Formation Of Transition State Research Articles

Gold(I) Catalysis in Alkyne-Alkene Reactions: A Systematic Exploration through Molecular Electrostatic Potential Analysis.

Gold catalysis enables selective chemical transformations with catalytic activity tunable through ligand selection. This study uses the density functional theory (DFT) to explore the impact of phosphine ligands (PR3) on gold(I)-catalyzed alkyne-alkene cyclobutene formation. We analyze the following key steps: (i) PR3-Au+ complexation, (ii) alkyne binding, (iii) alkene binding, (iv) C-C coupling transition state, (v) cyclobutene formation transition state, and (vi) cyclobutene dissociation. Molecular electrostatic potential (MESP) analysis provided a deeper understanding of electronic effects and revealed a strong correlation between the change in MESP at the gold nucleus (ΔNVAu+) upon complex formation with various ligands and the corresponding complexation energy, as well as between the change in MESP at the alkyne carbon (ΔVC) and the C-C coupling step activation barrier. This establishes MESP as a powerful tool for understanding ligand influence on catalysis. Our findings suggest that electron-donating phosphine ligands, combined with electron-withdrawing alkyne substituents, enhance catalyst turnover, promote cyclobutene product dissociation from the gold(I) complex, and facilitate catalyst regeneration. Solvent effects also play a crucial role. Bulky XPhos, JohnPhos, and CyJohnPhos ligands enhance gold(I) catalysis via steric protection, electron donation, and catalyst regeneration efficiency. In conclusion, this study provides insights into ligand effects in gold(I)-catalyzed cyclobutene formation, guiding future catalyst design.

Physicochemical Mechanics Instead of Transition State Theory.

This article initially reminds the basics of transition state theory (TST) and gives a textbook example illustrating the often-forgotten problems with TST-based description of reversible reactions. Then, we briefly describe a suggested by us approach called physicochemical mechanics. It was initially developed to describe both the rates and equilibria of chemical mass transport. Here, we show that the same classical mechanics-based approach is working for the kinetics of elementary mono-, bimolecular, and electrochemical reactions. Traditional assumptions regarding pseudoequilibrium for transition state formation are not necessary anymore. A simple interpretation of compensation and tunneling effects is given. The inversion zone for rate constants of strongly exothermic redox reactions is also explained.

Acid-base synergistic effect towards catalytic transfer hydrogenation reactions

Catalytic transfer hydrogenation (CTH) of aldehydes/ketones by using alcohols as hydrogen donors is an attractive and environmentally friendly hydrogenation technology, which has evoked widespread attention in synthesis of fine chemicals from biomass resources. In this work, a Co-Al mixed metal oxide catalyst (Co1Al2-MMO-200) was obtained through structural topological transformation process of layered double hydroxides, which was used in the CTH reaction of furfural with isopropanol. Notably, the reaction rate achieves 0.023 mol g−1 h−1, which is preponderate to acid-base catalysts earlier reported. The joint research based on CO2-TPD, NH3-TPD and poisoning experiment substantiates that the synergy effect of acid-base sites plays an essential role in this catalytic system. Isotopic labelling MS, in-situ FT-IR and DFT studies further verify that the CTH reaction of furfural occurs via the Meerwein-Ponndorf-Verley (MPV) route, in which the basic site promotes the deprotonation of isopropanol whilst the acid site facilitates the formation of a six-membered ring transition state. This work demonstrates an acid-base synergetic catalysis for the CTH reaction by revealing the structure-property correlation and exploring reaction route, which is instructive for designing high-performance heterogenous catalysts.

Effect of agitation speed on methylene blue discoloration kinetics via ambient air cold plasma

AbstractThis research investigates the kinetics of methylene blue (MB) discoloration using ambient air cold plasma, with a focus on the impact of agitation speed (100 and 750 rpm). The study revealed pseudo‐first‐order kinetics for MB discoloration, pinpointing optimal conditions at 35.00°C and 100 rpm. These parameters minimized half‐life times, correlated with observed kobs values. A decreasing pH trend, more pronounced at 750 rpm, was attributed to increased acidic nitrogen species (HNO3 and HNO2) production, adversely affecting dye discoloration. Concurrently, enhanced electrolyte concentration was noted from rising conductivity due to plasma production of reactive species followed by solubilization in the aqueous phase. The calculated thermodynamic activation parameters comprised: Ea = 7.96 kJ mol−1, ΔH‡ = +5.53 kJ mol−1, ΔS‡ = −253.23 J K−1 mol−1, and ΔG‡ = +79.77 kJ mol−1 (100 rpm); and Ea = 12.94 kJ mol−1, ΔH‡ = +13.78 kJ mol−1, ΔS‡ = −239.06 J K−1 mol−1, and ΔG‡ = +80.58 kJ mol−1, (750 rpm). The lowest Ea and ΔG‡ values at 100 rpm reinforced lower agitation favoring the reaction. The study demonstrated a linear decay of the reaction rate constant with the square root of ionic strength. This result, besides the negative activation entropy and moderate activation enthalpy led to a proposition to the determinant step for the transition state formation, involving an associative step between a solvated electron and the protonated substrate. The optimal dye discoloration rate and energy yield were observed at 35.00°C and 100 rpm, with values of 97.2% and 3.371 × 10−2 g kW−1 h−1, respectively.

Prebiotic chemical reactivity in solution with quantum accuracy and microsecond sampling using neural network potentials

While RNA appears as a good candidate for the first autocatalytic systems preceding the emergence of modern life, the synthesis of RNA oligonucleotides without enzymes remains challenging. Because the uncatalyzed reaction is extremely slow, experimental studies bring limited and indirect information on the reaction mechanism, the nature of which remains debated. Here, we develop neural network potentials (NNPs) to study the phosphoester bond formation in water. While NNPs are becoming routinely applied to nonreactive systems or simple reactions, we demonstrate how they can systematically be trained to explore the reaction phase space for complex reactions involving several proton transfers and exchanges of heavy atoms. We then propagate at moderate computational cost hundreds of nanoseconds of a variety of enhanced sampling simulations with quantum accuracy in explicit solvent conditions. The thermodynamically preferred reaction pathway is a concerted, dissociative mechanism, with the transient formation of a metaphosphate transition state and direct participation of water solvent molecules that facilitate the exchange of protons through the nonbridging phosphate oxygens. Associative-dissociative pathways, characterized by a much tighter pentacoordinated phosphate, are higher in free energy. Our simulations also suggest that diprotonated phosphate, whose reactivity is never directly assessed in the experiments, is significantly less reactive than the monoprotonated species, suggesting that it is probably never the reactive species in normal pH conditions. These observations rationalize unexplained experimental results and the temperature dependence of the reaction rate, and they pave the way for the design of more efficient abiotic catalysts and activating groups.

Solvent stabilization of alkene epoxidation transition states within Ti-MFI: Interactions near and far from active sites

Kinetics of alkene epoxidation in Ti incorporated MFI (Ti-MFI) zeolites that contact liquid methanol (CH3OH) depend strongly on the bulk concentration of water ([H2O]) and the density of silanol groups ((SiOH)x) within the framework, because these species influence excess free energy contributions (Gε) that stabilize transition states for epoxidation and hydrogen peroxide derived reactive intermediates. These effects rely on hydrogen bonds among intrapore molecules that couple catalytic events to the structure of the surrounding solvent molecules. Turnover rates for 1-hexene (C6H12) epoxidation with hydrogen peroxide over Ti-MFI zeolites increase by ten-fold both when either [H2O] or (SiOH)x densities increase. Activation enthalpies and entropies of hydrophilic and hydrophobic Ti-MFI materials are similar at the lowest [H2O] (0.005 M H2O), implying solvation environments near active sites do not depend on defect density in the near-absence of H2O. However, kinetic barriers for these same Ti-MFI materials increase and diverge from one another as non-monotonic functions of [H2O] (0.005–5 M H2O), and these differences reflect stabilizing contributions from discrete solvation shells both adjacent (near) and further (or far) from active sites. The structure of these solvation shells must reorganize to accommodate H2O2 activation and formation of epoxidation transition states. Adsorption enthalpies for the epoxide product become more exothermic with larger values of [H2O] over each Ti-MFI catalyst, and the apparent activation enthalpies generally increase as epoxide adsorption enthalpies become more exothermic. Comparisons to trends previously obtained for Ti-BEA catalysts suggest the negative correlation indicates that excess contributions (Hε, Gε) impact reactive species (Ti-OOH) within the 10-membered ring pores of MFI to a greater extent than 12-membered ring pores due to distinctions among hydrogen bonding interactions among bound reactive species, spectating solvent molecules, and extended surfaces of MFI pores.

Clumped isotope reordering kinetics in strontianite and witherite: Experiments and first-principles simulations

The carbonate clumped isotope (∆47) thermometer is a powerful tool for temperature reconstruction based on the thermodynamical 13C—18O bonding preference. Accurate interpretation of temperatures requires preservation of original carbonate ∆47 signatures, which are susceptible to resetting at elevated temperatures during burial. Kinetic models of carbonate 13C—18O bond reordering derived from experimental studies constrain the evaluation of ∆47 preservation and the reconstruction of thermal histories and initial temperatures for reordered carbonates. However, application of these models to different carbonates is limited because kinetic parameters vary with materials and are believed to be affected by factors such as crystal structure, cation, trace element composition, crystal defects, and internal water whose roles in reordering are still not well-understood. Here we present reordering data for strontianite and witherite from heating experiments and evaluate the effects of crystal structure, cation chemistry, cation vacancy and substitution, and internal water on reordering using constrained ab-initio molecular dynamics (cAIMD) simulations. We show that strontianite and witherite reorder significantly faster than other carbonates. Comparing experimental studies yields the following reordering rate sequence: strontianite > witherite > aragonite > calcite > dolomite. The general trend in Arrhenius activation energy for reordering is strontianite < witherite < aragonite < dolomite < calcite (with calcite values based on the average of individual materials). Our cAIMD simulations reveal a similar trend in free energy of activation for oxygen exchange in these carbonates. We suggest that orthorhombic carbonates are more susceptible to reordering than trigonal carbonates because of the shorter distance between carbonate groups and because the weaker M—O interaction in orthorhombic carbonates reduces the structural distortion and the energy cost during transition state formation. For carbonates sharing the same structure, the weak M—O bonding can be compensated by a large unit cell volume, leading to a non-systematic relationship between the free energy of activation and the cation radius. In simulations with lattice-bound water, the free energy of activation is greatly reduced compared with cation vacancy and substitution. The influence of fluid inclusions on measured reordering rates depends on the fraction of carbonates that can exchange with water as suggested by strontianite δ¹⁸O data. Our results serve as a starting point for a more sophisticated but flexible kinetic model containing material-specific factors (e.g., substituted ions, structure water, etc.) for reordering in abiotic and biotic carbonates.

Decreased Transition-State Analogue Affinity in Isotopically Heavy MTAN with Increased Catalysis.

5'-Methylthioadenosine/S-adenosylhomocysteine nucleosidase from Helicobacter pylori (HpMTAN) demonstrated faster chemistry when expressed as an isotopically heavy protein, with 2H, 13C, and 15N replacing the bulk of normal isotopes. The inverse heavy enzyme isotope effect has been attributed to improved enzyme-reactant interactions causing more frequent transition-state formation ( Proc. Natl. Acad. Sci. U.S.A. 2021, 118, e2109118118). Transition-state analogues stabilize the transient dynamic geometry of the transition state and inform on transition-state dynamics. Here, a slow-onset, tight-binding transition-state analogue of HpMTAN is characterized with heavy and light enzymes. Dissociation constants for the initial encounter complex (Ki) and for the tightly bound complex after slow-onset inhibition (Ki*) with hexylthio-DADMe-Immucillin-A (HTDIA) gave Ki values for light and heavy HpMTAN = 52 ± 10 and 85 ± 13 pM and Ki* values = 5.9 ± 0.3 and 10.0 ± 1.2 pM, respectively. HTDIA dissociates from heavy HpMTAN at 0.063 ± 0.002 min-1, faster than that from light HpMTAN at 0.032 ± 0.004 min-1. These values are consistent with transition-state formation by an improved catalytic site dynamic search and inconsistent with catalytic efficiency proportional to tight binding of the transition state.

Tuning Surface Reactivity and Electric Field Strength via Intermetallic Alloying.

Many electrosynthesis reactions, such as CO2 reduction to multicarbon products, involve the formation of dipolar and polarizable transition states during the rate-determining step. Systematic and independent control over surface reactivity and electric field strength would accelerate the discovery of highly active electrocatalysts for these reactions by providing a means of reducing the transition state energy through field stabilization. Herein, we demonstrate that intermetallic alloying enables independent and systematic control over d-band energetics and work function through the variation of alloy composition and oxophilic constituent identity, respectively. We identify several intermetallic phases exhibiting properties that should collectively yield higher intrinsic activity for CO reduction compared to conventional Cu-based electrocatalysts. However, we also highlight the propensity of these alloys to segregate in air as a significant roadblock to investigating their electrocatalytic activity.

Photodegradation of Flutamide and Halogen Derivatives of Nitrobenzotrifluoride: The NO Release Channel.

The photodegradation of the nonsteroidal antiandrogen drug flutamide has been long linked to the photoisomerization involving the nitro group. In this work, the dynamics of NO photoelimination upon photolysis at 266 nm of flutamide, nitrobenzotrifluoride, and its halogen derivatives were investigated. Similar to nitrobenzene and its derivatives, a bimodal translational energy distribution was observed for the NO photofragment indicating the presence of two distinct elimination channels resulting in slow and fast components. The trends in the slow/fast branching ratio show that halogen substitution at the para position increases the triplet state yield due to the internal heavy-atom effect leading to enhancement of the fast component. Furthermore, the topology of the triplet state potential energy surface showed that the minimum energy path favors the oxaziridine ring-type intermediate over the NO2 roaming mechanism in all five molecules investigated. The steric interaction between the NO2 group and the CF3 group, which are placed in the ortho position, lowers the barrier for the formation of the oxaziridine transition state compared to that of nitrobenzene.

Enantiospecific Synthesis of Aniline-Derived Sulfonimidamides.

Reaction of sulfonimidoyl fluorides with anilines and Ca(NTf2)2 results in the formation of chiral sulfonimidamides. The reaction proceeds with inversion of the stereocenter at a sulfur atom. Enantiospecificity of the reaction was observed for all studied non-heterocyclic anilines. Combined experimental and computational mechanistic studies highlight chelate-type coordination of the sulfonimidoyl group to Ca(NTf2)2 and the formation of a SN2-like transition state, in which leaving F- coordinates with the Ca2+ ion.

Virtual Free-Radical Polymerization of Vinyl Monomers in View of Digital Twins.

The first case of virtual polymerization based on the concept of digital twins (DTs) is presented. The free-radical polymerization of vinyl monomers is considered to be a chain reaction consisting of a set of elementary ones. Those three types, related to the polymerization initiation and propagation as well as to the termination of polymer chain growth, are discussed. Special sets of DTs, whose total number approaches 60, distinguish each reaction type. The calculations are carried out using a semi-empirical version of the unrestricted Hartree-Fock approximation. The main energy and spin-density parameters of the ground state of the DTs are determined. The barrier profiles of two pairs of DTs are calculated, based on which two Evans-Polanyi-Semenov relations, attributed to elementary reactions of type (1) and (2), are constructed. These provide a quite reliable evaluation of the activation energy for the initiation and propagation of the free-radical polymerization of vinyl monomers in all the cases. The decisive role of spins in the formation of the elementary reaction transition states is established.

Theoretical insight into the acceptorless dehydrogenation catalyzed by the transition metal bifunctional catalysts: Mechanism and metal effect

In this paper, the density functional theory study was performed to investigate the reaction mechanism of acceptorless dehydrogenation catalyzed by bifunctional catalysts. The calculation results indicate that the catalyst bearing the Co(III) center adopts the inner-sphere stepwise dehydrogenation mechanism. The H2 formation was found to be the rate-determining step, and the proton-shuttle type transition state effectively reduces the activation energy barrier. Furthermore, the catalytic activities of the noble metals (Rh and Ir) were investigated and compared. The results suggest that the noble metals prefer the outer-sphere bifunctional transfer mechanism for the dehydrogenation reaction. Frontier molecular orbital analysis shows that the HOMO-LUMO gap of the active species increases along with the periodic number, which leads to a weakening of the coordination strength of the substrate to the metal center, resulting in the different mechanistic selectivity toward dehydrogenation reaction. In addition, based on the distortion-interaction analysis, the different activation energy barrier in the H2 formation step is illuminated. The reduced ionic radii of the Co result in lower deformation energies of the catalyst and substrate structures in the H2 formation transition state, thus lowering the activation energy barrier. Our results reveal the advantages of base metal in dehydrogenation reactions, which is expected to provide theoretical guidance for future catalyst design.

Mechanism for the Formation of Nanoscale Oxides in a Medium of Supercritical CO2 Fluid

A possible mechanism is considered for the formation of nanoscale oxides based on titanium and aluminum isopropoxides in a medium of supercritical CO2 fluid. It is shown that because of intermolecular interactions and high pressure in the system, the supercritical fluid acquires the properties of a condensed medium, the main role of which is to restrain processes of hydrolysis. At the first stage of the hydrolysis of titanium isopropoxide, the water molecule is coordinated in the outer sphere of the central atom due to the formation of intermolecular hydrogen bonds. It is then coordinated into the inner sphere with the formation of a five-coordinate transition state and its destruction, creating a product substituted for the hydroxo group. The next steps proceed in a similar way. The described mechanism agrees with experimental findings and produces nanosized X-ray amorphous titanium oxide. (With aluminum isopropoxide, only the hydrolyzed hydroxo form can be produced.) Results suggest the production of nanosized oxides from isopropoxides in a medium of supercritical CO2 fluid is possible for transitional d-elements.

How a highly acidic SH3 domain folds in the absence of its charged peptide target.

Charged residues on the surface of proteins are critical for both protein stability and interactions. However, many proteins contain binding regions with a high net charge that may destabilize the protein but are useful for binding to oppositely charged targets. We hypothesized that these domains would be marginally stable, as electrostatic repulsion would compete with favorable hydrophobic collapse during folding. Furthermore, by increasing the salt concentration, we predict that these protein folds would be stabilized by mimicking some of the favorable electrostatic interactions that take place during target binding. We varied the salt and urea concentrations to probe the contributions of electrostatic and hydrophobic interactions for the folding of the yeast SH3 domain found in Abp1p. The SH3 domain was significantly stabilized with increased salt concentrations due to Debye-Huckel screening and a nonspecific territorial ion-binding effect. Molecular dynamics and NMR show that sodium ions interact with all 15 acidic residues but do little to change backbone dynamics or overall structure. Folding kinetics experiments show that the addition of urea or salt primarily affects the folding rate, indicating that almost all the hydrophobic collapse and electrostatic repulsion occur in the transition state. After the transition state formation, modest yet favorable short-range salt bridges are formed along with hydrogen bonds, as the native state fully folds. Thus, hydrophobic collapse offsets electrostatic repulsion to ensure this highly charged binding domain can still fold and be ready to bind to its charged peptide targets, a property that is likely evolutionarily conserved over 1 billion years.

Kinetic and thermodynamic characterization of keratinolytic protease from chicken feather waste degrading B. subtilis ES5

Kinetic and thermodynamic characterization of enzymes is of great important for understanding their industrial applications. The main objective of this study was to produce, purify and study the kinetic and thermodynamic properties of keratinase from B. subtilis ES5. Specific activity of the enzyme was improved by 126.16 % and 140.11 % using ammonium sulfate and dialysis purification methods, respectively. The activation energy (Ea), Gibbs free energy (∆G≠), entropy (∆S≠), enthalpy (∆H≠), free energy of substrate binding (∆G≠E−S), free energy of transition state formation (∆G≠E−T), and temperature coefficient (Q10) for casein hydrolysis were 17.59 KJ/mol, 66.11 KJ/mol, −160.88 J/mol/k, 14.95 KJ/mol, 2.61 KJ/mol, −9.21 KJ/mol, and 1.62, respectively. Thermal denaturation energy for keratinase was 110.83 KJ/mol. Kinetic studies revealed good enzyme-substrate complex formation and spontaneous conversion to product. Thermodynamic parameters indicate a relatively thermostable enzyme. These properties suggest that the present keratinase can be a potential candidate for use in different biotechnological applications.

Engineering C-C Bond Cleavage Activity into a P450 Monooxygenase Enzyme.

The cytochrome P450 (CYP) superfamily of heme monooxygenases has demonstrated ability to facilitate hydroxylation, desaturation, sulfoxidation, epoxidation, heteroatom dealkylation, and carbon-carbon bond formation and cleavage (lyase) reactions. Seeking to study the carbon-carbon cleavage reaction of α-hydroxy ketones in mechanistic detail using a microbial P450, we synthesized α-hydroxy ketone probes based on the physiological substrate for a well-characterized benzoic acid metabolizing P450, CYP199A4. After observing low activity with wild-type CYP199A4, subsequent assays with an F182L mutant demonstrated enzyme-dependent C-C bond cleavage toward one of the α-hydroxy ketones. This C-C cleavage reaction was subject to an inverse kinetic solvent isotope effect analogous to that observed in the lyase activity of the human P450 CYP17A1, suggesting the involvement of a species earlier than Compound I in the catalytic cycle. Co-crystallization of F182L-CYP199A4 with this α-hydroxy ketone showed that the substrate bound in the active site with a preference for the (S)-enantiomer in a position which could mimic the topology of the lyase reaction in CYP17A1. Molecular dynamics simulations with an oxy-ferrous model of CYP199A4 revealed a displacement of the substrate to allow for oxygen binding and the formation of the lyase transition state proposed for CYP17A1. This demonstration that a correctly positioned α-hydroxy ketone substrate can realize lyase activity with an unusual inverse solvent isotope effect in an engineered microbial system opens the door for further detailed biophysical and structural characterization of CYP catalytic intermediates.

Mechano-/seeding-triggered crystal-to-crystal phase transition in luminescent switching cocrystals

Currently, there are only a few cases of both mechanical stimulation-induced and seeding-triggered fluorescence conversion in which the mechanism of phase transition remains less well investigated. Herein, the first report of a luminescent switch based on mechano-/seeding-triggered crystal-crystal phase transition in a cocrystal polymorphic system is present. Based on the structure analysis and theoretical calculations, the luminescent switching can be attributed to the orbital overlap of the chromophores and exciton coupling. Furthermore, a mechanism of the phase transition was proposed, in which the synthons undergo movements including slipping and twisting during the phase transition. The effects of heating, local mechanical stimulus, and seed contact on the transition were discussed. It was proposed that contacting seeds can lower the energy barrier of the phase transition by inducing the formation of intermediate transition states of synthons via molecular recognition. The energy barrier was found to be the key factor in such mechano-/seeding-triggered phase transition.

Theoretical and Experimental Assessments of Elementary Steps and Bound Intermediates in Catalytic H2–O2 Reactions on Dispersed Pt Nanoparticles

Kinetic and isotopic data and H2 chemisorption uptakes measured under reaction conditions are combined here with theoretical assessments on model catalytic surfaces at relevant hydrogen (H*) coverages to establish the identity and kinetic relevance of elementary steps and bound species in H2–O2 reactions on Pt surfaces. Turnover rates are proportional to O2 pressure and decrease and then reach constant values as H2 pressures increase, leading to apparent first-order rate parameters (rO2/PO2) that reflect reactive collision probabilities of O2 with surfaces and which depend solely on the H2 pressure at all temperatures (540–680 K). H2–D2 isotopic exchange rates during reactions with O2 are much faster than water formation rates, consistent with quasi-equilibrated H2 dissociation steps and with prevalent H* coverages that can be determined independently from H2 uptakes; such measurements enable the decoupling of non-Langmuirian adsorption parameters from kinetic parameters in rate equations. These data indicate that H2–O2 reactions involve two kinetically-relevant O2 dissociation routes. One channel forms two bound O atoms on bare Pt atom ensembles available within H* adlayers, which react via fast subsequent reactions with H* to form H2O. A parallel O2 dissociation route involves reactions with a H*–H* pair to form weakly bound adsorbed hydrogen peroxide (*HOOH*), a highly reactive species that subsequently cleaves its O–O bond in steps that are not kinetically-relevant. The free-energy barriers are dominated by losses in translational entropy incurred upon the formation of the transition states from their gaseous O2 precursors. Kinetic isotope effects are near unity for both routes because H* is not involved in direct O2 dissociation steps, and the *HOOH* formation transition state occurs very early along the reaction coordinate (with nearly intact O–O and Pt–H bonds from reactant states), as confirmed by DFT-derived energies and isotope effects.

Mechanistic Insights into the Synergistic Effect of Palladium(0) and Copper(I) on the Selective Transformation of Isocyanate to Indole.

Density functional theory calculations have been utilized to investigate the synergistic effect of palladium(0) and copper(I) catalyzed selective formation of allylated indole from (2-alkynyl)-phenylisocyanate and allyl methyl carbonate. The main competing reaction yielding the N-allyl carbamate was also considered. Calculated results indicate that using the Pd(0)-complex alone, the generation of indole is kinetically much less favored than producing the N-allyl carbamate compound. However, the co-addition of Cu(I) catalyst can considerably decrease the barrier for the intramolecular cyclization step, leading to the formation of the indole product. Analysis of the cyclization process suggests that Cu(I) complex can act as a Lewis acid to activate the linear alkyne group via a π-coordination manner prior to the formation of a 5-membered ring transition state toward indole formation. Altogether, the mechanistic insights revealed in the present study aim at a better understanding of the mechanism and the factors governing the selectivity in synergistic Pd/Cu catalysis.