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Diamondoid ammonium salts (DAS) are known guest molecules capable of realizing extremely tight binding within cucurbituril (CB[n]) hosts in aqueous environment, with binding constants reaching up to 1015 mol–1 dm3. [1] Inspired by these properties, we broadened the scope of our research concerning the binding between DAS and other hydrophobic cavities, i.e., cyclodextrins (CDs).[2] Herein we present binding capabilities of various DAS regioisomers and evaluate the effect of different nitrogen-based functionalities on complex stabilities with CDs. Stability constants were determined by ITC and 1H NMR titrations in aqueous solutions. Additionally, we used a diffusion NMR 1H DOSY method to estimate the percentage of complexation based on the calculated diffusion coefficients. The structural features of the complexes were assessed by the 1H- 1H NOESY NMR experiments, and computational studies revealed key interactions acting within the inclusion complexes

The ultimate target of the ongoing development of anion and ion-pair receptors is their application in some real-world functions such as sensing and transport in biological systems, extraction in industrial processes, and new water purification technologies.[1–3] Among classical anion and ion- pair receptors containing hydrogen-bond donating groups, [4, 5] a significant place belongs to calixarenes containing (thio)urea moieties. Despite being known for a few decades, the fundamental and the application-oriented work with the latter ion-receptors is still in progress. [6, 7] In this talk, fundamental research of binding of anions on two new simple urea-derivatives of p- tert-butylcalix[4]arenes (1, 2 ; Figure 1) in acetonitrile will be presented. Thermodynamics of complexation of the selected anions (Cl–, HSO4–, H2PO4–, hydrogen pyrophosphate, acetate, benzoate) was investigated using UV/Vis, ITC, and 1H NMR titrations. Macrocycle with four urea-moieties (2) proved to be a better anion receptor in comparison to diureido-calix[4]arene derivative (1) which is in accordance with the pKa values of these calixarenes (experimentally determined by NMR). Furthermore, the cooperative effect in binding of Na+ and several anions (Cl–, HSO4–, H2PO4–) with receptor 1 (designed also as ion-pair receptor) was evaluated. The other part of this talk will demonstrate the realization of the idea of reversible formation of supramolecular dimeric calix[4]arene capsules (1 or 2 & 3 or 4) based on urea – carboxylate interactions which can be governed by changing the solution acidity.

Diamondoid ammonium salts are an intriguing class of compounds capable of forming ultra-stable complexes with cucurbituril (CB[n]) hosts in aqueous environment.[1] The host–guest chemistry of diamantane derivatives with different hydrophobic cavities, i.e., cyclodextrins (CDs), has not been explored as much.[2] We have therefore embarked on a study of inclusion complexes consisting of cage ammonium salts and CDs.[3] Herein we present the synthesis of a new series of diamantane amine derivatives and showcase the results of their binding with β- and γ-CDs. We used a diffusion NMR 1H-1H DOSY method to estimate the percentage of complexation based on the calculated diffusion coefficients. The binding strength of complexation was revealed by 1H NMR titrations, and the structural features of the complexes were assessed by the 1H-1H NOESY NMR experiments. Equilibrium constants and other thermodynamic parameters were additionally confirmed by ITC whereas computational studies revealed key interactions within the inclusion complexes.

Cyclodextrins (CDs) are important host macrocycles in supramolecular chemistry that possess deep, centrally positioned cavity, a structural feature essential for accommodation of hydrophobic guest molecules via their non-polar parts. Because of their properties and bioavailability, CDs have found application in pharmacology, biotechnology, catalysis, nanotechnology, etc.[1] Adamantane derivatives are known guest molecules that fit well into a CD cavity.[1] However, permethylated ammonium salts of adamantane have not been explored so far with this respect. Note that this class of compounds shows excellent binding abilities for cucurbituril hosts (CBs).[2] Inspired by these properties, we decided to broaden the scope of research regarding the binding between 1-substituited adamantane ammonium salts and CDs.[3] As a continuation of our study, herein we evaluated the binding capability of other regioisomers and the effect of other nitrogen-based functionalities on the complex stabilities. Various NMR spectroscopic techniques and ITC measurements were employed to determine the stability constants and explore host-guest interactions. Computational methods were used to gain more insight into structural features of formed complexes.

Chemical reactions in solid-state gained significant popularity in recent years1 due to their ability to expand the chemical space of organic synthesis, 2 which provides novel routes towards advanced materials for various applications.3 An important beneficial aspect of mechanochemistry is the fact that it requires environmentally acceptable conditions which includes the use of little or no organic solvent. Among the techniques for monitoring and characterization of solid-state reactions used so far (XRD methods, temperature and/or pressure monitoring, Raman, NMR and IR spectroscopy), 4 isothermal calorimetry (ITC) studies were scarcely applied, especially at ambient temperatures.5, 6 A lack of reaction enthalpy data for reactions in solid-state makes full thermodynamic characterization of these processes impossible without using thermodynamic cycles (requiring many different, long-lasting calorimetry experiments). Therefore, a crying need for direct detection of heat effect upon mixing of two or more solid reactants emerges in this reaserch area, the response to which, to the best of our knowledge, was not yet reported. In this work, a robust Calvet-type calorimeter (Setaram®), equipped with a cell originally designed for studies of dissolution processes, was used to directly measure the enthalpy of reactions between solid compounds at room temperature. Investigated reactions were complexation of KHSO4 with 18-crown-6 ether7 and proton transfer from salicylic acid to N, N-dimethylpyridin-4-amine combined with cocrystal formation. The reliability of the data was tested by comparing the directly obtained values of solid-state reaction enthalpies with the ones calculated using the appropriate thermodynamic cycles.

Covering many application areas such as sensing, extraction, self-assembly, transport, and catalysis, investigations in anion receptor chemistry are very important. Calixarenes functionalized with (thio)urea as hydrogen-bond donating groups can serve as classical anion receptors, but also as building blocks for molecular containers and, more recently, as selective binders and transporters of different biochemically relevant species. Recently, we have prepared two p-tert-butylcalix[4]arene derivatives bearing urea moieties , determined their pKa values and investigated their complexation with several anions (Cl–, HSO4–, H2PO4 –, benzoate, and hydrogen pyrophosphate) in acetonitrile. Macrocycle 2 is better anion binder than 1 due to more urea groups present in its structure and lower pKa values. Complexes of 1:2 and 2:1 stoichiometry (as receptor:anion) were observed with H2PO4 – and hydrogen pyrophosphate, respectively. Compound 1 was also designed as ion-pair receptor, so cooperative effect of binding of Na+ on the complexation of several anions with 1 was thermodynamically quantified. Herein, the thermodynamics of acetate binding with 1 and 2 was characterized using 1H NMR, UV-Vis, and ITC. Relatively high values of stability constants of the corresponding complexes (log β11 > 4) were determined and the formation of 12AcO– complex was detected. These results motivated the research of possible capsule formation between ureido-calix[4]arene derivatives and diacetatocalix[4]arenes via hydrogen bonding between the urea and carboxylate moieties. Indeed, the uniting of the two types of calixarenes into very stable (especially for 2) complexes was observed using the above methods as well as DOSY and conductometry. Tertiary amide groups in carboxylic calix[4]arene 4 lowered the affinity for its handshake with calixarene 2 in comparison to 1.

In the field of supramolecular chemistry, ditopic receptors capable of binding ion-pairs play a significant role. The binding of cation on a ditopic receptor often allosterically affects the binding of an anion (or vice versa) enhancing the stability of the resulting complexes. In order to fully understand and exploit such cooperativity it is necessary to characterize the underlying structural and thermodynamic aspects. Recently we synthesized amide-ureido-calix[4]arene derivative and investigated its ability as ion- pair receptor in acetonitrile. During this investigation a need for the values of equilibrium constants for ion-pairing in this solvent emerged. Namely, organic solvents are generally better media for the complexation of ions with organic receptors because ions are poorly solvated in them in comparison to water. However, the latter fact also results with the increase of significance of ion-pairing in organic solvents. As the literature lacks the constants of ion-pairings in acetonitrile, we investigated the thermodynamics of ion-pairing for several lithium and sodium salts using conductometric and microcalorimetric titrations. The obtained results were correlated with the basicities of the examined anions in acetonitrile, and compared with standard Gibbs energies of transfer of the appropriate ions from water to acetonitrile.

Functionalized diamondoid ammonium salts are an intriguing class of compounds capable of forming ultra-stable complexes with cucurbituril hosts (CB[n]) in aqueous environment with binding constants up to 1015 mol–1 dm3.1 Inspired by these properties, we decided to broaden the research scope of inclusion complexes stabilized by hydrophobic interactions between various cage ammonium salt guests and cyclodextrin (CD) as a different macrocycle host molecule.2 Herein we present the synthesis of a continued series of diamondoid ammonium salts and a detailed thermodynamic study of their complexation with β- and γ-CDs. The complex stability constants were determined by ITC and 1H NMR titrations in aqueous solutions. Additional NMR spectroscopic techniques (1H-1H NOESY, 1H DOSY) along with computational methods were employed to provide a deeper insight into the thermodynamics of hydrophobically driven complexations and structural features of the formed supramolecules. The binding strength was assessed as a function of diamondoid salt size, functional group position and cyclodextrin cavity size and by varying these parameters, a structure- selectivity relationship can be determined in order to facilitate the design of next generation of suitable guests.

Adamantane and diamantane derivatives are used as guest molecules in supramolecular inclusion complexes due to their unique structure.Cucurbituril hosts (CBs) bind diamondoid ammonium salts very strongly, with binding constants up to 1015 mol–1dm3 . [1] The next step was to broaden the scope of the research to a new series of guest compounds as well as other host molecules like cyclodextrins (CDs). [2a] Namely, CDs are important host macromolecules in supramolecular chemistry with broad applications in pharmacology, biotechnology, catalysis, nanotechnology, etc. [2b] Herein we present the synthesis of a continued series of diamondoid ammonium salts, and a detailed thermodynamic study of their complexation with β- and γ-CDs. The complex stability constants were determined by ITC and 1H NMR titrations in aqueous solutions. Structures of the complexes and relevant interactions that occur between host and guest species were examined by 1H1H NOESY NMR experiments. The obtained results provided a deeper insight into the thermodynamics of hydrophobically driven complexation and structural characteristics of the corresponding supramolecules as well as a useful tool for the design a next generation of guest compounds.

The field of anion receptor chemistry is nowadays spread over many areas such as sensing, extraction, self-assembly, catalysis, and transport. Most classical anion receptors employ hydrogen bonding to bind anions. Calixarenes are a fascinating family of compounds that can, by proper functionalisations of upper and/or lower rim, bind cationic, anionic, and neutral species. (Thio)urea-derivatives of calixarenes were designed as anion binders already in the 1990s. However, the full potential of their exploitation in ion-selective electrodes or for selective binding and transport of biologically important species is yet to be unraveled. In the scope of this work two calix[4]arenes bearing urea moieties were prepared. 1H-NMR titrations of these compounds were performed with the appropriate organic bases of known pKa values, which enabled determination of their pKa values in acetonitrile. Complexation of several anions (chloride, hydrogen sulfate, dihydrogen phosphate, hydrogen pyrophosphate, and benzoate) with M1 and M2 was thermodynamically investigated by 1H-NMR, UV/Vis and ITC titrations. Both receptors form 1:1 complexes with all examined anions except H2PO4 – and hydrogen pyrophosphate which bind with the receptors also as dimers. The affinity trend of both M1 and M2 towards anions matches the anion basicity-order with the exception of H2PO4 – for which M1 has a peak affinity. The anion binding equilibrium constants in the case of M2 are significantly larger than those for M1 which can be correlated with a higher number of urea groups in the former macrocycle. Reaction entropies for complexation of anions with two calixarenes point to significant differences in their conformational freedom in solution.

Since its beginnings, anion receptor chemistry relies on hydrogen bonds as one of the primary interactions stabilising complexes with negatively charged species. Molecules bearing NH moieties like amides, (thio)ureas, pyroles, tetrazoles, etc. are thus almost universal among anion receptors. Further advancement of anion receptor properties towards applicable and economically exploitable systems can be in detailed fundamental research of the interactions stabilising their complexes. On the other hand, it is essential to test new prospective candidates among H-bond donor functionalities by incorporating them in suitable molecular environment endorsing interactions with anions. In this lecture both approaches will be addressed dividing the talk into two main parts: i) In the first part a comprehensive study on amide-based anion receptors with the focus on detailed understanding of structure-binding relationship relying on NMR spectroscopy will be presented. In addition, anion binding properties of a hybrid receptor containing both amide and urea binding sites will be discussed providing an answer to an interesting question: What do anions prefer when offered both amide and urea as binding site? ii) A functional group almost unexplored in the scope of anion coordination chemistry, i.e. sulfonylurea will be in the spotlight of the second part of the talk.[10] Anion-binding properties of three aromatic sulfonyl urea derivatives in acetonitrile and dimethyl sulfoxide will be discussed. Since the sulfonylurea features high acidity, part of the lecture will be devoted to this aspect and the methodology for determination of protonation properties based on the NMR spectroscopy.

Supramolecular complexes are stabilized by non-covalent interactions between the host and the guest molecule. Molecular recognition studies can give insight into many processes occurring in nature and prove useful for technological applications. It was recently demonstrated that functionalized adamantane and diamantane ammonium salts are suitable guests for cucurbituril hosts. Moreover, some diamantane derivatives are capable of extremely tight binding with cucurbiturils in water, forming complexes with attomolar dissociation constants. Such ultrastable complexes rival the strength of binding processes acting in biomolecular receptors (e.g., avidin-biotin). As a continuation of our research, we explored complexation of selected adamantane and diamantane ammonium salts with cyclodextrin host molecules. The binding strength was assessed as a function of diamondoid salt size, functional group position and cyclodextrin cavity size. By changing these parameters, a structure-selectivity relationship can be determined and next generation of guests proposed. Various NMR spectroscopic techniques and ITC measurements were employed to determine the stability constants and explore host-guest interactions. Computation methods were used to gain further insight into structural features of formed complexes and to better understand the factors governing their stabilities.

Calixarenes are a useful family of compounds that can bind cationic, anionic, and neutral species, when properly functionalised at upper and/or lower rim. Although (thio)urea-derivatives of calixarenes are known for three decades, their applicability for selective binding or transport of biologically important species is still widely unexplored. Receptors M1 and M2, which belong to this compound class, have been recently investigated as anion binders. Thermodynamics of their complexation with various anions (Cl–, HSO4–, H2PO4–, benzoate, and hydrogen pyrophosphate) was studied in acetonitrile. Complexes of 1:1 stoichiometry were observed with all examined anions except H2PO4– and hydrogen pyrophosphate which also formed 2:1 complexes (anion:receptor). Due to the larger number of urea groups in M2, the anion binding equilibrium constants for this receptor were proven to be significantly higher than those for hybrid amide- urea analogue M1. In this work the supramolecular behaviour of these two calix[4]arenes was characterized in more detail. Firstly, the cation binding abilities of M1 and M2 were examined focusing on alkali and alkaline earth metal cations using several experimental methods (NMR, ITC, UV/Vis). Further on, the ability of M1 and M2 to act as ion-pair receptors was investigated. Structural features of the complexes were elucidated by means of NMR spectroscopy and the cooperative effect of binding two oppositely charged species was evaluated and discussed from the thermodynamic point of view.

Research on macrocyclic host molecules capable of encapsulating small guest molecules can inspire supramolecular architectures that mimic biological systems and can have useful technological applications.1 We have recently shown that functionalized diamondoid ammonium salts are suitable guests for cucurbituril (CB[n]) hosts in aqueous environment. Especially strong binding was found for the complex of 4, 9-diammonium diamantane derivative with CB[7], having an attomolar dissociation constant that rivals the interaction between avidin-biotin.2 As a continuation of our work, we explored complexation of diamondoid ammonium salts with β and γ cyclodextrins (CDs) in water (Figure 1). The key step in the synthesis of these permethylated diamondoid ammonium salts was selective functionalization of diamantane scaffold via nitroxylation and subsequent hydrolysis3 that was optimized in detail in the scope of this study. When assessing the binding strength, we considered the size of the diamondoid salts, substitution type and number of functional groups as well as the cyclodextrin cavity size. Equilibrium constants and other thermodynamic parameters for the complexation of diamondoid ammonium salts with CDs were determined by ITC, conductometric and/or 1H NMR titrations. Additional NMR spectroscopic techniques (1H-1H NOESY, 1H DOSY) were employed to elucidate specific interactions of guest encapsulated within host molecules, along with the corresponding computational analysis.

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.

As the field of supramolecular chemistry evolves, the systems based on non-covalent interactions find their application in various technologies as chemical sensors, transport systems etc. Consequently, it is of paramount importance to understand the thermodynamics of supramolecular reactions, which enables fine- tuning the properties of the corresponding supramolecules. To this end, the processes leading to their formation should be fully characterised and ever-new interactions stabilising the corresponding systems ought to be discovered. The reactions yielding supramolecular complexes in solution are often coupled with other processes, e.g. proton transfer, aggregation, homoassociation and ion pairing, especially in organic media. These reactions have rarely been taken into account in the course of complex characterisation, although ignoring them could lead to incomplete conclusions and erroneous interpretation of the results. In order to avoid this, it is necessary to carry out systematic identification and characterisation of all processes taking place in the solution. This often demands significant efforts, including innovative use of experimental techniques and elaborate data processing. In this lecture, several classes of anion binding hosts (urea, amine and amide derivatives) will be presented with a thorough overview of the methodology used for a complete characterisation of multiple equilibria occurring in the solutions containing the hosts and their anionic guests. With this respect, special emphasis will be on acid-base equilibria of the aforementioned ligands and several common, and biologically important anions (e.g. chloride, dihydrogen phosphate, acetate). Moreover, the aim of the lecture is to demonstrate that the extra work and time invested in such integrated approach is worthwhile, as it can provide invaluable insight in the behaviour of supramolecular systems, possibly leading to original approach of their further design.

Knowledge regarding the acid-base behaviour in non-aqueous media has remained relatively scarce in spite of its importance for many aspects of chemistry. Recently, we reported on a detailed study of acid-base properties of dihydrogen phosphate and acetate in aprotic organic solvents (acetonitrile, dimethyl sulfoxide, and dimethylformamide).[1] It was found that several processes, i.e. protonation, homoassociation, and dimerisation play important roles in defining the basicity of these widely important anions. A comprehensive thermodynamic characterisation of the corresponding processes was carried out which provided valuable information for the advancement of host-guest chemistry focusing on highly basic anions. In this field, urea derivatives have been among the most studied receptors, and numerous studies of their complexation with diverse anionic species have been reported. To gather reliable thermodynamic information about the anion binding processes, it is of great importance to identify and characterise the coupled reactions. In the case of anion receptors bearing urea moieties, one of the most commonly encountered side reactions is deprotonation of the NH group, accompanied by protonation of the anion, that is, receptor to anion proton transfer. This process is especially favorable in aprotic organic solvents of lower polarity owing to the drastic increase in basicity of the commonly used anions (e.g., F−, AcO− or H2PO4−) with respect to aqueous medium. As a continuation of our work, a series of aromatic bis-urea derivatives was prepared and their proton dissociation, as well as anion binding properties in DMSO were investigated revealing remarkably high acidities of the compounds (log K1H ≈ 14).[2] Studied receptors were selective for acetate and dihydrogen phosphate among several anions forming complexes of 1:1 and 1:2 (ligand:anion) stoichiometries. Proton transfer was taken into account in the course of data analysis, which was especially important in the case of AcO−. Knowledge regarding protonation properties proved to be essential for reliable quantitative determination of anion binding affinities.

Many anion receptors have been developed for selective recognition and binding of a specific negatively charged species. Their structure usually contains covalently linked groups with high affinity towards the desired ions [1]. The binding ability of the receptor for an anion in specific solvent once defined by its structure usually cannot be changed using external stimuli. In recent years there have been a few examples of responsive receptors which utilize groups capable of changing the affinity towards an anion in the presence of external stimuli [2]. They are comprised of photochromic moieties which have been till recently almost exclusively studied with larger guests [3]. That is in part because it is easier to prepare receptors in which photoresponsive change in the architecture controls binding of larger species as compared to small anions. Herein we present an anionic receptor with photoresponsive host‐guest properties designed for small anions. Basic motion is achieved through E‐Z isomerization of azocarboxamide. The simplest aromatic derivative containing azocarboxamide as well as photochemical isomerization is shown below.

Acid-base reactions are ubiquitous in chemistry, often playing the key role in biological systems, in the development of new pharmaceuticals or materials, etc. Although (de)protonation reactions in water are among the most studied equilibria, analogous investigations in non-aqueous media are rather scarce. This is partly due to experimental difficulties regarding the potentiometric measurement of pH, but also because the complexity of the corresponding equilibrium systems increases in such solutions. Namely, the protonation constants are much higher in organic solvents in comparison to water, and many acids are prone to homoconjugation (interaction with their conjugated bases) and dimerization. NMR spectroscopy has been extensively used as a tool for quantitative thermodynamic characterization of diverse reactions. However, its utilization for the study of (de)protonation equilibria commonly includes measurement of pH (pD) dependence of 1H NMR spectra, and it is in most cases limited to aqueous systems. In this work, the characterization of acid-base behavior of rather important and extensively studied organic (acetic acid) and inorganic (phosphoric acid) acids in dimethyl sulfoxide and acetonitrile was carried out by means of several experimental methods (UV and NMR spectroscopies, ITC, and conductometry). In addition, the deprotonation of aromatic urea derivatives acting as anion receptors was studied in DMSO using competitive NMR titrations. The focus of the talk will be on the results obtained by NMR spectroscopy which will be compared to those gathered by other techniques. The concepts, advantages, and limitations of the NMR-spectroscopic investigations of proton transfer, homoconjugation, and dimerization equilibria of the studied systems will be discussed in detail.

Traditional synthetic procedures in organic chemistry are generally very successful but global problems of pollution and growing energy demand have compelled the chemical industry to search for new, more efficient and “greener” synthetic methods. Mechanochemical reactions are induced by the direct absorption of mechanical energy and they are mainly promoted by hand grinding or mechanochemical milling. Mechanochemical organic reactions are carried out without the need for solvents or conventional catalysts, and most often feature higher product yield in shorter reaction time. [1] Contrary to the wide knowledge about organic reactions in solution, mechanisms of mechanochemical reactions are still mostly unknown. Only the recently developed in situ monitoring techniques[3] started to unveil the mechanisms of organic mechanochemical reactions, leading to wider application of this methodology in modern material and pharmaceutical industry. [4] Here we present mechanochemical reactions between acyl azide and primary amine as a model nucleophilic substitution reaction on the carbonyl group. We have examined the influence of different additives on reaction time and yields using in situ Raman spectroscopy monitoring and the products were confirmed by 1H and 13C NMR spectroscopy. As amide derivatives are widely investigated as receptors for anions, [5] we studied affinity of the prepared compounds towards biologically important acetate and dihydrogen phosphate anions in solution using 1H NMR spectroscopy.

In the field of anion binding peak selectivity and high binding affinity are rarely reported, especially in competitive media. In order to accomplish these goals it is necessary to expand the understanding of the anion binding reaction by indentifying all interactions that contribute to the stabilization of the complexes and gathering information regarding the structure of the compexes. In this work, the complexation of several anions by receptors based on dehydroacetic acid bearing urea (1), thiourea (2a and 2b), and amide (3a–c) moieties (scheme 1) was investigated in acetonitrile (MeCN) and dimethyl sulfoxide (DMSO). 1H NMR was proven to be a very efective technique for the study of anion complexation of the investigated compounds, due to pronounced changes in chemical shift of the (thio)urea and amide NH- proton signals upon complexation. Further on, the subtle changes regarding the signal of the amine proton during the titrations with H2PO4– strongly indicated that the carbonyl oxygen acted as a proton acceptor allowing the formation of additional hydrogen bond which stabilizes the complex. Recent microcalorimetric measurements regarding H2PO4– dimerisation were expanded using 31P NMR spectroscopy.1 Gathered data was used in order to obtain reliable stability constants of dihydrogenphosphate complexes. Acetate and dihydrogen phosphate complexes with thiourea derivatives were found to be the most stable ones. This could be attributed to the shape and size complementarity of these anions and the thiourea moiety, as well as to the highest proton donating properties of thioureas. It was also found that the arrangement of the amide groups in the structure of receptors 3a and 3b plays an important role in the stabilisation of the anion complexes. References 1. N. Bregović, N. Cindro, L. Frkanec, K. Užarević, V. Tomišić, Chem. Eur. J. 20 (2014) 15863–15871. Acknowledgements: The work was funded by Croatian science foundation (SupraCAR: IP-2014-09-7309) and European Regional Development Fund and Ministry of Science Education and Sports (RC.2.2.08-0024).

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.

The design of molecules which are capable to recognize and bind target anions is a vibrant area of modern research. Systematic research of anion coordination during the last few decades introduced a vast number of receptors for negatively charged species, mainly based on the binding functionalities equipped with hydrogen bond donors. The urea group is often used in such receptors due to its stability in acidic environment and the ability to form strong hydrogen bonds with certain anions. However, it has become evident that compounds containing a single urea moiety lack selectivity and rather rarely allow specific anion recognition. On the other hand, by linking two urea moieties via benzene, rigidity of the binding site is induced and significant increase in selectivity towards anions and stability of corresponding complexes can be achieved. In this work we have synthesized new phenyl diurea receptors (1a-d) and investigated both steric and resonance effects of the substituents on their complexation properties. In order to quantify binding affinities of anion receptors 1a-d towards several anions and to get a detailed insight into the processes occurring in the solutions, NMR and UV-VIS titrations were used.

Ditopic receptors are capable of binding both cations and anions at the same time on different sites in the molecule. Herein we present a new ditopic receptor L (Figure 1) with urea moiety which can bind vide variety of anions from ball-shaped halogen anions to acetate or phosphate. On the other hand, catechol units can strongly bind cations such as iron, copper, or aluminium. Tetradentade ligand L is water soluble, so most of the measurements were performed using this solvent. Compound L was synthesized by condensation of two catechol fragments and finally benzyl protections were cleaved from phenolic groups. The UV-Vis spectrophotometric measurements were carried out at different pH values with variations of iron(III) to ligand molar ratios. At higher pH values significant time-dependent changes in UV-Vis spectrum of L were observed indicating hydrolysis of the compound at these conditions. The NMR measurements are planned to access structural changes during this process. The stoichiometries and stability constants Fe(III)–L complexes of different stoichiometries present in aqueous solutions will be determined as well. We are also planning to study the formation of ternary Fe(III)-L-anion complexes.

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.

Calixarenes are macrocyclic oligomers consisted of four or more phenolic residues linked by methylene bridges in the ortho position. By their relatively easy functionalization, a vast number of efficient receptors for various ionic and neutral species have been prepared [1]. Calixarenes bearing fluorescent moieties could be considered as potential sensitive fluorimetric ion sensors due to the high sensitivity of fluorimetry [2, 3]. In the scope of this work novel fluorescent antracene- and diphenylantracene-based calix[4]arene derivatives 1 and 2 were designed and synthesized. Their complexation with alkali- metal cations was investigated as well. Antracene and diphenylantracene moieties were introduced at a lower calixarene rim and served as fluorescent groups positioned close to the cation-binding site. Due to the low solubilities of the prepared calix[4]arene derivatives in solvents of moderate permittivities, their complexation was studied in methanol–dichloromethane and acetonitrile– dichloromethane solvent mixtures (φ = 0.5). Stability constants of the corresponding complexes were determined (in some cases only assessed) by means of fluorimetry, UV spectrophotometry, and isothermal microcalorimetry. The latter technique also provided information on reaction enthalpies and entropies. The obtained thermodynamic quantities were discussed regarding the structural characteristics of the ligands and solvation properties of the solvents used.

The anion complexes are constantly in the spotlight of supramolecular chemistry research, being utilised in most different ways: controlling molecular motion, catalysing chemical reactions, allowing qualitative and quantitative detection of specific species, etc.3 It has been recognised that systematic thermodynamic studies of complex formation reactions are of great importance in the process of developing novel anion receptors with enhanced properties, thus expanding the possibilities of their application. This includes the identification and characterisation of diverse reactions coupled with the anion binding processes, such as proton transfer, ion pairing or aggregation, which have often been disclosed, but were rarely thoroughly studied. In this work we present the synthesis of a series of aromatic diureas (Scheme 1) and a detailed thermodynamic study of their deprotonation and binding of anions (dihydrogen phosphate and acetate) in DMSO by UV-Vis and NMR titrations. In contrast to the common assumption that the dissociation of urea group is highly unfavourable (pKa (urea) = 26.9), it was found that aromatic urea derivatives can be readily deprotonated in the presence of many bases. Namely, it was determined that the pKa values of the herein studied aromatic compounds bearing urea moieties were in the range of 13.1–15.27. Significant stabilisation of the anionic forms was attributed to the electron delocalisation through the aromatic substituents. It was found that fully protonated forms of the receptors form mono- and di-anionic complexes with H2PO4– and AcO– in DMSO. Proton-transfer processes were taken into account in the analysis of the gathered titration data rendering reliable complex stability constants. The results were discussed with respect to the substituents on the pendant arms of the receptors (R = H, OCH3, CH3, NO2) and relative positions of the urea groups (ortho- and meta- derivatives).

Formation of adducts between oxovanadium(IV) diketonates and Lewis bases is well documented [1]. The Lewis bases coordinate on sixth coordination site of the vanadium atom either in trans- or cis- position relative to the oxygen of vanadyl . The position in which the Lewis base is coordinated depends on the basicity and steric effect of the Lewis base [2]. In this study we have investigated formation of adducts between bis(pentane-2, 4-dionato)oxovanadium(IV) (VO(acac)2) and a series of pyridine derivatives in the solid state and solution. The stability constants of the adducts were determined by means of spectrophotometric titrations. The corresponding stability constants were correlated with the Hammett substituent coefficients and pKa values of the pyridine derivatives. Crystal structures of eight adducts were determined and it was found that in the solid state the pyridine, 3-methylpyridine and 4-methylpyridine formed trans- adducts with VO(acac)2, whereas in the case of 4-benzoylpyridine adduct the pyridine derivative is in cis-position, 2-amino-3-methylpyridine and 2-amino-5-methylpyridine also formed trans- adducts in addition of creating N-H...O hydrogen bond via pyridine amino group and chelate ring of complex. In case of 2, 4, 6-trimethylpiridine and 2-amino-6-methylpyridine, molecule of water was coordinated on VO(acac)2 and formed hydrogen bonds with 2 molecules of neighbouring pyridine molecules. It was found that the stereochemistry of the coordinated species (cis/trans) present in the solid state depends on the basicity of the Lewis base and it is reflected in the characteristic UV-spectra of the adducts.

Chemistry of anion recognition and complexation has developed into an important field of supramolecular chemistry, with ever-new application potentials of the corresponding systems discovered [1]. Despite a significant progress in the field, the search for receptors exhibiting peak selectivity and high binding affinity continues [2]. In order to facilitate the design of efficient anion ligands, it is of great importance to identify the interactions that lead to the complex formation and assess their individual contribution to the overall stability [3]. One of the feasible approaches towards this goal is to study series of relatively simple model compounds, gaining detailed insight into the interplay of their structure and reactivity [4]. Thus gathered knowledge can be employed in the systematic development of the novel anion receptors as it can point out the suitable type and number of the binding moieties as well as the appropriate linkers to achieve the desired properties. In this work we present the synthesis and the anion complexation study of a series of amide derivatives differing in number and arrangement of the binding sites (amide N–H groups). The stability of their complexes with acetate, dihydrogen phosphate, and chloride was studied in dimethyl sulfoxide using 1H NMR spectroscopy and conductometry. The stoichiometry of all complexes was found to be 1:1 and their stability was discussed with respect to the receptor structural properties as well as specific features of the anions.

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.

Although chemistry of anion recognition and complexation has developed into an important field of supramolecular chemistry, peak selectivity and high binding affinity are rarely reported, especially in competitive media. In order to accomplish these goals it is necessary to expand the understanding of the anion binding reaction by identifying all interactions that contribute to the stabilization of the complexes and gathering information regarding the structure of the complexes. In this work, the complexation of anions by receptors based on dehydroacetic acid bearing urea (1), thiourea (2a and 2b), and amide (3a–c) moieties (scheme 1) was investigated in acetonitrile (MeCN) and dimethyl sulfoxide (DMSO). Dihydrogen phosphate complexes of 1:1 and 2:1 (anion:receptor) stoichiometry were formed in MeCN, whereas in all other cases only the 1:1 complexes were detected. 1H NMR was proven to be a very effective technique for the study of anion complexation of the synthesized compounds due to pronounced changes in chemical shift of the (thio)urea and amide NH proton signals. Further on, the subtle changes regarding the signal of the amine proton during the titrations with H2PO4– strongly indicated that the carbonyl oxygen acts as a proton acceptor allowing the formation of additional hydrogen bond. Recent microcalorimetric investigations of H2PO4– dimerisation were expanded using 31P NMR spectroscopy. Gathered data was used in the course of the anion binding investigations. Acetate and dihydrogen phosphate complexes were found to be the most stable ones. which can be attributed to the shape and size complementarity of these anions and the urea moiety.1 Among the series of investigated receptors, the thiourea derivatives showed the highest anion-binding affinity which is most likely a consequence of the highest proton donating affinity / acidity of the thiourea group. It was found that the arrangement of the amide groups in the structure of receptors 3a and 3b plays an important role in the stabilisation of the anion complexes.

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.

The design of molecules which are capable to recognize and bind target anions is a vibrant area of modern research. Systematic studies of anion coordination during the last few decades introduced a vast number of receptors for negatively charged species, mainly based on the binding functionalities containing hydrogen bond donors. In this work we have synthesized phenyl diurea receptors (1a-d) and investigated both steric and resonance effects of the substituents on their complexation properties. Further on, a ditopic receptor 2 comprising the phenantroline moiety, which is capable of cation coordination, coupled with the diurea anion binding site was designed but its synthesis is still a work in progress.

Omeprazole is a member of the proton pump inhibitor family of drugs, extensively used in treatment of peptic ulcer, gastroesophageal reflux disease and Zollinger–Ellison syndrome. The fact that it is one of the drugs indexed in the World Health Organization's List of Essential Medicines points out the importance of enhancing the synthetic procedure used in the production of this pharmaceutic. In this work we present the results of thermodynamic and kinetic studies which served as a guide in the optimization of the synthetic procedure. One of the steps in the synthesis of Omeprazole is the condensation of OMP-Cl and MTX in a mixture of methanol and water, which involves reaction of deprotonated forms of these compounds. This indicates that the protonation equilibria have a significant impact on the condensation reaction. The medium in which the reaction takes place is one of the key factors affecting the protonation properties of the reactants. Therefore, the equilibrium protonation constants of the reactants (OMP-Cl and MTX) were determined at 25 °C by means of spectrophotometric-potentiometric titrations in the mixed solvent commonly used in the synthesis of Omeprazole and in pure methanol. A significant decrease in the protonation constants with increase of water volume fraction was observed suggesting that the use of solvent with higher water content could enhance the yield of the reaction product and possibly reduce the time needed for the synthesis. In order to gain a detailed insight into the kinetics of the first step in the Omeprazole synthesis, kinetic measurements were undertaken. Kinetics of the reaction of OMP-Cl with MTX was studied in the solution of NaOH in methanol/water mixture by means of stopped-flow spectrophotometry at 25 °C. At the experimental conditions applied, MTX is almost completely present as thiolate anion whereas OMP-Cl is in the neutral form. The reaction is of second order, first with respect to both reactants. There was no significant effect of solution pH on the reaction kinetics in the range of NaOH concentration studied (0.05–0.2 mol dm–3). Further on, the reaction enthalpies of OMP-Cl and MTX protonation were determined at 25 °C by calorimetric measurements. These values enabled estimation of the temperature effect on the protonation properties of the reactants and evaluation of the heat effects of these processes in the course of synthesis.

Molecular recognition, a process which emerges from weak non-covalent interactions, is of paramount importance in the chemistry of life and also for the design of functional supramolecular systems. Selective molecular recognition is traditionally performed in solution, where the host and guest have mobility to come close and to interact. However, recent advances in the field of mechanochemistry have shown that various concepts of supramolecular chemistry can be used also for solvent-free reactions. Herein we present flexible polyamine host(L) which recognizes and selectively binds maleic acid during the milling with solid mixtures where the fumaric acid or other investigated competitors were present in large excess. During the recognition, L adapts its conformation and forms specific complex with each of the six investigated dicarboxylic acids, regardless of whether the reaction was conducted in solution or in the solid state. Recognition via mechanochemistry involves intermediate phases, resulting with the same selectivity as achieved by crystallisation from solution. Milling techniques circumvent limitations of solution-based separation, as evidenced by facile binding of poorly soluble guests, while at the same time providing enough energy and mobility to the host and guest molecules required for selective recognition. Taken together, these results indicate a great potential of molecular recognition in the solid state for separation purposes.

The field of anion binding and recognition has been evolving rapidly in the past decade, with a rising number of highly diverse anion receptors reported and their binding properties studied in detail.1, 2 One of the most abundant type of the anion binders is the group of polyamine receptors. In order to develop polyamine receptors with desired properties, it is important to understand the factors that define the stability of the anion complexes in the solution. This is achieved by investigating the influence of anion geometry and basicity, number and arrangement of the binding moieties in the ligand structure, as well as solvent properties on the stability constants of the complexes formed. In the studies of binding properties of triamine derivative of dehydroacetic acid reported recently, it was found that only the protonated form of the ligand is active as an anion receptor.3, 4 The protonation properties and stability constants of a number of anion complexes with this receptor were determined. In this work we present an extensive study of anion binding and protonation properties of its tetramine analogue L (scheme 1) in methanol. Several experimental techniques (spectrophotometry, potentiometry, NMR-spectroscopy, microcalorimetry) were used and it was found that the additional NH binding group enabled binding of anions with different geometries (Cl−, NO3−, ClO4−) in the neutral, deprotonated form. As expected, the protonation of the receptor enhanced its binding properties. Further on, the binding of the anions was studied in acetonitrile and the influence of the solvent properties on the binding affinity of L was discussed.

A great number of highly selective and tunable anion receptors have been synthesized in the past decade. However, some challenges like employing small, flexible molecules for a highly selective binding in competitive media or creating ligands that are able to selectively bind enantiomeres or geometric isomeres still remained unsolved. In the recent studies the ability of N’-3-azapentane-1, 5-bis[3-(1-aminoethylidene)-6-methyl-3H-pyran-2, 4-dione] (L) to act as an anion binding ligand was thoroughly investigated.1, 2 These studies covered complexation of L with a wide range of inorganic anions (Cl−, NO3−, SO4−, ClO4−, SbF6−, PF6−) both in solid state and solution. Two highly diverse crystal structures and anion coordination types were observed, depending on the charge density of the anion present in the structure. Unlike in solid state, the distinctions among the complexes with anions of highly diverse properties appeared to be less expressed in methanol solutions. In the continuation of this work it has been found that beside inorganic anions, some organic species could be coordinated by L with highly accentuated resolution between geometric isomers. In order to explore the selectivity of L towards maleic (cis) in comparison to fumaric (trans) acid in more details, numerous methods were employed to study the binding in solution. For that reason, thorough NMR and UV-Vis spectrometric measurements were carried out in order to investigate the binding modes and to determine the stability constants of the complexes formed. The results obtained, namely the stability and stoichiometries of the complexes will be reasoned, and the experimental approach discussed in detail.