Predicting hydrogen-bond strengths from acid-base molecular properties. The pK(a) slide rule: toward the solution of a long-lasting problem.

Unlike normal chemical bonds, hydrogen bonds (H-bonds) characteristically feature binding energies and contact distances that do not simply depend on the donor (D) and acceptor (:A) nature. Instead, their chemical context can lead to large variations even for a same donor-acceptor couple. As a striking example, the weak HO-H...OH(2) bond in neutral water changes, in acidic or basic medium, to the 6-fold stronger and 15% shorter [H(2)O...H...OH(2)](+) or [HO...H...OH](-) bonds. This surprising behavior, sometimes called the H-bond puzzle, practically prevents prediction of H-bond strengths from the properties of the interacting molecules. Explaining this puzzle has been the main research interest of our laboratory in the last 20 years. Our first contribution was the proposal of RAHB (resonance-assisted H-bond), a new type of strong H-bond where donor and acceptor are linked by a short pi-conjugated fragment. The RAHB discovery prompted new studies on strong H-bonds, finally leading to a general H-bond classification in six classes, called the six chemical leitmotifs, four of which include all known types of strong bonds. These studies attested to the covalent nature of the strong H-bond showing, by a formal valence-bond treatment, that weak H-bonds are basically electrostatic while stronger ones are mixtures of electrostatic and covalent contributions. The covalent component gradually increases as the difference of donor-acceptor proton affinities, DeltaPA, or acidic constants, DeltapK(a), approaches zero. At this limit, the strong and symmetrical D...H...A bonds formed can be viewed as true three-center-four-electron covalent bonds. These results emphasize the role PA/pK(a) equalization plays in strengthening the H-bond, a hypothesis often invoked in the past but never fully verified. In this Account, this hypothesis is reconsidered by using a new instrument, the pK(a) slide rule, a bar chart that reports in separate scales the pK(a)'s of the D-H proton donors and :A proton acceptors most frequently involved in D-H...:A bond formation. Allowing the two scales to shift so to bring selected donor and acceptor molecules into coincidence, the ruler permits graphical evaluation of DeltapK(a) and then empirical appreciation of the D-H...:A bond strength according to the pK(a) equalization principle. Reliability of pK(a) slide rule predictions has been verified by extensive comparison with two classical sources of H-bond strengths: (i) the gas-phase dissociation enthalpies of charged [X...H...X](-) and [X...H...X](+) bonds derived from the thermodynamic NIST Database and (ii) the geometries of more than 9500 H-bonds retrieved from the Cambridge Structural Database. The results attest that the pK(a) slide rule provides a reliable solution for the long-standing problem of H-bond-strength prediction and represents an efficient and practical tool for making such predictions directly accessible to all scientists.

Interplay between steric and electronic factors in determining the strength of intramolecular N-H...O resonance-assisted hydrogen bonds in beta-enaminones.

The crystal structures of five beta-enaminones are reported: (2Z)-3-(benzylamino)-1,3-diphenyl-prop-2-en-1-one, (2Z)-3-(benzylamino)-3-(2-hydroxyphenyl)-1-phenyl-prop-2-en-1-one, (2Z)-3-(benzylamino)-3-(4-methoxyphenyl)-1-(3-nitrophenyl)-prop-2-en-1-one, 2-{1-[(4-methoxyphenyl)amino]ethylidene}cyclohexene-1,3-dione and 2-{1-[(3-methoxyphenyl)amino]ethylidene}cyclohexene-1,3-dione. The structures were analysed and compared with those of similar compounds in order to establish which factors determine the range (2.53-2.72 A) of N...O hydrogen-bond distances in intramolecularly hydrogen-bonded beta-enaminones. It has been shown that, beyond electronic resonance-assisted hydrogen-bond effects modulated by substituents, the necessary requirements to produce very short N-H...O hydrogen bonding are steric intramolecular repulsions, including the embedding of an enaminonic C-C or C-N bond in an aliphatic six-membered ring. By considering the structural features it is possible to expect the strength of N-H...O hydrogen bonds adopted by specific beta-enaminones.

pi-Bond cooperativity and anticooperativity effects in resonance-assisted hydrogen bonds (RAHBs).

Bond cooperativity effects, which are typical of ;resonant' chains or rings of pi-conjugated hydrocarbons, can also occur in hydrogen-bonded systems in the form of sigma-bond and pi-bond cooperativity or anticooperativity. sigma-Bond cooperativity is associated with the long chains of O-H...O bonds in water and alcohols while sigma-bond anticooperativity occurs when the cooperative chain is interrupted by a local defect reversing the bond polarity. pi-Bond cooperativity is the driving force controlling resonance-assisted hydrogen bonds (RAHBs), while pi-bond anticooperativity has never been considered so far and is investigated here by studying couples of hydrogen-bonded beta-enolone and/or beta-enaminone six-membered rings fused through a common C=O or C-C bond. The effect is studied by X-ray crystal structure determination of five compounds [(2Z)-1-(2-hydroxyphenyl)-3-phenyl-1,3-propanedione enol (1), (2Z)-1-(2-hydroxy-5-chlorophenyl)-3-phenyl-1,3-propanedione enol (2), (2Z)-1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione enol (3), (2Z)-1-(2-hydroxy-4-methyl-5-chlorophenyl)-3-phenyl-1,3-propanedione enol (4) and dimethyl(2E)-3-hydroxy-2-{[(4-chlorophenyl)amino]carbonyl}pent-2-enedioate (5)] and by extensive analysis of related fragments found in the CSD (Cambridge Structural Database). It is shown that fusion through the C=O bond is always anticooperative and such to weaken the symmetric O-H...O...H-O and N-H...O...H-N bonds formed, but not the asymmetric O-H...O...H-N bond. Fusion through the C-C bond may produce either cooperative or anticooperative hydrogen bonds, the former being more stable than the latter and giving rise to a unique resonance-assisted ten-membered ring running all around the two fused six-membered rings, which can be considered a type of tautomerism never described before.

Variable-temperature X-ray crystallographic and DFT computational study of the N-H...O/N...H-O tautomeric competition in 1-(Arylazo)-2-naphthols. Outline of a transition-state hydrogen-bond theory.

Phenyl-substituted 1-arylazo-2-naphthols (AAN) display ...HN-N=C-C=O... <==>...N=N-C=C-OH... ketohydrazone-azoenol tautomerism and can form intramolecular resonance-assisted H-bonds from pure N-H...O to pure N...H-O through tautomeric and dynamically disordered N-H...O <==>N...H-O bonds according to the electronic properties of their substituents. Three compounds of this series (m-OCH(3)-AAN = mOM; p-Cl-AAN = pCl; and p-NMe(2)-AAN = pNM2) have been studied by X-ray crystallography at four temperatures (100-295 K), showing that the remarkably short H-bonds formed (2.53 < or = d(N...O) < or = 2.55 A) are a pure N-H...O in mOM, a dynamically disordered mixture in pCl (N-H...O:N...H-O = 69:31 at 100 K), and a statically disordered mixture in pNM2 (N-H...O:N...H-O = 21:79 at 100 K). These compounds, integrated by the p-H-, p-NO(2)-, p-F-, and p-O(-)-substituted derivatives, have been emulated by DFT methods (B3LYP/6-31+G(d,p) level) with full geometry optimization of the stationary points along the proton-transfer (PT) pathway: N-H...O and N...H-O ground states and N...H...O transition state. Analysis of DFT-calculated energies and geometries by the methods of the rate-equilibrium Marcus theory shows that all H-bond features (stability and tautomerism, as well as position and height of the PT barrier) can be coherently interpreted in the frame of the transition-state (or activated-complex) theory by considering the bond as a chemical reaction N-H...O <==> N...H...O <==> N...H-O which is bimolecular in both directions and proceeds via the N...H...O PT transition state (the activated complex).

Binding thermodynamics as a tool to investigate the mechanisms of drug-receptor interactions: thermodynamics of cytoplasmic steroid/nuclear receptors in comparison with membrane receptors.

Drug-receptor binding thermodynamics has proved to be a valid tool for pharmacological and pharmaceutical characterization of molecular mechanisms of receptor-recognition phenomena. The large number of membrane receptors so far studied has led to the discovery of enthalpy-entropy compensation effects in drug-receptor binding and discrimination between agonists and antagonists by thermodynamic methods. Since a single thermodynamic study on cytoplasmic receptors was known, this paper reports on binding thermodynamics of estradiol, ORG2058, and R1881 bound to estrogen, progesterone, and androgen steroid/nuclear receptors, respectively, as determined by variable-temperature binding constant measurements. The binding at 25 degrees C appears enthalpy/entropy-driven (-53.0

Covalent versus electrostatic nature of the strong hydrogen bond: discrimination among single, double, and asymmetric single-well hydrogen bonds by variable-temperature X-ray crystallographic methods in beta-diketone enol RAHB systems.

Beta-diketone enols are known to form intramolecular...O=C-C=C-OH... resonance-assisted hydrogen bonds (RAHBs) with O...O distances as short as 2.39-2.44 A. However, even the most accurate diffraction studies have not been able to assess with certainty whether these very strong hydrogen bonds (H-bonds) are to be described as proton-centered O...H...O bonds in a single-well (SW) potential or as the dynamic or static mixing of two O-H...O <= => O...H-O tautomers in a double-well (DW) one. This contribution reexamines the problem and shows that diffraction methods are fairly able to assess the SW or DW nature of the H-bond formed and, in the second case, its dynamic or static nature, provided a Bayesian approach is used which associates a number of experimental techniques (X-ray crystallography at variable temperature, difference Fourier maps, least-squares refinement of proton populations, Hirshfeld's rigid-bond test) with a reasonable prior, that is the full set of possible proton-transfer (PT) pathways for the O-H...O system derived from theoretical calculations. The method is first applied to three beta-diketone enols, whose crystal structures were determined in the interval of temperatures 100-295 K and then generalized to the interpretation of a much wider set of beta-diketone enol structures derived from the literature, making it possible to establish a general relationship between chemical structure (symmetric or dissymmetric substitution, steric compression or stretching, increased pi-bond delocalizability), H-bond strength, and the shape of the PT-barrier. Final results are interpreted in terms of simplified VB theory and state-correlation (or avoided-crossing) diagrams.

Receptor binding thermodynamics at the neuronal nicotinic receptor.

Simple determination of K(A) or K(D) values makes it possible to calculate the standard free energy DeltaG degrees = -RTlnK(A) = RT lnK(D)(T= 298.15 K) of the binding equilibrium but not that of its two components as defined by the Gibbs equation DeltaG degrees = DeltaH degrees - TDeltaS degrees where DeltaH degrees and DeltaS degrees are the equilibrium standard enthalpy and entropy, respectively. Recently, it has been shown that the relative DeltaH degrees and DeltaS degrees magnitudes can often give a simple "in vitro" way for discriminating "the effect", that is the manner in which the drug interferes with the signal transduction pathways. This particular effect, called "thermodynamic discrimination", results from the fact that binding of antagonists may be enthalpy-driven and that of agonists entropy-driven, or vice-versa. In the past, the thermodynamic discrimination was reported for the beta-adrenergic G-protein-coupled receptor (GPCR) and confirmed later for adenosine A(1), A(2A) and A(3) receptors. Moreover, it has been found that the binding of all ligand-gated ion-channel receptors (LGICR) investigated was thermodynamically discriminated. In particular, affinity constants for typical neuronal nicotinic receptor ligands were obtained by both saturation and inhibition experiments with the radioligand [(3)H]-cytisine, a ganglionic nicotinic agonist. Thermodynamic parameters indicated that agonistic binding was both enthalpy- and entropy-driven, while antagonistic binding was totally entropy-driven. These results have shown that neuronal nicotinic receptor agonists and antagonists were thermodynamically discriminated. On these grounds, the thermodynamic behaviour makes it possible to discriminate drug pharmacological profiles in vivo through binding experiments in vitro.

The nature of solid-state N-H triplebondO/O-H triplebond N tautomeric competition in resonant systems. Intramolecular proton transfer in low-barrier hydrogen bonds formed by the triplebond O=C-C=N-NH triple bond --> <-- triplebond HO-C=C-N=N triplebond Ketohydrazone-Azoenol system. A variable-temperature X-ray crystallographic and DFT computational study.

The tautomeric.O=C-C=N-NH triplebond --> <-- HO-C=C-N=N triplebond ketohydrazone-azoenol system may form strong N-H triplebond O/O-H triplebond N intramolecular resonance-assisted H-bonds (RAHBs) which are sometimes of the low-barrier H-bond type (LBHB) with dynamic exchange of the proton in the solid state. The problem of the N-H triplebond O/O-H triplebond N competition in these compounds is studied here through variable-temperature (100, 150, 200, and 295 K) crystal-structure determination of pF = 1-(4-F-phenylazo)2-naphthol and oF = 1-(2-F-phenylazo)2-naphthol, two molecules that, on the ground of previous studies (Gilli, P; Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc. 2000, 122, 10405), were expected to represent an almost perfect balance of the two tautomers. According to predictions, the two molecules form remarkably strong bonds (d(N triplebond O) = 2.53-2.55 A) of double-minimum or LBHB type with dynamic N-H triplebond O/ O-H triplebond N exchange in the solid state. The enthalpy differences between the two minima, as measured by van't Hoff methods from the X-ray-determined proton populations, are very small and amount to DeltaH degrees = -0.120 and DeltaH degrees = -0.156 kcal mol(-)(1) in favor of the N-H triplebond O form for pF and oF, respectively. Successive emulation of pF by DFT methods at the B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level has shown that both energetic and geometric experimental aspects can be almost perfectly reproduced. Generalization of these results was sought by performing DFT calculations at the same level of theory along the complete proton-transfer (PT) pathway for five test molecules designed in such a way that the RAHB formed changes smoothly from weak N-H triplebond O to strong O-H.N through very strong N-H triplebond O/O-H triplebond N bond of LBHB type. A systematic correlation analysis of H-bond energies, H-bond and pi-conjugated fragment geometries, and H-bond Bader's AIM topological properties performed along the PT-pathways leads to the following conclusions: (a) any X-H triplebond Y H-bonded system is fully characterized by its intrinsic PT-barrier, that is, the symmetric barrier occurring when the proton affinities of X and Y are identical; (b) the intrinsic X-H triplebond Y bond associated with the symmetric barrier is the strongest possible bond in that system and will be single-minimum (single-well, no-barrier) or double-minimum (double-well, low-barrier) according to whether the intrinsic PT-barrier is lower or slightly higher than the zero-point vibrational level of the proton; (c) with reference to the intrinsic H-bond, the effect of chemical substitution can only be that of making more and more dissymmetric the PT-barrier, while the two H-bonds split in a higher-energy bond which is stronger because closer to the transition-state structure and in a lower-energy one (the stable form) which is weaker because farther from it; (d) complete dissymmetrization of the PT-barrier will increasingly weaken the more stable H-bond until the formation of an extreme dissymmetric single-minimum or dissymmetric single-well H-bond.