Jérôme Graton

The pKBHX Database: Toward a Better Understanding of Hydrogen-Bond Basicity for Medicinal Chemists

The hydrogen bond (HB) is one of the fundamental noncovalent interactions between a drug molecule and its local environment. For drug molecules, this local environment may be a biological target, a biological off-target, aqueous solution, a lipid membrane, or even a crystalline solid. Consequently, hydrogen bonding impacts a wide range of molecular properties critical to drug design including potency, selectivity, and permeability and solubility. Despite its importance, it is the authors’ experience that in general the medicinal chemistry community has a poor intuition for the relative basicity (i.e., strengths) of hydrogen-bond acceptors. In an attempt to assess the relative hydrogen-bond basicities of functional groups, it is common practice to resort to a simple correlation with pKBH, 8 which is generally incorrect and holds true only for closely related compounds in a series (i.e., a family dependent relationship). There is also a tendency to view hydrogen-bond acceptors as atomic sites and to consider them equivalent while disregarding the effects of organic functions and substituents that define the local molecular environment. This is evident in the lack of consideration for exploring hydrogen-bond basicity as an SAR parameter, as is commonly done to establish preferred steric, polar, basic, and acidic moieties. This poor intuition may partly stem from the lack of experimentally observable physical properties that are directly attributed to relative hydrogen-bondbasicities.Furthermore, despite thewell-known role of hydrogen bonds in protein-ligand interactions and the fact that hydrogen bonds are qualitatively well understood, it is generally admitted that quantitative data are needed. In the second section of this paper we review hydrogenbond basicity scales in general and introduce the pKBHX scale with a brief thermodynamic discussion on the treatment of polyfunctional compounds. In section 3 we discuss the effects of a medium more polar than the definition solvent CCl4 and changes in the reference HB donor on the pKBHX scale. In section 4, we present the pKBHX database and describe the fields of each entry,which correspond to threemain categories of data: HBA identification, thermodynamic, and spectroscopic. In section 5 we show that the pKBHX scale of HB basicity differs considerably from the pKBH scale of proton transfer basicity. This is important formedicinal chemistswho have a good knowledge of Broensted proton basicity scales and incorrectly consider HB basicity and proton basicity scales as equivalent. Section 6 reviews the hydrogen-bond basicities of functional groups relevant to medicinal chemistry while considering factors that modulate these values. Section 7 extends this medicinal chemistry discussion by providing examples of the role of hydrogen-bond basicity in properties of interest for drug design and briefly reviews computational approaches for addressing hydrogen bonding.

The Diiodine Basicity Scale: Toward a General Halogen‐Bond Basicity Scale

The new diiodine basicity scale pK(BI2) is quasi-orthogonal to most known Lewis basicity scales (hydrogen-bond, dative-bond and cation basicity scales). The diiodine basicity falls in the sequence N>P≈Se>S>I≈O>Br>Cl>F for the iodine-bond acceptor atomic site and SbO≈NO≈AsO>SeO>PO>SO>C=O>-O->SO(2) or PS≫-S->C=S≫N=C=S for the functionality of oxygen or sulfur bases. Substituent effects are quantified through linear free energy relationships, which allow the calculation of individual complexation constants for each site of polybases and thus the classification of aromatic ethers as carbon π bases and of aromatic amines, thioethers and selenoethers as N, S and Se bases, respectively. The pK(BI2) values of nBu(3)N(+)-N(-)C≡N, 2-aminopyridine and 1,10-phenanthroline reveal a superbasic nitrile, a hydrogen-bond-assisted iodine bond and a two-centre iodine bond, respectively. The diiodine basicity scale is a general inorganic but family-dependent organic halogen-bond basicity scale because organic halogen-bond donors such as IC≡N and ICF(3) have a stronger electrostatic character than I(2). The family independence can be restored by the addition of an electrostatic parameter, either the experimental pK(BHX) hydrogen-bond basicity scale or the computed minimum electrostatic potential.

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.

An Unexpected and Significantly Lower Hydrogen‐Bond‐Donating Capacity of Fluorohydrins Compared to Nonfluorinated Alcohols

The success of fluorination in improving molecular properties over a wide range of applications (including pharmaceuticals,1 agrochemicals,2 materials,3 and crystal engineering4) has been remarkable. Up to 20 % of the pharmaceuticals prescribed or administered in the clinic, and a third of the leading 30 blockbuster drugs, contain at least one fluorine atom1a and 30–40 % of currently marketed agrochemicals contain fluorine.5

Amino and cyano N atoms in competitive situations: which is the best hydrogen-bond acceptor? A crystallographic database investigation

The relative hydrogen-bond acceptor abilities of amino and cyano N atoms have been investigated using data retrieved from the Cambridge Structural Database and via ab initio molecular orbital calculations. Surveys of the CSD for hydrogen bonds between HX (X = N, O) donors, N-T-C identical with N (push-pull nitriles) and N-(Csp(3))(n)-C identical with N molecular fragments show that the hydrogen bonds are more abundant on the nitrile than on the amino nitrogen. In the push-pull family, in which T is a transmitter of resonance effects, the hydrogen-bonding ability of the cyano nitrogen is increased by conjugative interactions between the lone pair of the amino substituent and the C identical with N group: a clear example of resonance-assisted hydrogen bonding. The strength of the hydrogen-bonds on the cyano nitrogen in this family follows the experimental order of hydrogen-bond basicity, as observed in solution through the pK(HB) scale. The number of hydrogen bonds established on the amino nitrogen is greater for aliphatic aminonitriles N-(Csp(3))(n)-C identical with N, but remains low. This behaviour reflects the greater sensitivity of the amino nitrogen to steric hindrance and the electron-withdrawing inductive effect compared with the cyano nitrogen. Ab initio molecular orbital calculations (B3LYP/6-31+G** level) of electrostatic potentials on the molecular surface around each nitrogen confirm the experimental observations.

Halogen-bond interactions: a crystallographic basicity scale towards iodoorganic compounds

Halogen bond (X-bond) interactions involving organic iodine have been investigated using data retrieved from the Cambridge Structural Database (CSD) and Density Functional Theory (DFT) calculations. The analysis of the mean normalised intermolecular distances involving Csp–I, Csp2–I and Csp3–I X-bond donors first shows that, for interactions with the same acceptor site, the shortest mean distance is always measured for Csp–I X-bond donors. This experimental trend is rationalised through molecular electrostatic potential calculations on the iodine surface, along the σ-hole of the iodine atom, since Csp–I donors are characterised by the strongest VS,max values, that is to say the more electron poor iodine atoms. In agreement with the trends revealed from the analysis of the I⋯N distances, the X-bond with Csp–I donors appear more linear (mean of 169.5°) than with Csp2–I and Csp3–I donors, their respective values being close to 164°. From a survey of the geometries of the X-bond contacts observed in the most extended dataset (Csp2–I: 1213), a crystallographic order of X-bond acceptor strength has been obtained through a careful consideration of the chemical functions and subfunctions to which the acceptor atom belongs. This order is in good agreement with the one observed in solution on the diiodine basicity scale pKBI2. An exception to this trend is thioureas, which show unexpected long (weak) S⋯I distances. However, these observations are rationalised from the sulfur behaviour, which acts simultaneously as a X-bond acceptor and hydrogen-bond (H-bond) acceptor in these structures. Finally, an interesting correlation between the pKBI2 and the I⋯Y normalised intermolecular distances is found for a wide and varied collection of organic bases, since we have been able to delineate 22 families of organic compounds covering more than four pK units on the pKBI2 scale.

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.

New Insights on the Molecular Recognition of Imidacloprid with Aplysia californica AChBP: A Computational Study

The binding of imidacloprid (IMI), the forerunner of neonicotinoid insecticides, with the acetylcholine binding protein (AChBP) from Aplysia californica, the established model for the extracellular domain of insects nicotinic acetylcholine receptors, has been studied with a two-layer ONIOM partition approach (M06-2X/6-311G(d):PM6). Our calculations allow delineating the contributions of the key residues of AChBP for IMI binding. In particular, the importance of Trp147 and Cys190-191, through weak CH···π interactions and both van der Waals and hydrogen-bond (H-bond) interactions, respectively, are highlighted. Furthermore, H-bonds between hydroxyl groups of both Ser189 and Tyr55 and the IMI nitro group are pointed out. The participation of Ile118, whose main chain NH and carbonyl group are hydrogen-bonded with the IMI pyridinic nitrogen through a water molecule, is characterized. Our simulations also indicate the presence of a significant contribution of this residue through van der Waals interactions. The various trends obtained by the calculations of the pairwise interaction energies are confirmed through a complementary noncovalent interaction (NCI) analysis of selected IMI-AChBP amino acid pairs. Indeed, the contribution of a halogen-bond interaction between IMI and AChBP, recently proposed in the literature, is corroborated by our NCI analysis.

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}}}

Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OH⋅⋅⋅F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time—and in contrast to earlier reports—the occurrence of OH⋅⋅⋅F IMHBs in acyclic saturated γ-fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding h1JOH⋅⋅⋅F values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9Hz). The magnitude of OH⋅⋅⋅F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the “rule of shielding” applies to OH⋅⋅⋅F IMHB energies. Surprisingly, the predicted OH⋅⋅⋅F IMHB energies are only moderately weaker than these of the corresponding OH⋅⋅⋅OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design.