Tomasz Siodła

Toward a Physical Interpretation of Substituent Effects: The Case of Fluorine and Trifluoromethyl Groups

The application of ab initio and DFT computational methods at six different levels of theory (MP2/cc-pVDZ, MP2/aug-cc-pVTZ, B3LYP/cc-pVDZ, B3LYP/aug-cc-pVTZ, M06/cc-pVDZ, and M06/aug-cc-pVTZ) to meta- and para-substituted fluoro- and trifluoromethylbenzene derivatives and to 1-fluoro- and 1-trifluoromethyl-2-substituted trans-ethenes allowed the study of changes in the electronic and geometric properties of F- and CF3-substituted systems under the impact of other substituents (BeH, BF2, BH2, Br, CFO, CHO, Cl, CN, F, Li, NH2, NMe2, NO, NO2, OH, H, CF3, and CH3). Various parameters of these systems have been investigated, including homodesmotic reactions in terms of the substituent effect stabilization energy (SESE), the π and σ electron donor-acceptor indexes (pEDA and sEDA, respectively), the charge on the substituent active region (cSAR, known earlier as qSAR), and bond lengths, which have been regressed against Hammett constants, resulting mostly in an accurate correspondence except in the case of p-fluorobenzene derivatives. Moreover, changes in the characteristics of the ability of the substituent to attract or donate electrons under the impact of the kind of moiety to which the substituent is attached have been considered as the indirect substituent effect and investigated by means of the cSAR model. Regressions of cSAR(X) versus cSAR(Y) for any systems X and Y allow final results to be obtained on the same scale of magnitude.

Tri- and tetrafluoropropionamides derived from chiral secondary amines – synthesis and the conformational studies

A convenient procedure for the preparation of tri- and tetrafluoropropionamides derived from R-(+)/S-(−)-N-methyl-1-phenylethylamine and cyclic pyrrolidine derivatives has been described. The X-ray analysis and the theoretical calculations have been used to study conformational analysis of obtained compounds. In contrast to single α-fluorine substituted amides, which preferred anti conformation around the F–C–CO bond, for tetrafluorinated amides the additional trifluoromethyl group forces the conformation of the F–C–CO bond as nearly syn.

Inductive or Field Substituent Effect? Quantum Chemical Modeling of Interactions in 1-Monosubstituted Bicyclooctane Derivatives

Inductive substituent constants were obtained for systems lacking the resonance effect. The application of the charge of the substituent active region concept to study the substituent effect in 1-X-substituted bicyclooctane derivatives (B3LYP/6-311++G** calculations, X = NMe2, NH2, OH, OMe, CH3, H, F, Cl, CF3, CN, CHO, COMe, CONH2, COOH, NO2, NO) has revealed inductive interactions, which are through bonds.

Toward the Physical Interpretation of Inductive and Resonance Substituent Effects and Reexamination Based on Quantum Chemical Modeling

An application of a charge of the substituent active region concept to 1-Y,4-X-disubstituted derivatives of bicyclo[2.2.2]octane (BCO) [where Y = NO2, COOH, OH, and NH2 and X = NMe2, NH2, OH, OMe, Me, H, F, Cl, CF3, CN, CHO, COMe, CONH2, COOH, NO2, and NO] provides a quantitative information on the inductive component of the substituent effect (SE). It is shown that the effect is highly additive but dependent on the kind of substituents. An application of the SE stabilization energy characteristics to 1,4-disubstituted derivatives of BCO and benzene allows the definition of inductive and resonance contributions to the overall SE. Good agreements with empirical approaches are found. All calculations have been carried out by means of the B3LYP/6-311++G(d,p) method.

Difference in pi-electron delocalization for monosubstituted olefinic and aromatic systems

Application of HOMA (Harmonic Oscillator Model of Aromaticity) to a series of monosubstituted derivatives of cyclohexa-1,3-diene (olefinic) and benzene (aromatic) revealed an increase of the pi-electron delocalization in olefinic systems and a decrease in the case of aromatic systems (in comparison to unsubstituted species). Due to the nature of the system to which the substituents are attached, the range of changes of the electron donating/attracting (ED/EA) properties of the substituents may be as large as 30% of the total variation of ED/EA properties for all substituents considered.

How far the substituent effects in disubstituted cyclohexa-1,3-diene derivatives differ from those in bicyclo[2.2.2]octane and benzene?

Substituents effects in cyclic diene derivatives are studied using quantum chemical modeling and compared to the corresponding effects in aromatic (benzene) and fully saturated (bicyclo[2.2.2]octane) compounds. In particular, electronic properties of the fixed group Y in a series of 3- and 4-X-substituted cyclohexa-1,3-diene-Y derivatives (where Y = NO2, COOH, COO− OH, O−, NH2, and X = NMe2, NH2, OH, OMe, Me, H, F, Cl, CF3, CN, CHO, COMe, CONH2, COOH, NO2, NO) are examined using the B3LYP/6-311++G(d,p) method. For this purpose, quantum chemistry models of the substituent effect: cSAR (charge of the substituent active region) and SESE (substituent effect stabilization energy) as well as traditional Hammett’s substituent constants (σ) and their inductive (F) and resonance (R) components are used. π-electron delocalization of the transmitting moiety (butadiene fragment of the CHD) is described by the HOMA index. This comparative study reveals interplay between inductive and resonance contributions to the substituent effect.

Dependence of the Substituent Effect on Solvent Properties

The influence of a solvent on the substituent effect (SE) in 1,4-disubstituted derivatives of benzene (BEN), cyclohexa-1,3-diene (CHD), and bicyclo[2.2.2]octane (BCO) is studied by the use of polarizable continuum model method. In all X-R-Y systems for the functional group Y (NO2, COOH, OH, and NH2), the following substituents X have been chosen: NO2, CHO, H, OH, and NH2. The substituent effect is characterized by the charge of the substituent active region (cSAR(X)), substituent effect stabilization energy (SESE), and substituent constants σ or F descriptors, the functional groups by cSAR(Y), whereas π-electron delocalization of transmitting moieties (BEN and CHD) is characterized by a geometry-based index, harmonic oscillator model of aromaticity. All computations were carried out by means of B3LYP/6-311++G(d,p) method. An application of quantum chemistry SE models (cSAR and SESE) allows to compare the SE in water solutions and in the gas phase. Results of performed analyses indicate an enhancement of the SE by water. The obtained Hammett-type relationships document different nature of interactions between Y and X in aromatic and olefinic systems (a coexistence of resonance and inductive effects) than in saturated ones (only the inductive effect). An increase of electric permittivity clearly enhances communications between X and Y for BEN and CHD systems.

Synthesis, structural studies and stability of model cysteine containing DNA–protein cross-links

DNA–protein cross-links (DPCs) are bulky, helix-distorting lesions that are formed upon irreversible bonding of proteins to chromosomal DNA in the presence of cross-linking agents. Among a broad range of such agents are α,β-unsaturated carbonyl compounds, which act essentially as bifunctional alkylating agents and form adducts with DNA bases. These adducts can further undergo interactions with other cellular macromolecules leading to the formation of cross-linked products. We synthesized and structurally characterized N-acetylcysteine cross-links formed in the reactions with aldehydic adducts of adenine nucleosides, which possess enol functionality and represent model α,β-unsaturated carbonyl systems. Studies performed by the use of NMR spectroscopy, DFT and ab initio methods established that two of these cross-links exist as rotamers stable at room temperature. Application of Atoms in Molecules Theory enabled hydrogen bonding and other stabilizing interactions within the studied molecules to be estimated. Under physiological conditions the cross-links were found to be relatively stable until Nα-acetyllysine was present in the reaction medium. The presence of this amino acid caused fast transformation of the N-acetylcysteine cross-links into a range of their lysine derivatives. Although instability of the cysteine adduct with acrolein was reported, we showed that the mechanism involved in the gradual decomposition of the N-acetylcysteine cross-links differs from that proposed for acrolein adduct degradation. This demonstrates that in spite of similarities in their structures, numerous α,β-unsaturated carbonyl compounds can interact with nucleophilic biomolecules by different mechanisms leading to structural heterogeneity of the resulting products. Our findings provide an explanation for difficulties in identifying the cysteine containing DPCs in vivo and in vitro, and may be of great importance with respect to detection and isolation of such lesions from biological materials.

The conformations of new CF3 and CF3-CHF containing amides derived from carbohydrates: NMR, crystallographic and DFT study

A new convenient synthetic procedure for the preparation of tri- and tetrafluoropropanamides derived from sugars has been described. The conformations of fluorinated amides calculated for isolated molecules and those in the crystal state have been compared. In contrast to single α-fluorine substituted amides, which preferred the anti conformation around the F–C–CO bond, for tetrafluorinated amides the additional trifluoromethyl group forces the conformation of the F–C–CO bond to be nearly syn.