Influence of steric effects in solid-phase aza-peptide synthesis

Aza-peptides are peptide analogs with potential applications as drug candidates. However, due to difficulties associated with the synthesis of these compounds, information regarding their bioactivity is very limited. Herein, we identify steric hindrance as one reason for the slowness of the aza-peptide bond formation reaction. The steric effect of the side group of amino acids in their coupling with the semicarbazide moiety in the synthesis of a model peptide, H-AA-AzAla-Phe-NH₂, was studied and quantified using COMU as a coupling reagent. Characterization of the role of this structural factor in aza-peptide bond synthesis is essential for outlining a new and efficient synthesis protocol.     

Influence of steric, electric, and dielectric effects on membrane potential

The membrane potential arising through nanofiltration membranes separating two aqueous solutions of the same electrolyte at identical hydrostatic pressures but different concentrations is investigated within the scope of the steric, electric, and dielectric exclusion model. The influence of the ion size and the so-called dielectric exclusion on the membrane potential arising through both neutral and electrically charged membranes is investigated. Dielectric phenomena have no influence on the membrane potential through neutral membranes, unlike ion size effects which increase the membrane potential value. For charged membranes, both steric and dielectric effects increase the membrane potential at a given concentration but the diffusion potential (that is the high-concentration limit of the membrane potential) is affected only by steric effects. It is therefore proposed that membrane potential measurements carried out at high salt concentrations could be used to determine the mean pore size of nanofiltration membranes. In practical cases, the membrane volume charge density and the dielectric constant inside pores depend on the physicochemical properties of both the membrane and the surrounding solutions (pH, concentration, and chemical nature of ions). It is shown that the Donnan and dielectric exclusions affect the membrane potential of charged membranes similarly; namely, a higher salt concentration is needed to screen the membrane fixed charge. The membrane volume charge density and the pore dielectric constant cannot then be determined unambiguously by means of membrane potential experiments, and additional independent measurements are in need. It is suggested to carry out rejection rate measurements (together with membrane potential measurements).     

Influence of steric and electronic effects of substituents on the molecular structures and conformational flexibility of 1,8-naphthalenedicarboximides

A series of 1,8-naphthalenedicarboximide derivatives containing substituents of different steric and electronic nature were studied by X-ray diffraction analysis.Ab initio quantumchemical calculations in the HF/3–21G approximation demonstrated the high conformational flexibility of the imide tetrahydro ring in the molecules of these compounds. The electronic nature of the substituents has no effect on the geometry and conformational flexibility of naphthalenedicarboximides due to weak conjugation between the imide and naphthalene fragments in the molecules. However, the steric effects of the bulky substituents noticeably affect the equilibrium geometry of the imide ring by increasing its conformational flexibility. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 68–73, January, 2000.     

Influence of steric and electronic effects of substituents on the molecular structures and conformational flexibility of 1,8-naphthalenedicarboximides

A series of 1,8-naphthalenedicarboximide derivatives containing substituents of different steric and electronic nature were studied by X-ray diffraction analysis.Ab initio quantumchemical calculations in the HF/3–21G approximation demonstrated the high conformational flexibility of the imide tetrahydro ring in the molecules of these compounds. The electronic nature of the substituents has no effect on the geometry and conformational flexibility of naphthalenedicarboximides due to weak conjugation between the imide and naphthalene fragments in the molecules. However, the steric effects of the bulky substituents noticeably affect the equilibrium geometry of the imide ring by increasing its conformational flexibility. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 68–73, January, 2000.     

Influence of steric factors on the direction of reactions

Russian Journal of Organic Chemistry -     

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.     

Influence of steric factors on exciplex energy and magnetic field effect

With the advent of spin chemistry, magnetic field effect (MFE) on exciplex luminescence has emerged as an important domain of research. MFE is a diffusion controlled phenomenon and hence is solvent dielectric (epsilon) dependent. It maximizes at a particular epsilon (epsilon(max)) for a specific exciplex system. Various attempts have been made to explain the variation of this epsilon(max) from one exciplex to another. In our present work we have succeeded for the first time to enmark the energy of exciplex (E(ex)) as the prime factor in determining the epsilon(max). We have indicated a definite inverse correlation (1:1) between epsilon(max) and E(ex). We have also tried to correlate some parameters that are important in exciplex formation, e.g. Charton's steric constant (nu(c)), repulsive energy (R(e)) and E(ex).     

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.     

Reaction of dicarbonyl compounds with dimethyl 3-ketoglutarate. Influence of steric effects on success of the condensation

The influence of steric factors on the synthesis of substituted bicyclo[3.3.0]octane-3,7 diones $\text{via}$ the condensation of 1,2-dicarbonyl compounds with dimethyl 3-ketoglutarate $\text{2}$ is described.     

Comments on steric effects in buttressed methyl pyridine species

Using MINDO/3 calculations, we have investigated the importance of gear effects and pointing H-H interactions in several polymethylpyridine systems. Gear clashing of methyl groups on adjacent ring positions was found to produce about 0.6 kcal mole^-1 stabilization, while interaction between two pointing hydrogens destabilizes the molecule by about 1.1 kcal mo1e^-1. Calculated barriers for rotation of the isopropyl group in several 1-isopropyl-poly methyl pyridiniun cations were in good agreement with experimental results published recently by Roussel. The calculations indicate that the decrease in the rotational barrier upon additional buttressing of methyl groups can be attributed to destabilization of the ground rotational conformer for the more sterically hindered 1-isopropyl polymethyl pyridinium species.     

Curtin-Hammett and steric effects in HOBt acylation regiochemistry

While hydroxybenzotriazole is commonly used in a variety of bond-forming reactions, its acylation has been shown to produce a regiochemical (O vs N) mixture with complex kinetic behavior. Increased steric bulk on the electrophile favors formation of the oxygen-acylated product. Upon standing as a solid, the mixture can isomerize completely to the nitrogen adduct. An equilibrium ratio of regioisomers can be re-established in solution by adding either nucleophilic or electrophilic reagents, suggesting that the composition of the mixture is not significant to subsequent reactivity. Solvents can affect this regiochemical equilibrium through a Curtin-Hammett effect, where the shift in the tautomeric equilibrium of HOBt in polar solvents biases the reaction toward the oxygen adduct.     

Electronic and steric effects of substituents on the coordinating properties of porphyrins

Kinetics of the formation of zinc complexes of porphyrin with various substituents was studied in acetic acid and pyridine. The introduction of strong electron-withdrawing substituents (nitro groups) to the meso-positions of the porphyrin macrocycle was shown to change the reaction rate by an order of magnitude or less compared to the phenyl-substituted analogs. However, the introduction of a large number of bulky substituents leads to the deformation of the porphyrin ligand and thus affects much stronger the coordination properties of porphyrins, decreasing or increasing the rate of the complexation reaction by several orders of magnitude.     

The steric and electronic effects of aliphatic fluoroalkyl groups

Ab initio calculations were performed on 18 fluorinated and unfluorinated alcohols at the B3LYP and HF levels with the 6-311G^∗∗ basis set. Molar volumes of the alcohols were computed at each level and averaged to produce a scale of relative size. From this, various isosteric replacements of potential use in drug design were suggested: ethyl by FCH₂CH₂ or HCF₂CH₂, propyl by CF₃CH₂, isopropyl by CF₃(CH₃)CH or (FCH₂)₂CH, isobutyl or t-butyl by (CF₃)₂CH, and 3-methyl-2-butyl by CF₃(CH₃)₂C. Calculation of the charge on oxygen and the Wiberg index of the CO bond allowed an electronegativity scale to be constructed for the fluoroalkyl groups. Electronegativity decreased in the order: (CF₃)₃C>(CF₃)₂CH>C₂F₅CH₂>CF₃CH₂>CH₃(CF₃)₂C>HCF₂CH₂>CF₃(CH₃)CH>(FCH₂)₂CH>FCH₂CH₂>CF₃(CH₃)₂C. This ranking agreed with literature acid dissociation data for the alcohols studied.     

Electronic and steric effects in thermal denitrosation of N-nitrosoamides

N-Alkyl-N-nitrosoamides undergo competitive reactions whose rates are dependent upon the interplay of a number of factors. There already exists a significant body of work delineating the effects of pH on the partitioning of the nitrosoamides along their deaminative (-N(2)) and denitrosative (-"NO(+)") pathways. In this paper, the issue of pH dependence is discussed with particular attention to nitrosoamide decompositions in nonaqueous media. The role of the acidity of the medium in the partitioning of the nitrosoamide between deamination and denitrosation and in the choice of deaminative pathways is revisited. In nonaqueous media under near-neutral conditions, the partitioning's pH dependence is evidently accompanied by a sensitivity to structural features in the nitrosoamide. Thus, diminution of steric crowding around the N-nitroso moiety as well as the presence of strongly electron-withdrawing acyl units (i.e., those derived from strong acids, e.g., tosyl and trifyl) increase the relative yield of amides by encouraging the denitrosative pathway. A mechanism for thermal denitrosation of nitrosoamides under near-neutral conditions is proposed in which rapid protonation at the acyl O rather than slow protonation at the amidic N is the first step in the reaction profile. A rate-limiting, bimolecular reaction between the O-conjugate acid and adventitious nucleophiles at the nitrosyl group then occurs followed by rapid tautomerization to amide.