Dataset Information

Preferential N-H⋯:C[double bond splayed right] hydrogen bonding involving ditopic NH-containing systems and N-heterocyclic carbenes.

ABSTRACT: Hydrogen bonding plays a critical role in maintaining order and structure in complex biological and synthetic systems. N-heterocyclic carbenes (NHCs) represent one of the most versatile tools in the synthetic chemistry toolbox, yet their potential as neutral carbon hydrogen bond acceptors remains underexplored. This report investigates this capability in a strategic manner, wherein carbene-based hydrogen bonding can be assessed by use of ditopic NH-containing molecules. N-H bonds are unique as there are three established reaction modes with carbenes: non-traditional hydrogen bonding adducts (X-H⋯:C[double bond splayed right]), salts arising from proton transfer ([H-C[double bond splayed right]]⁺[X]^-), or amines from insertion of the carbene into the N-H bond. Yet, there are no established rules to predict product distributions or the strength of these associations. Here we seek to correlate the hydrogen bond strength of symmetric and asymmetric ditopic secondary amines with 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr, a representative NHC). In symmetric and asymmetric ditopic amine adducts both the solid-state (hydrogen bond lengths, NHC interior angles) and solution-state (¹H Δδ of NH signals, ¹³C signals of carbenic carbon) can be related to the pK _a of the parent amine.

SUBMITTER: Kinney ZJ

PROVIDER: S-EPMC9057831 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Preferential N-H⋯:C[double bond splayed right] hydrogen bonding involving ditopic NH-containing systems and N-heterocyclic carbenes.

Kinney Zacharias J ZJ Rheingold Arnold L AL Protasiewicz John D JD

RSC advances 20201120 69

Hydrogen bonding plays a critical role in maintaining order and structure in complex biological and synthetic systems. N-heterocyclic carbenes (NHCs) represent one of the most versatile tools in the synthetic chemistry toolbox, yet their potential as neutral carbon hydrogen bond acceptors remains underexplored. This report investigates this capability in a strategic manner, wherein carbene-based hydrogen bonding can be assessed by use of ditopic NH-containing molecules. N-H bonds a ...[more]

PMID: 35516763

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Project description:Computational studies are performed to analyze the physical properties of hydrogen bonds donated by Tyr16 and Asp103 to a series of substituted phenolate inhibitors bound in the active site of ketosteroid isomerase (KSI). As the solution pK(a) of the phenolate increases, these hydrogen bond distances decrease, the associated nuclear magnetic resonance (NMR) chemical shifts increase, and the fraction of protonated inhibitor increases, in agreement with prior experiments. The quantum mechanical/molecular mechanical calculations provide insight into the electronic inductive effects along the hydrogen bonding network that includes Tyr16, Tyr57, and Tyr32, as well as insight into hydrogen bond coupling in the active site. The calculations predict that the most-downfield NMR chemical shift observed experimentally corresponds to the Tyr16-phenolate hydrogen bond and that Tyr16 is the proton donor when a bound naphtholate inhibitor is observed to be protonated in electronic absorption experiments. According to these calculations, the electronic inductive effects along the hydrogen bonding network of tyrosines cause the Tyr16 hydroxyl to be more acidic than the Asp103 carboxylic acid moiety, which is immersed in a relatively nonpolar environment. When one of the distal tyrosine residues in the network is mutated to phenylalanine, thereby diminishing this inductive effect, the Tyr16-phenolate hydrogen bond becomes longer and the Asp103-phenolate hydrogen bond shorter, as observed in NMR experiments. Furthermore, the calculations suggest that the differences in the experimental NMR data and electronic absorption spectra for pKSI and tKSI, two homologous bacterial forms of the enzyme, are due predominantly to the third tyrosine that is present in the hydrogen bonding network of pKSI but not tKSI. These studies also provide experimentally testable predictions about the impact of mutating the distal tyrosine residues in this hydrogen bonding network on the NMR chemical shifts and electronic absorption spectra.

Dataset Information

Preferential N-H⋯:C[double bond splayed right] hydrogen bonding involving ditopic NH-containing systems and N-heterocyclic carbenes.

Publications

Preferential N-H⋯:C[double bond splayed right] hydrogen bonding involving ditopic <i>NH</i>-containing systems and <i>N</i>-heterocyclic carbenes.

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