Neighboring Group Effect Research Articles

Acetal Substitution Reactions: Stereoelectronic Effects, Conformational Analysis, Reactivity vs Selectivity, and Neighboring-Group Participation

AbstractAcetal substitution reactions can proceed by a number of mechanisms, but oxocarbenium ion intermediates are involved in many of these reactions. Our research has focused on understanding the conformational preferences, structures, and reactions of these intermediates. This account summarizes our observations that electrostatic effects play a significant role in defining the preferred conformations, and that torsional effects determine how those intermediates react. Neighboring-group effects are not as straightforward as they might seem, considering that oxocarbenium ion intermediates are in equilibrium with structures that involve stabilization by a nearby substituent.1 Introduction2 Unexpected Stereoselectivities3 Determining Conformational Preferences of Oxocarbenium Ions4 Structures of Carbocations by NMR Spectroscopy and X-ray Crystallography5 Stereoelectronic Models for Reactions Involving Other Oxocarbenium Ions6 Stereoselectivity and Reactivity: When They Correlate, When They Do Not7 Neighboring–Group Participation Is Not as Simple as It Seems8 What Is True for Carbocations Is True for Carbonyl Compounds9 Stereoelectronic and Torsional Effects in Reactions of Enolates10 Summary of Expected Selectivities for Reactions of Cyclic Acetals11 Conclusion

Ortho-Boronic Acid Carbonyl Compounds and Their Applications in Chemical Biology.

Iminoboronates and diazaborines are related classes of compounds that feature an imine ortho to an arylboronic acid (iminoboronate) or a hydrazone that cyclizes with an ortho arylboronic acid (diazaborine). Rather than acting as independent chemical motifs, the arylboronic acid impacts the rate of imine/hydrazone formation, hydrolysis, and exchange with competing nucleophiles. Increasing evidence has shown that the imine/hydrazone functionality also impacts arylboronic acid reactivity toward diols and reactive oxygen and nitrogen species (ROS/RNS). Untangling the communication between C=N linked functionalities and arylboronic acids has revealed a powerful and tunable motif for bioconjugation chemistries and other applications in chemical biology. Here, we survey the applications of iminoboronates and diazaborines in these fields with an eye toward understanding their utility as a function of neighboring group effects.

Accelerated Amidation of a Glycine Propargyl Ester on a Polymer and the Two-Way Use of One-Pot Double Postpolymerization Modification with Click Chemistry

Abstract The glycine propargyl (GP) ester moiety, as a newly activated ester, is a candidate for amidation in modification reactions and can be combined with click chemistry. Here, the amidation of GP esters on a polymer side chain was investigated using various amino-group-containing compounds. The amidation on the GP ester proceeded well when n-alkyl, cycloalkyl, and aromatic-group-containing primary amines were used without a catalyst under neutral conditions. Hydrophilic amines containing hydroxy and carboxy groups provided no amidation products. The amidation on the polymer was accelerated by the neighboring group effect on the polymer side chain. One-pot double postpolymerization modification was achieved using a GP ester-bearing polymer by combining amidation with the Huisgen cycloaddition.

Neighboring Group Effects on the Rates of Cleavage of Si-O-Si-Containing Compounds.

The presence of a nearby tethered functional group (G, G = tertiary amide or amine) can significantly impact the rate of cleavage of an Si-O bond. We report here an in situ 1H NMR spectroscopic investigation of the relative rates of cleavage of model substrates containing two different Si-O substructures, namely alkoxydisiloxanes [GRO-Si(Me2)-O-SiMe3] and carbodisiloxanes [GR-Si(Me2)-O-SiMe3]. The trends in the relative rates (which slowed with increasing chain length, with a notable exception) of alkoxydisiloxane hydrolyses were probed via computation. The results correlated well with the experimental data. In contrast to the hydrolysis of the alkoxydisiloxanes, the carbodisiloxanes were not fully hydrolyzed, but rather formed an equilibrium mixture of starting asymmetric disiloxane, two silanols, and a new symmetrical disiloxane. We also uncovered a facile siloxy-metathesis reaction of an incoming silanol with the carbodisiloxane substrate [e.g., Me2NR-Si(Me2)-O-SiMe3 + HOSiEt3 ⇋ Me2NR-Si(Me2)-O-SiEt3 + HOSiMe3] facilitated by the pendant dimethylamino group, a process that was also probed by computation.

Selective Formal Carbene Insertion into Carbon‐Boron Bonds of Diboronates byN‐Trisylhydrazones

AbstractBisborylalkanes play important roles in organic synthesis as versatile bifunctional reagents. The two boron moieties in these compounds can be selectively converted into other functional groups through cross‐coupling, oxidation or radical reactions. Thus, the development of efficient methods for synthesizing bisborylalkanes is highly demanded. Herein we report a new strategy to access bisborylalkanes through the reaction ofN‐trisylhydrazones with diboronate, in which the bis(boryl) methane is transformed into 1,2‐bis(boronates) via formal carbene insertion. Since theN‐trisylhydrazones can be readily derived from the corresponding aldehydes, this strategy represents a practical synthesis of 1,2‐diboronates with broad substrate scope. Mechanistic studies reveal an unusual neighboring group effect of 1,1‐bis(boronates), which accounts for the observed regioselectivity when unsymmetric 1,1‐diboronates are applied.

Selective Formal Carbene Insertion into Carbon-Boron Bonds of Diboronates by N-Trisylhydrazones.

Bisborylalkanes play important roles in organic synthesis as versatile bifunctional reagents. The two boron moieties in these compounds can be selectively converted into other functional groups through cross-coupling, oxidation or radical reactions. Thus, the development of efficient methods for synthesizing bisborylalkanes is highly demanded. Herein we report a new strategy to access bisborylalkanes through the reaction of N-trisylhydrazones with diboronate, in which the bis(boryl) methane is transformed into 1,2-bis(boronates) via formal carbene insertion. Since the N-trisylhydrazones can be readily derived from the corresponding aldehydes, this strategy represents a practical synthesis of 1,2-diboronates with broad substrate scope. Mechanistic studies reveal an unusual neighboring group effect of 1,1-bis(boronates), which accounts for the observed regioselectivity when unsymmetric 1,1-diboronates are applied.

Effects of intramolecular proton acceptors located near sulfhydryl groups on sulfhydryl compounds for acrylamide elimination

To explore the effects of intramolecular neighboring groups on sulfhydryl group reactivity in acrylamide removal, the reactions of three sulfhydryl-containing flavoring substances with derived structures, 1-propanethiol, 3-mercaptopropionic acid, and cysteine, with acrylamide were investigated. The results showed that the activation energies of the reactions decreased with the introduction of amino and carboxyl groups. Additional comparison reactions showed that other proton acceptors also promote the reactions of sulfhydryl groups with acrylamide. However, the reactivity was not enhanced if the proton acceptor was located far from the sulfhydryl group. This suggested that sulfhydryl compounds with the molecular structure of proton acceptors on the carbons located β or/and γ to the sulfhydryl group were efficient in eliminating acrylamide, and the results are expected to serve as a guide in the search for effective acrylamide elimination agents.

Size-Induced Inversion of Selectivity in the Acylation of 1,2-Diols.

Relative rates for the Lewis base‐catalyzed acylation of aryl‐substituted 1,2‐diols with anhydrides differing in size have been determined by turnover‐limited competition experiments and absolute kinetics measurements. Depending on the structure of the anhydride reagent, the secondary hydroxyl group of the 1,2‐diol reacts faster than the primary one. This preference towards the secondary hydroxyl group is boosted in the second acylation step from the monoesters to the diester through size and additional steric effects. In absolute terms the first acylation step is found to be up to 35 times faster than the second one for the primary alcohols due to neighboring group effects.

Palladium-Catalyzed Nucleophilic Isocyanation for the Synthesis of α-Aryl-α-Isocyanoacetoamide Derivatives

Abstract α-Aryl-α-isocyanoacetoamide derivatives were synthesized through palladium-catalyzed nucleophilic isocyanation. Diethylphosphates derived from N,N-disubstituted mandelamide derivatives reacted with trimethylsilyl cyanide in the presence of a catalytic amount of Pd(OAC)2 to afford the titled isonitriles (13 examples) in moderate to high yield. The silyl cyanopalladate complex formed in situ was a proposed catalyst, which behaved as a Lewis acid promoting elimination of the phosphate group and also the N-nucleophilic cyanide reagent. The isocyanation was applied to a gram-scale reaction with 0.2 mol% of the catalyst. The obtained isocyanoacetoamide was employable for the further transformation into the trisubstituted oxazole without any purification procedure. DFT calculation suggested that the neighboring group effect of the carbonyl moiety in the substrate amide group assisted the elimination of phosphate and stabilized the carbocation intermediate. A plausible reaction mechanism of the isocyanation is also described.

Exploitation of Intrinsic Confinement Effects of MOFs in Catalysis

AbstractIn catalysis research the design of bio‐inspired,'artificial enzymes‘ is a field of huge interest. These catalysts are distinguished by their high catalytic efficiency resulting from a close proximity of several active sites and secondary substrate‐catalyst interactions enabled by functional groups in the catalytic pocket. A class of materials which meets these requirements are metal‐organic frameworks (MOFs). Here, the pores confine a reaction environment where several functionalities can be incorporated and spatially positioned in a tunable fashion. Recently, a number of reports revealed the importance of such confinement effects for the control of catalytic activity and selectivity by exploiting the intrinsic properties like pore size and neighboring group effects and the alignment and distance of different active sites within one MOF pore. Thus, this concept aims to accentuate the potential of the exploitation of those effects in MOFs for the design of sophisticated catalysts.

Chiral Chalcogenyl-Substituted Naphthyl- and Acenaphthyl-Silanes and Their Cations.

Cyclic silylated chalconium borates 13[B(C6F5)4] and 14[B(C6F5)4] with peri‐acenaphthyl and peri‐naphthyl skeletons were synthesized from unsymmetrically substituted silanes 3, 4, 6, 7, 9 and 10 using the standard Corey protocol (Chalcogen Ch=O, S, Se, Te). The configuration at the chalcogen atom is trigonal pyramidal for Ch=S, Se, Te, leading to the formation of cis‐ and trans‐isomers in the case of phenylmethylsilyl cations. With the bulkier tert‐butyl group at silicon, the configuration at the chalcogen atoms is predetermined to give almost exclusively the trans‐configurated cyclic silylchalconium ions. The barriers for the inversion of the configuration at the sulfur atoms of sulfonium ions 13 c and 14 a are substantial (72–74 kJ mol−1) as shown by variable temperature NMR spectroscopy. The neighboring group effect of the thiophenyl substituent is sufficiently strong to preserve chiral information at the silicon atom at low temperatures.

Dedicated to a peptide chemist of few words and immense impact: Louis A. Carpino

Dedicated to a peptide chemist of few words and immense impact: Louis A. Carpino

Efficient synthesis of branched poly(acrylic acid) derivatives via postpolymerization modification

AbstractThe utility of pentafluorophenyl esters for the selective introduction of functional units and branch points in well‐defined poly(acrylic acid) (PAA) derivatives is demonstrated using a combination of controlled radical polymerization and postpolymerization modification. Reversible addition‐fragmentation chain transfer enables the synthesis of well‐defined copolymers—poly(pentafluorophenyl acrylate‐co‐tert‐butyl acrylate)—with the active ester repeat units serving as attachment points for reaction with primary amines, specifically tris(2‐(t‐butoxycarbonyl)ethyl)methyl amine (Behera's amine). Deprotection using trifluoroacetic acid removes both the backbone and side chain t‐butyl esters to give a series of branched PAA derivatives containing novel tricarboxylic acid side chains that are well suited to complexation and multidentate interactions. Surprisingly, the active ester homopolymer is shown to have the highest reactivity with Behera's amine when compared to copolymers with lower incorporation of pentafluorophenyl esters, suggesting an intriguing interplay of neighboring group effects and steric interactions. The ability to tune the efficiency of postpolymerization modification gives a library of PAA derivatives.

Enhancing the biocompatibility of rhodamine fluorescent probes by a neighbouring group effect.

Fluorescence microscopy is an essential tool for understanding dynamic processes in living cells and organisms. However, many fluorescent probes for labelling cellular structures suffer from unspecific interactions and low cell permeability. Herein, we demonstrate that the neighbouring group effect which results from positioning an amide group next to a carboxyl group in the benzene ring of rhodamines dramatically increases cell permeability of the rhodamine-based probes through stabilizing a fluorophore in a hydrophobic spirolactone state. Based on this principle, we create probes targeting tubulin, actin and DNA. Their superb staining intensity, tuned toxicity and specificity allows long-term 3D confocal and STED nanoscopy with sub-30 nm resolution. Due to their unrestricted cell permeability and efficient accumulation on the target, the new probes produce high contrast images at low nanomolar concentrations. Superior performance is exemplified by resolving the real microtubule diameter of 23 nm and selective staining of the centrosome inside living cells for the first time.

Novel R3M (M = Si, Ge) substituted furan and thiophene-derived aldimines: Synthesis, electrochemistry, and biological activity

New furan and thiophene derivatives of aldimines o -HO-C 6 H 4 N CHC 4 H 4 X(R) (X = O, S; R = H, SiMe 3 , SiEt 3 , GeMe 3 , GeEt 3 ) were synthesized by condensation of o -aminophenol with the substituted aldehyde precursor. Their structure, electrochemical reduction/oxidation (in CH 3 CN/0.1 M Bu 4 NPF 6 ), frontier orbital energies, and cytotoxicity have been studied. Their electrochemical redox potentials E p show good correlation with the corresponding orbital energies and the difference E p ox – E p red corresponds well to their orbital hardness. These new compounds have a pronounced cytotoxicity toward cancer cells of human fibrosarcoma HT-1080 and mouse hepatoma MG-22A (IC 50 ≅ 1–8 μg ml −1 ) that can be modulated by introducing a Me 3 M substituent into the fifth position of the heterocycle (e.g., IC 50 (Me 3 Si)/IC 50 (H) ≥ 50). R 3 M-substitution reduces the orbital hardness of the aldimines studied and facilitates oxidation, promoting their oxidative metabolism. The neighboring group effect in the α-Me 3 Si-substituted thiophene derivative favors S-oxidation, which supposedly makes its metabolic mechanism different compared to R 3 M-substituted furan series (or for M = Ge in the thiophene series). Interestingly, SiMe 3 and GeMe 3 groups in both heterocyclic series (furan and thiophene) cause opposite trends in cytotoxicity, while the silyl group increases it, the germyl group decreases it. De nouvelles aldimines o -HO-C 6 H 4 N CHC 4 H 4 X(R) (X = O, S; R = H, SiMe 3 , SiEt 3 , GeMe 3 , GeEt 3 ), dérivées du furanne et du thiophène, ont été synthétisées par la condensation d' o -aminophenol avec l'aldéhyde précurseur substitué correspondant. La structure, la réduction et l'oxydation électrochimique (dans CH 3 CN/0.1 M Bu 4 NPF 6 ), les énergies des orbitales frontières et la cytotoxicité de ces composés ont été étudiées. Les potentiels redox électrochimiques E p de ces composés montrent une bonne corrélation avec les énergies orbitalaires correspondantes, et la différence E p ox – E p red correspond bien à leur dureté orbitalaire. Ces nouveaux composés ont une cytotoxicité prononcée sur les cellules du fibrosarcome humain HT-1080 et de l'hépatome de souris MG-22A (IC 50 ≅ 1–8 μg ml −1 ); elle peut être modulée par l'introduction d'un substituant Me 3 M en position 5 de l'hétérocycle (par exemple, IC 50 (Me 3 Si)/IC 50 (H) ≥ 50). Cette substitution réduit la dureté orbitalaire des aldimines étudiées et facilite leur oxydation en favorisant le métabolisme oxydatif. L'effet d'un groupe voisin dans le thiophène substitué en position α par Me 3 Si favorise son S-oxydation, ce qui vraisemblablement rend son mécanisme métabolique différent par rapport à celui des dérivés R 3 M-substitués dans la série du furanne (ou pour M = Ge dans la série du thiophène). Il est intéressant de noter que les groupements SiMe 3 et GeMe 3 dans les deux séries hétérocycliques (furanne, thiophène) ont des effets opposés sur la cytotoxicité: le groupement silyle l'augmente, tandis que le groupement germyle la réduit.

Oxidative Damage in Aliphatic Amino Acids and Di- and Tripeptides by the Environmental Free Radical Oxidant NO3•: The Role of the Amide Bond Revealed by Kinetic and Computational Studies

Kinetic and computational data reveal a complex behavior of the important environmental free radical oxidant NO3• in its reactions with aliphatic amino acids and di- and tripeptides, suggesting that attack at the amide N-H bond in the peptide backbone is a highly viable pathway, which proceeds through a proton-coupled electron transfer (PCET) mechanism with a rate coefficient of about 1 × 106 M-1 s-1 in acetonitrile. Similar rate coefficients were determined for hydrogen abstraction from the α-carbon and from tertiary C-H bonds in the side chain. The obtained rate coefficients for the reaction of NO3• with aliphatic di- and tripeptides suggest that attack occurs at all of these sites in each individual amino acid residue, which makes aliphatic peptide sequences highly vulnerable to NO3•-induced oxidative damage. No evidence for amide neighboring group effects, which have previously been found to facilitate radical-induced side-chain damage in phenylalanine, was found for the reaction of NO3• with side chains in aliphatic peptides.

Neighboring group effect on the thermal degradation of polyacrylamide and its derivatives

Abstract Being an important class of water-soluble synthetic polymers, polyacrylamide (PAM) and its derivatives have found a wide range of applications in the oil and gas industry. Due to the increasingly active exploration of deep and ultra-deep wells, PAM-based polymers are more and more frequently applied under hostile subterranean conditions, particularly high temperature. Therefore, it becomes an imminent research topic to elucidate the thermal degradation pathways of PAM-based polymers in order to upgrade these chemicals for more challenging scenarios. Neighboring groups attached to the same polyvinyl backbone have been suggested to exert an effect to the degradation of the PAM-based polymers. Herein we report a combined theoretical and experimental study on the energetics of such neighboring group effect. Taking advantage of a computational method based on density functional theory, we have identified two competing degradation pathways in neutral medium and have calculated their respective activation energies. These results enable us to predict the relative thermal stabilities of a series of PAM-based polymers, and we have also used temperature-variant rheology measurements to verify these predictions. This work will guide the design of better heat-resistant PAM-based products.

Synthesis of α-Borylated Ketones by Regioselective Wacker Oxidation of Alkenylboronates

As part of a program aimed at metal-catalyzed oxidative transformations of molecules with carbon-metalloid bonds, the synthesis of α-borylated ketones is reported via regioselective TBHP-mediated Wacker-type oxidation of N-methyliminodiacetic acid (MIDA)-protected alkenylboronates. The observed regioselectivity correlates with the hemilabile nature of the B-N dative bond in the MIDA boronate functional group, which allows boron to guide selectivity through a neighboring group effect.

Deamidation of pseudopeptidic molecular hydrogelators and its application to controlled release

HypothesisThe incorporation of a succinic acid-derived moiety in amino acid derivatives would favor an intramolecular catalysis of a deamidation reaction. Such reaction would permit controlled disassembly of molecular hydrogelators and the use of the hydrogels for controlled release of actives. ExperimentalLow molecular weight hydrogelators containing a succinic acid-derived moiety were prepared by conventional organic synthesis procedures. Hydrogels were examined by electron microscopy and 1HNMR studies were carried out to evaluate the solubility in water of the hydrogelators and the deamidation reaction. Liberation of Rose Bengal entrapped in the hydrogels was monitored by UV–Vis spectroscopy. FindingsMolecular hydrogels formed by pseudopeptidic derivatives of l-valine suffer a thermal deamidation reaction, leading to partial disassembly. The succinic acid-derived moiety present in the gelators is responsible of intramolecular catalysis of a deamidation reaction. Such neighboring group effect is reminiscent of biochemical processes such as protein deamidation and self-excision of inteins. It has been found that the thermodynamic equilibrium of the deamidation reaction is regulated by the efficiency of hydrogelation. As a proof of concept, the thermally promoted deamidation is applied to controlled release of Rose Bengal.

One-Pot Synthesis of Unprotected Anomeric Glycosyl Thiols in Water for Glycan Ligation Reactions with Highly Functionalized Sugars.

Chemical synthesis of oligosaccharide conjugates is essential for studying the functional relevance of carbohydrates, and this task would be facilitated considerably if reliable methods for the anomeric ligation of unprotected sugars in water were available. Here, a method for the preparation of anomeric glycosyl thiols from complex unprotected mono-, di-, and oligosaccharides is presented. By exploiting the neighboring-group effect of the 2-acetamido-group, 1,2-oxazolines are generated and converted into 1-glycosyl thioesters through treatment with 1-thioacids. The unprotected anomeric glycosyl thiolates released in situ were conjugated to Michael acceptors, aliphatic halogenides, and aziridines to furnish versatile glycoconjugates. Conjugation of amino acids and proteins was accomplished using the thiol-ene reaction with terminal olefins. This method gives efficient access to anomeric glycosyl thiols and thiolates, which enables anomeric ligations of complex unprotected glycans in water.