Titanocene catalyzed 4-exo cyclizations: mechanism, experiment, catalyst design

A method for the preparation of a variety of cyclobutanes via 4-exo cyclization of radicals is presented. Radical generation is carried out by electron transfer from titanocene(III) chlorides to epoxides. The reaction relies on the acceleration of the cyclization through the use of alpha,beta-unsaturated carbonyl compounds as radical traps and the thermodynamic stabilization of the cyclobutylcarbinyl radicals through conjugation. The mechanism of the transformation was investigated by a combined theoretical and experimental study. The computational results provide the crucial energetic and structural features of pertinent intermediates and transition structures. Moreover, the origins of the diastereoselectivity of the 4-exo cyclization are outlined for the first time. Catalysts for those cases where "Cp2TiCl" did not perform in a satisfactory manner have been devised. Through the introduction of tert-butyl or cyclo-hexyl substituted cyclopentadienyl ligands the longevity of the pivotal beta-titanoxy radicals is increased sufficiently enough to enable the slow but often surprisingly diastereoselective formation of the cyclobutylcarbinyl radical. The resulting transformation constitutes the first general approach to cyclobutanes using radical chemistry.     

Diphenylnitrenium ion: cyclization, electron transfer, and polymerization reactions

Reactions of diphenylnitrenium ion were examined using laser flash photolysis (LFP), product analysis, and computational modeling using density functional theory (DFT). In the absence of trapping agents, diphenylnitrenium ion cyclizes to form carbazole. On the basis of laser flash photolysis experiments and DFT calculations it is argued that this process is a concerted cyclization/proton transfer that forms the H-4a tautomer of carbazole. Additional LFP experiments and product studies show that diphenylnitrenium ion reacts with electron-rich arenes (e.g., N,N-dimethylaniline, diphenylamine, and carbazole) through an initial one-electron transfer. The radical intermediates formed in this step then couple to form dimeric products. Secondary reactions between the diphenylnitrenium ion and these dimers results in the formation of oligomeric materials.     

Thermochemical and kinetic analyses on oxidation of isobutenyl radical and 2-hydroperoxymethyl-2-propenyl radical

In recognition of the importance of the isobutene oxidation reaction in the preignition chemistry associated with engine knock, the thermochemistry, chemical reaction pathways, and reaction kinetics of the isobutenyl radical oxidation at low to intermediate temperature range were computationally studied, focusing on both the first and the second O2 addition to the isobutenyl radical. The geometries of reactants, important intermediates, transition states, and products in the isobutenyl radical oxidation system were optimized at the B3LYP/6-311G(d,p) and MP2(full)/6-31G(d) levels, and the thermochemical properties were determined on the basis of ab initio, density functional theory, and statistical mechanics. Enthalpies of formation for several important intermediates were calculated using isodesmic reactions at the DFT and the CBS-QB3 levels. The kinetic analysis of the first O2 addition to the isobutenyl radical was performed using enthalpies at the CBS-QB3 and G3(MP2) levels. The reaction forms a chemically activated isobutenyl peroxy adduct which can be stabilized, dissociate back to reactants, cyclize to cyclic peroxide-alkyl radicals, and isomerize to the 2-hydroperoxymethyl-2-propenyl radical that further undergoes another O2 addition. The reaction channels for isomerization and cyclization and further dissociation on this second O2 addition were analyzed using enthalpies at the DFT level with energy corrections based on similar reaction channels for the first O2 addition. The high-pressure limit rate constants for each reaction channel were determined as functions of temperature by the canonical transition state theory for further kinetic model development.     

Regiochemistry in radical cyclization of allenes

The cyclization of allenic radicals was systematically studied for the first time by computational methods. It was found that the theoretical results at the ONIOM(QCISD(T)/6-311+G(2df,2p):UB3LYP/6-311+G(2df,2p)) level were in good agreement with all the available experimental data. For the cyclization of penta-3,4-dien-1-yl radicals the major product was penta-1,2-diene from direct reduction whereas a small amount of vinylcyclopropane may also be produced. For the cyclization of hexa-4,5-dien-1-yl radicals the major product is 1-methyl-cyclopentene. Furthermore, for the cyclization of hepta-5,6-dien-1-yl radicals both vinylcyclopentane and 1-methyl-cyclohexene are produced. Marcus theory analysis indicated that the formation of an olefinic radical product always had a lower intrinsic energy barrier than the formation of an allylic radical product. On the other hand, the formation of an olefinic radical product was always much less favorable than the formation of an allylic radical product in the thermodynamic term. For the cyclization of substituted hexa-4,5-dien-1-yl radicals, substitution at the allene moiety does not affect the regioselectivity where the allylic radical product is always favored. For the cyclization of hepta-5,6-dien-1-yl radicals, substitution at the allene moiety dramatically affects the regioselectivity, where some radical-stabilizing groups such as -CN and -COMe may even completely reserve the regioselectivity.     

Toluene combustion: reaction paths, thermochemical properties, and kinetic analysis for the methylphenyl radical + O2 reaction

Aromatic compounds such as toluene and xylene are major components of many fuels. Accurate kinetic mechanisms for the combustion of toluene are, however, incomplete, as they do not accurately model experimental results such as strain rates and ignition times and consistently underpredict conversion. Current kinetic mechanisms for toluene combustion neglect the reactions of the methylphenyl radicals, and we believe that this is responsible, in part, for the shortcomings of these models. We also demonstrate how methylphenyl radical formation is important in the combustion and pyrolysis of other alkyl-substituted aromatic compounds such as xylene and trimethylbenzene. We have studied the oxidation reactions of the methylphenyl radicals with O2 using computational ab initio and density functional theory methods. A detailed reaction submechanism is presented for the 2-methylphenyl radical + O2 system, with 16 intermediates and products. For each species, enthalpies of formation are calculated using the computational methods G3 and G3B3, with isodesmic work reactions used to minimize computational errors. Transition states are calculated at the G3B3 level, yielding high-pressure limit elementary rate constants as a function of temperature. For the barrierless methylphenyl + O2 and methylphenoxy + O association reactions, rate constants are determined from variational transition state theory. Multichannel, multifrequency quantum Rice-Ramsperger-Kassel (qRRK) theory, with master equation analysis for falloff, provides rate constants as a function of temperature and pressure from 800 to 2400 K and 1 x 10(-4) to 1 x 10(3) atm. Analysis of our results shows that the dominant pathways for reaction of the three isomeric methylphenyl radicals is formation of methyloxepinoxy radicals and subsequent ring opening to methyl-dioxo-hexadienyl radicals. The next most important reaction pathway involves formation of methylphenoxy radicals + O in a chain branching process. At lower temperatures, the formation of stabilized methylphenylperoxy radicals becomes significant. A further important reaction channel is available only to the 2-methylphenyl isomer, where 6-methylene-2,4-cyclohexadiene-1-one (ortho-quinone methide, o-QM) is produced via an intramolecular hydrogen transfer from the methyl group to the peroxy radical in 2-methylphenylperoxy, with subsequent loss of OH. The decomposition of o-QM to benzene + CO reveals a potentially important new pathway for the conversion of toluene to benzene during combustion. A number of the important products of toluene combustion proposed in this study are known to be precursors of polyaromatic hydrocarbons that are involved in soot formation. Reactions leading to the important unsaturated oxygenated intermediates identified in this study, and the further reactions of these intermediates, are not included in current aromatic oxidation mechanisms.     

In search of efficient 5-endo-dig cyclization of a carbon-centered radical: 40 years from a prediction to another success for the Baldwin rules

Despite being predicted to be stereoelectronically favorable by the Baldwin rules, efficient formation of a C-C bond through a 5-endo-dig radical cyclization remained unknown for more than 40 years. This work reports a remarkable increase in the efficiency of this process upon beta-Ts substitution, which led to the development of an expedient approach to densely functionalized cyclic 1,3-dienes. Good qualitative agreement between the increased efficiency and stereoselectivity for the 5-endo-dig cyclization of Ts-substituted vinyl radicals and the results of density functional theory analysis further confirms the utility of computational methods in the design of new radical processes. Although reactions of Br atoms generated through photochemical Ts-Br bond homolysis lead to the formation of cyclic dibromide side products, the yields of target bromosulfones in the photochemically induced reactions can be increased by recycling the dibromide byproduct into the target bromosulfones through a sequence of addition/elimination reactions at the exocyclic double bond. Discovery of a relatively efficient radical 5-endo-dig closure, accompanied by a C-C bond formation, provides further support to stereoelectronic considerations at the heart of the Baldwin rules and fills one of the last remaining gaps in the arsenal of radical cyclizations.     

Density functional theory study of the mechanisms and stereochemistry of the rh(i)-catalyzed intramolecular [3+2] cycloadditions of 1-ene- and 1-yne-vinylcyclopropanes

The mechanisms, structures of all stationary points involved, and kinetic and thermodynamic parameters of the Rh(I)-catalyzed intramolecular [3+2] cycloaddition reactions of 1-ene- and 1-yne-vinylcyclopropanes (1-ene-VCPs and 1-yne-VCPs) have been investigated using density functional theory (DFT) calculations. The computational results showed that the [3+2] reactions of 1-ene/yne-VCPs studied here occur through a catalytic cycle of substrate-catalyst complex formation, cyclopropane cleavage, alkene/alkyne insertion, and reductive elimination. Alkene/alkyne insertion is the rate- and stereoselectivity-determining step of these multistep [3+2] cycloadditions. The experimentally observed high reactivity of 1-yne-VCPs compared to 1-ene-VCPs is well rationalized by the differences of steric effects in the alkyne/alkene insertion transition states. DFT calculations unveiled that the relative orientation of the tethers in the 1-ene/yne-VCPs plays a key role in controlling the stereochemistry of the [3+2] cycloadducts. In addition, DFT calculation results are used to explain why, in some cases, the formation of the β-hydride elimination byproduct can compete with the [3+2] pathway.     

N-Alkenyl-2-aziridinylmethyl radicals and N-alkenylaminyl radicals in cascade cyclizations to pyrrolizidines and indolizidines

[reaction: see text] The radical cascade cyclizations of N-alkenyl-2-aziridinylmethyl radicals to pyrrolizidines and indolizidines were examined using density functional theory (DFT) calculations. A large preference for cyclization to pyrrolizidines was found. These predictions corroborated very well with experimental results, leading to an efficient synthesis of pyrrolizidines. No radical cascade cyclization to indolizidines could be performed in practice as only ring opening of N-alkenyl-2-aziridinylmethyl radicals to N-allyl-N-alkenylamines occurred.     

An exploratory study of ring closures of aryl radicals onto cyclopropyl- and oxiranyl-isocyanate acceptors

The idea that ring closures of C-centred radicals onto isocyanates could be made permanent by designing the cyclised radical to undergo a rapid onward beta-scission, was investigated for the 2-(2-isocyanato)cyclopropylphenyl and 2-(2-isocyanato)oxiranylphenyl radicals. The radical precursors, trans- and cis-1-bromo-(2-isocyanatocyclopropyl)benzene and (2-bromophenyl)-3-isocyanatooxirane, were prepared from the corresponding bromophenylcyclopropane and bromophenyloxirane carboxylic acids via Curtius rearrangements of the derived azides. The structure of the trans-2-(2-isocyanato)cyclopropylphenyl radical prevents cyclization, however, it was shown that isomerisation to the analogous cis-radical occurred, probably by scission of the disubstituted cyclopropane bond followed by internal rotation of the resulting resonance stabilised diradical. It was found, however, that the main product from homolytic reactions of both trans- and cis-isocyanatocyclopropyl compounds, with tributyltin hydride and tris(trimethylsilyl)silane, was the direct reduction product, trans-(2-isocyanatocyclopropyl)benzene. Only traces of cyclised products, that were probably 4,5-dihydrobenzo[c]azepin-1-one from the cyclopropane precursor and 5H-6-oxa-8-azabenzocyclohepten-9-one from the oxirane precursor, were detected. We conclude, therefore, that the rate of cyclization onto isocyanate acceptor groups must be slower in these systems than hex-5-enyl cyclization or that the reverse ring-opening process must be faster than for analogous radicals.     

Atmospheric oxidation mechanism of p-xylene: a density functional theory study

We report an investigation of the mechanistic features of OH-initiated oxidation reactions of p-xylene using density function theory (DFT). Reaction energies for the formation of the aromatic intermediate radicals have been obtained to determine their relative stability and reversibility, and their activation barriers have been analyzed to assess the energetically favorable pathways to propagate the p-xylene oxidation. OH addition is predicted to occur dominantly at the ortho position, with branching ratios of 0.8 and 0.2 for ortho and ipso additions, respectively, and the calculated overall rate constant is in agreement with available experimental studies. Under atmospheric conditions, the p-xylene peroxy radicals arising from initial OH and subsequent O(2) additions to the ring are shown to cyclize to form bicyclic radicals, rather than to react with NO to lead to ozone formation. With relatively low barriers, isomerization of the p-xylene bicyclic radicals to more stable epoxide radicals likely occurs, competing with O(2) addition to form bicyclic peroxy radicals. The study provides thermochemical and kinetic data for assessment of the photochemical production potential of ozone and formation of toxic products and secondary organic aerosol from p-xylene oxidation.     

8-endo versus 7-exo cyclization of alpha-carbamoyl radicals. A combination of experimental and theoretical studies

Atom transfer radical cyclization reactions of N-(4-pentenyl)iodoacetamides were investigated. The reactions were efficiently promoted by BF3.OEt2. For N-alkenyl-substituted iodoamides, excellent regioselectivity in favor of 8-endo cyclization was observed, while both 7-exo and 8-endo cyclization products were formed with the 8-endo cyclization preferred in the cases of N-(2-allylphenyl)-substituted iodoamides. Density functional theory calculations at the B3LYP/6-31G level revealed that both the s-trans and the s-cis conformational transition structures were feasible for the 8-endo cyclization of N-alkenyl-substituted alpha-carbamoyl radicals while 7-exo transition structures were much less stable. For the cyclization of N-(2-allylphenyl)-substituted alpha-carbamoyl radicals, the transition structures for 8-endo and 7-exo cyclizations were of comparable energy. These results were in excellent agreement with the experimental observations.     

Quantum-chemical calculations of the enthalpies and entropies of gas-phase reactions possible in chemical vapor deposition of Group III-Group V element binary compounds

The results of quantum-chemical modeling of possible gas-phase reactions in chemical vapor deposition of Group III-Group V element binary compounds are generalized. Modern computational methods are shown to be capable of obtaining the thermodynamic characteristics of gas-phase reactions in agreement with experimental data. Quantum-chemical methods can be used to estimate the possibility and determine the temperature conditions of formation of oligomeric intermediates during deposition, predict the feasibility of synthesizing new rod-like inorganic polymers, and develop the concept of precursors for the controlled synthesis of III–V composites.     

PdCl2催化炔酸烯丙酯环化反应的密度泛函研究

用密度泛函方法(DFT)研究了PdCl2催化炔酸烯丙酯环化反应的机理. 在B3LYP/6-311G**水平上优化了各反应中间体和过渡态的结构. 计算结果表明, 反应是放热的, 主要经历了炔键的卤钯化、烯烃对烯基钯的迁移插入以及β-杂原子消除等过程. 烯烃的迁移插入是反应的手性决定步骤, β-杂原子消除是反应的速率控制步骤. 理论预测的主要产物是与实验吻合的(Z,R)-α-亚烷基-γ-丁内酯.     

Carbonyl- and carboxyl-substituted enediynes: synthesis, computations, and thermal reactivity

The influence of electron-withdrawing groups (carbonyl and carboxyl) at the alkyne termini on the reactivity of enediynes was investigated by a combination of experimental and computational techniques. While the general chemical reactivity of such enediynes, especially if non-benzannelated, is increased markedly, the thermal cyclization, giving rise to Bergman cyclization products, is changed little relative to the parent enediyne system. This is evident from kinetic measurements and from density functional theory (DFT, BLYP/6-31G + thermal corrections) computations of the experimental systems which show that the Bergman cyclization barriers slightly (3-4 kcal/mol) increase, in contrast to earlier theoretical predictions. The effect on the endothermicities is large (DeltaDeltaH(r) = 7-12 kcal/mol). Hence, the increased reactivity of the substituted enediynes is entirely due to nucleophiles or radicals present in solution. This was demonstrated by quantitative experiments with diethylamine and tetramethyl piperidyl oxide (TEMPO) which both give fulvenes through 5-exo-dig cyclizations.     

Radical Reactions Induced by Visible Light in Dichloromethane Solutions of Hünig's Base: Synthetic Applications and Mechanistic Observations

β‐(3‐Iodopropoxy)‐substituted α,β‐unsaturated lactams, lactones, and cycloalkenones (eight examples) underwent reductive radical reactions in a dichloromethane solution of N,N‐diisopropylethylamine (Hünig's base) upon irradiation with visible light (λ=419 nm). Apart from plain reduction reactions (hydro‐de‐iodination), a significant degree of cyclization was observed in three cases. In parallel to the conversion of the substrates, the formation of intensely colored by‐products was observed. Based on mass spectrometric evidence and upon comparison with known compounds, the by‐products were identified as cyanine dyes. Their formation supports the hypothesis that irradiation of dichloromethane solutions of Hünig's base leads to the formation of radicals, which in turn can either initiate a radical reaction or combine with cyanine precursors. It was shown by deuterium‐labelling experiments, that one equivalent of dichloromethane is incorporated into the cyanine dyes and that the reductive quenching of radical intermediates is at least partially due to hydrogen abstraction from the solvent. As a consequence, a reductive cyclization of the starting materials is favored in CD₂Cl₂ solutions as shown for two β‐(3‐iodopropoxy)‐substituted tetronates, which underwent in dichloromethane almost exclusive reduction, but gave predominantly the cyclization products in CD₂Cl₂.     

Intramolecular homolytic substitution of sulfinates and sulfinamides--a computational study

Ab initio and density functional theory (DFT) calculations predict that intramolecular homolytic substitution by alkyl radicals at the sulfur atom in sulfinates proceeds through a smooth transition state in which the attacking and leaving radicals adopt a near collinear arrangement. When forming a five-membered ring and the leaving radical is methyl, G3(MP2)-RAD//ROBHandHLYP/6-311++G(d,p) calculations predict that this reaction proceeds with an activation energy (ΔE(1)(?)) of 43.2 kJ mol(-1). ROBHandHLYP/6-311++G(d,p) calculations suggest that the formation of five-membered rings through intramolecular homolytic substitution by aryl radicals at the sulfur atom in sulfinates and sulfinamides, with expulsion of phenyl radicals, proceeds with the involvement of hypervalent intermediates. These intermediates further dissociate to the observed products, with overall energy barriers of 45-68 kJ mol(-1), depending on the system of interest. In each case, homolytic addition to the phenyl group competes with substitution, with calculated barriers of 51-78 kJ mol(-1). This computational study complements and provides insight into previous experimental observations.     

Evidence of neutral radical induced analyte ion transformations in APPI and Near-VUV APLI

We report on the reactions of neutral radical species [OH, Cl, O(³P), H], generated in a typical atmospheric pressure ionization (API) source upon irradiation of the sample gases with either 193 nm laser radiation or 124 nm VUV light, the latter commonly used in atmospheric pressure photoionization (APPI). The present investigations focus on the polycyclic aromatic hydrocarbon pyrene as representative of the aromatic compound class. Experimental results are supported by computational methods: simple kinetic models are used to estimate the temporal evolution of the concentrations of reactants, intermediates, and final products, whereas density functional theory (DFT) energy calculations are carried out to further elucidate the proposed reaction pathways. The neutral radicals are generated upon photolysis of background water and oxygen always present in appreciable mixing ratios in typical API sources. Substantial amounts of oxygenated analyte product ions are observed using both techniques. In contrast, upon atmospheric pressure laser ionization (APLI) with 248 nm radiation, oxygenated products are virtually absent. In addition, kinetic data evaluation yielded a bimolecular rate constant of k=(1.9±0.9)×10⁻⁹ cm³ molecule⁻¹ s⁻¹ for the reaction of the pyrene radical cation with OH radicals.     

Quantum Chemical Approach for Determining Degradation Pathways of Phenol by Electrical Discharge Plasmas

This study uses density functional theory (DFT) simulations to predict the main pathways by which hydroxyl (OH) radicals oxidize phenol into monohydroxylated products during an electrical discharge directly in or contacting water. The calculated activation energies and reaction rate constants indicate that phenol ring H abstraction is less likely to occur than OH addition, which will be the fastest in the ortho and para positions. The chain propagation with molecular oxygen of such formed ortho and para radicals will result in the production of hydroquinone and catechol, which are, concurrently, the most likely products of phenol degradation by OH radicals. Electron transfer reactions between dihydroxycyclohexadienyl radicals and plasma oxidative species are another important reaction mechanism which may be contributing significantly to the formation of products. Good agreement between computed kinetic and experimental data demonstrates the feasibility of applying DFT to investigate chemical reaction mechanisms.     

Radical 4-exo cyclizations via template catalysis

The mechanism of catalytic 4-exo cyclizations without gem-dialkyl substitution was investigated by a comparison of cyclic voltammetry, EPR, and computational studies with previously published synthetic results. The most active catalyst is a super-unsaturated 13-electron titanocene(III) complex that is formed by supramolecular activation through hydrogen bonding. The template catalyst binds radicals via a two-point binding that is mandatory for the success of the 4-exo cyclization. The computational investigations revealed that formation of the observed trans-cyclobutane product is not possible from the most stable substrate radical. Instead, the most stable product is formed with the lowest energy of activation from a disfavored substrate in a Curtin-Hammett related scenario.