Acidic NH Protons Research Articles

ChemInform Abstract: Bifunctional Transition Metal Based Molecular Catalysts for Asymmetric C—C and C—N Bond Formation

AbstractReview: 35 refs.

Bifunctional Transition Metal-Based Molecular Catalysts for Asymmetric C–C and C–N Bond Formation

This paper describes recent advances in the development of the asymmetric catalytic reactions promoted by conceptually new bifunctional molecular catalysts. These reactions include the enantioselective Michael addition of 1,3-dicarbonyl compounds to cyclic enones and nitroalkenes, and the enantioselective direct amination of α-cyanoacetates to diazoesters. The nature of the catalyst in each particular case was delicately tuned by adjusting the combination of the central metal together with the structures of the cooperating ligands, applied solvents, and the reaction conditions to achieve the utmost catalytic performance in terms of reactivity and selectivity. In the presence of the optimized catalyst the addition reactions proceeded smoothly with a 1:1 M ratio of the reagents to give the corresponding chiral adducts with excellent yields and ee’s. Preliminary mechanistic studies based on NMR spectroscopy and DFT analysis showed that the key step of the catalytic cycle is the interaction of the bifunctional catalyst with a pronucleophilic reagent that leads to stereoselective formation of C-, O-, or N-bound amino complexes. The resulting amino catalyst bearing metal-bound nucleophiles readily reacts with an electrophile that acquires the reactive conformation through the cooperative effect of the acidic NH protons. This results in the formation of a C–C or a C–N bond yielding the corresponding products in a highly stereoselective manner.

Palladium-Catalyzed Cross-Couplings of Unsaturated Halides Bearing Relatively Acidic Hydrogen Atoms with Organozinc Reagents

A wide range of polyfunctional aryl, heteroaryl, alkyl, and benzylic zinc reagents were coupled with unsaturated aryl halides bearing an acidic NH or OH proton, using palladium(II) acetate (1 mol%), and S-Phos (2 mol%) as catalyst without the need of protecting groups.

Palladium- and Nickel-Catalyzed Cross-Couplings of Unsaturated Halides Bearing Relatively Acidic Protons with Organozinc Reagents

A wide range of polyfunctional aryl, heteroaryl, alkyl, and benzylic zinc reagents were coupled with unsaturated aryl halides bearing an acidic NH or OH proton, using Pd(OAc)2 (1 mol %) and S-Phos (2 mol %) as catalyst without the need of protecting groups. A similar nickel-catalyzed reaction is described. The relative kinetic basicity of organozinc compounds as well as their stability toward acidic protons is also described.

Magnesium amido N-heterocyclic carbene complexes

Magnesium dications bind strongly to a tridentate anionic dicarbene ligand L = [N{CH(2)CH(2)(CNCHCHNMes)}(2)] forming dinuclear and trinuclear Mg complexes with some particularly short Mg-C bonds. Treatment of the proligand H(4)LCl(3) with three equivalents of methyl magnesium chloride or benzyl magnesium chloride affords Mg(3)(HL)Cl(6) in high yield. A suspension of in thf was heated to 80 degrees C for 2 h to afford Mg(2)(L)Cl(3), consistent with the loss of one equivalent of MgCl(2), and the deprotonation of the remaining acidic NH, lost as HCl gas. Treatment of Mg(3)(HL)Cl(6) with one equivalent of KC(8) results in deprotonation of the ligand amine NH to afford Mg(3)(L)Cl(5); treatment with a second equivalent forms the radical anion of the complex, K[Mg(3)(L)Cl(5)], which decomposes upon storage, precluding its structural characterisation. The acidic NH proton of the ligand in Mg(3)(HL)Cl(6) can also be removed by deprotonation with Li{N(SiMe(3))(2)}; additional equivalents of which also exchange the magnesium-bound chlorides for silylamido ligands, affording Mg(2)(L)Cl(2)N'' and Mg(2)(L)Cl(N'')(2), which have both been characterised by single-crystal X-ray diffraction studies.

Theoretical study of the acidity and basicity of uric acid and its interaction with water

The proton affinity (PA) of the O atoms and the deprotonation enthalpies (DPE) of the NH bonds of isolated uric acid are calculated using the density functional theory (B3LYP) combined with the 6-31++G(d,p) basis set. The optimized geometries, energies and harmonic vibrational frequencies of monohydrated uric acid are calculated at the same level of theory. The five stable complexes between uric acid and water are the ones in which the oxygen atom of water accepts the acidic NH proton while donating a proton to the carbonyl oxygens of uric acid. The binding energies of these complexes ranging from 24 to 37 kJ mol −1 are analysed in terms of PAs for O atoms and the acidity of the NH groups of isolated uric acid. A natural bond orbital analysis is performed to understand the nature of hydrogen bonding interaction in monohydrated uric acid and also to reveal the inter-relations between electronic structure and other properties.

Spectroscopic Identification of Carbenium and Ammonium Isomers of Protonated Aniline (AnH+): IR Spectra of Weakly Bound AnH+−Ln Clusters (L = Ar, N2)

Infrared photodissociation (IRPD) spectra of mass-selected clusters composed of protonated aniline (C6H8N+ = AnH+) and a variable number of neutral ligands (L = Ar, N2) are obtained in the N-H stretch range. The AnH+ -Ln complexes (n < or = 3) are produced by chemical ionization in a supersonic expansion of An, H2, and L. The IRPD spectra of AnH+-Ln feature the unambiguous fingerprints of at least two different AnH+ nucleation centers, namely, the ammonium isomer (5) and the carbenium ions (1 and/or 3) corresponding to protonation at the N atom and at the C atoms in the para and/or ortho positions, respectively. Protonation at the meta and ipso positions is not observed. Both classes of observed AnH+-Ln isomers exhibit very different photofragmentation behavior upon vibrational excitation arising from the different interaction strengths of the AnH+ cores with the surrounding neutral ligands. Analysis of the incremental N-H stretch frequency shifts as a function of cluster size shows that microsolvation of both 5 and 1/3 in Ar and N2 starts with the formation of intermolecular H bonds of the ligands to the acidic NH protons and proceeds by intermolecular pi bonding to the aromatic ring. The analysis of both the photofragmentation branching ratios and the N-H stretch frequencies demonstrates that the N-H bonds in 5 are weaker and more acidic than those in 1/3, leading to stronger intermolecular H bonds with L. The interpretation of the spectroscopic data is supported by density functional calculations conducted at the B3LYP level using the 6-31G* and 6-311G(2df,2pd) basis sets. Comparison with clusters of neutral aniline and the aniline radical cation demonstrates the drastic effect of protonation and ionization on the acidity of the N-H bonds and the topology of the intermolecular potential, in particular on the preferred aromatic substrate-nonpolar ligand recognition motif.

2-Aryl-8-chloro-1,2,4-triazolo[1,5- a]quinoxalin-4-amines as highly potent A 1 and A 3 adenosine receptor antagonists

Some 2-aryl-8-chloro-1,2,4-triazolo[1,5- a]quinoxaline derivatives 2– 18, obtained by introducing different substituents on either the 4-amino moiety (acyl or carbamoyl groups) or the 2-phenyl ring (4-OCH 3) of previously reported 8-chloro-2-phenyl-1,2,4-triazolo[1,5- a]quinoxalin-4-amine ( 1), have been synthesized and tested in radioligand binding assays at bovine A 1 and A 2A and at cloned human A 1 and A 3 adenosine receptors. The rationally designed 8-chloro-2-(4-methoxy-phenyl)-1,2,4-triazolo[1,5- a]quinoxalin-4-acetylamine ( 14) can be considered one of the most potent and hA 3 versus hA 1 selective AR antagonists reported till now. The structure–activity relationships of compounds 2– 18 are in agreement with those of previously reported 2-aryl-1,2,4-triazolo[4,3- a]quinoxalines (series A) and 2-arylpyrazolo[3,4- c]quinolines (series B), thus suggesting a similar AR binding mode. In fact, the importance for the A 3 receptor–ligand interaction of both a strong acidic NH proton donor and a C O proton acceptor at position-4, able to engage hydrogen-bonding interactions with specific sites on the A 3 AR, has been confirmed. Using our recently published hA 3 receptor model, to better elucidate our experimental results, we decided to theoretically depict the putative TM binding motif of the herein reported 1,2,4-triazolo[1,5- a]quinoxaline derivatives on human A 3 receptor. Structure–activity relationships have been explained analyzing the three-dimensional structure of the antagonist-receptor models obtained by molecular docking simulation.

Activation of H2 and CO by Sulfur‐Rich Nickel Model Complexes for [NiFe] Hydrogenases and CO Dehydrogenases

AbstractReactions of the trinuclear complexes [Ni(RS3)]3 [HS32− = bis(2‐mercaptophenyl)sulfide(2−) (1a) or siS32− = bis(2‐mercapto‐3‐trimethylsilylphenyl)sulfide(2−) (1b)] with nucleophiles L (L = NHPnPr3, NHPCy3, NHSPh2, PnPr3) afforded the corresponding mononuclear complexes [Ni(L)(RS3)] [R = si = SiMe3; L = NHPnPr3 (2b); L = NHPCy3 (3a,b); L = NHSPh2 (4a,b); L = PnPr3 (5a)]. X‐ray structural determinations showed that 2b, 3a, 3b, 4a, and 5a exhibit tetrahedrally distorted planar [Ni(L)(RS3)] fragments. Complex 2b dimerizes through intermolecular N−H···N hydrogen bonding. In contrast to 2b, complexes 3a and 4a exhibit intramolecular hydrogen bonds between thiol groups and NH protons. Complexes 2−4 possess weakly acidic NH protons and undergo D+/NH exchange reactions with D2O or CD3OD. Complexes 2−4 and [Ni(StBu)(RS3)]− (9a,b) also catalyze D2/H+ exchange in [D8]THF/H2O under an elevated pressure of D2 (18 bar), as confirmed by 1H NMR spectroscopy. It is proposed that D2 heterolysis is achieved through attack of the Lewis‐acidic nickel centers and the Brönsted‐basic sulfur atoms at an η2‐D2 ligand. Complexes 9a and 9b are the first sulfur‐only nickel complexes that enable the modeling of the [NiFe] hydrogenase catalyzed D2/H+ exchange reaction. Evidence for labile five‐coordinate [Ni(CO)(L)(RS3)] has been found in the reaction between [Ni(L)(RS3)] complexes and CO. The CO adducts of complexes with nitrogenous ligands L such as N3−, NHPR3 (R = nPr3, Cy3), or NHSPh2 showed rapid consecutive reactions. The reaction between Et4N[Ni(N3)(siS3)] (8b) and CO gave Et4N[Ni(NCO)(siS3)] (10b), whereas reactions between 2−4 and CO afforded only 1a or 1b. Mechanisms are suggested which have the formation of reactive five‐coordinated [Ni(CO)(L)(RS3)] intermediates in common. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2004)

Theoretical study on protonated and deprotonated 5-substituted uracil derivatives and their complexes with water

The proton affinity (PA) of the oxygen atoms and the deprotonation enthalpies (DPE) of the NH bonds of 5-substituted uracil derivatives (X=CN, F, Cl, NH2) are computed using the density functional theory (B3LYP) at the 6-31+G(d,p) level. The PAs vary from 766 to 875kJ mol−1 and the DPEs from 1315 to 1442kJ mol−1. For all the studied uracils, the acidity of the N1H bond is larger than that of the N3H bond and the basicity of the O8 atom is larger than that of the O4 atom. The effect of the intramolecular hydrogen bond in 5-NH2 uracil is discussed. The three stable complexes with one water molecule are the ones in which the oxygen atom of water accepts the acidic NH proton while donating a proton to the carbonyl oxygen of uracils. The intermolecular distances and angles, and the binding energies with water are discussed in terms of the PA and DPE of the atoms or bonds involved in the interaction with one water molecule.

Zinc-mediated chain extension of beta-keto phosphonates

A variety of beta-keto phosphonates can be converted to gamma-keto phosphonates through reaction with ethyl(iodomethyl)zinc. The presence of alpha-alkyl substituents, Lewis basic functionality, and modestly acidic NH-protons are accommodated in substrates of this reaction. Chain extension of beta-keto phosphonates that contained olefinic functionality proceeded more quickly than cyclopropanation; however, it was not possible to effect the chain extension to the exclusion of cyclopropane formation. A primary reason for this imperfect chemoselectivity appears to be the slow chain extension of beta-keto phosphonates. Nevertheless, the simplicity, the scope, and efficiency of this method serve to make it an attractive alternative to the established methods for gamma-keto phosphonate formation.

Hydrogen Bonding and Isomerism Arising from the Coordination Modes of Bridging Benzimidazole-2-thiolate Ligands in Tetranuclear Rhodium Complexes

Reaction of the dinuclear complex [Rh(2)(&mgr;-HBzimt)(2)(cod)(2)] with [Rh(2)(&mgr;-Cl)(2)(cod)(2)] (cod = 1,5-cyclooctadiene) gives the neutral tetranuclear complex [Rh(4)(&mgr;-HBzimt)(2)Cl(2)(cod)(4)] (2) in dichloromethane and the trinuclear cationic complex [Rh(3)(&mgr;-HBzimt)(2)(cod)(3)]Cl (3) in methanol, respectively. The ionization ability of the solvent seems to be the driving force to give 3, while the ability to coordinate a further RhCl(cod) fragment leads to 2 in poorer ionizing media. The complexes [M(4)(&mgr;-HBzimt)(2)Cl(2)(diolefin)(4)] (M = Rh, diolefin = tetrafluorobenzobarrelene (tfbb) (5); M = Ir, diolefin = cod (6)), formally analogous to 2, were isolated from the reactions of the appropriate complexes [MCl(H(2)Bzimt)(diolefin)] and [M(acac)(diolefin)] in acetone. A X-ray diffraction study on 2 shows the HBzimt(-) ligands to bridge two rhodium atoms through the sulfurs, forming a basic four-membered Rh(2)(&mgr;-(1:2kappaS)-HBzimt)(2) ring along with two RhCl(cod) moieties bonded to the nitrogen atoms. Two intramolecular hydrogen bonds between the chloro ligands and the acidic NH protons should stabilize the syn-endo disposition of the thiolate type bridging ligands. Replacement of the olefin in 2 by carbon monoxide gives [Rh(4)(&mgr;-HBzimt)(2)Cl(2)(cod)(CO)(6)] and [Rh(4)(&mgr;-HBzimt)(2)Cl(2)(CO)(8)] (7) depending on the reaction conditions. The X-ray structure of 7 shows the HBzimt(-) ligands in a HT-Rh(2)(&mgr;-(1kappaN,2kappaS)-HBzimt)(2) disposition with two RhCl(CO)(2) fragments coordinated to the sulfur atoms. In addition, two tetranuclear units 7 are associated in a dimer through four intermolecular hydrogen bonds. This association occurs even in solution, where the two species are observed. The equilibrium constant for the dissociation fits a linear plot of ln K(eq) versus 1/T, which gives DeltaH = 43.3 kJ mol(-)(1) and DeltaS = 114.7 J K(-)(1) mol(-)(1). Deprotonation of 7 with [Rh(2)(&mgr;-OMe)(2)(cod)(2)] gives the hexanuclear complex [Rh(6)(&mgr;-Bzimt)(2)(&mgr;-Cl)(2)(cod)(2)(CO)(8)] (10). Complexes 7 and 10 show identical conformations of the eight-membered HT-Rh(2)(&mgr;-(1kappaN,2kappaS)-Bzimt)(2) metallacycle and identical configurations of the sulfur atoms.

ChemInform Abstract: Electro‐Carboxylation of 2‐Bromoisobutyramides. A Useful Synthetic Way to Ester‐Amides of 2,2‐Dimethylmalonic Acid.

AbstractElectroreduction (cyclic voltammetry, controlled‐potential electrolysis) of 2‐bromoisobutyramides (I) and (V) leads to the carbanion (Me2C‐CO‐NH‐R)‐ which in the absence of acid or CO2 is self‐protonated by the acidic NH proton of the parent compound to give Me2CH‐CO‐NH‐R and (Br‐CMe2‐CO‐N‐R)‐.