Rozwój metod syntezy fluorometylowanych N-, O-, i S-heterocykli o różnej wielkości pierścienia

Rozprawa doktorska stanowi cykl czterech monotematycznych publikacji.Mając na uwadze stale rosnące znaczenie chemii fluoroalkilowanych związków heterocyklicznych we współczesnej syntezie organicznej, farmacji, medycynie, agrotechnice oraz chemii materiałów, zaplanowano i zrealizowano program badań opartych na wykorzystaniu łatwo dostępnych fluorowanych nitronów, N-tlenków nitryli oraz diazoalkanów w reakcjach [3+2]-cykloaddycji ([1,3]-dipolarnej cykloaddycji), których produktami powinny być odpowiednie, fluoroalkilowe związki heterocykliczne. W pierwszej kolejności zbadano reakcję nitronów, pochodnych fluoralu oraz aldehydu difluorooctowego z terminalnymi alkinami w obecności zasady i jonów miedzi Cu(I) (tzw. reakcja Kinugasy). Otrzymano w ten sposób serię nowych β-laktamów (azetydyn-2-onów) zawierających w swojej strukturze grupę fluorometylową zlokalizowaną w pozycji C(4) pierścienia heterocyklicznego. Otrzymane produkty mogą stanowić potencjalnie użyteczne bloki budulcowe do syntez bardziej skomplikowanych struktur organicznych. Jest to pierwszy opisany przypadek zastosowania fluorowanych nitronów w syntezie układów β-laktamowych opartej na reakcji Kinugasy. W rozszerzeniu badań nad reakcją Kinugasy wykorzystano po raz pierwszy etynylofosfonian dietylu w syntezie β-laktamów zawierających w swojej strukturze grupę fosfonową w pozycji C(3). Nitrony, pochodne aldehydu tri- oraz difluorooctowego nie dawały oczekiwanych produktów i z tego powodu postanowiono wykorzystać nitrony, pochodne arylowych oraz hetarylowych aldehydów. Uzyskane wyniki wskazują, że etynylofosfonian dietylu wykazuje niższą reaktywność niż propiolan etylu jednak może być z powodzeniem wykorzystany w syntezie istotnych z punktu widzenia chemii medycznej 3-fosfonylo-β-laktamów. W kolejnym etapie badań wykorzystano fluorowane N-tlenki nitryli, pochodne tri- oraz difluoroacetonitrylu w reakcjach [3+2]-cykloaddycji z wybranymi tioketonami, które reprezentują grupę dipolarofili typu C=S. Ustalono, że łatwo ulegają one szybkim reakcjom [3+2]-cykloaddycji z tioketonami arylowymi, hetarylowymi, cykloalifatycznymi oraz ferrocenylowymi prowadząc do otrzymania odpowiednich, fluoroalkilowanych pochodnych 1,4,2-oksatiazolu w sposób całkowicie regioselektywny. W ostatniej części sprawdzono reaktywność 1,1,1-trifluorodiazoetanu wobec tioketonów jako odczynników o charakterze ‘superdipolarofilowym’. Fluorowane pochodne diazoetanu mogą być w łatwy sposób generowane ‘in situ’ a przeprowadzone badania wykazały, że charakteryzują się one niższą reaktywnością niż sam diazoetan. W przypadku użycia sterycznie zatłoczonych pochodnych 3-tiokso-2,2,4,4-tetrametylocyklobutan-1-onów otrzymano trwałe pochodne 2,5-dihydro-1,3,4-tiadiazolu zawierające w swojej strukturze grupę trifluorometylową CF3. Otrzymano również fluorowane pochodne tiiranu oraz alkeny, które stanowią potencjalnie atrakcyjne bloki budulcowe do syntez bardziej złożonych fluorowanych związków organicznych. Stwierdzono, że reakcje 1,1,1-trifluorodiazoetanu z tioketonami heteroaromatycznymi prowadziły do otrzymania mieszanin alkenów oraz sterycznie zatłoczonych 4,4,5,5-tetrapodstawionych 1,3-ditiolanów. Taki wynik wskazuje na nieuzgodniony, dirodnikowy mechanizm powstawania 1,3-ditiolanów w badanych reakcjach [3+2]-cykloaddycji, kontrastujący z przyjętym powszechnie mechanizmem uzgodnionym

Mites (Acari, Oribatida) of selected organic farms from the Kujawy-Pomerania Province

The experiment was carried out on 3 organic farms in the Kujawy-Pomerania Province in 5 different habitats to determine the number and species composition of mites. Ten replicate samples of 50 cm3 and 17 cm2 were collected in 2011 from 3 layers, so altogether 780 samples were collected. In total, 14 taxa of Oribatida were identified. The total number of mites and Oribatida significantly differed in the analyzed habitats. Tectocepheus velatus [Michael, 1880], Scheloribates laevigatus [C.L. Koch, 1835], Punctoribates punctum [C.L. Koch, 1839] and Eupelops occultus [C.L. Koch, 1835] were the most abundant oribatid mite species

Highly efficient thermally activated fluorescence of a new rigid Cu(I) complex [Cu(dmp)(phanephos)]+

The rigid [Cu(dmp)(phanephos)]+ complex displays a high luminescence quantum yield of 80% at ambient temperature. In contrast to the long-lived phosphorescence of 240 μs at T < 120 K with a radiative rate of kr = 3 × 103 s−1, the ambient-temperature emission represents a thermally activated delayed fluorescence (DF) with a decay time of only 14 μs and a radiative rate of kr(DF) = 6 × 104 s−1. Evidence for the involvement of the excited singlet state in the emission process is presented. This material has high potential to be applied in efficient OLEDs taking advantage of the singlet harvesting mechanism

Vitamin D status including 3-epi-25(OH)D3 among adult patients with thyroid disorders during summer months

Introduction: In the context of pleiotropic vitamin D effects, its role has also been investigated in thyroid pathology, in particular autoimmune thyroid diseases (AITD). However, available data concerning vitamin D status in Polish patients with thyroid disorders are inconclusive. In the study we investigated vitamin D status and adequacy of supplementation, as well as sunlight exposure during summer months among adult patients with thyroid diseases.Material and methods: Adults with diagnosed or suspected thyroid disease were recruited almost entirely in an ambulatory setting between June and September in Northern Poland. Questionnaire examinations were performed, and serum concentrations of 25(OH)D2, 25(OH)D3, 3-epi-25(OH)D3, and 24,25(OH)2D3 were determined by LC-MS/MS.Results: Thirty men and 194 women participated in the study, mean age ± standard deviation (SD): 42 ± 15 years, mean ± SD body mass index (BMI) 26 ± 6 kg/m2. Among the participants, 133 declared L-thyroxine treatment, 44 — Hashimoto’s thyroiditis, 40 — nodular goitre, and 20 — hyperthyroidism and/or Graves’ disease. Mean ± SD 25(OH)D level was 26.9 ± 8.2 ng/ml, and deficiency (&lt; 20 ng/ml) was stated in 12%, insufficiency (20 ≤ 25(OH)D &lt; 30 ng/ml) in 50.4% of study participants. Calcidiol was significantly higher in subjects who declared supplementation, mean ± SD: 29.4 ± 7.5 vs. 25.2 ± 8 ng/ml. Among participants without vitamin D supplementation sunlight exposure correlated with 25(OH)D. The C3 epimer of 25(OH)D3 was detected in all subjects; its concentration correlated strongly with that of 25(OH)D3. 24,25(OH)2D3 levels also strongly correlated with those of 25(OH)D3.Conclusions: To our knowledge, the current study is the first in Poland to analyse vitamin D status in summer months among patients with thyroid diseases, as well as serum 3-epi-25(OH)D3 and 24,25(OH)2D3 concentrations. The data presented here indicate that vitamin D sufficiency is not attained even in summer months in patients with thyroid diseases

Pyrene–nucleobase conjugates: synthesis, oligonucleotide binding and confocal bioimaging studies

Fluorescent pyrene–linker–nucleobase (nucleobase = thymine, adenine) conjugates with carbonyl and hydroxy functionalities in the linker were synthesized and characterized. X-ray single-crystal structure analysis performed for the pyrene–C(O)CH2CH2–thymine (2) conjugate reveals dimers of molecules 2 stabilized by hydrogen bonds between the thymine moieties. The photochemical characterization showed structure-dependent fluorescence properties of the investigated compounds. The conjugates bearing a carbonyl function represent weak emitters as compared to compounds with a hydroxy function in the linker. The self-assembly properties of pyrene nucleobases were investigated in respect to their binding to single and double strand oligonucleotides in water and in buffer solution. In respect to the complementary oligothymidine T10 template in water, compounds 3 and 5 both show a self-assembling behavior according to canonical base–base pairing. However, in buffer solution, derivative 5 was much more effective than 3 in binding to the T10 template. Furthermore the adenine derivative 5 binds to the double-stranded (dA)10–T10 template with a self-assembly ratio of 112%. Such a high value of a self-assembly ratio can be rationalized by a triple-helix-like binding, intercalation, or a mixture of both. Remarkably, compound 5 also shows dual staining pattern in living HeLa cells. Confocal microscopy confirmed that 5 predominantly stains mitochondria but it also accumulates in the nucleoli of the cells

Rapid method for Mycobacterium tuberculosis identification using electrospray ionization tandem mass spectrometry analysis of mycolic acids

Mycolic acids (MAs), which play a crucial role in the architecture of mycobacterial cell walls, were analyzed using electrospray ionization tandem mass spectrometry. A targeted analysis based on the 10 most abundant and characteristic multiple reaction monitoring pairs was used to profile the crude fatty acid mixtures from Mtb and several nontuberculous mycobacterial strains. Comparative analysis yielded unique profiles for MAs, enabling the reliable identification of mycobacterial species. In a case-control study of tuberculosis (TB) and non-TB Polish patients, we demonstrated the potential diagnostic utility of our approach for the rapid diagnosis of active TB with sensitivity and specificity surpassing those of existing methods. This robust method allows the identification of TB-positive patients after 2 h of sample preparation in the case of direct sputum analysis or 10 days of culturing, both of which are followed by 1 min of liquid chromatography– tandem mass spectrometry analysis

Gold-Induced Desulfurization in a Bis(ferrocenyl) Alkane Dithiol

Thiol-modified ferrocenes on gold have been archetypical model systems for many fundamental charge transfer and other studies, since both thiol-gold and ferrocene redox chemistry are considered to be well-understood. Thus unexpectedly, we found that for a representative of a new class of flexibly linked bis-ferrocenyl compounds, namely, 1-10-bis­(1-ferrocenyl)­decane dithiol, surface immobilization on gold failed. Instead, in the presence of gold, molecular decomposition took place, resulting in sulfur-based adlayers and well-defined molecular elimination products, for which we provide spectroscopic evidence. Careful control experiments and comparison with related ferrocene compounds provide insight into the mechanism of the observed elimination reactions, as a combined effect of the molecular structure and the nature of the gold/sulfur bond. These findings, thus, have a broader impact on the design of molecular adlayers, for example, in the context of surface functionalization in sensing or the synthesis of gold nanoparticles

Nuclear shadowing in Glauber-Gribov theory with Q2-evolution

We consider deep inelastic scattering off nuclei in the Regge limit within the Glauber-Gribov model. Using unitarized parton distribution functions for the proton, we find sizeable shadowing effects on the nuclear total and longitudinal structure functions, $F_2^A$ and $F_L^A$, in the low-x limit. Extending a fan-diagram analysis for the large-mass region of coherent diffraction off nuclei to high Q2, we also find significant shadowing effects in this kinematical regime. Finally, we discuss shortcomings of our approach and possible extensions of the model to other kinematical regimes.Comment: 16 pages, 9 figure

Synthesis and (spectro)electrochemistry of mixedvalent diferrocenyl–dihydrothiopyran derivatives

Three novel diferrocenyl complexes were prepared and characterised. 2,2-Diferrocenyl-4,5-dimethyl- 3,6-dihydro-2H-thiopyran (1, sulphide) was accessible by the hetero-Diels–Alder reaction of diferrocenyl thioketone with 2,3-dimethyl-1,3-butadiene. Stepwise oxidation of 1 gave the respective oxides 2,2- diferrocenyl-4,5-dimethyl-3,6-dihydro-2H-thiopyran-1-oxide (2, sulfoxide) and 2,2-diferrocenyl-4,5- dimethyl-3,6-dihydro-2H-thiopyran-1,1-dioxide (3, sulfone), respectively. The molecular structures of 1 and 3 in the solid state were determined by single crystal X-ray crystallography. The oxidation of sulphide 1 to sulfone 3, plays only a minor role on the overall structure of the two compounds. Electrochemical (cyclic voltammetry (= CV), square wave voltammetry (= SWV)) and spectroelectrochemical (in situ UV-Vis/NIR spectroscopy) studies were carried out. The CV and SWV measurements showed that an increase of the sulphur atom oxidation from −2 in 1 to +2 in 3 causes an anodic shift of the ferrocenylbased oxidation potentials of about 100 mV. The electrochemical oxidation of 1–3 generates mixedvalent cations 1+–3+. These monooxidised species display low-energy electronic absorption bands between 1000 and 3000 nm assigned to IVCT (= Inter-Valence Charge Transfer) electronic transitions. Accordingly, the mixed-valent cations 1+–3+ are classified as weakly coupled class II systems according to Robin and Day.Authors (K. K. and G. M.) thank the National Science Centre (Poland) for financial support (Project Maestro-3; Dec-2012/06/ A/ST5/00219) and R. C. thanks the German Federal Ministry of Education and Research (BMBF) for support. The support from the German Academic Exchange Service (DAAD) in the framework of the exchange program “Ostpartnerschaften” is highly appreciated