Walter Panzeri

Perfluorocarbon–hydrocarbon self-assembly: Part 16. 19F NMR study of the halogen bonding between halo-perfluorocarbons and heteroatom containing hydrocarbons

Abstract The halogen bonding between structurally different halo-perfluorocarbons (R f –X, R f =aliphatic or aromatic perfluorinated residue, X=I, Br, Cl) and heteroatom containing hydrocarbons (HC–D, HC=hydrocarbon residue, D=electron donor heteroatom) results in the formation of R f –X⋯D–HC complexes in the liquid phase. This formation strongly affects the 19 F NMR spectra of the perfluorinated partners. The Δ δ –C F 2 X and the Δ δ –C F CX– values of perfluoroalkyl and aryl derivatives is proven to be a simple, powerful, and versatile tool to rank the tendency of perfluorocarbon and HC modules to be involved in halogen bonding formation.

Intermolecular recognition between hydrocarbon oxygen-donors and perfluorocarbon iodine-acceptors: the shortest O⋯I non-covalent bond

Abstract Heteroaromatic N-oxides are shown to work as effective electron donors towards perfluorocarbon iodides. This non-covalent interaction is strong enough to drive the self-assembly of perfluorocarbon and hydrocarbon modules into discrete aggregates or one dimensional infinite networks and to give rise to the shortest O⋯I intermolecular distance reported to now in the crystallographic literature. The effectiveness of the O⋯I–RF halogen bonding with respect to the better studied N⋯I–RF interaction is discussed.

Perfluorocarbon-hydrocarbon self-assembly. Part 3. Liquid phase interactions between perfluoroalkylhalides and heteroatom containing hydrocarbons

Abstract In the liquid phase a specific and attractive intermolecular interaction exists between iodoor bromo-perfluoroalkanes (R f - X, R f = perfluorinated chain, X = Br, I) and heteroatom containing hydrocarbons (El) and it is robust enough to overcome the low affinity between perfluorocarbons and hydrocarbons. The interaction results in the formation of R f - X····El complexes and this formation strongly affects 14 N and 19 F NMR spectra of the partners. An association constant of 10.7 ± 1 mol −1 has been determined.

Validating a strategy for molecular dynamics simulations of cyclodextrin inclusion complexes through single-crystal X-ray and NMR experimental data: a case study.

A theoretical and experimental study about the formation and structure of the inclusion complex (-)-menthyl-O-beta-D-glucopyranoside 1 with beta-cyclodextrin (beta-CD) 2 is presented as paradigmatic case study to test the results of molecular dynamics (MD) simulations. The customary methodological approach-the use of experimental geometrical parameters as restraints for MD runs-is logically reversed and the calculated structures are a posteriori compared with those obtained from NMR spectroscopy in D(2)O solution and single crystal X-ray diffraction so as to validate the simulation procedure. The guest molecule 1 allows for a broad repertoire of intermolecular interactions (dipolar, hydrophobic, hydrogen bonds) concurring to stabilize the host-guest complex, thus providing the general applicability of the simulation procedure to cyclodextrin physical chemistry. Many starting geometries of the host-guest association were chosen, not assuming any a priori inclusion. The simulation protocol, involving energy minimization and MD runs in explicit water, yielded four possible inclusion geometries, ruling out higher-energy outer adducts. By analysis of the average energy at room temperature, the most stable geometry in solution was eventually obtained, while the kinetics of formation showed that it is also kinetically favored. The reliability of such geometry was thoroughly checked against the NOE distances via the pair distribution functions, that is, the statistical distribution of intermolecular distances among selected diagnostic atoms calculated from the MD trajectories at room temperature. An analogous procedure was adopted both with implicit solvent and in vacuo. The most stable geometry matched that found with explicit solvent but major differences were observed in the relative stability of the metastable complexes as a consequence of the lack of hydration on the polar moiety of the guest. Finally, a control set of geometrical parameters of the thermodynamically favored complex matched the corresponding one obtained from the X-ray structure, while local conformational differences were indicative of packing effects.

Synthesis of Nonracemic α-Trifluoromethyl α-Amino Acids from Sulfinimines of Trifluoropyruvate

We describe a novel and useful method for the synthesis of nonracemic α-trifluoromethyl α-amino acids (α-Tfm-AAs). Key building blocks are the sulfinimines (S)-1a and (S)-1b, prepared by Staudinger reaction from trifluoropyruvate esters and the chiral N-sulfinyl iminophosphorane (S)-8, which were treated with benzyl, allyl, and alkylmagnesium halides. The resulting diastereomeric N-sulfinyl α-Tfm α-amino esters, 12 and 13, were produced with moderate to good stereoselectivity and yields. When alkyl Grignard reagents were used, stereocontrol became progressively higher with increasing steric bulk, while reversed, though poor, stereocontrol was achieved with benzyl/allyl Grignard reagents. An explanation for the observed stereochemical outcome is proposed, on the basis of the exclusive E geometry (N-sulfinyl and CF3trans about the C=N bond) of the chiral sulfinimines 1. This assignment is the product of structural correlation and is supported by ab initio calculations and NOE experiments. Sulfinamides 12 and 13 were transformed into a series of nonracemic α-Tfm-AAs 16−22. The sulfinyl auxiliary can be regenerated and recycled.

Perfluorocarbon—hydrocarbon self assembling. Thermal and vibrational analyses of one-dimensional networks formed by α,ω-diiodoperfluoroalkanes with K.2.2. and K.2.2.2.

Abstract When perfluorocarbon diiodides 1 and hydrocarbon diamines 2,3 are co-crystallised from chloroform a donor-acceptor interaction between the nitrogen atoms of 1 and the iodine atoms of 2, 3 lead to the formation of infinite one-dimensional coordination networks 4 and 5 . Thermal and infrared analyses of these adducts are reported. Nitrogen-iodine interaction is proposed as a non-covalent bonding strong enough to drive the formation of co-crystals between fluorocarbon and hydrocarbon derivatives.

Perfluorocarbon-Hydrocarbon Discrete Intermolecular Aggregates: An Exceptionally Short N⋯I Contact

1-Iodoperfluoroheptane ( 1a ) and tetramethylethylenediamine ( 2 , TMEDA) form the 2:1 ratio stable aggregate 3a and a similar behaviour is shown by 1-iodoperfluoroalkanes 1b-e and iodopentafluorobenzene 1f . These aggregates have been characterised in solution by 1 H/ 19 F-NMR spectroscopy and in the solid state through IR and single crystal X-ray diffraction. The determined structure of 3a (triclinic, a =6.2283(10), b =9.250(2), c =15.098(3) Å, f =81.369(5), g =81.397(5), n = 86.010(5), V =849.3(3) A m 3 , T =175(3) K, space group P-1 (No. 2), Z =1; d (calc)=2.167 g cm m 3 ; 4121 independent reflections, 3665 with I o >2( I o ); final refinement gave R1=0.0400, wR2=0.0901) showed the second shortest N > I interaction found in the crystallographic literature [2.762(3) Å] and the interdigitation of perfluorocarbon and hydrocarbon modules due to co-operative -C-H > F-C- interactions. Calculations to quantify these latter interactions have been also performed.

Spectroscopic and Structural Investigation of the Confinement of d and l Dimethyl Tartrate in Lecithin Reverse Micelles

The confinement of D and L dimethyl tartrate in lecithin reverse micelles dispersed in cyclohexane has been investigated by FT-IR, polarimetry, electronic and vibrational circular dichroism (ECD and VCD), 1H NMR, and small-angle X-ray scattering (SAXS). Measurements have been performed at room temperature as a function of the solubilizate-to-surfactant molar ratio (R) at fixed lecithin concentration. The analysis of experimental data indicates that the dimethyl tartrate molecules are solubilized within reverse micelles in proximity to the surfactant head groups in the same way for the D and L forms. The encapsulation of dimethyl tatrate within lecithin reverse micelles involves changes in its H-bonds, from what is observed in the pure solid or in CCl4 solutions; this is a consequence of the establishment of specific solute-surfactant headgroup interactions and of confinement effects. In the 0 < or = R < or = 1.7 range, SAXS profiles of dimethyl tartrate/lecithin/ cyclohexane micellar solutions are well-described by a model of interacting polydisperse spherical micellar cores whose mean radius does not change appreciably with R (i.e., it changes from about 18 to 20 angstroms). 1H NMR diffusion measurements of both dimethyl tartrates and lecithin were rationalized in terms of collective translational motions of the entire micellar aggregate and of their molecular diffusion among clusters of reverse micelles. The association of optically active lecithin with D and L dimethyl tartrate leads to the formation of self-organized supramolecular aggregates whose interesting chiroptical features are evidenced by polarimetry and CD.

Total synthesis of a pepstatin analog incorporating two trifluoromethyl hydroxymethylene isosteres (Tfm-GABOB) and evaluation of Tfm-GABOB containing peptides as inhibitors of HIV-1 protease and MMP-9

Abstract We describe the asymmetric total synthesis of a trifluoromethyl (Tfm) analogue of the aspartate protease inhibitor pepstatin incorporating two γ-Tfm-γ-amino-β-hydroxybutyric acid (γ-Tfm-GABOB) units instead of the natural statine units. The title compound as well as several Tfm-substituted precursors were tested as inhibitors of HIV-1 protease and Gelatinase B (MMP-9)

Dimerizable Redox-Sensitive Triazine-Based Cationic Lipids for in vitro Gene Delivery.

Introduction of a missing gene into the cell nucleus (transfection), followed by its expression by the natural machinery of the cell, is a very well-established strategy to produce proteins. This process can also be used therapeutically to produce proteins needed to heal a certain pathological condition (gene therapy). However, achievement of efficient transfection remains a challenging endeavor. A number of transfection methods have been developed, essentially based on the use of viruses, chemical reagents (for example, cationic lipids and polymers), or physical methods (mechanical stimulation, electroporation, magnetic field induced, etc.). All of these transfection strategies have advantages and drawbacks, but it is apparent that the use of chemical reagents is a very attractive option, because of their ready availability (many transfection reagents are commercial products), their versatility (they can be used to transfect different kinds of cells with genetic material having a wide range of dimensions), low toxicity for the operator (viruses can be pathogenic), and simple experimental use. The main drawback with chemicals as transfectants is connected with their generally low performance, both in terms of number of cells which are transfected and alive at the end of the process and in terms of duration of the transfection. For this reason, chemical transfection reagents must be effective and with limited cytotoxicity, but also cheap and readily prepared from inexpensive, nonexotic starting materials to be competitive and of potential practical use. With these premises, it is not surprising that calcium phosphate is still widely used to achieve transfection, particularly with “difficult” and resistant cells, in addition to popular “organic” reagents (which are generally cationic liposomes comprised of a cationic lipid and a neutral, helper lipid for example, cholesterol) such as Lipofectamine, DOTAP, and related compounds. Although a number of active ingredients for transfection have been recently described in the literature, few of them are truly innovative in terms of structure. In this paper we present a conceptually new family of cationic lipids for transfection featuring a triazine scaffold, which allows for an easy derivatization, with three functionally different amino side chains: 1) a linear C12–C16 chain (the lipophilic tail), 2) a 3-propylammonium chain which acts as polar head, 3) a redox-sensitive dimerizable 2-thioethyl chain (according to the so-called disulfide-linker strategy). The corresponding disulfide dimers have been synthesized and evaluated as well. The new triazine-based transfectants feature very simple preparation from inexpensive materials, and the triazine core allows for a smooth introduction of structural diversity by means of subsequent nucleophilic dechloroaminations of the starting trichlorotriazine by different amines. Most importantly, these triazine-based cationic lipids exhibit low cytotoxicity and high transfection efficiency on a variety of eukaryotic cells, even without any formulation with helper lipids. The lead thiol compound 4, having a C14 chain, was synthesized in multigram amounts as portrayed in Scheme 1.