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This report investigates the fundamental basis for rather surprising patterns of reactivity in Bronsted acid-mediated cyclizations of pyrrole substrates bearing pendant Michael acceptors that were identified during syntheses of Stemona alkaloids. Integrated experimental and theoretical studies reveal the profound influence that substituent effects have on the viability of these transformations. Additionally, we identify that electronic effects, in addition to barrier-lowering secondary orbital interactions within transition states, account for the exclusive preference for 7-endo-trig cyclizations over 6-exo-trig cyclizations.

Computational studies support the key role of intramolecular coordination by a carboxylate group in the facile oxidative addition of the iodoarene 2,6-(HO2C)2C6H3I to a PdII center to form the pincer-PdIV motif Pd{2,6(O2C)C6H3-O,C,O}, Pd(OCO). Mechanisms of attack by an aryloxide nucleophile at the methylene group in a palladacycle PdIV(OCO)(CH2CRR′–E) to form ArOCH2CMe2–E (E = oxime) are examined; for RR′ = HEt and E = amine, it is mainly the formation of analogous ArOCH2CHEt–E together with CH2═CEt–E arising from β-hydrogen elimination. Computational results are in agreement with recent experimental results by Whitehurst, Gaunt. [J. Am. Chem. Soc. 2020, 142, 14169]. For β-hydrogen elimination, computation demonstrates that the conformational flexibility in the chelate ring is required to allow the hydrogen atom to be in an axial orientation relative to Pd–C, thus maximizing the dihedral angle Pd···C–C···H in the transition-state fragment Pd···CH2C(R)···H···OAr. Bulky substituents R′ at the β-position, CHR′, favor nucleophilic attack at the methylene carbon.

Density functional theory calculations were used to investigate the mechanisms of established hydroalkylation reactions of styrenes with 1,3-diketones that are promoted by either AuCl3/AgOTf or AgOTf catalyst systems. In the former case, our studies led us to propose an original mechanism that is initiated by the generation of highly electrophilic Au(OTf)3, which then coordinates the enol tautomer of the 1,3-diketone substrate. The ensuing highly Bronsted acidic π-complex serves to protonate the styrene to generate a relatively low-energy benzylic carbocation. Notably, this suggests that this benzylic carbocation represents the true catalytic species in the reaction, and thus, the role of the gold complex is solely to generate this active catalyst. AuCl3 alone does not serve as a good initiator for this process because it is not electrophilic enough to generate the relatively low-energy benzylic carbocation. Our investigation of the hydroalkylation facilitated by the slightly electron-deficient AgOTf catalyst revealed that an alternative mechanism predominates. Specifically, it is more likely that the reaction proceeds via a demetallation process directly mediated by the silver catalyst. We found a clear trend indicating that the electron deficiency of the metal center dictates which of these two mechanistic scenarios occurs. This article discusses these two mechanistic pathways in detail, providing key information for the experimental development of hydroalkylation processes.

Although Pd(OAc)2-catalysed alkoxylation of the C(sp3)–H bonds mediated by hypervalent iodine(III) reagents (ArIX2) has been developed by several prominent researchers, there is no clear mechanism yet for such crucial transformations. In this study, we shed light on this important issue with the aid of the density functional theory (DFT) calculations for alkoxylation of butyramide derivatives. We found that the previously proposed mechanism in the literature is not consistent with the experimental observations and thus cannot be operating. The calculations allowed us to discover an unprecedented mechanism composed of four main steps as follows: (i) activation of the C(sp3)–H bond, (ii) oxidative addition, (iii) reductive elimination and (iv) regeneration of the active catalyst. After completion of step (i) via the CMD mechanism, the oxidative addition commences with an X ligand transfer from the iodine(III) reagent (ArIX2) to Pd(II) to form a square pyramidal complex in which an iodonium occupies the apical position. Interestingly, a simple isomerization of the resultant five-coordinate complex triggers the Pd(II) oxidation. Accordingly, the movement of the ligand trans to the Pd–C(sp3) bond to the apical position promotes the electron transfer from Pd(II) to iodine(III), resulting in the reduction of iodine(III) concomitant with the ejection of the second X ligand as a free anion. The ensuing Pd(IV) complex then undergoes the C–O reductive elimination by nucleophilic attack of the solvent (alcohol) on the sp3 carbon via an outer-sphere SN2 mechanism assisted by the X− anion. Noteworthy, starting from the five coordinate complex, the oxidative addition and reductive elimination processes occur with a very low activation barrier (ΔG‡ 0–6 kcal mol−1). The strong coordination of the alkoxylated product to the Pd(II) centre causes the regeneration of the active catalyst, i.e. step (iv), to be considerably endergonic, leading to subsequent catalytic cycles to proceed with a much higher activation barrier than the first cycle. We also found that although, in most cases, the alkoxylation reactions proceed via a Pd(II)–Pd(IV)–Pd(II) catalytic cycle, the other alternative in which the oxidation state of the Pd(II) centre remains unchanged during the catalysis could be operative, depending on the nature of the organic substrate.

A simple gold‐catalyzed annulation of 1,8‐dialkynylnaphthalenes utilizing a cationic gold catalyst was developed. Such a peri‐position of two alkynyl substituents has not been studied in gold catalysis before. Dependent on the substrate, the reactions either follow a mechanism involving vinyl cation intermediates or involve a dual gold catalysis mechanism which in an initial 6‐endo‐dig‐cyclization generates gold(I) vinylidene intermediates that are able to insert into C−H bonds. Indenophenalene derivatives were obtained in moderate to high yields. In addition, the bidirectional gold‐catalyzed annulation of tetraynes provided even larger conjugated π‐systems. The optoelectronic properties of the products were also investigated., The 6‐endo‐cyclization of the first diyne unit (blue) with two alkynes in peri‐position induces a switch to a 5‐exo‐cyclization for the second peri‐diyne unit (red) in the fast modular synthesis of new extended π‐systems.

We thoroughly investigated mechanistic features of dichlorination of diazoacetates using PhICl2 catalysed by pyridine. We found that the pyridine serves as a catalyst for decomposition of PhICl2 to PhI and Cl2, leading to the dichlorination step being driven by the in situ generated Cl2. This type of activation was found to be applicable to other amine-catalysed chlorination reactions using PhICl2.

Density functional theory (DFT) was utilized to understand how bismuth(III) salts (BiX3) achieve greatest activation of organic Lewis bases in a catalytic reaction. It is reported in the literature that the BiX3 reactivity originates from its low lying Bi−X σ* orbital. In contrast to this belief, we will show here that for BiX3 to effectively serve as a catalyst, a p orbital of bismuth needs to be involved in activating organic substrates.

Density functional theory (DFT) at the SMD/M06‐2X/def2‐TZVP//SMD/M06‐2X/SDD,6‐31G(d) level was performed to interrogate the mechanistic details of two oxidative fluorination reactions mediated by hypervalent iodosoarenes (ArIO) in the presence of Lewis acid BF3: (i) formation of a 3‐fluoropyrrolidine from a homoallylic amine and (ii) formation of a fluorinated oxazoline from a benzamide. We found that in both cases, ArIO needs two Lewis acids to be sufficiently activated to mediate the oxidative reactions. When two Lewis acids bind to ArIO, its LUMO mainly centred on the iodine(III) atom becomes energetically more available, resulting in it interacting more strongly with the C–C π orbital of the organic substrate and thus the rate‐determining step of the reaction (an intramolecular nucleophilic attack) being accelerated. Finally, one of these Lewis acids serves as the catalyst and the other one supplies a fluorine atom to the organic substrate. A clear understanding of how ArIO reagents are activated in oxidation of organic substrates could be helpful in designing new oxidative reactions mediated by such hypervalent iodine compounds.

Efficient methods for the synthesis of fused-aromatic rings is a critical endeavour in the creation of new pharmaceuticals and materials. A direct method for preparing these systems is the tetradehydro-Diels–Alder reaction, however this is limited by the need for harsh reaction conditions. A potential, but underdeveloped, route to these systems is via transition metal-catalysed cycloaromatisation of ene-diynes. Herein, tethered unconjugated enediynes have been shown to undergo a facile room-temperature RhI-catalysed intramolecular tetradehydro-Diels–Alder reaction to produce highly substituted isobenzofurans, isoindolines and an indane. Furthermore, experimental and computational studies suggest a novel mechanism involving an unprecedented and complex RhI/RhIII/RhI/RhIII redox cycle involving the formation of an unusual strained 7-membered rhodacyclic allene intermediate and a RhIII-stabilized 6-membered ring allene complex.

A combination of iodosobenzene (PhIO) and molecular iodine (I2) is well-documented to produce a key species capable of conducting various organic reactions through radical mechanisms. This key species is identified here by density functional theory (DFT) calculations to be the hypoiodite radical (IO˙). The calculations show that two equivalents of IO˙ are generated when I2 reacts with two equivalents of PhIO. One of the ensuing IO˙ species acts as a hydrogen abstractor and thus forms an organic radical and the other one is involved in oxidation of the resultant organic radical to afford the final product.

Decomposition of donor-acceptor diazo compounds leads to the formation of reactive carbene intermediates. These can undergo a wide variety of carbene transfer reactions to yield synthetically useful products. Herein, we report a selective borane catalyzed cyclization reaction from the combination of two different diazo compounds to afford N-substituted pyrazoles. The selective decomposition of the more reactive α-aryl α-diazoester and subsequent reaction with a vinyl diazoacetate produces N-alkylated pyrazoles in a regioselective manner. Catalytic amounts of tris(pentafluorophenyl)borane (10 mol%) were employed to afford the pyrazole products (36 examples) in yields from 59 to 80%. Extensive DFT studies have been undertaken to interpret the mechanism for this reaction which was found to go through two tandem catalytic cycles, both catalyzed by B(C6F5)3.

Hypervalent iodine (HVI) compounds are efficient reagents for the double oxidative dearomatization of electron-rich phenols to o-quinones. We recently reported that an underexplored class of iodine(V) reagents possessing bidentate bipyridine ligands, termed Bi(N)-HVIs, could dearomatize electron-poor phenols for the first time. To understand the fundamental mechanistic basis of this unique reactivity, density functional theory (DFT) was utilized. In this way, different pathways were explored to determine why Bi(N)-HVIs are capable of facilitating these challenging transformations while more traditional hypervalent species, such as 2-iodoxybenzoic acid (IBX), cannot. Our calculations reveal that the first redox process is the rate-determining step, the barrier of which hinges on the identity of the ligands bound to the iodine(V) center. This crucial process is composed of three steps: (a) ligand exchange, (b) hypervalent twist, and (c) reductive elimination. We found that strong coordinating ligands disfavor these elementary steps, and, for this reason, HVIs bearing such ligands cannot oxidize the electron-poor phenols. In contrast, the weakly coordinating triflate ligands in Bi(N)-HVIs allow for the kinetically favorable oxidation. It was identified that trapping in situ-generated triflic acid is a key role played by the bidentate bipyridine ligands in Bi(N)-HVIs as this serves to minimize the decomposition of the ortho-quinone product.

Strategies that enable intermolecular site-selective C–H bond functionalisation of organic molecules provide one of the cornerstones of modern chemical synthesis. In chloroalkane synthesis, such methods for intermolecular site-selective aliphatic C–H bond chlorination have, however, remained conspicuously rare. Here, we present a copper(I)-catalysed synthetic method for the efficient site-selective C(sp3)–H bond chlorination of ketones, (E)-enones and alkylbenzenes by dichloramine-T at room temperature. A key feature of the broad substrate scope is tolerance to unsaturation, which would normally pose an immense challenge in chemoselective aliphatic C–H bond functionalisation. By unlocking dichloramine-T’s potential as a chlorine radical atom source, the product site-selectivities achieved are among the most selective in alkane functionalisation and should find widespread utility in chemical synthesis. This is exemplified by the late-stage site-selective modification of a number of natural products and bioactive compounds, and gram-scale preparation and formal synthesis of two drug molecules., Organochlorides are widespread in natural products, therefore the methods for site-selective chlorination at specific C–H bonds are of great interest. Here, the authors report a copper(I)-catalysed synthetic method for the efficient site-selective C(sp3)–H bond chlorination of ketones, (E)-enones and alkylbenzenes by dichloramine-T at room temperature.

Precise control of the selectivity in organic synthesis is important to access the desired molecules. We demonstrate a regiospecific annulation of unsymmetrically substituted 1,2‐di(arylethynyl)benzene derivatives for a geometry‐controlled synthesis of linear bispentalenes, which is one of the promising structures for material science. A gold‐catalyzed annulation of unsymmetrically substituted 1,2‐di(arylethynyl)benzene could produce two isomeric pentalenes, but both electronic and steric effects on the aromatics at the terminal position of the alkyne prove to be crucial for the selectivity; especially a regiospecific annulation was achieved with sterically blocked substituents; namely, 2,4,6‐trimetyl benzene or 2,4‐dimethyl benzene. This approach enables the geometrically controlled synthesis of linear bispentalenes from 1,2,4,5‐tetraethynylbenzene or 2,3,6,7‐tetraethynylnaphthalene. Moreover, the annulation of a series of tetraynes with a different substitution pattern regioselectively provided the bispentalene scaffolds. A computational study revealed that this is the result of a kinetic control induced by the bulky NHC ligands., Give me five: The regiospecific annulation of unsymmetrically substituted 1,2‐di(arylethynyl)benzene derivatives is reported. Both electronic and steric effects on the aromatic moieties of the substrates are crucial for the selectivity. Moreover, the annulation of a series of differently substituted tetraynes regioselectively provided the corresponding bispentalenes (see scheme). The selectivity of this transformation is rationalized by computational studies, and the opto‐electronic properties of the obtained bispentalene derivatives are also reported.

This Article describes the development of a stable Ni(IV) complex that mediates C(sp(2))–H trifluoromethylation reactions. This reactivity is first demonstrated stoichiometrically and then successfully translated to a Ni(IV)-catalyzed C–H trifluoromethylation of electron-rich arene and heteroarene substrates. Both experimental and computational mechanistic studies support a radical chain pathway involving Ni(IV), Ni(III), and Ni(II) intermediates.

Density functional theory calculations were utilized to investigate a PdCl2-catalyzed transformation involving double-bond migration (alkene isomerization), followed by condensation with methanol s...

In this study, we used density functional theory (DFT) to reinvestigate the mechanism proposed by Houk and Zhang et al. (J. Am. Chem. Soc. 2012, 134, 1078) for piperidinone formation through rearrangement of an acetylenic amine N-oxide catalysed by phosphine gold(I) complexes. For this rearrangement, the C-C coupling was proposed to be the rate-determining step with activation energy as high as 35.8 kcal/mol. Such a barrier seems inconsistent with the fact that the actual reaction proceeds under very mild conditions (0 °C, 1 h, in CH2Cl2). In the original report, it was proposed that the C-C coupling takes place via a mechanism which we called “front-side addition”. Interestingly, we found that the C-C coupling step becomes energetically more favourable if it occurs via another mechanism called “back-side addition”. We explored the effect of different phosphine ligands on all conceivable steps of the catalytic reaction and found that while the other steps are not highly sensitive to the phosphine identity, the C-C coupling one shows a considerable degree of dependency; the more electron-donating the phosphine ligand, the lower the rate-limiting step barrier.

We have demonstrated that air-stable cationic gold(I) cocatalysts have the capacity to enhance the efficiency of palladium-catalyzed cross-couplings. Specifically, we determined that a 1:1 [Pd{P(t-Bu)3}2]/[Au{P(t-Bu)3}(NTf2)] system provides superior reactivity relative to [Pd{P(t-Bu)3}2], across Suzuki–Miyaura, Stille, and Mizoroki–Heck reactions performed under mild conditions. Our results are consistent with cationic gold(I) species serving primarily as phosphine scavengers in this chemistry, as recently predicted by density functional theory (DFT).

Density functional theory (DFT) at the SMD/M06-2X/def2-TZVP//SMD/M06-2X/LANL2DZ,6-31G(d) level was employed to explore mechanistic aspects of BF3-catalyzed alcohol oxidation using a hypervalent iodine(III) compound, [ArI(OAc)2], to yield aldehydes/ketones as the final products. The reaction is composed of two main processes: (i) ligand exchange and (ii) the redox reaction. Our study for 1-propanol discovered that ligand exchange is preferentially accelerated if BF3 first coordinates to the alcohol. This coordination increases the acidity of the alcohol hydroxyl proton, resulting in ligand exchange between the iodane and the alcohol proceeding via a concerted interchange associative mechanism with an activation free energy of ∼10 kcal/mol. For the redox process, the calculations rule out the feasibility of the conventional mechanism (alkoxy Cα deprotonation) and introduce a replacement for it. This alternative route commences with α-hydride elimination of the alkoxy group promoted by BF3 coordination, which yields a BF3-stabilized aldehyde/ketone product and the iodane [ArI(OAc)(H)]. The ensuing iodane is extremely reactive toward reductive elimination to give ArI + HOAc in a highly exergonic fashion (ΔG = −62.1 kcal/mol). The reductive elimination reaction is the thermodynamic driving force for the alcohol oxidation to be irreversible. Consistent with the kinetic isotope effect reported experimentally, the α-hydride elimination is calculated to be the rate-determining step with an overall activation free energy of ∼24 kcal/mol.

Gas-phase ion trap mass spectrometry experiments and density functional theory calculations have been used to examine the routes to the formation of the 1,8-naphthyridine (napy) ligated geminally dimetallated phenyl complexes [(napy)Cu2(Ph)]+, [(napy)Ag2(Ph)]+ and [(napy)CuAg(Ph)]+ via extrusion of CO2 or SO2 under collision-induced dissociation conditions from their corresponding precursor complexes [(napy)Cu2(O2CPh)]+, [(napy)Ag2(O2CPh)]+, [(napy)CuAg(O2CPh)]+ and [(napy)Cu2(O2SPh)]+, [(napy)Ag2(O2SPh)]+, [(napy)CuAg(O2SPh)]+. Desulfination was found to be more facile than decarboxylation. Density functional theory calculations reveal that extrusion proceeds via two transition states: TS1 enables isomerization of the O, O-bridged benzoate to its O-bound form; TS2 involves extrusion of CO2 or SO2 with the concomitant formation of the organometallic cation and has the highest barrier. Of all the organometallic cations, only [(napy)Cu2(Ph)]+ reacts with water via hydrolysis to give [(napy)Cu2(OH)]+, consistent with density functional theory calculations which show that hydrolysis proceeds via the initial formation of the adduct [(napy)Cu2(Ph)(H2O)]+ which then proceeds via TS3 in which the coordinated H2O is deprotonated by the coordinated phenyl anion to give the product complex [(napy)Cu2(OH)(C6H6)]+, which then loses benzene.

Density functional theory (DFT) was utilized to investigate the mechanistic aspects of the oxidative dearomatization of phenols mediated by an iodine(iii) reagent. In this article, we will show that the conventional mechanism in which an iodine(iii) phenolate is proposed as the key intermediate is not operative, and the process is promoted if the phenolate ligand is dearomatized on the iodine(iii) center. The dearomatized phenolate is calculated to be a more potent reductant than phenolate itself. In such a case, the reaction is capable of proceeding via two competitive mechanisms (dissociative and associative). Consistent with the experimental findings, we found that while the less polar solvents considerably disfavor the dissociative mechanism, they have an insignificant effect on the associative one. The energetic order of these two mechanisms is calculated to be influenced by the nature of the counter anion coordinated to the iodine(iii) center.

Density functional theory (DFT) was used to investigate PR3AuOTf-catalyzed hydrofunctionalisation of nonactivated alkenes using acetic acid and phenol where OTf = triflate (CF3SO3−). The gold(I) complex itself is found to be unlikely to operate as the π-activator due to its relatively low electrophilicity. Instead, the concurrent coordination of two gold(I) complexes to a nucleophile (PhOH or AcOH) enhances the acidity of the latter's proton and causes the ensuing binuclear complex to serve as a strong proton supplier for activating the alkene π-bonds. Alternatively, the binuclear complex is also susceptible to produce a hidden HOTf. This hidden acid is accessible for hydrofunctionalization to occur but it is not in sufficient concentration to decompose the final product.

In contrast to early transition metal complexes of d0 electron configuration, their main group metal analogues are usually poor catalysts for ethylene polymerisation due to their diminished tendency to insert ethylene into an M-R bond. Interestingly, we found that ring strain in the transition structure of the insertion reaction is most likely responsible to set the ease of the process. Ethylene insertion into an M-R bond requires a four-membered ring transition structure. Strain in a four-membered ring was shown to be dependent on the metal identity (transition or main group/d or p block). For early transition metals, due to the presence of empty valence d orbitals, the strain is negligible but, for main group metals, the strain is significant and so destabilizes the corresponding transition structure. Our claim gains support from investigation of ethylene insertion into an M-allyl bond. In this case, the relevant insertion preferentially passes through a six-membered ring transition structure with an accessibly low activation barrier. In contrast to four-membered ring transition structures, six-membered ones do not suffer significantly from ring strain, causing the insertion activation barrier to become independent of the metal identity. It becomes obvious from our study that this previously undisclosed factor should play the pivotal role in determining the reactivity of many catalysts.

Hypervalent iodine(V) reagents are a powerful class of organic oxidants. While the use of I(V) compounds Dess–Martin periodinane and IBX is widespread, this reagent class has long been plagued by issues of solubility and stability. Extensive effort has been made for derivatizing these scaffolds to modulate reactivity and physical properties but considerable room for innovation still exists. Herein, we describe the preparation, thermal stability, optimized geometries, and synthetic utility of an emerging class of I(V) reagents, Bi(N)-HVIs, possessing datively bound bidentate nitrogen ligands on the iodine center. Bi(N)-HVIs display favorable safety profiles, improved solubility, and comparable to superior oxidative reactivity relative to common I(V) reagents. The highly modular synthesis and in situ generation of Bi(N)-HVIs provides a novel and convenient screening platform for I(V) reagent and reaction development.

The donor–acceptor ability of frustrated Lewis pairs (FLPs) has led to widespread applications in organic synthesis. Single electron transfer from a donor Lewis base to an acceptor Lewis acid can generate a frustrated radical pair (FRP) depending on the substrate and energy required (thermal or photochemical) to promote an FLP into an FRP system. Herein, we report the Csp3–Csp cross-coupling reaction of aryl esters with terminal alkynes using the B(C6F5)3/Mes3P FLP. Significantly, when the 1-ethynyl-4-vinylbenzene substrate was employed, the exclusive formation of Csp3–Csp cross-coupled products was observed. However, when 1-ethynyl-2-vinylbenzene was employed, solvent-dependent site-selective Csp3–Csp or Csp3–Csp2 cross-coupling resulted. The nature of these reaction pathways and their selectivity has been investigated by extensive electron paramagnetic resonance (EPR) studies, kinetic studies, and density functional theory (DFT) calculations both to elucidate the mechanism of these coupling reactions and to explain the solvent-dependent site selectivity.

Iodosobenzene (PhIO) is known to be a potent oxidant for alcohols in the presence of catalytic bromide in water. In order to understand this important and practical oxidation process, we have conducted density functional theory studies to shed light on the reaction mechanism. The key finding of this study is that PhIO is not the reactive oxidant itself. Instead, the active oxidant is hypobromite (BrO-), which is generated by the reaction of PhIO with bromide through an SN2-type reaction. Critically, water acts as a cocatalyst in the generation of BrO- through lowering the activation energy of this process. This investigation also demonstrates why BrO- is a more powerful oxidant than PhIO in the oxidation of alcohols. Other halide additives have been reported experimentally to be less effective catalysts than bromide - our calculations provide a clear rationale for these observations. We also examined the effect of replacing water with methanol on the ease of the SN2 reaction, finding that the replacement resulted in a higher activation barrier for the generation of BrO-. Overall, this work demonstrates that the hypervalent iodine(III) reagent PhIO can act as a convenient and controlled precursor of the oxidant hypobromite if the right conditions are present.

We have identified and extensively investigated the photochemical activation and reaction of a hydroxyquinone-derived phenyliodonium ylide in the presence of visible light using experiment and theory. These studies revealed that in its photoexcited state this iodonium is capable of facilitating a range of single-electron transfer (SET) processes, including hydrogen atom transfer (HAT), a Povarov-type reaction, and atom-transfer radical addition chemistry. Where possible, we have employed density functional theory (DFT) to develop a more complete understanding of these photoinduced synthetic transformations.

The oxidant diphenyldiselenide reacts with MIIMe2(bipy) (bipy = 2,2′-bipyridine) to form a pre-equilibrium involving weak adducts, from which [MMe2(bipy)]2·Ph2Se2 undergoes rate-limiting dissociation of phenylselenide preceded by the oxidative addition step to obtain [Me2(bipy)M-MMe2(bipy)(SePh)]+. Coordination of PhSe− gives the neutral MIII–MIII bonded dimers [MMe2(bipy)(SePh)]2. The dimers fragment in the presence of light to give radicals [MIIIMe2(bipy)(SePh)]˙. After reorientation in the solvent cage, the radicals interact to form triplet adducts [MIIIMe2(bipy)(SePh)·(bipy)MIIIMe2(SePh)]˙˙ with π-stacked ‘SePh·bipy’, followed by transformation via a Minimum Energy Crossing Point allowing [SePh]˙ transfer to give MIIMe2(bipy) and MIVMe2(bipy)(SePh)2. The regenerated MII reagent reacts with Ph2Se2 through the above sequence, allowing completion of reaction to give the MIV product only. The reaction of PtMe2(bipy) with diphenyldisulfide has been studied in an analogous manner to assist with interpretation of DFT results for reactions of diphenyldiselenide. In short, this study shows that photochemical cleavage of metal–metal bonds (Pd, Pt) via excitation to an M–M antibonding orbital facilates disproportionation of the MIII–MIII complex to MII and MIV complexes.

Lewis acidic boranes have been shown to be effective metal-free catalysts for highly selective reactions of donor-acceptor diazo compounds to a range of substrates. The reactions of α-aryl α-diazoesters with nitrogen heterocycles indole or pyrrole selectively generate C3 and C2 C–H insertion products, respectively, in good to excellent yields even when using unprotected indoles. Alternatively, benzofuran, indene, and alkene substrates give exclusively cyclopropanated products with α-aryl α-diazoesters, whereas the reactions with furans lead to ring-opening. Comprehensive theoretical calculations have been used to explain the differing reactivities and high selectivities of these reactions. Overall, this work demonstrates the selective metal-free catalytic reactions of α-aryl α-diazoesters with (hetero)cycles and alkenes. This simple, mild reaction protocol represents an alternative to the commonly used precious metal systems and may provide future applications in the generation of biologically active compounds.

Density Functional Theory studies of square-planar PtII pincer structures, (4-Z-NCN)PtCl ([4-Z-NCN]- =[4-Z-2,6-(Me2 NCH2 )2 C6 H2 -N,C,N]- , Z=H, NO2 , CF3 , CO2 H, CHO, Cl, Br, I, F, SMe, SiMe3 , tBu, OH, NH2 , NMe2 ), enable characterisation of mesomerism for the pincer-Pt interaction. Relationships between Hammett σp substituent parameters of Z and DFT data obtained from NBO6 and AOMix computation are used to probe the interaction of the 5dyz orbital of platinum with π-orbitals of the arene ring. Analogous computation for 2,6-(Me2 CH2 )2 C6 H3 Z (Z=H, CF3 , CHO, Cl, Br, I, F, SMe, SiMe3 , tBu, OH, NH2 ) and (4-H-NCN)PtZ allows an estimation of the relative substituent effects of "(CH2 NMe2 )2 PtZ" on π-delocalisation in the pincer system.

Herein we report a facile, mild reaction protocol to form carbon–carbon bonds in the absence of transition metal catalysts. We demonstrate the metal‐free alkenylation reactions of aryl esters with α‐diazoesters to give highly functionalized enyne products. Catalytic amounts of tris(pentafluorophenyl)borane (10–20 mol %) are employed to afford the C=C coupled products (31 examples) in good to excellent yields (36–87 %). DFT studies were used to elucidate the mechanism for this alkenylation reaction., 2 Become 1: Lewis acidic boranes are employed in the metal‐free alkenylation reactions of aryl esters with α‐diazoesters to give highly functionalized alkene, enyne, and diene products in good to excellent yields. DFT studies have elucidated the mechanism for the reaction.

The ability of halogenated triarylboranes to accept a lone pair of electrons from donor substrates renders them excellent Lewis acids which can be exploited as a powerful tool in organic synthesis. Tris(pentafluorophenyl)borane has successfully demonstrated its ability to act as a metal-free catalyst for an ever-increasing range of organic transformations. Herein we report the N-alkylation reactions of a wide variety of amine substrates including diarylamines, N-methylphenyl amines, and carbazoles with aryl esters using catalytic amounts of B(C6F5)3. This mild reaction protocol gives access to N-alkylated products (35 examples) in good to excellent yields (up to 95%). The construction of a C–N bond at the propargylic position has also been demonstrated to yield synthetically useful propargyl amines. On the other hand, unsubstituted 1H-indoles and 1H-pyrroles at the C3/C2 positions afforded exclusively C–C coupled products. Extensive DFT studies have been employed to understand the mechanism for this transformation.

We have used density functional theory to explore the copper(I)-catalyzed reaction between a mesyl azide and a terminal alkyne that leads to a ketenimine whose interaction with nucleophilic water produces an amide. It is well reported in the literature that a cuprated triazole intermediate is formed during the course of such a catalytic cycle. In this contribution, we investigated the stability of this key intermediate by varying the R substituent on the azide and found that electron-withdrawing R substituents make this intermediate more reactive toward ring opening/N2 elimination; an electron-withdrawing R substituent facilitates this process by weakening the N–N bond being cleaved. We also rationalized why the cycloaddition step in this class of click reactions is required to proceed via a binuclear mechanism. The copper(I) acetylide intermediate formed during the catalysis gains extra stability upon scavenging a second Cu complex, resulting in the cycloaddition step occurring with a lower activation ba...

Density functional theory (DFT) calculations were utilized to investigate the mechanism of the oxidation of an indolyl propargylic alcohol by a N-oxide in the presence of an imine and a gold(I) catalyst. The catalytic reaction is proposed to start from regioselective oxidation of the gold(I)-activated alkyne dictated by a hydrogen bond interaction between the OH group of the propargylic alcohol and the N-oxide. This oxidation was expected to give an α-carbonyl gold carbene complex. In contrast to this expectation, our calculations showed that the corresponding carbene is not a local minimum and the complex undergoes a very fast 1,2 aryl shift to form an alkene complex. Subsequently, an imine is added to the ensuing alkene complex to give an iminium cation from which a cycloaddition process occurs and an indolium is formed. Finally, an N-oxide deprotonates the indolium complex and affords an intermediate which is significantly reactive toward water elimination. Our calculations indicate that the 1,2-aryl s...

A palladium-mediated one-pot synthesis of amidines from aromatic carboxylic acids and carbodiimides (RNCNR) is reported as an isoelectronic adaption of CO2ExIn (ExIn = Extrusion–Insertion) reactions developed for the synthesis of thioamides from carboxylic acids and isothiocyanates (RNCS). Multistage mass spectrometry (MSn) experiments for model systems established “proof of concept”, demonstrating decarboxylation of [(L)Pd(O2CAr)]+ (L = 1,10-phenanthroline or py), to give [(L)PdAr]+, followed by reaction with a carbodiimide, RNCNR, to yield [(L)Pd(NRC(NR)Ar)]+ (R = isopropyl). DFT calculations predicted these reactions as highly exothermic and occurring via carbodiimide insertion into the Pd–Ph bond. 2,6-Dimethoxy and 2,4,6-trimethoxy substitution for the Pd–Ar moiety results in slower reactions with minor changes in mechanism. The individual reaction steps associated with the conversion of 2,6-dimethoxybenzoic acid and 2,4,6-trimethoxybenzoic acid into amidines in solution was probed by 1H NMR spectrosc...

A DFT study of alkyl halide exchange from Pd(IV) to Pd(II) centers supports proposals for an SN2 process in which nucleophilic Pd(II) square-planar complexes attack the axial alkyl group in electrophilic squarepyramidal Pd(IV) centers, leading to transfer of R+ from Pd(IV) to Pd(II) involving a transition structure of the form [R2(bpy)··R··PdR2 (bpy)]+ (bpy = 2,20’ -bipyridine). Computation accounts for the selectivity in benzyl (Bn) over methyl transfer from PhMeBnPdIV(bpy)Br to Me2PdII(bpy), giving PhMePdII(bpy) and BnMe2PdIV(bpy). Transition structures are formed by the interaction of a dz2-like HOMO at the Pd(II) nucleophile and the Pd-C σ* LUMO at the cationic Pd(IV) electrophile. Isomerization of octahedral palladium(IV) complexes via halide loss followed by involvement of trigonal-bipyramidal transition structures to facilitate isomerization is also examined. A lower barrier for Bn+ than Me+ transfer is attributed to stabilisation of the transition structure by delocalisation of positive charge within the benzyl group, reflected in a higher total charge density for the benzyl group than found for the methyl group.

An unprecedented, often almost quantitative access to tricyclic aromatic compounds by dual gold catalysis was developed. This synthetic route expands the scope of benzofulvene derivatives through a C(sp2)-H bond insertion in easily available starting materials. The insertion takes place with an exclusive chemoselectivity with respect to the competing aromatic C-H positions. A bidirectional synthesis with two competing ortho-aryl C-H bonds in the selectivity determining step also shows perfect selectivity; this result is explained by a computational investigation of the two conceivable intermediates. The intramolecular competition of two non-equivalent aryl C-H bonds with a benzylic methyl group also showed perfect selectivity.

Density functional theory (DFT) was utilized to explore the reduction of gold(III) complexes by the amino acid glycine (Gly). Interestingly, when the nitrogen atom of Gly coordinates to the gold(III) center, its Cα -hydrogen atom becomes so acidic that it can be easily deprotonated by a mild base like water. The deprotonation converts the amino acid into a potent reductant by which gold(III) is reduced to gold(I) with a moderate activation energy. To our knowledge, this is the first contribution suggesting that primary amines are oxidized to imines via direct a-carbon deprotonation. This finding may provide new insights into the mechanistic interpretation of amine oxidations catalyzed/mediated by a center with high cathodic reduction potential. This work also provides a rationalization behind why gold(III) complexes with amine-based polydentate ligands are reluctant to undergo a redox process. Gold(III) reduction occurs most efficiently if the Cα proton leaves in the plane of the Cα, N and Au atoms. Chelation prevents this alignment, resulting in the gold(III) complex being unreactive toward reduction. It has been experimentally found that gold(III) is capable of oxidizing Gly to glyoxylic acid (GA) as the initial product. The latter, in the presence of another gold(III) complex, has been reported to undergo oxidative decarboxylation to afford CO2 and HCOOH. This process is found to be mediated by formation of a geminal diol intermediate produced by reaction of water with the aldehyde functional group of the coordinated GA.

The Nazarov cyclisation is an important and reliable reaction for the synthesis of cyclopentenones. Density functional theory (DFT) has been utilised to study the mechanism of Nazarov cyclisations initiated by oxidation of pentadienyl ethers by a benzoquinone derivative (DDQ), as recently reported by West et al. (Angew. Chem., Int. Ed., 2017, 56, 6335). We determined that the reaction is most likely initiated by a hydride transfer from the pentadienyl ether to an oxygen of DDQ through a concerted pathway and not a single electron transfer mechanism. This oxidation by hydride abstraction leads to the formation of a pentadienyl cation from which the 4π electrocyclisation occurs, giving an alkoxycyclopentenyl cation. The ensuing cation is subsequently deprotonated by the reduced DDQ to afford an enol ether product. Consistent with experimental results, the hydride transfer is calculated to be the rate determining step and it can be accelerated by using electron donating substituents on the pentadienyl ether substrate. Indeed, the electron donating substituents increase the HOMO energy of the ether, making it more reactive toward oxidation. It is predicted that an unsubstituted benzoquinone, due to having a higher lying LUMO, shows much less reactivity than DDQ. Interestingly, we found an excellent correlation between the hydride transfer activation energy and the gap between the ether HOMO and the benzoquinone LUMO. From this correlation, we propose a predictive formula for reactivity of different types of substrates in the corresponding reaction.

This article describes a detailed comparison of the organometallic chemistry of high-valent nickel and palladium model complexes supported by tris(pyrazolyl)borate and cycloneophyl ligands. The accessibility of the MIII and MIV oxidation states with each metal is investigated through electrochemical and chemical oxidation of the MII precursors. These studies show that the NiII precursor readily undergoes both one- and two-electron oxidations to generate stable NiIII and NiIV products. In contrast, under the conditions examined, the PdII analogue undergoes exclusively two-electron-oxidation reactions to form PdIV. Reactivity studies of isolated NiIV and PdIV complexes show that both participate in C(sp3)–heteroatom coupling reactions and that the reactions at NiIV are approximately 2 orders of magnitude faster than those at PdIV. Experimental and computational mechanistic studies implicate outer-sphere SN2-type pathways for these processes. With most nucleophiles (e.g., phenoxide, acetate, thiophenoxide), ...

A combination of gas-phase ion trap mass spectrometry experiments and density functional theory (DFT) calculations have been used to examine the role of substituents on the decarboxylation of 25 different coordinated aromatic carboxylates in binuclear complexes, [(napy)Cu2(O2CC6H4X)]+, where napy is the ligand 1,8-naphthyridine (molecular formula, C8H6N2) and X = H and the ortho ( o), meta ( m) and para ( p) isomers of F, Br, CN, NO2, CF3, OAc, Me and MeO. Two competing unimolecular reaction pathways were found: decarboxylation to give the organometallic cation [(napy)Cu2(C6H4X)]+ or loss of the neutral copper benzoate to yield [(napy)Cu]+. The substituents on the aryl group influence the branching ratios of these product channels, but decarboxylation is always the dominant pathway. Density functional theory calculations reveal that decarboxylation proceeds via two transition states. The first enables a change in the coordination mode of the coordinated benzoate in [(napy)Cu2(O2CC6H4X)]+ from the thermodynamically favoured O, O-bridged form to the O-bound form, which is the reactive conformation for the second transition state which involves extrusion of CO2 with concomitant formation of the CO2 coordinated organometallic cation, [(napy)Cu2(C6H4X)(CO2)]+, which then loses CO2 in the final step to yield [(napy)Cu2(C6H4X)]+. In all cases the barrier is highest for the second transition state. The o-substituted benzoates show a lower activation energy than the m-substituted ones, while the p-substituted ones have the highest energy, which is consistent with the experimentally determined normalised collision energy required to induce fragmentation of [(napy)Cu2(O2CC6H4X)]+.

Gas-phase reactivity of the copper hydride anions [CuH2]– and [Cu2H3]– toward a range of neutral reagents has been examined via multistage mass spectrometry experiments in a linear ion trap mass spectrometer in conjunction with isotope labeling studies and Density Functional Theory (DFT) calculations. [CuH2]– is more reactive than [Cu2H3]–, consistent with DFT calculations, which show it has a higher energy HOMO. Experimentally, [CuH2]– was found to react with CS2 via hydride transfer to give thioformate (HCS2–) in competition with the formation of the organometallic [CuCS2]– ion via liberation of hydrogen; CO2 via insertion to produce [HCuO2CH]–; methyl iodide and allyl iodide to give I– and [CuHI]–; and 2,2,2-trifluoroethanol and 1-butanethiol via protonation to give hydrogen and the product anions [CuH(OCH2CF3)]− and [CuH(SBu)]−. In contrast, the weaker acid methanol was found to be unreactive. DFT calculations reveal that the differences in reactivity between CS2 and CO2 are due to the lower lying π* ...

This report describes a computational study of C(sp3)–OR bond formation from PdIV complexes of general structure PdIV(CH2CMe2-o-C6H4-C,C′)(F)(OR)(bpy-N,N′) (bpy = 2,2′-bipyridine). Dissociation of −OR from the different octahedral PdIV starting materials results in a common square-pyramidal PdIV cation. An SN2-type attack by −OR (−OR = phenoxide, acetate, difluoroacetate, and nitrate) then leads to C(sp3)–OR bond formation. In contrast, when −OR = triflate, concerted C(sp3)–C(sp2) bond-forming reductive elimination takes place, and the calculations indicate this outcome is the result of thermodynamic rather than kinetic control. The energy requirements for the dissociation and SN2 steps with different −OR follow opposing trends. The SN2 transition states exhibit “Pd⋯C⋯O” angles in a tight range of 151.5 to 153.0°, resulting from steric interactions between the oxygen atom and the gem-dimethyl group of the ligand. Conformational effects for various OR ligands and isomerisation of the complexes were also examined as components of the solution dynamics in these systems. In all cases, the trends observed computationally agree with those observed experimentally.

Density functional theory was utilized to investigate plausible mechanisms for amine and alcohol oxidation by an iodine(V) hypervalent reagent (IBX). In this contribution, we found that amine and alcohol oxidation both proceed by similar mechanisms. The reactions initiate from ligand exchange to give four coordinate intermediates followed by a redox process giving an iodine(III) species and oxidized substrates. Interestingly, for both the ligand-exchange and the redox steps a hypervalent twist is required for the reaction to proceed via an energetically more accessible route. The ligand-exchange process was found to be mediated by a proton-shuttling agent such as water, a second IBX, or a second substrate. While the ligand-exchange step for both amine and alcohol occurs with almost identical activation energy (particularly when water is considered as the shuttling agent), the redox step for the amine takes place with much lower activation energy than that for the alcohol. Finally, we ascertained that five coordinate amide iodine(V) complexes are unreactive toward redox reactions due to the fact that in such cases two electrons from the coordinated amide are required to occupy a 3c–4e σ* orbital which is too high in energy to be reachable.

We herein report the first total synthesis of the dibenzocycloheptanoide (±)-dihydroisosubamol. The key step includes a recently developed gold-catalysed hydroarylation reaction for the construction of the dibenzocycloheptene motif. Additional steps are a Suzuki-Miyaura cross coupling, a palladium-catalysed hydroxylation and an allylic oxidation. To access the saturated seven-membered ring system an iridium-catalysed hydrogenation proved to be successful.

The gold-catalyzed direct functionalization of aromatic C–H bonds has attracted interest for constructing organic compounds which have application in pharmaceuticals, agrochemicals, and other important fields. In the literature, two major mechanisms have been proposed for these catalytic reactions: inner-sphere syn-addition and outer-sphere anti-addition (Friedel–Crafts-type mechanism). In this article, the AuCl3-catalyzed hydrofurylation of allenyl ketone, vinyl ketone, ketone, and alcohol substrates is investigated with the aid of density functional theory calculations, and it is found that the corresponding functionalizations are best rationalized in terms of a novel mechanism called “concerted electrophilic ipso-substitution” (CEIS) in which the gold(III)-furyl σ-bond produced by furan auration acts as a nucleophile and attacks the protonated substrate via an outer-sphere mechanism. This unprecedented mechanism needs to be considered as an alternative plausible pathway for gold(III)-catalyzed arene fu...

Reductive elimination of imidazolium salts from Cu(III) is extremely sensitive to the anionic ligand (X or Y) type on Cu (e.g.ΔG(‡) ranges from 4.7 kcal mol(-1) to 31.8 kcal mol(-1), from chloride to benzyl). Weakly σ-donating ligands dramatically accelerate reductive elimination. Comparison with Ag/Au shows that the HOMO energy, strength of M-NHC and M-Y bonds and inherent stability of M(III) with respect to M(I) are critical to governing reaction feasibility.

The mechanism of twofold hydroarylation of terminal alkynes with pyrrole catalyzed by a cationic gold(i) complex was investigated using DFT. It was found that while both the hydroarylation reactions proceed via a Friedel-Crafts-type mechanism, the first hydroarylation is directly promoted by gold(i) but the second hydroarylation by a proton released through interaction of the alkene product with gold-bound acidic organic species such as acetic acid and terminal alkynes.

A PtIV prodrug needs to be reduced to PtII by a biomolecule in order to show efficacy. Among biomolecules, those containing an l-Cys residue have the highest potential to be involved in reduction. Tautomerisation from HSCH2CH(NH3+)CO2- to the unusual zwitterion form -SCH2CH(NH3+)CO2H is the prerequisite for l-Cys to become a potent reductant at a low pH.

An efficient chiral Brønsted acid-catalyzed enantioselective dehydrative Nazarov-type electrocyclization (DNE) of electron-rich aryl- and 2-thienyl-β-amino-2-en-1-ols is described. The 4π conrotatory electrocyclization reaction affords access to a wide variety of the corresponding 1 H-indenes and 4 H-cyclopenta[ b]thiophenes in excellent yields of up to 99% and enantiomeric excess (ee) values of up to 99%. Experimental and computational studies based on a proposed intimate contact ion-pair species that is further assisted by hydrogen bonding between the amino group of the substrate cation and chiral catalyst anion provide insight into the observed product enantioselectivities.