Synthesis of Difluoromethyl Thioethers from Difluoromethyl Trimethylsilane and Organothiocyanates Generated In Situ

A copper‐CF₂H complex generated in situ from copper thiocyanate and TMS? CF₂H smoothly converts organothiocyanates into valuable difluoromethyl thioethers. This reaction step can be combined with several thiocyanation methods to one‐pot protocols, allowing late‐stage difluoromethylthiolations of widely available alkyl halides and arenediazonium salts. This strategy enables the introduction of difluoromethylthio groups—a largely unexplored substituent with highly promising properties—into drug‐like molecules.     

Vapor-phase Beckmann rearrangement of oxime molecules over H-Faujasite zeolite.

The Beckmann rearrangement (BR) plays an important role in a variety of industries. The mechanism of this reaction rearrangement of oximes with different molecular sizes, specifically, the oximes of formaldehyde (H₂C?NOH), Z‐acetaldehyde (CH₃HC?NOH), E‐acetaldehyde (CH₃HC?NOH) and acetone (CH₃)₂C?NOH, catalyzed by the Faujasite zeolite is investigated by both the quantum cluster and embedded cluster approaches at the B3LYP level of theory using the 6‐31G (d,p) basis set. To enhance the energetic properties, single point calculations are undertaken at MP2/6‐311G(d,p). The rearrangement step, using the bare cluster model, is the rate determining step of the entire reaction of these oxime molecules of which the energy barrier is between 50–70 kcal mol^?1. The more accurate embedded cluster model, in which the effect of the zeolitic framework is included, yields as the rate determining step, the formaldehyde oxime reaction rearrangement with an energy barrier of 50.4 kcal mol^?1. With the inclusion of the methyl substitution at the carbon‐end of formaldehyde oxime, the rate determining step of the reaction becomes the 1,2 H‐shift step for Z‐acetaldehyde oxime (30.5 kcal mol^?1) and acetone oxime (31.2 kcal mol^?1), while, in the E‐acetaldehyde oxime, the rate determining step is either the 1,2 H‐shift (26.2 kcal mol^?1) or the rearrangement step (26.6 kcal mol^?1). These results signify the important role that the effect of the zeolite framework plays in lowering the activation energy by stabilizing all of the ionic species in the process. It should, however, be noted that the sizeable turnover of a reaction catalyzed by the Brønsted acid site might be delayed by the quantitatively high desorption energy of the product and readsorption of the reactant at the active center.     

Theoretical study of mechanism of extraction reaction between silylene carbene and its derivatives and ethylene oxide

The mechanism of the oxide extraction reaction between singlet silylene carbene and its derivatives [X₂Si = C: (X = H, F, Cl, CH₃)] and ethylene oxide has been investigated with density functional theory, including geometry optimization and vibrational analysis for the involved stationary points on the potential energy surface. The energies of the different conformations are calculated by B3LYP/6‐311G(d,p) method. From the potential energy profile, it can be predicted that the reaction pathway of this kind consists two steps, the first step is the two reactants firstly form an intermediate (INT) through a barrier‐free exothermic reaction; the second step is the INT then generates a product via a transition state (TS). This kind reaction has similar mechanism, when the silylene carbene and its derivatives [X₂Si = C: (X = H, F, Cl, CH₃)] and ethylene oxide close to each other, the shift of 2p lone electron pair of O in ethylene oxide to the 2p unoccupied orbital of C in X₂Si = C: gives a p → p donor–acceptor bond, thereby leading to the formation of INT. As the p → p donor–acceptor bond continues to strengthen (that is, the C? O bond continues to shorten), the INT generates product (P + C₂H₄) via TS. It is the substituent electronegativity, which mainly affects the extraction reactions. When the substituent electronegativity is greater, the energy barrier is lower, and the reaction rate is greater. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Catalytic activity of η-(olefin)palladium(0) complexes with iminophosphine ligands in the Suzuki-Miyaura reaction. Role of the olefin in the catalyst stabilization

The catalytic activity of η²-(olefin)palladium(0)(iminophosphine) complexes in the Suzuki-Miyaura coupling is strongly dependent on the reaction conditions and on the nature of the ligands. The reaction is at the best carried out in aromatic solvents in the presence of K₂CO₃ at 90-110 °C. Higher reaction rates are obtained when the R substituent on the N-imino group is an aromatic group of low steric hindrance and the olefin is a moderate π-accepting ligand such as dimethyl fumarate. At temperatures lower than 90 °C, a self-catalyzed process leading to catalyst deactivation becomes predominant. Preliminary mechanistic investigations indicate that the oxidative addition of the aryl bromide to a Pd(0) species is the rate determining step in the catalytic cycle and that the olefin plays a key role in catalyst stabilization. Systems in situ prepared by mixing Pd(OAc)₂ or Pd(dba)₂ with 1 equiv of iminophosphine appear substantially less active than the preformed catalysts.     

Theoretical study on the reaction mechanisms and stereoselectivities of DABCO‐catalyzed Rauhut–Currier/cyclization reaction of methyl acrylate with 2‐benzoyl‐3‐phenyl‐acrylonitrile

With the aid of density functional theory (DFT) calculations, we have investigated the mechanisms and stereoselectivities of the tandem cross Rauhut–Currier/cyclization reaction of methyl acrylate R₁ with (E)‐2‐benzoyl‐3‐phenyl‐acrylonitrile R₂ catalyzed by a tertiary amine DABCO. The results of the DFT calculations indicate that the favorable mechanism (mechanism A) includes three steps: the first step is the nucleophilic attack of DABCO on R₁ to form intermediates Int1 and Int1‐1, the second step is the reaction of Int1 and Int1‐1 with R₂ to generate intermediate Int2(SS,RR,SR&RS), and the last step is an intramolecular S_N2 process to give the final product P(SS,RR,SR&RS) and release catalyst DABCO. The S_N2 substitution is computed to be the rate‐determining step, whereas the second step is the stereoselectivity‐determining step. The present study may be helpful for understanding the reaction mechanism of similar tandem reactions.     

Monitoring of the formation of binuclear ruthenium carbonyl complexes during reactions by means of high performance liquid chromatography

Reversed-phase high performance liquid chromatography has been used to monitor the reactions of Ru₃(CO)₁₂ with 1,4-diazabutadiene (DAB) and of Ru₂(CO)₆ (DAB) with DAB. The kinetic data show that the formation of an intermediate in the former reaction is the rate determining step, which is first order in Ru₃(CO)₁₂ as well as in DAB. The reactivity depends strongly on the type of substituent on DAB. Exchange of free and coordinated ligands (isopropyl DAB and tert-butyl DAB) is demonstrated in the reaction of Ru₂(CO)₆ (DAB) with DAB. A reversible reaction is proposed to account for this exchange.     

Structure and isomerization of cyclotrimetallenes

The substituent migration on the X₂Y rings (X, Y=C, Si, Ge) was studied by theoretical method with silyl and hydrogen substituents and it was found that all the reactions (with the exception of cyclopropene) proceed in a two-step mechanism via a stable intermediate. The rate determining step of the reaction is the first step. The barrier of the second step is small and the energy of the intermediate is close to that of the reactant. Both the first transition state (T1) and the intermediate (I) are of monobridge structures of different types. Since the intermediate bridge structure is almost as stable as the product, it may be observed in the substituent migration reactions.     

Enthalpy–Entropy Correlations in Reactions of Aryl Benzoates with Potassium Aryloxides in Dimethylformamide

Temperature dependences of the relative reactivity of potassium aryloxides XC₆H₄O^?K⁺ toward 4‐nitrophenyl ( 1 ), 3‐nitrophenyl ( 2 ), 4‐chlorophenyl ( 3 ), and phenyl ( 4 ) benzoates in dimethylformamide (DMF) were studied using the competitive reactions technique. The rate constants k_X for the reactions of 1 with potassium 4‐cyanophenoxide, 2 with potassium 3‐bromophenoxide, 3 with potassium 3‐bromo‐, 4‐bromo‐, and unsubstituted phenoxides, 4 with potassium 4‐methoxy‐ and 3‐methylphenoxides were measured at 25°C. Correlation analysis of the relative rate constants k_X/k_H(3‐Me) and differences in the activation parameters (??Н^≠ and ??S^≠) of competitive reactions revealed the existence of six isokinetic series. We investigated the substituent effect of X on the activation parameters for each isokinetic series and concluded that the reactions of aryl benzoates PhCO₂C₆H₄Y with potassium aryloxides in DMF proceed via a four‐step mechanism. The large ρ⁰(Y) and ρ_XY values at 25°C obtained for the reactions of 1–3 with potassium aryloxides with an electron‐donating substituent refer to the rate‐determining formation of the spiro‐σ‐complex. The Hammett plots for the reactions of 1 and 2 exhibit a downward curvature, causing the motion of the transition state for the rate‐determining step according to a Hammond effect as the substituent in aryloxide changes from electron‐donating to electron‐withdrawing. Analysis of data in the terms of two‐dimensional reaction coordinate diagrams leads to the conclusion that significant anti‐Hammond effects arise in the cases of ortho‐substituted and unsubstituted substrates. It was shown that the isokinetic and compensation effects observed for the reactions of aryl benzoates with potassium aryloxides in DMF can be interpreted in the terms of the electrostatic bonding between the reaction centers.     

Synthesis and hydrolysis of substituted tetrahydropyrimidinium salts. Behaviour of the degradation products on varying pH

Reaction of 1,2-diaryl-3-methyl-1,4,5,6-tetrahydropyrimidinium iodides 1a-i with alkaline solutions afforded N-aroyl-N-aryl-N'-methyltrimethylenediamines 2a-i . Compounds 2 are stable under acid conditions but in neutral or alkaline media spontaneously rearrange giving N-aroyl-N'-aryl-N-methyltrimethylenediamines 3a-i . Treating compounds 3 with concentrated acids reverse reaction takes place. Kinetic studies were performed on this intramolecular N → N' aroyl transfer over the H_o-pH range -0.9 to 2.30. Compounds 3 undergo acyl transfer to give 2 by a mechanism which involves a change in the rate determining step from formation to acid-catalysed decomposition of a six-membered heterocyclic intermediate on going from H_o to pH values. The existence of maxima in the pH rate profile allow to determine apparent pKa values of the hexahydropyrimidine intermediates which gave good correlation with the Swain F substituent constants. Stability of these heterocycles was also predicted by determination of thermodinamic parameters. Comparisons are made with the behaviour of five-membered heterocyclic intermediates (imidazolidine derivatives) which were studied in an earlier paper.     

Mechanistic Origin of Chemoselectivity in Thiolate‐Catalyzed Tishchenko Reactions

The thiolate‐catalyzed Tishchenko reaction has shown high chemoselectivity for the formation of double aromatic‐substituted esters. In the present study, the detailed reaction mechanism and, in particular, the origin of the observed high chemoselectivity, have been studied with DFT calculations. The catalytic cycle mainly consisted of three steps: 1,2‐addition, hydride transfer, and acyl transfer steps. The calculation results reproduce the experimental observations that 4‐chlorobenzaldehyde acts as the hydrogen donor (carbonyl part in the ester product), while 2‐methoxybenzaldehyde acts as the hydrogen acceptor (alcohol part in the product). The two main factors are responsible for such chemoselectivity: 1) in the rate‐determining hydride transfer step, the para‐chloride substituent facilitates the hydride‐donating process by weakening the steric hindrance, and 2) the ortho‐methoxy substituent facilitates the hydride‐accepting process by stabilizing the magnesium center (by compensating for the electron deficiency).     

Hydroxypalladation Precedes the Rate‐Determining Step in the Wacker Oxidation of Ethene

The complete reaction mechanism and kinetics of the Wacker oxidation of ethene in water under low [Cl^?], [Pd^II], and [Cu^II] conditions are investigated in this work by using ab initio molecular dynamics. These extensive simulations shed light on the molecular details of the associated individual steps, along two different reaction routes, starting from a series of ligand‐exchange processes in the catalyst precursor PdCl₄^2? to the final aldehyde‐formation step and the reduction of Pd^II. Herein, we report that hydroxylpalladation is not the rate‐determining step and is, in fact, in equilibrium. The newly proposed rate‐determining step involves isomerization and follows the hydroxypalladation step. The mechanism proposed herein is shown to be in excellent agreement with the experimentally observed rate law and rate. Moreover, this mechanism is in consensus with the observed kinetic isotope effects. This report further confirms the outer‐sphere (anti) hydroxypalladation mechanism. Our calculations also ratify that the final product formation proceeds through a reductive elimination, assisted by solvent molecules, rather than through β‐hydride elimination.     

Unexpected Direct Hydride Transfer Mechanism for the Hydrogenation of Ethyl Acetate to Ethanol Catalyzed by SNS Pincer Ruthenium Complexes

The hydrogenation of ethyl acetate to ethanol catalyzed by SNS pincer ruthenium complexes was computationally investigated by using DFT. Different from a previously proposed mechanism with fac‐[(SNS)Ru(PPh₃)(H)₂] ( 5′ ) as the catalyst, an unexpected direct hydride transfer mechanism with a mer‐SNS ruthenium complex as the catalyst, and two cascade catalytic cycles for hydrogenations of ethyl acetate to aldehyde and aldehyde to ethanol, is proposed base on our calculations. The new mechanism features ethanol‐assisted proton transfer for H₂ cleavage, direct hydride transfer from ruthenium to the carbonyl carbon, and C?OEt bond cleavage. Calculation results indicate that the rate‐determining step in the whole catalytic reaction is the transfer of a hydride from ruthenium to the carbonyl carbon of ethyl acetate, with a total free energy barrier of only 26.9 kcal mol^?1, which is consistent with experimental observations and significantly lower than the relative free energy of an intermediate in a previously postulated mechanism with 5′ as the catalyst.     

First C-C bond formation in the Pauson-Khand reaction: Influence of carbon-carbon triple bond polarization on regiochemistry: A density functional theory study

The influence of carbon-carbon triple bond polarization on the regiochemistry of the Pauson-Khand reaction has been studied with the B3LYP functional. The regiochemistry determining step of this reaction, i.e., olefin insertion leading to cobaltacycle formation, has been examined with ethylene as the olefin and propyne, methyl 2-butynoate, and methyl propiolate as the acetylenes. From this study, it has been concluded that, in absence of overwhelming steric effects of an acetylene substituent, the regiochemistry is influenced by the polarization of the acetylenic bond, which arises from the different substituents. The initial C-C bond is preferentially formed with the acetylenic carbon that has the greater electron density: with propyne, this leads to a cyclopentenone having the methyl group in the α-position; with methyl 2-butynoate, to a cyclopentenone with the CO₂Me in the β-position; with methyl propiolate, which is virtually unpolarized in the complex, to a cyclopentenone with the CO₂Me in the α-position (a result of steric effects). These theoretical results are concordant with those observed experimentally with norbornene. The question of axial versus equatorial reactive positions for the coordinated olefin is also addressed and a kinetic simulation is presented.     

σ‐Insertive Mechanism versus Concerted Non‐insertive Mechanism in the Intramolecular Hydroamination of Aminoalkenes Catalyzed by Phenoxyamine Magnesium Complexes: A Synthetic and Computational Study

The phenoxyamine magnesium complexes [{ONN}MgCH₂Ph] ( 4 a : {ONN}=2,4‐tBu₂‐6‐(CH₂NMeCH₂CH₂NMe₂)C₆H₂O^?; 4 b : {ONN}=4‐tBu‐2‐(CH₂NMeCH₂CH₂NMe₂)‐6‐(SiPh₃)C₆H₂O^?) have been prepared and investigated with respect to their catalytic activity in the intramolecular hydroamination of aminoalkenes. The sterically more shielded triphenylsilyl‐substituted complex 4 b exhibits better thermal stability and higher catalytic activity. Kinetic investigations using complex 4 b in the cyclisation of 1‐allylcyclohexyl)methylamine ( 5 b ), respectively, 2,2‐dimethylpent‐4‐en‐1‐amine ( 5 c ), reveal a first‐order rate dependence on substrate and catalyst concentration. A significant primary kinetic isotope effect of 3.9±0.2 in the cyclisation of 5 b suggests significant N?H bond disruption in the rate‐determining transition state. The stoichiometric reaction of 4 b with 5 c revealed that at least two substrate molecules are required per magnesium centre to facilitate cyclisation. The reaction mechanism was further scrutinized computationally by examination of two rivalling mechanistic pathways. One scenario involves a coordinated amine molecule assisting in a concerted non‐insertive N?C ring closure with concurrent amino proton transfer from the amine onto the olefin, effectively combining the insertion and protonolysis step to a single step. The alternative mechanistic scenario involves a reversible olefin insertion step followed by rate‐determining protonolysis. DFT reveals that a proton‐assisted concerted N?C/C?H bond‐forming pathway is energetically prohibitive in comparison to the kinetically less demanding σ‐insertive pathway (ΔΔG^≠=5.6 kcal mol^?1). Thus, the σ‐insertive pathway is likely traversed exclusively. The DFT predicted total barrier of 23.1 kcal mol^?1 (relative to the {ONN}Mg pyrrolide catalyst resting state) for magnesium?alkyl bond aminolysis matches the experimentally determined Eyring parameter (ΔG^≠=24.1(±0.6) kcal mol^?1 (298 K)) gratifyingly well.     

Isomerization of olefins on hydride-halide compounds of titanium and aluminium of composition LmTiH2AlXX′. The role of the cocatalyst and the geometry of the ligand environment of the titanium atom in catalytic hydrogen transfer

Using bimetallic complexes of the compositions (C₅H₅)₂TiH₂MXX′ and (CH₂)_n(C₅H₄)₂TiH₂AlXX′ (M = B, Al; X,X′ = H,Hal, Alk, n = 1–3) as examples, the rate of homogeneous catalytic isomerization of α-olefins has been studied under the influence of the ligand environment, the nature of the transition metal, and the substituent at M. Only titanium and aluminium complexes with non-rigid ligand environments and involving terminal AlH bonds show catalytic activity in the reaction. An alkyl isomerization mechanism at the heterobinuclear centre is suggested. The first reaction step involves coordination of an olefin at the six-coordinate Al atom followed by the insertion of the olefin molecule in the terminal AlH bond.     

Deciphering a 20‐Year‐Old Conundrum: The Mechanisms of Reduction by the Water/Amine/SmI2 Mixture

The reaction of SmI₂ with the substrates 3‐methyl‐2‐butanone, benzyl chloride, p‐cyanobenzyl chloride, and anthracene were studied in the presence of water and an amine. In all cases, the water content versus rate profile shows a maximum at around 0.2 M H₂O. The rate versus amine content profile shows in all cases, except for benzyl chloride, saturation behavior, which is typical of a change in the identity of the rate‐determining step. The mechanism that is in agreement with the observed data is that electron transfer occurs in the first step. With substrates that are not very electrophilic, the intermediate radical anions lose the added electron back to samarium(III) relatively quickly and the reaction cannot progress efficiently. However, in a mixture of water/amine, the amine deprotonates a molecule of water coordinated to samarium(III). The negatively charged hydroxide, which is coordinated to samarium(III), reduces its electrophilicity, and therefore, lowers the rate of back electron transfer, which allows the reaction to progress. In the case of benzyl chloride, in which electron transfer is rate determining, deprotonation by the amine is coupled to the electron‐transfer step.     

Experimental and Computational Insights into Carbon Dioxide Fixation by RZnOH Species

Organozinc hydroxides, RZnOH, possessing the proton‐reactive alkylzinc group and the CO₂‐reactive Zn?OH group, represent an intriguing group of organometallic precursors for the synthesis of novel zinc carbonates. Comprehensive experimental and computational investigations on 1) solution and solid‐state behavior of tBuZnOH ( 1 ) species in the presence of Lewis bases, namely, THF and 4‐methylpyridine; 2) step‐by‐step sequence of the reaction between 1 and CO₂; and 3) the effect of a donor ligand and/or an excess of tBu₂Zn as an external proton acceptor on the reaction course are reported. DFT calculations for the insertion of carbon dioxide into the dinuclear alkylzinc hydroxide 1 ₂ are fully consistent with ¹H NMR spectroscopy studies and indicate that this process is a multistep reaction, in which the insertion of CO₂ seems to be the rate‐determining step. Moreover, DFT studies show that the mechanism of the rearrangement between key intermediates, that is, the primary alkylzinc bicarbonate with a proximal position of hydrogen and the secondary alkylzinc bicarbonate with a distal position of hydrogen, most likely proceeds through internal rotation of the dinuclear bicarbonate.     

Theoretical study of mechanism of extraction reaction between germylene carbene and its derivatives and thiirane

The mechanism of the sulfur extraction reaction between singlet germylene carbene and its derivatives [X₂Ge?C: (X = H, F, Cl, CH₃)] and thiirane has been investigated with density functional theory, including geometry optimization and vibrational analyses for the involved stationary points on the potential energy surface. The energies of the different conformations are calculated by B3LYP/6‐311G(d,p) method. From the potential energy profile, it can be predicted that the reaction pathway of this kind consists two steps: (1) the two reactants firstly form an intermediate (INT) through a barrier‐free exothermic reaction; (2) the INT then isomerizes to a product via a transition state (TS). This kind reaction has similar mechanism, when the germylene carbene and its derivatives [X₂Ge?C: (X = H, F, Cl, CH₃)] and thiirane get close to each other, the shift of 3p lone electron pair of S in thiirane to the 2p unoccupied orbital of C in X₂Ge = C: gives a p → p donor–acceptor bond, leading to the formation of INT. As the p → p donor–acceptor bond continues to strengthen (that is the C? S bond continues to shorten), the INT generates product (P + C₂H₄) via TS. It is the substituent electronegativity that mainly affects the extraction reactions. When the substituent electronegativity is greater, the energy barrier is lower, and the reaction rate is greater. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

The electron impact induced fragmentation of aromatic aldoximes—III. On the loss of HCNO,OH⋅ and substituents and the role of substituent effects in the decomposition of cyclohexadiene type intermediate ions

The mechanisms for loss of HCNO, OH^˙ and the substituent X^˙ from aromatic aldosimes were elucidated with the aid of deuterium labelling, metastable ion characteristics and substituent effects. It is proposed that the loss of HCNO occurs through a cyclohexadiene type intermediate ion generated via a 6-membered ring hydroxyl hydrogen transer to the ortho position of the phenyl ring. This is followd by a second step which involves the trnsfer of a hydrogen atom from the ortho position to C-1. It is inferred from the corelation with the mesomeric effect (σ_R⁺) of substituents that this step is rate determining. Loss of OH^˙ and X^˙ proceed via the same cyclohexadiene type intermediate ion but, depending upon the substituent, other pathways are also followed.     

Aminolysis of 2,4-dinitrophenyl X-substituted benzoates and Y-substituted phenyl benzoates in MeCN: effect of the reaction medium on rate and mechanism

Second‐order rate constants (k_N) have been determined spectrophotometrically for the reactions of 2,4‐dinitrophenyl X‐substituted benzoates ( 1 a – f ) and Y‐substituted phenyl benzoates ( 2 a – h ) with a series of alicyclic secondary amines in MeCN at 25.0±0.1 °C. The k_N values are only slightly larger in MeCN than in H₂O, although the amines studied are approximately 8 pK_a units more basic in the aprotic solvent than in H₂O. The Yukawa–Tsuno plot for the aminolysis of 1 a – f is linear, indicating that the electronic nature of the substituent X in the nonleaving group does not affect the rate‐determining step (RDS) or reaction mechanism. The Hammett correlation with σ^? constants also exhibits good linearity with a large slope (ρ_Y=3.54) for the reactions of 2 a – h with piperidine, implying that the leaving‐group departure occurs at the rate‐determining step. Aminolysis of 2,4‐dinitrophenyl benzoate ( 1 c ) results in a linear Brønsted‐type plot with a β_nuc value of 0.40, suggesting that bond formation between the attacking amine and the carbonyl carbon atom of 1 c is little advanced in the transition state (TS). A concerted mechanism is proposed for the aminolysis of 1 a – f in MeCN. The medium change from H₂O to MeCN appears to force the reaction to proceed concertedly by decreasing the stability of the zwitterionic tetrahedral intermediate (T^±) in aprotic solvent.