Triazole Proton Research Articles

Water-Soluble Triazolium Covalent Cages for ATP Sensing.

Water-soluble organic cages are attractive targets for their molecular recognition and sensing features of biologically relevant molecules. Here, we have successfully designed and synthesized a pair of water-soluble cationic cages employing click reaction as the fundamental step followed by the N-methylation of the triazole rings. The rigid and shape-persistent 3D hydrophobic cavity, positively charged surface, H-bonding triazolium rings, and excellent water solubility empower both cages to exhibit a superior affinity and selectivity for binding with adenosine-5'-triphosphate (ATP) compared to cyclophanes and other macrocyclic receptors. Both cage molecules (PCC⋅Cl and BCC⋅Cl) can bind a highly emissive dye HPTS (8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt) to form non-fluorescent complexes. The addition of ATP resulted in the stronger cage⊂ATP complexes with the retention of HPTS emission upon its displacement. The resultant indicator-displacement assay system can efficiently sense and quantify ATP in nanomolar detection limits in buffer solutions and human serum matrix. Spectroscopic and theoretical studies revealed the synergistic effect of π⋅⋅⋅π stacking interaction between the aromatic moiety of the cationic cages and the adenine moiety of ATP, as well as the electrostatic and hydrogen bonding interaction between the phosphate anion of ATP and triazole protons of cages, played the pivotal roles in the sensing process.

Synthesis of Dense 1,2,3-Triazole Oligomers Consisting Preferentially of 1,5-Disubstituted Units via Ruthenium(II)-Catalyzed Azide-Alkyne Cycloaddition.

Ruthenium(II)-catalyzed azide-alkyne cycloaddition (RuAAC) polymerization of t-butyl 4-azido-5-hexynoate (tBuAH), i.e., a heterobifunctional monomer carrying azide and alkyne moieties, was investigated in this study. RuAAC of the monofunctional precursors of tBuAH yielded a dimer possessing a 1,5-disubstituted 1,2,3-triazole moiety. 1H NMR data showed that the dimer was a mixture of diastereomers. Polymerization of tBuAH using ruthenium(II) (Ru(II)) catalysts produced oligomers of Mw ≈ (2.7-3.6) × 103 consisting of 1,5-disubstituted 1,2,3-triazole units (1,5-units) as well as 1,4-disubstituted 1,2,3-triazole units (1,4-units). The fractions of 1,5-unit (f1,5) were roughly estimated to be ca. 0.8 by comparison of signals of the methine and triazole protons in 1H NMR spectra, indicating that RuAAC proceeded preferentially and thermal Huisgen cycloaddition (HC) somehow took place during the polymerization. The oligomer samples obtained were also characterized by solubility test, size exclusion chromatography (SEC), ultraviolet-visible (UV-Vis) absorption spectroscopy, and thermogravimetric analysis (TGA). The UV-Vis and TGA data indicated that the oligomer samples contained a substantial amount of Ru(II) catalysts. To the best of our knowledge, this is the first report on dense 1,2,3-triazole oligomers consisting of 1,5-units linked via a carbon atom.

A “nucleophilic” iodine in a halogen-bonded iodonium complex manifests an unprecedented I+···Ag+ interaction

Summary When an electron is removed from a halogen atom, it forms a halenium ion X+ (X = I, Br, Cl). In halogen bonding (XB), X+ is considered as a strong XB donor, and when interacting with two XB acceptors (e.g., pyridine), it forms a halonium XB complex with a [N–I–N] three-center-four-electron bond with the two XB acceptors. An unprecedented I+···Ag+ interaction occurs between a [L1–I–L1]+ halogen-bonded complex and a [L2–Ag–L2]+ complex in which the iodonium ion acts like a nucleophile and donates electrons to the silver(I) cation. The X-ray diffraction analysis reveals a short contact [3.4608(3) A] between the I+ and Ag+ cations, and ITC measurements give a ΔG of −6.321 kcal/mol and Ka∼37,000 M−1 for the 1:1 complex. The DFT computational study on the nature of the I+···Ag+ interaction indicates that the I+ is nucleophilic in character, manifesting an unusual and strongly attractive interaction between the I+ and Ag+ cations.

A Track-Based Molecular Synthesizer that Builds a Single-Sequence Oligomer through Iterative Carbon-Carbon Bond Formation

Summary We report an artificial molecular machine that moves along a track, iteratively joining building blocks to form an oligomer of single sequence with a continuous backbone of carbon-carbon bonds. The rotaxane features a macrocycle bearing an aldehyde-terminated chain and an axle containing different phosphonium ylides separated by rigid spacers. Each ylide is large enough to block the passage of the macrocycle, trapping the ring between the stopper at the terminus of original threading and the next ylide along the track. Once a building block is reachable, it is removed from the track through a Wittig reaction that adds it to the terminus of the growing chain. Operation on a four-barrier tetra(phosphonium salt) track produces a tetra(diphenylpropane) of single sequence linked through alkene bonds. The prototype extends the principle for molecular machines that build polymers by moving along tracks to the synthesis of sequence-encoded chains with continuous carbon backbones.

A pillar[5]arene-based molecular grapple of hexafluorophosphate

A symmetric pillararene-based receptor containing ten triazole units was synthesized. Interestingly, it formed 1:1 complexes instead of 1:2 with different halide anions. This was caused by the cooperative multivalent hydrogen-bond interactions between the triazole protons on one side of the receptor and the halide anion, which changed its structure from pillar to conical. However, by the regulation of the effector Fˉ, it can work like an excavator grapple selectively grasps a PF6ˉ anion.

Chemical modification of functionalized polyhydroxyalkanoates via “Click” chemistry: A proof of concept

A novel approach to the post-biosynthetic chemical modification of bromo and alkyne functionalized poly(3-hydroxyalkanoates), (PHAs), via copper-catalyzed azide-alkyne cycloaddition (CuAAC) and strain promoted azide alkyne cycloaddition (SPAAC) is reported. Optimum conditions for the biosynthesis of the PHA copolymers, poly(3-hydroxynonanoate-co-3-hydroxy-11-bromoundecanoate) (PHNUBr) and poly(3-hydroxynonanoate-co-3-hydroxy-10-undecynoate) (PHNUD), using Pseudomonas oleovorans as cell factories were 20h of fermentation time and a total carbon substrate concentration of 40mM. Percent incorporation of brominated repeat units and alkyne repeat units were 38.5% and 50% respectively, as determined by 1H NMR. PHNUBr was converted into an azido-terminated precursor for the polymer analogous “click” reactions via SN2 nucleophilic substitution reaction using sodium azide with a yield of 96.7% and analyzed by FTIR and 1H NMR. CuAAC reactions were used to attach propargyl benzoate and methyl-2-azidoacetate to the PHAs with terminal azido and alkyne functional side groups respectively, with yields of 78.2% and 65.4% respectively. FTIR analysis of the products showed the disappearance of the azide peak at 2093.5cm−1 and the alkynyl CCH stretch at 3292cm−1. 1H NMR analysis confirmed the formation of the expected triazole linkage; showing the expected proton chemical shift corresponding to the triazole proton at 7.73 and 7.47ppm respectively. A strain promoted azide-alkyne reaction was used to attach (1R,8S,9s)-Bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN-OH) to the azido-terminated PHA with an average yield of 94.5%. Products were analyzed by FTIR and 1H NMR.

Conformational NMR Study of Bistriazolyl Anion Receptors

Conformational features of pyridine- and pyrimidine-based bistriazolyl anion receptors dissolved in acetonitrile-d3 were assessed by multidimensional, heteronuclear NMR spectroscopy. NOESY correlation signals suggested preorganization of both host molecules in solution in the absence of anions. In addition, only a single set of signals was observed in the 1H NMR spectra, which suggested a symmetrical conformation of anion receptors or their conformational exchange that is fast on the NMR time-scale. Furthermore, the predominant conformations of the pyridine- and pyrimidine-based anion receptors are preserved upon addition of chloride, bromide, and acetate anions. Chemical shift changes observed upon addition of anions showed that the NH (thio)urea and triazole protons are involved in anion-receptor interactions through hydrogen bonding.

Aromatic triazole foldamers induced by C-H···X (X = F, Cl) intramolecular hydrogen bonding.

Aryl-triazole oligomers based on isobutyl 4-fluorobenzoate and isobutyl 4-chlorobenzoate were designed and synthesized. Crystal structure and (1)H-(1)H NOESY experiments demonstrate that the oligomers adopt stable helical conformation, which are induced by C(5)-H···X-C (X = F, Cl) intramolecular hydrogen bonding between triazole protons and halogen atoms. The stabilities of the folded conformations are confirmed by DFT calculations, which show that each C(5)-H···F-C planar interaction lowers the energy by ~3 kcal mol(-1) on average, and by ~1 kcal mol(-1) when C(5)-H···Cl-C bridges are formed. The hydrogen-bonding networks are disrupted in competitive hydrogen-bonding media such as DMSO, generating the unfolded oligomers.

Isomeric Mono-, Di-, and Tri-Bromobenzo-1H-Triazoles as Inhibitors of Human Protein Kinase CK2α

To further clarify the role of the individual bromine atoms of 4,5,6,7-tetrabromotriazole (TBBt), a relatively selective inhibitor of protein kinase CK2, we have examined the inhibition (IC50) of human CK2α by the two mono-, the four di-, and the two tri- bromobenzotriazoles relative to that of TBBt. Halogenation of the central vicinal C(5)/C(6) atoms proved to be a key factor in enhancing inhibitory activity, in that 5,6-di-Br2Bt and 4,5,6-Br3Bt were almost as effective inhibitors as TBBt, notwithstanding their marked differences in pKa for dissociation of the triazole proton. The decrease in pKa on halogenation of the peripheral C(4)/C(7) atoms virtually nullifies the gain due to hydrophobic interactions, and does not lead to a decrease in IC50. Molecular modeling of structures of complexes of the ligands with the enzyme, as well as QSAR analysis, pointed to a balance of hydrophobic and electrostatic interactions as a discriminator of inhibitory activity. The role of halogen bonding remains debatable, as originally noted for the crystal structure of TBBt with CK2α (pdb1j91). Finally we direct attention to the promising applicability of our series of well-defined halogenated benzotriazoles to studies on inhibition of kinases other than CK2.

Triazole linked lower rim glycosyl appended 1,3-calix[4]arene conjugates: Synthesis, characterization, and their interaction with jacalin

Triazole linked lower rim galactosyl and lactosyl appended calix[4]arene conjugates have been synthesized by 1,3 dipolar addition of glycosyl azide and calix[4]arene alkyne. All these conjugates were characterized by 1H and 13C NMR, IR and mass spectrometry. Interaction of amino acids with the galactosyl conjugate of calix[4]arene (5) was studied using absorption and 1H NMR techniques. Absorption studies showed that Trp interacts with triazole ring of 5. This was further confirmed by 1H NMR study which showed an upfield shift in the triazole proton of 5 upon titrating with Trp. The preliminary studies of interaction of these conjugates with Jacalin were demonstrated by fluorescence and circular dichroism (CD) spectroscopy techniques.

Synthesis and Physico-Chemical Properties in Aqueous Medium of All Possible Isomeric Bromo Analogues of Benzo-1H-Triazole, Potential Inhibitors of Protein Kinases

In ongoing studies on the role of the individual bromine atoms of 4,5,6,7-tetrabromobenzotriazole (TBBt) in its relatively selective inhibition of protein kinase CK2α, we have prepared all the possible two mono-, four di-, and two tri-bromobenzotriazoles and determined their physicochemical properties in aqueous medium. They exhibited a general trend of a decrease in solubility with an increase in the number of bromines on the benzene ring, significantly modulated by the pattern of substitution. For a given number of attached bromines, this was directly related to the electronic effects resulting from different sites of substitution, leading to marked variations of pK(a) values for dissociation of the triazole proton. Experimental data (pK(a), solubility) and ab initio calculations demonstrated that hydration of halogenated benzotriazoles is driven by a subtle balance of hydrophobic and polar interactions. The combination of QM-derived free energies for solvation and proton dissociations was found to be a reasonably good predictor of inhibitory activity of halogenated benzotriazoles vs CK2α. Since the pattern of halogenation of the benzene ring of benzotriazole has also been shown to be one of the determinants of inhibitory potency vs some viruses and viral enzymes, the present comprehensive description of their physicochemical properties should prove helpful in efforts to elucidate reaction mechanisms, including possible halogen bonding, and the search for more selective and potent inhibitors.

Strong Binding Affinity of a Zinc–Porphyrin‐Based Receptor for Halides through the Cooperative Effects of Quadruple CH Hydrogen Bonds and Axial Ligation

A new type of host compound (1), tetraphenyl zinc-porphyrin (ZnTPP) that contains four triazole groups at the ortho-position of each phenyl group, has been synthesized and characterized by using (1)H, (13)C NMR, and MALDI-TOF-MS analyses. The host-guest complex formation between 1 and halides was investigated by using (1)H NMR spectroscopy in [D(6)]DMSO. The triazole, benzyl, and phenylene proton signals were shifted upfield by the addition of halides in the form of tetrabutylammonium salts, which implies that the triazole protons in 1 are allocated very closely to the porphyrin ring and are directed toward the binding pocket over the porphyrin ring during the formation of hydrogen bonds. The UV/Vis absorption spectra showed that both the Soret and Q band absorptions of 1 underwent a strong redshift due to the addition of halides. Compound 1 exhibited surprisingly strong binding affinities for the halides, where the association constants for Cl(-), Br(-), and I(-) binding were estimated to be larger than 10(8), 1.79×10(7), and 1.84×10(5) M(-1), respectively. The UV/Vis absorption changes and the result of competitive titration using 4-tert-butylpyridine indicated that the cooperative effects of axial coordination and C-H···X hydrogen bond interactions resulted in the strong binding affinity of 1 to halides.

Fluorescence emission properties of 8-azaxanthine and its N-alkyl derivatives: Excited-state proton transfer, and potential applications in enzymology

We have investigated the emission properties of 8-azaxanthine (8-azaXan) and its triazolo N-alkyl derivatives, with particular emphasis on N(8)-methyl-8-azaXan. In aqueous medium, both 8-azaXan and its 8-alkyl congener emit at 420 nm, with an unusually large Stokes’ shift, and decay times of 9 and 12 ns, respectively. With the parent 8-azaXan, emission is observed over a narrow pH range (2–6), where it is partially or predominantly in its neutral form in the ground state (p K a 4.9), whereas for 8-methyl-8-azaXan emission is observed in the pH range 2–12, hence for both the neutral and monoanionic species (p K a 7.2). Fluorescence excitation spectra are in accord with the absorption spectra at all pH values. In anhydrous methanol, 8-azaX, in its neutral form, emits at about 335 nm. In 10% aqueous methanol, acidified to pH ∼3, two emission bands are observed, at 420 and 335 nm. With the 8-methyl derivative, dual emission at 420 and ∼340 nm is observed in anhydrous methanol, but in isopropanol and acetonitrile the 420 band virtually disappears. It is concluded that the 420 nm emission band, ascribed to the monoanionic form of 8-methyl-8-azaXan, appears in neutral or acidic media as the result of rapid deprotonation of the N(3)–H in the excited states of both 8-azaXan and its 8-alkyl derivative. This leads to phototautomerism in the 8-azaXan monoanion which, in the ground state, is present in the form resulting from dissociation of the triazole proton, i.e., N(8)–H. This proton transfer is slowed down in non-aqueous solvents, where emission from the neutral molecules (335–340 nm) is observed. The foregoing interpretation is supported by determination, with the aid of the Foerster cycle, of the excited state p K * values, close to −0.5 for 8-methyl-8-azaXan. The strong emission of 8-azaXan and its N-alkyl derivatives should prove useful in studies on enzyme/ligand interactions, several examples of which are proposed. In particular, we report that 8-azaXan is a substrate for purine nucleoside phosphorylase II from E. coli, and show that the reaction can be monitored fluorimetrically.

Mechanistic aspects of chiral discrimination on an amylose tris(3,5-dimethylphenyl)carbamate.

The separation of [2R-[2alpha(R*),3alpha]]-5-[[2-[1-[3,5-bis-(trifluoromethyl)phenyl]ethoxy]-3(S)-4-fluorophenyl)4-morpholinyl]-methyl]-N,N-dimethyl-1H-1,2,3-triazole-4-methanamine hydrochloride from its enantiomer was achieved on an amylose tris-3,5-dimethylphenyl carbamate stationary phase. The retention of the enantiomers is dominated by weak hydrogen bonds while the enantioselectivity is governed by other kinds of interactions, e.g., inclusion in the amylose carbamate chains. Van't Hoffplots of 1nalpha vs. reciprocal temperature were non-linear and could be divided into two linear regions. One region at low temperature (5 degrees C- approximately 20 degrees C) and another one between 25 degrees C-70 degrees C with the change in slope occurring between 16 degrees C and 20 degrees C. DSC experiments suggested that the behavior can be attributed to breakage of H-bonds triggering a conformational change. Molecular simulation indicated a correlation between the interaction energies and the elution order obtained experimentally. The most retained enantiomer (R,R,S-enantiomer) interacts with the stationary phase through a hydrogen bond between the triazole proton and the C=O groups of the stationary phase, as well as through an inclusion in the cleft of the stationary phase. The other enantiomer exhibits a bifurcated H-bond between the triazolic proton and the C=O groups of the stationary phase leading to a less stable complex.

1H and 13C NMR study of novel fused 1,2,4‐triazole heterocycles

AbstractThe 1H and 13C NMR spectra of some novel 1,2,4‐triazolo [1,3] thiazinoquinoline isomeric pairs are interpreted in terms of structural assignments. The structure of most compounds has been confirmed by NOE difference spectroscopy. Characteristic differences have been observed in both 1H and 13C NMR spectra of these isomeric Pairs: some of the 1H and 13C chemical shifts, and also the one bond 13C1H couplings of triazole protons, differ consistently in the NMR spectra of the isomers. The coupling constants have been determined using a combination of INEPT and chemical shift selective filtering.

Proton‐ionizable crown compounds. 4. New macrocyclic polyether ligands containing a triazole subcyclic unit

AbstractA series of macrocyclic polyether (crown) ligands containing the proton‐ionizable s‐triazole subcyclic unit were prepared by reacting the 1‐THP blocked 3,5‐bis(chloromethyl)‐1H‐1,2,4‐triazole with various oligoethylene glycols. The starting bis(chloromethyl)triazole is a vessicant and must be used with caution. Triazolo‐18‐crown‐6 (5) formed stable complexes with barium, strontium, copper and benzylammonium cations but not with potassium or lithium. The crystal structure of 5 showed the triazole proton to be on nitrogen 3 which is outside the macroring cavity.