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Amongst macrocyclic receptors, cucurbit[7]uril (CB7) and β-cyclodextrin (β-CD) stand out as good receptors for hydrophobic species in aqueous solutions. In contrast to the frequently investigated hosting of aliphatic compounds, the inclusion of aromatic guests within these hosts is far less explored. Taking this into account, we have studied the complexation of various benzene derivatives with CB7 and β-CD in water by means of isothermal titration microcalorimetry and in a wide temperature range (5−65 °C). ROESY and 1H NMR experiments were carried out to investigate the inclusion of 4-tert-butylphenol into the host cavities. The inclusion of guests within the CB7 cavity in vacuo was also studied by performing DFT calculation using the bp86/tzvp level of theory. The examined host-guest systems exhibited distinct ΔrH° and ΔrS° temperature dependence, resulting in weak variation of standard Gibbs energy with temperature. The complexation thermodynamics at lower temperatures was in agreement with the classical interpretation of the hydrophobic effect, whereas the binding at higher temperatures was in line with the non-classical rationale.

Cyclodextrins and cucurbiturils are very good receptors of hydrophobic species in water. The product stability (logK > 10 for complexes involving neutral guests and cucurbiturils were reported) is a consequence of strongly exothermic association, rationalized by non-classical hydrophobic effect (release of energetically rich cavity water). However, our recent study of the adamantyl-based guest inclusion within β-cyclodextrin (β-CD) revealed an almost complete compensation of ΔrH°(T) and –TΔrS°(T) contributions to logK temperature dependence. The results could be explained by the Frank-Evans model of adamantane hydration at lower (classical hydrophobic effect) and gradual “iceberg melting” at higher temperatures. We have therefore decided to study the complexation of both (poly)cyclic and linear aliphatic compounds with cucurbit[7]uril (CB7) and β-CD in a wide temperature range, both experimentally (ITC, ROESY NMR spectroscopy) and computationally (classical, solvent-explicit MD simulations). The investigated guests were chosen with the aim of supressing all thermodynamic contributions to hosting apart those associated with the hydrophobic effect. The study provided missing pieces to a jigsaw puzzle explaining the thermodynamic contributions to standard complexation Gibbs energies, as well as insights into hydration of guest and host cavities. Apart from that, intriguing differences concerning the enthalpic and entropic effect of CB7 and β-CD cavity dehydration were revealed.

Diamantane derivatives combined with cucurbit[n]urils have received significant attention in the field of supramolecular chemistry due to their outstandingly high complex stability constants, reaching above petamolar values for positively charged diamantane diammonium salts and cucurbit[7]uril in water. On the other hand, their complexation with cyclodextrins has been rarely investigated.2 We have therefore studied temperature and solvent effects on the complexation of diamantane alcohols with cucurbit[7]uril and β-cyclodextrin in water and structured organic solvents (formamide, ethylene glycol) by means of isothermal titration calorimetry and NMR spectroscopy. The complexes of apical derivatives with CB7 in water were the most stable products (log K > 7), whereas the complexation of 4-DiaOH with β-CD was the most favorable in formamide. For most of the studied host-guest systems a significant temperature dependence of ΔrH° and ΔrS° was observed, which resulted in an almost complete enthalpy-entropy compensation. For these systems complexation thermodynamics was in line with the classical rationale of the solvophobic effect at lower temperatures, and the non-classical explanation at higher ones. The results of 1H NMR titrations were in accord with the thermodynamic studies and have revealed an interesting difference in complex formation kinetics between cucurbit[7]uril and β-cyclodextrin hosts.

Diamantane derivatives are excellent guests for cucurbiturils in aqueous solutions, forming complexes with stability constants reaching above petamolar values.[1] On the other hand, their complexation with cyclodextrins has been scarcely explored. We therefore studied temperature and solvent effects on the complexation of diamantane alcohols with cucurbit[7]uril, β- and γ- cyclodextrin by means of isothermal titration calorimetry and NMR spectroscopy. The stability constant among all investigated complexes was by far the highest in the case of the diol derivate with cucurbit[7]uril in water. A pronounced temperature dependence of ΔrH° and ΔrS°, resulting in an almost complete enthalpy-entropy compensation, was observed for most studied host- guest systems. The corres-ponding complexation thermodynamics were in line with the classical rationale of the solvophobic effect at lower temperatures, and the non-classical explanation at higher ones.[2, 3] The results of 1H NMR titrations and ROESY experiments were in line with the thermodynamic studies and have revealed an interesting difference in complex formation kinetics between cucurbit[7]uril and β- cyclodextrin.

Regioisomeric mannoconjugates of naphthyl alcohols were synthesized by coupling of protected mannopyranose and corresponding esters of bromoacetic acid with 1- and 2-naphthyl moieties. Their complexation and the complexation of corresponding nonfunctionalized alcohols with cyclodextrins (α-, β- and γ-) and cucurbit[7]uril was explored by means of isothermal titration calorimetry, spectrophotometry, fluorimetry and NMR spectroscopy. The complexation of 2-naphthol with cucurbit[7]uril was thermodynamically most favorable. A pronounced temperature dependence of ΔrH° and ΔrS°, resulting in an almost complete enthalpy-entropy compensation was observed for some of the examined host-guest systems. In these cases, the complexation thermodynamics was in line with the classical rationale of the hydrophobic effect at lower temperatures, and the non- classical explanation at higher ones. The results of 1H NMR titrations and ROESY experiments were in agreement with the results obtained by other experimental methods and have revealed an interesting difference in complex formation kinetics among the investigated host molecules.

Regioisomeric mannoconjugates of naphthyl alcohols were synthesized by coupling of protected mannopyranose and corresponding esters of bromoacetic acid with 1- and 2- naphthyl moieties. Their complexation and the complexation of corresponding nonfunctionalized alcohols with cyclodextrins (α-, β- and γ-) and cucurbit[7]uril was explored by means of isothermal titration calorimetry, spectrophotometry, fluorimetry and NMR spectroscopy. The complexation of 2- naphthol with cucurbit[7]uril was thermodynamically most favorable. A pronounced temperature dependence of ΔrH° and ΔrS°, resulting in an almost complete enthalpy- entropy compensation was observed for some of the examined host-guest systems. In these cases, the complexation thermodynamics was in line with the classical rationale of the hydrophobic effect at lower temperatures, and the non-classical explanation at higher ones. The results of 1H NMR titrations and ROESY experiments were in agreement with the results obtained by other experimental methods and have revealed an interesting difference in complex formation kinetics among the investigated host molecules.

The temperature and solvent effect on the complexation of various guests (Figure 1) with α-, β- and γ-cyclodextrin and cucurbit[7]uril was explored experimentally and by means of molecular dynamics simulations. The stability constants of all investigated complexes were by far the highest with cucurbit[7]uril in water. A pronounced temperature dependence of ΔrH° and ΔrS°, resulting in almost complete enthalpy-entropy compensation was observed for most explored host-guest systems. For those systems complexation thermodynamics was in line with the classical rationale of the hydrophobic effect at lower temperatures, and the non-classical explanation at higher ones. The optimized inclusion complex structures corresponded to those deduced by means of NMR spectroscopy and the experimentally obtained and calculated ΔrG° were in very good agreement.

Diamantane derivatives are excellent guests for cucurbiturils in aqueous solutions, forming complexes with stability constants reaching above petamolar values. On the other hand, their complexation with cyclodextrins has been scarcely explored. We therefore studied temperature and solvent effects on the complexation of diamantane alcohols with cucurbit[7]uril, β- and γ- cyclodextrin by means of isothermal titration calorimetry and NMR spectroscopy. The stability constant among all investigated complexes was by far the highest in the case of the diol derivate with cucurbit[7]uril in water. A pronounced temperature dependence of ΔrH° and ΔrS°, resulting in an almost complete enthalpy- entropy compensation, was observed for most studied host-guest systems. The corresponding complexation thermodynamics were in line with the classical rationale of the solvophobic effect at lower temperatures, and the non- classical explanation at higher ones. The results of 1H NMR titrations and ROESY experiments were in line with the thermodynamic studies and have revealed an interesting difference in complex formation kinetics between cucurbit[7]uril and β-cyclodextrin.

Hydrazones serve as a valuable platform for exploring fundamental aspects of soft material engineering, owing to their straightforward preparation and chemical robustness. Naturally, insight into their behaviour propels the development of novel chemosensors, biologically active materials and catalysts. Dihydrazones, while seldom explored, offer a plethora of compelling chemical and structural scenarios. Within this study, aryl dihydrazones derived from succinic and adipic acid dihydrazide were synthesized and thoroughly investigated in the solid-state and solution. The potential of the prepared ligands for the development of coordination polymers based on molybdenum(VI) species was investigated under various reaction conditions. The isolated compounds were characterized in the solid-state and solution by appropriate spectroscopic and diffraction methods and compared with the relevant data for neutral dihydrazones. The results unveil that while neutral dihydrazones demonstrate substantial conformational flexibility in solution, crystallization or chelation effectively lodges the dihydrazone framework in a robust anti conformation.

The temperature and solvent effect on the complexation of various guests with α-, β- and γ-cyclodextrin and cucurbit[7]uril was explored experimentally and by means of molecular dynamics simulations. The stability constants of all investigated complexes were by far the highest with cucurbit[7]uril in water. A pronounced temperature dependence of ΔrH° and ΔrS°, resulting in almost complete enthalpy- entropy compensation was observed solely in water. The complexation thermodynamics was in line with classical rationale of the hydrophobic effect at lower temperatures, and the non-classical explanation at higher ones. Unlike in water, the hosting in formamide and ethylene glycol could be attributed to non- classical solvophobic effect. The optimized inclusion complex structures corresponded to those deduced by means of NMR spectroscopy and the experimentally obtained and calculated ΔrG° were in very good agreement. The carried out research bridged the gap between the classical and non-classical rationale of hydrophobic effect and demonstrated that solvophobically driven formation of inclusion complexes is not a water-limited phenomenon. However, among explored structured solvents, water stood out as unique solvation and complexation medium.

Azithromycin belongs to an azalide subclass of 15- membered macrolide antibiotics. It was synthesized in the early 1980s as a semi- synthetic derivative of erythromycin.[1] With a much improved pharmacokinetic properties over erythromycin, azithromycin became the most widely used broad- spectrum antibiotic.[2] Thiosemicarbazones belong to a large group of thiourea derivatives and are well known as antibacterial, antiviral, anti- inflammatory, antifungal and anticancer therapeutics.[3] Furthermore, a new multi- functional thiosemicarbazones were designed to treat Alzheimer and malaria.[4, 5] Conjugation of the azithromycin and thiosemicarbazone derivatives resulted in novel compounds which showed good activity against some Gram positive and Gram negative bacterial strains. Modern approach to the drug impurity profiling is based on the use of hyphenated systems, such as LC-NMR and/or LC-MS. [6] One of the most efficient and powerful tools for on-line isolation and identification of compounds in complex mixtures in the pharmaceutical industry is the LC-SPE- NMR system. In this study, LC- SPE/CRYO NMR technique was used for impurity profiling of novel azithromycin conjugates.

Calixarenes are a class of supramolecular cavitands that can be easily functionalized to give receptors for ionic and neutral species. Structural evolution of these compounds has led to more selective receptors with improved physico-chemical properties. Most of the synthesized calixarene ionic receptors are not sufficiently soluble in water which makes their use quite limited [1]. Water-soluble calixarenes usually own this property to the introduced easily-ionized sulfonic groups. In the scope of this work novel neutral and water- soluble ligands 1–3 (Figure 1) were designed and prepared, and their complexation with alkali-metal cations was investigated. Glucose was embedded in the structure as hydrophilic domain whereas secondary and tertiary amides served as cation-binding sites. The latter motifs were used since the calixarene derivatives comprising such groups were previously proven to form highly stable complexes [2]. Complexation reactions with alkali-metal cations were studied in water, methanol, and formamide thus giving insight into the solvation as well as intra- and intermolecular hydrogen bonds effects. Several techniques were used, such as UV spectrophotometry, isothermal titration calorimetry and NMR spectroscopy.

The solvent influence on the complexation of amphiphilic mannosides containing different non-polar moities with β-cyclodextrin and cucurbit[7]uril was explored in a wide range of temperatures by means of microcalorimetry and NMR spectroscopy. The stabilities of the complexes formed were higher in water than in other hydrogen-bonded solvents (ethylene glycol, formamide, N-methylformamide, and methanol), whereby all reactions were enthalpically controlled. The explored guest preffered cucurbit[7]uril as host. In the case of complexation reactions involving β- cyclodextrin and investigated guests in water notable temperature dependence of ΔrH° and ΔrS° was noticed. This resulted in almost perfect enthalpy-entropy compensation. The standard thermodynamic parameters for mannoside bindng with β-cyclodextrin in organic solvents exhibited relatively weak temperature dependence. The complex stability was strongly influenced by the compatibilty of guest and host cavity sizes, as well as the flexibility and the structure of the mannoside hydrophobic group. The carried out investigations clearly demonstrate that solvophobically driven formation of cyclodextrin and cucurbit[7]uril inclusion complexes is not a water limited phenomenon.

Adulteration of high-priced, health beneficial hempseed oil of different geographical origin was studied by combination of 1H NMR spectroscopy and multivariate statistical analysis. The fatty acid composition of hempseed oil corresponds to the ideal ratio of essential fatty acids (EFAs) required by human body, which is roughly 3:1 of omega-6 to omega- 3. 15 hempseed oil samples were adulterated with 6 samples of sunflower oil, 4 samples of rapeseed oil and 4 samples of sesame oil. Each particular edible oil sample varies in producer and country of origin. Including binary mixtures there were altogether 105 oil samples. The aim of this study was to determine the content of each studied hempseed oil sample using established methodology regarding iodine value [1] and fatty acid composition [2], and to select optimal variables and establish optimal regression model for prediction of adulteration with already mentioned adulterant oils. Obtained results show that although hempseed oil samples vary considerably in iodine value (154.0 − 165.5) and omega-3 fatty acids (15.7 ‒ 20.0 %), interval ridge regression [3] and first-break forward interval partial-least square regression (FB- FiPLS) [4] obtain significantly lower root-mean error of prediction than PLS applied to the whole considered NMR spectral region (6 ‒ 0 ppm) in most studied cases. To the best of our knowledge merged-interval regression procedures are for the first time applied to NMR data. Obtained prediction accuracy for volume fraction of each adulterant oil in binary mixtures (1.4 ‒ 3.0 %, 0.991 < R2 < 0.998) are promising enough to conclude that 1H NMR combined with the inspected chemometric procedures can be used to effectively quantify adulteration in hempseed oils, even when many samples of different geographical origin are considered for both hempseed oil and adulterant oils. [1] Y. Miyake, K. Yokomizo, N. Matsuzaki, J. Am. Oil Chem. Soc. 1998, 75, 15. [2] R. Sacchi, F. Addeo, L. Paolillo, Magn. Reson. Chem. 1997, 35, S133. [3] O. Jović, N. Smrečki, Z. Popović, Talanta 2016, 150, 37. [4] O. Jović, Food Anal. Methods 2016, 9, 281.

Cyclodextrines (CDs) have been extensively studied due to their ability to host wide variety of hydrophobic compounds in water thus increasing their solubility in this solvent, and hence bioavailability.[1] The focus of our studies so far has been the synthesis of adamantyl glycosides and the evaluation of thermodynamic parameters of their complexation with b-CD in water.[2] Our present investigations have been directed to the complexation of other amphiphilic glycosides, namely, n-butyl, t-butyl, n-hexyl, cyclohexyl, n-octyl and cyclooctyl 2-(a- D-mannopyranosyloxy)acetates with b-CD in water and in organic solvents. Therefore, we present the synthesis of novel amphiphilic mannosylated esters of acetic acid possessing various alkyl parts (linear, branched or cyclic, Fig. 1). The esters were prepared by the reaction of acetylated or benzylated mannopyranose and corresponding esters of bromoacetic acid. Their complexation with b-CD was studied by means of titration calorimetry and NMR spectroscopy (1H, HSQC, COSY and ROESY techniques). The thermodynamic parameters of complexation (reaction enthalpies, standard reaction entropies, binding constants) were determined. Obtained results provide a deeper insight in correlations between guest structure and its complexation thermodynamics in investigated solvents.

The solvent influence on the complexation of amphiphilic mannosides, consisting of different non-polar moities, with β-cyclodextrin was explored in a range of temperatures (5 ≤ ϑ/ ºC ≤ 65) by means of microcalorimetry and NMR spectroscopy. The complexation was observed only in strongly hydrogen-bonded solvents (water, formamide, N-methylformamide, and ethylene glycol). The stabilities of complexes were higher in water than in investigated organic solvents, whereby all reactions were enthalpically controlled. A notable temperature dependence of ΔrH○ and ΔrS○ was noticed in water. In contrast, the standard complexation parameters in other investigated solvents exhibited relatively weak temperature dependence. As expected, the complex stability was strongly influenced by compatibilty of the guest and the β-cyclodextrin cavity sizes, as well as the flexibility and structure of the hydrophobic group of investigated mannosides. The carried out investigations provided a deeper insight into the hosting process, demonstrating that solvophobically driven formation of cyclodextrin inclusion complexes is not a water limited phenomenon.

Kaliksareni su makrociklički oligomerni spojevi sastavljeni od četiriju ili više fenolnih podjedinica povezanih metilenskim skupinama u ortho-položaju fenola. Raznolikost kaliksarenskih derivata posljedica je varijabilnog broja fenolnih podjedinica makrocikala te mogućnosti funkcionalizacije na gornjem i donjem kaliksarenskom obodu. Cilj ovoga rada bio je istražiti utjecaj otapala na kompleksiranje kationa alkalijskih metala (M+) ketonskim derivatom kaliks[4]arena (L). Mikrokalorimetrijskim i spektrofotometrijskim titracijama određene su konstante stabilnosti kompleksa ML+ u navedenim otapalima te je potvrđena entalpijska kontrola procesa kompleksiranja.1 Kompleksiranje Na+ s L uočeno je u svim ispitivanim otapalima, dok je kompleksiranje ostalih alkalijskih kationa opaženo samo u metanolu i acetonitrilu. Spektrofotometrijskim, mikrokalorimetrijskim i 1H-NMR titracijama ispitana je inkluzija molekula otapala u hidrofobnu šupljinu kompleksa NaL+ kao potencijalni dodatni pokretač nastanka kompleksa ML+. Uočen je slabi afinitet kaliksarenske hidrofobne šupljine prema metanolu i N-metilformamidu te nešto jači afinitet za vezanje acetonitrila. Primjena izotermne mikrokalorimetrije u istraživanju formiranja kompleksâ ML+, istraživanje temperaturne ovisnosti topljivosti liganda L u ispitivanim otapalima i poznavanje standardnih termodinamičkih funkcija tranfera kationa alkalijskih metala omogućili su konstruiranje termodinamičkih ciklusa iz kojih slijedi detaljna termodinamička interpretacija različitih utjecaja ispitivanih otapala na stabilnost kompleksa ML+. Različiti solvatacijski utjecaji na formiranje kompleksa mogu se za većinu promatranih otapala objasniti uzimajući u obzir samo solvataciju kationa i kompleksa, dok u slučaju acetonitrila važnu ulogu ima i inkluzija molekule otapala u kaliksarensku hidrofobnu šupljinu.

Calixarenes are a class of supramolecular cavitands that can be easily functionalized to give receptors for ionic and neutral species. In many papers published so far their use has been tested in a wide range of applications, from simple host-guest interactions to biomimetics and catalysis. Structural evolution of these compounds has led to more selective receptors with improved physico-chemical properties. Most of the synthesized calixarene ionic receptors are not sufficiently soluble in water which makes their use quite limited [1]. Water-soluble calixarenes usually own this property to the introduced easily-ionized sulfonic groups. In the scope of this work novel neutral and water-soluble ligands 1–3 (Figure 1) were designed and prepared, and their complexation with alkali-metal cations was investigated. Glucose was embedded in the structure as hydrophilic domain whereas secondary and tertiary amides served as cation- binding sites. The latter motifs were used since the calixarene derivatives comprising such groups were previously proven to form highly stable complexes [2]. Complexation reactions with alkali-metal cations were studied in water, methanol, and formamide thus giving insight into the solvation as well as intra- and intermolecular hydrogen bonds effects. Several techniques were used, such as UV spectrophotometry, isothermal titration calorimetry and NMR spectroscopy.

Adamant-1-yl, cyclohexyl and benzyl 2-(α-D-mannopyranosyloxy)acetate were prepared and their complexation with β-cyclodextrin in water, formamide and ethylene glycol was explored microcalorimetricaly and by means of NMR spectroscopy in a wide of range of temperatures (5 ≤ θ / °C ≤ 65). Formation of inclusion complexes with all explored derivatives was observed in water. The corresponding stability constants were the highest for adamantly based compound, somewhat lower for the cyclohexy mannoside and much lower for the benzyl derivative. The binding of adamantly mannoside in organic solvents occurred at all temperatures explored, whereas the complexation of cyclohexyl derivative could be noticed only at 5 °C. The inclusion of the benzene subunit into the macrocycle cavity in formamide and in ethylene glycol was not observed. The stabilities of the adamantly and cyclohexyl complexes were higher in water than in formamide and ethylene glycol. All reactions were enthalpically controlled at all temperatures examined. The less favourable complexation in formamide and ethylene glycol with respect to water is mainly due to low ΔrSº values in these solvents. In addition, ΔrHº and ΔrSº for complexation of cyclohexyl and adamantyl mannosides in water decreased significantly with temperature, whereas no such effect could be observed in organic solvents. The main driving force for complex formation can be attributed to solvofobic solvation of host cavity and that of the guest. Despite this fact, the solvation of hydrophobic subunit of the guest and the macrocycle cavity seems to be notably different in water when compared to explored organic solvents.

N-bromftalimid (nbf) pripada u skupinu N-haloimida, komercijalno dostupnih spojeva koji se najčešće primijenjuju kao sredstva za halogeniranje i katalizatori u različitim reakcijama ciklizacije i halolaktonizacije u organskoj kemiji.[1] Osim toga, u posljednjih desetak godina privukli su pažnju u sintezi kokristala jer mogu poslužiti kao donori halogenske veze.[2][3] U ovome radu izučavana je uloga nbf-a u Povarovljevoj reakciji o-vanilaldimina i acetona. Imin, dobiven kondenzacijom o-vanilina i 2-aminonaftalena, te nbf mljeveni su u stehiometrijskom odnosu 1:1 u kugličnom mlinu pri standardnim laboratorijskim uvjetima (25 °C, 40-50 % RH). Dobiveni praškasti produkt otopljen je u acetonu te je nakon evaporacije otapala izoliran aril[f]kinolin, [4] bromirani produkt Povarovljeve ciklizacije imina, koji kristalizira u dva polimorfna oblika. Produkti mehanokemijske sinteze i pokusa u otopini opisani su difrakcijom rentgenskog zračenja na praškastom uzorku i NMR spektroskopijom. Molekulska i kristalna struktura oba polimorfa određene su difrakcijom rentgenskih zraka na jediničnom kristalu. U monoklinskoj formi molekule su međusobno povezane C–H···O hidroksi vodikovim vezama u centrosimetrične dimere, tvoreći motiv R22(18), a nadalje se povezuju C–H···C vodikovim vezama u cik-cak lance i mreže. U triklinskoj formi molekule su povezane C–H···O metoksi vodikovim vezama u centrosimetrične dimere, tvoreći motiv R22(6), a nadalje se povezuju C–H···C kontaktima aromatskih sustava u dvije dimenzije.

Omeprazole is a trivial name for 6-methoxy-2- [(4- methoxy-3, 5-dimethylpyridin-2- yl)methanesulfinyl]-1H-1, 3-benzodiazole, an active pharmaceutical ingredient. This compound was the first proton pump inhibitor on the market, and is considered by the WHO to be one of the essential medications. Production of omeprazole usually follows the route shown below. The preparation procedure is conducted as a one- pot synthesis involving condensation of the benzimidazole moiety with pyridine moiety in reflux conditions, followed by the addition of appropriate catalytic compounds. The aim of this work was to modify the synthetic route according to the guidelines attained through thermodynamic and kinetic studies of both phases in the one-pot procedure, with the emphasis on the solvent effect. It has been shown that the MeOH/H2O ratio has dramatic effect on the first- step reaction rate which can in principle be used to carry out the reaction at room temperature almost ten times faster. In addition, the increase of water content leads to a lower product solubility which eventually results in higher reaction yields. In the second phase, i.e. oxidation step, it has been proven that after pH correction in order to maximize precipitation of omeprazole as the neutral species, relatively long trituration periods have virtually no effect on the overall yield and purity profile, and is thus unnecessary.

Adamant-1-yl, cyclohexyl and benzyl 2-(α-D- mannopyranosyloxy)acetate were prepared and their complexation with β-cyclodextrin in water, formamide and ethylene glycol was explored microcalorimetricaly and by means of NMR spectroscopy in a wide of range of temperatures (5 ≤ θ / °C ≤ 65). Formation of inclusion complexes with all explored derivatives was observed in water. The corresponding stability constants were the highest for adamantly based compound, somewhat lower for the cyclohexy mannoside and much lower for the benzyl derivative. The binding of adamantly mannoside in organic solvents occurred at all temperatures explored, whereas the complexation of cyclohexyl derivative could be noticed only at 5 °C. The inclusion of the benzene subunit into the macrocycle cavity in formamide and in ethylene glycol was not observed. The stabilities of the adamantly and cyclohexyl complexes were higher in water than in formamide and ethylene glycol. All reactions were enthalpically controlled at all temperatures examined. The less favourable complexation in formamide and ethylene glycol with respect to water is mainly due to low ΔrSº values in these solvents. In addition, ΔrHº and ΔrSº for complexation of cyclohexyl and adamantyl mannosides in water decreased significantly with temperature, whereas no such effect could be observed in organic solvents. The main driving force for complex formation can be attributed to solvofobic solvation of host cavity and that of the guest. Despite this fact, the solvation of hydrophobic subunit of the guest and the macrocycle cavity seems to be notably different in water when compared to explored organic solvents.

N-bromophthalimide (nbp) belongs to N-haloimides, a well-recognized group of commercially available compounds usually used as halogenation agents and catalysts in various cyclization or halolactonization reactions in organic chemistry (Nakatsuji et al., 2014). On the other hand, they have recently drawn attention due to their potential as halogen bond donors in the synthesis of cocrystals (Raatikainen & Rissanen, 2011 ; Mavračić et al., 2016). In effort to obtain cocrystals of nbp and an imine, derived from o-vanillin and 2-aminonaphthalene, we have obtained an aryl[f]quinoline as a product of the Povarov reaction (Povarov, 1967) with acetone. We first attempted the grinding of nbp and imine in the stoichiometric ratio 1:1 in a ball mill. After 10 minutes of grinding under normal laboratory conditions (temperature ca. 25 °C, 40–50% RH) the resulting solid was dissolved in acetone. The solution was allowed to evaporate slowly overnight at room temperature, yielding single crystals of two polymorphs. Crystal structure determination revealed that the prepared polymorphs display interesting and remarkably different molecular packing features. In the crystal structure of form 1, the molecules are connected into centrosymmetrical R22(18) dimers via C–H∙∙∙O(hydroxy) hydrogen bonds and further connected by C–H∙∙∙C hydrogen bonds into a 3D-network. In the crystal structure of form 2, the molecules are connected into centrosymmetrical R22(8) dimers via C–H∙∙∙O(methoxy) hydrogen bonds. By means of Br∙∙∙O contacts (d = 3.377 Å) of the same distance as the sum of the van der Waals radii of bromine and oxygen and C–H∙∙∙C hydrogen bonds 2D-sheets are formed.

7-Ethyltryptophol, 2(7-ethyl-1H-indol-3- yl)ethanol, is a key starting material in the synthesis of Etodolac, a non-steroidal anti- inflammatory drug. Depending on the synthetic pathway for 7-ethyltryptophol, commercially available material comprises many different impurities which can cause formation of coproducts in the synthesis of Etodolac thus complicating the purification of the final product.[1] Therefore, to develop an optimal purification procedure of Etodolac, it is important to know the structures of impurities in 7-ethyltryptophol. Classical methods for separation and isolation of impurities, such as preparative or semi- preparative liquid chromatography, are time and solvent consuming. Nowadays, hyphenated NMR techniques are becoming faster, more efficient and more sensitive tool for determination of impurities and degradation products in pharmaceuticals and natural products. [2, 3] In this study LC-SPE (cryo)NMR methodology was used to identify impurities in 7-ethyltryptophol. Chromatographic separation was achieved on Waters XBridge Phenyl and C18 columns (150 mm x 4.6 mm ; 3.5 μm) using a combination of gradient and isocratic elution. Compounds were trapped on HySphere Resin GP cartridges in a SPE multitrapping mode. 1H, COSY, 1H-13C HSQC, 1H-13C HMBC NMR spectra and MS spectra were recorded to determine the structures of impurities. In this way 17 compounds were identified. These results show a good potential of LC-SPE (cryo)NMR technique in an identification and structural characterization of low level impurities and degradation products in pharmaceuticals. References: [1] M. C. Sekharayya, G. V. Narayana, S. Nigam, G. Madhusudhan, Indian J. Chem. 51B (2012) 1763-1766. [2] S. Singh, T. Handa, M. Narayanam, A. Sahu, M. Junwal, R. P. Shah, J. Pharm. Biomed. Anal. 69 (2012) 148-173. [3] J. W. Jaroszewski, Planta Med. 71 (2005) 795-802

7-Ethyltryptophol, 2(7-ethyl-1H-indol-3- yl)ethanol, is a key starting material in the synthesis of Etodolac, a non-steroidal anti- inflammatory drug (Scheme 1). Depending on the synthetic pathway for 7- ethyltryptophol, commercially available material comprises many different impurities which can cause formation of coproducts in the synthesis of Etodolac thus complicating the purification of the final product.[1] Therefore, to develop an optimal purification procedure of Etodolac, it is important to know the structures of impurities in 7- ethyltryptophol. LC-SPE-NMR methodology is a powerful tool for fast identification and structural elucidation of low concentration level impurities and degradation products in pharmaceuticals.[2] In this study we report on the HPLC method for efficient separation of impurities in 7- ethyltryptophol as the first step in hyphenated LC-SPE-NMR analysis. References 1. M. C. Sekharayya, G. V. Narayana, S. Nigam, G. Madhusudhan, Indian J. Chem. 51B (2012) 1763-1766. 2. S. Singh, T. Handa, M. Narayanam, A. Sahu, M. Junwal, R. P. Shah, J. Pharm. Biomed. Anal. 69 (2012) 148-173. Acknowledgements: This work was funded by European Regional Development Fund and Croatian state budget (project Met4Pharm).

Thiosemicarbazones can exist in several tautomeric forms and conformations, with the possibility of intra- and intermolecular hydrogen bonding. Detailed structural characterization of thiosemicarbazones, as compounds that are associated with a wide spectrum of biological activities, is a prerequisite for better understanding of their bioactivity and for obtaining molecules with improved pharmacological properties. The aim of our research is to investigate the influence of substituents, the nature of the solvent (different polarity and different proton-donor and proton-acceptor abilities) and temperature on molecular conformation, tautomerism and nature of hydrogen bonding in salicylaldehyde and 2-methoxybenzaldehyde thiosemicarbazone derivatives. We present here a part of our study regarding the effect of substituting OH with OMe group in salycilaldehyde residue on the overall structure and thione-thiol tautomerism. Solid state structures of 1 (single polymorph) and 2 (two polymorphs) were characterized by single- crystal X-ray diffraction and high resolution 13C and 15N solid-state NMR spectroscopy. Since the crystal structure of 3 was reported previously, we employed 13C and 15N solid state NMR experiments which provided structural data complementary to those obtained by X-ray diffraction. Solid state NMR parameters were used as a reference for solution study results. Possible solvent induced conformational and tautomeric equilibrium changes were probed by multinuclear (1H, 13C and 15N) temperature dependent NMR experiments in CDCl3 and DMSO solutions. The experimental results were complemented with computational research of conformational space of selected compounds in a vacuum, and organic solvents (PCM approach), by combination of molecular- and quantum-mechanical methods. The most stable structures, obtained by molecular mechanics, were reoptimized in vacuum, CHCl3 and DMSO with B3LYP-D3/6-311++G(2df, 2p) computational model. QTAIM population analysis method was used for characterization of intramolecular hydrogen bonds in most stable conformers of investigated compounds.

Tryptophols are derivatives of 2-(1H-indol-3-yl)ethanol, indole class bearing a C-3 hydroxyethyl side chain. 7-Ethyltryptophol, 2-(7-ethyl-1H-indol-3-yl)ethanol, is a key starting material in the synthesis of Etodolac, an important non-steroidal anti-inflammatory drug. The currently available synthetic procedures for 7-ethyltryptophol usually result with formation of a high-level of various impurities. LC-NMR is a very powerful tool for obtaining detailed structural information of components in complex mixtures such as impurities and metabolites in pharmaceuticals, natural products and synthetic polymers. In the present study, we developed LC-NMR methodology for separation and structural analysis of impurities in commercially available 7-ethyltryptophol. Several impurity peaks were detected in chromatograms and the structures of major impurities were elucidated by analyzing 1D and 2D LC-NMR spectra.

Tiosemikarbazoni i njihovi metalni kompleksi pripadaju razredu biološki aktivnih spojeva koji pokazuju antikancerogeno, antivirusno, antibakterijsko, antiupalno i fungicidno djelovanje. Istraživanje strukture i vodikovih veza u otopini može značajno doprinjeti razumijevanju njihove biološke aktivnosti. Izotopni efekti u NMR spektrima dobar su pokazatelj strukture i reaktivnosti molekula. Dosadašnja istraživanja su pokazala da salicilaldehid-4-feniltiosemikarbazon postoji u lokaliziranom hidroksi-tionskom obliku koji je stabiliziran vodikovim vezama. 2-Metoksibenzaldehid-4-feniltiosemikarbazon umjesto OH ima OMe skupinu u položaju 2 pa je ovaj rad usmjeren prema istraživanju utjecaja ove supstitucije na ukupnu strukturu, tautomernu ravnotežu i prirodu vodikovih veza u otopini. U tu svrhu korišteni su spektroskopija NMR i kvantno kemijski izračuni. U svrhu daljnje karakterizacije spoja 1 pripravljen je i deuterirani izotopomer 1 (ND) te su izmjereni i analizirani sekundarni deuterijski izotopni efekti na 13C NMR kemijske pomake.

Tiosemikarbazoni mogu postojati u nekoliko tautomernih oblika i konformacija, s mogućnošću stvaranja intra- i intermolekulskih vodikovih veza. Detaljna strukturna karakterizacija tiosemikarbazona, kao spojeva koji se povezuju sa širokim spektrom bioloških aktivnosti, preduvjet je za bolje razumijevanje njihove bioaktivnosti, kao i dobivanje molekula s poboljšanim farmakološkim svojstvima. Primjenom višenuklearne spektroskopije NMR (1H, 13C i 15N) u čvrstom stanju i otopini istražen je utjecaj supstituenata, prirode otapala (različitih polarnosti, odnosno različitih proton-donorskih i proton-akceptorskih svojstava) i temperature na molekulsku konformaciju, tautomeriju i prirodu vodikovih veza (intra- i intermolekulskih) derivata salicilaldehid i 2-metoksibenzaldehid tiosemikarbazona. Kombinacija poznate kristalne strukture te izmjerenih kemijskih pomaka 13C i 15N u čvrstom stanju, korištena je kao temelj za detekciju strukturnih promjena u otopini. Eksperimentalni rezultati upotpunjeni su računalnim istraživanjem konformacijskog prostora odabranih spojeva u vakuumu, i organskim otapalima (PCM pristup), kombinacijom molekulsko- i kvantno-mehaničkih metoda. Najstabilnije strukture, dobivene molekulskom mehanikom, reoptimirane su u vakuumu, CHCl3 i DMSO primjenom računskog modela B3LYP-D3/6- 311++G(2df,2p). Metodom populacijske analize QTAIM, korištenjem Koch-Popelierovih kriterija, okarakterizirane su intramolekulske vodikove veze u najstabilnijim konformerima istraživanih spojeva. Thiosemicarbazones can exist in several tautomeric forms and conformations, with the possibility of intra- and intermolecular hydrogen bonding. Detailed structural characterization of thiosemicarbazones, as compounds that are associated with a wide spectrum of biological activities, is a prerequisite for better understanding of their bioactivity and for obtaining molecules with improved pharmacological properties. Solid and solution state multinuclear NMR spectroscopy (1H, 13C i 15N) was emloyed to explore the influence of the substituents, the nature of the solvent (different polarity and different proton-donor and proton-acceptor abbilities) and temperature on the molecular conformation, tautomerism and the nature of hydrogen bonding (intra- and intermolecular) of salicylaldehyde and 2-methoxybenzaldehyde thiosemicarbazone derivatives. The combination of known crystal structures and observed 13C and 15N chemical shifts in the solid state, was used as a basis for the detection of structural changes in solution. The experimental results were complemented with computational research of conformational space of selected compounds in a vacuum, and organic solvents (PCM approach), by combination of molecular- and quantum-mechanical methods. The most stable structures, obtained by molecular mechanics, were reoptimized in vacuum, CHCl3 and DMSO with B3LYP-D3/6-311++G(2df,2p) computational model. QTAIM population analysis method, together with Koch-Popelier criteria, was used for characterization of intramolecular hydrogen bonds in most stable conformers of investigated compounds.

Thiosemicarbazones can exist in several tautomeric forms and conformations, with the possibility of intra- and intermolecular hydrogen bonding. Detailed structural characterization of thiosemicarbazones, as compounds that are associated with a wide spectrum of biological activities, is a prerequisite for better understanding of their bioactivity and for obtaining molecules with improved pharmacological properties. The aim of our research is to investigate the influence of substituents, the nature of the solvent (different polarity and different proton-donor and proton-acceptor abilities) and temperature on molecular conformation, tautomerism and nature of hydrogen bonding in salicylaldehyde and 2-methoxybenzaldehyde thiosemicarbazone derivatives. We present here a part of our study regarding the effect of substituting OH with OMe group in salycilaldehyde residue on the overall structure and thione-thiol tautomerism. Solid state structures of 1 (single polymorph) and 2 (two polymorphs) were characterized by single- crystal X-ray diffraction and high resolution 13C and 15N solid-state NMR spectroscopy. Since the crystal structure of 3 was reported previously, we employed 13C and 15N solid-state NMR experiments which provided structural data complementary to those obtained by X-ray diffraction. Solid state NMR parameters were used as a reference for solution study results. Possible solvent induced conformational and tautomeric equilibrium changes were probed by multinuclear (1H, 13C and 15N) temperature dependent NMR experiments in CDCl3 and DMSO solutions. Experimental results were complemented with computational research of conformational space in vacuum and organic solvents, by combination of molecular- and quantum-mechanical methods.

Thiosemicarbazones and their corresponding metal complexes are widely known compounds possessing diverse pharmacological activities, such as antitumor, antivirial, antibacterial, antifungal, antimalarial, etc. Bioactivity is closely related to molecular conformation which can significantly be affected by the presence of intra- and inter-molecular hydrogen bonds. Salicylaldehyde thiosemicarbazones can exist in several tautomeric forms with both intra- and inter-molecular hydrogen bonds. An intra-molecular O―H•••N H-bond between the hydroxyl group and the azomethine N atom has been found in salicylaldehyde thiosemicarbazone family (resonance assisted H-bond). Additionally, an intramolecular N―H •••N H-bond between the thiourea NH group and the azomethine N atom was found in few salicylaldehyde thiosemicarbazones. The aim of this research is to investigate the influence of substituents and solvents (different polarities, i. e. of different proton donor and acceptor abilities) on molecular conformation, tautomerism and structure of H-bonds in salicylaldehyde thiosemicarbazone derivatives. We present here a part of our study regarding the effect of substituting OH with OMe group in salycilaldehyde residue (therefore, breaking the O―H•••N H-bond) on the overall structure and thione-thiol tautomerism. Solid state structures of two thiosemicarbazone derivatives 1 and 2 (two polymorphs) were characterized by high resolution 15N and 13C solid-state NMR spectroscopy and X-ray diffraction. The results were compared with those obtained for CDCl3 and DMSO solutions. Possible tautomeric equilibrium changes were probed by multinuclear temperature dependent NMR experiments.

Salicylaldehyde thiosemicarbazones and their metal complexes belong to an important class of biologically active compounds (anticancer, antivirial, antibacterial, antiinflammatory and antifungal activity). They can exist in several tautomeric forms e.g. hydroxy-thione, hydroxy- thiol, keto-thione and keto-thiol with both intra- and inter-molecular hydrogen bonds. X-ray structural analysis has confirmed the existence of intra-molecular hydrogen bonds in different salicylaldehyde thiosemicarbazone derivatives. Bioactivity is closely related to molecular structure which is governed by the presence of hydrogen bonds. Therefore, the aim of our study was to investigate the influence of solvent and substituents on molecular conformation and structure of hydrogen bonds in salicylaldehyde thiosemicarbazones by combining NMR and DFT methods. Solvents of different polarities, i. e. of different proton donor and acceptor abilities were used (chloroform, acetone, methanol, dimethyl sulfoxide). Also, the effect of substituting OH with OMe group in salycilaldehyde residue, on the overall thiosemicarbazone structure and tautomerism was explored. Two-dimensional NOESY spectra indicated conformational changes in solution with respect to the structure observed in solid state owing to a relatively low barrier of the rotation arround N-N single bond thus enabling a molecule to posses a higher conformational flexibility in solution. The results presented here can help in a better understanding of the role hydrogen bonds can play in bioactivity of related thiosemicarbazone derivatives and their metal complexes.

Enaminones have been recently a subject of comprehensive studies due to their wide applications in organic synthesis [1] and coordination chemistry, as well as their potential pharmacological importance. Studies have shown that enaminone derivatives possess anti-inflammatory, anticonvulsant, antimalarial and cardiovascular activities. Hydrogen bonds are an important structure and reactivity factor, and also a bioactivity modulator. The aim of this work is to investigate the intra- and intermolecular hydrogen bonding structure in solution of enaminones derived from dehydracetic acid by employing NMR and DFT methods. X-ray structural analysis has confirmed the existence of the keto-amine form (1a) in the solid state, stabilized by formation of intramolecular H-bonds [2]. However, the fundamental question is whether the nature of the intramolecular H-bond N― H∙ ∙ ∙ O and the proton transfer (Fig. 1) will be affected by solvents of different proton donor and acceptor abilities and the substitution pattern (ortho, meta, para) of enaminone isomers. In order to get further insight into these interactions secondary deuterium isotope effects on 13C chemical shifts have been measured and analyzed.

Salicylaldehyde thiosemicarbazones and their metal complexes belong to an important class of biologically active compounds (anticancer, antivirial, antibacterial, antiinflammatory and antifungal activity) [1]. They can exist in several tautomeric forms (hydroxy-thione, hydroxy-thiol, keto-thione and keto-thiol) with both intra- and intermolecular hydrogen bonds (Fig. 1). X-ray structural analysis has confirmed the existence of intramolecular hydrogen bonds in different salicylaldehyde thiosemicarbazone derivatives [2, 3]. Bioactivity is closely related to molecular structure which is governed by the presence of hydrogen bonds. Therefore, the aim of our study was to investigate the solvent influence on molecular conformation and structure of hydrogen bonds in methoxysalicylaldehyde thiosemicarbazones by combining NMR and DFT methods. Solvents of different polarities, i. e. of different proton donor and acceptor abilities were used (chloroform, acetone, methanol, dimethyl sulfoxide).

Heterociklički spojevi koji sadrže izoindolinsku skupinu prisutni su u mnogim prirodnim i sintetičkim spojevima koji pokazuju biološku aktivnost kao što su staurosporin (inhibitor protein kinaze C), indoprofen (protuupalno djelovanje) i sl. U ovom radu priređeni su 1-arilimino-2-arilizoindolini reakcijom o-ftalaldehida i aromatskih i heterocikličkih amina u neutralnim uvjetima (apsolutni etanol) pri sobnoj temperaturi i/ili uz zagrijavanje. Spojevi su okarakterizirani jednodimenzijskim i dvodimenzijskim 1H i 13C NMR-om. Kristalna struktura riješena je rendgenskom difrakcijom na monokristalu. [1] Takahashi, I. ; Miyamoto, R. ; Nishiuchi, K. ; Hatanaka, M. ; Yamano, A. ; Sakushima, A. ; Hosoi, S. ; Heterocycles 63 (2004) 1267-1271. [2] Takahashi, I. ; Hatanaka, M. ; Heterocycles 45 (1997) 2475-2499. [3] Kundu, N. G. ; Khan, M. W. ; Mukhopadhyay, R. ; J. Indian Chem. Soc. 78 (2001) 671.

Heterocyclic compounds containing isoindoline skeletons have been found interesting due to their presence in number of natural and synthetic bioactive compounds. Some examples of such compounds are staurosporine (protein kinase C inhibitor), idoprofen (anti-inflammatory agent) and pazinaclone (anxiolytic agent)1, 2. This report describes synthesis of imino derivatives of isoindoline as potentially biologically active compounds. 1:2 condensation of o-phthalaldehyde and primary aromatic and heterocyclic amines in absolute ethanol at room temperature gave desired 1-aril-imino-2-aril-isoindolines. Compounds 1 and 2 were prepared from amino-phenyl derivatives and compounds 3 and 4 were prepared from amino-pyridyl derivatives. Compound 5 was prepared from 2-amino-benzimidazole and compound 6 was prepared from 2-amino-benzothiazole. All compounds are characterized by 1H and 13C NMR spectroscopy. Furthermore structures of compounds 2, 3 and 4 are confirmed by X-ray diffraction on monocrystal. References [1] Takahashi, I. ; Hatanaka, M. ; Heterocycles 45 (1997) 2475-2499. [2] Kundu, N. G. ; Khan, M. W. ; Mukhopadhyay, R. ; J. Indian Chem. Soc. 78 (2001) 671. [3] Takahashi, I. ; Miyamoto, R. ; Nishiuchi, K. ; Hatanaka, M. ; Yamano, A. ; Sakushima, A. ; Hosoi, S. ; Heterocycles 63 (2004) 1267-1271.