Milovan Stojanović

High regioselectivity in the heterocyclization of β-oxonitriles to 4-oxothiazolidines: X-ray structure proof

Base-catalyzed reactions of β-oxonitriles 1 with diethyl mercaptosuccinate favour heterocyclization to afford 2-alkylidene-4-oxothiazolidines 3, rather than 2-alkylidene-4-oxo-1,3-thiazinanes 4. The observed regioselectivity is based on spectroscopic and experimental evidence, including a single-crystal X-ray structure determination.

Stereocontrolled synthesis of new tetrahydrofuro[2,3-d]thiazole derivatives via activated vinylogous iminium ions

Heterocyclization of (Z)-5-(2-hydroxyethyl)-3-methyl-4-oxothiazolidines, bearing electron-withdrawing groups conjugated to an exocyclic double bond at C(2)-position, afforded under reductive conditions, cis-tetrahydroftiro[2,3- d]thiazole derivatives. The reactions of these functionalized push-pull beta-enamines occur in a stereocontrolled fashion via activated vinylogous N-methyliminium ions, which are trapped by an internal hydroxyethyl group

Origin of Fluorine/Sulfur Gauche Effect of β-Fluorinated Thiol, Sulfoxide, Sulfone, and Thionium Ion.

The well-known gauche preference in FCCX systems, where X is an electronegative element from Period 2, is widely exploited in synthetic, medicinal, and material chemistry. It is rationalized on the basis of σ(C-H) → σ*(C-F) hyperconjugation and electrostatic interactions. The recent report (Thiehoff, C.; et al. Chem. Sci. 2015, 6, 3565) showed that the fluorine gauche effect can extend to Period 3 elements, such as sulfur. The aim of the present work is to disclose factors governing conformational behavior of FCCS containing systems. We examine conformational preferences in seven classes of compounds by ab initio and DFT calculations and rationalize the results by quantitatively decomposing the anti/gauche isomerization energy into contributions from electrostatic, orbital, dispersion, and Pauli interactions, and energy spent on structural changes. The results show that the fluorine/sulfur gauche effect is primarily electrostatic (63-75%), while all orbital interactions contribute 22-41% to stabilizing interactions. Stereoelectronic effects, involved in orbital interactions, also play a role in gauche conformer stabilization.

1H NMR chemical shifts of cyclopropane and cyclobutane: a theoretical study.

This study was undertaken in order to rationalize the peculiar (1)H NMR chemical shifts of cyclopropane (δ 0.22) and cyclobutane (δ 1.98) which are shifted upfield and downfield with respect to larger cycloalkanes (δ 1.44-1.54). This is conventionally accounted for by shielding contributions arising from an aromatic-like ring current in cyclopropane, involving six electrons in the three C-C bonds, and deshielding coming from the σ antiaromatic CC framework of cyclobutane. The shielding pattern arising from the cyclopropane and cyclobutane CC framework response to a perpendicular magnetic field was visualized as two-dimensional grid distribution of NICS values. Further insight into the origin of chemical shift values was obtained by the NCS-NBO analysis of proton shielding tensor. In the case of cyclopropane, the CC framework shielding pattern implies the existence of both delocalized and localized currents that have a dominant shielding effect on protons. The magnitude of C-H bonds shielding effect is significant, too. Unlike the conventional interpretation, the CC framework shields cyclobutane hydrogens, and its response to a perpendicular magnetic field is quite similar to responses of other planar σ CC frameworks.

ESTIMATION OF LIPOPHILICITY OF N-SUBSTITUTED 2-ALKYLIDENE-4-OXOTHIAZOLIDINES BY MEANS OF REVERSED-PHASE THIN-LAYER CHROMATOGRAPHY

The chromatographic behavior of 23 new 2-alkylidene-4-oxothiazolidine derivatives was investigated by means of the reversed-phase thin-layer chromatography (RP TLC) on the C18 and CN stationary phases. Binary mixtures of methanol-water, acetonitrile-water, and tetrahydrofuran-water were used as mobile phases. Linear relationships between the volume fraction of the organic mobile phase modifier and the RM values were established for each solute with high correlation coefficient values (r > 0.99). The investigated 4-oxothiazolidines are a congeneric set of compounds, and significant correlations were obtained between the chromatographically determined and m values. The lipophilicity parameters obtained from the reversed-phase experiments were compared with the calculated log P values. Some of these correlations offer very good predicting models, which are important for a better understanding of the relationships between chemical structure and retention, and can prove helpful in the structure-activity studies as well. Finally, our investigation was focused on chemometric processing of the retention data in different chromatographic systems. To this effect, Principal Component Analysis (PCA) was performed, yielding the results helpful in interpretation of interactions among investigated substances, binary mobile phases, and the two different stationary phases.

Aromaticity of Diazaborines and Their Protonated Forms

Substitution of a CH group in benzene with nitrogen has a little effect on its aromaticity (Wang et al., Org. Lett. 2010, 12, 4824). How does the same type of substitution affect aromatic character of the three isomeric azaborines? Does further protonation change aromaticity of diazaborines? This work is aimed at answering these questions. Such a knowledge should be of interest for further exploration and application of BN/CC isosterism. Aromaticity of diazaborines and their protonated forms is studied with the aid of four aromaticity indices, HOMA, NICS(0)πzz, PDI and ECRE. Generally, NICS(0)πzz and PDI point to similar aromaticity of diazaborines and their parent azaborines, while HOMA and ECRE indicate some changes. Thus, aromaticity of 1,2-azaborine slightly decreases/increases when CH meta/ortho,para to B is substituted with nitrogen. Aromaticity of the most aromatic 1,3-azaborine remains almost unchanged when CH meta to B and N is replaced with nitrogen, and becomes slightly weaker when any other CH group is substituted with nitrogen. Replacement of the CH ortho to N in 1,4-azaborine does not change much its cyclic delocalization, while replacement of the CH ortho to B leads to smaller cyclic delocalization. Protonated forms are either of similar or decreased aromaticity compared with neutral molecules.

Energy decomposition analysis of gauche preference in 2-haloethanol, 2-haloethylamine (halogen = F, Cl), their protonated forms and anti preference in 1-chloro-2-fluoroethane

2-Haloethanol and 2-haloethylamine (halogen = F, Cl) prefer gauche conformation. This preference is significantly increased upon protonation. Commonly used explanations are based on intramolecular hydrogen bonding and hyperconjugation. 1,2-Difluoroethane prefers gauche conformation, too, while gaseous 1-chloro-2-fluoroethane is more stable as the anti conformer. The origin of these conformational preferences has been investigated by a quantitative partitioning of the gauche/anti energy difference into contributions from electrostatic, orbital, dispersion and Pauli interactions, and structural changes accompanying the rotation. The results show that, with two exceptions, the most important contributor to the gauche preference is electrostatic attraction, which is larger in gauche forms relative to the anti ones. Next come orbital interactions, while dispersion forces provide the smallest stabilizing energy. These energy components override destabilizing Pauli interactions and energetically costly structural changes. All gauche preferences also benefit from stereoelectronic effects, except in protonated 2-chloroethanol which, instead, shows a significant Cl lone pair → O–H antibond mixing, associated with hydrogen bonding. The increase in the Pauli repulsion upon anti to gauche isomerization is more pronounced for fluorine than for chlorine derivatives. Thus, the smaller gauche effect in chloro-compounds and the anti preference in 1-chloro-2-fluoroethane have their origin in the decrease in electrostatic and orbital stabilizing interactions, a drop in the former being more pronounced.

Substituent effects on cyclic electron delocalization in symmetric B- and N-trisubstituted borazine derivatives

Aromaticity is an important concept in chemistry, useful to rationalize structure, physical properties and chemical behaviour of molecules. Aromaticity of an inorganic relative of benzene, borazine, has been the topic of a number of studies which resulted in its description as weakly aromatic or nonaromatic. However, influence of substituents on its aromatic character is poorly understood. This study shows that an appropriate choice of aromaticity indices can establish a connection between substituent effects and aromaticity of the ring. The changes in cyclic π electron delocalization (aromaticity) were traced by means of the most refined NICS(0)πzz index, the electron delocalization-based index PDI and extra cyclic resonance energy ECRE, computed by using the Natural Bond Orbital (NBO) method. Although various indices often do not correlate well with each other, owing to the multidimensional nature of aromaticity, these three indices agreed quite well. However, the HOMA index failed to give reliable information in this case.

Theoretical study of azido gauche effect and its origin

The strength of the azido gauche effect in 1,2-diazidoethane, N-(2-azidoethyl)ethanamide, (protonated) 2-azidoethanamine and (protonated) 2-azidoethanol and its origin were theoretically studied at the MP2/6-311++G(d,p) level of theory. The results show that the azido gauche effect in the amine and alcohol can exert a control over the molecular conformation to a similar extent as the fluorine gauche effect, but to a greater extent in the charged species, amide and vicinal diazido fragment. A quantitative partitioning of isomerization energy into contributions from electrostatic, orbital, dispersion and Pauli interactions and energy consumed in structural changes revealed that electrostatic forces play an important role in the stabilization of the gauche isomer in the two charged species and alcohol. Electrostatic and dispersion interactions are the main contributors to the gauche effect in the amide, whereas dispersion and orbital interactions can be considered to be the two most important stabilizing factors of the gauche form in the vicinal diazido fragment. The interplay of all three stabilizing interactions determines the gauche preference in the amine. Stereoelectronic effects, which are involved in orbital interactions, contribute to the gauche effect in all the molecules except the 2-azidoethylammonium ion and protonated 2-azidoethanol. Hydrogen-bonding interactions were found only in the protonated alcohol.

A theoretical study on borenium ion affinities toward ammonia, formaldehyde and chloride anions

Various borenium ion affinities toward three ligands (L′ = NH3, HCHO and Cl−) have been evaluated by DFT calculations in the gas-phase and in solvent (CH2Cl2). The gas-phase results have been rationalized on the basis of quantitative decomposition of the total binding energy into contributions from electrostatic, orbital, dispersion and Pauli interactions, and energy needed to deform the interacting fragments from their optimal geometry to that they adopt in an adduct. Twenty six borenium cations, differing in the type of the two R/R′ substituents covalently bound to the boron atom and the neutral stabilizing ligand L, have been examined. With a few exceptions, the most important stabilizing interaction is electrostatic, more pronounced in the case of the charged ligand Cl−. Next come orbital interactions, involving the coordinate covalent bond formation, other charge transfer interactions between the cation and ligand, and polarization. Dispersion forces provide the smallest attraction, except in four complexes with long B–L′ distances. We present how substituent (R/R′)/ligand (L) variations affect binding enthalpies (ΔH)/energies (ΔE). Our results also show that the observed trend in the magnitudes of ΔHs/ΔEs represents an interplay of the above mentioned (de)stabilizing energies, and can be explained by consideration of the boron–ligand distance and all charge/orbital interactions, rather than partial ones involving boron and ligand L′. Under solvent conditions, the Cl− affinities are drastically reduced and made very similar to NH3 affinities, but still larger than HCHO affinities.