C_α–H Carries Information of a Hydrogen Bond Involving the Geminal Hydroxyl Group: A Case Study with a Hydrogen-Bonded Complex of 1,1,1,3,3,3-Hexafluoro-2-propanol and Tertiary Amines

Abstract

Experimental measurement of the contribution of H-bonding to intermolecular and intramolecular interactions that provide specificity to biological complex formation is an important aspect of macromolecular chemistry and structural biology. However, there are very few viable methods available to determine the energetic contribution of an individual hydrogen bond to binding and catalysis in biological systems. Therefore, the methods that use secondary deuterium isotope effects analyzed by NMR or equilibrium or kinetic isotope effect measurements are attractive ways to gain information on the H-bonding properties of an alcohol system, particularly in a biological environment. Here, we explore the anharmonic contribution to the C-H group when the O-H group of 1,1,1,3,3,3-hexafluoro-2-propanol (HFP) forms an intermolecular H-bond with the amines by quantum mechanical calculations and by experimentally measuring the H/D effect by NMR. Within the framework of density functional theory, ab initio calculations were carried out for HFP in its two different conformational states and their H-bonded complexes with tertiary amines to determine the (13)C chemical shielding, change in their vibrational equilibrium distances, and the deuterium isotope effect on (13)C2 (secondary carbon) of HFP upon formation of complexes with tertiary amines. When C2-OH was involved in hydrogen bond formation (O-H as hydrogen donor), it weakened the geminal C2-H bond; it was reflected in the NMR chemical shift, coupling constant, and the equilibrium distances of the C-H bond. The first derivative of nuclear shielding at C2 in HFP was -48.94 and -50.73 ppm Å(-1) for anti and gauche conformations, respectively. In the complex, the values were -50.28 and -50.76 ppm Å(-1), respectively. The C-H stretching frequency was lower than the free monomer, indicating enhanced anharmonicity in the C-H bond in the complex form. In chloroform, HFP formed a complex with the amine; δC2 was 69.107 ppm for HFP-triethylamine and 68.766 ppm for HFP-d2-triethylamine and the difference in chemical shift, the ΔδC2 was 341 ppb. The enhanced anharmonicity in the hydrogen-bonded complex resulted in a larger vibrational equilibrium distance in C-H/D bonds. An analysis with the Morse potential function indicated that the enhanced anharmonicity encountered in the bond was the origin of a larger isotope effect and the equilibrium distances. Change in vibrational equilibrium distance and the deuterium isotope effect, as observed in the complex, could be used as parameters in monitoring the strength of the H-bond in small model systems with promising application in biomacromolecules.

Mechanistic Insights into RNA Transphosphorylation from Kinetic Isotope Effects and Linear Free Energy Relationships of Model Reactions

“…Previous studies showed that ionization of alcohols enhances the electron density of the alcohol oxygen atom, which effectively decreases the CaÀH bond strength due to hyperconjugation resulting in normal secondary deuterium isotope effects. [55][56][57][58] Indeed, the secondary deuterium KIE on the 5' carbon atom for the model reactions are 1.15-1.2 which is near the EIE for ionization of an aliphatic alcohol (1.15) reflecting advanced leaving group bond cleavage (see the Supporting Information, Table S2). The secondary deuterium effects on the 2' carbon atom of the nucleophilic alcohol are observed to be inverse (0.85) reflecting the loss of ionization upon going from an oxyanion to a phosphoester due to advanced OÀP bond formation.…”

“…The success of the computational framework described here is best evaluated by the ability to identify and predict KIEs that provide insight into mechanism and, importantly, are amenable to subsequent experimental measurement. Previous studies showed that ionization of alcohols enhances the electron density of the alcohol oxygen atom, which effectively decreases the CαH bond strength due to hyperconjugation resulting in normal secondary deuterium isotope effects 55–58. Indeed, the secondary deuterium KIE on the 5′ carbon atom for the model reactions are 1.15–1.2 which is near the EIE for ionization of an aliphatic alcohol (1.15) reflecting advanced leaving group bond cleavage (see the Supporting Information, Table S2).…”

O–H hydrogen bonding promotes H-atom transfer from α C–H bonds for C-alkylation of alcohols

“…This so-called “oxy anionic substituent effect” (16, 17) leads to the acceleration of a wide range of organic reactions [such as oxyanionic [1,3] and [3,3] sigmatropic rearrangements and HAT from alkoxides (18)]. More recently, it has been shown that intermolecular hydrogen bonding between alcohols and various acceptor molecules gives rise to a similar polarization and weakening of the adjacent C–H bond (19), the strength of which is reflected in the 13 C nuclear magnetic resonance (NMR) chemical shift and the one-bond 13 C– 1 H coupling constant ( 1 J CH ) (20, 21). In particular, it was found that a 1 kJ/mol increase in the enthalpy of the H-bond resulted in a 0.2-Hz decrease in 1 J CH for hexafluoroisopropanol complexed to various amines (20).…”

Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease

“…Hydrogen bond interactions also play crucial role in biomolecular recognition [41]. Hydrogen bond profiles between the selected molecules and the target protein DENV1 (PDB: 3L6P)…”