Loretta Pretto

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.

Hydrogen-bonded supramolecular structures in co-crystals of β- or ζ-diketone enols with 2,6-diaminopyridine or 2,4-diaminopyrimidine

Preparation and single-crystal X-ray structure determination of five co-crystals of conjugated β- or ζ-diketoenolate anions (1,3-cyclopentanedionate, 1,3-cyclohexanedionate, 5-methyl-1,3-cyclohexanedionate and tropolonate) with aromatic protonated nitrogen bases (2,6-diaminopyridinium and 2,4-diaminopyrimidinium) are reported. Their packings are discussed in terms of the relative energies of the intermolecular hydrogen bonds formed, calculated by the Lippincott and Schroeder method, showing that such bonds largely determine the supramolecular net of interconnections within the crystal. The β- and ζ-diketoenolate anions are shown to have specific properties, being π-conjugated fragments with two terminal oxygens sharing a single negative charge that is partially displaced on one side or another according to the strength of the hydrogen bonds formed. The β-cyclohexanedionate anion displays, moreover, the ability to form a dimeric association with its neutral form through a very strong central [O–H⋯O]− bond of charge-assisted nature.

Structure and tautomerism of azo coupling products from N-alkylenaminones derived from acetylacetone and benzoylacetone in solid phase and in solution

A series of azo coupling products have been prepared by reaction of substituted benzenediazonium tetrafluoroborates with N-alkyl 4-aminopent-3-en-2-ones or 3-amino-1-phenylbut-2-en-1-ones. The structure and tautomerism of the reaction products were studied by means of single-crystal X-ray study and by NMR spectroscopy in deuteriochloroform solution. The azo coupling products obtained from 4-methylaminopent-3-en-2-ones (3a–i) exist in CDCl3 solution as E/Z isomer mixtures with the Z isomer strongly predominating. The major isomer is a mixture of enamino–azo and imino–hydrazo tautomers with the former predominating. The proportion of the azo form depends on substitution of the benzene ring of the diazonium salt and decreases in the order of MeO > Me > Br > NO2. The position of tautomeric equilibrium is practically unaffected by switching from 4-methylaminopent-3-en-2-ones to 3-methylamino-1-phenylbut-2-en-1-ones. In the solid phase, the azo form always predominates; substitution of diazonium salt and at N3 nitrogen does not significantly affect the position of the tautomeric equilibrium. The azo coupling products always exist in the form of a single Z isomer. All determined structures, in the solid state, consist of a mixture of the two tautomeric forms, amino–diazenyl and imino–hydrazone, in ratios ranging from 82/18 to 91/9%. The weighed superimposition of both the hydrogen-bonded N1N2–C1C2–N3H/ HN1–N2C1–C2N3 heterodienic fragments, however, do not allow to clarify the effects of the para-substituents at the N1-phenyl ring both on the N1⋯N3 hydrogen-bond distances and on the bond lengths in the heterodienic systems within the series 3a–c,f and 4a–c,e,f.

Hydrogen-bonded aggregations of oxo-cholic acids

The crystal structures of six new crystals of oxo-cholic acids (oxo-CA) are reported: (I) 3alpha,12alpha-dihydroxy-7-oxo-5beta-cholan-24-oic acid; (II) 3alpha,7alpha-dihydroxy-12-oxo-5beta-cholan-24-oic acid; (III) 7alpha-hydroxy-3,12-dioxo-5beta-cholan-24-oic acid; (IV-alpha) and (IV-beta) 12alpha-hydroxy-3,7-dioxo-5beta-cholan-24-oic acid; (V) 3,7,12-trihydroxy-5beta-cholan-24-oic acid. (IV-beta) is a pseudopolymorphic solvated form of (IV-alpha) and contains small channels which can trap disordered water molecules. In all the structures the four saturated cycles, forming the common alicyclic skeleton, have the same conformation, while the carboxylic side chain adopts flexible conformations in order to produce the most efficient crystal aggregations. The structures display a variety of supramolecular architectures dominated by networks of cooperative O-H...O hydrogen bonds forming different packing motifs often supported by weaker C-H...O interactions.

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

Vinyl ester-based cyclic peptide proteasome inhibitors.

The 20S proteasome is a multicatalytic protease complex responsible for the degradation of many proteins in mammalian cells. Specific inhibition of proteasome enzymatic subunits represents a topic of great interest for the development of new drug therapies. Following our previous development of a new class of peptide-based inhibitors bearing a C-terminal vinyl ester residue as a pharmacophoric unit that are able to interact with the catalytic threonine, we report here the synthesis and biological properties of a new series of vinyl ester cyclopeptide analogues. Some of these derivatives were shown to inhibit the chymotrypsin-like activity of the proteasome at nanomolar concentration and their potency was found to depend on the size of the tetrapeptidic cyclic portion.

Role of strong intramolecular N—H⋯N hydrogen bonds in determining the conformation of adenosine-receptor antagonists

Over the last few years many efforts have been devoted to the discovery of new adenosine antagonists which can selectively bind to one of the four adenosine receptors, called A(1), A(2A), A(2B) and A(3), in order to develop new drugs with few side effects. The present paper reports the crystal structures of four newly synthesized antagonists belonging to the chemical class of pyrazolo-triazolo-pyrimidine derivatives, which display good affinity and selectivity properties towards the A(2A) or A(3) receptor subtypes. These molecules assume an overall planar conformation due to the formation of strong intramolecular N-H...N hydrogen bonds. A systematic investigation on molecules containing the ureidic -NH-C(=O,S)-NH-C=N- fragment has shown that the formation of such interactions is a common feature for this class of compounds. The associated energy, evaluated through DFT calculations, is some 50.24 kJ mol(-1), leading to the conclusion that the hydrogen bond, and consequently the planar conformation, is retained not only in the solid state but also in solution during the interaction of the molecule with its receptor.

A cobalt(III) complex containing coordinated and non-coordinated carboxylates: trans -[(nitro)bis(ethylenediamine)(3,5-dinitrobenzoato)- cobalt(III)][3,5-dinitrobenzoate]

Trans-[(nitro)bis(ethylenediamine)(3,5-dinitrobenzoato)cobalt(III)][3,5-dinitrobenzoate] ([trans- Co(en)2NO2(C7H3N2O6)]C7H3N2O6) has been obtained by mixing aqueous solutions of trans-dinitrobis(ethylenediamine)cobalt(III)nitrate and sodium 3,5-dinitrobenzoate in 1 : 1 molar ratio. Elemental analyses and spectroscopic techniques (IR, electronic, 1H and 13C NMR) were used to characterize the complex salt. An X-ray structure determination revealed the salt to consist of discrete [trans-Co(en)2NO2(C7H3N2O6)]+ and (C7H3N2O6)− ions. The salt is triclinic, space group , with a = 10.3790(1), b = 14.4421(2), c = 14.4421(2) Å, α = 88.0100(4), β = 79.1820(4), γ = 84.8690(6)°, Z = 6, V = 3789.50(9) Å3. The crystal lattice is stabilized by electrostatic forces and N–H ··· O hydrogen bonds between cations and anions resulting in a unique salt containing coordinated and non-coordinated 3,5-dinitrobenzoate groups.

A structural study of new potent and selective antagonists to the A2B adenosine receptor

Xanthines, including the natural derivatives theophylline and caffeine, are non-selective antagonists of adenosine. They are able to bind with good affinity to all four adenosine-receptor subtypes A1, A2A, A2B and A3. In order to develop new drugs with few side effects, over the last few years many efforts have been devoted to the discovery of new adenosine antagonists with enhanced selectivity properties. The present paper reports the crystal structures of five new xanthinic derivatives, which display different affinities and selectivity properties towards the A2B receptor. Besides the crystallographic study, a structural comparison has been made with the calculated geometry of other xanthinic derivatives which are reported to have similar biological characteristics to understand the structural features controlling their affinity capabilities and selectivity. This structural comparison has been interpreted in the light of a recently published study on the binding of N-benzo[1,3]-dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1-H-pyrazol-3-iloxy]-acetamide to a model of the A2B receptor, which shows the most interesting affinity and selectivity properties.