Roberto Gobetto

Solvent effect in a “solvent free” reaction

Vapour digestion of a mixture of solid [Fe(η5-C5H4–C5H4N)2] and solid pimelic acid HOOC(CH2)5COOH in the presence of solvent vapours generates co-crystals of different stoichiometry depending on the protic or aprotic nature of the solvent. The nature of the products has been ascertained by a combined use of SSNMR and X-ray diffraction.

Solid-state NMR studies of weak interactions in supramolecular systems

The field of application of solid-state NMR to the study of supramolecular systems is growing rapidly, with many research groups involved in the development of techniques for the study of crystalline and amorphous phases. This Feature Article aims to provide an overview of the recent contributions of our research group to this field, paying particular attention to the study of the weak interactions such as hydrogen bonds in supramolecular systems through solid-state NMR investigations. The structure and dynamic behaviour of selected host-guest systems will be also discussed.

Halogen Bonding and Pharmaceutical Cocrystals: The Case of a Widely Used Preservative

3-Iodo-2-propynyl-N-butylcarbamate (IPBC) is an iodinated antimicrobial product used globally as a preservative, fungicide, and algaecide. IPBC is difficult to obtain in pure form as well as to handle in industrial products because it tends to be sticky and clumpy. Here, we describe the preparation of four pharmaceutical cocrystals involving IPBC. The obtained cocrystals have been characterized by X-ray diffraction, solution and solid-state NMR, IR, and DSC analyses. In all the described cases the halogen bond (XB) is the key interaction responsible for the self-assembly of the pharmaceutical cocrystals thanks to the involvement of the 1-iodoalkyne moiety of IPBC, which functions as a very reliable XB-donor, with both neutral and anionic XB-acceptors. Most of the obtained cocrystals have improved properties with respect to the source API, in terms, e.g., of thermal stability. The cocrystal involving the GRAS excipient CaCl2 has superior powder flow characteristics compared to the pure IPBC, representing a promising solution to the handling issues related to the manufacturing of products containing IPBC.

The Thermodynamically Stable Form of Solid Barbituric Acid: The Enol Tautomer

Barbituric acid, which has been known since 1863, is drawn in textbooks always as the keto tautomeric form 1 (Scheme 1). Indeed, this is the most stable form in the gas phase and in solution. Also in the solid state, the keto tautomer is observed in the metastable phase I, the commercial phase II, and a high-temperature phase III, as well as in its dihydrates. In contrast, we now observe that the recently discovered tautomeric polymorph IV consists of molecules in the enol form 2, and that this polymorph is actually the thermodynamically stable phase at ambient conditions. The preference for the enol form in the solid state is explained by the formation of an additional strong hydrogen bond in the crystal, leading to a more favorable lattice energy. Polymorph IV is obtained from phase II by grinding or milling. Solid-state NMR (SSNMR), IR, and Raman experiments revealed this to be a tautomeric polymorph, which does not consist of the keto tautomer 1, but of one of the enol forms. The spectroscopic data suggested the trienol tautomer, but other enol tautomers could not be ruled out. All attempts to obtain single crystals of phase IV by recrystallization failed, and dehydration of the dihydrate yielded only phase II. The grinding or milling processes resulted in powders of poor crystallinity. However, it was possible to index the laboratory X-ray powder data and to solve the crystal structure by simulated annealing, while refinement was carried out by the Rietveld method from synchrotron data (Figure 1). The bond lengths in the OCN framework revealed phase IV to consist of molecules in the enol form 2. Scheme 1. Barbituric acid in the keto (1) and enol (2) tautomeric forms.

Making crystals from crystals: three solvent-free routes to the hydrogen bonded co-crystal between 1,1′-di-pyridyl-ferrocene and anthranilic acid

The organometallic complex [Fe(η5-C5H4–C5H4N)2] has been reacted with the anthranilic acid (C6H4)NH2COOH to generate the hydrogen bonded supramolecular macrocycle {[Fe(η5-C5H4–C5H4N)2] [(C6H4)NH2COOH]}2. The product has been fully characterized by means of X-ray powder diffraction, 13C and 15N solid-state NMR and single crystal X-ray diffraction. It has been shown that the same product can be obtained, quantitatively, by three different processes, namely kneading, i.e. solid-state mixing in the presence of a catalytic amount of MeOH, wet compression, i.e. pressure without mixing in the presence of MeOH, and vapour digestion, i.e. a mixture of the solid reactants is left in an atmosphere of MeOH vapours. The product can also be obtained via thermally induced reaction of a mixture of the two solid reactants, while no reaction is observed by dry mixing and dry compression. These experiments provide new insights into the factors controlling the process suggesting that the reaction requires the intermediacy of a catalytic amount of solvent or melting of one reactant to take place.

Cationic Heteroleptic Cyclometalated Iridium Complexes with 1‐Pyridylimidazo[1,5‐α]pyridine Ligands: Exploitation of an Efficient Intersystem Crossing

Luminescent ligands in Ir(III) cyclometalated complexes. The photophysical and photochemical properties of Ir-cyclometalated complexes containing luminescent ligands are evaluated (see figure). Significant admixture between Ir and ligand orbitals induces an efficient intersystem crossing. Photochemical reactions performed in the presence of oxygen lead to new Ir-cyclometalated complexes containing N(amido) groups directly bound to Ir.A series of phosphorescent cyclometalated heteroleptic iridi um(III) phenylpyridinato (ppy) complexes containing luminescent 1-pyridylimidazo[1,5-alpha]pyridine (pip) ligands, namely [Ir(ppy)(2)(pip)](+), have been synthesised, characterised and their electrochemical, photophysical and electronic properties studied. Seven X-ray structures have been resolved. Excitation of [Ir(ppy)(2)(pip)](+) in acetonitrile at room temperature results in a dual luminescence, strongly quenched by O(2). Four complexes show, in absence of O(2), a high-energy emission (assigned to a (3)MLLCT transition) with two maxima in the blue region of the visible spectra, and a second structured emission (assigned largely to a (3)LC pi-pi* transition) centred around lambda=555 nm. Lifetimes of high-energy emissions are between 0.6 and 1.3 mus. Time-dependent density functional calculations combined with the conductor-like polarisable continuum model method, with acetonitrile as solvent, have been used to calculate a series of ground and excited states of the derivatives under investigation, and the transitions compared with the experimental UV/Vis absorption spectra. A quick and efficient photochemical reaction has been observed for these iridium derivatives that leads to the formation of a new class of cyclometalated iridium complexes containing a stable deprotonated amide unusually coordinated to the metal through a nitrogen bond. The synthesis of a (15)N enriched selected ligand has been performed to investigate, by means of NMR, the particular facile route to these new set of derivatives. The electrochemical behaviour of all complexes is also reported.

Didanosine Polymorphism in a Supercritical Antisolvent Process

Solid-state properties of active ingredients are crucial in pharmaceutical development owing to their significant clinical and economical implications. In the present work we investigated the solid-state properties and the solubility in water of didanosine, DDI, re-crystallized from a dimethylsulfoxide solution using supercritical CO(2) as an antisolvent (SAS process) for comparison with the commercially available drug product. We also applied modern solid-state NMR (SS NMR) techniques, namely 2D (1)H DQ CRAMPS (Combined Rotation And Multiple Pulse Spectroscopy) and (1)H-(13)C on- and off-resonance CP (cross polarization) FSLG-HETCOR experiments, known for providing reliable information about (1)H-(1)H and (1)H-(13)C intra- and intermolecular proximities, in order to address polymorphism issues arising from the crystallization of a new form in the supercritical process. A new polymorph of didanosine was obtained from the supercritical antisolvent process and characterized by means of 1D and 2D multinuclear ((1)H, (13)C, (15)N) SS NMR. The particle size of the new crystal phase was reduced by varying the antisolvent density through a pressure increase. The structural differences between the commercial product and the SAS re-crystallized DDI are highlighted by X-ray diffractometry and well described by solid-state NMR. The carbon C6 (13)C chemical shift suggests that both commercial and re-crystallized didanosine samples are in the enol form. The analysis of homo- and heteronuclear proximities obtained by means of 2D NMR experiments shows that commercial and SAS re-crystallized DDI possess very similar molecular conformation and hydrogen bond network, but different packing. The new polymorph proved to be a metastable form at ambient conditions, showing higher solubility in water and lower stability to mechanical stress.

Synthesis and characterisation of bis(ferrocenylethynyl) complexes of platinum (II) A re-investigation of their electrochemical behaviour

Abstract We describe herein the synthesis and the electrochemical behaviour of a series of bis(ferrocenylethynyl) complexes of platinum(II). In all complexes, the electronic interaction between the redox-active iron cores of the ferrocenyl termini is small, indicating a moderate electronic delocalisation over the bis(cyclopentadienyl-acetylide)Pt chain.

Relationships between structure and ligand dynamics: II. Alkyne and carbonyl dynamics in Os3(CO)9(alkyne)(L) (L = CO, PR3)

Abstract The synthesis of the phosphine substituted complexes Os3(CO)9(μ3-η2-CH3CH2-CCCH2CH3)L (L = P(C6H5)3 (III), P(CH3)3 (IV)) and Os3(CO)9(μ3-η2-CH3CCCH3)L (L = P(OCH3)3 (V)) are reported. A detailed analysis of the VT-1H and VT-13C NMR of these complexes is presented and compared with the same studies on the parent complexes Os3(CO)9(μ3-η2-RCCR)(μ-CO) (R = CH2CH3 (I), CH3 (II)). In the parent complexes I and II a two stage exchange process is observed: (1) a low energy process involving axial radial exchange at the carbonyl bridged osmium atoms, (2) a higher energy exchange process in which alkyne motion over the face of the metal triangle is coupled with bridge-terminal exchange of the carbonyls, and with axialradial exchange at the unique osmium atom. The phosphine derivatives III–V, all show a three stage exchange process: (1) a localized axial-radial exchange at the unsubstituted osmium atoms; (2) a semibridging terminal carbonyl exchange at the phosphine substituted osmium coupled with a restricted oscillation of the alkyne, pivoted on this osmium atom; (3) free motion of the alkyne and averaging of all the carbonyl groups. The relationship between the differences in the observed dynamic processes are understood by a comparison of the solid state structures of I and III which are also reported. Compound I crystallizes in the triclinic space group P 1 , with unit cell parameters a 9.292(2), b 15.340(3), c 8.391(2) A, α 91.27(2), β 116.70 (1), γ 105.24(2)°, V 1017.3(4) A3, and Z = 2. Compound III belongs to the monoclinic space group P21/c, with a 14.271(4), b 11.370(2), c 21.192(5) A, β 104.43(2)3, V 3330(1) A3, and Z = 4. The structures were refined by full matrix least squares to RF = 0.044, RwF = 0.058 for I, and RF = 0.033, RwF = 0.041 for III, respectively.

Hyperpolarization transfer from parahydrogen to deuterium via carbon-13

Hyperpolarization arising from para-hydrogen (p-H2) can be transferred via carbon-13 to deuterium after hydrogenation of a perdeuterated substrate. The model compound is acetylene-d2, hydrogenated to yield ethylene-d2. Transfer to deuterium occurs in ALTADENA experiments (the hydrogenation reaction being performed outside the magnet of the NMR spectrometer prior to the insertion of the sample tube into the NMR probe). The proposed theory, limited to the case where the two p-H2 protons remain isochronous (same chemical shift), is based on the concept of a steady-state density operator which prevails subsequently to the hydrogenation reaction. The outcome quantity is the carbon–deuterium longitudinal spin order, denoted as IzCIzD. Calculations simply involve commutators of all relevant spin quantities with the J-coupling Hamiltonian (denoted as HJ). In particular, it is shown that the necessary condition for polarization transfer toward deuterium via carbon-13 is that IzCIzD does not commute with HJ. The st...