Paola Gilli

Towards an unified hydrogen-bond theory

Abstract Though the hydrogen bond (H-bond) is known since 1920, all attempts to predict its geometry and energetics from the structure of the interacting molecules have been so far unsuccessful. This problem is addressed here through the Electrostatic-Covalent H-Bond Model (ECHBM) derived from the systematic analysis of structural and spectroscopic data of a large number of O–H⋯O H-bonds, according to which: (i) weak H-bonds are electrostatic in nature but become increasingly covalent with increasing strength, very strong bonds being essentially three-centre-four-electron covalent bonds ; (ii) strong H-bonds belong to a limited number of classes (three for X–H ⋯ X homonuclear and four for X–H ⋯ Y heteronuclear H-bond); and (iii) within each class, H-bonds are the stronger the smaller is ΔPA, the difference between the proton affinities of the H-bond donor and acceptor atoms. It is shown that this model leads to a thorough classification of H-bonds in chemical classes which, in turn, can be used to predict the H-bond strength from the simple knowledge of the chemical formula. A number of applications to homonuclear O–H⋯O and heteronuclear N–H⋯O/O–H⋯N H-bonds is illustrated by both systematic analysis of crystal structure data and DFT theoretical calculations at the B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level of theory.

Predicting Hydrogen-Bond Strengths from Acid−Base Molecular Properties. The pKa 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.

Resonance-assisted hydrogen bonding. III: Formation of intermolecular hydrogen-bonded chains in crystals of β-diketone enols and its relevance to molecular association

The β-diketone enol (or enolone) HO-C=C-C=O fragment produced by enolization of β-diketones is known to form strong intramolecular O-H...O hydrogen bonds where the decrease of the O...O contact distance (up to 2.40 A) is correlated with the increased π-delocalization of the O-C=C-C=O heteroconjugated system; the phenomenon has been interpreted by the resonance-assisted hydrogen-bonding (RAHB) model [Gilli, Bellucci, Ferretti & Bertolasi (1989). J. Am. Chem. Soc. 111, 1023-1028; Bertolasi, Gilli, Ferretti & Gilli (1991). J. Am. Chem. Soc. 113, 4917-1925]

Interplay between steric and electronic factors in determining the strength of intramolecular resonance-assisted NH···O hydrogen bond in a series of β-ketoarylhydrazones

The crystal structures of six β-ketoarylhydrazones are reported: 1,(Z)-2-(2-bromophenylhydrazono)-3-oxobutanenitrile; 2, (Z)-2-(2-methylphenylhydrazono)-3-oxobutanenitrile; 3, (E)-methyl-2-(2-methoxyphenylhydrazono)-3-oxobutanoate; 4, E, methyl-2-(2-cyanophenylhydrazono)-3-oxobutanoate; 5, (Z)-methyl-2-(4-cyanophenylhydrazono)-3-oxobutanoate; 6, pentane-2,3,4-trione-3-(2-carboxyphenylhydrazone). All of them form intramolecular hydrogen bonds assisted by resonance (RAHB), with N···O distances in the range 2.541(5)–2.615(3) A. These hydrogen bonds are differently affected by the substituents at the heterodienic fragment, being strengthened by electronwithdrawing substituents in position 2 (more by 2-COMe than 2-CN substitution), and weakened in β-esterhydrazones and when the N–H forms a bifurcated hydrogen bond. The role played by the different steric and electronic properties of the substituents in strengthening the H-bond is investigated, besides X-ray crystallography, by IR and 1H NMR characterization of the NH proton, and quantum mechanical DFT calculations at the B3LYP/6-31+G(d,p) level of theory on test molecules.

Intramolecular N–H ⋯ O hydrogen bonding assisted by resonance. Part 2. Intercorrelation between structural and spectroscopic parameters for five 1,3-diketone arylhydrazones derived from dibenzoylmethane

The crystal structures of five propane-1,2,3-trione arylhydrazones are reported. All molecules are chelated to form a six-membered π-conjugated ring via strong intramolecular N–H ⋯ O hydrogen bonding. The N ⋯ O hydrogen bond distances are correlated with the resonance entity within the ring and with spectroscopic data such as ν(NH)IR frequencies δ(NH)1H NMR chemical shifts and λmax UV absorption bands of charge transfer from hydrazone to carbonyl group. The structural and spectroscopic variations of the hydrogen bond parameters are modulated by the electronic properties of substituents on the aryl group in the sense that electron donating groups produce the strongest hydrogen bonds. The intercorrelation between N ⋯ O hydrogen bond strength and π delocalization in all the structures of this class retrieved from the Cambridge Structural Database shows that the interplay between π resonance and hydrogen bond magnitude, which we have called Resonance Assisted Hydrogen Bonding (RAHB), is a general phenomenon in the whole class of 1,3-diketone arylhydrazones.

Associations of squaric acid and its anions as multiform building blocks of hydrogen-bonded molecular crystals

Squaric acid, H(2)C(4)O(4) (H(2)SQ), is a completely flat diprotic acid that can crystallize as such, as well as in three different anionic forms, i.e. H(2)SQ.HSQ(-), HSQ(-) and SQ(2-). Its interest for crystal engineering studies arises from three notable factors: (i) its ability of donating and accepting hydrogen bonds strictly confined to the molecular plane; (ii) the remarkable strength of the O-H...O bonds it may form with itself which are either of resonance-assisted (RAHB) or negative-charge-assisted [(-)CAHB] types; (iii) the ease with which it may donate a proton to an aromatic base which, in turn, back-links to the anion by strong low-barrier N-H+...O(1/2-) charge-assisted hydrogen bonds. Analysis of all the structures so far known shows that, while H(2)SQ can only crystallize in an extended RAHB-linked planar arrangement and SQ(2-) tends to behave much as a monomeric dianion, the monoanion HSQ(-) displays a number of different supramolecular patterns that are classifiable as beta-chains, alpha-chains, alpha-dimers and alpha-tetramers. Partial protonation of these motifs leads to H(2)SQ.HSQ(-) anions whose supramolecular patterns include ribbons of dimerized beta-chains and chains of emiprotonated alpha-dimers. The topological similarities between the three-dimensional crystal chemistry of orthosilicic acid, H(4)SiO(4), and the two-dimensional one of squaric acid, H(2)C(4)O(4), are finally stressed.

The role of the non-participating groups in substitution reactions at cationic Pt(II) complexes containing tridentate chelating nitrogen donors. Crystal structure of {Pt[bis(2-pyridylmethyl)amine](py)}(CF3SO3)2

Abstract Kinetic measurements on the displacement of chloride with the nucleophiles Br−, I− and N (N=a number of isosteric pyridines and morpholine) from the substrates [Pt(NNN)Cl]+ [NNN=bis(2-pyridylmethyl)amine (bpma); 2,6-bis(aminomethyl)pyridine (dap); diethylenetriamine (dien)] have been carried out in methanol at 25°C. The results, compared with those previously obtained on the complex [Pt(terpy)Cl]+ (terpy=2,2′:6′,2′′-terpyridine), are discussed in terms of reactivity and discrimination ability of the reaction centre. The significant differences in kinetic behaviour along the series are particularly related to the presence of pyridine rings in the non-participating chelate ligand and steric effects. The study of the reverse process, i.e. the displacement of N with a chloride ion from the complexes [Pt(NNN)(N)]2+, allows the determination of the equilibrium constants from the ratio of the rate constants. The crystal structure of [Pt(bpma)(py)](CF3SO3)2 has been determined by the X-ray diffraction technique. It consists of essentially SP (square-planar) [Pt(bpma)(py)]2+ cations. The plane through the pyridine ring makes an angle of 86.1(3)° with that of Pt and the three nitrogen atoms of bpma. The packing is characterised by a hydrogen bond between the NH of the ligand and one oxygen of a triflate anion.

Binding Thermodynamics at the Human Neuronal Nicotine Receptor

The thermodynamic parameters deltaGo (standard free energy), deltaHo (standard enthalpy) and deltaSo (standard entropy) of the binding equilibrium of eleven ligands (six agonists and five antagonists) to the neuronal nicotinic receptor were determined by affinity measurements carried out on human thalamus membranes at six different temperatures (0, 10, 20, 25, 30, 35 degrees) and deltaG vs. T plot analysis. Affinity constants were obtained by saturation experiments for [3H]-cytisine, a ganglionic nicotinic agonist, or its displacement in inhibition assays for the other compounds. The deltaG vs T plots appeared to be reasonably linear in the full temperature range for most of the compounds investigated (equilibrium heat capacity change,deltaCo(p) approximately 0), with the exception of the three agonists cytisine, nicotine and methylcarbachol (deltaCo(p) of the order of -720 / -1610 J mol(-1) K(-1)). Thermodynamic parameters were in the range -53.3 < or =deltaHo < or = -28.9 kJ mol(-1) and -41 < or = deltaSo < or = 69 J mol(-1) K(-1) for agonists, and 8.7 < or = deltaHo < or = 68.2 kJ mol(-1) and 99 < or = deltaSo < or = 311 J mol(-1) K(-1) for antagonists, indicating that agonistic binding was both enthalpy- and entropy-driven, while antagonistic binding was totally entropy-driven. Agonists and antagonists were, therefore, thermodynamically discriminated. Experimental results were discussed with particular regard to the following points: 1) reasons why membrane receptors displayed unusually low values of deltaCo(p); 2) possible reasons for the phenomenon of thermodynamic discrimination between agonists and antagonists particularly in connection with ligand-gated ion channel receptors; and 3) the origin of the recurrent phenomenon of enthalpy-entropy compensation which has been observed for neuronal nicotinic receptor ligands as well as for all membrane receptors studied thus far.

Intermolecular N‐H⋯O Hydrogen Bonding Assisted by Resonance. II. Self Assembly of Hydrogen‐Bonded Secondary Enaminones in Supramolecular Catemers

The crystal structures of 15 compounds containing the 2-en-3-amino-1-one heterodienic system and forming intermolecular N—H⋯O hydrogen bonds assisted by resonance (RAHB) are reported: (1) 3-phenylamino-2-cyclohexen-1-one; (2) 3-(4-methoxyphenylamino)-2-cyclohexen-1-one; (3) 3-(4-chlorophenylamino)-2-cyclohexen-1-one; (4) 3-(4-methoxyphenylamino)-2-methyl-2-cyclohexen-1-one; (5) 3-(4-methoxyphenylamino)-5-methyl-2-cyclohexen-1-one; (6) 3-isopropylamino-5,5-dimethyl-2-cyclohexen-1-one; (7) 3-phenylamino-5,5-dimethyl-2-cyclohexen-1-one; (8) 3-(3-methoxyphenylamino)-5,5-dimethyl-2-cyclohexen-1-one; (9) N,N-3-aza-pentane-1,5-bis[1-(3-oxo-5,5-dimethyl-1-cyclohexenyl)]; (10) 3-phenylamino-6,6-dimethyl-2-cyclohexen-1-one; (11) 3-(2-methoxyphenylamino)-6,6-dimethyl-2-cyclohexen-1-one; (12) 3-(3-chlorophenylamino)-6,6-dimethyl-2-cyclohexen-1-one; (13) 3-(4-chlorophenylamino)-6,6-dimethyl-2-cyclohexen-1-one; (14) 1-(4-chlorophenyl)-4-(4-chlorophenylamino)-6-methyl-2-pyridone; (15) 3-(4-chlorophenylamino)-5-phenyl-2-cyclopenten-1,4-dione. All compounds form intermolecular N—H⋯O=C hydrogen bonds assisted by resonance connecting the heteroconjugated enaminonic groups in infinite chains. Chain morphologies are analyzed to find out crystal engineering rules able to predict and interpret the crystal packing. Simple secondary enaminones [i.e. (1)–(13) together with a number of structures retrieved from the Cambridge Structural Database] are found to form hydrogen bonds having π-delocalizations, as characterized by a C=O bond-length average of 1.239 ± 0.004 A, and hydrogen-bond strengths, represented by the N⋯O average distance of 2.86 ± 0.05 A, very similar to those previously found for amides. Enaminones, however, can be easily substituted by chemical groups able to influence both π-conjugations and N⋯O hydrogen-bond distances. Some substituted enaminones, retrieved from the literature, display, in fact, N⋯O hydrogen-bond distances as short as 2.627 A and large π-delocalizations with C=O double-bond distances as long as 1.285 A. These effects appear to be associated with (a) the presence of further π-conjugated systems involving the C=O and NH groups of the enaminone moiety or (b) the transformation of the enaminone carbonyl group in an amidic function.

Substituent effects on keto–enol tautomerization of β-diketones from X-ray structural data and DFT calculations

Single crystal X-ray structure determinations of six crystals 1–6 of β-diketones, the related DFT calculations as well as a systematic investigation, on the CSD (Cambridge Structural Database) files, of all acyclic β-diketones having at least one α-hydrogen, in both β-diketo and β-keto–enol tautomeric forms, are reported. In spite of the stabilization energy gained by the formation of strong intramolecular O–H⋯O resonace assisted hydrogen bonds (RAHB) a certain number of non-enolized structures were retrieved. The structural data show that the steric and electronic properties of the substituents play a definite role in tuning the hydrogen bond strength and determining the enolic site but the driving force able to shift from the more common β-keto–enol tautomer to the β-diketo one can be only the steric hindrance of bulky groups. In this context the substituents in position 2 play a crucial role in establishing the tautomeric form. In fact, while the 2-unsubstituted β-diketones (or 2-substitued by a group linked by a sp2carbon) assume almost exclusively the β-keto–enol form with some exceptions for very bulky substituents, β-diketones carrying 2-alkyl substituents, in general, display the β-diketo tautomeric form. The only exceptions are the 2-alkyl curcumin derivatives where the planar β-keto–enol group is stabilized by extended π-conjugation within the whole molecule and by the absence of short contacts between the alkyl R2groups and R1 or R3 substituents. DFT calculations on the six compounds, 1–6, show that in the four more overcrowded structures, 3–6, the trans-β-diketo tautomer is more stable than the Z-β-keto–enol isomer unlike what happens for 1 and 2 where the Z-β-keto–enol isomer is the most stable by a few kcal mol−1. Thereby, the occurrence of the trans-β-diketo tautomer for all compounds, in the crystal, can be interpreted in terms of the existence of a large activation energy in the mechanism to attain the Z-β-keto–enol isomer containing an intramolecular O–H⋯O hydrogen bond.