Kinetic Comparison of Trifluoroacetic Acid Cleavage Reactions of Resin-Bound Carbamates, Ureas, Secondary Amides, and Sulfonamides from Benzyl-, Benzhydryl-, and Indole-Based Linkers

The kinetics of cleavage reactions of 16 resin-bound carbamates, ureas, secondary amides, and sulfonamides from four different acid labile linkers including benzyl, benzhydryl, and indole linkers has been investigated. The optimized cleavage conditions are generally milder than those commonly used and reported (e.g., 0.5% TFA as opposed to 5%). Among various linkers studied in this work, the indole linker has been found to be the most acid labile followed by the Rink linker. The rate of cleavage of compounds linked to the resin via various functional groups can be summarized as follows: sulfonamide >carbamate approximately urea > amide. This study shows that cleavages of 16 compounds from four different acid labile linkers have been optimized to much milder conditions in terms of TFA concentration and the reaction time. It also demonstrates that single bead FTIR is an effective tool for optimizing cleavage conditions.     

Linkers for oligonucleotide microarray synthesis

A number of linkers for microchip-based (microarray) synthesis of oligonucleotides were synthesized here using photolabile intermediates. The resulting linkers are designed for covalent immobilization on slides containing both hydroxyl and amino groups.The first series of linkers was intended for the synthesis of oligonucleotide arrays for hybridization analysis. These linkers provide a strong covalent bond with the slide surface when amino groups in oligonucleotide heterocyclic bases are deprotected.The second series of linkers allows to cleave the synthesized oligonucleotides from the support on which they were synthesized. Furthermore, the use of such linkers yields oligonucleotides devoid of the phosphate group at their 3′ end.The obtained linkers were successfully tested in the synthesis of oligonucleotides on a microchip for subsequent hybridization analysis and assembly of a DNA fragment.     

Synthesis,structure, and photochemistry of exceptionally stable synthetic DNA hairpins with stilbene diether linkers

The structure and properties of 18 hairpin-forming bis(oligonucleotide) conjugates possessing stilbene diether linkers are reported. Conjugates possessing bis(2-hydroxyethyl)stilbene 4,4'-diether linkers form the most stable DNA hairpins reported to date. Hairpins with as few as two T:A base pairs or four noncanonical G:G base pairs are stable at room temperature. Increasing the length of the hydroxyalkyl groups results in a decrease in hairpin thermal stability. On the basis of the investigation of their circular dichroism spectra, all of the hairpins investigated adopt B-DNA structures, except for a hairpin with a short poly(G:C) stem which forms a Z-DNA structure. Both the strong fluorescence of the stilbene diether linkers and their trans-cis photoisomerization are totally quenched in hairpins possessing neighboring T:A and G:C base pairs. Quenching is attributed to an electron-transfer mechanism in which the singlet stilbene serves as an electron donor and T or C serves as an electron acceptor. In contrast, in denatured hairpins and hairpins possessing neighboring G:G base pairs the stilbene diether linkers undergo efficient photoisomerization.     

Solution- and solid-phase syntheses of guanidine-bridged, water-soluble linkers for multivalent ligand design

[reaction: see text] Efficient syntheses of guanidine-bridged poly(ethylene glycol) linkers of various lengths in fully protected form are reported for both solution- and solid-phase protocols. The application of such linkers in the construction of water-soluble and high-affinity multivalent ligands against cholera toxin is demonstrated. Synthetic intermediates for multivalent ligands as large as 20 kDa in molecular weight have been assembled using presynthesized linkers. The final ligands are highly water-soluble, thus enabling proper biophysical characterization.     

Multivalent, high-relaxivity MRI contrast agents using rigid cysteine-reactive gadolinium complexes

MRI contrast agents providing very high relaxivity values can be obtained through the attachment of multiple gadolinium(III) complexes to the interior surfaces of genome-free viral capsids. In previous studies, the contrast enhancement was predicted to depend on the rigidity of the linker attaching the MRI agents to the protein surface. To test this hypothesis, a new set of Gd-hydroxypyridonate based MRI agents was prepared and attached to genetically introduced cysteine residues through flexible and rigid linkers. Greater contrast enhancements were seen for MRI agents that were attached via rigid linkers, validating the design concept and outlining a path for future improvements of nanoscale MRI contrast agents.     

Silicon-based aromatic transferring linkers for traceless solid-phase synthesis of aryl-, polyaryl-, and heteroaryl-containing compounds

A number of arylsilane-based linkers are prepared for traceless solid-phase synthesis. General methodologies for introduction of the silyl group and various functional groups to aromatic, polyaromatic, and heteroaromatic rings are developed. Also, broad utilities of the linkers are demonstrated by on-resin preparation of small organic molecules and subsequent cleavage of the products either by protiodesilylation (TFA) or ipso-substitution (Br₂).     

Stepwise "click" chemistry for the template independent construction of a broad variety of cross-linked oligonucleotides: influence of linker length, position, and linking number on DNA duplex stability

Cross-linked DNA was constructed by a "stepwise click" reaction using a bis-azide. The reaction is performed in the absence of a template, and a monofunctionalized oligonucleotide bearing an azido-function is formed as intermediate. For this, an excess of the bis-azide has to be used compared to the alkynylated oligonucleotide. The cross-linking can be carried out with any alkynylated DNA having a terminal triple bond at any position of the oligonucleotide, independent of chain length or sequence with identical or nonidentical chains. Short and long linkers with terminal triple bonds were introduced in the 7-position of 8-aza-7-deaza-2'-deoxyguanosine (1 or 2), and the outcome of the "stepwise" click and the "bis-click" reaction was compared. The cross-linked DNAs form cross-linked duplexes when hybridized with single-stranded complementary oligonucleotides. The stability of these cross-linked duplexes is as high as respective individual duplexes when they were ligated at terminal positions with linkers of sufficient length. The stability decreases when the linkers are incorporated at central positions. The highest duplex stability was reached when two complementary cross-linked oligonucleotides were hybridized.     

固相有机合成中的连接基团

介绍了固相有机合成中的连接基团,特别是带有隔离单元的连接基团、无痕迹连接基团、安全拉手型连接基团和复合型连接基团的基本概念、发展近况以及它们的应用.     

Linker molecules in surfactant mixtures

Linker molecules are amphiphiles that segregate near the microemulsion membrane either near the surfactant tail (lipophilic linkers) or the surfactant head group (hydrophilic linkers). The idea of the lipophilic linkers was introduced a decade ago as a way to increase the surfactant–oil interaction and the oil solubilization capacity. Long chain (>9 tail carbons) alcohols were first used as lipophilic linkers. Later it was found that the solubilization enhancement plateaus (saturates) above a certain lipophilic linker concentration. Hydrophilic linkers have been recently introduced as a way to compensate for the saturation effect observed for lipophilic linkers. Hydrophilic linkers are surfactant-like molecules with 6–9 tail carbons that coadsorb with the surfactant at the oil/water interface, thereby increasing the surfactant–water interaction, but have a poor interaction with the oil phase due to their short tail. A special synergism emerges when combining hydrophilic and lipophilic linkers, which further increases the solubilization enhancement over lipophilic linkers alone. We will discuss the profound impact of linker molecules on interfacial properties such as characteristic length, interfacial rigidity and dynamics (coalescence, solubilization and relaxation experiments) of the interface. We also demonstrate how these properties affect the performance of cleaning formulations designed around linker molecules. We describe linker-based formulations for a wide range of oils, including highly hydrophobic oils (e.g. hexadecane) that have proven very hard to clean. We also report on the use of ‘extended’ surfactants as an alternative to self-assembled linker systems.     

An Aldehyde Responsive,Cleavable Linker for Glucose Responsive Insulins

A glucose responsive insulin (GRI) that responds to changes in blood glucose concentrations has remained an elusive goal. Here we describe the development of glucose cleavable linkers based on hydrazone and thiazolidine structures. We developed linkers with low levels of spontaneous hydrolysis but increased level of hydrolysis with rising concentrations of glucose, which demonstrated their glucose responsiveness in vitro. Lipidated hydrazones and thiazolidines were conjugated to the LysB29 side-chain of HI by pH-controlled acylations providing GRIs with glucose responsiveness confirmed in vitro for thiazolidines. Clamp studies showed increased glucose infusion at hyperglycemic conditions for one GRI indicative of a true glucose response. The glucose responsive cleavable linker in these GRIs allow changes in glucose levels to drive the release of active insulin from a circulating depot. We have demonstrated an unprecedented, chemically responsive linker concept for biopharmaceuticals.     

Investigation of the redox property of a metalloprotein layer self-assembled on various chemical linkers

Myogloblin, a well-known metalloprotein, was immobilized on a gold surface using various chemical linkers to investigate the length effect of chemical linker on the electron transfer in protein layers, because chemical linkers play roles in the pathway that transfers the electron from the protein to the gold substrate and act as protein immobilization reagents. Chemical linkers with 2, 6, 11, and 16 carbons were utilized to confirm length-effects. The immobilization of protein and chemical linker was validated with surface plasmon resonance (SPR) and atomic force microscopy (AFM). The electrochemical property was evaluated by cyclic voltammetry (CV) and chronocoulometry (CC). In those results, redox peaks of immobilized protein were controlled via the length of chemical linkers, and it could be directly applied to the realization of bioelectronic device.     

A folded,secondary structure in step-growth oligomers from covalently linked,crowded aromatics

This study delineates general methods to create a new class of folded oligomers by covalently attaching overcrowded aromatics to each other. Crucial to observing the secondary structure in these oligomers was the employment of C-shaped linkers. These linkers preorganize the strands to form intramolecular hydrogen bonds. In solution, one- and two-dimensional (1)H NMR data show well-defined columnar conformations. The side chains in these oligomers are critical for the secondary structure to emerge in solution. Using tris(dodecyloxy)phenethyl side chains in combination with tert-butyl side chains in the terminal subunit provides a soluble trimer and prevents intermolecular association above millimolar concentrations. This new folding motif, formed through a synergy between hydrogen bonds and pi-stacking, is so robust that even dimers have secondary structure in solution.     

Adsorption of CO2, CH4, and N2 on Zeolitic Imidazolate Frameworks: Experiments and Simulations

Experimental measurements and molecular simulations were conducted for two zeolitic imidazolate frameworks, ZIF‐8 and ZIF‐76. The transferability of the force field was tested by comparing molecular simulation results of gas adsorption with experimental data available in the literature for other ZIF materials (ZIF‐69). Owing to the good agreement observed between simulation and experimental data, the simulation results can be used to identify preferential adsorption sites, which are located close to the organic linkers. Topological mapping of the potential‐energy surfaces makes it possible to relate the preferential adsorption sites, Henry constant, and isosteric heats of adsorption at zero coverage to the nature of the host–guest interactions and the chemical nature of the organic linker. The role played by the topology of the solid and the organic linkers, instead of the metal sites, upon gas adsorption on zeolite‐like metal–organic frameworks is discussed.     

Synthetic approaches to a variety of covalently linked porphyrin--fullerene hybrids

There is substantial interest in dyads in which C(60) is covalently linked to electron donors, such as porphyrins, which absorb light strongly in the visible region. We present here the details of the syntheses of such compounds, which can be broadly organized into categories depending upon the nature of the linker joining the two chromophores. The structural aspects of intramolecular electronic interaction that we have sought to explore have dictated the synthetic strategies employed to generate these classes of molecules. Flexible glycol linkers were used to allow close approach between the fullerene and porphyrin, facilitating through-space interactions. These linkers also allowed studies of the effects of metal cation complexation. Naphthalene and alkyne linkers were used to examine the possible effects a conjugated or aromatic linker might have on photophysical properties. Finally, steroids were used as linkers in dyads expected to possess a large distance between the two chromophores, in which only through-bond interactions between the fullerene and porphyrin should be possible.     

Macrocyclic diketopiperazine receptors: effect of macrocyclization on the binding properties of two-armed receptors

The synthesis of macrocyclic two-armed diketopiperazine receptors and their binding properties toward peptides is described. Macrocyclization with short linkers led to receptors with significantly modified binding properties compared to their flexible open chain parent receptors, whereas with long linkers the original binding selectivities were largely retained.     

Hierarchical self-assembly of bolaamphiphiles with a hybrid spacer and L-glutamic acid headgroup: pH- and surface-triggered hydrogels, vesicles, nanofibers, and nanotubes

Bolaamphiphiles with L-glutamic acid headgroups and hybrid linkers, each composed of two rigid benzene rings and different polymethylene units, were designed, and morphological controls of the hierarchical self-assemblies were realized via changing solution pH and application to solid surfaces. At a low pH of 3, bolaamphiphiles formed hydrogels with water and molecules with short and long spacers formed nanofibers and helical nanoribbon-nanotubes, respectively. In a pH 12 aqueous solution, vesicles were observed from cryo-TEM measurements for amphiphiles with short spacers that could transfer to huge vesicles when cast onto a mica surface. Amphiphiles with longer spacers self-assembled into nanoparticles in a pH 12 aqueous solution while micellar fibers were formed on a mica surface. Those assemblies were characterized with UV-vis, CD, and FT-IR spectroscopy and AFM and TEM observations. With molecular structure modification and the fine tuning of conditions, morphology transitions between various nanostructures were obtained from the self-assembled bolaamphiphiles. The environmental pH can induce different interaction modes between the headgroups, and at high pH, there are strong interactions between molecular assemblies and the mica surface. It is suggested that the active headgroups, rigid necks, and flexible linkers with different lengths render molecules with diverse aggregation morphologies.     

Competitive Excimer Formation and Energy Transfer in Zr‐Based Heterolinker Metal–Organic Frameworks

The spectroscopy and dynamics of a series of Zr‐based MOFs in dichloromethane suspension are reported. These Zr‐NADC MOFs were constructed by using different mixtures of 2,6‐naphthalenedicarboxylate (NDC) and 4‐amino‐2,6‐naphthalenedicarboxylate (NADC) as organic linkers. The fraction of NADC relative to NDC in these heterolinker MOFs ranges from 2 to 35 %. The results indicate two competitive photoprocesses: NDC excimer formation and an energy transfer (ET) from excited NDC linkers to NADC linkers. Increasing the fraction of NADC linkers in the Zr‐NADC nanostructure decreases the mean time constant of NDC excimer formation, while the NADC emission intensity experiences a drop at the highest fraction of this linker in the MOF. The first observation is explained by an increase in the energy‐transfer probability between the two linkers, and the second by emission quenching in the NADC linkers due to ultrafast charge transfer assisted by the amino group. Femtosecond time‐resolved emission studies showed that the ET process (recorded as decaying and rising components) from excited NDC to NADC takes place in 1.2 ps. Direct excitation of the NADC linkers (at 410 nm) shows a decaying, but not rising, component of 250–480 fs, which could reflect the formation of a nonemissive charge‐separation state. The results show that by using MOFs having heterolinkers it is possible to trigger and tune excimer formation and ET processes.     

Selective diphosphorylation, dithiodiphosphorylation, triphosphorylation, and trithiotriphosphorylation of unprotected carbohydrates and nucleosides

[chemical reaction: see text]. Aminomethyl polystyrene resin-bound linkers of p-acetoxybenzyl alcohol were subjected to reactions with diphosphitylating and triphosphitylating reagents to yield the corresponding polymer-bound diphosphitylating and triphosphitylating reagents, respectively. A number of unprotected carbohydrates and nucleosides were reacted with the polymer-bound reagents. Oxidation with tert-butyl hydroperoxide or sulfurization with Beaucage's reagent, followed by removal of cyanoethoxy group with DBU and the acidic cleavage, respectively, afforded only one type of monosubstituted nucleoside and carbohydrate diphosphates, dithiodiphosphates, triphosphates, and trithiotriphosphates with high regioselectivity.     

6-Endo-dig versus 5-exo-dig: Exploring Radical Cyclization Preference with First-, Second-, and Third-row Linkers using High-level Quantum Chemical Methods

As an expansion upon Baldwin rules, the cyclization reactions of hex-5-yn-1-yl radical systems with different first-, second-, and third-row linkers are explored at the CCSD(T) level via means of the SMD(benzene)-G4(MP2) thermochemical protocol. Unlike C, O, and N linkers, systems with B, Si, P, S, Ge, As, and Se linkers are shown to favor 6-endo-dig cyclization. This offers fundamental insights into the rational synthetic design of cyclic compounds. A thorough analysis of stereoelectronic effects, cyclization barriers, and intrinsic barriers illustrates that structural changes alter the cyclization preference by mainly impacting 5-exo-dig reaction barriers. Based on the high-level computational modeling, we proceed to develop a new tool for cyclization preference prediction from the correlation between cyclization barriers and radical structural parameters (e. g., linker bond length and bond angle). A strong correlation is found between the radical attack trajectory angle and the reaction barrier heights, i. e., cyclization preference. Finally, the influence of stereoelectronic effects on the two radical cyclization pathways is further investigated in stereoisomers of hypervalent silicon system, which provides novel insight into cyclization control.     

Pore‐Environment Engineering with Multiple Metal Sites in Rare‐Earth Porphyrinic Metal–Organic Frameworks

Multi‐component metal–organic frameworks (MOFs) with precisely controlled pore environments are highly desired owing to their potential applications in gas adsorption, separation, cooperative catalysis, and biomimetics. A series of multi‐component MOFs, namely PCN‐900(RE), were constructed from a combination of tetratopic porphyrinic linkers, linear linkers, and rare‐earth hexanuclear clusters (RE₆) under the guidance of thermodynamics. These MOFs exhibit high surface areas (up to 2523 cm² g^?1) and unlimited tunability by modification of metal nodes and/or linker components. Post‐synthetic exchange of linear linkers and metalation of two organic linkers were realized, allowing the incorporation of a wide range of functional moieties. Two different metal sites were sequentially placed on the linear linker and the tetratopic porphyrinic linker, respectively, giving rise to an ideal platform for heterogeneous catalysis.