Valeria Ferretti

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]

α,β-Unsaturated Carbonyl System of Chalcone-Based Derivatives is Responsible for Broad Inhibition of Proteasomal Activity and Preferential Killing of Human Papilloma Virus (HPV)-Positive Cervical Cancer Cells

Proteasome inhibitors have potential for the treatment of cervical cancer. We describe the synthesis and biological characterization of a new series of 1,3-diphenylpropen-1-one (chalcone) based derivatives lacking the boronic acid moieties of the previously reported chalcone-based proteasome inhibitor 3,5-bis(4-boronic acid benzylidene)-1-methylpiperidin-4-one and bearing a variety of amino acid substitutions on the amino group of the 4-piperidone. Our lead compound 2 (RA-1) inhibits proteasomal activity and has improved dose-dependent antiproliferative and proapoptotic properties in cervical cancer cells containing human papillomavirus. Further, it induces synergistic killing of cervical cancer cell lines when tested in combination with an FDA approved proteasome inhibitor. Exploration of the potential mechanism of proteasomal inhibition by our lead compound using in silico docking studies suggests that the carbonyl group of its oxopiperidine moiety is susceptible to nucleophilic attack by the γ-hydroxythreonine side chain within the catalytic sites of the proteasome.

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.

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.

Competition between hydrogen bonding and donor–acceptor interactions in co-crystals of 1,3-dimethylbarbituric acid with aromatic amines

In contrast to cyclohexane-1,3-diones, 1,3-dimethylbarbituric acid (DMBA) does not enolize in crystals with formation of infinite H-bonded chains. Conversely, it forms crystals that completely lack traditional H-bond donors and hence are held together by C–H···O H-bonds and Cδ+Oδ−···Cδ+ interactions of a putative donor–acceptor nature. In view of these specific features, the DMBA molecule appeared to be a good candidate to study the competition of the various intermolecular forces in its co-crystals with traditional H-bond donors such as o-nitrophenylhydrazine, p-nitroaniline, 2,6-diamino-4-phenyl-1,3,5-triazine, 2,6-diaminopyridine and p-aminopyridine. X-Ray crystallographic results are analyzed in terms of crystal packing forces and formation of specific packing leitmotifs (supramolecular synthons). The conclusions indicate that, though a rational crystal engineering of co-crystals is far from being accomplished, a reasonable rationalization of the complex intermolecular forces acting in competition in the crystal packing is henceforth achievable.

Metal–Metal Interactions in Trinuclear Copper(II) Complexes [Cu3(RCOO)4(H2TEA)2] and Binuclear [Cu2(RCOO)2(H2TEA)2]. Syntheses and Combined Structural, Magnetic, High-Field Electron Paramagnetic Resonance, and Theoretical Studies

The trinuclear [Cu3(RCOO)4(H2TEA)2] copper(II) complexes, where RCOO(-) = 2-furoate (1), 2-methoxybenzoate (2), and 3-methoxybenzoate (3, 4), as well as dimeric species [Cu2(H2TEA)2(RCOO)2]·2H2O, have been prepared by adding triethanolamine (H3TEA) at ambient conditions to hydrated Cu(RCOO)2 salts. The newly synthesized complexes have been characterized by elemental analyses, spectroscopic techniques (IR and UV-visible), magnetic susceptibility, single crystal X-ray structure determination and theoretical calculations, using a Difference Dedicated Configuration Interaction approach for the evaluation of magnetic coupling constants. In 1 and 2, the central copper atom lies on an inversion center, while in the polymorphs 3 and 4, the three metal centers are crystallographically independent. The zero-field splitting parameters of the trimeric compounds, D and E, were derived from high-field, high-frequency electron paramagnetic resonance spectra at temperatures ranging from 3 to 290 K and were used for the interpretation of the magnetic data. It was found that the dominant interaction between the terminal and central Cu sites J12 is ferromagnetic in nature in all complexes, even though differences have been found between the symmetrical or quasi-symmetrical complexes 1-3 and non-symmetrical complex 4, while the interaction between the terminal centers, J23, is negligible.

Synthesis and characterization of square-planar platinum(II) and palladium(II) complexes with pyridine-2,6-dicarboxylic acid (H2dipic). X-Ray crystal structure of trans-Na2[Pt(dipic)2]6H2O and K[Pt(dipic)I]1/2H2O

Abstract The tetra-coordinate complexes trans-[Pt(Hdipic)2]·2H2O (1) and trans-[Pd(Hdipic)2]·2H2O (2) as well as their potassium and sodium derivatives trans-K2[Pt(dipic)2] (3), trans-Na2[Pt(dipic)2]·6H2O (4) and trans-Na2[Pd(dipic)2]·2H2O (5) have been obtained in high yield by reacting aqueous solutions of K2[PtCl4] and K2[PdCl4] with pyridine-2,6-dicarboxylic acid (H2dipic) or its potassium or sodium salts, respectively, in 1:2 molar ratio. 1 and 2 are also formed on reacting equimolar amounts of reagents in water (pH 1.4) leaving in solution unreacted K2[PtCl4] and K2[PdCl4]. The resulting mixtures brought to pH 5 with KOH undergo a redistribution reaction with formation of the monoanionic species K[Pt(dipic)Cl]·H2O (6) and K[Pd(dipic)Cl]·H2O (7), respectively. The iodo derivative K[Pt(dipic)l]·1/2H2O (8) was obtained from the chloro species by replacement of the coordinated chloride with iodide in aqueous solution. All the complexes have been characterized by a number of physico-chemical measurements including the X-ray analysis of trans-Na2[Pt(dipic)2]·6H2O (4) and K[Pt(dipic)I]·1/2H2O (8). Crystals of 4 are monoclinic, space group P21/c, Z=2, with unit-cell dimensions a=11.912(1), b=6.544(1), c=12.699(1) A, β=91.56(1)°. Crystals of 8 are triclinic, space group P 1 , Z=4, with unit- cell dimensions a=11.018(1), b=11.585(2), c=9.946(1) A, a=97.99(1), β=115.07(1), γ=73.14(1)°. The structures were solved from three dimensional counter data by Patterson and Fourier methods and refined by full-matrix least-squares to R=0.019 and 0.030 for 1556 and 4118 observed reflections, respectively. The crystal of 4 is built up by centrosymmetric Pt(dipic)22− anions and Na+ cations hexacoordinated by four water molecules and two carboxylate oxygens belonging to the ligands. Each dipicolinate ion behaves as a bidentate ligand, and the resulting coordination around the platinum is square planar. The asymmetric unit of compound 8 contains two independent square planar Pt(dipic)l− anions, in each of them the dipicolinate ion acts as a tridentate ligand and the fourth position is occupied by an iodine atom. The planar complex anions Pt(dipic)l− are stacked but not parallel and Pt atoms form infinite zigzag chains.