Amide Deprotonation Research Articles

Kinetic Investigation of Pd(II)-Catalyzed Ortho C-H Iodination of Benzamide with I2

Abstract Intimate kinetic investigation of Pd(II)-catalyzed ortho C-H iodination of benzamide substrate via cyclopalladation was performed for the first time by using molecular I2 as a sole oxidant and acetate as a base. The reaction rate of the cyclopalladation step is independent of benzamide concentration but increased with an increase in acetate concentration and then gradually decreased due to blocking on coordination sites of Pd(II) by acetate. On the other hand, the reaction rate of the subsequent iodination step was first-order with respect to I2 concentration. Though the total activation energies of the cyclopalladation and iodination processes are comparable, it is reasonable that the cyclopalladation appears to be the rate-determining step of Pd(II)-catalyzed ortho C-H iodination, in which substrates, I2, and acetate are used in large excess. From the present results, it can be proposed that a minimum amount of acetate required for deprotonation of amide and ortho proton for cyclopalladation and rather excess I2 should be used to provide acceleration and high performance of Pd(II)-catalyzed ortho C-H iodination.

Crystal structures and physicochemical studies of some novel divalent and trivalent transition metal chelates of N-morpholine-N'-benzoylthiourea

A series of Fe(III), Co(III), Ni(II), Cu(II), Zn(II) and In(III) N-morpholine-N'-benzoylthiourea complexes have been synthesised and characterised by elemental analysis, thermal analysis, infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy and single crystal X-ray crystallography. Thermogravimetric analysis shows that all the complexes undergo a two-step decomposition process except for the iron(III) complex and the indium(III) complexes, which show three-step and one-step decompositions, respectively. The complexes are thermally stable up to approximately 300 °C. The ligand coordinates the various metal ions in a bidentate (L-kO,S) chelating mode, facilitated by deprotonation of the acidic amide (–C(O) N'HC (S)) moiety. This mode of coordination allows for the facile formation of neutral bis/tris-6-membered chelates of type [M(L-kS,O)x] where x = 2 or 3 for divalent or trivalent metal ions, respectively.

Unexpected linkage isomerism in chiral tetranuclear bis-tridentate (1,2,3-triazol-4-yl)-picolinamide (tzpa) grids.

The synthesis of a chiral bis-tridentate (1,2,3-triazol-4-yl)-picolinamide (tzpa) ligand is described and its coordination chemistry with Cu(NO3)2 and [Cu(MeCN)4]PF6 is explored in the crystalline phase as well as in solution. Chiral [2 × 2] tetranuclear square grid complexes [Cu4(H21)4](NO3)8 and [Cu4(H1)4](PF6)4 were observed, and crystallographically analysed, these being linkage isomers with N4O2 and N5O coordination spheres, respectively. These come about by an unusual in situ amide deprotonation and coordination, which accompanies a CuI → CuII oxidation process.

Interaction of Na+ and K+ ions with DTPA-amide dioxa-pentaaza-cyclophanes: effect of electrostatic field in macrocyclic cavity on UV absorption spectra and protonation

The effects of electrolytes on protonation were studied by UV spectrometry on the geometrical isomers of dioxapentaazacyclophanes that were synthesized by 1+1-cyclization of diethylenetriaminepentaacetic (DTPA) dianhydride with aromatic diamine involving 1,3- or 1,4-phenylenebis(methyleneoxy) group. Absorption bands at 245 and 280 nm respond to pH in association with the protonation status confirmed by 1H NMR. The logarithmic first-protonation constants, determined from the absorptivity versus pH curves, depend on coexisting alkali metal ions in a range of 7.7−8.2 in 0.01 M solutions of the chlorides. The more pronounced effect of alkali metals occurs in the dissociation of amide proton; the logarithmic deprotonation constant, log Kp−1, of the 1,3-oxymethyl isomer is −9.48 in 0.01 M NaCl and −10.35 in 0.01 M KCl; the constant of the 1,4-oxymethyl isomer, −9.79 in 0.01 M NaCl and −11.58 in 0.01 M KCl; no amide deprotonation is observable in 0.01 M LiCl. Alkali metal ions Na+ and K+ are accommodated in a macrocyclic cavity through interaction with the oxa-donor sites, and produce an intense electrostatic field within the cavity. The resulting field causes large changes in absorptivity, and also enforces amide deprotonation. Sodium ion is so effective that the deprotonation occurs at pH as low as 9.5−9.8. Potassium ion is less effective on the amide deprotonation, but the action is selective towards the isomers.

Phosphine-Catalyzed (3 + 2) Annulation of δ-Acetoxy Allenoates with 2-Sulfonamidomalonate: Synthesis of Highly Substituted 3-Pyrrolines and Mechanistic Insight.

A mild and efficient synthetic protocol for 3-pyrrolines via the phosphine-catalyzed (3 + 2) annulation of δ-acetoxy allenoates with 2-sulfonamidomalonate is reported. The asymmetric version (up to 83% ee) is also achieved by using phosphine ( R)-SITCP as the catalyst. Mechanistic experiments disclose that the involved deprotonation of amide N-H and aza-addition to vinyl phosphonium might proceed in a concerted manner.

A novel luminol derivative and its functionalized filter-paper for reversible double-wavelength colorimetric pH detection in fruit juice

A novel luminol derivative combining with azobenzene chromophore (LABD) and its functionalized filter-paper were developed and evaluated for double-wavelength visible pH detection for the first time. By virtue of the reversible protonation or deprotonation of amide or tertiary amino groups, the present sensors displayed high sensitivity and selectivity for reversible double-wavelength colorimetric response to pH at A433 and A529 respectively, with a wide linear recognition range between pH 4.0 and pH 11.0 and a visible color change from purple to bright yellow. After it was confirmed to be quite low-toxic to mouse fibroblast cells, LABD and its functionalized filter-paper were successfully applied to selectively detect pH in some real fruit juices with satisfied results.

Copper-assisted interaction between amyloid-β and prion: Ternary metal complexes with Aβ N-terminus and octarepeat

Alzheimer and prion diseases are neurodegenerative disorders in which amyloid-beta (Aβ) and prion protein (PrP), respectively, failed their normal functions inducing cellular apoptosis. Histidine-based high-affinity metal-binding sites in the N-terminus domains, which favor the binding of transition metals such as copper and zinc, feature both Aβ and PrP. Recently, the biological role of copper(II) on the two protein interaction has been revealed. Many studies have been focused on copper(II) binding affinity for both Aβ or prion protein while ternary complexes formed by this metal with both proteins have not been investigated. Here we report a combined ESI MS, potentiometric and spectroscopic (CD, UV-Vis) study on ternary complexes formed by copper(II) ion with Aβ and PrP peptides fragments containing potential metal binding sites. In particular, Aβ(1-4), Aβ(1-6), Ac-Aβ(1-6), Aβ(1-16)PEG and the octarepeat (PHGGGWGQ) of prion protein were studied. ESI-MS results indicate that the formation of 1:1:1 ternary complexes occurred at the physiological pH range. Potentiometric and spectroscopic data demonstrate that in a large pH range, ternary species prevail over binary species with the histidine-driven amide deprotonation.

Increasing the histidine ‘density’ in tripodal peptides by gradual N -functionalization of tris (2-aminoethyl)amine (tren) with l -histidyl units: The effect on zinc(II) complexes

Abstract Tripodal peptidomimetics have received increasing interest among others as efficient metal ion chelators. Most of these studies have focused on symmetrical, tri-substituted ligands. Our aim was to establish how the increasing donor group ‘density’, i.e. the gradual N-histidyl substitution, alters the coordination chemical properties of the tripodal platform. To this end we synthesized mono- , bis- and tris ( l -histidyl)-functionalized tren derivatives ( L1 , L2 and L3 , respectively), and studied their zinc(II) complexes by pH potentiometry, 1 H NMR and MS spectroscopy. The three ligands provide a variety of donor sites, and consequently different stability and structure for their zinc(II) complexes depending on the pH and metal-to-ligand ratios. In the neutral pH range histamine-like coordination is operating in all cases. Due to the formation of macrochelate between the two/three {N im ,NH 2 } binding sites, L2 and L3 have considerably higher zinc(II) binding ability than histamine, or any other simple peptide with N-terminal His unit. The situation is fundamentally different at higher pH. The tren-like subunit in L1 acts as an anchoring site for amide deprotonation, and the {3NH 2 ,N − ,N tert } type coordination, a rare example where zinc(II)-amide N − coordination takes place, results in outstanding stability. Although L1 provides tight binding above pH 7, it forms only mononuclear species. However, the increasing level of functionalization in L2 and L3 allows the formation of oligonuclear complexes, and at threefold zinc(II) excess the three ligands share nearly the same amount of zinc(II). Moreover, the high histidine ‘density’ in L2 and L3 also provides the formation of imidazolato-bridged structures, which has never been observed before in zinc(II) complexes of simple linear peptides.

Potentiometric and Speciation Studies on the Complex Formation Reactions of [Pd(2-methylaminomethyl)-pyridine)(H2O)2]2+ with Some Bio-active Ligands and Displacement Reaction of Coordinated Inosine

The stoichiometry and stability constants of the complexes formed between [Pd(MAMP)(H2O)2]2+ and various biologically relevant ligands containing different functional groups were investigated. The ligands used are amino acids, peptides and DNA constituents. The results show the formation of 1:1 complexes with amino acids and peptides and the corresponding deprotonated amide species. Structural effects of peptides on amide deprotonation were investigated. The purine and pyrimidine bases uracil, uridine, cytosine, inosine, inosine 5′-monophosphate (5′-IMP) and thymine form 1:1 and 1:2 complexes. The concentration distribution of the various complex species was calculated as a function of pH. The effect of chloride ion concentration on the formation constant of CBDCA with Pd(MAMP)2+ was also reported. The results show ring opening of CBDCA and monodentate complexation of the DNA constituent with the formation of [Pd(MAMP)(CBDCA-O)DNA], where (CBDCA-O) represents cyclobutane dicarboxylate coordinated by one carboxylate oxygen. The equilibrium constant of the displacement reaction of coordinated inosine, as a typical DNA constituent, by SMC and/or methionine was calculated. The results are expected to contribute to the chemistry of antitumor agents. The calculated parameters of the optimized complexes support the measured formation constants.

Phosphazene-Promoted Metal-Free Ring-Opening Polymerization of 1,2-Epoxybutane Initiated by Secondary Amides

The in situ generation of an anionic initiator X– obtained by the deprotonation of various secondary amides with tBuP4 phosphazene base was tested as possible way to initiate the polymerization of 1,2-epoxybutane. The initiation efficiency of different amide-containing molecules was investigated. Particular attention was given to the detection of eventual transfer or side reactions, especially due to nucleophilic attacks on the initiator moiety at the α-chain end. In all cases, the initiation of the polymerization by the amidate anion was effective. And in most cases, the polymerization proceeded in a controlled manner to afford amide end-capped poly(butylene oxide) with narrow molar mass distribution and expected molar masses.

Zinc(ii) and cadmium(ii) complexes of N-terminally free peptides containing two separate cysteinyl binding sites

The novel synthesized cysteine peptides form stable zinc(ii) and cadmium(ii) complexes; the specific sequence makes possible metal induced amide deprotonation.

ChemInform Abstract: Asymmetric Transformations by Deprotonation Using Chiral Lithium Amides

AbstractReview: 392 refs.

Pb(II)-Promoted Amide Cleavage: Mechanistic Comparison to a Zn(II) Analogue

Two new Pb(II) complexes of the amide-appended nitrogen/sulfur epppa (N-((2-ethylthio)ethyl)-N-((6-pivaloylamido-2-pyridyl)methyl)-N-((2-pyridyl)methyl)amine) chelate ligand, [(epppa)Pb(NO3)2] (4-NO3) and [(epppa)Pb(ClO4)2] (4-ClO4), were prepared and characterized. In the solid state, 4-NO3 exhibits κ(5)-epppa chelate ligand coordination as well as the coordination of two bidentate nitrate ions. In acetonitrile, 4-NO3 is a 1:1 electrolyte with a coordinated NO3(-), whereas 4-ClO4 is a 1:2 electrolyte. Treatment of 4-ClO4 with 1 equiv Me4NOH·5H2O in CH3CN:CH3OH (3:5) results in amide methanolysis in a reaction that is akin to that previously reported for the Zn(II) analogue [(epppa)Zn](ClO4)2 (3-ClO4). (1)H NMR kinetic studies of the amide methanolysis reactions of 4-ClO4 and 3-ClO4 as a function of temperature revealed free energies of activation of 21.3 and 24.5 kcal/mol, respectively. The amide methanolysis reactions of 4-ClO4 and 3-ClO4 differ in terms of the effect of the concentration of methanol (saturation kinetics for 4-ClO4; second-order behavior for 3-ClO4), the observation of a small solvent kinetic isotope effect (SKIE) only for the reaction of the Zn(II)-containing 3-ClO4, and the properties of an initial intermediate isolated from each reaction upon treatment with Me4NOH·5H2O. These experimental results, combined with computational studies of the amide methanolysis reaction pathways of 4-ClO4 and 3-ClO4, indicate that the Zn(II)-containing 3-ClO4 initially undergoes amide deprotonation upon treatment with Me4NOH·5H2O. Subsequent amide protonation from coordinated methanol yields a structure containing a coordinated neutral amide and methoxide anion from which amide cleavage can then proceed. The rate-determining step in this pathway is either amide protonation or protonation of the leaving group. The Pb(II)-containing 4-ClO4 instead directly forms a neutral amide-containing, epppa-ligated Pb(II)-OH/Pb(II)-OCH3 equilibrium mixture upon treatment with Me4NOH·5H2O in methanol. The rate-determining step in the amide methanolysis pathway of 4-ClO4 is nucleophilic attack of the Pb(II)-OCH3 moiety on the coordinated amide. Overall, it is the larger size of the Pb(II) center and the availability of coordination positions that enable direct formation of a Pb(II)-OH/Pb(II)-OCH3 mixture versus the initial amide deprotonation identified in the reaction of the Zn(II)-containing 3-ClO4.

Amidothiourea based colorimetric receptors for basic anions: evidence of anion induced deprotonation of amide –NH proton and hydroxide induced anion⋯π interaction with the deprotonated receptors

Two amidothiourea based receptors (L1 and L2) containing a π-acidic 3,5-dinitrophenyl chromophore have been synthesized in good yields and their anion recognition properties were evaluated both in organic and aqueous organic environment by spectroscopic techniques. Anions such as F−, AcO− and H2PO4− were examined to be suitable analytes for the receptor molecules, displaying optical signaling from colorless to orange/red, whereas anions of lower basicity such as Cl−, Br−, I−, NO3− and HSO4− did not cause any discernable spectral changes. The detailed 1H NMR titration experiments and single crystal X-ray structural analyses revealed that the receptor–anion(s) interaction encourages deprotonation of the amide –NH proton of the amidothiourea function. Interestingly, the highly basic OH− ion showed stepwise color changes with increasing equivalents, from colorless to red to green. The step wise color changes were found to be the outcome of OH− (1 equiv.) induced mono-deprotonation of the individual receptors (colorless to red), followed by anion⋯π interaction (red to green) with the π-acidic 3,5-dinitrophenyl ring of the receptors beyond one equiv. of OH− addition. This anion⋯π interaction between the OH− ion and the synthesized receptors has also been confirmed by monitoring the OH− induced absorption spectral changes of a control receptor (LC).

Complex formation reactions and equilibrium studies of mixed ligand complexes of diaqua (1-Phenyl piperazine)(Palladium)(II) with some biologically relevant ligands.

With the purpose of the search of new antitumor metal complexes, the complex-formation reactions of [Pd(Phenpip)(H2O)2] 2+ (Phenpip = 1-Phenylpiperazine) with some selected bio-relevant ligands, containing different functional groups (amino acids, peptides, DNA constituents and dicarboxylic acids) were investigated. Stoichiometry and stability constants for the complexes formed are reported. The results show the formation of 1 : 1 complexes with amino acids and dicarboxylic acids. The effect of chelate ring size of the dicarboxylic acid complexes on their stability constants was examined. Peptides form both 1 : 1 complexes and the corresponding deprotonated amide species. Structural effects of the peptide on the amide deprotonation were investigated. DNA pyrimidinic constituents, such as uracil, uridine, thymidine and thymine, form 1 : 1 and 1 : 2 complexes, whereas purinic constituents, such as inosine, inosine 5´-monophosphate (5-IMP) form only 1 : 1 complexes. The stability constant of the complexes formed in solution were determined and the binding centers of the ligands were assigned. The concentration distribution diagrams of the complexes were evaluated

A Comparison of the Effects of Amide and Acid Groups at the C-Terminus on the Collision-Induced Dissociation of Deprotonated Peptides

The dissociative behavior of peptide amides and free acids was explored using low-energy collision-induced dissociation and high level computational theory. Both positive and negative ion modes were utilized, but the most profound differences were observed for the deprotonated species. Deprotonated peptide amides produce a characteristic c(m-2)(-) product ion (where m is the number of residues in the peptide) that is either absent or in low abundance in the analogous peptide acid spectrum. Peptide acids show an enhanced formation of c(m-3)(-); however, this is not generally as pronounced as c(m-2)(-) production from amides. The most notable occurrence of an amide-specific product ion is for laminin amide (YIGSR-NH(2)) and this case was investigated using several modified peptides. Mechanisms involving 6- and 9-membered ring formation were proposed, and their energetic properties were investigated using G3(MP2) molecular orbital theory calculations. For example, with C-terminal deprotonation of pentaglycine amide, formation of c(m-2)(-) and a 6-membered ring diketopiperazine neutral requires >31.6 kcal/mol, which is 26.1 kcal/mol less than the analogous process involving the peptide acid. The end group specific fragmentation of peptide amides in the negative ion mode may be useful for identifying such groups in proteomic applications.

Evidence of Deprotonation of Aromatic Acids and Amides Adsorbed on Silver Colloids by Surface-Enhanced Raman Scattering

The surface-enhanced raman scattering (SERS) of benzoic acid/benzamide and salicylic acid/salicylamide on silver colloids show important wavenumber shifts with respect to the Raman spectrum of the band assigned to mode 1;ν(ring) when adsorbed on the metal surface (ca. +50 cm(-1)). In the case of the acids, this shift is originated by the deprotonation of the carboxylic group in agreement with the well-known fact that aromatic acids are adsorbed on silver as carboxylates. However, the main conclusion of this work is that a similar behavior is found for the respective amides that do not behave as acids in water solution. The here studied aromatic amides are adsorbed as azanions on silver nanoparticles even at pH 7 and link to the metal through the nitrogen and oxygen atoms of the ionized carboxamide group. This is a very surprising result given that amides are not significantly ionized even at pH 13-14. The deprotonation of these amides is not determined exclusively by the pH, but it is mainly caused by the strong affinity of the anionic species to the metal. Therefore, the SERS must be cautiously used as a universal pH sensor if the adsorption occurs through the ionizable group. In order to support this conclusion, theoretical DFT force field calculations have been carried out, confirming that deprotonated benzamide and salicylamide interact with the metallic surface.

The role of terminal amino group and histidine at the fourth position in the metal ion binding of oligopeptides revisited: Copper(II) and nickel(II) complexes of glycyl-glycyl-glycyl-histamine and its N-Boc protected derivative

Copper(II) and nickel(II) binding properties of two pseudo tetrapeptides, N-Boc-Gly-Gly-Gly-Histamine (BGGGHa) and Gly-Gly-Gly-Histamine (GGGHa) have been investigated by pH-potentiometric titrations, UV–visible-, EPR-, NMR- and ESI-HRMS (electrospray ionization high resolution MS) spectroscopies, in order to compare the role of N-terminal amino group and imidazole moiety at the fourth position in the complex formation processes. Substantially higher stabilities were determined for the ML complexes of GGGHa, compared to those of BGGGHa, supporting the coordination of the terminal amino group and the histamine imidazole of the non-protected ligand. A dimeric Cu2H−2L2 species, formed through the deprotonation of peptide groups of the ligands, was found in the GGGHa–copper(II) system. Deprotonation and coordination of further amide nitrogens led to CuH−2L and, above pH~10, CuH−3L. Experimental data supports a {NH2,2×Namide,Nim} macrochelate structure in CuH−2L whereas a {NH2,3×Namide} coordination environment in CuH−3L. The first two amide deprotonation processes were found to be strongly cooperative with nickel(II) and spectroscopic studies proved the transformation of the octahedral parent complexes to square planar, yellow, diamagnetic species, NiH−2L and above pH~9, NiH−3L. In the basic pH-range deprotonation and coordination of the amide groups also took place in the BGGGHa containing systems, leading to complexes with a {3×Namide,Nim} donor set, and in parallel the re-dissolving of precipitate. Above pH~11, a further proton release from the pyrrolic NH group of the imidazole ring of BGGGHa occurred providing an additional proof for the different binding modes of the two ligands.

NMR studies of zinc binding in a multi-histidinic peptide fragment

A multi-histidinic peptide and its minimal models have been investigated for Zn(ii) binding. We have used NMR spectroscopy to probe the binding of zinc to the three repeats (T(1)R(2)S(3)R(4)S(5)H(6)T(7)S(8)E(9)G(10))(3) and to its mono-histidinic minimal models, the 9- and 10-aminoacid fragment. (1)H-(1)H TOCSY, (1)H-(13)C HSQC, (1)H-(1)H NOESY and (1)H-(1)H ROESY multidimensional NMR techniques were performed to understand the details of metal binding sites and the conformational behaviour of the peptides at different pH values and at different ligand to metal molar ratios. Zinc coordination involves imidazole N(delta) of His6 and carboxyl gamma-O of Glu9 residues; interaction with peptide oxygens of the His6-Thr7 or Thr7-Ser8 bonds in a tetrahedral arrangement with the minimal model peptides, cannot be excluded. Zinc coordination involves, at physiologic pH, all the three imidazole N(delta) donors of His6, His16 and His26 as well as carboxyl gamma-O of Glu residues in a tetra, penta or octahedral arrangement with the three repeats, the 30-aminoacid fragment. Zinc complexation induces important structural changes with the C-terminal portion of the ligand, constraining it to leave its disordered conformation. Our results give rise to a model of the induced structure of the peptides when bound to zinc. At high pH, amide deprotonation does not take place and hydroxo or high molecular weight polymeric species may be formed.

Copper and nickel binding in multi-histidinic peptide fragments

Multi-histidinic peptides have been investigated for Cu(II) and Ni(II) binding. We present spectroscopic evidence that, at low pH and from sub-stoichiometric to stoichiometric amounts of metals, macrochelate and multi-histidinic Cu(II) and Ni(II) complexes form; but, from neutral pH and above, both copper and nickel bind to individual histidine residues. NMR, EPR, UV-Visible (UV-Vis) and UV-Visible CD spectroscopy were used to understand about the variety of complexes obtained at low pHs, where amide deprotonation and coordination is unfavoured. A structural transition between two coordination geometries, as the pH is raised, was observed. Metal binds to N(delta) of histidine imidazole when main-chain coordination is involved and coordinates via N(epsilon) under mildly acidic conditions and sub-stoichiometric amounts of metals. From EPR results a distortion from planarity has been evidenced for the Cu(II) multi-histidinic macrochelate systems, which may be relevant to biological activity. The behaviour of our peptides was comparable to the pH dependent effect on Cu(II) coordination observed in octapeptide repeat domain in prion proteins and in amyloid precursor peptides involved in Alzheimer's disease. Changes in pH and levels of metal affect coordination mode and can have implications for the affinity, folding and redox properties of proteins and peptide fragments.