Exploring the relationship between the conformation and pK_a: can a pK_avalue be used to determine the conformational equilibrium?

Abstract

Four substituted cis and trans-4,5-dihydroxyhexahydropyridazines that were expected to undergo pH induced conformational switching were synthesized and carefully investigated by NMR analyses and calculations. For two of the compounds a large difference in pKa existed between the two possible chair conformers and for one compound this resulted in conformational switching as a result of pH change. For the first time it is shown that the pKa directly reflects the conformational equilibrium of conformers.

Furanosyl Oxocarbenium Ion Conformational Energy Landscape Maps as a Tool to Study the Glycosylation Stereoselectivity of 2‐Azidofuranoses, 2‐Fluorofuranoses and Methyl Furanosyl Uronates

“…Although steric effects are often decisive in determining the overall shape of a neutral molecule, in charged molecules electronic effects become more important and they may in fact outweigh steric effects. For example, protonated iminosugars, that is, carbohydrates having the endocyclic oxygen replaced by a nitrogen, may change their conformation to place their ring substituents in a sterically unfavourable (pseudo)‐axial orientation to stabilise the positive charge on the ring nitrogen . In line with these stereoelectronic effects, glycosyl donors that feature an “axial‐rich” substitution pattern, are generally more reactive than glycosyl donors equipped with equatorially disposed functional groups .…”

“…For example, protonatedi minosugars, that is, carbohydrates having the endocyclic oxygen replaced by an itrogen, may change their conformation to place their ring substituents in as terically unfavourable (pseudo)-axial orientation to stabilise the positive charge on the ring nitrogen. [5][6][7][8][9][10] In line with these stereoelectronic effects, glycosyl donors that feature an "axial-rich" substitution pattern, are generally more reactive than glycosyl donors equipped with equatorially disposed functional groups. [11][12][13] However,i ti se xtremelyc hallenging to understand-leta lone predict-what the overall effect of multiple ring substituents is on the reactivity of ap articularg lycosyl donor and as ar esult the effect on the stereoselectivity in ag lycosylation reaction.…”

“…Understanding these effects will enable the development of effective glycosylation methodologies and aid in the interpretation of the outcome of glycosylation reactions. We have studied the effect of C2‐fluoride and C2‐azide substituents, as well as C4‐carboxylic acid ester groups, as these functionalities are commonly employed in the assembly of fluorinated, cis ‐linked glycosamine‐containing or glycuronic acid‐featuring oligosaccharides, respectively …”

Accurate Computation of Aqueous pKas of Biologically Relevant Organic Acids: Overcoming the Challenges Posed by Multiple Conformers, Tautomeric Equilibria, and Disparate Functional Groups with the Fully Black-Box pK-Yay Method

“…(d) The total number of tautomers and conformers we start with is 1139 (260 tautomers +879 conformers). These are obtained based on the conformer ordering from the literature. ,− In references and − , we list the name of the acid followed by the paper wherein we started our conformational sampling. From among these 1139 tautomers and conformers, 705 of them have conformers that are less than 2 kcal/mol (628 conformers and 77 tautomers).…”

“…The pK a of the encircled hydrogen in Figure 3 was determined experimentally at 298 K by Bols and co-workers. 175 In this molecule, the different R groups can exist in both axial and equatorial forms. The experimental pK a s correspond to an ensemble average wherein due to the ease of ring flipping, the R group may be either axial or equatorial.…”