Beta-hydrogen Atom Research Articles

Acceleration of Reductive Elimination of [Ar‐Pd‐C] by a Phosphine/Electron‐Deficient Olefin Ligand: A Kinetic Investigation

The kinetics of the reductive elimination step of a C(sp(3))-C(sp(2)) Negishi cross-coupling catalyzed by a 1:1 complex 2 of palladium and the phosphine/electron-deficient olefin ligand (E)-3-(2-diphenylphosphanylphenyl)-1-phenyl-propenone (1) was studied. Complex 2 is an exceptionally efficient and highly selective catalyst for Negishi cross-coupling reactions involving primary and secondary alkylzinc reagents bearing beta-hydrogen atoms. Turnover numbers (TONs) as high as 10(5) and turnover frequencies (TOFs) as high as 1000 s(-1) were observed. The reactions occurred rapidly and selectively even at 0 degrees C. The fact that the reaction was first order in [Pd] is consistent with homogeneous catalysis by Pd complexes rather than by Pd nanoparticles (NPs). Through systematic kinetic investigations of the Negishi coupling of ethyl 2-iodobenzoate with alkylzinc chlorides, the rate constants for reductive elimination of [Ar-Pd-C(sp(3))] were determined to be >0.3 s(-1), which is about 4 or 5 orders of magnitude greater than the values previously reported for [Pd(dppbz)] and [Pd(PPh(3))(2)] systems (dppbz = 1,2-bis(diphenylphosphino)benzene). The use of a 2:1 ratio of 1:Pd resulted in reduced catalytic activity and selectivity, presumably because the olefin moiety could no longer assist in the reductive elimination step. Importantly, hydrogenation of the C=C double bond in ligand 1 generated a saturated ligand (1H(2)), which was not only less effective than 1, but also gave rise to substantial amount of ethylbenzoate formed by competing beta-hydride elimination. Thus, the pi-accepting olefin moiety in 1 must enhance reductive elimination rates, and, consequently, inhibit formation of byproducts resulting from beta-hydride elimination.

Pincer Thioamide and Pincer Thioimide Palladium Complexes Catalyze Highly Efficient Negishi Coupling of Primary and Secondary Alkyl Zinc Reagents at Room Temperature

Pincer thioamide Pd(II) complex 2 was prepared, and its reaction with cyclohexylzinc chloride yielded novel pincer thioimide Pd(II) complex 3 besides Pd(0) species. The structures of complexes 2 and 3 were confirmed by X-ray analysis. Both complexes are efficient catalysts for Negishi couplings involving primary and secondary alkyl zinc reagents bearing beta-hydrogen atoms. At a concentration of 0.1-0.5 mol % both catalysts readily promoted reactions at room temperature or even at 0 degrees C. The operational simplicity of these processes, in conjunction with the easy accessibility of both catalysts and substrates, promises synthetic utility of this new methodology. An experiment on a scale of 19.35 g carried out at very low catalyst loading of 2 (turnover number: 6,100,000) highlighted the potential application of the catalytic system. Monoalkyl and dialkyl zinc reagents displayed different reactivities and selectivities in reactions with aryl iodides catalyzed by complexes 2 or 3, and isomerization in reactions involving acyclic secondary alkyl zinc derivatives was suppressed by using appropriate amounts of dialkyl zinc reagents. Based on preliminary kinetic profiles and reaction evidence, three possible pathways are proposed for the reactions involving acyclic secondary alkyl zinc reagents to rationalize the difference between mono-alkyl and dialkyl zinc derivatives.

Convenient syntheses and structural characterizations of mono-substituted alkylimido hexamolybdates: [Mo6O18(NR)]2−(R = Me, Et, n-Pr, i-Pr, n-Bu, t-Bu, Cy, Hex, Ode)

Monofunctionalized alkylimido derivatives of hexamolybdate, (Bu(4)N)(2)[Mo(6)O(18)( identical withN-R)] (R = methyl, Me; ethyl, Et; n-propyl, n-Pr; i-propyl, i-Pr; n-butyl, n-Bu; t-butyl, t-Bu; cyclohexyl, Cy; n-hexyl, Hex; and n-octadecyl, Ode), have been prepared in high purity and good yield by the reaction of [Bu(4)N](4)[alpha-Mo(8)O(26)] with appropriate aliphatic amine hydrochlorides in anhydrous acetonitrile, using N,N'-dicyclohexylcarbodiimide (DCC) as the dehydrating agent. Eight compounds have been determined by single crystal X-ray diffraction analysis and all compounds have been studied with (1)H-NMR, IR, UV-vis, ESI mass spectrometry and cyclic voltammetry. A structural and (1)H-NMR study show beta hydrogen atoms of those alkylimido derivatives of hexamolybdate have strong Brønsted acidity compared to the hydrogen atoms in other positions.

Reactions of nitroxides with metalloporphyrin alkyls bearing beta hydrogens: Aliphatic carbon–carbon bond activation by metal centered radicals

Nitroxide-induced beta-hydrogen atom abstraction and beta-elimination of rhodium porphyrin alkyls have been observed. Rhodium(II) porphyrin radical were proposed intermediates to form first and subsequently reacted via aliphatic carbon–carbon bond activation with alkyl substituted nitroxides to yield rhodium porphyrin alkyl complexes.

On the Mechanism of Reaction of Radicals with Tirapazamine

Ketyl radicals produced by photolysis of ketones or di-tert-butyl peroxide (DTBP) in alcohol solvents react rapidly with tirapazamine (TPZ). The acetone ketyl radical (ACOH) reacts with TPZ with an absolute second-order rate constant of (9.7 +/- 0.4) x 108 M-1 s-1. The reaction kinetics can be followed by monitoring the bleaching of TPZ absorption at 475 nm or the formation of a reaction product which absorbs at 320 and 410 nm. The ACOD radical reacts with TPZ in 2-propanol-OD with an absolute rate constant of (6.7 +/- 0.5) x 108 M-1 s-1, corresponding to a kinetic isotope effect (KIE) of 1.4. Deuteration of the radical on carbon (ACOH-d6) retards the reaction of the radical with TPZ even further (absolute rate constant = (4.8 +/- 0.04) x 108 M-1 s-1). This result corresponds to a KIE of 2.0. Radicals derived from dioxane and diisopropyl ether by flash photolysis of DTBP in ethereal solvent react with TPZ more slowly than do ketyl radicals. It is concluded that ketyl radicals react, in part, with TPZ in organic solvents by transfer of a hydrogen atom from the OH and CH3 groups of the ketyl radical to the oxygen atom at the N4 position of TPZ to form acetone or acetone enol and a radical derivative of TPZ (TPZH). The latter species absorbs at 320 and 405 nm, has a lifetime of hundreds of microseconds in alcohol solvents, and decays by disproportionation to form TPZ and a reduced heterocycle. The reduced heterocycle eventually forms a desoxytirapazamine by a polar mechanism. The results are supported by density functional theory calculations. It is proposed that dioxanyl radical will also react, in part, with TPZ by transfer of a hydrogen atom from the carbon adjacent to the radical center to the oxygen atom at the N4 position of TPZ. This produces the enol ether and the previously mentioned TPZH radical. It is further posited that ether radicals react a bit more slowly than ketyl radicals because they lack the second mode of hydrogen transfer (from the OH group) that is present in the ACOH radical. Our data are permissive of the possibility that ether radicals add to TPZ at a rate that is competitive with beta-hydrogen atom transfer.

Rearrangements and stereomutations of metallacycles derived from allenes and imidozirconium complexes.

The mechanisms of the rearrangements and stereoinversion of azametallacyclobutenes generated via [2+2] cycloaddition of allenes and imidozirconium complexes have been studied. Metallacycles derived from allenes bearing beta-hydrogen atoms racemize at room temperature by reversible beta-hydride elimination, a process which is also responsible for their eventual conversion to monoazadiene complexes. Metallacycles derived from diarylallenes racemize by reversible thermal bond homolysis at 95 degrees C; racemization of these metallacycles is also catalyzed by mild oxidants.

Catalysts for Cross‐Coupling Reactions with Non‐activated Alkyl Halides

Despite the problems inherent to metal-catalyzed cross-coupling reactions with alkyl halides, these reactions have become increasingly important during the last few years. Detailed mechanistic investigations have led to a variety of novel procedures for the selective cross-coupling of non-activated alkyl halides bearing beta hydrogen atoms with a variety of organometallic nucleophiles under mild reaction conditions. This Minireview highlights selected examples of metal-catalyzed coupling methods and is intended to encourage chemists to exploit the potential of these approaches in organic synthesis.

Axial and Equatorial Cyclohexylacyl and Tetrahydropyranyl-2-acyl Radicals. An Experimental and Theoretical Study

Axial and equatorial cyclohexylacyl and tetrahydropyranyl-2-acyl radicals gave distinct EPR spectra thanks to surprisingly large beta-hydrogen atom hyperfine splittings that enabled them to be characterized and monitored. DFT computations indicated that the axial species (X = CH(2)) had a higher barrier to rotation about the (O)C(alpha)-C(beta) bond. The computed difference Delta H degrees for the axial and equatorial radicals (R = H, X = CH(2)) was 0.8 kcal mol(-)(1).

Ni-catalyzed, ZnCl(2)-assisted domino coupling of enones, alkynes, and alkenes.

A Ni(0)/ZnCl(2) system effectively promotes the coupling of enones and alkene-tethered alkynes. In the reaction with 1,6-enynes, the oxidative cyclization of Ni(0) species on enones across the alkyne part followed by ZnCl(2)-promoted cleavage generates alkenylnickel intermediates. Subsequent migratory insertion of the tethered alkene occurs with 5-exo-cyclization. When the resulting sigma-alkylnickel intermediates have beta-hydrogen atoms, the reaction terminates by beta-hydrogen elimination to provide cyclopentane derivatives. On the other hand, a sigma-alkylnickel intermediate that does not have beta-hydrogen atoms undergoes the insertion of a second alkene unit to cause a domino effect via a three-fold C-C bond formation process with and without the cleavage of one C-C bond.

Unprecedented living olefin polymerization derived from an attractive interaction between a ligand and a growing polymer chain.

Ti complexes incorporating fluorine-containing phenoxy-imine chelate ligands (fluorinated Ti-FI catalysts) have been demonstrated to induce an unprecedented living polymerization effect with both ethylene and propylene, through an attractive interaction between the fluorine atom in the ligand and a beta-hydrogen atom on the growing polymer chain. With the aid of this attractive interaction, highly controlled living ethylene polymerization, highly-syndiospecific living propylene polymerization, the synthesis of unique block copolymers from ethylene and propylene, and the catalytic production of monodisperse polyethylene and Zn-terminated polyethylene have been realized. The attractive interaction provides a conceptually new strategy for the achievement of controlled living olefin polymerization.

Mycobacterium tuberculosis ketopantoate hydroxymethyltransferase: tetrahydrofolate-independent hydroxymethyltransferase and enolization reactions with alpha-keto acids.

The panB gene that encodes ketopantoate hydroxymethyltransferase has been cloned from Mycobacterium tuberculosis, expressed, and purified to homogeneity. 1H NMR spectroscopy was used to determine the rate of (i) tetrahydrofolate-independent hydroxymethyltransferase chemistry between formaldehyde and alpha-ketoisovalerate and (ii) deuterium exchange in the methylenetetrahydrofolate-independent enolization of alpha-ketoisovalerate and other alpha-keto acids, catalyzed by PanB. These studies have demonstrated that substrate enolization by PanB is divalent metal-dependent with a preference of Mg2+ > Zn2+ > Co2+ > Ni2+ > Ca2+. The rate of enolization is pH-dependent with optimal activity in the range of 7.0-7.5. The pH profile was bell-shaped, depending on the ionization state of two ionizable groups with apparent pK values of 6.2 and 8.3. Enolization and isotope exchange occurs with some alpha-keto acids (e.g., pyruvate and alpha-ketobutyrate), resulting in the complete exchange of all beta-hydrogens. Enzyme-catalyzed enolization and isotope exchange occur with other long-chain and branched alpha-keto acids, resulting in the stereospecific exchange of only one of the beta-hydrogen atoms. These results are discussed in the context of steric restrictions present in the enzyme active site and the stereochemistry of base-catalyzed isotope exchange.

Suzuki cross-couplings of alkyl tosylates that possess beta hydrogen atoms: synthetic and mechanistic studies.

A striking dependence of reactivity on phosphane structure was observed in the first Suzuki-type cross-coupling process that is effective for functionalized alkyl tosylates. In this reaction, in which solely commercially available reagents are used, PtBu2Me is the ligand of choice. Through the use of deuterium-labeled compounds, it has been established that the coupling proceeds with predominant inversion of configuration at the carbon atom [Eq. (1), 9-BBN=9-borabicyclo[3.3.1]nonane].

Synthetic and Structural Studies of Titanium Aminotroponiminate Complexes.

The synthesis and characterization of a series of Ti(III) and Ti(IV) aminotroponiminate complexes are described. Six-coordinate [TiMe(2)(Me(2)ATI)(2)] and [TiPh(2)(Me(2)ATI)(2)] were synthesized and structurally characterized, where Me(2)ATI is N,N'-dimethylaminotroponiminate. The mono-alkyl complexes [TiClR(Me(2)ATI)(2)], R = Me, CH(2)SiMe(3), were prepared, and treatment of the former, generated in situ, with PhMgCl yielded the alkyl-aryl complex [TiMePh(Me(2)ATI)(2)]. The solid state structures of most of these complexes were determined and reveal slightly distorted, trigonal-prismatic coordination geometries. Attempts to prepare alkyl complexes containing beta-hydrogen atoms resulted instead in the isolation of [Ti(Me(2)ATI)(3)] or [Ti(2)Cl(2)(Me(2)ATI)(4)], depending on the alkyl reagent and stoichiometry. Because of the modest steric requirements of the {Ti(Me(2)ATI)(2)}(2+) fragment, five-coordinate Ti(IV) complexes were only generated with a bulky sigma-2pi donor ligand, [Ti(N-(2,6)-i-Pr(2)C(6)H(3))(Me(2)ATI)(2)] being a specific example. Attempts to prepare the isoelectronic oxo analogue afforded only dimeric [Ti(2)O(2)(Me(2)ATI)(4)]. Comparison of the metrical parameters for these complexes with those in the literature containing aryloxide and benzamidinate ligands indicate that the {Ti(Me(2)ATI)(2)}(2+) fragment is quite electron releasing.

The Basicity of p-Substituted Phenolates and the Elimination-Substitution Ratio in p-Nitrophenethyl Bromide: A HSAB Theoretical Study.

The influence of basicity in a set of para-substituted phenolates on the elimination-substitution ratio obtained upon reaction with p-nitrophenethyl bromide has been studied. A correlation between experimental equilibrium data (pK(a)) and reactivity indices obtained from density functional theory (DFT) was looked for in order to show that the hard and soft acids and bases principle (HSAB) is well suited to describe the basicity properties of the para-substituted phenolates. When the basicity of para-substituted phenolates increases, their global hardness and their condensed softness at the oxygen atom increase; the negative net charge, condensed nucleophilic fukui function, and condensed nucleophilic softness of the oxygen atom increase. The proposal that the alkyl halide substrate possesses a hard beta-hydrogen atom and a soft alpha-carbon was studied for p-nitrophenethyl bromide; it turns out that the beta-hydrogen atom is soft, even softer than the carbon atom. The experimental results for the elimination-substitution ratio for p-nitrophenethyl bromide can be explained from a local-local HSAB viewpoint for the para-substituted phenolates and p-nitrophenethyl bromide and not from a global-local level viewpoint as suggested before. The results suggest that para-substituted phenolates with higher basicity (harder), less delocalized negative charge into the fragment R-C(6)H(4), and a more polarizable oxygen atom (softer) do have a lower (relative) attraction toward an alkyl carbon atom (soft) than toward a hydrogen atom (softer) from p-nitrophenethyl bromide. The beta-hydrogen and alpha-carbon atoms can be considered to act as a Lewis acid toward the para-substituted phenolate nucleophile considered as a base.

Synthesis and Structural Characterization of Nonplanar Tetraphenylporphyrins and Their Metal Complexes with Graded Degrees of beta-Ethyl Substitution.

Different porphyrin conformations are believed to play a role in controlling the cofactor properties in natural tetrapyrrole-protein complexes. In order to study the correlation between macrocycle nonplanarity and physicochemical properties in detail, a series of six porphyrins with graded degrees of macrocycle distortion were synthesized via mixed condensation of pyrrole, diethylpyrrole, and benzaldehyde. The formal introduction of successively more beta-ethyl groups into the tetraphenylporphyrin parent macrocycle gave access to diethyltetraphenylporphyrin (H(2)DETPP), two regioisomers of tetraethyltetraphenylporphyrin (H(2)tTETPP, H(2)cTETPP), and hexaethyltetraphenylporphyrin (H(2)HETPP). These conformationally designed compounds bridge the gap between the well-known tetraphenylporphyrin (H(2)TPP) and the very nonplanar octaethyltetraphenylporphyrin (H(2)OETPP), which are also formed during the reaction. Crystallographic studies showed that the macrocycle distortion in the solid state increases gradually in the order TPP < DETPP < tTETPP < cTETPP < HETPP < OETPP, i.e. with increasing degree of beta-ethyl substitution and the number and localization of potential beta-ethyl meso-phenyl interactions. This correlates well with increasing bathochromic shifts of the absorption bands in solution. Depending on the substituent pattern, different saddle-shaped macrocycle conformations were observed. While the conformation of tTETPP was symmetric, DETPP, cTETPP, and HETPP showed asymmetric distortion modes with individual beta-pyrrole displacements reaching those described for dodecasubstituted porphyrins. Overall, higher displacements from planarity were found close to beta-ethyl-meso-phenyl groups whereas smaller displacements were observed in parts of the molecules bearing beta-hydrogen atoms. Nevertheless, a certain amount of redistribution of steric strain occurs as evidenced by significant displacements for pyrrole carbon atoms with beta-hydrogens. Synthesis and structural investigation of the respective metal complexes with M = Cu(II), Ni(II), and Zn(II) showed similar correlations between beta-ethyl substitution, bathochromic shift of absorption bands and nonplanarity as described for the free bases. The only exception was found for Ni(II)tTETPP, which exhibited a highly nonplanar ruffled conformation. Additionally, the metal complexes allowed a study of the conformational effects of different metals at each level of macrocycle distortion. As observed for symmetric, nonplanar porphyrins larger metals led to a decrease in conformational distortion with associated changes in bond lengths and bond angles.

Structure of the novel heme adduct formed during the reaction of human hemoglobin with BrCCl3 in red cell lysates.

It was previously shown that the reductive debromination of BrCCl3 to trichloromethyl radical by human hemoglobin leads to formation of dissociable altered heme products, two of which are identical to those formed from myoglobin and one which is novel. In this study, we have elucidated the structure of this novel adduct with the use of mass spectrometry, as well as 1H and 13C NMR as a substitution product of a -C(Cl) = CCl2 moiety for a beta-hydrogen atom on the prosthetic heme's ring I vinyl group. From studies with the use of 13C-enriched BrCCl3, it was determined that the added carbon atoms were derived from 2 eq of BrCCl3. A mechanism that involves multiple reductive events and a radical cation heme intermediate is proposed. Consistent with this mechanism, cellular reductants were found to selectively enhance the amount of this novel dissociable heme adduct. These studies reveal fine differences between myoglobin and hemoglobin in the accessibility of reactive intermediates to the ring I vinyl group, as well as the potential importance of cellular reductants on the course of heme alteration.

Theoretical studies on the mechanism of conversion of androgens to estrogens by aromatase.

Semiempirical molecular orbital calculations (AM1) were used to model several possible reaction mechanisms for the third oxidation of the aromatase-catalyzed conversion of androgens to estrogens. The reaction mechanisms considered are based on the assumption that the third oxidation is initiated by 1 beta-hydrogen atom abstraction. Homolytic cleavage of the C10-C19 bond was modeled for both the 3-keto and 2-en-3-ol forms of the androgen 1-radicals. The addition of a protein nucleophile to the 19-oxo intermediate was also considered, and -OCH3, -SCH3, and -NHCH3 were used to represent the Ser, Cys, and Lys adducts. The transition states were estimated and optimized from the reaction coordinates obtained by constraining and increasing the C10-C19 bond lengths. The enthalpies of activation range from 14 to 21 kcal and are approximately 2 kcal lower for cleavage of the enol form. Given the tendency for AM1 to overestimate activation energies, all reactions may be energetically accessible. Other reactions modeled include a homolytic cleavage reaction from a thioether radical cation and the direct additions of oxygen radical compounds to the carbonyl of the 1-radical-2-en-3-ol-19-oxo androgen. A mechanism is proposed in which the 19-oxo intermediate is subject to initial nucleophilic attack by the protein. Since rotation of the 19-carbonyl can bring the oxygen within 2.1 A of the 2 beta-hydrogen, the formation of a tetrahedral intermediate can occur with concomitant removal of the 2 beta-proton. Enolization activates the C1-position for hydrogen atom abstraction, since the resulting radical is resonance stabilized.(ABSTRACT TRUNCATED AT 250 WORDS)

Regioselectivity and stereoselectivity of the metabolism of the chiral quinolizidine alkaloids sparteine and pachycarpine in the rat

1. The metabolism of (-)-sparteine and (+)-sparteine (pachycarpine) was investigated in male Sprague-Dawley rats by g.l.c.-mass spectrometry, and 13C- and 2H-n.m.r. spectroscopy. The structure of the major metabolite of (-)-sparteine was confirmed to be 2,3-didehydrosparteine by g.l.c.-mass spectrometry after alkaline sample work-up. 2H-n.m.r. spectroscopy showed that this metabolite exhibits the structure of the carbinolamine (2S)-hydroxysparteine in aqueous solution of neutral pH. No other metabolites with an enamine structure were observed by g.l.c.-mass spectrometry and 13C-n.m.r. spectroscopy. 2. Pachycarpine is metabolized in vivo and in vitro stereoselectively to the aliphatic alcohol (4S)-hydroxypachycarpine as the main metabolite. 3. The formation of the 2,3-didehydrosparteine proceeds via stereospecific abstraction of the axial 2 beta hydrogen atom. Inhibition in vitro studied with purified rat liver microsomes demonstrated that both sparteine enantiomers are metabolized by the same cytochrome P450 isozyme. Therefore this enzyme exhibits marked substrate and product stereoselectivity for the metabolism of the two enantiomeric quinolizidine alkaloids.

Indium(III) compounds containing the neopentyl substituent, In(CH2CMe3)3, In(CH2CMe3)2Cl, In(CH2CMe3)Cl2, and In(CH2CMe3)2CH3. Crystal and molecular structure of dichloroneopentyl indium(III), an inorganic polymer

Abstract : Organometallic chemical vapor deposition (OMCVD) is one of the most useful techniques for making compound semiconductors such as InP. The most desireable organometallic sources for OMCVD should be easily prepared,readily purified volatile liquids with excellent stability at room temperature. A number of homoleptic organoindium (III) compounds (InR3 R=Me, 3 Et, 4,5 n-Pr, 5 i-Pr, 5 n-Bu, 5 i-Bu, 5 s-Bu, 5 t-Bu 6 and Ch2SiMe3 7) are known but only InMe3 and InEt3 are readily available for use in electronic applications. However, neither InMe3 nor InEt3 has all of the desireable physical properties. Trimethylindium has the disadvantage of being a solid with a relatively high melting point of 89.5 C. In contrast, triethylindium is a liquid at room temperature (mp -32 C) but the presence of beta-hydrogen atoms on the ligands reduces its thermal stability. Both compounds have the disadvantage of being prepared by relatively involved time-consuming procedures. In an attempt to provide alternative indium sources which can be prepared and purified easily, the chemistry of indium compounds with neopentyl ligands was investigated.

Androgen synthesis and aromatization by equine corpus luteum microsomes

Whereas mare corpus luteum does not produce androgens or estrogens in vivo, the incubation of mare corpus luteum microsomes with progesterone and NADPH resulted in 17 alpha-hydroxyprogesterone and estrogen production with a small yield of androstenedione. In the presence of an aromatase inhibitor (4-hydroxyandrostenedione), 17 alpha-hydroxyprogesterone and androstenedione were accumulated. Aromatization of testosterone and androstenedione occurred via stereospecific loss of the 1 beta, 2 beta hydrogen atoms and was inhibited by MgCl2, KCl, and EDTA. The Km of estrogen synthetase from equine corpus luteum for testosterone was 18.5 +/- 2.7 nM and for androstenedione was 11.5 +/- 1.5 nM. 19-Norandrogens were aromatized with a slightly higher efficiency than were androgens, but the affinity of the aromatase was lower for 19-norandrogens than for androgens. Our results suggest that aromatases from equine testis and corpus luteum are closely related enzymes. On the other hand, the question arises as to the relationship among the cell origin, the synthetizing abilities, and in vivo production of the corpus luteum in different mammalian species.