Palladium-catalyzed cycloisomerizations of (Z)-1-iodo-1,6-dienes: iodine atom transfer and mechanistic insight to alkyl iodide reductive elimination

A palladium-catalyzed iodine atom transfer cycloisomerization of (Z)-1-iodo-1,6-diene has been developed, which provides a facile method to construct six-memebered heterocycles bearing an alkyl iodide group. The ligand screening shows that both the type and the quantity of ligand impose significant influences on this transformation, and the combination of 30 mol % 1,1'-bis(diphenylphosphino)ferrocene (DPPF) and 10 mol % Pd(OAc)(2) is the optimal choice. The catalytic cycle, consisting of oxidative addition of Pd(0) to vinyl iodide, intramolecular alkene insertion, and alkyl iodide reductive elimination, has been proposed and eventually supported by convincing evidence from a series of control experiments. More importantly, these control experiments disclose some features of the event of alkyl iodide reductive elimination: (1) this reductive elimination is proved to be a stereospecific process; and (2) both alkyl iodide oxidative addition and reductive elimination are not effected by a TEMPO additive. Besides its ability to undergo oxidative addition, the catalyst (palladium + DPPF) could also promote a radical transfer process. The findings described in this paper will be helpful for further development of the metal-catalyzed formation of a carbon-halide bond.     

Mechanistic characterization of aerobic alcohol oxidation catalyzed by Pd(OAc)(2)/pyridine including identification of the catalyst resting state and the origin of nonlinear [catalyst] dependence

The Pd(OAc)(2)/pyridine catalyst system is one of the most convenient and versatile catalyst systems for selective aerobic oxidation of organic substrates. This report describes the catalytic mechanism of Pd(OAc)(2)/pyridine-mediated oxidation of benzyl alcohol, which has been studied by gas-uptake kinetic methods and (1)H NMR spectroscopy. The data reveal that turnover-limiting substrate oxidation by palladium(II) proceeds by a four-step pathway involving (1) formation of an adduct between the alcohol substrate and the square-planar palladium(II) complex, (2) proton-coupled ligand substitution to generate a palladium-alkoxide species, (3) reversible dissociation of pyridine from palladium(II) to create a three-coordinate intermediate, and (4) irreversible beta-hydride elimination to produce benzaldehyde. The catalyst resting state, characterized by (1)H NMR spectroscopy, consists of an equilibrium mixture of (py)(2)Pd(OAc)(2), 1, and the alcohol adduct of this complex, 1xRCH(2)OH. These in situ spectroscopic data provide direct support for the mechanism proposed from kinetic studies. The catalyst displays higher turnover frequency at lower catalyst loading, as revealed by a nonlinear dependence of the rate on [catalyst]. This phenomenon arises from a competition between forward and reverse reaction steps that exhibit unimolecular and bimolecular dependences on [catalyst]. Finally, overoxidation of benzyl alcohol to benzoic acid, even at low levels, contributes to catalyst deactivation by formation of a less active palladium benzoate complex.     

Theoretical analysis of the mechanism of palladium(II) acetate-catalyzed oxidative Heck coupling of electron-deficient arenes with alkenes: effects of the pyridine-type ancillary ligand and origins of the meta-regioselectivity

A systematic theoretical study is carried out on the mechanism for Pd(II)-catalyzed oxidative cross-coupling between electron-deficient arenes and alkenes. Two types of reaction pathways involving either a sequence of initial arene C-H activation followed by alkene activation, or the reverse sequence of initial alkene C-H activation followed by arene activation are evaluated. Several types of C-H activation mechanisms are discussed including oxidative addition, σ-bond metathesis, concerted metalation/deprotonation, and Heck-type alkene insertion. It is proposed that the most favored reaction pathway should involve an initial concerted metalation/deprotonation step for arene C-H activation by (L)Pd(OAc)(2) (L denotes pyridine type ancillary ligand) to generate a (L)(HOAc)Pd(II)-aryl intermediate, followed by substitution of the ancillary pyridine ligand by alkene substrate and direct insertion of alkene double bond into Pd(II)-aryl bond. The rate- and regio-determining step of the catalytic cycle is concerted metalation/deprotonation of arene C-H bond featuring a six-membered ring transition state. Other mechanism alternatives possess much higher activation barriers, and thus are kinetically less competitive. Possible competing homocoupling pathways have also been shown to be kinetically unfavorable. On the basis of the proposed reaction pathway, the regioselectivity predicted for a number of monosubstituted benzenes is in excellent agreement with experimental observations, thus, lending further support for our proposed mechanism. Additionally, the origins of the regioselectivity of C-H bond activation is elucidated to be caused by a major steric repulsion effect of the ancillary pyridine type ligand with ligands on palladium center and a minor electronic effect of the preinstalled substituent on the benzene ring on the cleaving C-H bond. This would finally lead to the formation of a mixture of meta and para C-H activation products with meta products dominating while no ortho products were detected. Finally, the multiple roles of the ancillary pyridine type ligand have been discussed. These insights are valuable for our understanding and further development of more efficient and selective transition metal-catalyzed oxidative C-H/C-H coupling reactions.     

Detection of Palladium(I) in Aerobic Oxidation Catalysis

Palladium(II)‐catalyzed oxidation reactions exhibit broad utility in organic synthesis; however, they often feature high catalyst loading and low turnover numbers relative to non‐oxidative cross‐coupling reactions. Insights into the fate of the Pd catalyst during turnover could help to address this limitation. Herein, we report the identification and characterization of a dimeric Pd^I species in two prototypical Pd‐catalyzed aerobic oxidation reactions: allylic C−H acetoxylation of terminal alkenes and intramolecular aza‐Wacker cyclization. Both reactions employ 4,5‐diazafluoren‐9‐one (DAF) as an ancillary ligand. The dimeric Pd^I complex, [Pd^I(μ‐DAF)(OAc)]₂, which features two bridging DAF ligands and two terminal acetate ligands, has been characterized by several spectroscopic methods, as well as single‐crystal X‐ray crystallography. The origin of this Pd^I complex and its implications for catalytic reactivity are discussed.     

Two-faced reactivity of alkenes: cis- versus trans-aminopalladation in aerobic Pd-catalyzed intramolecular aza-Wacker reactions

A number of different PdII catalyst systems have been reported recently for the Wacker-type aerobic oxidative cyclization of alkenes bearing tethered nitrogen nucleophiles. This study examines the stereochemistry of the aminopalladation step with five different catalyst systems: Pd(OAc)2/DMSO (A), PdX2/pyridine [X = OAc (B), O2CCF3 (C)], Pd(IMes)(O2CCF3)2(OH2) (D), and Pd(O2CCF3)2/(-)-sparteine (E). Use of a stereospecifically deuterated cyclopentene substrate reveals that four of the five catalyst systems (A, B, C, and E) promote exclusive cis-aminopalladation of the alkene, whereas both cis- and trans-aminopalladation occur with the N-heterocyclic-carbene (NHC) catalyst system. If stoichiometric Br?nsted base (NaOAc, Na2CO3) is added to the latter reaction conditions, however, only cis-aminopalladation is observed. The identity of the nitrogen nucleophile also affects the aminopalladation pathway, with results ranging from exclusively cis- to exclusively trans-aminopalladation. These results have important implications for ongoing efforts to develop enantioselective methods for Pd-catalyzed oxidative amination of alkenes.     

Study of the Transient Reactive Pd(IV) Intermediate in the Pd(OAc)2‐Catalyzed Oxidative Coupling Reaction System by Electrospray Ionization Tandem Mass Spectrometry

Pd‐catalyzed oxidative coupling reaction was of great importance in the aromatic C? H activation and the formation of new C? O and C? C bonds. Sanford has pioneered practical, directed C? H activation reactions employing Pd(OAc)₂ as catalyst since 2004. However, until now, the speculated reactive Pd(IV) transient intermediates in these reactions have not been isolated or directly detected from reaction solution. Electrospray ionization tandem mass spectrometry (ESI‐MS/MS) was used to intercept and characterize the reactive Pd(IV) transient intermediates in the solutions of Pd(OAc)₂‐catalyzed oxidative coupling reactions. In this study, the Pd(IV) transient intermediates were detected from the solution of Pd(OAc)₂‐catalyzed oxidative coupling reactions by ESI‐MS and the MS/MS of the intercepted Pd(IV) transient intermediate in reaction system was the same with the synthesized authentic Pd(IV) complex. Our ESI‐MS(/MS) studies confirmed the presence of Pd(IV) reaction transient intermediates. Most interestingly, the MS/MS of Pd(IV) transient intermediates showed the reductive elimination reactivity to Pd(II) complexes with new C? O bond formation into product in gas phase, which was consistent with the proposed reactivity of the Pd(IV) transient intermediates in solution.     

Improved catalysts for the palladium-catalyzed synthesis of oxindoles by amide alpha-arylation. Rate acceleration, use of aryl chloride substrates, and a new carbene ligand for asymmetric transformations

Catalysts comprised Pd(OAc)(2) and either PCy(3) or sterically hindered N-heterocyclic carbene ligands provide fast rates for a palladium-catalyzed synthesis of oxindoles by amide alpha-arylation. This catalyst system allowed for room-temperature reactions in some cases and reactions of aryl chlorides at 70 degrees C. Most important, reactions occurred in high yields under mild conditions to form the quaternary carbon in alpha,alpha-disubstituted oxindoles. The combined inter- and intramolecular reaction afforded an efficient synthetic method for formation of alpha-aryloxindole derivatives. Surprisingly, catalysts containing tert-butylphosphine ligands, which have been most reactive for ketone arylations, were less active than those containing PCy(3). Use of new, optically active heterocyclic carbene ligands gave substantial enantioselectivity in formation of an alpha,alpha-disubstituted oxindole. In contrast, a variety of optically active phosphine ligands that were tested gave poor enantioselectivity. Mechanistic studies showed that the reaction involves rate-limiting oxidative addition of aryl halide. Base-induced formation of and reductive elimination from an arylpalladium enolate intermediate were both faster than oxidative addition. Deprotonation of the tethered amide appeared to be faster than reductive elimination of the resulting palladium enolate to form the oxindole product.     

Using mechanistic and computational studies to explain ligand effects in the palladium-catalyzed aerobic oxidation of alcohols

The experimental and computational mechanistic details of the Pd(OAc)(2)/TEA-catalyzed aerobic alcohol oxidation system are disclosed. Measurement of various kinetic isotope effects and the activation parameters as well as rate law derivation support rate-limiting deprotonation of the palladium-coordinated alcohol. Rate-limiting deprotonation of the alcohol is contrary to the majority of related kinetic studies for Pd-catalyzed aerobic oxidation of alcohols, which propose rate-limiting beta-hydride elimination. This difference in the rate-limiting step is supported by the computational model, which predicts the activation energy for deprotonation is 3 kcal/mol higher than the activation energy for beta-hydride elimination. The computational features of the similar Pd(OAc)(2)/pyridine system were also elucidated. Details of the study illustrate that the use of TEA results in an active catalyst that has only one ligand bound to the Pd, resulting in a significant lowering of the activation energy for beta-hydride elimination and, therefore, a catalyst that is active at room temperature.     

Pd(OAc)2-catalyzed oxidative coupling reaction of benzenes with olefins in the presence of molybdovanadophosphoric acid under atmospheric dioxygen and air

The direct oxidative coupling reaction of benzenes with alkenes bearing an electron-withdrawing group was successfully achieved by the use of Pd(OAc)(2)/molybdovanadophosphoric acid (HPMoV) as the key catalyst under O(2) or air atmosphere. Thus, the reaction of benzene with ethyl acrylate under air (1 atm) assisted by Pd(OAc)(2)/HPMoV afforded ethyl cinnamate as a major product in satisfactory yield (74%). This catalytic system could be extended to the coupling reactions between various substituted benzenes and alkenes through the direct aromatic C-H bond activation. In the reaction of benzene with ethyl acrylate under O(2) (1 atm), the best turn-over number (TON) of Pd(OAc)(2) reached was 121. This reaction provides a green route to cinnamate derivatives, which are important precursors of a variety of pharmaceuticals.     

Palladium-catalyzed synthesis of 2,1'-disubstituted tetrahydrofurans from gamma-hydroxy internal alkenes. Evidence for alkene insertion into a Pd-O bond and stereochemical scrambling via beta-hydride elimination

Palladium-catalyzed reactions of gamma-hydroxy internal acyclic alkenes with aryl bromides afford 2,1'-disubstituted tetrahydrofurans in good yields with diastereoselectivities of 3-5:1. The analogous transformations of substrates bearing internal cyclic alkenes afford fused bicyclic and spirocyclic tetrahydrofuran derivatives in good yields with excellent diastereoselectivities (>20:1). A series of deuterium labeling experiments indicate that the origin of the modest diastereoselectivity in reactions of acyclic internal alkene substrates likely derives from a series of reversible beta-hydride elimination and sigma-bond rotation processes that occur following a rare intramolecular alkene syn-insertion into an intermediate Pd(Ar)(OR) complex. In addition, these studies shed light on the chemoselectivity of insertion, suggesting that the alkene inserts into the Pd-O bond in preference to the Pd-C bond.     

Insertion of molecular oxygen into a palladium-hydride bond: computational evidence for two nearly isoenergetic pathways

The reaction of a palladiumII-hydride species with molecular oxygen to form palladiumII-hydroperoxide has been proposed as a key step in Pd-catalyzed aerobic oxidation reactions. We recently reported one of the first experimental precedents for such a step (Angew. Chem., Int. Ed. 2006, 45, 2904-2907). DFT calculations have been used to probe the mechanism for this reaction, which consists of formal insertion of O2 into the palladium-hydride bond of trans-(NHC)2Pd(H)OAc (NHC = N-heterocyclic carbene). Four different pathways were considered: (1) hydrogen atom abstraction (HAA) of the Pd-H bond by molecular oxygen, (2) reductive elimination of HX followed by oxygenation of Pd0 and protonolysis of the (eta2-peroxo)-PdII species, (3) oxygenation of palladiumII-hydride with subsequent reductive elimination of the O-H bond from an eta2-peroxo-PdIV center, and (4) formation of a cis-superoxide adduct of the palladium-hydride species followed by O-H bond formation via hydrogen atom migration. The calculations reveal that pathways 1 and 2 are preferred energetically, and both pathways exhibit very similar kinetic barriers. This result suggests that more than one pathway is possible for catalyst reoxidation in Pd-catalyzed aerobic oxidation reactions.     

Palladium-catalyzed aerobic intermolecular cyclization of acrylic acid with 1-octene to afford α-methylene-γ-butyrolactones: the remarkable effect of continuous water removal from the reaction mixture and analysis of the reaction by kinetic, ESI-MS, and XAFS measurements

Further study of our aerobic intermolecular cyclization of acrylic acid with 1-octene to afford α-methylene-γ-butyrolactones, catalyzed by the Pd(OCOCF(3))(2)/Cu(OAc)(2)?H(2)O system, has clarified that the accumulation of water generated from oxygen during the reaction causes deactivation of the Cu cocatalyst. This prevents regeneration of the active Pd catalyst and, thus, has a harmful influence on the progress of the cyclization. As a result, both the substrate conversion and product yield are efficiently improved by continuous removal of water from the reaction mixture. Detailed analysis of the kinetic and spectroscopic measurements performed under the condition of continuous water removal demonstrates that the cyclization proceeds in four steps: 1)?equilibrium coordination of 1-octene to the Pd acrylate species, 2)?Markovnikov-type acryloxy palladation of 1-octene (1,2-addition), 3)?intramolecular carbopalladation, and 4)?β-hydride elimination. Byproduct 2-acryloxy-1-octene is formed by β-hydride elimination after step 2). These cyclization steps fit the Michaelis-Menten equation well and β-hydride elimination is considered to be a rate-limiting step in the formation of the products. Spectroscopic data agree sufficiently with the existence of the intermediates bearing acrylate (Pd-O bond), η(3)-C(8)H(15) (Pd-C bond), or C(11)H(19)O(2) (Pd-C bond) moieties on the Pd center as the resting-state compounds. Furthermore, not only Cu(II), but also Cu(I), species are observed during the reaction time of 2-8?h when the reaction proceeds efficiently. This result suggests that the Cu(II) species is partially reduced to the Cu(I) species when the active Pd catalytic species are regenerated.     

Palladium(II)-catalyzed enyne coupling reaction initiated by acetoxypalladation of alkynes and quenched by protonolysis of the carbon-palladium bond

[reaction: see text] Divalent palladium-catalyzed inter- and intramolecular enyne coupling reactions initiated by acetoxypalladation of alkynes were developed. The reaction involves the acetoxypalladation of the alkyne, followed by the insertion of the alkene and the protonolysis of the carbon-palladium bond. The protonolysis of the carbon-palladium bond in the presence of bidentate nitrogen containing ligands is the key step in completing the Pd(II) catalytic cycle. The nitrogen-containing ligands, like halides, served to favor the protonolysis of the carbon-palladium bond over the beta-H elimination in the Pd(II)-mediated reactions. The intermolecular coupling reactions provide an efficient method for synthesizing gamma,delta-unsaturated carbonyls. The intramolecular coupling reactions offer a method to construct a variety of synthetically important carbo- and heterocycles. The asymmetric version of such a cyclization was developed with moderate enantioselectivity when employing pymox (pyridyl monooxazoline) as the ligand.     

Ligand-modulated palladium oxidation catalysis: mechanistic insights into aerobic alcohol oxidation with the Pd(OAc)(2)/pyridine catalyst system

Pd(OAc)(2):pyridine (1:4) is an efficient catalyst system for the oxidation of alcohols with molecular oxygen. A mechanistic study of this reaction reveals that pyridine promotes the aerobic oxidation of palladium(0) but inhibits the oxidation of alcohol by palladium(II). Kinetic results reveal that turnover-limiting substrate oxidation consists of (i) formation of a palladium(II)-alkoxide, (ii) pyridine dissociation, and (iii) beta-hydride elimination. These results provide a framework for the design and/or screening of more effective aerobic oxidation catalysts.     

Palladium-catalyzed aerobic oxidative amination of alkenes: development of intra- and intermolecular aza-Wacker reactions

Palladium-catalyzed methods for the aerobic oxidative coupling of alkenes and oxygen nucleophiles (e.g., water and carboxylic acids) have been known for nearly 50 years. The present account summarizes our development of analogous aerobic oxidative amination reactions, including the first intermolecular aza-Wacker reactions compatible with the use of unactivated alkenes. The reactions are initiated by intra- or intermolecular aminopalladation of the alkene. The resulting alkylpalladium(II) intermediate generally undergoes beta-hydride elimination to produce enamides or allylic amide products, but in certain cases, the Pd-C bond can be trapped to achieve 1,2-difunctionalization of the alkene, including carboamination and aminoacetoxylation. Mechanistic studies have provided a variety of fundamental insights into the reactions, including the effect of ancillary ligands on palladium catalysts, the origin of the Br?nsted-base-induced switch in regioselectivity in the oxidative amination of styrene, and evidence that both cis- and trans-aminopalladations of alkenes are possible. Overall, these reactions highlight the potential utility of an "organometallic oxidase" strategy for the selective aerobic oxidation of organic molecules.     

ESI-MS studies of the dehydrogenative Heck reaction of furans with acrylates using benzoquinone as the reoxidant and DMSO as the solvent

Electrospray ionization mass spectrometry, subsequent MS/MS, and high-resolution mass spectrometry were used to study the dehydrogenative Heck reaction of 2-alkylfurans 1 with acrylates 2, using [Pd(OAc)(2)](3) as the precatalyst, benzoquinone (BQ) as the stoichiometric oxidant, and a mixture of DMSO and AcOH as the solvent. Complexation of [Pd(OAc)(2)](3) by DMSO afforded mononuclear and dinuclear Pd(II) species, which proved to be active catalysts for the C-H activation of 1. Mononuclear and dinuclear Pd(II) species seem also to be involved in the insertion of 2 into the furyl-Pd bond. The C-H activation of 2 and DMSO by mononuclear complexes was observed. The reaction leads to 5,5'-dialkyl-2,2'-bifuran 4 as a byproduct. Bifuryl-palladium, which is an intermediate in the formation of 4, showing the coordination of BQ, was obtained and characterized.     

Reaction of molecular oxygen with a Pd(II)-hydride to produce a Pd(II)-hydroperoxide: experimental evidence for an HX-reductive-elimination pathway

The reaction of molecular oxygen with a Pd(II)-hydride species to form a Pd(II)-hydroperoxide represents one of the proposed catalyst reoxidation pathways in Pd-catalyzed aerobic oxidation reactions, but well-defined examples of this reaction were discovered only recently. Here, we present a mechanistic study of the reaction of O2 with trans-(IMes) 2Pd(H)(OBz), 1 (IMes = 1,3-dimesitylimidazol-2-ylidene), which yields trans-(IMes) 2Pd(OOH)(OBz), 2. The reaction was monitored by (1)H NMR spectroscopy in benzene-d6, and kinetic studies reveal a two-term rate law, rate = k1[1] + k2[1][BzOH], and a small deuterium kinetic isotope effect, k(Pd-H)/k(Pd-D) = 1.3(1). The rate is independent of the oxygen pressure. The data support a stepwise mechanism for the conversion of 1 into 2 consisting of rate-limiting reductive elimination of BzOH from 1 followed by rapid reaction of molecular oxygen with (IMes) 2Pd(0) and protonolysis of a Pd-O bond of the eta(2)-peroxo complex (IMes) 2Pd(O2). Benzoic acid and other protic additives (H2O, ArOH) catalyze the oxygenation reaction, probably by stabilizing the transition state for reductive elimination of BzOH from 1. This study provides the first experimental validation of the mechanism traditionally proposed for aerobic oxidation of Pd-hydride species.     

Rate and mechanism of the reaction of alkenes with aryl palladium complexes ligated by a bidentate P,P ligand in Heck reactions

The regioselectivity of the Heck reaction is supposed to be highly affected by the electronic properties of the alkene and the ionic or neutral character of the aryl palladium(II) complexes involved in the reaction with alkenes. In Heck reactions performed in dmf, [Pd(dppp){dppp(O)}Ph](+) (dppp=1,2-bis(diphenylphosphino)propane) is generated in the oxidative addition of PhI with [Pd(0)(dppp)(OAc)](-) formed in situ from Pd(OAc)(2) associated to two equivalents of dppp. [Pd(dppp){dppp(O)}Ph](+) is not very reactive with alkenes (styrene or methyl acrylate); however, it reacts with iodide ions (released in the catalytic reactions) to give [Pd(dppp)IPh] and with acetate ions (used as base) to give [Pd(dppp)(OAc)Ph]. [Pd(dppp)(OAc)Ph] reacts with styrene and methyl acrylate exclusively by an ionic mechanism, that is, via the cationic complex [Pd(dppp)(dmf)Ph](+) formed by dissociation of the acetate ion. The reaction of [Pd(dppp)IPh] is more complex and substrate dependent. It reacts with styrene exclusively by the ionic mechanism via [Pd(dppp)(dmf)Ph](+). [Pd(dppp)IPh] (neutral mechanism) and [Pd(dppp)(dmf)Ph](+) (ionic mechanism) react in parallel with methyl acrylate. [Pd(dppp)(dmf)Ph](+) is more reactive than [Pd(dppp)IPh] but is always generated at lower concentration.     

Palladium-catalyzed carbonylative cyclization of unsaturated aryl iodides and dienyl triflates,iodides, and bromides to indanones and 2-cyclopentenones

Indanones and 2-cyclopentenones have been successfully prepared in good to excellent yields by the palladium-catalyzed carbonylative cyclization of unsaturated aryl iodides and dienyl triflates, iodides, and bromides, respectively. The best results are obtained by employing 10 mol % of Pd(OAc)(2), 2 equiv of pyridine, 1 equiv of n-Bu(4)NCl, 1 atm of CO, a reaction temperature of 100 degrees C, and DMF as the solvent. This carbonylative cyclization is particularly effective on substrates that contain a terminal olefin. The proposed mechanism for this annulation includes (1) Pd(OAc)(2) reduction to the active palladium(0) catalyst, (2) oxidative addition of the organic halide or triflate to Pd(0), (3) coordination and insertion of carbon monoxide to produce an acylpalladium intermediate, (4) acylpalladation of the neighboring carbon-carbon double bond, (5) reversible palladium beta-hydride elimination and re-addition to form a palladium enolate, and (6) protonation by H(2)O to produce the indanone or 2-cyclopentenone.     

Importance of palladium-carbon bond energies in direct arylation of polyfluorinated benzenes

Fagnou et al. reported direct arylation reactions that use palladium catalysts to couple Ar(1)-X to Ar(2)-H with the aid of a coordinated base. These reactions are particularly favourable for polyfluorinated arenes Ar(2)-H (see S. I. Gorelsky, D. Lapointe and K. Fagnou, J. Am. Chem. Soc. 2008, 130, 10848). In this paper, we show by means of a DFT analysis how the energetics and activation energies vary with fluorine substitution and examine the structures of intermediates and transition states. The reactant is modelled by Pd(OAc)(Ph)(PMe(3))(DMA) (DMA = dimethylacetamide). The sequence consists of (a) replacement of DMA by arene, (b) Concerted Deprotonation Metallation (CMD), (c) decoordination of AcOH, (d) reductive elimination of biaryl. Many of the variations are dominated by the number of fluorine substituents ortho to the C-H bond and fall into three groups labelled accordingly: Set0Fo, Set1Fo, and Set2Fo. In the first step a coordinated solvent is replaced by the arene. The arenes of Set0Fo and Set1Fo coordinate in a conventional η(2)-CH=CH mode, whereas the arenes of Set2Fo coordinate in an η(1)-CH mode assisted by an OH-C hydrogen bond from the coordinated acetate. Both the energy barriers to CMD and the product energies fall into the three typical sets with the highest barrier and highest product energy being for Set0Fo. They correlate more satisfactorily with the variations in Pd-C bond energies than with the C-H acidities. The barriers to reductive elimination from Pd(Ph)(Ar(F))(PMe(3))(AcOH) increase systematically from Set0Fo to Set2Fo as the Pd-C bond becomes stronger in a regular fashion from Set0Fo to Set2Fo. Again there is a strong correlation between the energy barriers to reductive elimination and the Pd-C bond energies. It is found overall that the key aspects of the reactions are: (a) the lowering of the energy of the CMD step by the ortho fluorine substituents, (b) the regioselective activation of C-H bonds ortho to fluorine which is also determined at the CMD step, (c) the decoordination of AcOH, which maintains the transition state for reductive elimination at low Gibbs free energy. The presence of fluorine increases the effectiveness of the reaction in the sense of points a and b via the increasing strength of the palladium-carbon bond.