Pedro Lameiras

MeLi + LiCl in THF: One Heterodimer and No Tetramers†

The structure of the aggregates formed when mixing methyllithium and lithium chloride in THF has been studied by multinuclear magnetic resonance at 170 K. The data suggest that only one new entity is observed, that is the dimer [(MeLi)(LiCl)], in equilibrium (K approximately 0.6) with [MeLi](4) and [LiCl](2). NMR diffusion measurements lead to the conclusion that this dimer is trisolvated in THF at 170 K, a solvation scheme in agreement with DFT computations.

Glycerol and glycerol carbonate as ultraviscous solvents for mixture analysis by NMR.

NMR of weakly polar analytes in an apolar ultraviscous solvent has recently been proposed for mixture analysis as a pertinent alternative to the DOSY experiment. The present article reports the first use of glycerol and glycerol carbonate as polar solvents for the NMR analysis of a model mixture of dipeptides. This work demonstrates the high potentiality of these solvents for the analysis of mixtures made of polar and potentially bioactive compounds. Medium-sized molecules slowly reorient in glycerol and glycerol carbonate under particular temperature conditions, so that solute resonances may show spin diffusion in NOESY spectra, thus opening the way to mixture analysis. Glycerol and glycerol carbonate have turned out to be ultraviscous solvents of choice for the individualization of four structurally close mixed dipeptides: Leu-Val, Leu-Tyr, Gly-Tyr and Ala-Tyr by means of 1D and 2D NOESY experiments. Selective sample excitation and signal detection were implemented to eliminate the intense proton signals of the non-deuterated solvents. Moreover, the recording of a multiplet selective 2D NOESY-TOCSY has shown that the analytical power of NMR in highly viscous solvents is not limited to the extraction of mixture component 1D subspectra but may also yield some supplementary information about atom connectivity within components.

Ion-exchange centrifugal partition chromatography: A methodological approach for peptide separation

This article presents the scope and optimization strategies employed in ion-exchange centrifugal partition chromatography (IXCPC). Both the weak and the strong modes were used to separate the constituents of a model mixture of dipeptides. Thus, the combined use of the quaternary biphasic solvent system, methyl-tert-butylether/acetonitrile/n-butanol/water (2:1:2:5, v/v) in the descending mode, of the lipophilic di(2-ethylhexyl)phosphoric acid (DEHPA) cation-exchanger, and of two displacers: calcium chloride and hydrochloric acid, has proven to be efficient for the preparative separation of the model mixture of five dipeptides (GG, GY, AY, LV and LY, in the order they were collected). The separation was optimized by splitting the stationary phase into two sections that differed by their triethylamine concentration. Moreover, the chemical nature of the exchanger/analyte entities that were involved in the chromatographic process was determined by (31)P and (1)H DOSY NMR experiments.

Atropisomerism about aryl-csp3 bonds: The electronic and steric influence of ortho -substituents on conformational exchange in cannabidiol and linderatin derivatives

Terpenylation reactions of substituted phenols were used to prepare cannabidiol and linderatin derivatives, and their structure and conformational behavior in solution were investigated by NMR and, for some representative examples, by DFT. VT-NMR spectra and DFT calculations were used to determine the activation energies of the conformational change arising from restricted rotation about the aryl-Csp(3) bond that lead to two unequally populated rotameric epimers. The NBO calculation was applied to explain the electronic stabilization of one conformer over another by donor-acceptor charge transfer interactions. Conformational control arises from a combination of stereoelectronic and steric effects between substituents in close contact with each other on the two rings of the endocyclic epoxide atropisomers. This study represents the first exploration of the stereoelectronic origins of atropisomerism around C(sp(2))-C(sp(3)) single bonds through theoretical calculations.

FIRST SYNTHESIS, ROTAMERISM AND HERBICIDAL EVALUATION OF SUBSTITUTED s-TRIAZINES WITH SERINOLIC FRAGMENT

First example of melamines and precursors, based on commercially C-substituted-2-amino1,3-propanediols (pharmaceutical chemistry nomenclature as serinols) in reaction with cyanuryl chloride is reported, e.g. starting from 2-amino-2-methyl-l,3-propanediol. The diastereomerism generated by the more or less restricted rotation about the C(j -triazine) -N< (serinol) bond in this series is for the first time discussed along with a preliminary herbicidal evaluation of a representative term.

Atropisomerism about Aryl–C(sp3) Bonds: Conformational Behavior of Substituted Phenylcyclohexanes in Solution

A catalytic hydrogenation of cannabidiol derivatives known as phenylcyclohexenes was used to prepare epimeric (1R,1S) and/or rotameric (M,P) phenylcyclohexanes. The reaction is diastereoselective, in favor of the 1S epimer, when large groups are attached to the phenyl ring. For each epimer, variable-temperature NMR experiments, including EXSY spectroscopy and DFT calculations, were used to determine the activation energies of the conformational exchange arising from the restricted rotation about the aryl-C(sp(3)) bond that led to two unequally populated rotamers. The conformational preference arises essentially from steric interactions between substituents vicinal to the pivot bond. The conformers of epimers (1S)-2e,f show high rotational barriers of up to 92 kJ mol(-1), unlike those of (1R)-2e,f and with much lower barriers of ∼72 kJ mol(-1). The height of the barriers not only depends on the substituents at the axis of chirality but also is influenced by the position of a methyl group on the monoterpene ring. The feature most favorable to high rotational barriers is when the methyl at C1 lies equatorially. This additional substituent effect, highlighted for the first time, seems fundamental to allowing atropisomerism in hindered ortho-substituted phenylcyclohexanes.

Highly Viscous Binary Solvents: DMSO-d6/Glycerol and DMSO-d6/Glycerol-d8 for Polar and Apolar Mixture Analysis by NMR

The use of two new highly viscous binary solvents, DMSO-d6/glycerol (GL) and DMSO-d6/glycerol-d8 (GL-d8), is reported for the first time in order to give access to the individual NMR spectra of mixture components. Their high dissolution power offers a wide range of potential applications to mixture analysis, regardless of polarity. Under particular conditions of viscosity, the tumbling rate of small and medium-sized molecules slows down in solution, so that the longitudinal cross-relaxation regime favors the observation of spin diffusion. As a consequence, all the resonances of the (1)H nuclei within the same molecule tend to correlate together in a 2D nuclear Overhauser effect spectroscopy (NOESY) spectrum, thus opening the way to mixture analysis. This work reports the analysis of a polar mixture composed of Leu-Val, Leu-Tyr, Gly-Tyr, and Ala-Tyr dissolved in DMSO-d6/GL (8:2, v/v) and of an apolar mixture made of β-ionone, (±)-citronellal, (+)-limonene, and flavone dissolved in DMSO-d6/GL-d8 (5:5, v/v) by means of spin diffusion in homonuclear selective 1D NOESY, selective 2D NOESY, NOESY-correlation spectroscopy (COSY), NOESY-total correlation spectroscopy (TOCSY) experiments, and 2D heteronuclear single-quantum correlation spectroscopy (HSQC)-NOESY. DMSO-d6/GL must be preferred to DMSO-d6/GL-d8 for the study of biological active compounds in which labile protons must not be exchanged by deuterium nuclei. DMSO-d6/GL-d8 is more appropriate for organic compounds in which labile protons are not essential to the structure elucidation. DMSO-d6/GL and DMSO-d6/GL-d8 binary mixture solvents seem to be so far the most efficient viscous solvents described in the literature for the resolution of both polar and apolar complex mixtures components by NMR spin diffusion.

Convergent Versus Divergent Three-Step Synthesis of the First (4-Aminophenoxy)alkanoic Acid–Based Tripodal Melamines

Abstract Starting from N-(4-hydroxyphenyl)acetamide (Paracetamol, convergent approach) or from cyanuric chloride in reaction with 4-aminophenol (divergent approach), two synthetic routes toward novel tripodal N-substituted melamines as s-triazine derivatives of (4-aminophenoxy)acetic acid or of 4-(4-aminophenoxy)butyric acid are comparatively defined. The key steps consist of Williamson etherification of N-masked forms of 4-aminophenol and acidic hydrolysis of the N- and/or O-protected (4-aminophenoxy)alkanoic segments. GRAPHICAL ABSTRACT

New serinolic amino-s-triazines by chemoselective amination of cyanuric chloride and their (pro)diastereomerism in restricted rotational phenomena

AbstractThe highly chemoselective preparation of new elaborated N-unsymmetrically substituted chlorodiamino-s-triazines and melamines, seen as building-blocks for iterative synthesis, is reported. It consisted of amination of cyanuric chloride with commercial C-2-substituted 2-aminopropane-1,3-diols (“serinols”), playing the role as “open-chain” unit and enantiopure (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diols (“p-nitrophenylserinols”) based amino-1,3-dioxanes (“closed-chain” unit). Issued from the restricted rotation about C(s-triazine)-N(exocyclic) partial double bonds, seen as axes of (pro)diastereomerism, a global four-component rotational equilibrium involving the title compounds is discussed based on DFT computation and (VT) NMR data. Depending on π-deficiency of the s-triazine core, an (un)synchronised deblocking of the generated rotational diastereomers was observed. They are discussed as influence of intra-vs. intermolecular NH...OH (dynamic) interactions occurring in the “open-chain” unit and the anancomeric, axial vs. equatorial, amino-anchorage of the “closed-chain” unit.

Synthesis of Some Selectively N-Protected (1S,2S)-p-Nitrophenylserinol–Based Diamino-1,3-dioxanes and Tripodands

Abstract The unconventional methodology for the non-epimerizable cycloacetalization of optically active (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol (p-nitrophenylserinol) (condensed H2SO4 96% as solvent and catalyst, i.e., sulfuric transacetalization) producing (2R,4S,5S) diamino-1,3-dioxanes was enlarged by the use of N-protected forms of 2,2-dimethoxyethylamine (DMEA, aminoacetaldehyde dimethylacetal). Conversely, N-protected derivatives of p-nitrophenylserinol were successfully cyclocondensed with DMEA in the same sulfuric conditions. N-Functionalization of DMEA upon treatment with trimesic acid trichloride and cyanuric chloride yielded the corresponding triple amide and melamine, respectively. Their adapted sulfuric transacetalization in triplicate in reaction with arylserinols (aryl: phenyl, p-nitrophenyl) afforded a new series of optically active tripodands. GRAPHICAL ABSTRACT