François Besseau

An Enthalpic Scale of Hydrogen-Bond Basicity. 4. Carbon π Bases, Oxygen Bases, and Miscellaneous Second-Row, Third-Row, and Fourth-Row Bases and a Survey of the 4-Fluorophenol Affinity Scale

The thermodynamics of the O-H...B hydrogen bond (HB) has been determined in CCl(4) by FTIR spectrometry for a wide variety of carbon pi bases, oxygen bases, and miscellaneous first- to fourth-row bases, using 4-fluorophenol as a reference hydrogen-bond donor (HBD). After inclusion of previously studied nitrogen, sulfur, and halogen bases, this 4-fluorophenol affinity scale contains 314 varied organic bases and ranges over 40 kJ mol(-1). The 4-fluorophenol affinity scale in CCl(4) is shown to be applicable to most HBDs in most media, provided a small family dependence is taken into account. The HB affinity orders are quantitatively established according to the atomic acceptor site or to its bearing functional group. A comprehensive survey of the influence of substituents on these affinity orders is then achieved, considering electronic and steric effects, as well as effects of vinylogy or iminology. Iminology is found to be more efficient than vinylogy for transmitting resonance effects. Steric effects are shown to be less important in HB affinity than in HB basicity since they mainly act on the HB entropy. The spatial proximity of two acceptor sites can favor complexation through three-center hydrogen bonds, leading to superhydrogen-bond bases on the affinity scale.

The Hydrogen‐Bond Basicity pKHB Scale of Peroxides and Ethers

Using 4-fluorophenol as a reference hydrogen-bond donor, equilibrium constants, Kf, for the formation of 1:1 hydrogen-bonded complexes have been obtained by FTIR spectrometry for 39 ethers of widely different structure (cyclic and acyclic ethers, crown ethers, glymes, acetals, orthoesters, and disiloxane) and 3 peroxides, in CCl4 at 298 K. The pKHB scale of monoethers extends from 1.44 for 2,3-diadamant-2-yloxirane to –0.53 for hexamethyldisiloxane. The main effects explaining the variation of the hydrogen-bond basicity of sp3 oxygen atoms are (i) the electron-withdrawing field-inductive effect [e.g. in (CF3)2CHOMe], (ii) the electron-withdrawing resonance effect (e.g. in EtOCH=CH2) (iii) the steric effect (e.g. in tBu2O), (iv) the lone-pair–lone-pair repulsion (e.g. in cyclic peroxides), and (v) the cyclization giving the basicity order: oxetane > tetrahydrofuran > tetrahydropyran > oxirane. A spectroscopic scale of hydrogen-bond basicity is constructed from the infrared frequency shift Δν(OH) of methanol hydrogen-bonded to peroxides and ethers. The thermodynamic pKHB scale does not correlate with the ν(OH) scale because of (i) statistical effects in polyethers and peroxides (ii) secondary hydrogen-bond acceptor sites (e.g. in benzyl ether), (iii) variations of the s character of oxygen lone pairs either by conjugation or cyclization, (iv) steric effects, (v) lone-pair–lone-pair repulsions, and (vi) anomeric effects. The ν(OH···O) band shape reveals two stereoisomeric complexes, the most stable being tetrahedral at the ether oxygen atom.

Hydrogen-Bond Acidity of OH Groups in Various Molecular Environments (Phenols, Alcohols, Steroid Derivatives, and Amino Acids Structures): Experimental Measurements and Density Functional Theory Calculations

The hydrogen-bond (H-bond) donating strengths of a series of 36 hydroxylic H-bond donors (HBDs) with N-methylpyrrolidinone have been measured in CCl4 solution by FTIR spectrometry. These data allow the definition of a H-bond acidity scale named pKAHY covering almost three pK units, corresponding to 16 kJ mol(-1). These results are supplemented by equilibrium constants determined in CH2Cl2 for one-third of the data set to study compounds showing a poor solubility in CCl4. A systematic comparison of these experimental results with theoretical data computed in the gas phase using DFT (density functional theory) calculations has also been carried out. Quantum electrostatic parameters appear to accurately describe the H-bond acidity of the hydroxyl group, whereas partial atomic charges according to the Merz-Singh-Kollman and CHelpG schemes are not suitable for this purpose. A substantial decrease of the H-bond acidity of the OH group is pointed out when the hydroxyl moiety is involved in intramolecular H-bond interactions. In such situations, the interactions are further characterized through AIM and NBO analyses, which respectively allow localizing the corresponding bond critical point and the quantification of a significant charge transfer from the available lone pair to the σ*OH antibonding orbital. Eventually, the H-bond ability of the hydroxyl groups of steroid derivatives and of lateral chains of amino acids are evaluated on the basis of experimental and/or theoretical data.

A Theoretical Evaluation of the pKHB and Δ

The experimental pKHB hydrogen-bond (HB) basicity scale and the corresponding DeltaH[symbol: see text]HB enthalpic scale of nitrogen compounds are extended and analysed in light of simple theoretical descriptors using the B3LYP density functional method and a medium-size basis set (6-31+G(d,p)).The selected training set includes 59 monofunctional unhindered nitrogen bases for which homogeneous and accurate experimental pKHB and DeltaH[symbol: see text]HB data have been determined by means of the association equilibrium of the bases with a reference hydrogen-bond acid, 4-fluorophenol, in CCl4. The three hybridisation states encountered in the nitrogen atom, sp, sp2 and sp3, are equally represented in this data set. A proper estimation of their experimental enthalpy (DeltaH[symbol: see text]HB) is directly attainable from the theoretical enthalpy of the complexation reaction with hydrogen fluoride (DeltaH[symbol: see text](HF)). However, a second parameter is required to calculate with good accuracy the experimental free energy of association represented by pKHB. About 99% of the variance of the pKHB scale is described by a bilinear equation using the minimum electrostatic potential (Vs,min) of the monomer in addition to the interaction energy (D0(HF). The equations are tested for an external set of 99 additional compounds including very different nitrogen bases such as ortho-substituted pyridines, polyazines and azoles.Theoretical calculations give a reliable estimation of hydrogen-bond basicity provided that the populations of the different isomers of the bases are taken into account by using the Boltzmann law, and that a specific halogen-bond interaction with the solvent CCl4 is considered for polybasic molecules.The pKHB scale can thus be extended to important classes of species experimentally inaccessible in CCl4, to polynitrogen compounds and to molecules of biological significance.

H{{{\,\ominus}\hfill \atop {\rm HB}\hfill}}}

The effect of fluorination on the conformational and hydrogen-bond (HB)-donating properties of a series of benzyl alcohols has been investigated experimentally by IR spectroscopy and theoretically with quantum chemical methods (ab initio (MP2) and DFT (MPWB1K)). It was found that o-fluorination generally resulted in an increase in the HB acidity of the hydroxyl group, whereas a decrease was observed upon o,o′-difluorination. Computational analysis showed that the conformational landscapes of the title compounds are strongly influenced by the presence of o-fluorine atoms. Intramolecular interaction descriptors based on AIM, NCI and NBO analyses reveal that, in addition to an intramolecular OH⋅⋅⋅F interaction, secondary CH⋅⋅⋅F and/or CH⋅⋅⋅O interactions also occur, contributing to the stabilisation of the various conformations, and influencing the overall HB properties of the alcohol group. The benzyl alcohol HB-donating capacity trends are properly described by an electrostatic potential based descriptor calculated at the MPWB1K/6-31+G(d,p) level of theory, provided solvation effects are taken into account for these flexible HB donors.

Hydrogen‐Bond Scales of Nitrogen Bases

The thermodynamic hydrogen bond basicity scale pKHB(logarithm of the formation constant of 4-fluorophenol–base complexes in CCl4) has been determined for esters, lactones and carbonates, and correlated to a spectroscopic basicity scale. In the esters R1CO2R2 the hydrogen bond basicity is decreased by bulky alkyl R1 substituents (steric effect) but increased by branched and lengthened alkyl R2 substituents (electronic effects). Quantitative structure–basicity relationships have been established in the XCO2Et (X varying from CF3 to NMe2) and XC6H4CO2Et (X varying from 4-NO2 to 4-NMe2) series. Vinylology strongly increases hydrogen bond basicity—Me2NCHCHCO2Et is the most basic ester presently known. Cyclisation increases the hydrogen bond basicity of esters and carbonates.

Influence of fluorination on the conformational properties and hydrogen-bond acidity of benzyl alcohol derivatives

Using 4-fluorophenol as a reference hydrogen-bond donor, equilibrium constants, Kf, for the formation of 1∶1 hydrogen-bonded complexes have been obtained by FTIR spectrometry for 22 aliphatic primary amines, in C2Cl4 at 298 K. The pKHB (log Kf) scale shows that most primary amines are weaker hydrogen-bond bases than many oxygen bases. The pKHB scale of primary amines extends from 2.31 for adamantan-1-amine to 0.67 for CF3CH2NH2. The main effects explaining the pKHB variations are (i) field-inductive effects (e.g. in CF3CH2NH2), (ii) resonance effects (cyclopropylamine), (iii) polarizability effects (alkylamines), and (iv) intramolecular hydrogen bonding (e.g. in 2-methoxyethylamine). Except for intramolecularly hydrogen-bonded methoxyamines and diamines, the pKHB and pKa scales are correlated. The pKHB scale also correlates with the minimum electrostatic potential on the nitrogen lone pair.

Hydrogen-bond basicity of esters, lactones and carbonates

Rational modulations of molecular interactions are of significant importance in compound properties optimization. We have previously shown that fluorination of conformationally rigid cyclohexanols leads to attenuation of their hydrogen-bond (H-bond) donating capacity (designated by pKAHY ) when OH⋅⋅⋅F intramolecular hydrogen-bond (IMHB) interactions occur, as opposed to an increase in pKAHY due to the fluorine electronegativity. This work has now been extended to a wider range of aliphatic β-fluorohydrins with increasing degrees of conformational flexibility. We show that the observed differences in pKAHY between closely related diastereomers can be fully rationalized by subtle variations in populations of conformers able to engage in OH⋅⋅⋅F IMHB, as well as by the strength of these IMHBs. We also show that the Kenny theoretical Vα (r) descriptor of H-bond acidity accurately reflects the observed variations and a calibration equation extended to fluorohydrins is proposed. This work clearly underlines the importance of the weak OH⋅⋅⋅F IMHB in the modulation of alcohol H-bond donating capacity.

Hydrogen-bond basicity pKHB scale of aliphatic primary amines

The conformational preferences of o-cresols driven by fluorination were thoroughly investigated from a theoretical point of view with quantum-chemical methods, and the results were compared to those recently reported for benzyl alcohols. The key conformers of both families exhibit a six-membered intramolecular hydrogen-bond (IMHB) interaction. A significant enhancement in the strength of the IMHB is observed in α-fluoro-o-cresols, owing to a simultaneous increase in the hydrogen bond (HB) basicity of the aliphatic fluorine and the HB acidity of the aromatic hydroxyl relative to that observed for o-fluorobenzyl alcohols, which are characterized by aromatic fluorine atoms and aliphatic hydroxyl groups. In the cases of the di- and trifluorinated derivatives, the occurrence of a three-centered HB is emphasized, and its features are discussed. The impact of these structural predilections on the HB properties of o-cresol was characterized from the estimation of the HB acidity parameter, pKAHY , weighted according to their conformational populations. We found that α-fluorination led to a decrease in the HB acidity of the hydroxyl group (in contrast with the o-fluorination of benzyl alcohols), whereas α,α-difluorination resulted in no significant variation in pKAHY . Finally, an increase in the HB acidity was predicted upon methyl perfluorination, which was confirmed experimentally. Theoretical descriptors based on atoms in molecules, noncovalent interactions, and natural bond orbital analyses allowed rationalization of the predicted trends and revealed a relationship with the strength of the established OH⋅⋅⋅F IMHB.

Influence of Alcohol β-Fluorination on Hydrogen-Bond Acidity of Conformationally Flexible Substrates

The experimental pKHB hydrogen-bond (HB) basicity scale and the corresponding DeltaH[symbol: see text]HB enthalpic scale of nitrogen compounds are extended and analysed in light of simple theoretical descriptors using the B3LYP density functional method and a medium-size basis set (6-31+G(d,p)).The selected training set includes 59 monofunctional unhindered nitrogen bases for which homogeneous and accurate experimental pKHB and DeltaH[symbol: see text]HB data have been determined by means of the association equilibrium of the bases with a reference hydrogen-bond acid, 4-fluorophenol, in CCl4. The three hybridisation states encountered in the nitrogen atom, sp, sp2 and sp3, are equally represented in this data set. A proper estimation of their experimental enthalpy (DeltaH[symbol: see text]HB) is directly attainable from the theoretical enthalpy of the complexation reaction with hydrogen fluoride (DeltaH[symbol: see text](HF)). However, a second parameter is required to calculate with good accuracy the experimental free energy of association represented by pKHB. About 99% of the variance of the pKHB scale is described by a bilinear equation using the minimum electrostatic potential (Vs,min) of the monomer in addition to the interaction energy (D0(HF). The equations are tested for an external set of 99 additional compounds including very different nitrogen bases such as ortho-substituted pyridines, polyazines and azoles.Theoretical calculations give a reliable estimation of hydrogen-bond basicity provided that the populations of the different isomers of the bases are taken into account by using the Boltzmann law, and that a specific halogen-bond interaction with the solvent CCl4 is considered for polybasic molecules.The pKHB scale can thus be extended to important classes of species experimentally inaccessible in CCl4, to polynitrogen compounds and to molecules of biological significance.