [«CH3)2Si(indenyJ)2ZrCH3MIL-CH3)]+' The latter appears to act, in the presence of propene, as a source of the mononuclear cation [(CH3)2Si(indenyJ)2ZrCH3(C3H6)]+' rather than as a polymerization catalyst by itself.

Stereoselective Synthesis of Both Enantiomers of Axially Chiral Biaryls Utilizing Planar Chiral Tricarbonyl(arene)chromium Complexes

Abstract: Tricarbonyl(2,6-disubstituted 1-bromobenzene)chromium complexes were treated with ortho-substituted arylboronic acids in the presence of Pd(0) catalyst to give mono Cr(CO)3 complexes of biphenyl compounds with complementary axial chirality, with extremely high stereoselectively depending upon the steric bulkiness of the ortho substituents. Cross-coupling of o-alkyl- or hydroxymethyl-substituted phenylboronic acids with (arene)chromium complexes diastereoselectively gave Cr(CO)3-complexed biaryls in which the ortho substituents are in a syn-orientation to the tricarbonylchromium fragment. With o-formyl phenylboronic acids, diastereoisomeric anti-coupling products were stereoselectively obtained. The kinetically controlled coupling products were easily isomerized to thermodynamically more stable mono-Cr(CO)3-complexed biaryls by modification of the o-substituents to less hindered ones, or the thermal conditions assisted the axial isomerization. The overall process can be considered to be an enantioselective...

Peptide Coupling in the Presence of Highly Hindered Tertiary Amines

Abstract: Previously, 2,4,6-trimethylpyridine (collidine), due to steric shielding around the N-atom, was found to be an efficient base for effecting peptide segment coupling via azabenzotriazole-based onium-style coupling reagents. A number of even more highly hindered bases, including 2,3,5,6-tetramethylpyridine, 2,6-di-tert-butyl-4-(dimethylamino)pyridine, triisopropylamine, and N-tert-butylmorpholine, have been compared with collidine in such reactions. Some of the newer bases showed advantages in terms of convenience in handling and maintenance of configuration during segment coupling processes, although dramatic differences based on steric effects were not observed. On the basis of results with a number of test peptides and many base-coupling reagent combinations, it was noted that most efficient results are obtained if 1 equiv of HOAt is present as an additive during the coupling process. For rapid activation of onium-style coupling reagents during stepwise solid-phase coupling reactions, the stronger base 2...

Quantum‐chemical Descriptors for Estimating the Acute Toxicity of Electrophiles to the Fathed minnow (Pimephales promelas): An Analysis Based on Molecular Mechanisms

Abstract: Estimating the toxicity of reactive xenobiotics to aquatic organisms requires physicochemical descriptors of passive transport and chemical reactions with nucleophilic biological ligands. Herein, electrophiles whose toxic action is attributed to nucleophilic substitution (SN), Michael-type addition and Schiff-base formation were examined. Training sets for each molecular mechanism were generated through substructure search applied to chemicals in a fathead minnow (Pimephales promelas) database. Based on a delineation of compounds by a presumed molecular mechanism, relationships between modes of toxic action, potency (96-hour LC50 values) and mechanistically-appropriate quantum-chemical descriptors were explored. Monohalo-C(sp3) function which may give rise to SN reactivity was encountered in 35 compounds. The inclusion of ELUMO, a nonspecific electrophilicity descriptor, to the generic LC50 - hydrophobicity relation increased the explained variance from r2 = 36% to 69%. Eighteen potential Michael-type acceptors, mainly acrylates, were identified by the presence of a localized CC double bond at an α, β position to a polar group. Due to different modes of action, the toxic potency of these chemicals varies almost independently of hydrophobicity (r2 = 0.12). Two additional electronic descriptors that are consistent with the likely molecular mechanism provide a multivariate QSAR with r2 = 0.78. Forty-five aldehydes and 3 formamides comprised the training set associated with probable Schiff-base mechanism of toxicity. The results suggest a marginal increase of toxic potency from that expected due to narcosis for more electrophilic carbonyl groups. Overall, it was concluded that regressions based on data sets that combine reactive chemicals with narcotics typically require an electronic descriptor in addition to hydrophobicity, even if the compounds all contain a common electrophilic moiety related to the putative specific reaction mechanism. However, without the generation of additional toxicity data from chemical sets that incorporate a broader range of electronic and steric character, it will likely remain extremely difficult to develop a quantitative ability to predict the potency of electrophilic compounds.

Activation of H−H, Si−H, and C−H Bonds by nsnp Excited States of Metal Atoms

Abstract: We present a comprehensive overview of our current knowledge of the interactions of valence M(nsnp 3P) and M(nsnp 1P1) excited states with H−H, Si−H, and C−H bonds, where M = Mg, Zn, Cd, and Hg. It is proposed that the high reactivity of M(nsnp 3P1) states with H−H and Si−H bonds compared to C−H bonds is due to the lack of steric hindrance in the localized, side-on, M(npπ)−XH(σ*) donor−acceptor molecular orbital interactions, since the Si−H bond length in SiH4 is ∼1.5 A compared to C−H bond lengths of ∼1.1 A. It is also concluded that Mg(3s3p 1P1) and Zn(4s4p 1P1) efficiently activate C−H bonds as well as H−H and Si−H bonds not just because of their higher energy but because of better M(npπ)−XH(σ*) energy matches and overlap, which overcomes M(ns)−XH(σ) repulsion and the steric hindrance. It is further proposed that the striking differences in the microscopic mechanisms of attack of C−H bonds by Mg(1P1) versus Zn(1P1) may be due to the fact that the Zn(4s) “core” is substantially (∼0.2 A) smaller than the...

Synthesis of Cyclopropylpyrrolidines via Reaction of N-Allyl-N-propargylamides with a Molybdenum Carbene Complex. Effect of Substituents and Reaction Conditions

Abstract: Previous studies have demonstrated that group 6 carbene complexes react with α,ω-enynes to form vinylcyclopropane derivatives in good to excellent yield, and that the length and composition of the tether between the alkyne and the alkene often has a dramatic impact on the viability of this reaction pathway. The reactivity of allylpropargyl amine derivatives with pentacarbonyl(1-methoxypentylidene)molybdenum(0) (14a) was investigated in order to provide further insight into the steric and electronic factors controlling this reaction. Treatment of allylpropargyl amines with 14a failed to produce the desired cyclization products while treatment of allylpropargyl amides with 14a led to the expected cyclopropylpyrrolidine systems in good to excellent yields. Higher yields are obtained when the reaction is conducted in a sealed vial in the presence of atmospheric oxygen.

Diastereoselectivity in the epoxidation of substituted cyclohexenes by dimethyldioxirane

Abstract: Three series of compounds based on the cyclohexene framework have been epoxidized by dimethyldioxirane. A pronounced dependence of epoxide diastereoselectivity on substituent has been observed. In addition there is a solvent influence on this stereoselectivity. The results have been explained by invoking steric, H-bonding, and dipole−dipole influences on the epoxide stereochemistry.

Retinal analog study of the role of steric interactions in the excited state isomerization dynamics of rhodopsin.

Abstract: The role of intramolecular steric interactions in the isomerization of the 11-cis-retinal chromophore in the photoreceptor protein rhodopsin is examined with resonance Raman and CD spectroscopy combined with quantum yield experiments. The resonance Raman spectra and CD spectra of 13-demethylrhodopsin indicate that its chromophore, an analog in which the nonbonded interaction between the 10-H and the 13-CH3 groups is removed, is less distorted in the C10···C13 region than the native chromophore. The reduced torsional and hydrogen-out-of-plane resonance Raman intensities further indicate that the excited state potential energy surface has a much shallower slope along the isomerization coordinate. This is consistent with the decrease in quantum yield from 0.67 in rhodopsin to 0.47 in 13-demethylrhodopsin. The resonance Raman intensities show that the steric twist is reintroduced by addition of a methyl group at the C10 position. However, the quantum yield of 10-methyl-13-demethylrhodopsin is found to be only...

Homochiral and heterochiral dimers of the methylzinc alkoxide formed from dimethylzinc and enantiomeric 3-exo-(dimethylamino)isoborneol - Origin of the distinct differences in solution-phase behavior and crystal structures

Abstract: Dimethylzinc reacts with (2S)-or (2R)-3-exo-(dimethylamino)isoborneol [(2S)- or (2R)-DAIB] to eliminate methane and produce a tricoordinate methylzinc aminoalkoxide, which forms a dimeric structure The homochiral dimerization of the enantiomeric compound leads to the chiral, (S,S) or (R,R) dinuclear Zn complex, while the heterochiral interaction forms the meso (S,R) dinuclear compound In both solution and crystalline state, the heterochiral dimer is more stable than the homochiral dimer This stability difference in solution is the origin of the chirality amplification observed in the amino alcohol promoted asymmetric addition of dimethylzinc to benzaldehyde In toluene, the homochiral dimer dissociates more readily into the monomer than the heterchiral isomer and also undergoes dissociation of the N-Zn dative bond making the two N-methyl groups equivalent The differences in solution behavior between the diastereomers can be understood by comparing their crystal structures X-ray analysis indicates that the labile Zn-O and Zn-N bonds in the (S,S) dimer are longer than those in the (S,R) isomer Skeletal congestion caused by the polycyclic framework is the prime factor determining the properties of the dinuclear Zn complexes, with both steric and electronic factors governing their geometries The distances between the C-2 proton and N-CH3 of the other DAIB moiety in the homochiral dimer are close to the sum of the van der Waals radii A significant nuclear Overhauser effect is seen between these protons in the homochiral dimer The tetrahedral Zn atoms in the dinuclear complexes are linked covalently to the methyl group, to two oxygen atoms through covalent/electrostatic hybrid bonds, and to the dimethylamino group through electrostatic interaction The repulsive interaction of the 1, 3-synoriented Zn-CH3 bonds significantly contributes to the lower stability of the homochiral dimeric complex The N-Zn interaction in the homochiral dimer is labile, owing to the increase in the electrostatic interaction between the Zn atom and the neighboring oxygen atoms This view is supported by the ab initio molecular orbital calculations of the model systems