Catalytic Ni(II) in reactions of SmI2: Sm(II)- or Ni(0)-based chemistry?

The addition of catalytic amounts of Ni(II) salts provide enhanced reactivity and selectivity in numerous reactions of SmI(2), but the mechanistic basis for their effect is unknown. We report spectroscopic and kinetic studies on the mechanistic role of catalytic Ni(II) in the samarium Barbier reaction. The mechanistic studies presented herein show that the samarium Barbier reaction containing catalytic amounts of Ni(II) salts is driven solely by the reduction of Ni(II) to Ni(0) in a rate-limiting step. Once formed, Ni(0) inserts into the alkyl halide bond through oxidative addition to produce an organonickel species. During the reaction, the formation of colloidal Ni(0) occurs concomitantly with Ni(0) oxidative addition as an unproductive process. Overall, this study shows that a reaction thought to be driven by the unique features of SmI(2) is in fact a result of known Ni(0) chemistry.     

Catalytic asymmetric cyano-ethoxycarbonylation reaction of aldehydes using a YLi3 tris(binaphthoxide) (YLB) complex: mechanism and roles of achiral additives

Full details of a catalytic asymmetric cyano-ethoxycarbonylation reaction promoted by a heterobimetallic YLi3 tris(binaphthoxide) complex (YLB 1), especially mechanistic studies, are described. In the cyanation reaction of aldehydes with ethyl cyanoformate, three achiral additives, H2O, tris(2,6-dimethoxyphenyl)phosphine oxide (3a), and BuLi, were required to achieve high reactivity and enantioselectivity (up to >99% yield and up to 98% ee). The roles of achiral additives and the reaction pathway were investigated in detail. In situ IR analysis revealed that the initiation step to generate LiCN from H2O, BuLi, and ethyl cyanoformate is rather slow. On the basis of mechanistic studies of the initiation step to generate an active nucleophilic species, reaction conditions were optimized by using a catalytic amount of acetone cyanohydrin as an initiator. Under the optimized conditions, the induction period decreased and the reaction completed within 9 min using 5 mol % YLB at -78 degrees C. Catalyst loading was successfully reduced to 1 mol %. Kinetic experiments and evaluation of the substituent effects of phosphine oxide revealed that phosphine oxide had beneficial effects on both the reaction rate and the enantioselectivity. The putative active species as well as the catalytic cycle of the reaction are also discussed.     

Synthesis, structure, and reactivity of a zirconocene-carboryne precursor

Transition metal-benzyne complexes have found many applications in organic synthesis, mechanistic studies, and the synthesis of functional materials. In sharp contrast, the reaction chemistry of transition metal-carboryne complexes is virtually unknown although the theoretical calculations indicated that the formation of carboryne (1,2-C2B10H10) and benzyne is very energetically comparable. This communication reports a novel zirconocene-carboranyl complex Cp2Zr(mu-Cl)(mu-C2B10H10)Li(OEt2)2 (1), an efficient precursor of the zirconocene-carboryne species, prepared from the reaction of Cp2ZrCl2 with 1 equiv of Li2C2B10H10 in Et2O. The reactivity studies indicated that 1 resembles zirconocene-benzyne in reactions with polar unsaturated organic molecules. On the other hand, it shows no reactivity toward alkynes and alkenes, a reactivity pattern which is quite different from that of zirconocene-benzyne. This work also furnishes a novel method for the preparation of functional o-carboranes and their metal complexes which cannot be synthesized by other methods presently known.     

Alpha,beta-unsaturated delta-lactones from copper-catalyzed asymmetric vinylogous Mukaiyama reactions of aldehydes: scope and mechanistic insights

A direct regio-, diastereo-, and enantiocontrolled access to alpha,beta-unsaturated delta-lactones is described, based on the reaction of a silyl dienolate and an aldehyde in the presence of 10 % of Carreira's catalyst. The scope and limitations of this reaction, as well as mechanistic insights concerning the reactivity of an allyl copper species, are discussed.     

Does the TauD Enzyme Always Hydroxylate Alkanes, While an Analogous Synthetic Non-Heme Reagent Always Desaturates Them?

This theoretical work addresses the mechanistic switch between hydroxylase (alcohol formation) and desaturase (olefin formation) activities during alkane oxidation by two non-heme high-valent oxoiron reagents, the enzyme taurine:α-ketoglutarase dioxygenase (TauD) and the synthetic shape-selective catalyst (TpOBzFe), toward cyclohexadiene, cyclohexane, cyclopentane, and ethane. As we show, the desaturase/hydroxylase steps obey unique orbital selection rules, and the mechanistic switch is determined by intrinsic reactivity factors that depend on the ligand-sphere flexibility of the oxoiron species, the substrate, and the spin states of the reaction pathways. Testable predictions are outlined.     

A Photophysical Study of Sensitization-Initiated Electron Transfer: Insights into the Mechanism of Photoredox Activity

The development of photocatalytic reactions has provided many novel opportunities to expand the scope of synthetic organic chemistry. In parallel with progress towards uncovering new reactivity, there is consensus that efforts focused on providing detailed mechanistic insight in order to uncover underlying excited-state reactions are essential to maximise formation of desired products. With this in mind, we have investigated the recently reported sensitization-initiated electron transfer (SenI-ET) reaction for the C−H arylation of activated aryl halides. Using a variety of techniques, and in particular nanosecond transient absorption spectroscopy, we are able to distinguish several characteristic signals from the excited-state species involved in the reaction, and subsequent kinetic analysis under various conditions has facilitated a detailed insight into the likely reaction mechanism.     

Manipulation of Spiroindolenine Intermediates for Enantioselective Synthesis of 3‐(Indol‐3‐yl)‐Pyrrolidines

By manipulating the reactivity of spiroindolenine species, a sequential Michael/retro‐Mannich/Mannich reaction of ω‐indol‐3‐yl α,β‐unsaturated ketones was developed. In the presence of 10 mol % of a chiral phosphoric acid as the catalyst, a series of 3‐(indol‐3‐yl)‐pyrrolidines were synthesized in high yields (up to 91 %) with excellent stereoselectivities (up to 92 % ee, >19:1 d.r.). The products obtained here undergo diverse functional‐group transformations. The mechanistic proposal of this reaction is supported by DFT calculations.     

Theoretical study of N-demethylation of substituted N,N-dimethylanilines by cytochrome P450: the mechanistic significance of kinetic isotope effect profiles

The mechanism of N-demethylation of N,N-dimethylanilines (DMAs) by cytochrome P450, a highly debated topic in mechanistic bioinorganic chemistry (Karki, S. B.; Dinnocenczo, J. P.; Jones, J. P.; Korzekwa, K. R. J. Am. Chem. Soc. 1995, 117, 3657), is studied here using DFT calculations of the reactions of the active species of the enzyme, Compound I (Cpd I), with four para-(H, Cl, CN, NO2) substituted DMAs. The calculations resolve mechanistic controversies, offer a consistent mechanistic view, and reveal the following features: (a) the reaction pathways involve C-H hydroxylation by Cpd I followed by a nonenzymatic carbinolamine decomposition. (b) C-H hydroxylation is initiated by a hydrogen atom transfer (HAT) step that possesses a "polar" character. As such, the HAT energy barriers correlate with the energy level of the HOMO of the DMAs. (c) The series exhibits a switch from spin-selective reactivity for DMA and p-Cl-DMA to two-state reactivity, with low- and high-spin states, for p-CN-DMA and p-NO2-DMA. (d) The computed kinetic isotope effect profiles (KIEPs) for these scenarios match the experimentally determined KIEPs. Theory further shows that the KIEs and TS structures vary in a manner predicted by the Melander-Westheimer postulate: as the substituent becomes more electron withdrawing, the TS is shifted to a later position along the H-transfer coordinate and the corresponding KIEs increases. (e) The generated carbinolaniline can readily dissociate from the heme and decomposes in a nonenzymatic environment, which involves water assisted proton shift.     

A Photophysical Study of Sensitization‐Initiated Electron Transfer: Insights into the Mechanism of Photoredox Activity

The development of photocatalytic reactions has provided many novel opportunities to expand the scope of synthetic organic chemistry. In parallel with progress towards uncovering new reactivity, there is consensus that efforts focused on providing detailed mechanistic insight in order to uncover underlying excited‐state reactions are essential to maximise formation of desired products. With this in mind, we have investigated the recently reported sensitization‐initiated electron transfer (SenI‐ET) reaction for the C?H arylation of activated aryl halides. Using a variety of techniques, and in particular nanosecond transient absorption spectroscopy, we are able to distinguish several characteristic signals from the excited‐state species involved in the reaction, and subsequent kinetic analysis under various conditions has facilitated a detailed insight into the likely reaction mechanism.     

Catalytic oxidation with a non-heme iron complex that generates a low-spin Fe(III)OOH intermediate

The antitumor drug bleomycin (BLM) is proposed to act via a low-spin iron(III) hydroperoxide intermediate called "activated bleomycin". To gain more insight into the mechanistic aspects of catalytic oxidation by these intermediates we have studied the reactivity of [(N4Py)Fe(CH3CN)](ClO4)2 (1) (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine) with excess H2O2. Under these conditions a transient purple species is generated, [(N4Py)FeOOH]2- (2), which has spectroscopic features and reactivity strongly reminiscent of activated bleomycin. The catalytic oxidation of alkanes such as cyclohexane, cyclooctane, and adamantane by 1 with H2O2 gave the corresponding alcohols and ketones in up to 31% yield. It was concluded, from the O2 sensitivity of the oxidation reactions, the formation of brominated products in the presence of methylene bromide, and the nonstereospecificity of the oxidation of cis- or trans-dimethylcyclohexane, that long-lived alkyl radicals were formed during the oxidations. Oxidation of alkenes did not afford the corresponding epoxides in good yields but resulted instead in allylic oxidation products in the case of cyclohexene, and cleavage of the double bond in the case of styrene. Addition of hydroxyl radical traps, such as benzene and acetone, led to only partial quenching of the reactivity. The kinetic isotope effects for cyclohexanol formation, ranging from 1.5 in acetonitrile to 2.7 in acetone with slow addition of H2O2, suggested the involvement of a more selective oxidizing species in addition to hydroxyl radicals. Monitoring the UV/Vis absorption of 2 during the catalytic reaction showed that 2 was the precursor for the active species. On the basis of these results it is proposed that 2 reacts through homolysis of the O-O bond to afford two reactive radical species: [(N4Py)Fe(IV)O]2+ and *OH. The comparable reactivity of 1 and Fe-BLM raises the possibility that they react through similar mechanistic pathways.     

Highly chemoselective reductive amination of carbonyl compounds promoted by InCl3/Et3SiH/MeOH system

A new strategy has been developed for reductive amination of aldehydes and ketones with the InCl3/Et3SiH/MeOH system, which is a nontoxic system with highly chemoselective and nonwater sensitive properties. The methodology can be applied to a variety of cyclic, acyclic, aromatic, and aliphatic amines. Functionalities including ester, hydroxyl, carboxylic acid, and olefin are found to be stable under our conditions. The reaction shows a first-order kinetics profile with respect to both InCl3 and Et3SiH. Spectroscopic techniques such as NMR and ESI-MS have been employed to probe the active and resulting species arising from InCl3 and Et3SiH in MeOH, which are important in deriving a mechanistic proposal. In the ESI-MS studies, we have first discovered the existence of stable methanol-coordinated indium(III) species which are presumably responsible for the gentle generation of indium hydride at room temperature. The solvent attribution was crucial in tuning the reactivity of [In-H] species, leading to the establishment of mild reaction conditions. The system is superior in flexible tuning of hydride reactivity, resulting in the system being highly chemoselective.     

Mechanistic aspects of vanadium catalysed oxidations with peroxides

The enhancement of the reactivity of peroxides, particularly hydrogen peroxide and alkylhydroperoxides, in the presence of vanadium catalysis is a very well known process. The catalytic effect is determined by the formation of an intermediate whose nature depends on the peroxides used and on its interaction with the metal precursor, high-valent peroxo vanadium species being usually the reactive oxidants. During the last decades the mechanistic details for several types of oxidation reactions have been elucidated. Interestingly, in a number of cases theoretical calculations offered support to the proposed reaction pathways.In general, V(V) peroxo species behave as electrophilic oxygen transfer reagents thus reacting preferentially with the more nucleophilic functional group present in the molecule. In several instances the chemoselectivity observed in such processes is very high when not absolute. As far as vanadium peroxides are concerned, a radical oxidative reactivity toward alkanes and aromatics has been also observed; also for this latter chemistry, diverse research groups studied in detail the mechanism. On the other hand, no clear-cut evidence of nucleophilic reactivity of vanadium peroxo complexes has been obtained.Here we collect a selection of recent achievements concerning the reaction mechanisms in the vanadium catalysed oxidation and bromination reactions with peroxides.     

Photochemically initiated oxidative carbon-carbon bond-cleavage reactivity in chlorodiketonate Ni(II) complexes

Three mononuclear Ni(II) complexes containing a 2-chloro-1,3-diketonate ligand and supported by the 6-Ph(2)TPA chelate, as well as analogues that lack the 2-chloro substituent on the β-diketonate ligand, have been prepared and characterized. Upon irradiation at 350 nm under aerobic conditions, complexes containing the 2-chloro-substituted ligands undergo reactions to generate products resulting from oxidative cleavage, α-cleavage, and radical-derived reactions involving the 2-chloro-1,3-diketonate ligand. Mechanistic studies suggest that the oxidative cleavage reactivity, which leads to the production of carboxylic acids, is a result of the formation of superoxide, which occurs through reaction of reduced nickel complexes with O(2). The presence of the 2-chloro substituent was found to be a prerequisite for oxidative carbon-carbon bond-cleavage reactivity, as complexes lacking this functional group did not undergo these reactions following prolonged irradiation. The approach toward investigating the oxidative reactivity of metal β-diketonate species outlined herein has yielded results of relevance to the proposed mechanistic pathways of metalloenzyme-catalyzed β-diketonate oxidative cleavage reactions.     

Stereocontrolled aziridination of imines via a sulfonium ylide route and a mechanistic study

The reaction of N-diphenylphosphinoyl imines 1 with [3-(trimethylsilyl)allyl]dimethylsulfonium bromide (5) in the presence of NaH at room temperature predominantly gave trans-vinylaziridines 4. On the other hand, cis-vinylaziridines 4 were the main products when the preformed ylide prepared from the reaction of [3-(trimethylsilyl)allyl]diphenylsulfonium perchlorate (6) was reacted with the same imines 1 at low temperature. trans-Aziridines were also obtained when imines 1 and sulfinimines 9 were reacted with N,N-dimethylacetamide-2-dimethylsulfonium bromide (7) in the presence of a base, respectively. A mechanistic study showed that the stereochemistry of these reactions was controlled by the reactivity of the imines and ylides. A higher reactivity of imines and ylides favors the formation of cis-aziridines, whereas a lower reactivity leads to trans-products.     

Friedel-Crafts sulfonylation in 1-butyl-3-methylimidazolium chloroaluminate ionic liquids.

1-Butyl-3-methylimidazolium chloroaluminate ionic liquids have been employed as an unconventional reaction media and as Lewis acid catalyst for Friedel-Crafts sulfonylation reaction of benzene and substituted benzenes with 4-methyl benzenesulfonyl chloride. The substrates exhibited enhanced reactivity, furnishing almost quantitative yields of diaryl sulfones, under ambient conditions. Studies concerning the effect of Lewis acidity of the ionic liquid on the initial extent of conversion of this reaction has been carried out. (27)Al NMR spectroscopy has been exploited as a tool to investigate the mechanistic details of the reaction. (27)Al NMR spectral studies show the predominance of [Al(2)Cl(7)](-) species in [bmim]Cl-AlCl(3), N = 0.67, acidic ionic liquid in the presence of 4-methyl benzenesulfonyl chloride, and after the reaction with the aromatic hydrocarbon, [AlCl(4)](-) species predominates. This change in speciation of aluminum can be attributed to the interaction of the Lewis acidic species [Al(2)Cl(7)](-) of the ionic liquid with the formed HCl during the sulfonylation reaction, which is evidenced by the control experiment. Preliminary investigations on Friedel-Crafts acylation further substantiate the argument.     

Generation of carbanions through stibine-metal and bismuthine-metal exchange reactions and its applications to precision synthesis of ω-end-functionalized polymers

Generation of carbanions from organostibines and organobismuthines through heteroatom-metal exchange reactions was examined from synthetic and mechanistic viewpoints. The exchange reaction proceeded spontaneously upon treatment with various organometallic reagents, such as alkyl lithiums, tetraalkyl zincates, and alkyl magnesium halides to afford the corresponding carbanions quantitatively. Due to the high reactivity of these heteroatom compounds, the exchange reactions took place exclusively even in the presence of various polar functional groups, which potentially react with organometallic species. The advantage of this method was exemplified by the end-group transformation of living polymers that bear these heteroatom species at the ω-polymer end, prepared by using organostibine and bismuthine-mediated living radical polymerizations. Various polymers that bear polar functional groups and acidic hydrogen-for example, poly(methyl methacrylate), poly(butyl acrylate), poly(N-isopropyl acrylamide), and poly(2-hydroxyethyl methacrylate)-could be used in the exchange reactions, and subsequent trapping with electrophiles afforded the corresponding polymers with controlled molecular weights, molecular weight distributions, and end-group functionalities. Competition experiments showed that organostibines and organobismuthines were among the most reactive heteroatom compounds towards organometallic reagents and that their high reactivity was responsible for the high chemoselectivity in the exchange reaction.     

The Electrophilic Fluorination of Enol Esters Using SelectFluor: A Polar Two-Electron Process

The reaction of enol esters with SelectFluor is facile and leads to the corresponding α-fluoroketones under mild conditions and, as a result, this route is commonly employed for the synthesis of medicinally important compounds such as fluorinated steroids. However, despite the use of this methodology in synthesis, the mechanism of this reaction and the influence of structure on reactivity are unclear. A rigorous mechanistic study of the fluorination of these substrates is presented, informed primarily by detailed and robust kinetic experiments. The results of this study implicate a polar two-electron process via an oxygen-stabilised carbenium species, rather than a single-electron process involving radical intermediates. The structure–reactivity relationships revealed here will assist synthetic chemists in deploying this type of methodology in the syntheses of α-fluoroketones.     

Reaction mechanism and structure-reactivity relationships in the stereospecific 1,4-polymerization of butadiene catalyzed by neutral dimeric allylnickel(II) halides [Ni(C3H5)X]2 (X- = Cl-, Br-, I-): a comprehensive density functional theory study

For the first time, a comprehensive and consistent picture of the catalytic cycle of 1,4-polymerization of butadiene with neutral dimeric allylnickel(II) halides [Ni(C3H5)X]2 (X = Cl- (I), Br- (II), and I- (III)) as single-site catalysts has been derived by means of quantum chemical calculations that employ a gradient-corrected density-functional method. All crucial reaction steps of the entire catalytic course have been scrutinized, taking into account butadiene pi complex formation, symmetrical and asymmetrical splitting of dimeric pi complexes, cis-butadiene insertion, and anti-syn isomerization. The present investigation examines, in terms of located structures, energies and activation barriers, the participation of postulated intermediates, in particular it aimed to clarify whether monomeric or dimeric species are the catalytically active species. Prior qualitative mechanistic assumptions are substituted by the presented theoretically well-founded and detailed analysis of both the thermodynamic and the kinetic aspects, that substantially improve the insight into the reaction course and enlarge them with novel mechanistic proposals. From a mechanistic point of view, all three catalysts exhibit common characteristics. First, chain propagation occurs by cis-butadiene insertion into the pi-butenylnickel(II) bond with nearly identical intrinsic free-energy activation barriers. Second, the reactivity of syn-butenyl forms is distinctly higher than that of anti forms. Third, the chain-propagation step is rate-determining in the entire polymerization process, and the pre-established anti-syn equilibrium can always be regarded as attained. Accordingly, neutral dimeric allylnickel(II) halides catalyze the formation of a stereo-regular trans-1,4-polymer under kinetic control following the k1t channel with butenyl(halide)(butadiene)NiII complexes being the catalytically active species. Production of a stereoregular cis-1,4-polymer with allylnickel chloride can only be explained by making the k2c channel accessible by the formation of polybutadienyl(butadiene) complexes, which is accompanied by the coordination of the next double bond in the growing chain to the NiII center.     

Remarkable efficiency of the aryne chemistry of (dehydro)octafluoro[2.2]paracyclophane when using the Cadogan method

Generation of the aryne, (dehydro)octafluoro[2.2]paracyclophane, from its acetamide derivative utilizing the Cadogan method led to remarkable results with respect to Diels-Alder and ene reactivity. A comparison was made between this new and virtually unused method and our earlier reported results using Cram methodology (reaction of aryl iodide with potassium tert-butoxide). Surprisingly, no ene reactivity was observed with the Cram methodology. This mechanistic conundrum was examined extensively with no unambiguous explanation for the difference in reactivity being found.