Lucie Čechová

A switchable intramolecular hydrogen bond in polysubstituted 5-nitrosopyrimidines.

The formation of strong intramolecular hydrogen bonds was observed in a series of 2-amino-5-nitrosopyrimidines with alkylamino and arylamino substituents at positions 4 and 6. Mixtures of two rotamers differing in the orientation of the nitroso group were observed in the NMR spectra of the compounds where two distinct intramolecular hydrogen bonds could be formed. The ratio of the two rotamers depends strongly on the character of the substituents at positions 4 and 6 and can be finely tuned over a broad range of conformation ratios. The experimental results were supported by DFT calculations, which also made it possible to explain the apparent contradiction in the experimental dependence of the rotamer ratio on the Hammett constants for the arylamino substituents. The UV/vis spectra of the compounds also significantly depend on the nature of the substituents; however, the orientation of the nitroso group does not have any influence on the position of the absorption bands in the spectra.

A conversion of aromatic thiocyanates into sulfothioates: new synthetic route to aromatic Bunte salts

A new synthetic route leading to polysubstituted S-aryl sulfothioates, aromatic Bunte salts, is reported. Treatment of polysubstituted aromatic thiocyanates with sodium sulfite in aqueous DMF at room temperature affords polysubstituted S-(het)aryl sulfothioates. The novel transformation tolerates presence of a wide range of functional groups.

Tunable Push–Pull Interactions in 5-Nitrosopyrimidines

The effect of push-pull interactions in a series of variously substituted 5-nitrosopyrimidines on the strength of intramolecular hydrogen bonds, the height of rotational barriers around formally single bonds, UV-vis spectra and electrochemical behavior is explored. Intramolecular charge transfer (ICT) leads to a shift of electron density from electron-donating substituents, which is readily observable by NMR spectroscopy. The 5-nitroso group is able to form strong intramolecular hydrogen bonds with neighboring amino substituents. As a result, two rotamers with reversed orientation of the 5-nitroso group are observed for compounds with two different hydrogen-bond donors in neighboring positions. The barriers of interconversion between the two rotamers are strongly influenced by ICT, whereas the ratio of such rotamers depends primarily on the character of the hydrogen-bond donors. The ICT also significantly affects the position of UV-vis absorption maxima, which can be tuned in a broad range of 100 nm by the selection of appropriate substituents. Finally, ICT influences oxidation potential of the 5-nitrosopyrimidines and the stability of the resulting nitroso radical cations, the structures of which are determined by EPR spectroscopy.

Compound instability in dimethyl sulphoxide, case studies with 5-aminopyrimidines and the implications for compound storage and screening.

The oxidation reactions of 5-aminopyrimidine derivatives in dimethyl sulphoxide (DMSO) were studied. The DMSO solutions of the studied compounds became deeply coloured within a few hours or days. The oxidation products can undergo further condensation reactions with the starting pyrimidines to yield bipyrimidines and/or pyrimidopteridines. The reaction mechanism of the oxidation-condensation reaction was also supported by reactions of the 5-aminopyrimidines with alloxan (2,4,5,6-tetraoxopyrimidine). DMSO is often used as the solvent in in vitro tests of biological activities, but it is also an oxidising agent and may react with solute molecules and significantly affect the quality of the generated biochemical data.

Influence of Intramolecular Charge Transfer and Nuclear Quantum Effects on Intramolecular Hydrogen Bonds in Azopyrimidines

Intramolecular hydrogen bonds (IMHBs) in 5-azopyrimidines are investigated by NMR spectroscopy and DFT computations that involve nuclear quantum effects. A series of substituted 5-phenylazopyrimidines with one or two hydrogen bond donors able to form IMHBs with the azo group is prepared by azo coupling. The barrier of interconversion between two rotamers of the compounds with two possible IMHBs is determined by variable temperature NMR spectroscopy and it is demonstrated that the barrier is significantly affected by intramolecular charge transfer. Through-hydrogen-bond scalar coupling is investigated in 15N labeled compounds and the stability of the IMHBs is correlated with experimental NMR parameters and rationalized by path integral molecular dynamics simulations that involve nuclear quantum effects. Detailed information on the hydrogen bond geometry upon hydrogen-to-deuterium isotope exchange is obtained from a comparison of experimental and calculated NMR data.

Photoswitchable intramolecular hydrogen bonds in 5-phenylazopyrimidines revealed by in situ irradiation NMR spectroscopy

NMR spectroscopy with in situ irradiation uncovered unique photoswitchable intramolecular hydrogen bonds (IMHBs) in 5-phenylazopyrimidines with two hydrogen bond donors. These compounds form two stable rotamers, each with one IMHB, and the rotamer ratio changes reversibly upon UV or visible light irradiation. Strong substituent dependence of photoinduced structural changes was observed; using suitable substituents, orthogonal photoswitching can be achieved. For example, whereas UV irradiation caused switching between the two rotamers of the trans isomer of a compound with electron-donating methoxy substituent, visible light enabled to obtain the cis photoisomer. No cis isomer was detected for compounds with electro-neutral or electron-accepting substituents, but photoswitching between the two trans isomers was observed. On the other hand, compounds without hydrogen-bond donors or with one donor only formed stable cis isomers. A mechanism of the photoswitching was proposed by DFT computations.

Photoswitching Behavior of 5-Phenylazopyrimidines: In Situ Irradiation NMR and Optical Spectroscopy Combined with Theoretical Methods

The photoswitching behavior of 5-phenylazopyrimidines was investigated by optical methods and NMR spectroscopy with in situ irradiation sustained by mathematical modeling and DFT calculations. Irradiation of various compounds with electron-donating groups on the pyrimidine ring and substituents with electron-withdrawing as well as electron-donating substituent in the para-position of the phenyl ring were examined. All compounds could be successfully converted to the cis isomer; this isomerization and the subsequent thermal fading were studied. Switching cycles can be repeated without signs of photodegradation for most of the compounds, which makes them adept to molecular photoswitches. Interestingly, the chloro and cyano derivatives can be switched without UV light, which makes them vis(π → π*)-vis(n → π*) photoswitches. Surprisingly equal trans-to- cis photoisomerization quantum yields for π → π* and n → π* excitation indicate the blocking of the inversion pathway following π → π* excitation. In contrast to that, DFT computations suggest the inversion mechanism for the reverse thermal cis-to- trans isomerization of 5-phenylazopyrimidines.

Separation of rotamers of 5-nitrosopyrimidines and estimation of binding constants of their complexes with β-cyclodextrin by capillary electrophoresis

For the first time, capillary electrophoresis has been successfully employed for the fast and highly efficient separations of a novel type of stereoisomers - planar rotamers (planamers) of four newly synthesized 5-nitrosopyrimidine derivatives. These derivatives can form two rotamers differing in the orientation of nitroso group due to strong intramolecular hydrogen bonds. Partial separation of rotamers of two 5-nitrosopyrimidines was achieved in alkaline 50 mM sodium tetraborate, pH 9.3, and in acidic 18.5/42 mM Tris/phosphate, pH 2.3, background electrolytes (BGEs) free of stereoselectors. To improve the separation of these rotamers and to attain the baseline or better separation of rotamers of other two 5-nitrosopyrimidines, various BGEs and different cyclodextrins-based stereoselectors were tested. The most effective, i.e. the fastest and baseline or better separations of rotamers of all analyzed 5-nitrosopyrimidines were achieved within a short time, 3.7-9.3 min, in the above alkaline or acidic BGEs using β-cyclodextrin (β-CD) or carboxymethyl-β-CD as stereoselectors. Moreover, since the experiments with β-CD resulted in good separations of rotamers of all the investigated 5-nitrosopyrimidines, the apparent binding constants of their complexes with this selector were determined from the dependence of their effective mobilities on the β-CD concentration in the BGEs. The examined complexes were found to be relatively weak, with the apparent binding constants in the range 11.3-153.0 L/mol.