Efficient catalyst-free direct amidation of non-activated carboxylic acids from carbodiimides.

A novel and efficient catalyst- and activating agent-free amidation method via direct amidation of carboxylic acids where carbodiimides act as a reagent instead of an activating agent is reported. The reaction is conducted under non-traditional coupling conditions where a higher temperature is employed. Besides not using stoichiometric ratios of activating agent or catalyst, this approach is made even more attractive by occurring in the presence of the environmentally friendly and recyclable non-toxic solvent of DMSO. A wide variety of benzylic, aliphatic, α,ß-unsaturated and aromatic carboxylic acids provide related amides in up to 95% yield. The excellent yield from a gram-scale reaction shows that this application is particularly convenient for larger-scale synthesis applications.

H-Bond Mediated Phase-Transfer Catalysis: Enantioselective Generating of Quaternary Stereogenic Centers in ß-Keto Esters.

In this work, we would like to present the development of a highly optimized method for generating the quaternary stereogenic centers in ß-keto esters. This enantioselective phase-transfer alkylation catalyzed by hybrid Cinchona catalysts allows for the efficient generation of the optically active products with excellent enantioselectivity, using only 1 mol% of the catalyst. The vast majority of phase-transfer catalysts in asymmetric synthesis work by creating ionic pairs with the nucleophile-attacking anionic substrate. Therefore, it is a sensible approach to search for new methodologies capable of introducing functional groups into the precursor's structure, maintaining high yields and enantiomeric purity.

Anion Recognition by a Pincer-Type Host Constructed from Two Polyamide Macrocyclic Frameworks Jointed by a Photo-Addressable Azobenzene Switch.

A sterically crowded light-responsive host 1 was synthetized with a 93% yield by applying a post-functionalization protocol utilizing the double amidation of 4,4'-azodibenzoyl dichloride with a readily available 26-membered macrocyclic amine. X-ray structures of two hydrates of trans-1 demonstrate a very different alignment of the azobenzene linkage, which is involved in T-shape or parallel-displaced π⋯π stacking interactions with the pyridine-2,6-dicarboxamide moieties from the macrocyclic backbone. Despite the rigidity of the macrocyclic framework, which generates a large steric hindrance around the azobenzene chromophore, the host 1 retains the ability to undergo a reversible cis⟷trans isomerization upon irradiation with UVA (368 nm) and blue (410 nm) light. Moreover, thermal cis→trans back-isomerization (ΔG0 = 106.5 kJ∙mol-1, t½ = 141 h) is markedly slowed down as compared to the non-macrocyclic analog. 1H NMR titration experiments in DMSO-d6/0.5% water solution reveal that trans-1 exhibits a strong preference for dihydrogenphosphate (H2PO4-) over other anions (Cl-, MeCO2-, and PhCO2-), whereas the photogenerated metastable cis-1 shows lower affinity for the H2PO4- anion.

Recognition of Chiral Carboxylates by Synthetic Receptors.

Recognition of anionic species plays a fundamental role in many essential chemical, biological, and environmental processes. Numerous monographs and review papers on molecular recognition of anions by synthetic receptors reflect the continuing and growing interest in this area of supramolecular chemistry. However, despite the enormous progress made over the last 20 years in the design of these molecules, the design of receptors for chiral anions is much less developed. Chiral recognition is one of the most subtle types of selectivity, and it requires very precise spatial organization of the receptor framework. At the same time, this phenomenon commonly occurs in many processes present in nature, often being their fundamental step. For these reasons, research directed toward understanding the chiral anion recognition phenomenon may lead to the identification of structural patterns that enable increasingly efficient receptor design. In this review, we present the recent progress made in the area of synthetic receptors for biologically relevant chiral carboxylates.

Ion mobility mass spectrometry - an efficient tool for the analysis of conformational switch of macrocyclic receptors upon anion binding.

Interactions between anions and synthetic macrocyclic receptors belong to the extensively explored area of research due to the particularly important functions of anions in biological and environmental sciences. Structures of anion-macrocycle complexes are closely related to their function, highlighting the importance of structural analysis of the complexes. Here, we discuss the application of ion mobility mass spectrometry (IM-MS) and theoretical calculations to the structural analysis of tetralactam macrocycles (M) with varying flexibility and structural properties, and their complexes with anions [M + X]-. Collision cross section (CCS) values obtained from both direct drift tube (DT) and indirect using traveling-wave (TW) IM-MS measurements supplemented by theoretical calculations were successfully used to describe the structural properties of various macrocycle-anion complexes, proving the suitability of the IM-MS approach for sensitive, selective, and fast detection of anion complexes and characterization of their structures and conformations.

Stabilization of Near Identical Hydrogen Bonded Octameric Water Clusters in Crystal Structures of Three Distinct Non-Charged Polyamide Macrocyclic Host Molecules.

In this paper, we present a comparative analysis of the solid state structures of three well-resolved hydrates of macrocyclic host molecules 1a, 1b, and 2 containing an intrannular amide-aryl substituent (lariat arm) connected to a fixed 26-membered ring in a normal (-NHCOAr, hosts 1a and 1b) or reverse manner (-CONHAr, host 2). Despite different chemical structures, these hosts crystallize as isostructural tetrahydrates in the same P-1 space group. Moreover, their crystals exhibit identical hydrogen bond motifs resulting in a stabilization of an almost identical unusual octameric water cluster built from the cyclic tetramer core and four water molecules, attached sequentially in an "up-and-down" manner. Further analysis reveals that, among the series, the structure of host 2 provides the most suitable environment for the accommodation of this type of water cluster.

Solution and Solid State Studies of Urea Derivatives of DITIPIRAM Acting as Powerful Anion Receptors.

Herein, we present the synthesis and anion binding studies of a family of homologous molecular receptors 4-7 based on a DITIPIRAM (8-propyldithieno-[3,2-b:2',3'-e]-pyridine-3,5-di-amine) platform decorated with various urea para-phenyl substituents (NO2, F, CF3, and Me). Solution, X-ray, and DFT studies reveal that the presented host-guest system offers a convergent array of four urea NH hydrogen bond donors to anions allowing the formation of remarkably stable complexes with carboxylates (acetate, benzoate) and chloride anions in solution, even in competitive solvent mixtures such as DMSO-d6/H2O 99.5/0.5 (v/v) and DMSO-d3/MeOH-d3 9:1 (v/v). The most effective derivatives among the series turned out to be receptors 5 and 6 containing electron-withdrawing F- and -CF3para-substituents, respectively.

Stereoselective α-Chlorination of ß-Keto Esters in the Presence of Hybrid Amide-Based Cinchona Alkaloids as Catalysts.

We report an enantioselective phase transfer α-chlorination of ß-keto esters catalyzed by hybrid amide-based Cinchona derivatives. The chlorination process proceeds with proper quantitative yields (up to <99%) and high asymmetric induction (up to 97% ee). We show that the use of only 0.5 mol % hybrid catalyst based on a Cinchona core allows the chlorination reaction to be conducted in a highly enantioselective manner with various indanone and tetralone carboxylate esters.

Tuning Anion-Binding Properties of 22-Membered Unclosed Cryptands by Structural Modification of the Lariat Arm.

A series of 22-membered unclosed cryptands end-capped with intra-annular methyl (1), phenyl (2), p-tert-butylphenyl (3), and p-nitrophenyl (4) amide substituents (lariat arm) were synthesized to elucidate the effect of steric and electronic factors on their anion recognition behavior. The 1H NMR titrations in DMSO-d 6 with 0.5% water reveal enhanced selectivity for H2PO4 - vs Cl- and PhCO2 -. The para-attachment of the electron-withdrawing nitro group (-NO2 vs -H and -t-Bu) was found to increase anion-binding affinity, whereas the steric bulkiness of lariat arm (methyl vs aryl) has a marginal effect. DFT calculations reveal that binding of H2PO4 - is associated with minimal conformational change in the lariat arm moiety and involve four hydrogen bond acceptor and one donor sites of host.

One-Pot Parallel Synthesis of Unclosed Cryptands-Searching for Selective Anion Receptors via Static Combinatorial Chemistry Techniques.

We present the synthesis of 17 macrocyclic compounds having the structure of so-called unclosed cryptands, acting as anion receptors. These compounds possess amide functions playing the role of hydrogen-bond-donating systems. We have synthesized the presented compounds both by standard methods (using batch conditions) and by static combinatorial chemistry methods, using tetrabutylammonium dihydrogen phosphate as a template, promoting the lariat arm postfunctionalization reaction.

Highly Enantioselective Epoxidation of α,ß-Unsaturated Ketones Using Amide-Based Cinchona Alkaloids as Hybrid Phase-Transfer Catalysts.

A series of 20 one chiral epoxides were obtained with excellent yields (up to 99%) and enantioselectivities (up to >99% ee) using hybrid amide-based Cinchona alkaloids. Our method is characterized by low catalyst loading (0.5 mol %) and short reaction times. Moreover, the epoxidation process can be carried out in 10 cycles, without further catalyst addition to the reaction mixture. This methodology significantly enhance the scale of the process using very low catalyst loading.

The Impact of Solvent and the Receptor Structure on Chiral Recognition Using Model Acyclic Bisamides Decorated with Glucosamine Pendant Arms.

We investigated the influence of various factors (including solvent mixtures) on chiral recognition of chiral carboxylates, using the titration method under 1H NMR control. We found that strong binding carboxylates (geometrical matching) is not enough for the satisfactory differentiation of enantiomers. Moreover, solvent mixture studies indicate a significant influence of environment on the formation of diastereomeric complexes and variations among them. Our findings offer insights into the complementarity of chiral recognition processes.

Selective Carboxylate Recognition Using Urea-Functionalized Unclosed Cryptands: Mild Synthesis and Complexation Studies.

Herein we present the synthesis and evaluation of anion-binding properties of 12 new receptors from the unclosed cryptand family. Their core is built on the stable 26-membered tetraamidic macrocyclic scaffold, whereas various alkyl and aryl urea substituents were introduced after a yield-limiting macrocyclization step (65-98%). The receptors strongly bind anions, in particular carboxylates, even in a highly competitive solvent mixture (DMSO-d6 + H2O 95:5 v/v).

Static Combinatorial Chemistry: A High-Pressure Approach to the Synthesis of Macrocyclic Benzoamide Libraries.

We investigated the yield and distribution of macrocyclic products formed in combinatorial libraries (CLs) obtained via double-amidation reactions of methyl diesters with α,ω-diamines. The application of the static combinatorial chemistry (SCC) approach allowed us to generate a large number of macrocyclic diamides and tetraamides in single experiments. We show that high-pressure conditions accelerate the macrocyclization process but also have a great impact on the distribution of macrocyclic products in the presented libraries, promoting the formation of macrocyclic compounds and eliminating the linear ones. The distribution of macrocyclic products was also found to be strongly dependent on the structural features of the substrates employed. Furthermore, in three- and four-substrate CLs we observed the formation of a new type of hybrid tetraamides consisting of three different components.

A General Method for High-Pressure-Promoted Postfunctionalization of Unclosed Cryptands: Potential Phase-Transfer Catalysts.

We report a high-pressure approach to facile late-stage functionalization of unclosed cryptands (UCs) (11 examples, yield up to 99%). Direct comparison of classic and high-pressure conditions of the quaternization reaction in a sterically crowded intraannular position is investigated, and differences in the reactivity of tertiary amine substrates are discussed. Finally, we demonstrated the application of UCs as catalysts for synthetically important alkylation reactions under phase-transfer conditions.

Amide-Based Cinchona Alkaloids as Phase-Transfer Catalysts: Synthesis and Potential Application.

Herein we present a library of simple amide derivatives of Cinchona alkaloids in the form of quaternary ammonium salts. The obtained derivatives can be generated very easily and efficiently from inexpensive and commercially available substrates. We tested this class of alkaloids in the alkylation of glycine derivative, carried out under phase-transfer catalyst conditions. The presented hybrid catalysts offer both high reaction yields (up to 97%) and high enantioselectivities of the obtained product (up to 94% ee).

Chiral Recognition of Carboxylate Anions by (R)-BINOL-Based Macrocyclic Receptors.

Three (R)-BINOL-based macrocyclic receptors obtained via double-amidation reaction were used for chiral recognition of four anions derived from α-hydroxy and α-amino acids. The structural factors of hosts and guests that affect chiral recognition processes were also investigated, indicating that the proper geometry of both receptor and guest molecules plays a crucial role in effective enantio-discrimination.

Late-Stage Functionalization of ( R)-BINOL-Based Diazacoronands and Their Chiral Recognition of α-Phenylethylamine Hydrochlorides.

Five BINOL-based hosts with a variable macroring size were synthesized in a two-step postfunctionalization protocol by double N-benzylation followed by BMS-mediated reduction of tertiary amide groups (53-93%). UV-vis titration in MeCN reveals that all hosts exhibit a preference for the ( R)-enantiomer over the ( S)-enantiomer of PEA-HCl. The enantioselectivity depends on the number of hydrogen bond (HB) acceptors and the size and flexibility of the macroring. The highest enantiodiscrimination was observed for the 20-membered host 10, containing six HB acceptors ( KR/ KS = 2.13).

An Indirect Synthetic Approach toward Conformationally Constrained 20-Membered Unclosed Cryptands via Late-Stage Installation of Intraannular Substituents.

A new protocol for PTC-mediated O-alkylation of the intraannular position of 20-membered unclosed cryptands (UCs) is reported. In contrast to the classical, "direct" strategy, which requires functionalization of the lariat arm at the beginning of synthesis, this "indirect" approach enables the late-stage introduction of various benzylic substituents after an unfavorable macrocyclization step (11 examples, yields up to 98%). Notably, this method permits preparation of, previously inaccessible, crowded UCs bearing 1-acetylpyrene substituent and dimer joined by p-xylene linker.

The Influence of Binding Site Geometry on Anion-Binding Selectivity: A Case Study of Macrocyclic Receptors Built on the Azulene Skeleton.

An understanding of host-guest noncovalent interactions lies at the very heart of supramolecular chemistry. Often a minute change to the structure of a host molecule's binding site can have a dramatic impact on a prospective host-guest binding event, changing the relative selectivity for potential guest molecules. With the overall goal of aiding the rational design of selective and effective receptors for anions, we have studied the influence of small perturbations in binding site geometry for a series of five closely related 20-membered macrocyclic tetra-amide receptors, constructed from two building blocks from a pool of azulene-5,7-bisamide, azulene-1,3-bisamide, and dipicolinic bisamide units. The solid-state structures revealed that the conformational preferences of the free receptors are driven by the inherent preferences of the building blocks, yet in some cases the macrocyclic topology is able to over-ride these to promote pre-organized conformations favorable for anion binding. The solid-state structures of the chloride complexes of these receptors revealed that although all the receptors can adapt to binding to the challenging small Cl- guest with all the NH groups, only receptors containing azulene-5,7-bisamide units form short and linear, and therefore strong, hydrogen-bonding interactions. These conclusions are further supported by studies in solution. Although all the receptors showed high affinities toward a series of anions (H2 PO4- , PhCO2- , Cl- , and Br- ), even in a highly competitive polar medium (DMSO/25 % MeOH), only receptors containing azulene-5,7-bisamide units exhibited non-inherent selectivity for Cl- over PhCO2- , breaking the Hofmeister trend of selectivity. The data presented herein highlight the privileged properties of the azulene-5,7-bisamide building block for binding to chloride anions and provide guidelines for the construction of selective and efficient anion receptors with prospective practical applications.