Steric effects

About: Steric effects is a research topic. Over the lifetime, 16112 publications have been published within this topic receiving 319615 citations. The topic is also known as: steric hindrance.

Amide-amide and amide-water hydrogen bonds : implications for protein folding and stability

Abstract: As a protein folds, many of its main-chain amide groups exchange hydrogen bonds with water for hydrogen bonds with other main-chain amides. The energetic contribution of this exchange to the folding and stability of proteins is unclear.1 Theoretical2, calorimetric3, and spectroscopic4,5 studies indicate that amide–amide hydrogen bonds form readily in nonpolar media. In contrast, amide–amide hydrogen bonds form only at extremely high amide concentrations in water.6 Extensive efforts7 to evaluate the contribution of amide–amide hydrogen bonds to the aqueous stability of a particular receptor–ligand complex ultimately failed to exclude contributions to binding from other forces.8 To assess the importance of amide–amide hydrogen bonds in protein folding and stability, we have determined the relative strength of amide–amide and amide–water hydrogen bonds. Our analyses were performed on the simple peptide Ac-Gly–[β,δ-13C]Pro-OMe (1) and the related amide [13C=O]Ac-Pro-OMe (2).9 In a previous study, the kinetic barrier to prolyl peptide bond isomerization of 1 was shown to depend on the ability of the solvent to donate a hydrogen bond to the amidic carbonyl group.10 Here, the effects of amide solvents and water on this same kinetic barrier were determined using inversion transfer 13C NMR spectroscopy.11 Solvent effects on the amide I vibrational mode of 2 were determined using IR spectroscopy.12 The amide solvents studied mimic amide groups found in proteins.13 The relationship between the free energy of activation for the isomerization of 1 and the frequency of the amide I absorption band of 2 is shown in Figure 1. The amide I vibrational mode absorbs at lower frequencies with increasing strength of a hydrogen bond to the amide oxygen.14 Also, the rate of prolyl peptide bond isomerization is related inversely to the strength of hydrogen bonds formed to the amide oxygen.11 The axes in Figure 1 report independent measures of the ability of a solvent to donate a hydrogen bond to an amide oxygen.15 Figure 1 Plots of ΔG‡ for isomerization of 1 vs υ of amide I vibrational mode of 2 in different solvents. The solvents (neat concentration, M; pKa in Me2SO, if known24) were as follows: ◇, dioxane (11.7); △, N,N-dimethylformamide ... The data in Figure 1 show that water donates a strong hydrogen bond to an amidic carbonyl group. The analogous ability of secondary amide solvents, which resemble the main chain of proteins, to donate a hydrogen bond is dramatically less. The concentration of each solvent studied here was >10 M, which is likely to exceed the effective concentration of peptide bonds to one another, at least during the early stages of protein folding. These results suggest that amide–amide hydrogen bond formation alone is unlikely to drive protein folding.16 The data in Figure 1 also show that formamide, which mimics the primary amide in the side chains of asparagine and glutamine residues, is a significantly better hydrogen bond donor than is any of the secondary amides studied, and is almost as good as water.17 This result suggests that side-chain–main-chain hydrogen bonds can contribute more to protein stability than can main-chain–main-chain hydrogen bonds. This idea is consistent with asparagine, glutamine, and glycine being preferred residues at the C-terminus of α-helices.18 There, an amide side chain can donate a hydrogen bond to a main-chain carbonyl group, and a glycine residue can maximize the exposure of a main-chain carbonyl group to solvent water.19 What is the origin of the dramatic difference observed between the hydrogen bond donating abilities of secondary amides and formamide? An important contribution may arise from the effective concentration of donors, since an additional potential donor is always proximal to every hydrogen bond donated by formamide. Alternatively, the observed difference may result largely from steric constraints that restrict the number or geometry of hydrogen bonds donated by secondary amides, as has been proposed for large alcohols.4c,20 Regardless of its origin, the observed differences in hydrogen bond donating abilities are likely to be manifested during protein folding and in folded proteins. Approximately ¾ of the main-chain amides in globular proteins form hydrogen bonds with other main-chain amides.21 Although the formation of such intramolecular amide–amide hydrogen bonds in water can be exothermic,22 the results presented here and elsewhere4 indicate that amides form stronger intermolecular hydrogen bonds with water than with other amides. We conclude that main-chain–main-chain hydrogen bonds can form only in a cooperative process, which is likely to be facilitated by the hydrophobic collapse of the unfolded protein and the consequent shedding of water molecules from main-chain amides.1a We also suggest that the desolvation of individual main-chain amides diminishes the stability of folded proteins.1b,23

C-H arylation of pyridines: high regioselectivity as a consequence of the electronic character of C-H bonds and heteroarene ring.

Abstract: We report a new catalytic protocol for highly selective C–H arylation of pyridines containing common and synthetically versatile electron-withdrawing substituents (NO2, CN, F and Cl). The new protocol expands the scope of catalytic azine functionalization as the excellent regioselectivity at the 3- and 4-positions well complements the existing methods for C–H arylation and Ir-catalyzed borylation, as well as classical functionalization of pyridines. Another important feature of the new method is its flexibility to adapt to challenging substrates by a simple modification of the carboxylic acid ligand or the use of silver salts. The regioselectivity can be rationalized on the basis of the key electronic effects (repulsion between the nitrogen lone pair and polarized C–Pd bond at C2-/C6-positions and acidity of the C–H bond) in combination with steric effects (sensitivity to bulky substituents).

Analyzing Site Selectivity in Rh2(esp)2-Catalyzed Intermolecular C–H Amination Reactions

Abstract: Predicting site selectivity in C-H bond oxidation reactions involving heteroatom transfer is challenged by the small energetic differences between disparate bond types and the subtle interplay of steric and electronic effects that influence reactivity. Herein, the factors governing selective Rh2(esp)2-catalyzed C-H amination of isoamylbenzene derivatives are investigated, where modification to both the nitrogen source, a sulfamate ester, and substrate are shown to impact isomeric product ratios. Linear regression mathematical modeling is used to define a relationship that equates both IR stretching parameters and Hammett σ(+) values to the differential free energy of benzylic versus tertiary C-H amination. This model has informed the development of a novel sulfamate ester, which affords the highest benzylic-to-tertiary site selectivity (9.5:1) observed for this system.