Neighboring Amide Group Research Articles

Regiodivergent Synthesis of 1,3‐ and 1,4‐Enynes through Kinetically Favored Hydropalladation and Ligand‐Enforced Carbopalladation

AbstractPd‐catalyzed hydroalkynylations were developed that involve ligand‐enabled regiodivergent addition of an alkyne to an allenamide, giving branched and linear products stereoselectively and facilitated by the neighboring amide group. Regioselectivity was achieved with the use of (o‐OMePh)3P and BrettPhos, which allowed the functionalization of various alkynes, including steroids, carbohydrates, alkaloids, chiral ligands, and vitamins. Based on the experimental results, it was proposed that hydro‐ and carbopalladation processes operated during the formations of the branched and linear products, respectively.

Regiodivergent Synthesis of 1,3- and 1,4-Enynes through Kinetically Favored Hydropalladation and Ligand-Enforced Carbopalladation.

Pd-catalyzed hydroalkynylations were developed that involve ligand-enabled regiodivergent addition of an alkyne to an allenamide, giving branched and linear products stereoselectively and facilitated by the neighboring amide group. Regioselectivity was achieved with the use of (o-OMePh)3 P and BrettPhos, which allowed the functionalization of various alkynes, including steroids, carbohydrates, alkaloids, chiral ligands, and vitamins. Based on the experimental results, it was proposed that hydro- and carbopalladation processes operated during the formations of the branched and linear products, respectively.

ChemInform Abstract: Regioselective Hydrolysis and Transesterification of Dimethyl 3‐Benzamidophthalates Assisted by a Neighboring Amide Group.

An efficient, highly regioselective hydrolysis and transesterification of dimethyl 3-benzamidophthalates into the corresponding carboxylic acid monoesters and mixed esters (including tert-butyl esters) under basic conditions is presented. The selectivity is governed by the neighboring 3-benzamido moiety’s participation and by the nature of the solvent. In alcohols the reaction occurred exclusively at the ortho-position to the benzamido functionality, in pyridine or acetonitrile at both ester groups. An insight into the mechanistic pathway was obtained from a 1H NMR study in perdeuteromethanol.

Regioselective Hydrolysis and Transesterification of Dimethyl 3-Benzamidophthalates Assisted by a Neighboring Amide Group.

An efficient, highly regioselective hydrolysis and transesterification of dimethyl 3-benzamidophthalates into the corresponding carboxylic acid monoesters and mixed esters (including tert-butyl esters) under basic conditions is presented. The selectivity is governed by the neighboring 3-benzamido moiety's participation and by the nature of the solvent. In alcohols the reaction occurred exclusively at the ortho-position to the benzamido functionality, in pyridine or acetonitrile at both ester groups. An insight into the mechanistic pathway was obtained from a (1)H NMR study in perdeuteromethanol.

Proline as a charge stabilizing amino acid in peptide radical cations

Long distance electron transfer in proteins requires relay stations that can be transitorily oxidized or reduced. Although individual prolines cannot assume this function, because of their high ionization energy, it has been shown that polyprolines have the ability to transfer charges. In order to determine the role of the proline in the hole distribution and transport within a PheProPhe tripeptide, the radical cation of a model compound where the phenylalanines carry two or three methoxy groups, respectively, was generated by flash photolysis. Surprisingly, after equilibration, about two thirds of the holes were found to reside on the phen(OMe)2 instead of the more easily oxidizable phen(OMe)3 moiety. DFT calculations showed that, in most of the accessible conformations, the phen(OMe)2• +‐moiety profits more from stabilization by N‐ and/or O‐lone pairs of neighboring amide groups than the phen(OMe)3• + moiety can, which explains the apparently counterthermodynamic hole distribution. Similar calculations showed that, in several conformers of the natural PheProPhe radical cation, the unpaired electron is delocalized over two amide groups, by residing in a σ MO which links the N‐lone pair of the central proline unit with the O‐lone pair of a proximate amino acid, through hyperconjugation via the intervening C―Cα σ‐bond. The same pattern is found in a model compound, N‐acetylproline dimethylamide. It seems that prolines favor conformers which foster hyperconjugation of two amide groups, which lowers the ionization energy of peptides. One should thus consider such interacting amide groups as potential relay stations in the course of electron transfer in polyprolines. Copyright © 2015 John Wiley & Sons, Ltd.

A γ-amino acid that favors 12/10-helical secondary structure in α/γ-peptides.

H-bonded helices in conventional peptides (containing exclusively homochiral α-amino acid residues) feature a uniform H-bonding directionality, N-terminal side C═O to C-terminal side NH. In contrast, heterochiral α-peptides can form helices in which the H-bond directionality alternates along the backbone because neighboring amide groups are oriented in opposite directions. Alternating H-bond directions are seen also in helices formed by unnatural peptidic backbones, e.g., those containing β- or γ-amino acid residues. In the present study, we used NMR spectroscopy and crystallography to evaluate the conformational preferences of the novel γ-amino acid (1R,2R,3S)-2-(1-aminopropyl)-cyclohexanecarboxylic acid (APCH), which is constrained by a six-membered ring across its Cα-Cβ bond. These studies were made possible by the development of a stereoselective synthesis of N-protected APCH. APCH strongly enforces the α/γ-peptide 12/10-helical secondary structure, which features alternating H-bond directionality. Thus, APCH residues appear to have a conformational propensity distinct from those of other cyclically constrained γ-amino acid residues.

Strength of NH···S Hydrogen Bonds in Methionine Residues Revealed by Gas-Phase IR/UV Spectroscopy.

Despite of being ubiquitous in proteins, NHbackbone···S hydrogen bonds linking the sulfur atom of methionine or cysteine to backbone NH groups remain poorly documented. Here, we report vibrationally resolved IR NH stretch spectra of two methionine-containing dipeptides (Ac-Phe-Met-NH2 and Ac-Met-Phe-NH2). The conformations observed for both molecules, assigned with the help of DFT-D quantum chemistry, provide spectroscopic evidence for the formation of NHbackbone···S H-bonds, surprisingly strong enough to challenge the classical intrabackbone NH···O═C H-bonds. The methionine side chain is found to fold locally, forming a H-bond with the neighboring amide groups (NH(i) or NH(i+1)). Comparison with protein data bank structural information shows that such a local folding is also common in proteins where it concerns 24% of the methionine residues that have a sulfur atom linked to a backbone NH group. This convergence between the strength of these NH···S H-bonds and protein structural data illustrates their contribution to the stability of protein chains.

Gas-phase Infrared Spectroscopy of Monopeptides from 10 to 3 µm

Abstract Infrared spectra of protected amino acids, N-benzoxycarbonyl-l-proline and N-benzoxycarbonyl-l-isoleucine were measured in the gas phase from 10 to 3 µm. 4 and 3 conformers were found, respectively. The spectra in the 3 µm region reveal the carboxylic OH and amide NH bonds do not participate in hydrogen bonding with neighboring amide groups despite the highest acidity in the molecule. The spectra in the 10–5 µm region imply the main chain structure is the same among the conformers.

ChemInform Abstract: Azomethine Ylide Generation via the Dipole Cascade.

Abstract A series of N-acyl 2-diazo-3-oxobutanoates, when treated with a catalytic quantity of a rhodium(II) carboxylate, were found to afford substituted pyrroles derived from an azomethine ylide intermediate. The initial reaction involves generation of the expected carbonyl ylide dipole by intramolecular cyclization of the keto carbenoid onto the oxygen atom of the neighboring amide group. The primary cycloadduct undergoes a subsequent rearrangement-fragmentation reaction to give the pyrrole derivative. When the α-position of the α-diazoketone was blocked with two methyl groups, the rhodium(II)-catalyzed cycloaddition with dimethyl acetylenedicarboxylate led to the carbonyl vlide cycloadduct in high yield. MNDO calculations show that the cyclic carbonyl ylide derived from ethyl 2-diazo-4-dibenzoylamino-3-oxobutyrate is 3.3 kcal lower in its heat of formation than the corresponding azomethine ylide. This thermodynamic difference in stability of dipoles nicely accounts for why the carbonyl ylide cycloadduct is the major product from the rhodium(II) catalyzed reaction of ethyl 2-diazo-4-dibenzoylamino-3-oxobutyrate.

Effects of Water and Temperature on Conformational Order in Model Nylon Thin Films

Nylon 6,6 thin films have been examined by Raman spectroscopy to determine how chain conformation is influenced by environmental parameters such as exposure to water and temperature variations. The motivation for this work is to elucidate how interactions between water and the model polymers mediate polymer structures in applications such as the removal of salt from water in reverse osmosis membranes. Raman spectra show that model self-assembled monolayers containing Nylon 6,6 chains are semicrystalline under ambient conditions. The native chains adopt an unusual kinked and folded conformation related to that found in γ-Nylon 6,6. The regular chain deformations allow adjacent tethered chains to maximize hydrogen-bonding between neighboring amide groups under the constraints imposed by surface tethering. With increasing temperature, the films undergo a phase transition associated with the disruption of hydrogen bonds leading to structures containing more linear regions that are closer to the “all trans” case. Similar structural changes are observed on exposing the Nylon films to water. The salt content of the water does not appear to have a significant impact on the structure or phase transition in the Nylon 6,6. These results suggest that while inclusion of water has a profound effect on the polymer structure, either salt is excluded from the polymer or there is sufficient free volume within the films to accommodate hydrated ions without inducing further structural changes.

Single-Conformation and Diastereomer Specific Ultraviolet and Infrared Spectroscopy of Model Synthetic Foldamers: α/β-Peptides

Resonant two-photon ionization (R2PI), UV hole-burning (UVHB), and resonant ion-dip infrared (RIDIR) spectroscopies have been used to record single-conformation infrared and ultraviolet spectra of three model synthetic foldamers with heterogeneous backbones, alpha/beta-peptides Ac-beta(3)-hAla-L-Phe-NHMe (betaalphaL), Ac-beta(3)-hAla-D-Phe-NHMe (betaalphaD), and Ac-L-Phe-beta(3)-hAla-NHMe (alphabetaL), isolated and cooled in a supersonic expansion. BetaalphaL and betaalphaD are diastereomers, differing only in the configuration of the alpha-amino acid residue; betaalphaL and alphabetaL contain the same residues, but differ in residue order. In all three alpha/beta-peptides the beta(3)-residue has S absolute configuration. UVHB spectroscopy is used to determine that there are six conformers of each molecule and to locate and characterize their S(0)-S(1) transitions in the origin region. RIDIR spectra in the amide NH stretch region reflect the number and strength of intramolecular H-bonds present. Comparison of the RIDIR spectra with scaled, harmonic vibrational frequencies and infrared intensities leads to definite assignments for the conformational families involved. C8/C7(eq) double-ring structures are responsible for three conformers of betaalphaL and four of betaalphaD, including those with the most intense transitions in the R2PI spectra. This preference for C8/C7(eq) double rings appears to be dictated by the C7(eq) ring of the alpha-peptide subunit. Three of the conformers of betaalphaL and betaalphaD form diastereomeric pairs (A/A', C/C', and G/G') that have nearly identical S(0)-S(1) origin positions in the UV and belong to the same conformational family, indicating no significant change associated with the change in chirality of the alpha-peptide subunit. However, betaalphaL favors formation of a C6/C5 conformer over C11, while the reverse preference holds in betaalphaD. Calculations indicate that the selective stabilization of the lowest-energy C11(g(+)) structure in betaalphaD occurs because this structure minimizes steric effects between the beta(2) methylene group and C=O(1). In the alpha/beta-peptide alphabetaL, two conformers dominate the spectrum, one assigned to a C5/C8 bifurcated double-ring, and the other to a C5/C6 double-ring structure. This preference for C5 rings in the alpha/beta-peptide occurs because the C5 ring is further stabilized by an amide NH...pi interaction involving an NH group on the adjacent amide, as it is in the alpha-peptides. Comparison of the NH stretch spectra of C8/C7(eq) structures in betaalphaL with their C7(eq)/C8 counterparts in alphabetaL shows that the central amide NH stretch is shifted to lower frequency by some 50-70 cm(-1) due to cooperative effects associated with the central amide accepting and donating a H-bond to neighboring amide groups. This swaps the ordering of the C8 and C7 NH stretch fundamentals in the two molecules.

Dioxotungsten 1,2-Benzenedithiolate Complex Stabilized by NH···S Hydrogen Bonds

Novel dioxo-tungsten(VI) bis(1,2-benzenedithiolate) complexes with neighboring amide groups, as models for tungsten enzymes, (NEt4)2[W(VI)O2{1,2-S(2)-3,6-(RCONH)2C6H2}2] (R = CH3, t-Bu), were designed and synthesized. The presence of the NH...S hydrogen bond was confirmed through IR spectrometry and X-ray crystallographic analysis. In the W(VI)O2 complexes, the NH...S hydrogen bond trans to the oxo ligand is stronger than that cis to oxo. On the basis of comparisons with [W(VI)O2(1,2-S2C6H4)2](2-), the NH...S hydrogen bond positively shifted the W(VI)/W(V) redox potentials and depressed the reduction by benzoin or triphenylphosphine. These results suggest that the NH...S hydrogen bond stabilizes the oxo ligand through trans influence and regulates O-atom transfer in tungsten and molybdenum enzymes.

O-Atom-Transfer Oxidation of [Molybdenum(IV) Oxo{3,6-(acylamino)2-1,2-benzenedithiolato}2]2- Promoted by Intramolecular NH···S Hydrogen Bonds

Novel molybdenum dithiolene compounds having neighboring amide groups as models for molybdoenzymes, (NEt(4))(2)[Mo(IV)O{1,2-S(2)-3,6-(RCONH)(2)C(6)H(2)}(2)] (R = CH(3), CF(3), t-Bu, Ph(3)C), were designed and synthesized. The contributions of the NH...S hydrogen bond to the electrochemical properties of the metal ion and the reactivity of the O-atom-transfer reaction were investigated by a comparison with [Mo(IV)O(1,2-S(2)C(6)H(4))(2)](2)(-). The MoOS(4) core of [Mo(IV)O{1,2-S(2)-3,6-(CH(3)CONH)(2)C(6)H(2)}(2)](2)(-) shows no significant geometrical difference from that of [Mo(IV)O(1,2-S(2)C(6)H(4))(2)](2)(-) in the crystal. The hydrogen bonds positively shifted the Mo(IV/V) redox potential and accelerated the reduction of Me(3)NO.

IRRAS Studies on Chain Orientation in the Monolayers of Amino Acid Amphiphiles at the Air−Water Interface Depending on Metal Complex and Hydrogen Bond Formation with the Headgroups

Monolayers of N-octadecanoyl-L-alanine at the air-water interface on pure water and metal ion containing subphases have been studied using polarized infrared reflection-absorption spectroscopy (IRRAS). The metal complex and hydrogen bond formation with the headgroups give rise to a change in chain order depending on metal ion in the subphase. On pure water and Ag(+)-/Pb(2+)-containing subphase, the antisymmetric CH(2) stretching band intensity [nu(a)(CH(2))] undergoes a slower increase than the symmetric one [nu(s)(CH(2))] below the Brewster angle, so the intensity ratios of nu(a)(CH(2))/nu(s)(CH(2)) are less than 1 in the cases of Ag(+) and Pb(2+). Beyond the Brewster angle, the nu(a)(CH(2)) band intensities are substantially reduced in comparison with the nu(s)(CH(2)) ones in the cases of pure water and Ag(+), but the nu(a)(CH(2)) bands still remain negative-oriented in the presence of Pb(2+). These unusual spectral features indicate that the alkyl chains take a preferential orientation with their C-C-C planes parallel to the water surface. The parallel packing of the alkyl chains results from the intermolecular hydrogen bonds C=O...H-N between the neighboring amide groups, strengthened by the metal complex of covalent interaction. On the Ca(2+)-/Cu(2+)-containing subphase, the corresponding polarized spectra display a usual behavior. The alkyl chains are roughly estimated to be inclined around 35-40 degrees from the surface normal on the assumption of chain segment orientation for the monolayers in the liquid-expanded phase. The chain conformation and tilt are closely related to the formation of intramolecular hydrogen bonds and the ionic interaction of the metal complex in the cases of Ca(2+) and Cu(2+).

Mobility Enhancement in Amorphous Polyamide 6,6 Induced by Water Sorption: A Molecular Dynamics Simulation Study

The local dynamics of water and its effect on the segmental mobility in the amorphous phase of polyamide 6,6 have been investigated. At 300 K and below, where the polymer segments undergo no significant motion (displacements below 2 Å, no reorientation) in the time scale of the simulation, water molecules exhibit mostly orientational freedom, and a bimodal distribution of reorientation times is observed. As the temperature is increased, an increasing fraction of the water molecules also experience hopping behavior between polyamide 6,6 cavities, but true diffusion on a nanosecond time scale is observed only above 400 K. The analysis of amide and methylene group reorientation clearly shows lubrication of the intermolecular amide−amide hydrogen bond, detected above 350 K only at the time scale of 2 ns. This phenomenon goes beyond a simple free volume effect, as is shown through the analysis of the local hydration of individual amide groups. The motion of inner methylene segments is also affected by water, but in a more limited extent. The enhancement of their mobility with water content is probably an indirect effect of the lower reorientation times of neighboring amide groups.

Three-dimensional Solution Structure of the Cytoplasmic B Domain of the Mannitol Transporter IIMannitol of the Escherichia coli Phosphotransferase System

The solution structure of the cytoplasmic B domain of the mannitol (Mtl) transporter (II(Mtl)) from the mannitol branch of the Escherichia coli phosphotransferase system has been solved by multidimensional NMR spectroscopy with extensive use of residual dipolar couplings. The ordered IIB(Mtl) domain (residues 375-471 of II(Mtl)) consists of a four-stranded parallel beta-sheet flanked by two helices (alpha(1) and alpha(3)) on one face and helix alpha(2) on the opposite face with a characteristic Rossmann fold comprising two right-handed beta(1)alpha(1)beta(2) and beta(3)alpha(2)beta(4) motifs. The active site loop is structurally very similar to that of the eukaryotic protein tyrosine phosphatases, with the active site cysteine (Cys-384) primed in the thiolate state (pK(a) < 5.6) for nucleophilic attack at the phosphorylated histidine (His-554) of the IIA(Mtl) domain through stabilization by hydrogen bonding interactions with neighboring backbone amide groups at positions i + 2/3/4 from Cys-384 and with the hydroxyl group of Ser-391 at position i + 7. Modeling of the phosphorylated state of IIB(Mtl) suggests that the phosphoryl group can be readily stabilized by hydrogen bonding interactions with backbone amides in the i + 2/4/5/6/7 positions as well as with the hydroxyl group of Ser390 at position i + 6. Despite the absence of any significant sequence identity, the structure of IIB(Mtl) is remarkably similar to the structures of bovine protein tyrosine phosphatase (which contains two long insertions relative to IIB(Mtl)) and the cytoplasmic B component of enzyme II(Chb), which fulfills an analogous role to IIB(Mtl) in the N,N'-diacetylchitobiose branch of the phosphotransferase system. All three proteins utilize a cysteine residue in the nucleophilic attack of a phosphoryl group covalently bound to another protein.

Effect of neighbouring amide group bulkiness on anchimerically assisted ether bond cleavage: Part 7

AbstractThe effect of the bulkiness of the amide group vicinal to the ether bond on the acid hydrolysis rate of substrates 1b–d was investigated. The kinetic data showed that increased bulkiness of the acyl group has a considerable effect on the reaction rate, accelerating the anchimerically assisted hydrolytic process of the ether bond. A different mechanism is proposed for 1d, which is supported by the thermodynamic activation parameters values. The hydrolysis rate of 1d is about 3 × 105‐fold higher than that of the reference compound. Copyright © 2004 John Wiley &amp; Sons, Ltd.

Formation of 6-, 7- or 8-membered ring intra-side-chain NH[rad]O hydrogen bond toward Ca-binding oxyanion in poly(allylaminocarboxylate) ligands stabilizes CaCO3 vaterite crystals

Novel poly(allylaminocarboxylate) ligands, which have a carboxylate and the neighboring amide group in the same side-chain, were synthesized as model ligands for crystalline CaCO3 biominerals. Poly{N-allyl-malonamate}, poly{N-allyl-succinamate} and poly{4-allylcarbamoyl-butyrate} form 6-, 7- or 8-membered ring intra-side-chain NHO hydrogen bonds, respectively, between the carboxylate and the neighboring amide NH in the carboxylate anion state, although the formation of each intra-side-chain NHO hydrogen bond is independent on the stereoisomers of the polymer main-chain. In the polymer ligand–CaCO3 composites, strong binding of polymer ligands to CaCO3 crystals is caused by stabilizing a Ca–O (carboxylate) bond due to the pKa shift of carboxylic acid by the NHO hydrogen bond. Furthermore, the strong Ca binding in CaCO3 composites stabilizes the meta-stable morphology of CaCO3 vaterite crystals.

Crystal and molecular structure of an (S)-(+)-enantiomer of modafinil, a novel wake-promoting agent.

The (+)-enantiomer of modafinil [(RS)-2-(diphenylmethylsulfinyl)acetamide], a novel wake-promoting agent, was clarified to be S-configuration by X-ray crystal structure analysis. The crystal consists of two crystallographically independent conformers that are different at the torsion angles around the sulfinylacetamide moiety, and this results from the molecular packing requirement to form a two-dimensional hydrogen-bonding network via neighboring amide groups in the crystal. The crystal structure is characterized by the formation of alternative hydrophobic and hydrophilic layers, which are formed among the symmetry-translated assemblies of diphenylmethyl and sulfinylacetamide moieties, respectively. The spatial orientation between the diphenyl and amide groups is believed to be important for the activity of modafinil.

Acid Hydrolysis of an Ether Bond Assisted by the Neighbouring Amide Group: Effects Induced by Salts and by Structural Changes Part 61-5

The acid hydrolysis of 1 assisted by the neighbouring amide group was kinetically investigated and salt effects were studied; the thermodynamic activation parameters calculated for the acid hydrolysis of other substrates (3–6) indicate that the methyl group in the side chain works on the enthalpic or on the entropic factor depending on the size of ring formed.